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5 Benefits of Learning Through the Case Study Method

• 28 Nov 2023

While several factors make HBS Online unique —including a global Community and real-world outcomes —active learning through the case study method rises to the top.

In a 2023 City Square Associates survey, 74 percent of HBS Online learners who also took a course from another provider said HBS Online’s case method and real-world examples were better by comparison.

Here’s a primer on the case method, five benefits you could gain, and how to experience it for yourself.

Access your free e-book today.

What Is the Harvard Business School Case Study Method?

The case study method , or case method , is a learning technique in which you’re presented with a real-world business challenge and asked how you’d solve it. After working through it yourself and with peers, you’re told how the scenario played out.

HBS pioneered the case method in 1922. Shortly before, in 1921, the first case was written.

“How do you go into an ambiguous situation and get to the bottom of it?” says HBS Professor Jan Rivkin, former senior associate dean and chair of HBS's master of business administration (MBA) program, in a video about the case method . “That skill—the skill of figuring out a course of inquiry to choose a course of action—that skill is as relevant today as it was in 1921.”

Originally developed for the in-person MBA classroom, HBS Online adapted the case method into an engaging, interactive online learning experience in 2014.

In HBS Online courses , you learn about each case from the business professional who experienced it. After reviewing their videos, you’re prompted to take their perspective and explain how you’d handle their situation.

You then get to read peers’ responses, “star” them, and comment to further the discussion. Afterward, you learn how the professional handled it and their key takeaways.

HBS Online’s adaptation of the case method incorporates the famed HBS “cold call,” in which you’re called on at random to make a decision without time to prepare.

“Learning came to life!” said Sheneka Balogun , chief administration officer and chief of staff at LeMoyne-Owen College, of her experience taking the Credential of Readiness (CORe) program . “The videos from the professors, the interactive cold calls where you were randomly selected to participate, and the case studies that enhanced and often captured the essence of objectives and learning goals were all embedded in each module. This made learning fun, engaging, and student-friendly.”

If you’re considering taking a course that leverages the case study method, here are five benefits you could experience.

5 Benefits of Learning Through Case Studies

1. take new perspectives.

The case method prompts you to consider a scenario from another person’s perspective. To work through the situation and come up with a solution, you must consider their circumstances, limitations, risk tolerance, stakeholders, resources, and potential consequences to assess how to respond.

Taking on new perspectives not only can help you navigate your own challenges but also others’. Putting yourself in someone else’s situation to understand their motivations and needs can go a long way when collaborating with stakeholders.

2. Hone Your Decision-Making Skills

Another skill you can build is the ability to make decisions effectively . The case study method forces you to use limited information to decide how to handle a problem—just like in the real world.

Throughout your career, you’ll need to make difficult decisions with incomplete or imperfect information—and sometimes, you won’t feel qualified to do so. Learning through the case method allows you to practice this skill in a low-stakes environment. When facing a real challenge, you’ll be better prepared to think quickly, collaborate with others, and present and defend your solution.

3. Become More Open-Minded

As you collaborate with peers on responses, it becomes clear that not everyone solves problems the same way. Exposing yourself to various approaches and perspectives can help you become a more open-minded professional.

When you’re part of a diverse group of learners from around the world, your experiences, cultures, and backgrounds contribute to a range of opinions on each case.

On the HBS Online course platform, you’re prompted to view and comment on others’ responses, and discussion is encouraged. This practice of considering others’ perspectives can make you more receptive in your career.

“You’d be surprised at how much you can learn from your peers,” said Ratnaditya Jonnalagadda , a software engineer who took CORe.

In addition to interacting with peers in the course platform, Jonnalagadda was part of the HBS Online Community , where he networked with other professionals and continued discussions sparked by course content.

“You get to understand your peers better, and students share examples of businesses implementing a concept from a module you just learned,” Jonnalagadda said. “It’s a very good way to cement the concepts in one's mind.”

4. Enhance Your Curiosity

One byproduct of taking on different perspectives is that it enables you to picture yourself in various roles, industries, and business functions.

“Each case offers an opportunity for students to see what resonates with them, what excites them, what bores them, which role they could imagine inhabiting in their careers,” says former HBS Dean Nitin Nohria in the Harvard Business Review . “Cases stimulate curiosity about the range of opportunities in the world and the many ways that students can make a difference as leaders.”

Through the case method, you can “try on” roles you may not have considered and feel more prepared to change or advance your career .

5. Build Your Self-Confidence

Finally, learning through the case study method can build your confidence. Each time you assume a business leader’s perspective, aim to solve a new challenge, and express and defend your opinions and decisions to peers, you prepare to do the same in your career.

According to a 2022 City Square Associates survey , 84 percent of HBS Online learners report feeling more confident making business decisions after taking a course.

“Self-confidence is difficult to teach or coach, but the case study method seems to instill it in people,” Nohria says in the Harvard Business Review . “There may well be other ways of learning these meta-skills, such as the repeated experience gained through practice or guidance from a gifted coach. However, under the direction of a masterful teacher, the case method can engage students and help them develop powerful meta-skills like no other form of teaching.”

How to Experience the Case Study Method

If the case method seems like a good fit for your learning style, experience it for yourself by taking an HBS Online course. Offerings span seven subject areas, including:

• Business essentials
• Leadership and management
• Entrepreneurship and innovation
• Finance and accounting
• Business in society

No matter which course or credential program you choose, you’ll examine case studies from real business professionals, work through their challenges alongside peers, and gain valuable insights to apply to your career.

Are you interested in discovering how HBS Online can help advance your career? Explore our course catalog and download our free guide —complete with interactive workbook sections—to determine if online learning is right for you and which course to take.

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Home » Case Study – Methods, Examples and Guide

Case Study – Methods, Examples and Guide

Table of Contents

A case study is a research method that involves an in-depth examination and analysis of a particular phenomenon or case, such as an individual, organization, community, event, or situation.

It is a qualitative research approach that aims to provide a detailed and comprehensive understanding of the case being studied. Case studies typically involve multiple sources of data, including interviews, observations, documents, and artifacts, which are analyzed using various techniques, such as content analysis, thematic analysis, and grounded theory. The findings of a case study are often used to develop theories, inform policy or practice, or generate new research questions.

Types of Case Study

Types and Methods of Case Study are as follows:

Single-Case Study

A single-case study is an in-depth analysis of a single case. This type of case study is useful when the researcher wants to understand a specific phenomenon in detail.

For Example , A researcher might conduct a single-case study on a particular individual to understand their experiences with a particular health condition or a specific organization to explore their management practices. The researcher collects data from multiple sources, such as interviews, observations, and documents, and uses various techniques to analyze the data, such as content analysis or thematic analysis. The findings of a single-case study are often used to generate new research questions, develop theories, or inform policy or practice.

Multiple-Case Study

A multiple-case study involves the analysis of several cases that are similar in nature. This type of case study is useful when the researcher wants to identify similarities and differences between the cases.

For Example, a researcher might conduct a multiple-case study on several companies to explore the factors that contribute to their success or failure. The researcher collects data from each case, compares and contrasts the findings, and uses various techniques to analyze the data, such as comparative analysis or pattern-matching. The findings of a multiple-case study can be used to develop theories, inform policy or practice, or generate new research questions.

Exploratory Case Study

An exploratory case study is used to explore a new or understudied phenomenon. This type of case study is useful when the researcher wants to generate hypotheses or theories about the phenomenon.

For Example, a researcher might conduct an exploratory case study on a new technology to understand its potential impact on society. The researcher collects data from multiple sources, such as interviews, observations, and documents, and uses various techniques to analyze the data, such as grounded theory or content analysis. The findings of an exploratory case study can be used to generate new research questions, develop theories, or inform policy or practice.

Descriptive Case Study

A descriptive case study is used to describe a particular phenomenon in detail. This type of case study is useful when the researcher wants to provide a comprehensive account of the phenomenon.

For Example, a researcher might conduct a descriptive case study on a particular community to understand its social and economic characteristics. The researcher collects data from multiple sources, such as interviews, observations, and documents, and uses various techniques to analyze the data, such as content analysis or thematic analysis. The findings of a descriptive case study can be used to inform policy or practice or generate new research questions.

Instrumental Case Study

An instrumental case study is used to understand a particular phenomenon that is instrumental in achieving a particular goal. This type of case study is useful when the researcher wants to understand the role of the phenomenon in achieving the goal.

For Example, a researcher might conduct an instrumental case study on a particular policy to understand its impact on achieving a particular goal, such as reducing poverty. The researcher collects data from multiple sources, such as interviews, observations, and documents, and uses various techniques to analyze the data, such as content analysis or thematic analysis. The findings of an instrumental case study can be used to inform policy or practice or generate new research questions.

Case Study Data Collection Methods

Here are some common data collection methods for case studies:

Interviews involve asking questions to individuals who have knowledge or experience relevant to the case study. Interviews can be structured (where the same questions are asked to all participants) or unstructured (where the interviewer follows up on the responses with further questions). Interviews can be conducted in person, over the phone, or through video conferencing.

Observations

Observations involve watching and recording the behavior and activities of individuals or groups relevant to the case study. Observations can be participant (where the researcher actively participates in the activities) or non-participant (where the researcher observes from a distance). Observations can be recorded using notes, audio or video recordings, or photographs.

Documents can be used as a source of information for case studies. Documents can include reports, memos, emails, letters, and other written materials related to the case study. Documents can be collected from the case study participants or from public sources.

Surveys involve asking a set of questions to a sample of individuals relevant to the case study. Surveys can be administered in person, over the phone, through mail or email, or online. Surveys can be used to gather information on attitudes, opinions, or behaviors related to the case study.

Artifacts are physical objects relevant to the case study. Artifacts can include tools, equipment, products, or other objects that provide insights into the case study phenomenon.

How to conduct Case Study Research

Conducting a case study research involves several steps that need to be followed to ensure the quality and rigor of the study. Here are the steps to conduct case study research:

• Define the research questions: The first step in conducting a case study research is to define the research questions. The research questions should be specific, measurable, and relevant to the case study phenomenon under investigation.
• Select the case: The next step is to select the case or cases to be studied. The case should be relevant to the research questions and should provide rich and diverse data that can be used to answer the research questions.
• Collect data: Data can be collected using various methods, such as interviews, observations, documents, surveys, and artifacts. The data collection method should be selected based on the research questions and the nature of the case study phenomenon.
• Analyze the data: The data collected from the case study should be analyzed using various techniques, such as content analysis, thematic analysis, or grounded theory. The analysis should be guided by the research questions and should aim to provide insights and conclusions relevant to the research questions.
• Draw conclusions: The conclusions drawn from the case study should be based on the data analysis and should be relevant to the research questions. The conclusions should be supported by evidence and should be clearly stated.
• Validate the findings: The findings of the case study should be validated by reviewing the data and the analysis with participants or other experts in the field. This helps to ensure the validity and reliability of the findings.
• Write the report: The final step is to write the report of the case study research. The report should provide a clear description of the case study phenomenon, the research questions, the data collection methods, the data analysis, the findings, and the conclusions. The report should be written in a clear and concise manner and should follow the guidelines for academic writing.

Examples of Case Study

Here are some examples of case study research:

• The Hawthorne Studies : Conducted between 1924 and 1932, the Hawthorne Studies were a series of case studies conducted by Elton Mayo and his colleagues to examine the impact of work environment on employee productivity. The studies were conducted at the Hawthorne Works plant of the Western Electric Company in Chicago and included interviews, observations, and experiments.
• The Stanford Prison Experiment: Conducted in 1971, the Stanford Prison Experiment was a case study conducted by Philip Zimbardo to examine the psychological effects of power and authority. The study involved simulating a prison environment and assigning participants to the role of guards or prisoners. The study was controversial due to the ethical issues it raised.
• The Challenger Disaster: The Challenger Disaster was a case study conducted to examine the causes of the Space Shuttle Challenger explosion in 1986. The study included interviews, observations, and analysis of data to identify the technical, organizational, and cultural factors that contributed to the disaster.
• The Enron Scandal: The Enron Scandal was a case study conducted to examine the causes of the Enron Corporation’s bankruptcy in 2001. The study included interviews, analysis of financial data, and review of documents to identify the accounting practices, corporate culture, and ethical issues that led to the company’s downfall.
• The Fukushima Nuclear Disaster : The Fukushima Nuclear Disaster was a case study conducted to examine the causes of the nuclear accident that occurred at the Fukushima Daiichi Nuclear Power Plant in Japan in 2011. The study included interviews, analysis of data, and review of documents to identify the technical, organizational, and cultural factors that contributed to the disaster.

Application of Case Study

Case studies have a wide range of applications across various fields and industries. Here are some examples:

Business and Management

Case studies are widely used in business and management to examine real-life situations and develop problem-solving skills. Case studies can help students and professionals to develop a deep understanding of business concepts, theories, and best practices.

Case studies are used in healthcare to examine patient care, treatment options, and outcomes. Case studies can help healthcare professionals to develop critical thinking skills, diagnose complex medical conditions, and develop effective treatment plans.

Case studies are used in education to examine teaching and learning practices. Case studies can help educators to develop effective teaching strategies, evaluate student progress, and identify areas for improvement.

Social Sciences

Case studies are widely used in social sciences to examine human behavior, social phenomena, and cultural practices. Case studies can help researchers to develop theories, test hypotheses, and gain insights into complex social issues.

Law and Ethics

Case studies are used in law and ethics to examine legal and ethical dilemmas. Case studies can help lawyers, policymakers, and ethical professionals to develop critical thinking skills, analyze complex cases, and make informed decisions.

Purpose of Case Study

The purpose of a case study is to provide a detailed analysis of a specific phenomenon, issue, or problem in its real-life context. A case study is a qualitative research method that involves the in-depth exploration and analysis of a particular case, which can be an individual, group, organization, event, or community.

The primary purpose of a case study is to generate a comprehensive and nuanced understanding of the case, including its history, context, and dynamics. Case studies can help researchers to identify and examine the underlying factors, processes, and mechanisms that contribute to the case and its outcomes. This can help to develop a more accurate and detailed understanding of the case, which can inform future research, practice, or policy.

Case studies can also serve other purposes, including:

• Illustrating a theory or concept: Case studies can be used to illustrate and explain theoretical concepts and frameworks, providing concrete examples of how they can be applied in real-life situations.
• Developing hypotheses: Case studies can help to generate hypotheses about the causal relationships between different factors and outcomes, which can be tested through further research.
• Providing insight into complex issues: Case studies can provide insights into complex and multifaceted issues, which may be difficult to understand through other research methods.
• Informing practice or policy: Case studies can be used to inform practice or policy by identifying best practices, lessons learned, or areas for improvement.

Advantages of Case Study Research

There are several advantages of case study research, including:

• In-depth exploration: Case study research allows for a detailed exploration and analysis of a specific phenomenon, issue, or problem in its real-life context. This can provide a comprehensive understanding of the case and its dynamics, which may not be possible through other research methods.
• Rich data: Case study research can generate rich and detailed data, including qualitative data such as interviews, observations, and documents. This can provide a nuanced understanding of the case and its complexity.
• Holistic perspective: Case study research allows for a holistic perspective of the case, taking into account the various factors, processes, and mechanisms that contribute to the case and its outcomes. This can help to develop a more accurate and comprehensive understanding of the case.
• Theory development: Case study research can help to develop and refine theories and concepts by providing empirical evidence and concrete examples of how they can be applied in real-life situations.
• Practical application: Case study research can inform practice or policy by identifying best practices, lessons learned, or areas for improvement.
• Contextualization: Case study research takes into account the specific context in which the case is situated, which can help to understand how the case is influenced by the social, cultural, and historical factors of its environment.

Limitations of Case Study Research

There are several limitations of case study research, including:

• Limited generalizability : Case studies are typically focused on a single case or a small number of cases, which limits the generalizability of the findings. The unique characteristics of the case may not be applicable to other contexts or populations, which may limit the external validity of the research.
• Biased sampling: Case studies may rely on purposive or convenience sampling, which can introduce bias into the sample selection process. This may limit the representativeness of the sample and the generalizability of the findings.
• Subjectivity: Case studies rely on the interpretation of the researcher, which can introduce subjectivity into the analysis. The researcher’s own biases, assumptions, and perspectives may influence the findings, which may limit the objectivity of the research.
• Limited control: Case studies are typically conducted in naturalistic settings, which limits the control that the researcher has over the environment and the variables being studied. This may limit the ability to establish causal relationships between variables.
• Time-consuming: Case studies can be time-consuming to conduct, as they typically involve a detailed exploration and analysis of a specific case. This may limit the feasibility of conducting multiple case studies or conducting case studies in a timely manner.
• Resource-intensive: Case studies may require significant resources, including time, funding, and expertise. This may limit the ability of researchers to conduct case studies in resource-constrained settings.

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• What Is a Case Study? | Definition, Examples & Methods

What Is a Case Study? | Definition, Examples & Methods

Published on May 8, 2019 by Shona McCombes . Revised on November 20, 2023.

A case study is a detailed study of a specific subject, such as a person, group, place, event, organization, or phenomenon. Case studies are commonly used in social, educational, clinical, and business research.

A case study research design usually involves qualitative methods , but quantitative methods are sometimes also used. Case studies are good for describing , comparing, evaluating and understanding different aspects of a research problem .

Table of contents

When to do a case study, step 1: select a case, step 2: build a theoretical framework, step 3: collect your data, step 4: describe and analyze the case, other interesting articles.

A case study is an appropriate research design when you want to gain concrete, contextual, in-depth knowledge about a specific real-world subject. It allows you to explore the key characteristics, meanings, and implications of the case.

Case studies are often a good choice in a thesis or dissertation . They keep your project focused and manageable when you don’t have the time or resources to do large-scale research.

You might use just one complex case study where you explore a single subject in depth, or conduct multiple case studies to compare and illuminate different aspects of your research problem.

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Once you have developed your problem statement and research questions , you should be ready to choose the specific case that you want to focus on. A good case study should have the potential to:

• Provide new or unexpected insights into the subject
• Challenge or complicate existing assumptions and theories
• Propose practical courses of action to resolve a problem
• Open up new directions for future research

TipIf your research is more practical in nature and aims to simultaneously investigate an issue as you solve it, consider conducting action research instead.

Unlike quantitative or experimental research , a strong case study does not require a random or representative sample. In fact, case studies often deliberately focus on unusual, neglected, or outlying cases which may shed new light on the research problem.

Example of an outlying case studyIn the 1960s the town of Roseto, Pennsylvania was discovered to have extremely low rates of heart disease compared to the US average. It became an important case study for understanding previously neglected causes of heart disease.

However, you can also choose a more common or representative case to exemplify a particular category, experience or phenomenon.

Example of a representative case studyIn the 1920s, two sociologists used Muncie, Indiana as a case study of a typical American city that supposedly exemplified the changing culture of the US at the time.

While case studies focus more on concrete details than general theories, they should usually have some connection with theory in the field. This way the case study is not just an isolated description, but is integrated into existing knowledge about the topic. It might aim to:

• Exemplify a theory by showing how it explains the case under investigation
• Expand on a theory by uncovering new concepts and ideas that need to be incorporated
• Challenge a theory by exploring an outlier case that doesn’t fit with established assumptions

To ensure that your analysis of the case has a solid academic grounding, you should conduct a literature review of sources related to the topic and develop a theoretical framework . This means identifying key concepts and theories to guide your analysis and interpretation.

There are many different research methods you can use to collect data on your subject. Case studies tend to focus on qualitative data using methods such as interviews , observations , and analysis of primary and secondary sources (e.g., newspaper articles, photographs, official records). Sometimes a case study will also collect quantitative data.

Example of a mixed methods case studyFor a case study of a wind farm development in a rural area, you could collect quantitative data on employment rates and business revenue, collect qualitative data on local people’s perceptions and experiences, and analyze local and national media coverage of the development.

The aim is to gain as thorough an understanding as possible of the case and its context.

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In writing up the case study, you need to bring together all the relevant aspects to give as complete a picture as possible of the subject.

How you report your findings depends on the type of research you are doing. Some case studies are structured like a standard scientific paper or thesis , with separate sections or chapters for the methods , results and discussion .

Others are written in a more narrative style, aiming to explore the case from various angles and analyze its meanings and implications (for example, by using textual analysis or discourse analysis ).

In all cases, though, make sure to give contextual details about the case, connect it back to the literature and theory, and discuss how it fits into wider patterns or debates.

If you want to know more about statistics , methodology , or research bias , make sure to check out some of our other articles with explanations and examples.

• Normal distribution
• Degrees of freedom
• Null hypothesis
• Discourse analysis
• Control groups
• Mixed methods research
• Non-probability sampling
• Quantitative research
• Ecological validity

Research bias

• Rosenthal effect
• Implicit bias
• Cognitive bias
• Selection bias
• Negativity bias
• Status quo bias

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What the Case Study Method Really Teaches

• Nitin Nohria

Seven meta-skills that stick even if the cases fade from memory.

It’s been 100 years since Harvard Business School began using the case study method. Beyond teaching specific subject matter, the case study method excels in instilling meta-skills in students. This article explains the importance of seven such skills: preparation, discernment, bias recognition, judgement, collaboration, curiosity, and self-confidence.

During my decade as dean of Harvard Business School, I spent hundreds of hours talking with our alumni. To enliven these conversations, I relied on a favorite question: “What was the most important thing you learned from your time in our MBA program?”

• Nitin Nohria is the George F. Baker Jr. Professor at Harvard Business School and the former dean of HBS.

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What is the Case Study Method?

Overview Dropdown up

Overview dropdown down, celebrating 100 years of the case method at hbs.

The 2021-2022 academic year marks the 100-year anniversary of the introduction of the case method at Harvard Business School. Today, the HBS case method is employed in the HBS MBA program, in Executive Education programs, and in dozens of other business schools around the world. As Dean Srikant Datar's says, the case method has withstood the test of time.

Case Discussion Preparation Details Expand All Collapse All

In self-reflection in self-reflection dropdown down, in a small group setting in a small group setting dropdown down, in the classroom in the classroom dropdown down, beyond the classroom beyond the classroom dropdown down, how the case method creates value dropdown up, how the case method creates value dropdown down, in self-reflection, in a small group setting, in the classroom, beyond the classroom.

How Cases Unfold In the Classroom

How cases unfold in the classroom dropdown up, how cases unfold in the classroom dropdown down, preparation guidelines expand all collapse all, read the professor's assignment or discussion questions read the professor's assignment or discussion questions dropdown down, read the first few paragraphs and then skim the case read the first few paragraphs and then skim the case dropdown down, reread the case, underline text, and make margin notes reread the case, underline text, and make margin notes dropdown down, note the key problems on a pad of paper and go through the case again note the key problems on a pad of paper and go through the case again dropdown down, how to prepare for case discussions dropdown up, how to prepare for case discussions dropdown down, read the professor's assignment or discussion questions, read the first few paragraphs and then skim the case, reread the case, underline text, and make margin notes, note the key problems on a pad of paper and go through the case again, case study best practices expand all collapse all, prepare prepare dropdown down, discuss discuss dropdown down, participate participate dropdown down, relate relate dropdown down, apply apply dropdown down, note note dropdown down, understand understand dropdown down, case study best practices dropdown up, case study best practices dropdown down, participate, what can i expect on the first day dropdown down.

Most programs begin with registration, followed by an opening session and a dinner. If your travel plans necessitate late arrival, please be sure to notify us so that alternate registration arrangements can be made for you. Please note the following about registration:

HBS campus programs – Registration takes place in the Chao Center.

India programs – Registration takes place outside the classroom.

Other off-campus programs – Registration takes place in the designated facility.

What happens in class if nobody talks? Dropdown down

Professors are here to push everyone to learn, but not to embarrass anyone. If the class is quiet, they'll often ask a participant with experience in the industry in which the case is set to speak first. This is done well in advance so that person can come to class prepared to share. Trust the process. The more open you are, the more willing you’ll be to engage, and the more alive the classroom will become.

Does everyone take part in "role-playing"? Dropdown down

Professors often encourage participants to take opposing sides and then debate the issues, often taking the perspective of the case protagonists or key decision makers in the case.

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Case Study Research Method in Psychology

Saul Mcleod, PhD

Editor-in-Chief for Simply Psychology

BSc (Hons) Psychology, MRes, PhD, University of Manchester

Saul Mcleod, PhD., is a qualified psychology teacher with over 18 years of experience in further and higher education. He has been published in peer-reviewed journals, including the Journal of Clinical Psychology.

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Olivia Guy-Evans is a writer and associate editor for Simply Psychology. She has previously worked in healthcare and educational sectors.

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Case studies are in-depth investigations of a person, group, event, or community. Typically, data is gathered from various sources using several methods (e.g., observations & interviews).

The case study research method originated in clinical medicine (the case history, i.e., the patient’s personal history). In psychology, case studies are often confined to the study of a particular individual.

The information is mainly biographical and relates to events in the individual’s past (i.e., retrospective), as well as to significant events that are currently occurring in his or her everyday life.

The case study is not a research method, but researchers select methods of data collection and analysis that will generate material suitable for case studies.

Freud (1909a, 1909b) conducted very detailed investigations into the private lives of his patients in an attempt to both understand and help them overcome their illnesses.

This makes it clear that the case study is a method that should only be used by a psychologist, therapist, or psychiatrist, i.e., someone with a professional qualification.

There is an ethical issue of competence. Only someone qualified to diagnose and treat a person can conduct a formal case study relating to atypical (i.e., abnormal) behavior or atypical development.

 Famous Case Studies

• Anna O – One of the most famous case studies, documenting psychoanalyst Josef Breuer’s treatment of “Anna O” (real name Bertha Pappenheim) for hysteria in the late 1800s using early psychoanalytic theory.
• Little Hans – A child psychoanalysis case study published by Sigmund Freud in 1909 analyzing his five-year-old patient Herbert Graf’s house phobia as related to the Oedipus complex.
• Bruce/Brenda – Gender identity case of the boy (Bruce) whose botched circumcision led psychologist John Money to advise gender reassignment and raise him as a girl (Brenda) in the 1960s.
• Genie Wiley – Linguistics/psychological development case of the victim of extreme isolation abuse who was studied in 1970s California for effects of early language deprivation on acquiring speech later in life.
• Phineas Gage – One of the most famous neuropsychology case studies analyzes personality changes in railroad worker Phineas Gage after an 1848 brain injury involving a tamping iron piercing his skull.

Clinical Case Studies

• Studying the effectiveness of psychotherapy approaches with an individual patient
• Assessing and treating mental illnesses like depression, anxiety disorders, PTSD
• Neuropsychological cases investigating brain injuries or disorders

Child Psychology Case Studies

• Studying psychological development from birth through adolescence
• Cases of learning disabilities, autism spectrum disorders, ADHD
• Effects of trauma, abuse, deprivation on development

Types of Case Studies

• Explanatory case studies : Used to explore causation in order to find underlying principles. Helpful for doing qualitative analysis to explain presumed causal links.
• Exploratory case studies : Used to explore situations where an intervention being evaluated has no clear set of outcomes. It helps define questions and hypotheses for future research.
• Descriptive case studies : Describe an intervention or phenomenon and the real-life context in which it occurred. It is helpful for illustrating certain topics within an evaluation.
• Multiple-case studies : Used to explore differences between cases and replicate findings across cases. Helpful for comparing and contrasting specific cases.
• Intrinsic : Used to gain a better understanding of a particular case. Helpful for capturing the complexity of a single case.
• Collective : Used to explore a general phenomenon using multiple case studies. Helpful for jointly studying a group of cases in order to inquire into the phenomenon.

Where Do You Find Data for a Case Study?

There are several places to find data for a case study. The key is to gather data from multiple sources to get a complete picture of the case and corroborate facts or findings through triangulation of evidence. Most of this information is likely qualitative (i.e., verbal description rather than measurement), but the psychologist might also collect numerical data.

1. Primary sources

• Interviews – Interviewing key people related to the case to get their perspectives and insights. The interview is an extremely effective procedure for obtaining information about an individual, and it may be used to collect comments from the person’s friends, parents, employer, workmates, and others who have a good knowledge of the person, as well as to obtain facts from the person him or herself.
• Observations – Observing behaviors, interactions, processes, etc., related to the case as they unfold in real-time.
• Documents & Records – Reviewing private documents, diaries, public records, correspondence, meeting minutes, etc., relevant to the case.

2. Secondary sources

• News/Media – News coverage of events related to the case study.
• Academic articles – Journal articles, dissertations etc. that discuss the case.
• Government reports – Official data and records related to the case context.
• Books/films – Books, documentaries or films discussing the case.

3. Archival records

Searching historical archives, museum collections and databases to find relevant documents, visual/audio records related to the case history and context.

Public archives like newspapers, organizational records, photographic collections could all include potentially relevant pieces of information to shed light on attitudes, cultural perspectives, common practices and historical contexts related to psychology.

4. Organizational records

Organizational records offer the advantage of often having large datasets collected over time that can reveal or confirm psychological insights.

Of course, privacy and ethical concerns regarding confidential data must be navigated carefully.

However, with proper protocols, organizational records can provide invaluable context and empirical depth to qualitative case studies exploring the intersection of psychology and organizations.

• Organizational/industrial psychology research : Organizational records like employee surveys, turnover/retention data, policies, incident reports etc. may provide insight into topics like job satisfaction, workplace culture and dynamics, leadership issues, employee behaviors etc.
• Clinical psychology : Therapists/hospitals may grant access to anonymized medical records to study aspects like assessments, diagnoses, treatment plans etc. This could shed light on clinical practices.
• School psychology : Studies could utilize anonymized student records like test scores, grades, disciplinary issues, and counseling referrals to study child development, learning barriers, effectiveness of support programs, and more.

How do I Write a Case Study in Psychology?

Follow specified case study guidelines provided by a journal or your psychology tutor. General components of clinical case studies include: background, symptoms, assessments, diagnosis, treatment, and outcomes. Interpreting the information means the researcher decides what to include or leave out. A good case study should always clarify which information is the factual description and which is an inference or the researcher’s opinion.

1. Introduction

• Provide background on the case context and why it is of interest, presenting background information like demographics, relevant history, and presenting problem.
• Compare briefly to similar published cases if applicable. Clearly state the focus/importance of the case.

2. Case Presentation

• Describe the presenting problem in detail, including symptoms, duration,and impact on daily life.
• Include client demographics like age and gender, information about social relationships, and mental health history.
• Describe all physical, emotional, and/or sensory symptoms reported by the client.
• Use patient quotes to describe the initial complaint verbatim. Follow with full-sentence summaries of relevant history details gathered, including key components that led to a working diagnosis.
• Summarize clinical exam results, namely orthopedic/neurological tests, imaging, lab tests, etc. Note actual results rather than subjective conclusions. Provide images if clearly reproducible/anonymized.
• Clearly state the working diagnosis or clinical impression before transitioning to management.

3. Management and Outcome

• Indicate the total duration of care and number of treatments given over what timeframe. Use specific names/descriptions for any therapies/interventions applied.
• Present the results of the intervention,including any quantitative or qualitative data collected.
• For outcomes, utilize visual analog scales for pain, medication usage logs, etc., if possible. Include patient self-reports of improvement/worsening of symptoms. Note the reason for discharge/end of care.

4. Discussion

• Analyze the case, exploring contributing factors, limitations of the study, and connections to existing research.
• Analyze the effectiveness of the intervention,considering factors like participant adherence, limitations of the study, and potential alternative explanations for the results.
• Identify any questions raised in the case analysis and relate insights to established theories and current research if applicable. Avoid definitive claims about physiological explanations.
• Offer clinical implications, and suggest future research directions.

5. Additional Items

• Thank specific assistants for writing support only. No patient acknowledgments.
• References should directly support any key claims or quotes included.
• Use tables/figures/images only if substantially informative. Include permissions and legends/explanatory notes.
• Provides detailed (rich qualitative) information.
• Provides insight for further research.
• Permitting investigation of otherwise impractical (or unethical) situations.

Case studies allow a researcher to investigate a topic in far more detail than might be possible if they were trying to deal with a large number of research participants (nomothetic approach) with the aim of ‘averaging’.

Because of their in-depth, multi-sided approach, case studies often shed light on aspects of human thinking and behavior that would be unethical or impractical to study in other ways.

Research that only looks into the measurable aspects of human behavior is not likely to give us insights into the subjective dimension of experience, which is important to psychoanalytic and humanistic psychologists.

Case studies are often used in exploratory research. They can help us generate new ideas (that might be tested by other methods). They are an important way of illustrating theories and can help show how different aspects of a person’s life are related to each other.

The method is, therefore, important for psychologists who adopt a holistic point of view (i.e., humanistic psychologists ).

Limitations

• Lacking scientific rigor and providing little basis for generalization of results to the wider population.
• Researchers’ own subjective feelings may influence the case study (researcher bias).
• Difficult to replicate.
• Time-consuming and expensive.
• The volume of data, together with the time restrictions in place, impacted the depth of analysis that was possible within the available resources.

Because a case study deals with only one person/event/group, we can never be sure if the case study investigated is representative of the wider body of “similar” instances. This means the conclusions drawn from a particular case may not be transferable to other settings.

Because case studies are based on the analysis of qualitative (i.e., descriptive) data , a lot depends on the psychologist’s interpretation of the information she has acquired.

This means that there is a lot of scope for Anna O , and it could be that the subjective opinions of the psychologist intrude in the assessment of what the data means.

For example, Freud has been criticized for producing case studies in which the information was sometimes distorted to fit particular behavioral theories (e.g., Little Hans ).

This is also true of Money’s interpretation of the Bruce/Brenda case study (Diamond, 1997) when he ignored evidence that went against his theory.

Breuer, J., & Freud, S. (1895).  Studies on hysteria . Standard Edition 2: London.

Curtiss, S. (1981). Genie: The case of a modern wild child .

Diamond, M., & Sigmundson, K. (1997). Sex Reassignment at Birth: Long-term Review and Clinical Implications. Archives of Pediatrics & Adolescent Medicine , 151(3), 298-304

Freud, S. (1909a). Analysis of a phobia of a five year old boy. In The Pelican Freud Library (1977), Vol 8, Case Histories 1, pages 169-306

Freud, S. (1909b). Bemerkungen über einen Fall von Zwangsneurose (Der “Rattenmann”). Jb. psychoanal. psychopathol. Forsch ., I, p. 357-421; GW, VII, p. 379-463; Notes upon a case of obsessional neurosis, SE , 10: 151-318.

Harlow J. M. (1848). Passage of an iron rod through the head.  Boston Medical and Surgical Journal, 39 , 389–393.

Harlow, J. M. (1868).  Recovery from the Passage of an Iron Bar through the Head .  Publications of the Massachusetts Medical Society. 2  (3), 327-347.

Money, J., & Ehrhardt, A. A. (1972).  Man & Woman, Boy & Girl : The Differentiation and Dimorphism of Gender Identity from Conception to Maturity. Baltimore, Maryland: Johns Hopkins University Press.

Money, J., & Tucker, P. (1975). Sexual signatures: On being a man or a woman.

Further Information

• Case Study Approach
• Case Study Method
• Enhancing the Quality of Case Studies in Health Services Research
• “We do things together” A case study of “couplehood” in dementia
• Using mixed methods for evaluating an integrative approach to cancer care: a case study

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• v.24(6); 2019 Sep

Lessons learnt: examining the use of case study methodology for nursing research in the context of palliative care

Paula brogan.

School of Communication and Media, University of Ulster, Northern Ireland, UK

Felicity Hasson

Institute of Nursing Research, University of Ulster, Northern Ireland, UK

An empirical social research approach, facilitating in-depth exploration of complex, contemporary contextualised phenomena, case study research has been used internationally in healthcare studies across clinical settings, to explore systems and processes of care delivery. In the United Kingdom, case study methods have been championed by nurse researchers, particularly in the context of community nursing and palliative care provision, where its applicability is well established. Yet, dogged by conceptual confusion, case study remains largely underutilised as a research approach.

Drawing on examples from nursing and palliative care studies, this paper clarifies case study research, identifies key concepts and considers lessons learned about its potential for nursing research within the unique and complex palliative and end of life context.

A case study approach offers nurse researchers the opportunity for in-depth, contextualised understanding of the systems and processes which influence their role in palliative care delivery across settings. However, philosophical and conceptual understandings are needed and further training in case study methodology is required to enable researchers to articulate and conduct case study.

Introduction

An empirical social research approach, facilitating in-depth exploration of a contemporary phenomenon ( Yin, 2009 ), case study research has been used internationally in healthcare studies ( Anthony and Jack, 2009 ) to explore systems of palliative care ( Lalor et al., 2013 ), diverse contexts for palliative care delivery ( Sussman et al., 2011 ), roles of professional groups such as pharmacy ( O’Connor et al., 2011 ), the impact of services such as complementary therapy ( Maddalena et al., 2010 ) and nursing (Kaasalainen et al., 2013). In the United Kingdom, case study methods have been championed by nurse researchers ( Payne et al., 2006 ), particularly in the context of community nursing and palliative care provision ( Kennedy, 2005 ; Walshe et al., 2004 , 2008 ) and its applicability to palliative and end-of-life care research is established ( Goodman et al., 2012 ). Suited to the study of complex processes ( Walshe, 2011 ), case study methodology is embedded in professional guidance on the development of complex interventions ( Medical Research Council, 2008 ). Yet, case study is dogged by conceptual confusion (Flyvberg, 2006), and, despite sporadic use, remains underutilised as a research approach in healthcare settings ( Froggatt et al., 2003 ).

Illustrated by examples from nursing and palliative care studies, this paper aims to clarify conceptual understanding and identify key lessons for its application within these unique and complex contexts and, more broadly, for nursing research.

Origins and definitions

French sociologist Frederic Le Play (1806–1882) is associated with the origin of the case study approach ( Hamel et al., 1993 ). Using a purposive sample of working class families and fieldwork methods of observation and individual interview, he sought a contextualised and in-depth understanding of their individual experiences. Each family case study uncovered the unique experience of that family, but each additional family studied was another ‘ case of the lived experience’ of working class families in mid-18th century France. Thereby, Le Play used the lens of individual experience ( Yin, 2013 ) to build comparisons across families and enrich overall understanding of that complex society.

This early glimpse of the case study approach showed it to be a straightforward ‘field investigation’ ( Hamel et al., 1993 ); epistemologically pragmatic as it generated knowledge through data drawn from diverse sources, such as family members, and used the best available data collection methods then, to inform a holistic and contextualised understanding of how people operated within a complex social system ( Stake, 1995 ).

However, defining case study has become increasingly challenging since its expansion into North America in the 1800s ( Platt, 1992 ), and its use across a range of disciplines such as politics ( Gerring, 2004 ), social science ( George and Bennett, 2005 ), education ( Merriam, 1998 ) and healthcare ( Yin, 2013 ). Variously characterised as a case report, data collection method and methodology ( Anthony and Jack, 2009 ), the development of case histories as illustrations in health and social care and in education ( Merriam, 1998 ) has contributed to further confusion for researchers and readers of case study research ( Gomm et al., 2000 ). Critiques of case study note that it lacks a single definition, such that a plethora of discipline dependant interpretations ( Simons, 2009 ) and loose use of the term case study ( Tight, 2010 ) have contributed to confusion and undermined case study credibility. However, Simons ( 2009 , p. 63) advises researchers that case study must be seen within the complex nexus of political, methodological and epistemological convictions that constitute the field of enquiry, and variations of these may be glimpsed in Table 1 as definitions from four eminent and frequently cited case study authors illustrate philosophical and discipline-influenced differences in emphasis. Consequently, the case study definition selected, with its underpinning ontology and epistemology has important implications for the coherent outworking of the overall research design. It is therefore notable that many of the palliative care case studies contained in Table 2 fail to identify any such definition and this may have implications for interpretation of the quality of studies.

Definitions of case study by four key authors, showing the variation in meaning and interpretation.

Examples of Case Studies (CS) conducted in palliative care contexts.

Case study as a philosophy for the epistemology of knowledge generation

Although frequently linked to naturalistic inquiry ( Lincoln and Guba, 1986 ), interpretative/constructivist philosophy and qualitative methodology ( Stake, 1995 ), case study is not in fact bound to any single research paradigm ( Creswell, 2013 ). It is philosophically pragmatic, such that the case study design should reflect the ontological positions and epistemological considerations of the researchers and their topic of interest ( Luck et al., 2006 ). In practice, this means that case study research may pragmatically employ both qualitative and quantitative methods independently or together in order to respond to the research objectives ( Cooper et al., 2012 ; Simons, 1987 ; Stake, 2006 ). So whilst Table 2 shows that qualitative case studies are common in palliative care, epistemological variation is evident and reflects the study topic, purpose and context of the research. For example, Maddalena et al. (2010) used in-depth interview and discourse analysis to understand individual patient meaning-making; Brogan et al. (2017) used focus groups and thematic analysis as part of an embedded element of a multiple case study, to contrast the diverse perspectives of multi-disciplinary healthcare practitioners on end-of-life decision-making; Sussman et al. (2011) incorporated survey data into a mixed methods multiple case study which explored health system characteristics and quality of care delivery for cancer patients across four regions of Canada. Consequently, it is useful to ‘conceptualise (case study) as an approach to research rather than a methodology in its own right’ ( Rosenberg and Yates, 2007 , p. 448), so that a non-standardised approach exists and the case study design, its boundaries, numbers of cases and methods are guided by the stated underpinning ontological perspectives of the researcher and their topic of interest. The study then flexibly adopts the best methods to gain an in-depth, holistic and contextualised understanding of the phenomenon of interest – the latter objectives being at the core of any definition of case study research.

Key case study concepts and lessons for practice

When considering the utility of a case study approach, research conducted in complex palliative care contexts offers several insights into how central concepts translate to practice.

Contextualised understanding

Drawing on the definitions in Table 1 , Stake emphasised the particularity and intrinsic value of each individual case ( Stake, 1995 ), to emphasise the usefulness of multiple cases to increase insight ( Stake, 2006 ), analyse patterns ( Gerring, 2004 ; George and Bennett, 2005 ) and develop causal hypotheses ( Yin, 2013 ). Yet, whatever the purpose, all case studies are concerned with the crucial relationship between a phenomenon and the environment in which it has occurred. In practice therefore, case study researchers must be concerned with understanding the background systems, structures and processes that influence and interact with the phenomenon under study. This capacity for contextualised and holistic understanding is underpinned by use of multiple data collection methods, such as observation, interview and document review, used simultaneously or sequentially ( Stake, 2006 ; Scholz and Tietje, 2002 ), to mine multiple sources of data, such as participant experience ( Brogan et al., 2017 ; Kaasalainen et al., 2012 ), documents (Lalor et al., 2003) service evaluations ( Walshe et al., 2008 ), and diaries ( Skilbeck and Seymour, 2002 ). This is exemplified in a study by Walshe et al. (2011) , who investigated referral decisions made by community palliative care nurses in the UK, by capturing interview data on the self-reported perspectives of healthcare professionals, in combination with observed team meetings in which decisions were influenced, and review of the written referral policies, protocols and palliative healthcare strategies specific to those decisions. This comprehensive and complex data enabled comparison of decisional processes and their influencing factors both within and across three Primary Care Trusts, thus providing a contemporaneous understanding of the complex relationship between individual nurse's referral decisions and the impact of the organisational and professional systems that underpinned them. Enhancing rigor, such methodological triangulation importantly contributed to the richness of data analysis and the development of assertions which might be drawn from the findings ( Cooper et al., 2012 ; Stake, 2006 ).

Process-focused

Flexible data collection methods, linked to the research purpose, enables case study researchers to gather both historical and real-time data in a variety of ways. For example, Kennedy’s longitudinal case study ( Kennedy, 2002 ) observed snapshots of the initial and follow-up assessment conducted by 11 district nurses over the subsequent 12 months, enabling an exploration of the outcome and impact of their decision-making, demonstrating the usefulness of case study to understand complex roles and processes which are fluid and elusive ( Yin, 2013 ), or otherwise difficult to capture, particularly in the intimate interpersonal contexts where nursing happens.

Analytic frame

Palliative care studies reviewed frequently report the use of thematic analysis. However, whilst this approach is certainly useful to process data generated in qualitative case studies, the approach to analysis must be congruent with the research design and reflect the purpose of the research and methods used. Moreover, beyond decisions about use of thematic analysis or descriptive statistics etc., in case study, important decisions must be made about the analytic frame of the research. Gerring’s definition (2004) set out the analytic frame in which the cases studied might be understood, explaining that each unit of analysis (or case), sheds light on other units (or cases). Thus defined, an individual case offers intrinsically valuable information about a phenomenon ( Stake, 1995 ) and the purposeful selection of cases is central to case study design. This is because, viewed from a certain angle, each case is also a case of something else, such that the findings have broader implications ( Gerring, 2004 ; Simons, 2009 , 1987 ; Yin, 2013 ). In practice, this means that the case and what it is a case of, must be clearly identified and well defined at the outset of a study, since this has implications for the relevance of findings. This can be seen in a study by O’Connor et al., (2011) , who considered the perceived role of community pharmacists in palliative care teams in Australia. Each unique case included multi-disciplinary healthcare team members, such as pharmacists, doctors and nurses working in localities, whose perspectives were sought. Each locality group was a case of community pharmacy provision in palliative care settings in Australia, and findings had implications for the planning of community services overall. So, insight development was possible at an individual, group and organisational level, and inferences were made directly in relation to the parameters of that case study.

The addition of several carefully selected cases, as in multiple case studies, offers the opportunity to analyse data gained within and across cases ( Stake, 2006 ). Case selection may be made in order to explore similarities and contrasting perspectives ( Brogan et al., 2017 ), understand the various impacts of geographical differences ( Sussman et al., 2011 ), and different organisational influences ( Walshe et al., 2008 ). However, whilst repetition of data across cases may reinforce propositions made at the outset of a study, the purpose of increasing the number of cases in case study research is primarily about increasing insight development into the complexity of a phenomenon ( Stake, 2006 ). Since case study is the study of a boundaried phenomenon ( Yin, 2013 ), establishing the analytic frame then underpins the selection criteria for potentially useful cases. Such clarification is essential since it provides the lens through which to focus research ( Gerring, 2004 ; Scholz and Tietje, 2002 ; Stake, 2006 ) and permits key decisions to be made about data which may be included and that which is not applicable.

However, significantly, this information is rarely articulated within published case studies in palliative care. This is an important issue for the quality of case study research, since description of the process of refining case study parameters, establishing clear boundaries of the case, articulating propositions based on existing literature, identifying the sources of data (people, records, policies, etc.) and the ways in which data would be captured, establishes clarity and underpins a rigorous, systematic and comprehensive process ( Gibbert et al., 2008 ), which can usefully contribute to practice and policy development ( George and Bennett, 2005 ).

Shaped by organisational systems, intimate settings and significant life stage contexts, the interconnection between context and participant experience of palliative care is one example of a process of healthcare provision that is often complex, subtle and elusive ( Walshe et al., 2011 ). Case studies conducted in these swiftly changing contexts illustrate several characteristics of case study research, which make it an appropriate methodological option for nurse researchers, providing the opportunity for in-depth, contextualised understanding of the systems and processes which influence their role in palliative care delivery across settings ( Walshe et al., 2004 ) and many others who seek a contextualised, contemporaneous understanding of any complex role or process ( Yin, 2013 ; Simons, 2009 ). This fieldwork-based approach has the potential to achieve depth and breadth of insight through the pragmatic, but carefully planned and articulated, use of multiple methods of data collection in order to answer the research question ( Stake, 2006 ) when analysed systematically within a frame determined at the outset by the definition of the case and its boundaries ( Gerring, 2004 ). Yet, the methodological flexibility that is advantageous in complex contexts, may be misunderstood ( Hammersley, 2012 ), particularly where terminology is unclear ( Lather, 1996 ) or where description of the systematic and rigorous application of the approach is missing from the report ( Morrow, 2005 ). Taken as an example of one area of healthcare research, evidence suggests that palliative care studies that deal meaningfully with underpinning philosophical perspectives for their selected case study approach, or which articulate coherent links between the defined case, its boundaries and the analytical frame are rare. The impact of such omissions may be the perpetuation of confusion and out-dated perceptions about the personality and quality of case study research ( King et al., 1994 ), with implications for its wider adoption by nurses in healthcare research. Further training in case study methodology is required to promote philosophical and conceptual understanding, and to enable researchers to fully articulate, conduct and report case study, to underpin its credibility, relevance and future use ( Hammersley et al., 2000 ; Stake and Turnbull, 1982).

Key points for policy, practice and/or research

• Case study is well suited to nursing research in palliative care contexts, where in-depth understanding of participant experience, complex systems and processes of care within changing contexts is needed.
• Not bound to any single paradigm, nor defined by any methodology, case study’s pragmatism and flexibility makes it useful for studies in palliative care.
• Training is needed in the underpinning philosophical and conceptual basis of case study methodology, in order to articulate, conduct and report credible case study research, and take advantage of the opportunities it offers for the conduct of palliative and end-of-life care research.

Paula Brogan is a Lecturer in counselling and communication in the School of Communication and Media, and was recently appointed as Faculty Partnership Manager, University of Ulster. Dual qualified as a Registered Nurse with specialism in District Nursing and as a Counsellor/couple psychotherapist (Reg MBACPaccred), she has over 30 years’ clinical practice experience in community palliative care nursing and the provision of psychological care to patients and families dealing with palliative and chronic illness. Having worked across statutory, voluntary and private sectors, her PhD focused on multi-disciplinary decision-making at the end of life with patients and families in the community setting. Currently secretary of the Palliative Care Research Forum for Northern Ireland (PCRFNI), Paula’s ongoing research interests include communication and co-constructed decision-making in palliative and chronic illness, and the psychological support of individuals, couples, patient-family groups and multi-disciplinary staff responding to challenges of advanced progressive illness.

Felicity Hasson is a Senior Lecturer in the Institute of Nursing Research at the University of Ulster with 20 years’ experience in research. A social researcher by background, she has extensive experience and knowledge of qualitative, quantitative and mixed method research and has been involved in numerous research studies in palliative and end-of-life care. She completed her MSc in 1996 and her PhD from University of Ulster in 2012. Felicity sits on the Council of Partners for the All Ireland Institute of Hospice and the Palliative Care Palliative Care Research Network (PCRN) and is an executive board member for the UK Palliative Care Research Society. She holds an editorial board position on Futures and Foresight Science. Felicity has an established publication track recorded and successful history of grant applications. Her research interests include nurse and assistant workforce, workforce training, palliative care and chronic illness (malignant and non-malignant with patients, families and multi-disciplinary health care professionals) and public awareness of palliative care and end of life issues.

Sonja McIlfatrick is a Professor in Nursing and Palliative Care and has recently been appointed as the Head of School of Nursing at University of Ulster. She is an experienced clinical academic with experience in nursing and palliative care practice, education and research. She previously worked as the Head of Research for the All Ireland Institute of Hospice and Palliative Care (2011-2014) and led the establishment of the All Ireland Palliative Care Research Network (PCRN) and is the current Chair of the Strategic Scientific Committee for the PCRN (AIIHPC). Sonja is an Executive Board member for the UK, Palliative Care Research Society and is member of the Research Scientific Advisory Committee for Marie Curie, UK. Sonja holds an Editorial Board position on the International Journal of Palliative Nursing and Journal of Research in Nursing. Professor McIlfatrick has published widely in academic and professional journals focused on palliative care research and has a successful history of grant acquisition. Sonja has a keen interest in doctoral education and is the current President of the International Network of Doctoral Education in Nursing (INDEN). Her research interests include, palliative care in chronic illness, decision making at end of life; public awareness of palliative care and psychosocial support for family caregivers affected by advanced disease.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethics statement

Ethical permission was not required for this paper.

The author(s) received no financial support for the research, authorship, and/or publication of this article.

• Anthony S, Jack S. (2009) Qualitative case-study methodology in nursing research: An integrative review . Journal of Advanced Nursing 65 ( 6 ): 1171–1181. [ PubMed ] [ Google Scholar ]
• Brogan P, Hasson F, McIlfatrick S. (2017) Shared decision-making at the end of life: A focus group study exploring the perceptions and experiences of multi-disciplinary healthcare professionals working in a home setting . Palliative Medicine 32 ( 1 ): 123–132. [ PubMed ] [ Google Scholar ]
• Cooper B, Glaesser J, Gomm R, et al. (2012) Challenging the Qualitative-Quantitative Divide: Explorations in Case-focused Causal Analysis , London: Continuum. [ Google Scholar ]
• Creswell JW. (2013) Qualitative Inquiry and Research Design: Choosing among five approaches , 3rd ed. Thousand Oaks: SAGE. [ Google Scholar ]
• Flyvbjerg B. (2006) Five misunderstandings about case-study research . Qualitative Inquiry 12 ( 2 ): 219–245. [ Google Scholar ]
• Froggatt KA, Field D, Bailey C, et al. (2003) Qualitative research in palliative care 1990–1999: A descriptive review . International Journal of Palliative Nursing 9 ( 3 ): 98–104. [ PubMed ] [ Google Scholar ]
• George AL, Bennett A. (2005) Case Studies and Theory Development in the Social Sciences , Cambridge, MA: MIT Press. [ Google Scholar ]
• Gerring J. (2004) What is case-study and what is it good for? The American Political Science Review 98 ( 2 ): 341–354. [ Google Scholar ]
• Gibbert M, Ruigrok W, Wicki B. (2008) What passes as rigorous case-study? Strategic Management Journal 29 : 1465–1474. [ Google Scholar ]
• Gomm R, Hammersley M, Foster P. (2000) Case Study Method: Key Issues, Key Texts , London: SAGE. [ Google Scholar ]
• Goodman C, Froggatt KA, Mathie E. (2012) End-of-life Care. Methods Review 12 , London: National Institute for Health Research and School for Social Care Research. [ Google Scholar ]
• Hamel J, Defour S, Fortin D. (1993) Case-study Methods. Qualitative Research Methods Series. 32 , Newbury Park: SAGE. [ Google Scholar ]
• Hammersley M, Foster P, Gomm R. (2000) Case study and generalisation . In: Gomm R, Hammersley M, Foster P. (eds) Case Study Method: Key Issues, Key Texts , London: SAGE, pp. 98–115. [ Google Scholar ]
• Hammersley M. (2012) Troubling theory in case study research . Higher Education Research and Development 31 ( 3 ): 393–405. [ Google Scholar ]
• Kaasalainen S, Ploeg J, McAiney C, et al. (2012) Role of the nurse practitioners in providing palliative care in long-term care homes . International Journal of Palliative Nursing 19 ( 10 ): 477–485. [ PubMed ] [ Google Scholar ]
• Kennedy C. (2005) District nursing support for patients with cancer requiring palliative care . British Journal of Community Nursing 10 ( 12 ): 566–574. [ PubMed ] [ Google Scholar ]
• Kennedy C. (2002) The decision-making process in a district nursing assessment . British Journal of Community Nursing 7 ( 10 ): 505–513. [ PubMed ] [ Google Scholar ]
• King G, Keohane RO, Verba S. (1994) Designing Social Inquiry: Scientific Inference in Qualitative Research , Princeton: Princeton University Press. [ Google Scholar ]
• Lalor JG, Casey D, Elliott N, et al. (2013) Using case-study within a sequential explanatory design to evaluate the impact of specialist and advanced practice roles on clinical outcomes: The SCAPE study . BMC Medical Research Methodology 13 ( 1 ): 55. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Lather P. (1996) Troubling clarity: The politics of accessible language . Harvard Educational Review 66 ( 3 ): 525–554. [ Google Scholar ]
• Lincoln YS, Guba EG. (1986) But is it rigorous? Trustworthiness and authenticity in naturalistic evaluation . In: Williams DD. (eds) Naturalistic Evaluation , San Francisco: Josey-Bass, pp. 73–84. [ Google Scholar ]
• Luck L, Jackson D, Usher K. (2006) Case-study: A bridge across paradigms . Nursing Inquiry 13 ( 2 ): 103–109. [ PubMed ] [ Google Scholar ]
• Maddalena VJ, Bernard WT, Etowa J, et al. (2010) Cancer care experiences and the use of complementary and alternative medicine at the end-of-life in Nova Scotia’s black communities . J Transcultural Nursing 21 ( 2 ): 114–122. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Medical Research Council (2008) Complex Interventions Guidance, www.mrc.ac.uk/complexinterventionsguidance (accessed 14 March 2014).
• Merriam SB. (1998) Qualitative research and case-study applications in education , San Francisco: Jossey-Bass. [ Google Scholar ]
• Morrow SL. (2005) Quality and trustworthiness in qualitative research in counselling psychology . Journal of Counseling Psychology 52 ( 2 ): 256–260. [ Google Scholar ]
• O’Connor M, Fisher C, French L, et al. (2011) Exploring the community pharmacist’s role in palliative care: Focusing on the person not just the prescription . Patient Education and Counseling 83 : 458–464. [ PubMed ] [ Google Scholar ]
• Payne S, Field D, Rolls L, et al. (2006) Case-study research methods in end-of-life care: Reflections on three studies . Journal of Advanced Nursing 58 ( 3 ): 236–245. [ PubMed ] [ Google Scholar ]
• Platt J. (1992) Case study in American methodological thought . Current Sociology 40 ( 1 ): 17–48. [ Google Scholar ]
• Rosenberg JP, Yates PM. (2007) Schematic representation of case-study research designs . Journal of Advanced Nursing 60 ( 4 ): 447–452. [ PubMed ] [ Google Scholar ]
• Scholz RW, Tietje O. (2002) Embedded Case Study Methods: Integrating Quantitative and Qualitative Knowledge , Los Angeles: SAGE. [ Google Scholar ]
• Simons H. (1987) The paradox of case-study . Cambridge Journal of Education 26 ( 2 ): 225–240. [ Google Scholar ]
• Simons H. (2009) Case-study Research in Practice , Thousand Oaks: SAGE. [ Google Scholar ]
• Skilbeck J, Seymour J. (2002) Meeting complex needs: And analysis of Macmillan nurses’ work with patients . International Journal of Palliative Nursing 8 ( 12 ): 574–582. [ PubMed ] [ Google Scholar ]
• Stake RE. (1995) The Art of Case-study Research , Thousand Oaks: SAGE. [ Google Scholar ]
• Stake RE, Trumbull DJ. (1987) Naturalistic generalizations . Review Journal of Philosophy and Social Science 7 : 1–12. [ Google Scholar ]
• Stake RE. (2006) Multiple case-study analysis , New York: The Guilford Press. [ Google Scholar ]
• Sussman J, Barbera L, Bainbridge D, et al. (2011) Health system characteristics and quality of care delivery: A comparative case-study examination of palliative care for cancer patients in four regions in Ontario, Canada . Palliative Medecine 26 ( 4 ): 322–335. [ PubMed ] [ Google Scholar ]
• Tight M. (2010) The curious case of case study: A viewpoint . International Journal of Social Research Methodology 13 ( 4 ): 329–339. [ Google Scholar ]
• Walshe C. (2011) The evaluation of complex interventions in palliative care: An exploration of the potential of case-study . Palliative Medicine 25 ( 8 ): 774–781. [ PubMed ] [ Google Scholar ]
• Walshe C, Chew-Graham C, Todd C, et al. (2008) What influences referrals within community palliative care services? A qualitative case-study . Social Science and Medicine 6 : 137–146. [ PubMed ] [ Google Scholar ]
• Walshe CE, Caress AL, Chew-Graham C, et al. (2004) Case studies: A research strategy appropriate for palliative care?’ . Palliative Medicine 18 : 677–684. [ PubMed ] [ Google Scholar ]
• Yin RK. (2013) Case-study Research: Design and Methods (Applied Social Research Methods) , Newbury Park: SAGE. [ Google Scholar ]
• Yin RK. (2009) Case-study Research: Design and Methods , 4th ed. Newbury Park: SAGE. [ Google Scholar ]

• Open access
• Published: 26 April 2022

Definition and conceptualization of the patient-centered care pathway, a proposed integrative framework for consensus: a Concept analysis and systematic review

• Jean-Baptiste Gartner 1 , 2 , 3 , 4 , 5 ,
• Kassim Said Abasse 1 , 2 , 3 , 5 ,
• Frédéric Bergeron 6 ,
• Paolo Landa 3 , 7 ,
• Célia Lemaire 8 &
• André Côté 1 , 2 , 3 , 4 , 5  

BMC Health Services Research volume  22 , Article number:  558 ( 2022 ) Cite this article

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Confusion exists over the definition of the care pathway concept and existing conceptual frameworks contain various inadequacies which have led to implementation difficulties. In the current global context of rapidly changing health care systems, there is great need for a standardized definition and integrative framework that can guide implementation. This study aims to propose an accurate and up-to-date definition of care pathway and an integrative conceptual framework.

An innovative hybrid method combining systematic review, concept analysis and bibliometric analysis was undertaken to summarize qualitative, quantitative, and mixed-method studies. Databases searched were PubMed, Embase and ABI/Inform. Methodological quality of included studies was then assessed.

Forty-four studies met the inclusion criteria. Using concept analysis, we developed a fine-grained understanding, an integrative conceptual framework, and an up-to-date definition of patient-centered care pathway by proposing 28 subcategories grouped into seven attributes. This conceptual framework considers both operational and social realities and supports the improvement and sustainable transformation of clinical, administrative, and organizational practices for the benefit of patients and caregivers, while considering professional experience, organizational constraints, and social dynamics. The proposed attributes of a fluid and effective pathway are (i) the centricity of patients and caregivers, (ii) the positioning of professional actors involved in the care pathway, (iii) the operation management through the care delivery process, (iv) the particularities of coordination structures, (v) the structural context of the system and organizations, (vi) the role of the information system and data management and (vii) the advent of the learning system. Antecedents are presented as key success factors of pathway implementation. By using the consequences and empirical referents, such as outcomes and evidence of care pathway interventions, we went beyond the single theoretical aim, proposing the application of the conceptual framework to healthcare management.

Conclusions

This study has developed an up-to-date definition of patient-centered care pathway and an integrative conceptual framework. Our framework encompasses 28 subcategories grouped into seven attributes that should be considered in complex care pathway intervention. The formulation of these attributes, antecedents as success factors and consequences as potential outcomes, allows the operationalization of this model for any pathway in any context.

Peer Review reports

While having a performant healthcare system is a crucial issue for every country, the health sector operates in silos that need to be challenged. Indeed, many authors have pointed to fragmented care processes as a cause of breakdowns in the continuity of healthcare services [ 1 ], unnecessary waiting times [ 2 , 3 ], flaws in the flow of information between the different episodes [ 4 ] and the realization of exams that may be superfluous [ 5 ]. This fragmentation results in a sub-optimal use of material and financial resources and unsatisfactory team management [ 4 ]. Based on this observation, several repeated calls to improve the quality and performance of healthcare services have been made since 2001 by national and international institutions such as the Institute of Medicine of America (IOM) in 2001 [ 6 ] and 2013 [ 7 ], the National Academies of Sciences, Engineering, Medicine in 2018 [ 8 ] and the World Health Organization (WHO) in 2016 [ 9 ] and 2020 [ 10 ]. These calls have progressively shifted from an injunction to improve quality based on criteria to provide safe, effective, efficient, timely, equitable and patient-centered care [ 6 ], to the development of models for the organization of health care and services that meet the current challenges of effectiveness and efficiency in healthcare systems. The WHO urges member countries to base their quality improvement policies on the entire continuum of care, taking into account at least the criteria of effectiveness, safety, equity, efficiency, integrated care and timeliness [ 11 ]. These calls also emphasize the need to improve care pathways by focusing on outcomes that matter to the patient from a clinical, quality of life and health system experience perspective [ 12 , 13 , 14 , 15 ], rather than on the needs of the production units. This change of perspective leads to the study of the redesign of performance evaluation models by focusing on the needs and expectations of the patient [ 16 , 17 ]. The problem is that there is confusion about the definition and characterization of a care and health service pathway. Indeed, Bergin et al. [ 2 ] identified 37 different definitions of the term care pathway based on a review of the literature. Definitions and characteristics vary across countries and include multiple phases ranging from prevention or screening to cure or palliative care. This confusion has led to wide variability in the outcomes of these interventions, resulting in underutilization of care pathway improvement programs [ 2 ]. Furthermore, such confusion leads to great variability in the analysis and modeling of care pathways. For example, in their scoping review, Khan et al. [ 18 ] showed the great variability that exists among studies of oncology care pathways in both the phases of care represented, and their characteristics. The lack of a common definition and clearly defined criteria leads to a lack of standardization, resulting in an inability to conduct reliable comparative studies of care pathway programs internationally [ 19 ].

The Oxford Concise Medical Dictionary 10th ed. [ 20 ] and the Oxford Dictionary of Nursing 8th ed. [ 21 ] define, in a concise way, care pathway as “a multidisciplinary plan for delivering health and social care to patients with a specific condition or set of symptoms. Such plans are often used for the management of common conditions and are intended to improve patient care by reducing unnecessary deviation from best practice”. The concept of a care pathway is one originally used in the field of Health Operations Management, whose definition was proposed by Vissers and Beech [ 22 ]. However, these definitions seem to be too imprecise and address neither the aim nor the social reality of implementing such pathways. The European Pathway Association (EPA) adopts the more precise definition from the 2007 thesis of Vanhaecht [ 23 ]. However this has not yet led to an international consensus, as confusion over the concepts remains high. Moreover, this definition does not clearly define the antecedents or factors favoring the success of such interventions, the means by which to implement them or the best practices through which to support them; nor does it sufficiently take into account the importance of the patient-centered care and patient-centered services approach. Similarly, the proposed implementation models largely neglected the social reality and the social dynamic of organizations [ 24 ], resulting in major implementation difficulties, as care pathways still being considered as complex interventions [ 25 , 26 ].

However, care pathway programs have recently demonstrated encouraging results in terms of reduced variation in care, improved accessibility, quality, sustainability, and cost effectiveness of care [ 2 ]. The definition we aim to develop through this research is significant and timely, in that it has the potential to guide the ongoing development, implementation, monitoring and evaluation of care pathway programs within the rapidly changing service and system contexts that we are experiencing. For example, the following initial barriers to the systemic and holistic implementation of care pathways have recently been removed. Firstly, limited access to valid and reliable data from multiple organizations [ 27 ] has been offset by a massive investment in Electronic Medical Records [ 28 ]. Secondly, the main difficulties in highlighting the complexity of the referral trajectory [ 29 ], frequently resulting from the clinicians’ perspective, have been overcome by proposing new approaches such as data mining or qualitative methods, focusing on the real care trajectory and the qualitative part of the patients’ experience [ 16 , 17 , 30 ]. Therefore, the evolution of knowledge and information technology and the investment of health systems in data-sharing infrastructure, as well as a definition of the levers of patient engagement and the advent of patient-centered-care and patient-centered services, make it possible to define a powerful model for improving them by placing the patient’s needs and expectations at the center of the care pathway. It is therefore the right time to define a recognized definition and an integrative conceptual framework that meets the demand for sharing knowledge internationally regarding the development, implementation, and evaluation of care pathways.

The concept of patient-centered care is defined as “care provision that is consistent with the values, needs, and desires of patients and is achieved when clinicians involve patients in healthcare discussions and decisions” [ 31 ]. This approach is known to provide benefits by improving health outcomes, patient satisfaction, but also to reducing health costs [ 32 ].

A preliminary search for existing reviews was conducted in Cochrane Database, JBI Database of Systematic Reviews and Implementation Reports and PROSPERO. Care pathways have been the subject of few reviews, but these were limited to a single pathology such as cancer in general [ 33 ], blunt thoracic injury [ 34 ], cardiovascular disease [ 35 ], adolescent idiopathic scoliosis [ 36 ] or for particular pathway phases [ 37 ]. In the end, focusing on a single condition is not entirely consistent with a patient-centered approach to care insofar as patients often have comorbidities. The only review that did not focus on one specific pathology was made in 2006 [ 38 ] and was interested in the concept of clinical pathway. Authors reviewed literature published within 3 years using only one bibliographic database. Therefore, the aim of this article is to propose an accurate and up-to-date definition of care pathway and to develop an integrative conceptual framework for the patient-centered care pathway concept in a holistic operational approach of the concept.

Combining systematic review, concept analysis and bibliometric analysis

To achieve a fine-grained understanding of the concept, we have chosen a hybrid method combining the systematic review, the concept analysis and the bibliometric analysis methodologies. We followed the latest PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) statement for conducting and reporting a systematic review [ 39 ]. However, the systematic review methodology presents some limitations on the qualitative analysis of literature, hence derives our interest to use Concept analysis. Concept analysis [ 40 ] aims specifically to clarify a specific concept including a semantic field linked to a specific theoretical framework. This approach is based on eight steps allowing to: (1) select the concept, (2) determine the aims or purposes of the analysis, (3) identify all uses of the concept, (4) determine the defining attributes, (5) identify a model case, (6) identify additional cases, (7) identify antecedents and consequences and (8) define empirical referents. However, this method does not provide a systematic and rigorous procedure for identifying and selecting relevant literature. Therefore, we decided to combine the strengths of both methods to overcome the limitations of each. In order to make our analysis more robust and to base our inferences, specifically in the comparative analysis of the related concepts, we performed a bibliometric analysis allowing us to link the attributes of each of the concepts to make a comparison.

Information sources and search strategy

We developed a search strategy, in collaboration with a Health Sciences Librarian who specializes in systematic literature review in healthcare, to identify relevant peer-reviewed studies. An initial limited search of MEDLINE and CINAHL was conducted, followed by analysis of the text words containing title and abstract and index terms used to describe the article. This informed the development of a search strategy that was tailored toward each information source. The search strategy was applied to the following databases: PubMed, Embase and ABI/Inform. The complete search strategy is provided in Additional file  1 .

Eligibility criteria

This review considers studies that focus on quantitative and/or qualitative data, with no limitation in terms of methodology. Our search focused on peer-reviewed scientific articles. Therefore, books, doctoral or master’s theses were excluded due to time and resource limitations. In order to guide the selection, we chose the Population, Context, Concept (PCC) mnemonic criteria [ 41 ]. The population considers all types of patients managed by healthcare delivery systems. The context studied is composed of healthcare providers in any geographic area, including all providers of primary, secondary, tertiary, and quaternary care. For the concept, this review focuses on theoretical and empirical studies that contribute to the definition and conceptualization of the different related concepts of care processes at the organizational or system level, such as care pathway, clinical pathway, patient journey and care processes. Quantitative, qualitative and mixed method studies involving a single episode of care limited in time (a one-time treatment) or space (a single hospital service/department) were excluded to the extent that care pathway involves multiple points of interaction over time [ 13 , 42 ] and multiple organizational structures or intra-organizational entities along the care continuum [ 43 ]. In addition, studies with no theoretical or conceptual input were excluded. Finally, there was no language or geographic restrictions applied to the search, and the study period was limited from 1995 to 2020.

These studies were imported into the Covidence® software (version 2020). The team developed screening questions and forms for levels 1 (abstract) and 2 (full text) screening based on the inclusion and exclusion criteria. Two reviewers independently screened the titles and abstracts. In case of disagreement, two senior reviewers decided after analysis and discussion. Review author pairs then screened the full-text articles against inclusion and exclusion criteria. In case of disagreement, the same process as for the title and abstract selection was implemented. Reasons for excluding studies were recorded.

Assessment of methodological quality

Because of the heterogeneity of the methods used in the selected articles, we decided to use a separate appraisal tool for each study type. The following appraisal tools were selected for their clarity, relevance, and because their items covered the most common assessment criteria comparing to other tools:

For qualitative studies: the JBI Qualitative Assessment Research Instrument (QARI) [ 41 ]

For surveys: the Center for Evidence Based Management (CEBMa) Appraisal Questions for a Survey [ 44 ]

For descriptive cross-sectional studies: the Institute for Public Health Sciences 11 questions to help you make sense of descriptive/cross-sectional studies [ 45 ]

For mixed-method: the scoring system for appraising mixed methods research [ 46 ]

No articles were excluded from this systematic review due to the weaknesses of their methodological quality, so as not to exclude valuable information [ 47 ].

Data extraction and analysis

Descriptive numerical summary analysis followed the systematic review guidelines, and the following items were systematically extracted: Reference, Title, First Author country, Case country, Year of publication, Type of publication, Target patient population, Phases of the pathway included, People involved in the modeling process, Study parameters and level of analysis.

Qualitative data were extracted using MaxQDA® software (version 2020) by two independent analysts. The data extraction followed the concept analysis guideline [ 40 ] and the following items were systematically extracted: Variant concept studied, Concept uses, Concept definition, Concept attributes, Antecedents, Consequences and empirical referents. In order to develop a detailed analysis and arrive at a robust theoretical framework, we relied on general inductive analysis [ 48 ], consisting of coding, categorization, linking, integration and modeling. Each step has been validated by at least two senior authors.

A bibliometric analysis was performed with the complete texts of the 44 selected studies using Vosviewer® software (version 2020).

The systematic review was reported following the latest PRISMA statement for conducting and reporting a systematic review [ 39 ] and mobilized the PRISMA 2020 checklist (see Additional file  2 ).

The interrogation of the three databases resulted in 15,281 articles. Figure  1 details the selection process following the PRISMA 2020 statement [ 39 ]. After deleting the duplicates, 15,072 records were reviewed but only 44 publications ultimately met the inclusion and exclusion criteria.

PRISMA 2020 flow diagram of the systematic review process

Description and methodological quality appraisal of studies

A summary table containing a brief description of selected studies and their evaluation results for methodological quality is presented in Table  1 . Quality appraisal of selected studies is presented in Additional file  3 .

Published articles, describing care pathways as multiple points, in time and space, of patient interaction appeared in the early 2000s. However, most of this work has been published since 2010, with a progressive and growing interest, whatever the theoretical position, to reach 22 articles in the last 3 years (see Fig.  2 ).

Frequency of selected publications over time

The countries of the first authors interested in this concept are predominantly anglophone such as the United Kingdom (k = 9), Australia (k = 5), the United States (k = 4), and Canada (k = 3). Researchers from other countries are less represented.

Three types of publications were found; 34 were original research studies, eight were literature reviews and two were perspective studies. In the original research studies, 23 used a qualitative approach to study either the implementation of a care pathway program or patient experience of a care pathway, four used a descriptive cross-sectional approach, four used a mix-method approach and three used a survey.

Since the definition of the concept is still unclear and terminology is important, the studies meeting the selection criteria reported several terminologies. The most frequently used terms in the selected studies were the patient journey (k = 14) and the care pathway (k = 13) with their some country-specific modifications namely integrated care pathway mainly in the United Kingdom [ 73 , 74 ], optimal care pathway in Australia [ 2 ] and standardized care pathway in Sweden [ 15 ]. The other terms used were clinical pathway (k = 8), patient-centered care (k = 4), care process (k = 3), disease pathway management (k = 1) and value-based integrated care (k = 1).

Studies focused mainly on the care of chronic conditions (k = 24), followed by acute diseases (k = 11). Of those with a chronic care focus, cancer was by far the most studied disease (k = 10), followed by stroke, hearing impairment and mental disease. Acute care studies covered, articular pathologies of the hip and knee, and pregnancy.

Concerning the level of the study, most addressed the systemic (k = 31) rather than the organizational (k = 13) level. Most authors, in their approach to the concept, largely focused on the treatment phase (k = 39), but some included, more or less, pretreatment and subsequent phases. Only seven articles took a global approach starting from the prevention phase and screening to survivorship or palliative care phase.

Concept analysis results

The conceptual analysis followed an automatic data extraction method in the proposed main categories and then, after several iterations, resulted in a coding of subcategories grouped into main themes. The detailed results of the coding are presented in Additional file  4 .

Concept uses

Uses of the concepts of care pathway have evolved in the literature over time with a strong tendency to focus on the care pathway at the systemic level. Main objectives have been improving quality and safety (k = 26), improving efficiency in the delivery of care (k = 24), optimizing the delivery process through an operation management point of view (k = 22) and integrating best practices through guidelines and evidence-based medicine (k = 17). These objectives were widely shared and present throughout the period. However, interest emerged in 2009 and quickly grew, in improving the patient experience through the analysis of the patient journey (k = 17). To a lesser extent, the goals of developing patient-centered care (k = 13), improving patient outcomes (k = 13), improving coordination of service delivery (k = 13), and standardizing care delivery (k = 12) were also present. Beyond standardization, reduced variation in care practices (k = 9) was not well addressed, nor was continuous performance assessment (k = 8). The aim of meeting the patient’s needs (k = 6) has been addressed more frequently in recent years, since its first appearance in 2011 [ 71 ], and is considered of crucial importance by some authors. Other concept uses were proposed, such as to improve interprofessional collaboration (k = 5), support changes (k = 5), support clinical decision making (k = 4), improve communication (k = 3), consider needs of healthcare workers, improve referral system, define shared purposes and meaningful objectives (k = 2), monitor staff compliance, support the knowledge management, improve patient and family member access to information, adopt a system approach and understanding power dynamics and relational factors (k = 1). As described previously, these concept uses came mainly from the chronic disease care context, although acute care was also represented.

Defining attributes

Definitional attributes are features commonly encountered in definitions of the concept or frequently used to describe it [ 40 ]. Twenty-eight attributes were inductively extracted and categorized into seven main themes, ordered by level of empirical importance: (1) The centricity of patients and caregivers; (2) the positioning of professional actors involved in the care pathway; (3) the operation management through the care delivery process; (4) the particularities of coordination structures; (5) the structural context of the system and organizations; (6) the special role of the information system and data management; and (7) the advent of the learning system (k = 3).

Attribute theme 1: The centricity of patients and caregivers

Firstly, there has been a growing interest in the patient experience (k = 15), mainly through the concept of the patient journey [ 5 , 13 , 14 , 15 , 24 , 30 , 42 , 51 , 52 , 58 ], which has progressively emerged as the third pillar of quality in healthcare with clinical effectiveness and patient quality and safety [ 30 ]. It is formed by all the interactions at the meeting point, or point of contact, between health services and patient [ 14 , 30 , 42 , 51 ]. However, taking the patient experience into account is complex insofar as it requires a detailed understanding of what influences it. Therefore, some authors have defined the dimensions that can influence the patient experience as the temporal dimension, meaning that accessibility and short waiting times are valued [ 13 , 15 , 30 , 42 , 51 ], the spatial dimension [ 30 ], and the geographical position of the services [ 42 ], the emotional dimension [ 13 , 30 , 42 ] and the social and cognitive dimensions [ 13 , 42 ]. All these dimensions can be the source of both positive outcomes [ 13 , 30 ] and negative outcomes [ 15 ] or for socio-political authors, a feeling of considerable disempowerment [ 53 ]. Although authors are increasingly interested in it, the patient experience is still sometimes overlooked [ 14 ].

Patient information and education (k = 15) were addressed in numerous studies. Patient information contributes to the quality of the patient experience [ 3 , 15 , 36 , 42 , 53 , 64 , 71 , 75 ]. Beyond the simple satisfaction, the provision of information, at an appropriate health literacy level, increases patient awareness [ 36 , 51 ] and thus increases patient education. This results in a better detection of the symptoms at an early stage by the patient [ 3 , 36 ], the development of the “expert patient” [ 51 , 57 , 58 , 71 ], which aids adherence to treatment, supports shared decision-making [ 57 ] and improves self-management [ 51 , 58 ]. However, many empirical studies showed there to be a lack of patient information throughout patient journeys [ 5 , 14 , 15 , 42 , 51 , 53 , 64 ].

Patient engagement (k = 15) was an important attribute of this theme in the more recent literature. The management by the patient of his or her care treatment plan has become increasingly important [ 24 , 50 , 51 , 53 , 67 ]. This translates into shared decision-making on care and treatment [ 3 , 14 , 24 , 35 , 51 , 53 , 55 , 54 , 55 , 58 , 64 , 65 ]. According to Devi et al. [ 51 ], this process can only be viable if supported by good information about treatment possibilities and possible outcomes. However, socio-political authors see this as a major issue of patient empowerment, which is “seen as a solution to many of the most pressing problems facing modern healthcare” [ 53 ].

Proposed only since 2014, and strongly present in the last 3 years, relationship as the basic need (k = 9) is also a subject of interest. Part of the patient experience, the relational quality reflects how patients perceive their interactions [ 13 , 42 ]. Some empirical studies have shown that a poor relationship can negatively affect other processes and tasks [ 3 , 5 ]. Therefore, quality of the relationship seems a fundamental prerequisite [ 14 , 64 ]. For this reason, some authors have placed the notion of trust as essential to the quality of interactions and to the patient’s follow-up through the care pathway [ 3 , 12 , 58 ].

Patient and Public Involvement (k = 9) is part of these new topics. Its importance in the design and improvement of the care pathway is supported by some international organizations [ 9 ]. The objective is to improve the quality of care provided by assessing patients’ perceptions [ 12 , 13 ]. In this way, the design of care delivery can be based on the real needs and expectations of patients [ 12 , 13 , 51 , 56 , 62 ]. However, some models have been criticized as tokenistic rather than being viable solution for balancing power between patients and health care providers [ 53 ].

Although the stated goal of care pathways incorporates an approach aimed at standardizing care practices, several authors have raised the need for individualized care (k = 8). Joosten et al. [ 74 ] saw a potential conflict between standardization and the demand for a personalized approach to healthcare. However, several authors have subsequently agreed that there is still room for individualization of care beyond the standardization [ 55 ], in particular through the definition of personalized treatment goals [ 51 ], or even maintaining flexibility in the interaction to better adapt to the patient’s specific needs [ 64 , 65 ].

Developed only since 2016, the importance of psychosocial support (k = 8) has increased rapidly. Although the need has been clearly identified and documented [ 5 , 15 , 42 , 58 ] and many international guidelines have integrated it, it seems that its translation within the care pathway is still complex [ 62 ] and no obvious answer was provided.

The inclusion of family and caregiver (k = 8) is also a new topic of the last 5 years which highlights the potential of family or caregivers involvement in decision-making [ 50 , 51 , 57 , 65 ]; notably by supporting both the integration of information and personal decision-making [ 14 , 15 ].

Attribute theme 2: The positioning of professional actors involved in the care pathway

Firstly, most authors consider the care pathway as a tool to develop patient-centered care (k = 18). The patient-centered care approach has a disease-specific orientation [ 25 ] and considers the patient as a real partner [ 51 , 25 ]. In doing so, this approach recognizes an individual’s specific health needs and preferences as the driving force in all healthcare decisions [ 13 , 51 , 65 , 67 ]. Thus, professional actors emphasize their accessibility and their attitudes and behaviors towards patients [ 13 ]. In addition, this approach considers the importance of integrating family and caregivers and is recognized as a necessary attribute of healthcare quality [ 65 ]. Finally, its implementation seems to improve patient satisfaction by moving toward an individualized therapy approach and personalized treatment goals [ 51 ].

Not surprisingly, multidisciplinary team-working (k = 17), and attribute which is consistent with previous definitions, is supported by several authors. The enrollment of all professional categories involved directly or indirectly in the care pathway at all steps is valued [ 2 , 50 , 75 ]. The multidisciplinary teamwork allows tackling the complexity of patient care across the pathway and developing a shared understanding supported by knowledge sharing among professionals [ 53 , 72 ]. In addition, it allows outlining the optimal sequence and timing of interventions [ 38 , 59 ] and to focus only on patient needs and engagement rather than on problems of a particular profession [ 56 ]. From an operational view, multidisciplinary care teams make it possible to share formal screening between disciplines [ 62 ]. Recently, multidisciplinary engagement was identified as a mandatory prerequisite for successful care pathway programs [ 24 , 50 ].

Staff skills (k = 10) could be considered equally important for care pathways. However, they were not addressed in this literature before 2014. Authors gave little attention to technical skills, except to point out possible deficiencies, particularly in diagnosis [ 3 , 13 ], but also in training [ 3 ]. Rather, authors focused almost exclusively on interpersonal skills [ 3 , 12 , 13 , 15 , 51 , 64 ], which were considered critical, both in the relations between professionals [ 12 , 15 , 51 , 56 , 64 ] as well as those with patients and their caregivers [ 15 , 51 , 64 ]. Interpersonal skills could be seen as facilitators or barriers to the patient experience [ 64 ]. Some authors have recently suggested that peer cooperation was critical [ 5 , 50 , 56 ] and that creating a culture of mutual respect among both medical and administrative colleagues can ultimately improve the fluidity of care [ 3 , 5 ].

Few authors have highlighted that the implementation of a care pathway leads professionals to examine their roles and responsibilities (k = 6). The need to define each step in the care process requires professionals to describe precisely the tasks and roles of professional actors [ 25 ]. In doing so, it creates a rare opportunity to step back from daily tasks and reassess competences, roles and responsibilities [ 12 , 51 , 73 ].

Finally, very recently, authors have been interested in the experience of staff (k = 2) in care pathway programs. These authors have demonstrated the link between staff experiences and their individual performance [ 24 , 53 ]. They therefore support the idea that staff well-being is directly related to engagement and performance and, thus, a negative staff experience can influence patient, clinician, and organizational outcomes.

Attribute theme 3: The operation management through the care delivery process

This analysis has shown, unsurprisingly, that the process approach to care delivery (k = 23) was the core of the care pathway approach across the literature to date. From an engineering perspective, as define by the International Organization for Standardization, a process is “a set of interrelated or interacting activities that transforms inputs into outputs” (ISO 9000:2000 clause 3.4.1). Through this approach, the care process can be defined as an arrangement of tasks or actions sequenced in time resulting in a time matrix [ 24 , 30 , 38 , 52 , 60 , 68 , 25 , 73 ]. What distinguishes the different process approaches to care delivery are the tasks and actions included with them. Some authors tend to focus on operational planning by treating tasks, actions and their timing through business processes [ 43 , 49 , 54 , 60 , 69 ], while other authors consider both the context of action through the physical and organizational environment [ 24 , 30 ] and social dynamic through the experience of actors [ 24 , 52 , 53 ]. Through this approach to care processes, some authors focus on patients and caregivers [ 52 ] and other authors focus on human actors, both patients and caregivers and the professional actors involved in the care pathway [ 24 ]. In 2018, Ponsignon et al. [ 13 ] proposed to differentiate the direct, indirect and independent interactions (those disconnected from the delivery system), in care processes. Direct interactions constitute the points of contact between patients and the system, and so are responsible, along with indirect interactions, for the patient version of the pathway that some authors call the patient journey [ 5 , 13 , 30 , 51 , 53 ]. More recently, the complexity of the care process has led some authors to consider that the care pathway should involve pathway rules which control the process [ 70 ]. Thus, decision-making becomes a central element in the smooth running of the care pathway [ 60 ]. In addition, many authors consider that healthcare decisions and care pathways are intertwined so that it becomes imperative to co-design both care pathways and the decision-making activities [ 60 ].

The issue of process management for the delivery of care naturally raises the question of process modeling methods (k = 18). In the empirical articles, the use of the Business Process Modeling Notation (BPMN) developed by the Object Management Group seems to be progressively imposed, sometimes improved by decision modeling [ 4 , 43 , 54 , 60 , 68 , 69 ]. The use of process mapping or flowcharts with sometimes less formal rules seems to be favored for global approaches to processes, especially for the patient journey, although some authors such as Combi et al. [ 60 ], have demonstrated that BPMN modeling was quite compatible with the systemic approach.

For healthcare service designers, the methods for building care pathways are important considerations. Several methods exist, but all involve the discovery of a different path, thus change is inevitable and change management a necessity. The initial method came mainly from the expertise of professionals through interviews, focus groups or Delphi methods [ 49 , 59 ]. The advantage of collaboration with staff and experts is that more information can be gathered about certain decisions and possible variances from the pathway [ 49 ]. However, this method did not consider the real trajectory or the ideal pathway but rather the one integrating the constraints of the professionals. Since these early efforts, data driven approaches has developed considerably [ 43 , 49 ]. Their advantage is that they inform pathway development from data derived factually and objectively from actual occurrences of the pathway [ 49 ]. Moreover, data on the perspectives of patients through experience mapping, interviews, focus groups or observations [ 5 , 13 , 30 ], and patient shadowing [ 53 ] can be integrated to better reflect the real trajectory and to define the ideal pathway according to the needs and expectations of patients and caregivers. However, this approach does not allow for the integration of context and organizational constraints. Finally, few authors adopt an approach that consists of comparing the experience of professionals and patients, making it possible to define the lived experience, the patient’s journey, and its confrontation with operational realities and constraints through the experience of professionals [ 1 , 3 , 4 , 15 , 65 , 71 ].

Regarding the process of care delivery, the management of operations aims to integrate the organization of the delivery process with its ongoing improvement (k = 11) by focusing as much on analyzing the variations as on eliminating the wastes [ 74 ]. Process improvement tools serve as much to redesign the processes as define a workflow management system to monitor the care pathway [ 4 ]. The information generated [ 60 , 61 , 63 ] can be used for process re-engineering, objective reassessment or supporting non-clinical decision-making [ 60 ], such as the identification of bottlenecks [ 61 , 67 ] or highlighting interfacing problems between organizations [ 61 ]. The output generated by the analysis of the process-related data allows defining standardized expedited diagnostic processes [ 4 , 60 ]. Finally, the data obtained allows the use of simulation and optimization models. On this subject, Aspland et al.’s literature review [ 49 ] provides an exhaustive review of available methods.

Attribute theme 4: The particularities of coordination structures

In line with most of the definitions, the integration of the clinical practice guidelines, based on evidenced-based medicine, into the care pathway (k = 24) has been accepted since the beginning of such programs. The clinical decisions directly affect the flow of the care delivery process and thus the process performance and the quality of outcomes [ 60 ]. Therefore, the adherence to clinical practice guidelines must support decision-making [ 70 , 73 ] and aid diagnosis and treatment in order to improve patient outcomes [ 50 , 51 , 58 ]. In 2010, Vanhaecht et al. [ 25 ] expressed concern about a lack of evidence-based key interventions within care pathways. The care pathway can be an effective method to integrate and guarantee the appropriate use of evidence-based interventions and clinical practice guidelines [ 55 ] and may help to overcome two limitations of clinical practice guideline use, which are emerging as key issues [ 60 , 66 ]. Firstly, that they should not be followed blindly as they represent only explicit medical knowledge [ 67 ], but rather require integration of the contextual knowledge of healthcare professionals for appropriate use [ 72 ]. Secondly, it has been shown that physicians can be unaware of updates and changes to clinical guidelines [ 3 ], and so, integrating them into care pathway maps may improve guideline use and adherence. Finally, collectively integrating and discussing clinical practice guidelines appears to improve interprofessional collaboration and clarify roles [ 36 ], but also could benefit the involvement of patients in the co-design of the care pathway [ 35 ].

Some authors consider information continuity (k = 13) as a key factor. Not only because sharing information must support decision-making [ 60 , 75 ] and facilitate communication [ 2 , 12 , 38 ], but more broadly because the disruption of the information flow can lead to coordination problems and easily avoidable costs linked to the repetition of examinations [ 5 , 56 , 59 ]. Therefore, the continuity of information must be supported to ensure sustainable health improvements [ 51 , 70 ]. Some authors insist on the importance of defining an information medium throughout the pathway which is as accessible to care professionals as it is to patients and caregivers [ 65 ].

Recently, some authors have dealt with the subject of leadership of the care pathway (k = 9). The importance of defining a leader for each step of the care pathway was noted [ 25 ]. The lack of coordination without a responsible actor has been shown, especially when the care pathway includes actors in several contexts such as primary care [ 3 ]. Thus, new roles have been defined, such as case managers, joint program or nurse coordinators [ 4 , 15 , 42 , 65 ], roles that enhance coordination among providers through the improvement of the continuity and quality of the information as well as communication [ 15 ].

More recently, the integration of services (k = 9) has been addressed. Because the care pathway approach can involve multiple partnerships between organizations and primary care, it is essential to integrate all stakeholders. The integration needs to be both organizational, at the macro and meso-level through shared purpose and priorities [ 4 , 57 , 25 ] and shared governance mechanisms [ 4 , 12 , 14 , 59 ], and functional at the micro level through communication mechanisms and tools [ 4 , 12 , 14 ]. The unifying element is discussed between the shared interest for the patient [ 56 , 57 ] or the outcomes [ 12 ] to align strategic goals. For Louis et al. [ 56 ], achieving shared purpose is part of the structural context.

Finally, the care pathway is seen as a means of health knowledge management (k = 7) that optimizes quality, efficiency, and organization [ 68 , 70 , 72 ]. But this topic, although strongly addressed between 2011 and 2012, did not seem to be unanimously agreed upon because it was not very well addressed afterwards. However, particular attention can be paid to the elicitation and integration of the contextual knowledge of the various actors involved throughout the care pathway into daily healthcare routine [ 3 , 70 , 72 ].

Attribute theme 5: The structural context of the system and organizations

Firstly, the local physical context (k = 10), topical in the recent literature, includes both the number of units and their positions [ 12 , 67 ], but also the variety of services offered [ 13 ], and can be either an asset in terms of choice and accessibility or a constraint becoming a source of delay [ 14 ]. These barriers are important as the pathway crosses several formal healthcare organizations or informal care settings [ 24 ]. Therefore, the challenge of service integration has become essential [ 51 ].

Secondly, the availability of resources (k = 10) (human, material and financial) has a direct impact on the care pathway and the ability to meet the needs of the population [ 2 , 62 , 25 ]. A lack of adequate resources is an obvious obstacle to care pathways [ 50 ]. A lack of material and human resources, such as the availability of time at each service point [ 52 , 53 ], or the lack of an electronic medical record [ 5 ], meant the unnecessary repetition of history taking, examinations and full investigations. From a financial point of view, the financial and personal resources that people have, are also key to determinants of the care pathways followed by patients [ 51 ].

Thirdly, the social context (k = 7) is less addressed in the current literature but has shown rapid growth in recent years. Social structure includes material and social resources including roles, rules, norms, and values [ 3 , 24 , 53 , 68 ]. Some authors consider the social context as regularities of perception, behavior, belief and value that are expressed as customs, habits, patterns of behavior and other cultural artifacts [ 68 ]. Other authors consider that social structures shape people’s actions and that through people’s interactions they can then reproduce or change these social structures [ 53 ]. While others consider, for their part, that social and physical contexts can be at the origin of boundaries that mitigate against collaboration, adding to the complexity of shared clinical practices in this field [ 3 , 24 ].

Attribute theme 6: The special role of the information system and data management

Data management (k = 14) plays an increasingly important role in the analysis and improvement of care pathways. The implementation of a care flow management system aligned to clinical workflows [ 67 , 69 ], allows real-world data to be used [ 51 ], and visualized through performance dashboards to generate timely corrective action [ 4 ]. It also enables the analysis and monitoring of the variance in time and space within care pathways [ 43 ]. It is considered responsible for the rise of accountability [ 12 , 75 ].

The Electronic Health Record system is a support tool (k = 13) in several aspects. Numerous authors consider that it supports the patient-centered approach [ 51 , 67 ]. In particular, it has the capacity to support communication between health professionals, and between them and the patient [ 5 , 12 , 65 , 67 , 73 , 75 ], but also to support healthcare knowledge learning [ 67 , 73 ], and integrate clinical decision support into IT applications and clinical workflows [ 70 ]. This support throughout the care pathway can improve the quality of care and health outcomes by reducing medication errors and unnecessary investigations [ 5 ]. As stated by Fung-Kee-Fung et al. [ 4 ], the information system provides the fundamental connectivity across silos and professional groups to support the creation of care pathways and sustainable change at the system level.

The issue of digitalization (k = 5) has been treated very recently. It raises the issue of system integration throughout the care pathway. Despite the technological advances and the support of international organizations such as the guidelines on evidence-based digital health interventions for health system strengthening released by the WHO [ 76 ], there are still inefficiencies associated with trying to integrate EHRs across organizations [ 56 ]. These are frequently due to the use of different technological solutions by different stakeholders [ 30 ]. The challenge is therefore to propose a model for integrating information systems throughout the care pathway that are accessible to all stakeholders including patients themselves [ 4 , 50 , 51 , 65 ].

Attribute theme 7: The advent of the learning system

Although it was not frequently addressed, some authors have developed, very recently, the importance of setting up a learning system (k = 3) to support the care pathway. Resulting from the work of Quinn [ 77 ] and Senge [ 78 ], it consists of the development of a system to learn from itself and its past experience and improve the effectiveness, efficiency, safety, and patient and family/caregiver experiences [ 65 ] through a feedback loop [ 24 ]. Data on outcomes can be used as feedback to identify improvement opportunities at various stages of the process or at specific interfaces between stakeholders. The learning system promotes “individual competence, systems thinking, cohesive vision, team learning, and integrating different perspectives” [ 4 ].

Related concepts

The related concepts are confusingly close or even integrated with the main concept studied [ 40 ]. Given the complexity of the use of concepts, we have relied, in addition to definitions found on an analysis of a bibliometric network by integrating all 44 articles, excluding abstracts and bibliographies, into the Vosviewer® software (version 2020). The results help us to refine our understanding of the concepts which define the links between the different keywords. The care pathway bibliometric links are provided as a comparator (see Fig.  3 ).

Care pathway bibliometric links

Clinical pathway (Fig.  4 ) was initially defined by De Bleser et al. [ 38 ]. It is a multidisciplinary intervention that aims to integrate the guidelines into daily routine and manage medical activities in order to improve the quality of service and optimize the use of resources [ 70 ]. It integrates a process of care approach [ 72 ] and aims at standardize care on a procedure or an episode of care [ 38 , 49 , 68 ], integrating decision-making supported by knowledge. What differentiates it from the care pathway is that it is restrained in time and is anchored in an organization [ 25 ], or even a service, and does not deal with the patient experience in any way. Clinical pathways are thus integrated in care pathways at the local level and focus on a single phase of care.

Clinical pathway bibliometric links

Patient journey (Fig.  5 ) consisted of sequential steps in the clinical process of the patient through their experience. It can be defined as “the spatiotemporal distribution of patients’ interactions with multiple care settings over time” [ 24 ]. By analyzing and mapping the patient experience from their perspective [ 5 , 14 , 57 , 58 , 71 ], the objective is to improve the quality of the service provided [ 14 , 52 ]. In this approach, the patient journey is an integral part, and an essential component, of the care pathway. Although it also integrates the process approach, it is not linked to decision-making or knowledge management and does not consider structural constraints or the perception of the providers.

Patient journey bibliometric links

Finally, the care process (Fig.  6 ) is involved across the care continuum to standardize and streamline end-to-end care using management tools [ 4 ]. It is directly linked to the care pathway, the clinical pathway and the patient journey. However, although it supports coordination through decision-making and knowledge management, it does not consider the patient experience, the social relationships and the social dynamics. So, the care process is an integral part of the care pathway but does not consider all the characteristics of the latter.

Care process bibliometric links

Antecedents of the concept

Antecedents are events occurring or in place before the concept can emerge [ 40 ]. Our analysis has highlighted several prerequisites for care pathway implementation (see Additional file 4 ).

Firstly, several authors have stressed the importance of the availability of managerial skills (k = 10). They recommend the creation of a change management team [ 49 , 55 ] consisting of a multidisciplinary team integrating not only knowledge about care pathways [ 60 , 70 ], but also knowledge about operations research, information systems and industrial engineering [ 49 , 55 ]. In addition, some authors advocate the presence of key change leaders in the group included clinicians, administrators, IT leaders, process experts, data analysts, nurses, and patient and family members [ 4 , 24 ]. The project leaders must be available on a long-term basis [ 50 , 75 ], have the ability to understand system interdependencies [ 24 ] and have the ability to create a safe learning environment in which openness is encouraged and everyone’s opinion is valued [ 3 , 50 ]. This could be achieved by using consensus-driven approaches that could address institutional process barriers, resistance to change, and conflicting targets and priorities [ 4 ].

Secondly, care pathway projects should have a priori the adequate resources (k = 4), but their availability must be verified [ 62 , 75 ]. The presence of an EHR is necessary to have access to reliable data at the pre-analysis phase and during the implementation phase to identify the relationships between the context, the mechanisms and the results obtained [ 2 , 73 ].

Finally, other key success factors emerged from the literature (k = 10). Some authors noted that rules of co-involvement and a bottom-up strategy was needed [ 55 ]. Other authors emphasized that the selection of areas where there were clearly established deficiencies was essential given the cost of such projects, but also that the identification of any subgroups for whom its use may not be appropriate, was also required [ 73 ]. They highlighted the importance of following guidelines to achieve professional adherence [ 2 , 50 , 62 , 72 , 73 ], while maintaining flexibility in the approach to implementing a care pathway improvement program [ 62 ]. They also pointed to the importance of communicating on the progress of the project [ 50 ] and of monitoring the applicability of daily work tasks [ 73 ]. Finally, they consider it essential to embed the pathway into policy and strategy [ 2 , 50 , 72 , 75 ]. While others, for their part, highlighted the importance of defining an iterative feedback loop for individuals and aggregated operational and clinical data [ 4 , 24 ].

Consequences (outcomes) and identification of empirical referents

Consequences are events that are the results of the mobilization of the concept [ 40 ] and empirical referents, for their part, consist of observable phenomena by which defining attributes are recognized [ 40 ] (see Additional file 4 ). In a larger sense, this could be the Key Performance Indicators (KPIs) by which one can recognize the defining attributes and their outcomes.

Although the terms of quality and safety, efficiency and process improvement were the first themes in terms of aims, the most frequently occurring theme in the findings pertained to effects on the patient experience (k = 16). These were measured in different ways, including the impact of waiting times (k = 10), patient satisfaction (k = 7) and the patient quality of life (QALYs) (k = 4). There were also attempts to analyze the patient experience more broadly (k = 5), and to integrate patient needs into the redesign of the care pathway [ 5 , 13 , 56 ].

Efficiency of care (k = 15) was strongly supported by some authors as a desired outcome in care pathways. This outcome was first seen, as an objective, through the costs and cost effectiveness of programs [ 49 , 55 , 61 , 70 ], however, more recently it has been considered a consequence of process improvements, rather than a program objective. It has been clearly defined as the reduction of costs through the reduction of the use of healthcare services [ 57 ]. Moreover, reduction in time spent in care, such as the length of stay or cycle time [ 2 , 55 ], is commonly the consequence of process improvements.

Quality of care (k = 11) was addressed but much less frequently than expected. In the global approach, time to diagnostic is a good empirical referent to analyze the capacity of the first steps of the care pathway [ 4 , 69 ]. Other referents such as reduction of unnecessary investigations and medication errors are also addressed but the number and types of complaints were addressed only by socio-political authors [ 53 ].

Health outcomes (k = 11) were also proposed but only since 2009 [ 73 ]. Clinical outcomes and mortality rates are empirical referents that are unanimously accepted. Recovery time and readmission rates were less frequently considered. Single disease index evaluation was proposed by very few authors [ 49 , 70 ].

Process metrics and patient flow (k = 11) was addressed but only the execution time was unanimously accepted as an empirical referent. Apart from the process variance which is shared, only few authors have developed other KPIs such as the percentage of pathway completion [ 70 ], and evaluation for the reasons of pathway failure [ 70 ].

The variance of practices (k = 9) was not frequently addressed as an empirical referent; however, this is one of the objectives of the care pathway addressed in the literature. The introduction of guidelines [ 2 ] aims to decrease the variation within or between practices (k = 3).

Continuity of care (k = 6) was poorly addressed, even though we might assume that this is one of the primary objectives of the care pathway. This may be due to the difficulty of providing tangible results given the duration of such interventions.

Some authors noted an improvement in documentation and data collection (k = 5), measured by rate of documentation [ 54 ], the ability to better understand resource adequacy (k = 3) and a better comprehension of the links between decision outcomes and process performance (k = 2).

Not defined as an outcome, the Human Resources metrics are proposed by some authors and notably diagnostic quality and referral appropriateness, professional competences and staffing levels. Only Carayon et al. [ 24 ] proposed to integrate the quality of working life as an indicator, based on the principle that well-being at work has a direct impact on individual performance and on the results of the care pathway.

Moreover, not present in the empirical references, the measure of the team relationship and coordination (k = 4) has been proposed by some authors, however, the type of indicator has not been clearly explained.

An integrative definition and conceptual framework of patient-centered care pathways

Given the results of our systematic review and concept analysis and our main objective of defining an integrative framework, we suggest the following definition:

“A patient-centered care pathway is a long-term and complex managerial intervention adopting a systemic approach, for a well-defined group of patients who journey across the entire continuum of care, from prevention and screening to recovery or palliative care. This intervention:

prioritizes the centricity of patients and caregivers by analyzing the patient experience through their needs and expectations, taking into account the need for information, education, engagement and involvement and integrates the patient relationships as a fundamental need.

supports the roles of professional actors involved in the care pathway by developing adherence to the patient-centered care approach; working on interdisciplinarity through the development of skills, both technical and above all relational; the clarification of roles and responsibilities; and by taking into account the experience of professionals both in understanding the organizational constraints and their well-being at work.

integrates a process of care approach through the modeling and improvement of the care pathway by continuously integrating the latest knowledge and information to support clinical decision-making and by defining feedback loops to continuously improve clinical and non-clinical process supported by operation management contained within process improvement methodology approaches;

embeds coordination structures through: the implementation of best practices and the translation of guidelines into daily practice; the support of informational continuity through the integration of services at the systemic level; the implementation of knowledge management along the care continuum; and the identification of leaders at each step of the care pathway;

adapts to the contexts of both the physical and social structures by integrating the human, material, economic and financial resource constraints, as well as the social dynamics of power and trust relationships;

is supported by information systems and data management, enabled by digitalization, which ensure the flow of information within the right context at the right time and place, and allows the continuous integration of the latest knowledge into the care flow and the management of accessible data in real time to monitor and evaluate variances in practices and outcomes;

promotes the development of a learning health system to support the care pathway.

The aim and shared goal of a care pathway is to meet the needs and expectations of patients through continuous improvement of patient experience, patient outcomes, quality and safety while taking into account operational and social realities of the system.”

We know that this definition is important but feel that there is a great need for clarification of this concept and how these interventions can be successful given the costs involved. Furthermore, we consider that the proper sequencing of the care pathway should be defined according to the following eight phases: (1) Prevention and screening; (2) Signs and symptoms; (3) Early detection; (4) Diagnostic; (5) Referral systems; (6) Treatment; (7) Follow-ups; (8) Reeducation or Palliative care. In this way, the development of recognized KPIs enabling international comparisons of care pathways should finally make it possible to share knowledge and improve care pathways.

According to this definition and based on the literature review, we propose the following integrative conceptual framework illustrated in Fig.  7 .

Integrative conceptual framework of care pathway

Using systematic review, concept analysis and bibliometric analysis, it was possible to develop a detailed understanding of the care pathway concept enabling us to propose an integrative conceptual framework and definition to try to meet the need for an international consensus and thus enabling international comparisons and improvement of care pathways.

The results of our work have highlighted the evolution and advances of the various uses of care pathways. Initially focused more on an organizational approach, there is growing support in the literature for a holistic approach that addresses the entire care across the continuum at the system level [ 4 , 24 , 42 , 60 ]. Thus, patient centeredness has become the primary focus as more and more authors focus on the patient experience as the unit of quality analysis. In doing so, they have given greater importance to social relationships and especially to the relationship as a basic need and highlighted the need to design the service line structures mirroring patients’ needs [ 56 ]. They therefore approach the patient, not only as the individual who follows the pathway, but as a social being who has needs and expectations to fulfill, making meeting the needs and expectations of the patient and caregivers the core of the care pathway [ 24 , 50 , 51 , 57 ]. However, the evaluation of the quality of healthcare services by the patient still raises several methodological questions to finally go beyond the simple consideration of satisfaction. Finally, patient and public involvement and patient engagement are also important issues to the point that some authors see a real power struggle between patients and clinicians [ 53 ] that can lead to tokenistic involvement.

The professional actors involved in the care pathway are naturally essential players, both because of their professional competencies and their ability to orient themselves towards the needs of the patient. However, they are also often part of a neglected factor. Some authors have shown one of the key criteria for the potential failure of care pathways is a failure to take into account the prevailing social dynamics and the importance of the buy-in of all stakeholders [ 65 ]. Moreover, some authors insist on the importance of the actors involved in the pathway to both integrate the social dynamics and confront the patient’s needs with operational realities and organizational constraints [ 24 ].

The operation management of process approach to care delivery also raises many challenges. Thus, some authors have developed tools for modeling and improving care processes by applying them in a systemic approach to incorporate clinical decision support into the modeling method [ 60 ]. This issue of continuous integration of updated guidelines into care pathways is indeed a major challenge given the rapid evolution of knowledge and the limited capacity of professionals to continuously integrate new knowledge. In addition, data simulation and data analysis methods coupled with process improvement methods are undeniable contributions to improve the issue of fluidity of processes and therefore the overall performance [ 49 ]. However, one of the pitfalls of staying focused on the process would be a failure to consider the social dimension, particularly the prevailing social dynamics.

Coordination structures are one of the points of improvement in the systemic approach. Ensuring the continuity of information along the care pathway, as well as having a formal leader for each portion of the pathway, would solve many of the problems of path breaks or unnecessary repetition of exams that cause unnecessary costs [ 5 , 56 , 59 ]. This begins with the implementation of a single information system and the integration of IT infrastructures across the entire care pathway at the system level and accessible to care professionals as well as patients and caregivers [ 4 , 50 , 51 , 65 ].

The structural context of the system and organizations cannot be neglected because it directly impacts the results of the implementation of the care pathway. Firstly, because some physical constraints such as distances between several organizational entities [ 12 , 14 ] can only be solved by major transformations in the infrastructures or in the initial process. Secondly, because failing to consider the dominant social dynamics could immediately call into question the entire care pathway intervention [ 3 , 24 ] by implementing only cosmetic changes and not transforming clinical, administrative and organizational practices in a sustainable manner.

The information system plays a special role in care pathway, not only because it is the support of the informational continuity, but also because it enables real-time data analysis to support decision-making within the care pathway in the form of feedback loops [ 4 , 24 , 51 ].

Finally, it seems clear that care pathway programs at the systemic level are one potential intervention which could benefit from the implementation of a learning system [ 4 ]. Care pathway outcome data can be used as feedback to identify improvement opportunities at various stages of the process or at specific interfaces between stakeholders. This approach makes it possible to support the continuous improvement of the care process.

Given the richness of the contributions of the last 20 years, we advocate an integrated approach resulting in a fine-grained and comprehensive understanding of care pathway. Our proposal is compatible with the definition of Vanhaecht et al. [ 25 ] currently used by the EPA, but in our opinion, enriches it. It allows users to specify the operational realities to which stakeholders should pay attention. Moreover, it insists on adaptation to the social realities and the changes that inevitably accompany it and directly impact the success or failure. However, we were surprised that the approach to managing organizational change and transformation of practices were little addressed. Only Van Citters et al. [ 65 ] had noted that change management approaches were critical for successful care transformation and that they had been largely neglected in care pathways. We share this point of view and believe that care pathway intervention leaders must develop communicative action skills to support practices transformation. Not mentioned in the selected literature, we propose to enrich our conceptual framework of communicative action proposed by Habermas [ 79 ]. From our point of view, this dimension could explain the failures of such interventions or at least the difficulty in developing sustainable transformations in practices.

In general, the concept analysis approach has raised several questions about the depth of concept analysis and its place in knowledge advancement [ 80 ]. However, we believe that the combination of systematic review rigor and concept analysis richness, was necessary to meet the aims of this study and produced an integrated conceptual framework which is ready for use. However, this research has some limitations. Although interest is growing, few studies offer comprehensive empirical results on the deployment of a care pathway and its outcomes in a global systemic approach over the entire continuum of care. Moreover, there are a few examples of in-depth analysis of car pathways over a long period of time. Together, this means that the literature still offers little insight into potential outcomes of care pathways. Lastly, our analysis was limited to peer-reviewed articles; including other contributions such as theses and dissertations as well as grey literature could have brought out other categories or themes.

This study has resulted in a fine-grained understanding of care pathways and in a clear definition relying on a powerful conceptual framework. It responds to a strong need for conceptual precision, as previous reviews have not addressed the care pathway on a systemic scale and in a holistic manner. In addition, our framework offers a holistic view of the pathway without being specific to a particular condition or context. Our framework encompasses 28 subcategories grouped into seven care pathway attributes that should be considered in complex care pathway intervention. It considers both operational and social realities and supporting the improvement and sustainable transformation of clinical, administrative, and organizational practices for the benefit of patients and caregivers, while taking into account professional experience, organizational constraints, and social dynamics. The formulation of these attributes, antecedents as success factors and consequences as potential outcomes, linked to their KPIs, allows the operationalization of this model for any pathway in any context. We believe that these results are of particular interest to policymakers, decision makers, managers and researchers alike, and that they could lead to an international consensus that would finally allow comparison of care pathway improvement programs. However, we consider that the development of a framework for analyzing the performance of such an intervention has yet to be developed in a more in-depth manner, such as by focusing on certain particularities of each phase so that managers and decision makers can rely on validated dashboards and KPIs. More empirical work needs to be done on the comprehensive approach, as defined in our proposed definition, to provide reliable results on the ability of these interventions to result in an overall improvement. In addition, the question of the understanding of social evaluation of the quality of care by the patient remains an open question, as the patient experience does not yet have conclusive KPIs as it is too often limited to patient satisfaction or QALYs.

Availability of data and materials

This systematic review is based on an analysis of 44 published papers which are all referenced within this manuscript. Data supporting our findings are included in the form of additional files.

Abbreviations

European Pathway Association

Institute of Medicine of America

Key Performance Indicator

Preferred Reporting Items for Systematic reviews and Meta-Analyses

Quality Adjusted Life Year

World Health Organization

Kelly J, Dwyer J, Mackean T, O’Donnell K, Willis E. Coproducing Aboriginal patient journey mapping tools for improved quality and coordination of care. Aust J Prim Health. 2018;23(6):536–42. https://doi.org/10.1071/PY16069 .

Article   Google Scholar  

Bergin RJ, Whitfield K, White V, et al. Optimal care pathways: a national policy to improve quality of cancer care and address inequalities in cancer outcomes. J Cancer Policy. 2020;25:100245. https://doi.org/10.1016/j.jcpo.2020.100245 .

Hutchinson K, Herkes G, Shih P, et al. Identification and referral of patients with refractory epilepsy from the primary to the tertiary care interface in New South Wales, Australia. Epilepsy Behav. 2020;111:107232. https://doi.org/10.1016/j.yebeh.2020.107232 .

Article   PubMed   Google Scholar  

Fung-Kee-Fung M, Maziak D, Pantarotto J, et al. Regional process redesign of lung cancer care: a learning health system pilot project. Curr Oncol. 2018;25(1):59–66. https://doi.org/10.3747/co.25.3719 .

Article   CAS   PubMed   PubMed Central   Google Scholar  

Alkandari M, Ryan K, Hollywood A. The experiences of people living with peripheral neuropathy in Kuwait-a process map of the patient journey. Pharmacy (Basel, Switzerland). 2019;7(3):127. https://doi.org/10.3390/pharmacy7030127 .

Institute of Medicine of America. Committee on quality of health Care in a. crossing the quality chasm: a new health system for the 21st century. Washington, D.C.: National Academy Press; 2001. https://doi.org/10.1136/bmj.323.7322.1192 .

Book   Google Scholar  

Institute of Medicine of America. Committee on improving the quality of cancer care: addressing the challenges of an aging population, board on healthcare services, Institute of Medicine, delivering high-quality Cancer care: charting a new course for a system in crisis. Washington, D.C.: National Academy Press; 2013. https://doi.org/10.17226/18359 .

National Academies of sciences, engineering, medicine. Committee on improving the quality of health care globally. Crossing the global quality chasm: improving healthcare worldwide. Washington (DC): National Academies Press (US); 2018. https://doi.org/10.17226/25152 .

World Health Organization. Framework on integrated, people-centered health services: report by the secretariat. Geneva, Switzerland: World Health Organization; 2016. https://apps.who.int/gb/ebwha/pdf_files/WHA69/A69_39-en.pdf . Accessed June 16, 2020

Google Scholar  

World Health Organization. Report on Cancer: setting priorities, investing wisely and providing Care for all. Geneva, Switzerland: World Health Organization; 2020. https://apps.who.int/iris/handle/10665/330745 . Accessed June 20, 2020

World Health Organization. Guide to developing a national quality policy and strategy: a practical approach to formulating a policy and strategy for quality of care improvement. Geneva, Switzerland: World Health Organization; 2020. https://www.who.int/publications/i/item/9789241565561 . Accessed June 21, 2020

Valentijn PP, Biermann C, Bruijnzeels MA. Value-based integrated (renal) care: setting a development agenda for research and implementation strategies. BMC Health Serv Res. 2016;16(1):1–11. https://doi.org/10.1186/s12913-016-1586-0 .

Ponsignon F, Smart A, Phillips L. A customer journey perspective on service delivery system design: insights from healthcare. Int J Qual Relia Manag. 2018;35(10):2328–47. https://doi.org/10.1108/IJQRM-03-2018-0073 .

Gualandi R, Masella C, Viglione D, Tartaglini D. Exploring the hospital patient journey: what does the patient experience? PLoS One. 2019;14(12):1–15. https://doi.org/10.1371/journal.pone.0224899 .

Article   CAS   Google Scholar  

Schildmeijer K, Frykholm O, Kneck Å, Ekstedt M. Not a straight line-Patients' experiences of prostate Cancer and their journey through the healthcare system. Cancer Nurs. 2019;42(1):E36–43. https://doi.org/10.1097/NCC.0000000000000559 .

Burns K. ISQUA18-2613Patients measuring their experiences with their healthcare system: targeting improvement in access, quality, safety and patient and family Centred care outcomes. Int J Qual Health Care. 2018;30((suppl_2):22–3. https://doi.org/10.1093/intqhc/mzy167.29 .

Nuti S, De Rosis S, Bonciani M, Murante AM. Rethinking healthcare performance evaluation systems towards the people-Centredness approach: their pathways, their experience, their evaluation. Healthc Pap. 2018;17(2):56–64. https://doi.org/10.12927/hcpap.2017.25408 .

Khan AI, Arthurs E, Gradin S, MacKinnon M, Sussman J, Kukreti V. Integrated care planning for cancer patients: a scoping review. Int J Integr Care. 2017;17(6):5. https://doi.org/10.5334/ijic.2543 .

Article   PubMed   PubMed Central   Google Scholar  

Ran T, Cheng C-Y, Misselwitz B, Brenner H, Ubels J, Schlander M. Cost-effectiveness of colorectal cancer screening strategies—a systematic review. Clin Gastroenterol Hepatol. 2019;17(10):1969–1981. e1915. https://doi.org/10.1016/j.cgh.2019.01.014 .

Oxford Dictionaries. Concise medical dictionary: Main edition (10th edition). Oxford University Press. 2020. https://www.oxfordreference.com/view/10.1093/acref/9780198836612.001.0001/acref-9780198836612 . Accessed June 18, 2020.

Oxford Dictionaries. A dictionary of nursing (8th edition). Oxford University Press 2021. https://www.oxfordreference.com/view/10.1093/acref/9780198864646.001.0001/acref-9780198864646 . Accessed June 18, 2020.

Visser J, Beech R. Health operations management: patient flow logistics in health care. Psychol Press. 2005. https://doi.org/10.4324/9780203356791 .

Vanhaecht K. The impact of clinical pathways on the organisation of care processes. [PhD Thesis, Katholieke Universiteit Leuven]. 2007; https://lirias.kuleuven.be/1718750?limo=0 . Accessed January 18, 2020.

Carayon P, Wooldridge A, Hoonakker P, Hundt AS, Kelly MM. SEIPS 3.0: human-centered design of the patient journey for patient safety. Appl Ergon. 2020;84:103033. https://doi.org/10.1016/j.apergo.2019.103033 .

Vanhaecht K, Panella M, van Zelm R, Sermeus W. An overview on the history and concept of care pathways as complex interventions. Int J Care Coord. 2010;14(3):117–23. https://doi.org/10.1016/j.apergo.2019.103033 .

Seys D, Panella M, VanZelm R, et al. Care pathways are complex interventions in complex systems: new European pathway association framework. Int J Care Coord. 2019;22(1):5–9. https://doi.org/10.1177/2053434519839195 .

Solomon R, Damba C, Bryant S. Measuring quality at a system level: an impossible task? The Toronto central LHIN experience. Healthc Q. 2013;16(4):36–42.

Rayner J, Khan T, Chan C, Wu C. Illustrating the patient journey through the care continuum: leveraging structured primary care electronic medical record (EMR) data in Ontario, Canada using chronic obstructive pulmonary disease as a case study. Int J Med Inform. 2020;140:104159. https://doi.org/10.1016/j.ijmedinf.2020.104159 .

Galvin M, Madden C, Maguire S, et al. Patient journey to a specialist amyotrophic lateral sclerosis multidisciplinary clinic: an exploratory study. BMC Health Serv Res. 2015;15(1):1–8. https://doi.org/10.1186/s12913-015-1229-x .

McCarthy S, O'Raghallaigh P, Woodworth S, Lim YL, Kenny LC, Adam F. An integrated patient journey mapping tool for embedding quality in healthcare service reform. J Decis Syst. 2016;25:354–68. https://doi.org/10.1080/12460125.2016.1187394 .

Mead N, Bower P. Patient-centredness: a conceptual framework and review of the empirical literature. Soc Sci Med. 2000;51(7):1087–110. https://doi.org/10.1016/S0277-9536(00)00098-8 .

Article   CAS   PubMed   Google Scholar  

Stewart M, Brown JB, Weston W, McWhinney IR, McWilliam CL, Freeman T. Patient-centered medicine: transforming the clinical method. Abingdon: Radcliffe Medical Press; 2003.

Van Hoeve JC, Vernooij RW, Fiander M, Nieboer P, Siesling S, Rotter T. Effects of oncological care pathways in primary and secondary care on patient, professional and health systems outcomes: a systematic review and meta-analysis. Syst Rev. 2020;9(1):1–15. https://doi.org/10.1186/s13643-018-0693-x .

Baker E, Woolley A, Xyrichis A, Norton C, Hopkins P, Lee G. How does the implementation of a patient pathway-based intervention in the acute care of blunt thoracic injury impact on patient outcomes? A systematic review of the literature. Injury. 2020;51(8):1733–43. https://doi.org/10.1016/j.injury.2020.06.002 .

Seguin ML, Rangnekar A, Renedo A, Palafox B, McKee M, Balabanova D. Systematic review of frameworks used to conceptualise health pathways of individuals diagnosed with cardiovascular diseases. BMJ Glob Health. 2020;5(9):e002464. https://doi.org/10.1136/bmjgh-2020-002464 .

Beausejour M, Goulet L, Debbie Ehrmann F, et al. Pathways of healthcare utilisation in patients with suspected adolescent idiopathic scoliosis: a cross-sectional study. BMC Health Serv Res. 2015;15:500. https://doi.org/10.1186/s12913-015-1152-1 .

Chan RJ, Webster J, Bowers A. End-of-life care pathways for improving outcomes in caring for the dying. Cochrane Database Syst Rev. 2016;2(2):CD008006. https://doi.org/10.1002/14651858.CD008006.pub4 .

De Bleser L, Depreitere R, Waele KD, Vanhaecht K, Vlayen J, Sermeus W. Defining pathways. J Nurs Manag. 2006;14(7):553–63. https://doi.org/10.1111/j.1365-2934.2006.00702.x .

Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 Statement: an updated guideline for reporting systematic reviews. BMJ. 2021:372. https://doi.org/10.1136/bmj.n71 .

Walker L, Avant K, Concept analysis. Strategies for theory construction in nursing (pp. 157–179). Upper Saddle River: Pearson; 2011.

Aromataris E, Munn Z (Editors). Joanna Briggs Institute Reviewer’s Manual (pp. 1-487). The Joanna Briggs Institute; 2017. Available from: https://reviewersmanual.joannabriggs.org/ .

Cherif E, Martin-Verdier E, Rochette C. Investigating the healthcare pathway through patients’ experience and profiles: implications for breast cancer healthcare providers. BMC Health Serv Res. 2020;20:1–11. https://doi.org/10.1186/s12913-020-05569-9 .

Kempa-Liehr AW, Lin CY-C, Britten R, et al. Healthcare pathway discovery and probabilistic machine learning. Int J Med Inform. 2020;137:104087. https://doi.org/10.1016/j.ijmedinf.2020.104087 .

Center for Evidence-Based Management. Critical appraisal of a survey [Available from: https://www.cebma.org/wp-content/uploads/Critical-Appraisal-Questions-for-a-Survey.pdf ]. Accessed September 27, 2020.

Institute for Public Health Sciences. 11 questions to help you make sense of descriptive/cross-sectional studies. Yeshiva University New York; 2002. [Available from: https://reache.files.wordpress.com/2010/03/cross-sectional-appraisal-tool.pdf ]. Accessed October 03, 2020.

Pluye P, Gagnon M-P, Griffiths F, Johnson-Lafleur J. A scoring system for appraising mixed methods research, and concomitantly appraising qualitative, quantitative and mixed methods primary studies in mixed studies reviews. Int J Nurs Stud. 2009;46(4):529–46. https://doi.org/10.1016/j.ijnurstu.2009.01.009 .

Hannes K, Booth A, Harris J, et al. Celebrating methodological challenges and changes: reflecting on the emergence and importance of the role of qualitative evidence in Cochrane reviews. Syst Rev. 2013;2:84. https://doi.org/10.1186/2046-4053-2-84 .

Thomas DR. A general inductive approach for analyzing qualitative evaluation data. Am J Eval. 2006;27(2):237–46. https://doi.org/10.1177/1098214005283748 .

Aspland E, Gartner D, Harper P. Clinical pathway modelling: a literature review. Health Syst. 2020;10(1):1–23. https://doi.org/10.1080/20476965.2019.1652547 .

Busari JO, Yaldiz H, Gans RO, Duits AJ. Clinical leadership as an agent for change: a health system improvement intervention in Curaçao. J Multidiscip Healthc. 2020;13:787–98. https://doi.org/10.2147/JMDH.S262415 .

Devi R, Kanitkar K, Narendhar R, Sehmi K, Subramaniam K. A narrative review of the patient journey through the Lens of non-communicable diseases in low- and middle-income countries. Adv Ther. 2020;37(12):4808–30. https://doi.org/10.1007/s12325-020-01519-3 .

Elkhuizen SG, Vissers JM, Mahdavi M, Van De Klundert JJ. Modeling patient journeys for demand segments in chronic care, with an illustration to type 2 diabetes. Front. Public Health. 2020;8:428. https://doi.org/10.3389/fpubh.2020.00428 eCollection 2020.

Ocloo J, Goodrich J, Tanaka H, Birchall-Searle J, Dawson D, Farr M. The importance of power, context and agency in improving patient experience through a patient and family centred care approach. Health Res Policy Syst. 2020;18(1):10. https://doi.org/10.1186/s12961-019-0487-1 .

Ayachi FL, Rahmouni HB, Ammar MB, Mahjoubi H. A reverse-engineering methodology for medical enhancement processes. Proc Comput Sci. 2019;164:714–23. https://doi.org/10.1016/j.procs.2019.12.240 .

De Belvis AG, Lohmeyer FM, Barbara A, et al. Ischemic stroke: clinical pathway impact. Int J Health Care Qual Assur. 2019;32(3):588–98. https://doi.org/10.1108/IJHCQA-05-2018-0111 .

Louis CJ, Clark JR, Gray B, Brannon D, Parker V. Service line structure and decision-maker attention in three health systems: implications for patient-centered care. Health Care Manag Rev. 2019;44(1):41–56. https://doi.org/10.1097/HMR.0000000000000172 .

Meyer MA. Mapping the patient journey across the continuum: lessons learned from one Patient's experience. J Patient Exp. 2019;6(2):103–7. https://doi.org/10.1177/2374373518783763 .

Mohr P, Galderisi S, Boyer P, et al. Value of schizophrenia treatment I: The patient journey. Eur Psychiatry. 2018;53:107–15. https://doi.org/10.1016/j.eurpsy.2018.06.007 .

Aziz AFA, Nordin NAM, Ali MF, Abd Aziz NA, Sulong S, Aljunid SM. The integrated care pathway for post stroke patients (iCaPPS): a shared care approach between stakeholders in areas with limited access to specialist stroke care services. BMC Health Serv Res. 2017;17(1):35. https://doi.org/10.1186/s12913-016-1963-8 .

Combi C, Oliboni B, Zardini A, Zerbato F. Ieee Seamless Design of Decision-Intensive Care Pathways. 2016:35–45. https://doi.org/10.1109/ICHI.2016.9 .

Gillespie J, McClean S, Garg L, Barton M, Scotney B, Fullerton K. A multi-phase DES modelling framework for patient-centred care. J Oper Res Soc. 2016;67(10):1239–49. https://doi.org/10.1057/jors.2015.114 .

Shaw JM, Price MA, Clayton JM, et al. Developing a clinical pathway for the identification and management of anxiety and depression in adult cancer patients: an online Delphi consensus process. Support Care Cancer. 2016;24(1):33–41. https://doi.org/10.1007/s00520-015-2742-5 .

Walker C, O’Sullivan M, Ziedins I, Furian N. Faster Cancer treatment: using timestamp data to improve patient journeys. Healthc. 2016;4:252–8. https://doi.org/10.1016/j.hjdsi.2016.04.012 .

Grenness C, Hickson L, Laplante-Lévesque A, Davidson B. Patient-centred audiological rehabilitation: perspectives of older adults who own hearing aids. Int J Audiol. 2014;53(sup1):S68–75. https://doi.org/10.3109/14992027.2013.866280 .

Van Citters AD, Fahlman C, Goldmann DA, et al. Developing a pathway for high-value, patient-centered Total joint Arthroplasty. Clin Orthop Relat Res. 2014;472(5):1619–35. https://doi.org/10.1007/s11999-013-3398-4 .

Evans WK, Ung YC, Assouad N, Chyjek A, Sawka C. Improving the quality of lung cancer care in Ontario: the lung cancer disease pathway initiative. J Thorac Oncol. 2013;8(7):876–82. https://doi.org/10.1097/JTO.0b013e31828cb548 .

Huang B, Zhu P, Wu C. Customer-centered careflow modeling based on guidelines. J Med Syst. 2012;36(5):3307–19. https://doi.org/10.1007/s10916-012-9823-5 .

Tehrani J, Liu K, Michel V. Ontology modeling for generation of clinical pathways. J Ind Eng Manag. 2012;5(2):442–56. https://doi.org/10.3926/jiem.586 .

Vandborg MP, Edwards K, Kragstrup J, Vedsted P, Hansen DG, Mogensen O. A new method for analyzing diagnostic delay in gynecological cancer. Int J Gynecol Cancer. 2012;22(5):712–7. https://doi.org/10.1097/IGC.0b013e31824c6d0e .

Yang H, Li W, Liu K, Zhang J. Knowledge-based clinical pathway for medical quality improvement. Inf Syst Front. 2012;14(1):105–17. https://doi.org/10.1007/s10796-011-9307-z .

Manchaiah VK, Stephens D, Meredith R. The patient journey of adults with hearing impairment: the patients’ views. Clin Otolaryngol. 2011;36(3):227–34. https://doi.org/10.1111/j.1749-4486.2011.02320.x .

Yamazaki T, Ikeda M, Umemoto K. Enhancement of healthcare quality using clinical-pathways activities. Vine. 2011;41(1):63–71. https://doi.org/10.1108/03055721111115557 .

Allen D, Gillen E, Rixson L. Systematic review of the effectiveness of integrated care pathways: what works, for whom, in which circumstances? Int J Evid Based Healthc. 2009;7(2):61–74. https://doi.org/10.1111/j.1744-1609.2009.00127.x .

Joosten TC, Bongers IM, Meijboom IBR. Care programmes and integrated care pathways. Int J Health Care Qual Assur. 2008;21(5):472–86. https://doi.org/10.1108/09526860810890440 .

Bond S, Balogh R, McKeever M. Care pathways: integrated clinical record or management information tool? J Integr Care Pathways. 2001;5(2):54–63. https://doi.org/10.1177/147322970100500204 .

World Health Organization. WHO guideline: recommendations on digital interventions for health system strengthening. Geneva: World Health Organization; 2019.

Quinn JB. Intelligent Enterprise: a knowledge and service based paradigm for Industr: Simon and Schuster; 1992.

Senge PM. The fifth discipline: The art and practice of the learning organization (pp. 1-464). Currency; 2006[1990].

Habermas J. The theory of communicative action: Reason and the rationalization of society. Vol 1: Beacon press; 1984.

Lam Wai Shun P, Swaine B, Bottari C. Combining scoping review and concept analysis methodologies to clarify the meaning of rehabilitation potential after acquired brain injury. Disabil Rehabil. 2020:1–9. https://doi.org/10.1080/09638288.2020.1779825 .

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Gartner, JB., Abasse, K.S., Bergeron, F. et al. Definition and conceptualization of the patient-centered care pathway, a proposed integrative framework for consensus: a Concept analysis and systematic review. BMC Health Serv Res 22 , 558 (2022). https://doi.org/10.1186/s12913-022-07960-0

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Multiple pathogens and prostate cancer

• James S. Lawson   ORCID: orcid.org/0000-0002-2385-8304 1 &
• Wendy K. Glenn 1  

Infectious Agents and Cancer volume  17 , Article number:  23 ( 2022 ) Cite this article

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The aim of this review is to consider whether multiple pathogens have roles in prostate cancer.

We have reviewed case control studies in which infectious pathogens in prostate cancer were compared to normal and benign prostate tissues. We also reviewed additional evidence from relevant published articles.

We confirmed that high risk human papilloma viruses are a probable cause of prostate cancer. We judged Escherichia coli , Cutibacterium acnes , Neisseria gonorrhoea , Herpes simplex , Epstein Barr virus and Mycoplasmas as each having possible but unproven roles in chronic prostatic inflammation and prostate cancer. We judged Cytomegalovirus, Chlamydia trachomatis, Trichomonas vaginalis and the Polyoma viruses as possible but unlikely to have a role in prostate cancer.

Conclusions and actions

The most influential cause of prostate cancer appears to be infection induced chronic inflammation. Given the high prevalence of prostate cancer it is important for action to can be taken without waiting for additional conclusive evidence. These include:

Encouragement of all boys (as well as girls) to have HPV vaccines

The vigorous use of antibiotics to treat all bacterial pathogens identified in the urogenital tract

The use of antiviral medications to control herpes infections

Education about safe sexual practices

Introduction

The aim of this review is to consider whether multiple pathogens have roles in prostate cancer. Multiple pathogens have long been hypothesised as an underlying cause of prostate cancer. However, apart from high-risk for cancer human papilloma viruses (HPVs), no specific pathogens have confirmed causal roles.

We have previously shown that high risk for cancer human papilloma viruses have a probable, but not conclusive, causal role in prostate cancer [ 1 ]. This is important because of the availability of safe and effective vaccines against HPV infections. In this review we have updated the evidence which may implicate other infectious pathogens.

We consider it is unlikely that any acute infectious pathogens cause prostate cancer. On the other hand, infectious pathogens that cause long term chronic inflammation are likely to have roles in prostate cancer.

Epidemiology

Prostate cancer develops in 1 in 8 Western men [ 2 ]. About 60% of cases occurs in men aged 65 years or older. It is rare in men under the age of 40 years. About 30% of men have undiagnosed prostate cancer at the time of their death, hence the saying “many men die with, rather than from, prostate cancer”. Prostate cancer occurs more frequently in Western than Asian men [ 2 ]. When Asian men migrate from low to high risk countries the risk of developing prostate cancer increases [ 3 ]. The reason is not known. However, the number of immigrants developing prostate cancer is still lower than that of men in Western countries [ 4 ]. This phenomena is also present in breast cancer for Asian women who migrate from low to high risk countries, the risk of breast cancer rapidly increases within two generations to almost equal that of the host country [ 5 ].

We have conducted a review of selected English language publications listed in PubMed from 1960 to 2021 relevant to infectious pathogens and prostate cancer. Only studies which included controls were reviewed. Any form of selection introduces bias. For this reason the two authors independently selected the studies that were considered. Any differences in the selection were discussed and joint decisions were made. Additional problems in the assessment of the role of specific pathogens in prostate cancer include (1) the variations in outcomes of studies using similar methods in the same populations, (2) contamination of the prostate specimens and (4) the absence of benign or normal prostate controls.

The selection of pathogens for this review was based on the many previous studies of infections and prostate cancer. These pathogens included Human papilloma viruses, Cetabacterium acnes, Herpes viruses including Epstein Barr virus, Neisseria gonorrhoea, Herpes simplex, Epstein Barr virus, Cytomegalovirus, Chlamydia bacteria, Trichomonas bacteria, Mycoplasmas and Polyoma viruses. Case control studies were available for each of these pathogens. Other pathogens, for which no case controls have been conducted, may also have roles in prostate cancer, for example Escherichia coli, fungal prostatitis, mouse mammary tumour virus and human immunodeficiency virus [ 6 , 7 ].

The use of case control studies for the study of infections and prostate cancer can be misleading. This is because in most studies the non-cancer controls were benign prostate tissues. Chronic infections are common in the prostate and this can negate the comparisons between cancer and controls.

The Bradford Hill criteria have been frequently used for assessing causal roles of pathogens and other agents [ 8 ]. These criteria have been immensely influential. They have largely replaced the famous Koch postulates. Over the last 50 years, it has been estimated that over 100,000 published articles have used the Hill criteria [ 9 ]. Hill developed nine criteria in the context of his research into the links between tobacco smoking and lung cancer [ 10 ]. At that time the role of viruses in various human cancers was not known. In addition, since 1965 there have been major developments in knowledge and technology. It has also been realised that the relevance of the individual criteria vary according to the nature of the pathogen or harmful agent. Accordingly, there has been a need to add and modify the classic Hill criteria. The list of the Hill and extended criteria in some order of importance include:

(1) Identification and history of the candidate pathogen. (2) Epidemiology. (3) Strength of the association between the pathogen and prostate cancer. (4). Temporality (timing) of the association which includes evidence of infection by a pathogen in normal tissues before the development of the cancer. (5). Does exposure to the pathogen lead to infection, oncogenesis and cancer? (6) Experimental evidence, for example, capacity of the pathogen to cause cancer in experimental animals, capacity to infect human cells, ability to transform normal human cells into malignant cells, evidence that a vaccine or therapy can inhibit the pathogen from infecting or transforming cells. (7) Coherence, analogy, biological plausibility. (8) Transmission including identification of the source and means of transmission of the pathogen. (9) Oncogenic mechanisms. (10) Multiple viral and causal factors. (11) Specificity- this criteria was in Hill’s original list but is rarely helpful as many viruses and other pathogens can lead to cancer in different organs.

Hill [ 8 ] strongly cautioned against dogmatism.” None of my nine viewpoints can bring indisputable evidence for or against the cause-and-effect hypothesis and none can be required as a sine qua non (meaning an essential requirement).

In this current review these criteria could only be fully used with respect to human papilloma viruses because of the limited evidence available for the other pathogens listed above.

Human papilloma viruses (HPV)

We have recently reviewed the evidence and concluded that it is highly likely that high risk for cancer HPVs have a causal role in prostate cancer [ 1 ]. The most important evidence is the demonstration that the prevalence of high-risk HPVs is consistently higher in prostate cancer than in benign prostate controls. This is shown in Table 1 [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. In brief the evidence is as follows:

High risk for cancer HPVs have been identified in many countries by a range of methods in normal, benign and malignant prostate tissues [ 37 ].

In 10 of 27 case control studies conducted with PCR techniques, the prevalence of high-risk HPV DNA was significantly higher in prostate cancers as compared to normal and benign prostate controls (studies in which HPVs were not identified have not been included in Table 1 ). In these 27 studies there were 399 HPV positive of 1678 prostate cancers (24%) and129 HPV positive of 1331 benign prostate controls (10%) ( p  = 0.001).

High risk HPV types 16 and 18 have the capacity to immortalise and transform normal prostate cells into malignant cells [ 38 , 39 ].

HPVs are mainly transmitted by sexual activity [ 40 ]. HPVs can be transmitted throughout the body via circulating extra-cellular vesicles and blood [ 41 ].

High risk HPVs are associated with inflammatory prostatitis which can lead to benign prostate hyperplasia and later prostate cancer [ 42 , 43 ].

High risk HPVs of the same type have been identified in benign prostate tissues 1–11 years before the development of HPV positive prostate cancer in the same patients [ 44 ].

While the highest prevalence of HPV genital infections occurs in younger people there is an increased prevalence in older age groups (over 55 years) [ 45 , 46 ]. This increase in older people is unlikely to be due to increased sexual activity. Prostate cancer is much more prevalent in older men. Accordingly there may be an association between older age HPV reactivation and prostate cancer.

The reason for the reactivation of HPVs is not known. An explanation may be the concept of “trained immunity” [ 47 ]. This concept involves the long-term reprogramming of innate immune cells, which can be reactivated by stimuli such as infections or chemicals. While this response can be protective against a harmful stimulus, over- reactions such as inflammation can develop. In turn, chronic inflammation can be oncogenic. While there is no direct evidence available with respect to prostate cancer, HPVs can remain dormant in the host cell genome, thus evading the host immune response until they are reactivated [ 48 ].

The oncogenic mechanisms for HPV oncogenesis in prostate cancer are not clear and may differ from HPV oncogenesis in cervical cancer. There is evidence that HPV E7 oncogenic proteins may be directly involved early in prostate oncogenesis [ 17 ]. HPV infections may have an indirect role by inhibiting the protective function of APOBEC3B enzymes against other virus infections [ 49 , 50 ].

Effective and safe vaccines are available for the prevention of a wide range of different types of HPV infections [ 51 ].

With respect to Silvestre et al. [ 22 ], Tachezy et al. [ 26 ] and Mokhtari et al. [ 28 ] the numbers of positive cases are too few to justify statistical analysis.

Cutibacterium (Propionbacterium) acnes

Cutibacterium acnes ( C. acnes ) are part of the commensal flora of the skin where they colonize hair follicles and sebaceous glands [ 52 ]. Different types of C. acnes can also cause serious post-operative infections. Cutibacterium acnes may also be present in the urogenital tract including the prostate. Cutibacterium acnes can damage blood cells, cause host tissue degradation and disrupt cell surface components.

Cutibacterium acnes has been identified in prostate cancer tissues. In 2 of 6 case control studies C. acnes was significantly more prevalent in prostate cancer than in control benign prostate tissues (Table 2 ) [ 53 , 54 , 55 , 56 , 57 , 58 ]. Most C. acnes from prostate cancer tissues differ genetically from common skin C. acnes [ 59 ]. Alexeyev et al. [ 53 ] have identified C. acnes in benign prostate tissues taken up to 6 years apart from individual subjects. This indicates that C. acnes infection can be chronic and a cause of chronic inflammation. Cutibacterium acnes infections induce upregulation of inflammatory genes and cytokine secretion in prostate epithelial cells [ 60 ].

Accordingly C. acnes is a candidate pathogen in prostatitis and prostate cancer.

The evidence that antibiotics can control C. acnes infections is based on skin infections [ 61 ]. Resistance to antibiotics is an increasing problem.

Escherichia coli

Escherichia coli have been consistently identified by PCR and Next Generation Sequencing in prostate cancer and benign prostate tissues [ 54 , 62 ]. Unfortunately, good controls have not been used in these studies and no case control studies have been identified. A problem in studying E. coli and prostate cancer is that biopsies are usually conducted by gaining access to the prostate via the rectum. This can cause contamination of the prostate tissues by rectal located E. coli .

Escherichia coli is usually a harmless commensal bacteria that colonizes the human gut. However, many different types and strains exist, some of them have virulence properties that can result in inflammation and damage of the prostate. Jain et al. [ 63 ] have isolated E. coli from benign prostate tissues and demonstrated that this pathogen activated NF-kB and induced damage to normal cultured prostate epithelial cells. NF-kB proteins are activated by carcinogens and are known to be involved in oncogenesis [ 64 ]. Hemolysin and necrotizing factor type 1 occur significantly more frequently among C. coli isolates causing prostatitis than among those causing cystitis or pyelonephritis [ 65 ].

It is considered likely that some types of E. coli have causal roles in colon cancer [ 66 ]. Accordingly it is possible that E. coli can also cause prostate cancer.

Neisseria gonorrhoea (N. gonorrhoea)

Neisseria gonorrhoeae is the well known cause of the sexually transmitted disease gonorrhea [ 67 ]. The organism can manipulate the immune response which leads to a lack of protective immunity. Therefore individuals can become repeatedly infected. Gonorrhoea is generally a mucosal infection of the urethra with a pustular discharge. More severe sequalae include salpingitis and pelvic inflammatory disease which may lead to sterility and/or ectopic pregnancy. Neisseria gonorrhoeae can cause chronic inflammation of the prostate which in turn can be oncogenic [ 68 ]. Gonorrhoea is susceptible to an array of antibiotics. Antibiotic resistance is becoming a major problem.

There have been 22 case control studies in which the prevalence of N. gonorrhoea in prostate cancer has been compared to controls (Table 3 ) [ 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 ]. In six of these studies it was shown that N. gonorrhoea was significantly more prevalent in the prostate cancer cases. In 16 of these studies there was no significant difference been the cases and controls.

There is a possible explanation for these conflicting data, namely that sexually transmitted diseases are frequently due to multiple pathogens. In the meta-analysis by Taylor et al. [ 91 ] there were significant correlations between both N. gonorrhoea and HPVs and increased prevalence of prostate cancer (odds ratios gonorrhoea 1.35, HPV 1.39). It is possible that high risk HPVs were the cause of prostate cancer in these studies and that N. gonorrhoea was also present but not oncogenic.

Herpes viruses

Herpes simplex.

Herpes simplex virus 1 (HSV-1) commonly causes infections of the mouth (cold sores).

HSV-2 is associated with anogenital infections and is a sexually transmitted infection.

Both virus types can cause both kinds of infection. Infections due to herpes simplex do not usually confer immunity. No vaccines are currently available.

In four of 12 studies Herpes simplex 1 or 2 were significantly more prevalent in the prostate cancer cases (Table 4 ) [ 70 , 87 , 88 , 92 , 93 , 94 , 95 , 96 , 97 , 98 ]. Dennis et al. demonstrated that herpes simplex 2 could be identified in prostate cancer tissues over a period of 8 years [ 98 ]. These findings suggest that if herpes simplex has an oncogenic capacity there may be a long latency period for prostate cancer development after HSV-2 infection.

Acyclovir has been successfully used to treat genital herpes simplex infections [ 99 ].

Epstein Barr virus (EBV) (Herpes virus 4)

Cancers including breast and prostate cancer [ 1 , 100 ].

There have been four case control studies of EBV and prostate cancer. In one study by Sfanos et al. [ 54 ], EBV was significantly more prevalent in prostate cancer compared to controls (Table 5 ) [ 54 , 97 , 100 , 101 ].

The effectiveness of antiviral agents (acyclovir, valomaciclovir and valacyclovir) in acute infectious mononucleosis is uncertain [ 99 , 102 ].

Cytomegalovirus (CMV) (herpes virus 5)

Human CMV is present in over 80% of most populations. Transmission can occur during foetal life, via breast milk, saliva and during sexual activities. Human CMV infections in healthy people are mostly mild or without symptoms. In contrast, CMV can cause serious defects during foetal life and life threatening illness among immunocompromised patients such as transplant recipients and patients with AIDS [ 103 ].

As shown in Table 6 [ 23 , 87 , 93 , 104 , 105 ] in four of five case control studies there were no significant differences between the prevalence of CMV in prostate cancers and controls. In one study CMV was identified in the controls but not in prostate cancers [ 23 ].

Chlamydia trachomatis (C. trachomatis)

Chlamydia trachomatis is a common, sexually transmitted bacteria. Chlamydia trachomatis initiates and can maintain inflammation and persistent infection including prostatitis [ 105 ]. Human prostate cancer epithelial cells are susceptible to C. trachomatis infection and initiate inflammation [ 106 , 107 ]. As inflammation is associated with prostate cancer it has been hypothesized that C. trachomatis could have a causal role.

However, as shown in Table 7 [ 81 , 87 , 88 , 98 , 106 , 108 , 109 , 110 ] in eight case control studies there were no positive associations between C. trachomatis infections and prostate cancer. On the other hand, all these studies are based on serology, and it is possible that these case control studies are misleading as C. trachomatis may be causing chronic infection in the prostate leading to prostate cancer. This would lead to positive antibodies in both benign prostate controls and prostate cancer.

Azithromycin and Doxycycline antibiotics appear to be effective in the treatment of sexually transmitted C. trachomatis [ 111 ].

Trichomonas vaginalis (T.vaginalis)

Trichomonas vaginalis is a common protozoan infection frequently transmitted during sexual activities [ 112 ]. Trichomonas vaginalis in men is usually asymptomatic but may cause urethritis, prostatitis, epididymitis and infertility [ 113 ].

As shown in Table 8 [ 86 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 ] in eight of nine case control studies there is no increase in risk of prostate cancer in association with T. vaginalis infections. In two studies positive antibodies were higher in the controls than the cancer. These nine studies were all based on serology and involved a high number of subjects.

In a large serology based study by Tsang et al. [ 122 ] there was no increase in prostate cancer deaths associated with T. vaginalis . This finding makes it unlikely that T. vaginalis is associated with prostate cancer.

The 5-nitroimidazoles (metronidazole, tinidazole, secnidazole) are the only class of antimicrobials effective against T. vaginalis [ 113 ]. Unfortunately, there is growing concern over drug resistance with metronidazole.

Mycoplasma bacteria frequently infect prostate tissues and prostate cancer. The most common are M. hominus , M. ureaplasma and M. hyorhinus [ 123 ]. A recent meta-analysis showed that Mycoplasma bacterial infections were 2.24 times more frequent in patients with prostate cancer as compared to benign prostate hyperplasia [ 124 ]. These data are shown in Table 9 [ 88 , 123 , 125 , 126 , 127 , 128 , 129 ].

Of particular interest are the studies based on PCR analyses of tissues as compared to studies based on serology. Three of the PCR studies with positive results were significant, and two showed a trend that Mycoplasma infections were more frequent in prostate cancers than benign prostate controls. Accordingly, it is possible that Mycoplasma bacteria may have a role in prostate cancer. However additional evidence is required.

Antibiotics can be effective in treating Mycoplasma bacterial infections. Unfortunately, resistance to antibiotic treatment is emerging [ 130 ].

Polyoma viruses (hPy)

The two human polyomaviruses (hPy), BK virus (BKV), and JC virus (JCV), are commonly present in human populations. Infections usually occurs in childhood but rarely cause clinical symptoms. In immunocompromised patients JCV can cause serious neurodegenerative conditions. There is no direct evidence that hPy viruses are oncogenic [ 131 ].

We have identified 11 case control studies of BKV and JCV and their associations with prostate cancer in which polyoma viruses were identified (Table 10 ) [ 97 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 ]. In two small studies based on PCR there was a significant association with prostate cancer. There were no significant associations in 9 studies.

Accordingly it is unlikely that these polyomaviruses have causal roles in prostate cancer.

Fungal prostatitis

Infections of the prostate by several fungi are the unusual cause of prostatitis. These fungi include Blastomycosis, Candida albicans and Cryptococcus [ 140 ]. There is no evidence that these fungi are associated with prostate cancer. However, there must be suspicions about any pathogen which leads to chronic inflammation.

Mouse mammary tumour virus (MMTV)

MMTV is the proven cause of breast cancer in mice. There is compelling evidence that MMTV—like viruses are also causal in human breast cancer [ 7 ]. MMTV has been identified in prostate glands of mice [ 141 ]. MMTV—like viruses have been identified in human prostate cancers [ 6 ]. However, no studies have been conducted to determine if MMTV is causal in human prostate cancer.

Human immunodeficiency virus (HIV)

Compared to the general population, people living with HIV have a lower prevalence of prostate cancer [ 142 , 143 ]. This is probably due to the suppression of immune related B and T cells associated with both HIV and MMTV infections.

The gut microbiome and prostate cancer

The gut microbiome may also play an indirect role in various cancers [ 144 ]. In a study which compared the gut microbiota in men with prostate cancer and benign controls there was a significant difference in gut microbiol composition [ 145 ]. The meaning of these observations is not known.

High risk human papilloma viruses are the only pathogens for which there is sufficient evidence to indicate a probable causal role in prostate cancer. Fortunately, there are safe and effective vaccines available to prevent HPV infections [ 146 ].

Other pathogens may have roles in prostate cancer but the evidence is limited. These include Cutibacterium acnes, Neisseria gonorrhoea, Herpes simplex, Epstein Barr virus, and Mycoplasmas. In our view it is unlikely that Cytomegalovirus, Trichomonis vaginalis, Chlamydia trachomonis, Polyoma viruses, Human immunodeficiency virus and fungi have causal roles in prostate cancer.

HPVs are the only pathogen considered in this review which have a proven oncogenic capacity. However, in its acute stage it is unlikely that an HPV infection leads to prostate cancer as HPV infections are common in young men and prostate cancer occurs mainly in older men. On the other hand, as considered above, the influence of HPV may be reactivated and lead to prostate oncogenesis via long-term reprogramming of innate immune cells.

While the oncogenic mechanisms probably differ between these pathogens, of particular relevance is the potential role of inflammation in prostate cancer. Different pathogens may each cause chronic inflammation. Multiple pathogens are frequently present in prostate tissues and chronic exposure can lead to chronic inflammation and ultimately to prostate cancer. The relevant evidence has been reviewed in detail by De Bono et al. [ 147 ] and Gobel et al. [ 148 ].

A precise mechanism linking inflammation to cancer is the nuclear transcription factor “kappa-light-chain-enhancer” of B-cells known as NF-kB. This is a protein activated by many carcinogens. It controls genes commonly associated with oncogenesis [ 64 ]. Almost all infectious agents linked with cancer activate NF-nB. This has been confirmed experimentally in mice by the inactivation of NF-kB which reduced inflammation initiated cancer formation [ 149 ]. Infectious pathogens can activate inflammatory pathways which lead to genomic instability in tissue cells which in turn lead to malignant transformation. HPV, human herpes virus, and EBV, have been specifically shown to activate NF-kB. Confirmation of this evidence has been provided by the reduction in risk of cancer by anti-inflammatory agents such as aspirin [ 150 ].

The most influential cause of prostate cancer appears to be infection induced chronic inflammation.

Given the high prevalence of prostate cancer it is important for action to can be taken without waiting for additional conclusive evidence. These include:

Availability of data and materials

Not applicable.

Abbreviations

Human papilloma viruses

Cutibacterium acnes

Neisseria gonorrhoea

Herpes simplex virus

Epstein Barr virus

Cytomegalovirus

Chlamydia trachomatis

Trichomonas vaginalis

Polyoma virus

Mouse mammary tumour virus

Human immunodeficiency virus

Lawson JS, Glenn WK. Evidence for a causal role by human papillomaviruses in prostate cancer: a systematic review. Infect Agent Cancer. 2020;15:41.

Article   PubMed   PubMed Central   Google Scholar  

Ferlay J, Colombet M, Soerjomataram I, Parkin DM, Piñeros M, Znaor A, Bray F. Cancer statistics for the year 2020: an overview. Int J Cancer. 2021. https://doi.org/10.1002/ijc.33588 .

Article   PubMed   Google Scholar  

Muir CS, Nectoux J, Staszewski J. The epidemiology of prostatic cancer. Geographical distribution and time-trends. Acta Oncol. 1991;30:133–40.

Article   CAS   PubMed   Google Scholar  

Kumar S, Singh R, Malik S, Manne U, Mishra M. Prostate cancer health disparities: an immuno-biological perspective. Cancer Lett. 2018;414:153–65.

Stanford JL, Herrington LJ, Schwartz SM, Weiss NS. Breast cancer incidence in Asian migrants to the US and their descendants. Epidemiology. 1995;6:181–3.

Johal H, Faedo M, Faltas J, Lau A, Mousina R, Cozzi P, Defazio A, Rawlinson WD. DNA of mouse mammary tumor virus-like virus is present in human tumors influenced by hormones. J Med Virol. 2010;82:1044–50.

Lawson JS, Glenn WK. Evidence for a causal role by mouse mammary tumour-like virus in human breast cancer. NPJ Breast Cancer. 2019;5:40.

Article   PubMed   PubMed Central   CAS   Google Scholar  

Hill AB. The environment and disease: association or causation? Proc R Soc Med. 1965;58:295–330.

CAS   PubMed   PubMed Central   Google Scholar  

Kleinberg S. On the use and abuse of Hill’s viewpoints on causality. Obs Stud. 2020;6:17–9.

Google Scholar  

Doll R, Hill AB. Smoking and carcinoma of the lung; preliminary report. Br Med J. 1950;2(4682):739–48.

Article   CAS   PubMed   PubMed Central   Google Scholar  

McNicol PJ, Dodd JG. High prevalence of human papillomavirus in prostate tissues. Urol J. 1991;145:850–3.

Article   CAS   Google Scholar  

Anwar K, Nakakuki K, Shiraishi T, Naiki H, Yatani R, Inuzuka M. Presence of ras oncogene mutations and human papillomavirus DNA in human prostate carcinomas. Cancer Res. 1992;52:5991–6.

CAS   PubMed   Google Scholar  

Ibrahim GK, Gravitt PE, Dittrich KL, Ibrahim SN, Melhus O, Anderson SM, et al. Detection of human papillomavirus in the prostate by polymerase chain reaction and in situ hybridization. J Urol. 1992;148:1822–6.

Rotola A, Monini P, Di Luca D, Savioli A, Simone R, Secchiero P, et al. Presence and physical state of HPV DNA in prostate and urinary-tract tissues. Int J Cancer. 1992;52:359–65.

Dodd JG, Paraskevas M, McNicol PJ. Detection of human papillomavirus 16 transcription in human prostate tissue. J Urol. 1993;149:400–2.

Moyret-Lalle C, Marçais C, Jacquemier J, Moles JP, Daver A, Soret JY, et al. Ras, p53 and HPV status in benign and malignant prostate tumors. Int J Cancer. 1995;64:124–9.

Wideroff L, Schottenfeld D, Carey TE, Beals T, Fu G, Sakr W, et al. Human papillomavirus DNA in malignant and hyperplastic prostate tissue of black and white males. Prostate. 1996;28:117–23.

Terris MK, Peehl DM. Human papillomavirus detection by polymerase chain reaction in benign and malignant prostate tissue is dependent on the primer set utilized. Urology. 1997;50:150–6.

Serth J, Panitz F, Paeslack U, Kuczyk MA, Jonas U. Increased levels of human papillomavirus type 16 DNA in a subset of prostate cancers. Cancer Res. 1999;59:823–5.

Carozzi F, Lombardi FC, Zendron P, Confortini M, Sani C, Bisanzi S, et al. Association of human papillomavirus with prostate cancer: analysis of a consecutive series of prostate biopsies. Int J Biol Markers. 2004;19:257–61.

Leiros GJ, Galliano SR, Sember ME, Kahn T, Schwarz E, Eiguchi K. Detection of human papillomavirus DNA and p53 codon 72 polymorphism in prostate carcinomas of patients from Argentina. BMC Epidemiol Health. 2015;37:e2015005.

Silvestre RV, Leal MF, Demachki S, Nahum MC, Bernardes JG, Rabenhorst SH, et al. Low frequency of human papillomavirus detection in prostate tissue from individuals from northern Brazil. Mem Inst Oswaldo Cruz. 2009;104:665–7.

Martinez-Fierro ML, Leach RJ, Gomez-Guerra LS, Garza-Guajardo R, Johnson-Pais T, Beuten J, et al. Identification of viral infections in the prostate and evaluation of their association with cancer. BMC Cancer. 2010;10:326.

Aghakhani A, Hamkar R, Parvin M, Ghavami N, Nadri M, Pakfetrat A, et al. The role of human papillomavirus infection in prostate carcinoma. Scand J Infect Dis. 2011;43:64–9.

Chen AC, Waterboer T, Keleher A, Morrison B, Jindal S, McMillan D, et al. Human papillomavirus in benign prostatic hyperplasia and prostatic adenocarcinoma patients. Pathol Oncol Res. 2011;17:613–7.

Tachezy R, Hrbacek J, Heracek J, Salakova M, Smahelova J, Ludvikova V, et al. HPV persistence and its oncogenic role in prostate tumors. J Med Virol. 2012;84:1636–45.

Ghasemian E, Monavari SH, Irajian GR, Jalali Nodoshan MR, Roudsari RV, Yahyapour Y. Evaluation of human papillomavirus infections in prostatic disease: a cross-sectional study in Iran. Asian Pac J Cancer Prev. 2013;14:3305–8.

Mokhtari M, Taghizadeh F, Hani M. Is prostatic adenocarcinoma in a relationship with human papilloma virus in Isfahan -Iran. J Res Med Sci. 2013;18:707–10.

PubMed   PubMed Central   Google Scholar  

Michopoulou V, Derdas SP, Symvoulakis E, Mourmouras N, Nomikos A, Delakas D, et al. Detection of human papillomavirus (HPV) DNA prevalence and p53 codon 72 (Arg72Pro) polymorphism in prostate cancer in a Greek group of patients. Tumour Biol. 2014;35:12765–73.

Singh N, Hussain S, Kakkar N, Singh SK, Sobti RC, Bharadwaj M. Implication of high risk Human papillomavirus HR-HPV infection in prostate cancer in Indian population: a pioneering case-control analysis. Sci Rep. 2015;5:7822.

Huang L, Wu MG, He J, Wei ZS, Lü WX, Song XJ, et al. Correlation of highrisk HPV 16/18 infections with prostate cancer. Zhonghua Nan Ke Xue. 2016;22:501–5.

Dávila-Rodríguez MI, Ignacio Morales CV, Aragón Tovar AR, Olache Jimenez D, Castelán Maldonado E, Lara Miranda S, et al. Human papilloma virus detection by INNOLiPA HPV in prostate tissue from men of Northeast Mexico. Asian Pac J Cancer Prev. 2016;17:4863–5.

PubMed   Google Scholar  

Atashafrooz F, Rokhbakhsh-Zamin F. Frequency and type distribution of human papilloma virus in patients with prostate Cancer, Kerman, southeast of Iran. Asian Pac J Cancer Prev. 2016;17:3953–8.

Medel-Flores O, Valenzuela-Rodríguez VA, Ocadiz-Delgado R, Castro-Muñoz LJ, Hernández-Leyva S, Lara-Hernández G, et al. Association between HPV infection and prostate cancer in a Mexican population. Genet Mol Biol. 2018;41:781–9.

Nahand JS, Esghaei M, Hamidreza Monavari S, Moghoofei M, Jalal Kiani S, Mostafaei S, Mirzaei H, Bokharaei-Salim F. The assessment of a possible link between HPV-mediated inflammation, apoptosis, and angiogenesis in Prostate cancer. Int Immunopharmacol. 2020;88:106913.

Fatemipour M, Nahand JS, Fard Azar ME, Baghi HB, Taghizadieh M, Sorayyayi S, Hussen BM, Mirzaei H, Moghoofei M, Bokharaei-Salim F. Human papillomavirus and prostate cancer: the role of viral expressed proteins in the inhibition of anoikis and induction of metastasis. Microb Pathog. 2021;152:104576.

Whitaker NJ, Glenn WK, Sahrudin A, Orde MM, Delprado W, Lawson JS. Human papillomavirus and Epstein Barr virus in prostate cancer: Koilocytes indicate potential oncogenic influences of human papillomavirus in prostate cancer. Prostate. 2013;73:236–41.

Rhim JS, Webber MM, Bello D, Lee MS, Arnstein P, Chen LS, et al. Stepwise immortalization and transformation of adult human prostate epithelial cells by a combination of HPV-18 and v-Ki-ras. Proc Natl Acad Sci U S A. 1994;91:11874–8.

Schütze DM, Snijders PJ, Bosch L, Kramer D, Meijer CJ, Steenbergen RD. Differential in vitro immortalization capacity of eleven (probable) high-risk human papillomavirus types. J Virol. 2014;88:1714–24.

Crocetto F, Arcaniolo D, Napolitano L, Barone B, La Rocca R, Capece M, Caputo VF, Imbimbo C, De Sio M, Calace FP, Manfredi C. Impact of sexual activity on the risk of male genital tumors: a systematic review of the literature. Int J Environ Res Public Health. 2021;18:8500.

Guenat D, Hermetet F, Prétet J-L, Mougin C. Exosomes and other extracellular vesicles in HPV transmission and carcinogenesis. Viruses. 2017;9:211.

Article   PubMed Central   CAS   Google Scholar  

La Vignera S, Condorelli RA, Cannarella R, Giacone F, Mongioi L, Scalia G, et al. High rate of detection of ultrasound signs of prostatitis in patients with HPV-DNA persistence on semen: role of ultrasound in HPV-related male accessory gland infection. J Endocrinol Invest. 2019;42:1459–65.

Article   PubMed   CAS   Google Scholar  

Zhang L, Wang Y, Qin Z, Gao X, Xing Q, Li R, et al. Correlation between prostatitis, benign prostatic hyperplasia and prostate cancer: a systematic review and meta-analysis. J Cancer. 2020;11:177–89.

Glenn WK, Ngan CC, Amos TG, Edwards RJ, Swift J, Lutze-Mann L, et al. High risk human papillomaviruses (HPVs) are present in benign prostate tissues before development of HPV associated prostate cancer. Infect Agent Cancer. 2017;12:46.

Sudenga SL, Torres BN, Silva R, Villa LL, Lazcano-Ponce E, Abrahamsen M, Baggio ML, Salmeron J, Quiterio M, Giuliano AR. Comparison of the natural history of genital HPV infection among men by country: Brazil, Mexico, and the United States. Cancer Epidemiol Biomark Prev. 2017;26:1043–52.

Article   Google Scholar  

Wei F, Gaisa MM, D’Souza G, Xia N, Giuliano AR, Hawes SE, Gao L, Cheng SH, Donà MG, Goldstone SE, et al. Epidemiology of anal human papillomavirus infection and high-grade squamous intraepithelial lesions in 29 900 men according to HIV status, sexuality, and age: a collaborative pooled analysis of 64 studies. Lancet HIV. 2021;8:e531–43.

Netea MG, Domínguez-Andrés J, Barreiro LB, Chavakis T, Divangahi M, Fuchs E, Joosten LAB, van der Meer JWM, Mhlanga MM, Mulder WJM, Riksen NP, Schlitzer A, Schultze JL, Stabell Benn C, Sun JC, Xavier RJ, Latz E. Defining trained immunity and its role in health and disease. Nat Rev Immunol. 2020;20:375–88.

Korostil IA, Regan DG. The potential impact of HPV-16 reactivation on prevalence in older Australians. BMC Infect Dis. 2014;14:312.

Ohba K, Ichiyama K, Yajima M, Gemma N, Nikaido M, Wu Q, et al. in vivo and in vitro studies suggest a possible involvement of HPV infection in the early stage of breast carcinogenesis via APOBEC3B induction. PLoS ONE. 2014;9:e97787.

Vieira VC, Leonard B, White EA, Starrett GJ, Temiz NA, Lorenz LD, et al. Human papillomavirus E6 triggers upregulation of the antiviral and cancer genomic DNA deaminase APOBEC3B. MBio. 2014;5:e02234-e2314.

Markowitz LE, Schiller JT. Human papillomavirus vaccines. J Infect Dis. 2021;224(Supplement_4):S367–78.

Dekio I, Asahina A, Shah HN. Unravelling the eco-specificity and pathophysiological properties of Cutibacterium species in the light of recent taxonomic changes. Anaerobe. 2021;71:102411.

Alexeyev O, Bergh J, Marklund I, Thellenberg-Karlsson C, Wiklund F, Grönberg H, Bergh A, Elgh F. Association between the presence of bacterial 16S RNA in prostate specimens taken during transurethral resection of prostate and subsequent risk of prostate cancer (Sweden). Cancer Causes Control. 2006;17:1127–33.

Sfanos KS, Sauvageot J, Fedor HL, Dick JD, De Marzo AM, Isaacs WB. A molecular analysis of prokaryotic and viral DNA sequences in prostate tissue from patients with prostate cancer indicates the presence of multiple and diverse microorganisms. Prostate. 2008;68:306–20.

Severi G, Shannon BA, Hoang HN, Baglietto L, English DR, Hopper JL, Pedersen J, Southey MC, Sinclair R, Cohen RJ, Giles GG. Plasma concentration of Propionibacterium acnes antibodies and prostate cancer risk: results from an Australian population-based case–control study. Br J Cancer. 2010;103:411–5.

Bae Y, Ito T, Iida T, Uchida K, Sekine M, Nakajima Y, Kumagai J, Yokoyama T, Kawachi H, Akashi T, Eishi Y. Intracellular Propionibacterium acnes infection in glandular epithelium and stromal macrophages of the prostate with or without cancer. PLoS ONE. 2014;9:e90324.

Davidsson S, Molling P, Rider JR, Unemo M, Karlsson MG, Carlsson J, Andersson SO, Elgh F, Soderquis B, Andren O. Frequency and typing of Propionibacterium acnes in prostate tissue obtained from men with and without prostate cancer. Infect Agent Cancer. 2016;11:26.

Kakegawa T, Bae Y, Ito T, Uchida K, Sekine M, Nakajima Y, Furukawa A, Suzuki Y, Kumagai J, Akashi T, Eishi Y. Frequency of propionibacterium acnes infection in prostate glands with negative biopsy results is an independent risk factor for prostate cancer in patients with increased serum PSA Titers. PLoS ONE. 2017;12:e0169984.

Cohen RJ, Shannon BA, McNeal JE, Shannon T, Garrett KL. Propionibacterium acnes associated with inflammation in radical prostatectomy specimens: a possible link to cancer evolution? J Urol. 2005;173:1969–74.

Drott JB, Alexeyev O, Bergström P, Elgh F, Olsson J. Propionibacterium acnes infection induces upregulation of inflammatory genes and cytokine secretion in prostate epithelial cells. BMC Microbiol. 2010;10:126.

Dessinioti C, Dreno B. Acne treatments: future trajectories. Clin Exp Dermatol. 2020;45:955–61.

Brüggemann H, Al-Zeer MA. Bacterial signatures and their inflammatory potentials associated with prostate cancer. APMIS. 2020;128:80–91.

Jain S, Samal AG, Das B, Pradhan B, Sahu N, Mohapatra D, Behera PK, Satpathi PS, Mohanty AK, Satpathi S, Senapati S. Escherichia coli, a common constituent of benign prostate hyperplasia-associated microbiota induces inflammation and DNA damage in prostate epithelial cells. Prostate. 2020;80:1341–52.

Aggarwal BB, Vijayalekshmi RV, Sung B. Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clin Cancer Res. 2009;15:425–30.

Ruiz J, Simon K, Horcajada JP, Velasco M, Barranco M, Roig G, Moreno-Martínez A, Martínez JA, Jiménez de Anta T, Mensa J, Vila J. Differences in virulence factors among clinical isolates of Escherichia coli causing cystitis and pyelonephritis in women and prostatitis in men. J Clin Microbiol. 2002;40:4445–9.

Alhinai EA, Walton GE, Commane DM. The role of the gut microbiota in colorectal cancer causation. Int J Mol Sci. 2019;20:5295.

Article   CAS   PubMed Central   Google Scholar  

Hill SA, Masters TL, Wachter J. Gonorrhea: an evolving disease of the new millennium. Microb Cell. 2016;3:371–89.

Sfanos KS, Yegnasu Bramanian S, Nelson WG, De Marzo AM. The inflammatory microenvironment and microbiome in prostate cancer development. Nat Rev Urol. 2018;15:11–24.

Heshmat MY, Kovi J, Herson J, Jones GW, Jackson MA. Epidemiologic association between Gonorrhea and prostatic carcinoma. Urology. 1975;6:457–60.

Baker LH, Mebust WK, Chin TD, Chapman AL, Hinthorn D, Towle D. The relationship of herpesvirus to carcinoma of the prostate. J Urol. 1981;125:370–4.

Lees RE, Steele R, Wardle D. Arsenic, syphilis, and cancer of the prostate. J Epidemiol Community Health. 1985;39:227–30.

Mishina T, Watanabe H, Araki H, Nakao M. Epidemiological study of prostatic cancer by matched-pair analysis. Prostate. 1985;6:423–36.

Checkoway H, DiFerdinando G, Hulka BS, Mickey DD. Medical, life-style, and occupational risk factors for prostate cancer. Prostate. 1987;10:79–88.

Honda GD, Bernstein L, Ross RK, Greenland S, Gerkins V, Henderson BE. Vasectomy, cigarette smoking, and age at first sexual intercourse as risk factors for prostate cancer in middle-aged men. Br J Cancer. 1988;57:326–31.

Oishi K, Okada K, Yoshida O, Yamabe H, Ohno Y, Hayes RB, Schroeder FH. Case-control study of prostatic cancer in Kyoto, Japan: demographic and some lifestyle risk factors. Prostate. 1989;14:117–22.

La Vecchia C, Franceschi S, Talamini R, Negri E, Boyle P, D’Avanzo B. Marital status, indicators of sexual activity and prostatic cancer. J Epidemiol Community Health. 1993;47:450–3.

Hiatt RA, Armstrong MA, Klatsky AL, Sidney S. Alcohol consumption, smoking, and other risk factors and prostate cancer in a large health plan cohort in California (United States). Cancer Causes Control. 1994;5:66–72.

Ilić M, Vlajinac H, Marinković J. Case-control study of risk factors for prostate cancer. Br J Cancer. 1996;74:1682–6.

Hsieh CC, Thanos A, Mitropoulos D, Deliveliotis C, Mantzoros CS, Trichopoulos D. Risk factors for prostate cancer: a case-control study in Greece. Int J Cancer. 1999;80:699–703.

Hayes RB, Pottern LM, Strickler H, Rabkin C, Pope V, Swanson GM, Greenberg RS, Schoenberg JB, Liff J, Schwartz AG, Hoover RN, Fraumeni JF Jr. Sexual behaviour, STDs and risks for prostate cancer. Br J Cancer. 2000;82:718–25.

Rosenblatt KA, Wicklund KG, Stanford JL. Sexual factors and the risk of prostate cancer. Am J Epidemiol. 2001;153:1152–8.

Sanderson M, Coker AL, Logan P, Zheng W, Fadden MK. Lifestyle and prostate cancer among older African-American and Caucasian men in South Carolina. Cancer Causes Control. 2004;15:647–55.

Patel DA, Bock CH, Schwartz K, Wenzlaff AS, Demers RY, Severson RK. Sexually transmitted diseases and other urogenital conditions as risk factors for prostate cancer: a case-control study in Wayne County, Michigan. Cancer Causes Control. 2005;16:263–73.

Pelucchi C, Talamini R, Negri E, Franceschi S, La Vecchia C. Genital and urinary tract diseases and prostate cancer risk. Eur J Cancer Prev. 2006;15:254–7.

Sarma AV, McLaughlin JC, Wallner LP, Dunn RL, Cooney KA, Schottenfeld D, Montie JE, Wei JT. Sexual behavior, sexually transmitted diseases and prostatitis: the risk of prostate cancer in black men. J Urol. 2006;176:1108–13.

Sutcliffe S, Giovannucci E, De Marzo AM, Leitzmann MF, Willett WC, Platz EA. Gonorrhea, syphilis, clinical prostatitis, and the risk of prostate cancer. Cancer Epidemiol Biomark Prev. 2006;15:2160–6.

Huang WY, Hayes R, Pfeiffer R, Viscidi RP, Lee FK, Wang YF, Reding D, Whitby D, Papp JR, Rabkin CS. Sexually transmissible infections and prostate cancer risk. Cancer Epidemiol Biomark Prev. 2008;17:2374–81.

Hrbacek J, Urban M, Hamsikova E, Tachezy R, Eis V, Brabec M, Heracek J. Serum antibodies against genitourinary infectious agents in prostate cancer and benign prostate hyperplasia patients: a case-control study. BMC Cancer. 2011;11:53.

Vázquez-Salas RA, Torres-Sánchez L, López-Carrillo L, Romero-Martínez M, Manzanilla-García HA, Cruz-Ortíz CH, Mendoza-Peña F, Jiménez-Ríos MÁ, Rodríguez-Covarrubias F, Hernández-Toríz N, Moreno-Alcázar O. History of gonorrhea and prostate cancer in a population-based case-control study in Mexico. Cancer Epidemiol. 2016;40:95–101.

Wang YC, Chung CH, Chen JH, Chiang MH, Ti-Yin CH, Tsao CH, Lin FH, Chien WC, Shang ST, Chang FY. Gonorrhea infection increases the risk of prostate cancer in Asian population: a nationwide population-based cohort study. Eur J Clin Microbiol Infect Dis. 2017;36:813–21.

Taylor ML, Mainous AG 3rd, Wells BJ. Prostate cancer and sexually transmitted diseases: a meta-analysis. Fam Med. 2005;37:506–12.

Lüleci G, Sakizli M, Günalp A, Erkan I, Remzi D. Herpes simplex type 2 neutralization antibodies in patients with cancers of urinary bladder, prostate, and cervix. J Surg Oncol. 1981;16:327–31.

Boldogh I, Baskar JF, Mar EC, Huang ES. Human cytomegalovirus and herpes simplex type 2 virus in normal and adenocarcinomatous prostate glands. J Natl Cancer Inst. 1983;70:819–26.

Haid M, Sharon N. Immunofluorescent evidence of prior herpes simplex virus type-2 infection in prostate carcinoma. Urology. 1984;24:623–5.

Leskinen MJ, Vainionp R, Syrjnen S, Leppilahti M, Marttila T, Kylml T, Tammela TL. Herpes simplex virus, cytomegalovirus, and papillomavirus DNA are not found in patients with chronic pelvic pain syndrome undergoing radical prostatectomy for localized prostate cancer. Urology. 2003;61:397–401.

Korodi Z, Wang X, Tedeschi R, Knekt P, Dillner J. No serological evidence of association between prostate cancer and infection with herpes simplex virus type 2 or human herpesvirus type 8: a nested case-control study. J Infect Dis. 2005;191:2008–11.

Bergh J, Marklund I, Gustavsson C, Wiklund F, Grönberg H, Allard A, Alexeyev O, Elgh F. No link between viral findings in the prostate and subsequent cancer development. Br J Cancer. 2007;96:137–9.

Dennis LK, Coughlin JA, McKinnon BC, Wells TS, Gaydos CA, Hamsikova E, Gray GC. Sexually transmitted infections and prostate cancer among men in the U.S. military. Cancer Epidemiol Biomark Prev. 2009;18:2665–71.

Taylor M, Gerriets V. Acyclovir. 2021 Jun 28. In: StatPearls [Internet]. Treasure Island: StatPearls Publishing; 2021.

Nahand JS, Khanaliha K, Mirzaei H, Moghoofei M, Baghi HB, Esghaei M, Khatami AR, Fatemipour M, Bokharaei-Salim F. Possible role of HPV/EBV coinfection in anoikis resistance and development in prostate cancer. BMC Cancer. 2021;21:926.

Grinstein S, Preciado MV, Gattuso P, Chabay PA, Warren WH, De Matteo E, Gould VE. Demonstration of Epstein-Barr virus in carcinomas of various sites. Cancer Res. 2002;62:4876–8.

De Paor M, O'Brien K, Fahey T, Smith SM. Antiviral agents for infectious mononucleosis (glandular fever). Cochrane Database Syst Rev. 2016;12:CD011487.

Griffiths P, Reeves M. Pathogenesis of human cytomegalovirus in the immunocompromised host. Nat Rev Microbiol. 2021;19:759.

Eizuru Y, Hyman RW, Nahhas WA, Rapp F. Herpesvirus RNA in human urogenital tumors. Proc Soc Exp Biol Med. 1983;174:296–301.

Samanta M, Harkins L, Klemm K, Britt WJ, Cobbs CS. High prevalence of human cytomegalovirus in prostatic intraepithelial neoplasia and prostatic carcinoma. J Urol. 2003;170:998–1002.

Dillner J, Knekt P, Boman J, Lehtinen M, Af Geijersstam V, Sapp M, et al. Sero-epidemiological association between human-papillomavirus infection and risk of prostate cancer. Int J Cancer. 1998;75:564–7.

Sellami H, Said-Sadier N, Znazen A, Gdoura R, Ojcius DM, Hammami A. Chlamydia trachomatis infection increases the expression of inflammatory tumorigenic cytokines and chemokines as well as components of the Toll-like receptor and NF-κB pathways in human prostate epithelial cells. Mol Cell Probes. 2014;28:147–54.

Anttila T, Tenkanen L, Lumme S, Leinonen M, Gislefoss RE, Hallmans G, Thoresen S, Hakulinen T, Luostarinen T, Stattin P, Saikku P, Dillner J, Lehtinen M, Hakama M. Chlamydial antibodies and risk of prostate cancer. Cancer Epidemiol Biomark Prev. 2005;14:385–9.

Sutcliffe S, Giovannucci E, Gaydos CA, Viscidi RP, Jenkins FJ, Zenilman JM, et al. Plasma antibodies against chlamydia trachomatis, human papillomavirus, and human herpesvirus type 8 in relation to prostate cancer: a prospective study. Cancer Epidemiol Biomark Prev. 2007;16:1573–80.

Lumme S, Tenkanen L, Langseth H, Gislefoss R, Hakama M, Stattin P, Hallmans G, Adlercreutz H, Saikku P, Stenman UH, Tuohimaa P, Luostarinen T, Dillner J. Longitudinal biobanks-based study on the joint effects of infections, nutrition and hormones on risk of prostate cancer. Acta Oncol. 2016;55:839–45.

Blanco JL, Fuertes I, Bosch J, De Lazzari E, Gonzalez-Cordón A, Vergara A, Blanco-Arevalo A, Mayans J, Inciarte A, Estrach T, Martinez E, Cranston RD, Gatell JM, Alsina-Gibert M. Effective treatment of lymphogranuloma venereum proctitis with azithromycin. Clin Infect Dis. 2021;73:614–20.

Johnston VJ, Mabey DC. Global epidemiology and control of Trichomonas vaginalis. Curr Opin Infect Dis. 2008;21:56–64.

Van Gerwen OT, Camino AF, Sharma J, Kissinger PJ, Muzny CA. Epidemiology, natural history, diagnosis, and treatment of trichomonas vaginalis in men. Clin Infect Dis. 2021;73:1119–24.

Sutcliffe S, Alderete JF, Till C, Goodman PJ, Hsing AW, Zenilman JM, De Marzo AM, Platz EA. Trichomonosis and subsequent risk of prostate cancer in the prostate cancer prevention trial. Int J Cancer. 2009;124:2082–7.

Stark JR, Judson G, Alderete JF, Mundodi V, Kucknoor AS, Giovannucci EL, Platz EA, Sutcliffe S, Fall K, Kurth T, Ma J, Stampfer MJ, Mucci LA. Prospective study of Trichomonas vaginalis infection and prostate cancer incidence and mortality: Physicians’ Health Study. J Natl Cancer Inst. 2009;101:1406–11.

Chen YC, Huang YL, Platz EA, Alderete JF, Zheng L, Rider JR, Kraft P, Giovannucci E, Sutcliffe S. Prospective study of effect modification by Toll-like receptor 4 variation on the association between Trichomonas vaginalis serostatus and prostate cancer. Cancer Causes Control. 2013;24:175–80.

Shui IM, Kolb S, Hanson C, Sutcliffe S, Rider JR, Stanford JL. Trichomonas vaginalis infection and risk of advanced prostate cancer. Prostate. 2016;76:620–3.

Fowke JH, Han X, Alderete JF, Moses KA, Signorello LB, Blot WJ. A prospective study of Trichomonas vaginalis and prostate cancer risk among African American men. BMC Res Notes. 2016;9:224.

Marous M, Huang WY, Rabkin CS, Hayes RB, Alderete JF, Rosner B, Grubb RL 3rd, Winter AC, Sutcliffe S. Trichomonas vaginalis infection and risk of prostate cancer: associations by disease aggressiveness and race/ethnicity in the PLCO Trial. Cancer Causes Control. 2017;28:889–98.

Kim JH, Moon HS, Kim KS, Hwang HS, Ryu JS, Park SY. Comparison of seropositivity to trichomonas vaginalis between men with prostatic tumor and normal men. Korean J Parasitol. 2019;57:21–5.

Saleh NE, Alhusseiny SM, El-Zayady WM, Aboelnaga EM, El-Beshbishi WN, Saleh YM, Abou-ElWafa HS, El-Beshbishi SN. Trichomonas vaginalis serostatus and prostate cancer risk in Egypt: a case-control study. Parasitol Res. 2021;120:1379–88.

Tsang SH, Peisch SF, Rowan B, Markt SC, Gonzalez-Feliciano AG, Sutcliffe S, Platz EA, Mucci LA, Ebot EM. Association between Trichomonas vaginalis and prostate cancer mortality. Int J Cancer. 2019;144:2377–80.

Barykova YA, Logunov DY, Shmarov MM, Vinarov AZ, Fiev DN, Vinarova NA, Rakovskaya IV, Baker PS, Shyshynova I, Stephenson AJ, Klein EA, Naroditsky BS, Gintsburg AL, Gudkov AV. Association of mycoplasma hominis infection with prostate cancer. Oncotarget. 2011;2:289–97.

Tantengco OAG, Aquino IMC, de Castro SM, Rojo RD, Abad CLR. Association of mycoplasma with prostate cancer: a systematic review and meta-analysis. Cancer Epidemiol. 2021;75:102021.

Urbanek C, Goodison S, Chang M, Porvasnik S, Sakamoto N, Li CZ, Boehlein SK, Rosser CJ. Detection of antibodies directed at M. hyorhinis p37 in the serum of men with newly diagnosed prostate cancer. BMC Cancer. 2011;11:233.

Erturhan SM, Bayrak O, Pehlivan S, Ozgul H, Seckiner I, Sever T, Karakök M. Can mycoplasma contribute to formation of prostate cancer? Int Urol Nephrol. 2013;45:33–8.

Yow MA, Tabrizi SN, Severi G, Bolton DM, Pedersen J, Longano A, et al. Detection of infectious organisms in archival prostate cancer tissues. BMC Cancer. 2014;14:579.

Miyake M, Ohnishi K, Hori S, Nakano A, Nakano R, Yano H, Ohnishi S, Owari T, Morizawa Y, Itami Y, Nakai Y, Inoue T, Anai S, Torimoto K, Tanaka N, Fujii T, Furuya H, Rosser CJ, Fujimoto K. Mycoplasma genitalium infection and chronic inflammation in human prostate cancer: detection using prostatectomy and needle biopsy specimens. Cells. 2019;8:212.

Saadat S, Karami P, Jafari M, Kholoujini M, Rikhtegaran Tehrani Z, Mohammadi Y, Alikhani MY. The silent presence of Mycoplasma hominis in patients with prostate cancer. Pathog Dis. 2020;78:ftaa037.

Seña AC, Bachmann L, Johnston C, Wi T, Workowski K, Hook EW 3rd, Hocking JS, Drusano G, Unemo M. Optimising treatments for sexually transmitted infections: surveillance, pharmacokinetics and pharmacodynamics, therapeutic strategies, and molecular resistance prediction. Lancet Infect Dis. 2020;20:e181–91.

Imperiale MJ. The human polyomaviruses, BKV and JCV: molecular pathogenesis of acute disease and potential role in cancer. Virology. 2000;267:1–7.

Monini P, Rotola A, Di Luca D, De Lellis L, Chiari E, Corallini A, Cassai E. DNA rearrangements impairing BK virus productive infection in urinary tract tumors. Virology. 1995;214:273–9.

Zambrano A, Kalantari M, Simoneau A, Jensen JL, Villarreal LP. Detection of human polyomaviruses and papillomaviruses in prostatic tissue reveals the prostate as a habitat for multiple viral infections. Prostate. 2002;53:263–76.

Lau SK, Lacey SF, Chen YY, Chen WG, Weiss LM. Low frequency of BK virus in prostatic adenocarcinomas. APMIS. 2007;115:743–9.

Das D, Wojno K, Imperiale MJ. BK virus as a cofactor in the etiology of prostate cancer in its early stages. J Virol. 2008;82:2705–14.

Russo G, Anzivino E, Fioriti D, Mischitelli M, Bellizzi A, Giordano A, Autran-Gomez A, Di Monaco F, Di Silverio F, Sale P, Di Prospero L, Pietropaolo V. p53 gene mutational rate, Gleason score, and BK virus infection in prostate adenocarcinoma: Is there a correlation? J Med Virol. 2008;80:2100–7.

Delbue S, Matei DV, Carloni C, Pecchenini V, Carluccio S, Villani S, Tringali V, Brescia A, Ferrante P. Evidence supporting the association of polyomavirus BK genome with prostate cancer. Med Microbiol Immunol. 2013;202:425–30.

Taghavi A, Mohammadi-Torbati P, Kashi AH, Rezaee H, Vaezjalali M. Polyomavirus hominis 1(BK virus) Infection in prostatic tissues: cancer versus hyperplasia. Urol J. 2015;12:2240–4.

Gorish BMT, Ournasseir MEH, Shammat IM. A correlation study of BK polyoma virus infection and prostate cancer among sudanese patients - immunofluorescence and molecular based case-control study. Infect Agent Cancer. 2019;14:25.

Wise GJ, Shteynshlyuger A. How to diagnose and treat fungal infections in chronic prostatitis. Curr Urol Rep. 2006;7:320–8.

Wajjwalku W, Takahashi M, Miyaishi O, Lu J, Sakata K, Yokoi T, Saga S, Imai M, Matsuyama M, Hoshino M. Tissue distribution of mouse mammary tumor virus (MMTV) antigens and new endogenous MMTV loci in Japanese laboratory mouse strains. Jpn J Cancer Res. 1991;82:1413–20.

Grulich AE, Vajdic CM. The epidemiology of cancers in human immunodeficiency virus infection and after organ transplantation. Semin Oncol. 2015;42:247–57.

Coghill AE, Engels EA, Schymura MJ, Mahale P, Shiels MS. Risk of breast, prostate, and colorectal cancer diagnoses among HIV-infected individuals in the United States. J Natl Cancer Inst. 2018;110:959–66.

Jiang Z, Li L, Chen J, Wei G, Ji Y, Chen X, Liu J, Huo J. Human gut-microbiome interplay: analysis of clinical studies for the emerging roles of diagnostic microbiology in inflammation, oncogenesis and cancer management. Infect Genet Evol. 2021;93:104946.

Golombos DM, Ayangbesan A, O’Malley P, Lewicki P, Barlow L, Barbieri CE, et al. The role of gut microbiome in the pathogenesis of prostate cancer: a prospective. Pilot Study Urol. 2018;111:122–8.

Gallego L, Dominguez A, Parmar M. Human papilloma virus vaccine. In: StatPearls [Internet]. Treasure Island: StatPearls Publishing; 2021.

de Bono JS, Guo C, Gurel B, De Marzo AM, Sfanos KS, Mani RS, Gil J, Drake CG, Alimonti A. Prostate carcinogenesis: inflammatory storms. Nat Rev Cancer. 2020;20:455–69.

Göbel A, Dell’Endice S, Jaschke N, Pählig S, Shahid A, Hofbauer LC, Rachner TD. The role of inflammation in breast and prostate cancer metastasis to bone. Int J Mol Sci. 2021;22:5078.

Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ, Kagnoff MF, Karin M. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell. 2004;118:285–96.

Qiao Y, Yang T, Gan Y, Li W, Wang C, Gong Y, Lu Z. Associations between aspirin use and the risk of cancers: a meta-analysis of observational studies. BMC Cancer. 2018;18:288.

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The impact of lipidome on breast cancer: a Mendelian randomization study

• Yuchen Cao 1 ,
• Meichen Ai 2 &
• Chunjun Liu 1  

Lipids in Health and Disease volume  23 , Article number:  109 ( 2024 ) Cite this article

Metrics details

This study aims to investigate the association between specific lipidomes and the risk of breast cancer (BC) using the Two-Sample Mendelian Randomization (TSMR) approach and Bayesian Model Averaging Mendelian Randomization (BMA-MR) method.

The study analyzed data from large-scale GWAS datasets of 179 lipidomes to assess the relationship between lipidomes and BC risk across different molecular subtypes. TSMR was employed to explore causal relationships, while the BMA-MR method was carried out to validate the results. The study assessed heterogeneity and horizontal pleiotropy through Cochran's Q, MR-Egger intercept tests, and MR-PRESSO. Moreover, a leave-one-out sensitivity analysis was performed to evaluate the impact of individual single nucleotide polymorphisms on the MR study.

By examining 179 lipidome traits as exposures and BC as the outcome, the study revealed significant causal effects of glycerophospholipids, sphingolipids, and glycerolipids on BC risk. Specifically, for estrogen receptor-positive BC (ER + BC), phosphatidylcholine ( P  < 0.05) and phosphatidylinositol (OR: 0.916–0.966, P  < 0.05) within glycerophospholipids play significant roles, along with the importance of glycerolipids (diacylglycerol (OR = 0.923, P  < 0.001) and triacylglycerol, OR: 0.894–0.960, P  < 0.05)). However, the study did not observe a noteworthy impact of sphingolipids on ER + BC. In the case of estrogen receptor-negative BC (ER − BC), not only glycerophospholipids, sphingolipids (OR = 1.085, P  = 0.008), and glycerolipids (OR = 0.909, P  = 0.002) exerted an influence, but the protective effect of sterols (OR: 1.034–1.056, P  < 0.05) was also discovered. The prominence of glycerolipids was minimal in ER-BC. Phosphatidylethanolamine (OR: 1.091–1.119, P  < 0.05) was an important causal effect in ER − BC.

Conclusions

The findings reveal that phosphatidylinositol and triglycerides levels decreased the risk of BC, indicating a potential protective role of these lipid molecules. Moreover, the study elucidates BC's intricate lipid metabolic pathways, highlighting diverse lipidome structural variations that may have varying effects in different molecular subtypes.

Introduction

Despite significant advancements in cancer research, breast cancer (BC) remains the most common malignancy among women worldwide, representing a leading cause of cancer-related deaths and ranking as one of the top three most prevalent cancers globally [ 1 , 2 ]. The incidence of this aggressive disease affects approximately one in eight women in the United States, while in Asia, the alarming rate stands at one in every 35 women diagnosed with BC. The accumulated pieces of evidence underscore the ongoing need for intensified efforts in prevention, providing high-quality screening, diagnosis, and treatment to the population [ 3 , 4 ]. Current clinical management of BC offers diverse options, including surgery, chemotherapy, radiotherapy, and targeted therapies [ 5 ]. Disparities in BC survival rates are substantial worldwide, with an estimated 5-year survival rate of 80% in developed countries contrasted with less than 40% in developing nations [ 6 , 7 ]. The American Cancer Society projects a staggering 297,790 deaths due to BC in women by the year 2023 [ 8 ], highlighting the urgent imperative to develop more effective and safe treatment modalities tailored for different regions of varying developmental stages.

Lipidomes are spherical vesicles composed of one or more concentric phospholipid bilayers surrounding an aqueous core [ 9 ]. Classified within the realm of nanomedicine, lipidomes represent a prominent category of lipid-based nanocarriers, standing out as one of the most sophisticated systems in this domain [ 10 ]. This non-toxic and biodegradable nature makes lipidomes a versatile drug delivery platform for a plethora of therapeutic agents. By stabilizing compounds, surmounting barriers to cellular and tissue uptake, and enhancing the pharmacokinetics and biodistribution of drugs at targeted sites within the body, lipidomes enhance the therapeutic efficacy while minimizing systemic toxicity [ 11 ]. Their pivotal role spans across various health fields [ 12 , 13 ], playing a critical role in drug delivery systems for small molecules, peptides, genes, and monoclonal antibodies, as extensively documented and recognized in plenty of research [ 14 , 15 , 16 ]. Lipidomes, benefiting from their self-assembly process with inherent thermodynamic advantages, have emerged as a versatile tool in cancer therapy. They have been harnessed to enhance tumor targeting efficacy, minimize off-target toxicity [ 17 ], and treat patients with severe infections or compromised immune function [ 10 ], including those afflicted with BC [ 18 ]. Amid the recognized physical and psychological toll of conventional treatments like surgery and chemotherapy on patients, there is a pressing need to explore safer and more effective therapeutic modalities. Leveraging the distinctive characteristics of lipidomes, there is a growing interest in unraveling their role in BC treatment, particularly in exploring lipidome-associated viable gene therapy strategies for BC [ 19 ]. This burgeoning attention underscores the potential for lipidomes to revolutionize BC management and potentially offer personalized treatment options with enhanced outcomes and diminished adverse effects, aligning with the evolving landscape of precision medicine and targeted therapies across oncology.

Mendelian randomization (MR) has emerged as a prevalent method in genetic epidemiological research, probing causal inferences between exposures and outcomes. While randomized controlled trials (RCTs) stand as the gold standard in clinical evidence, MR methodology serves as a vital alternative strategy when RCTs are unfeasible, furnishing robust evidence concerning causal relationships between exposures and disease risks [ 20 , 21 , 22 ]. Utilizing single nucleotide polymorphisms (SNPs) as instrumental variables (IVs), MR assesses the causal impact of exposures on outcomes [ 23 ]. Considering that genetic variants are randomly allocated during gametogenesis and genotypes are typically unaffected by external environments, a rigorously designed MR study can largely mitigate confounding and reverse causality concerns.

Given the limited understanding of the causal impact of liposomes on BC, this study aims to establish a causal relationship between lipidomes and BC by providing compelling evidence. Ultimately, this research endeavours to advance the early detection and treatment of BC. As a result, this study aims to employ Two-Sample Mendelian randomization (TSMR) to investigate the underlying relationship between lipidomes and BC, and bayesian model averaging multivariate mendelian randomization (BMA-MR) was applied to further verify the results.

GWAS data for lipidome

Genome-Wide Association Study (GWAS) summary statistics for lipidome were acquired from the GWAS Catalog ( https://www.ebi.ac.uk/gwas/ , GCST90277238-GCST90277416). A total of 7174 unrelated Finnish individuals from the GeneRISK cohort were included, and SNPs for 179 lipid species (sTable 1 ) belonging to 13 lipid classes and 4 categories were tested [ 24 ].

GWAS data for breast cancer

The SNPs linked to BC were collected from the Breast Cancer Association Consortium (BCAC) GWAS database, accessible at https://gwas.mrcieu.ac.uk/ . The dataset comprised 228,951 samples ( N  = 122,977 BC cases and 105,974 controls) and 10,680,257 SNPs. Meanwhile, a total of 175,475 samples ( N  = 69,501 Estrogen receptor-positive BC (ER + BC) cases; 105,974 controls) and 10,680,257 SNPs related to ER + BC were investigated. Additionally, 127,442 samples ( N  = 21,468.

Estrogen receptor-negative BC (ER − BC) cases; 105,974 controls) and 10,680,257 SNPs associated with ER − BC were examined [ 25 ].

Instrumental variable extraction

The selection of SNPs as IVs for assessing the impact of lipidome on BC requires meeting three key assumptions of MR. Firstly, there should be a significant association between genetic variations and lipidomes. Secondly, confounding factors should not influence the chosen IVs, which are known to affect the relationship between lipidomes and BC. Lastly, the IVs should only influence the incidence of BC through lipidomes. Certain criteria were employed to ensure the selection of appropriate SNPs. Firstly, SNPs were required to exhibit a strong correlation with lipidomes, with a significance level of P  < 5 × 10 –6 . Furthermore, SNPs were chosen in a manner that ensured their independence from one another, thereby minimizing potential confounding effects resulting from linkage disequilibrium (LD). In cases where the LD r 2 value was equal to or exceeded 0.001, one of the SNPs was excluded from further analysis. Additionally, a genetic distance of 10,000 kb, representative of the region's length, was set. SNPs with an r 2 value greater than 0.001 and located within this 10,000 kb region were eliminated to remove any remaining LD. These stringent SNP selection criteria were implemented to satisfy the assumptions of MR and ensure robustness and validity in evaluating the correlated impact of lipidome on BC. Additionally, SNPs with palindromic intermediate allele frequencies were also excluded. To identify suitable IVs for this study, the study utilized the PhenoScanner website ( http://www.phenoscanner.medschl.cam.ac.uk/ ). Any SNPs of exposure found to be directly associated with the outcomes (BC, ER + BC, and ER − BC) were also excluded ahead of the MR analysis, respectively. Furthermore, the study comprehensively assessed the selected SNPs to evaluate their potential pleiotropic effects, utilizing the MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test [ 26 ]. Fortunately, none of the SNPs exhibited any indications for removal after undergoing this evaluation. Next, the study employed a two-sample MR analysis to investigate the relationship between the exposure and outcome variables initially.

Two samples of MR analysis

The inverse variance weighting (IVW) technique is commonly employed to combine multiple random variables in order to effectively reduce the overall variance. This approach assigns weights to each random variable in the aggregate based on their level of divergence. With IVW, it becomes possible to integrate the findings from distinct investigations. The IVW method was employed as the principal analytical approach, yielding the most accurate and reliable estimations when all genetic variants are considered legitimate instruments [ 27 ]. P values acquired from IVW method were subjected to False Discovery Rate (FDR) adjustment to account for multiple testing and enhance the reliability of our findings. To ensure the accuracy of our results, the study also employed various methods, including MR-Egger, weighted median, simple mode, and weighted mode. These additional analyses were conducted as safeguards in order to provide robust and reliable outcomes. For instance, if multiple methods indicate the same causal direction, confidence in that causal relationship would be strengthened. Further, The study employed the MR-BMA to further verify the causal effects of the exposure on the outcome by reducing potential biases, which enables the modelling of multiple correlated risk factors together and identifies the true causal risk factors, particularly suitable for high-throughput and highly correlated data [ 28 ].

Sensitivity analysis

Sensitivity analysis was conducted to ensure the robustness of our findings. First, the study examined the intercept term of the MR-Egger regression model to assess the potential presence of pleiotropic effects [ 29 ]. If the P-value of the intercept term exceeded 0.05, it suggested that any influence of genetic pleiotropy was minimal. In such cases, the study concluded that the IVs solely impacted the risk of BC through lipidomes. To investigate the heterogeneity of the IVs and its potential impact on the causal estimate, the study employed the Cochran's Q test [ 30 ]. Funnel plots were also utilized to visually represent any heterogeneity within the obtained data. Furthermore, The study conducted a leave-one-out analysis to assess the sensitivity of the results. This involved performing MR analysis repeatedly, gradually eliminating one SNP at a time. Subsequently, the MR-PRESSO test was used to evaluate the presence of any disparities between the outcomes of MR analysis before to and after correction. Conducting both MR-Egger intercept test and MR-PRESSO allows the study to conduct sensitivity analyses from different perspectives. If the MR-Egger intercept test indicates the presence of directional pleiotropy, MR-PRESSO can further identify and correct for outliers that may be contributing to this bias.

Causal effects of lipidomes and BC

The causal effects of lipidomes on BC were evaluated through TSMR. The results indicated that glycerophospholipids, sphingolipids, and glycerolipids could potentially impact BC risk. Specifically, phosphatidylethanolamine and various phosphatidylinositol structures were found to be protective factors. In contrast, different forms of phosphatidylcholine displayed inconsistent effects on BC (Fig.  1 ). Notably, sphingomyelin, a member of the sphingolipids family, was associated with an increased risk of BC (OR = 1.05, 95%CI 1.02–1.08, P  = 0.0036). On the other hand, diacylglycerol and several triacylglycerol variants within the glycerolipids family exhibited a protective role against BC (Fig.  1 ). The results of the different analysis methods are presented in Supplementary Table  2 . The results from IVW are our primary reference metric. If the causal relationships determined by the other four analysis methods align with the direction of the IVW results and have a P  < 0.05, it would greatly enhance our confidence in the establishment of the causal relationship.The results from both TSMR and BMA-MR analyses were generally consistent, except for phosphatidylcholine (O-18:1/20:4).

Forest plot of Mendelian randomization and Bayesian Model Averaging Mendelian Randomization method of the effect of lipidomes on BC. The OR, P-val, and 95% CI are results obtained from the IVW method, while P-adj represents the outcomes adjusted via the FDR method. The B-OR and B-Pval are results derived from the MR-BMA analysis, and the forest plot displays the IVW results. (Phosphatidylcholine(O-16:1/18:1) represents a specific type of phospholipid molecule with a defined composition. Here is a breakdown of its components: O-16:1: This notation refers to the fatty acid composition of the molecule. In this case, O-16:1 signifies that there is an unsaturated fatty acid with 16 carbon atoms and 1 double bond attached to the glycerol backbone at the first position; 18:1: Similarly, 18:1 denotes an 18-carbon atom unsaturated fatty acid with 1 double bond attached to the glycerol backbone at the second position. In essence, Phosphatidylcholine(O-16:1/18:1) specifies a phospholipid molecule consisting of a choline head group linked to a glycerol backbone, with a 16-carbon unsaturated fatty acid at the first position and an 18-carbon unsaturated fatty acid at the second position. The specific arrangement and composition of these components play a crucial role in the structure and function of the phospholipid within biological membranes. Phosphatidylcholine, Phosphatidylethanolamine, and Phosphatidylinositol have the same naming principles. Sphingomyelin(d40:2) is a specific type of sphingomyelin lipid molecule. The term "d40:2" refers to the fatty acid composition of the sphingomyelin molecule. In this case, "d40:2" indicates that the sphingomyelin molecule contains a 40-carbon backbone with 2 double bonds. Diacylglycerol(18:1/18:1) refers to a specific type of diacylglycerol lipid molecule. In this case, the notation "18:1/18:1" denotes the fatty acid composition of the two acyl chains attached to the glycerol backbone in the diacylglycerol molecule. Each "18:1" specifies that the fatty acid chain contains 18 carbon atoms and one double bond, also known as an oleic acid. In the context of lipid nomenclature, Triacylglycerol 50:5 is a specific way of expressing the composition of a triglyceride molecule. Here is a breakdown of what this designation means; "50:5" represents the fatty acid composition of the triglyceride molecule. In this case: "50" denotes the total number of carbon atoms in the three fatty acid chains. Therefore, the sum of carbon atoms in all three fatty acids is 50. "5" signifies the total number of double bonds present in the three fatty acid chains combined)

Causal effects of lipidomes and ER + BC

The analysis of TSMR revealed potential causal effects of glycerophospholipids and glycerolipids on ER + BC. Specifically, phosphatidylinositols within the glycerophospholipids group continued to exhibit a protective role, while the impact of phosphatidylcholines varied depending on their structure (Fig.  2 ). Within the glycerolipids family, the diacylglycerol variant 18:1/18:1 and several triacylglycerols demonstrated a protective effect against ER + BC (Fig.  2 ). The results of the different analysis methods are presented in Supplementary Table 3 . The results from IVW are our primary reference metric. If the causal relationships determined by the other four analysis methods align with the direction of the IVW results and have a P  < 0.05, it would greatly enhance our confidence in the establishment of the causal relationship. The overall findings were consistent between TSMR and BMA-MR analyses, with a few exceptions that included specific phosphatidylinositols (16:0/18:0 and 18:0/18:2), as well as triacylglycerols (48:1, 49:1, and 53:3) (Fig.  2 ).

Forest plot of Mendelian randomization and Bayesian Model Averaging Mendelian Randomization method of the effect of lipidomes on ER + BC. The OR, P-val, and 95% CI are results obtained from the IVW method, while P-adj represents the outcomes adjusted via the FDR method. The B-OR and B-Pval are results derived from the MR-BMA analysis, and the forest plot displays the IVW results

Causal effects of lipidomes and ER − BC

The TSMR analysis indicated that glycerophospholipids, sphingolipids, glycerolipids, and sterols may have a significant impact on ER − BC. Among the glycerophospholipids, an increased incidence of ER − BC was associated with specific phosphatidylcholines, with the risk and protective effects varying depending on their molecular structure (Fig.  3 ). Furthermore, phosphatidylethanolamine emerged as a clear risk factor for ER − BC, while phosphatidylinositols exhibited a protective role. In the sphingolipids category, the presence of sphingomyelin was found to promote the development of ER − BC. Conversely, within the glycerolipids family, the triacylglycerol variant 53:4 demonstrated a protective effect against ER − BC. Notably, the sterols category showed a consistent protective effect against ER − BC incidence. The results of the different analysis methods are presented in Supplementary Table 4 . The results from IVW are our primary reference metric. If the causal relationships determined by the other four analysis methods align with the direction of the IVW results and have a P  < 0.05, it would greatly enhance our confidence in the establishment of the causal relationship. Overall, the findings from both the TSMR and BMA-MR analyses were largely in agreement, with a few exceptions, such as phosphatidylethanolamine (O-18:2/20:4) (Fig.  3 ).

Forest plot of Mendelian randomization and Bayesian Model Averaging Mendelian Randomization method of the effect of lipidomes on ER. − BC. The OR, P-val, and 95% CI are results obtained from the IVW method, while P-adj represents the outcomes adjusted via the FDR method. The B-OR and B-Pval are results derived from the MR-BMA analysis, and the forest plot displays the IVW results. (Sterol ester (27:1/20:4) refers to a specific type of sterol ester lipid molecule. In this case, the notation "27:1/20:4" denotes the fatty acid composition of the two acyl chains attached to the sterol backbone in the sterol ester molecule. For the "27:1" component, it indicates that one of the fatty acid chains contains 27 carbon atoms and one double bond, which is commonly seen in monounsaturated fatty acids like oleic acid. For the "20:4" component, it specifies that the other fatty acid chain contains 20 carbon atoms and four double bonds, which is characteristic of polyunsaturated fatty acids like arachidonic acid)

A sensitivity analysis was performed to assess the robustness of the findings, and the results are presented in Supplementary Tables  2 – 4 . In the context of BC, neither the IVW test nor the MR-Egger test indicated any heterogeneity. The absence of substantial heterogeneity was similarly observed for ER − and ER + BC. The MR-Egger intercept test yielded a p-value greater than 0.05, suggesting the absence of horizontal pleiotropy in the results. Furthermore, the MR-PRESSO test did not detect pleiotropy, thus confirming the accuracy of the findings. The scatter plots depicting the MR analyses are in Supplementary Figs.  1 , 2 and 3 . Examination of the funnel plot showed no significant heterogeneity (Supplementary Figs.  1 , 2 and 3 ). Additionally, no single SNP significantly impacted the MR estimates, as demonstrated by the leave-one-out analysis. While a few SNPs were found to potentially influence the results for specific ER status subgroups, their odds ratio values consistently remained on the same side of the zero line (Supplementary Figs.  1 , 2 and 3 ).

This is the first study to comprehensively and meticulously explore the impact of various structurally different lipidomes on BC incidence, presenting a panoramic view of the research on 179 lipidomes. By examining 179 lipidome traits as exposures and BC as the outcome, the study delved into the intricate causal associations between lipidomes and BC occurrence. Our findings revealed significant effects of glycerophospholipids, sphingolipids, and glycerolipids on BC risk. Specifically, for ER + BC, phosphatidylcholine and phosphatidylinositol within glycerophospholipids continued to play significant roles, along with the importance of glycerolipids. However, The study did not observe a noteworthy impact of sphingolipids on ER + BC. In the case of ER − BC, not only glycerophospholipids, sphingolipids, and glycerolipids exerted an influence, but the protective effect of sterols was also discovered. It is worth noting that the prominence of glycerolipids (diglycerides and triglycerides), which played a vital role in ER + BC, was minimal in ER − BC. Conversely, phosphatidylethanolamine within the glycerophospholipid family played an important role in ER − BC.

The findings of our study highlight the consistent protective role of phosphatidylinositol within glycerophospholipids for overall BC, ER + BC, and ER − BC. Our results demonstrate that various structurally diverse forms of phosphatidylinositol significantly decrease the risk of BC and ER + BC, whereas only Phosphatidylinositol (18:0/18:2) significantly affects ER − BC. Phosphatidylinositols are well-known for their involvement in intracellular signaling pathways [ 31 , 32 ], particularly through the Phosphatidylinositol 3-kinase (PI3K) pathway, which regulates various cellular functions, including lipid metabolism. It is noteworthy that this pathway is frequently mutated or activated in BC tissues [ 33 , 34 ]. Phosphatidylinositol stands out among other phospholipids due to its limited fatty acid composition and characteristic patterns in mammalian cells [ 35 , 36 ]. Changes in the composition of phosphatidylinositol can be induced by specific stimuli, thereby regulating the PI3K signaling pathway [ 37 ]. Previous studies have shown that the matrix composition of BC tissues is predominantly occupied by phosphatidylinositol (18:0/20:4), with no significant inter-individual variation. Phosphatidylinositol (18:0/20:3) tends to distribute in the adjacent stromal area, while phosphatidylinositol (18:0/18:1) tends to cluster in the central region of tumor cell populations. Discrimination between these two distinct tissue areas can be achieved by the expression of either phosphatidylinositol (18:0/18:1) or phosphatidylinositol (18:0/20:3). The association between the accumulation of phosphatidylinositol (18:0/20:3) and stromal contact, as well as nodal status, suggests a plausible hypothesis that this accumulation in BC cells may contribute to their invasion capacity [ 38 ]. This hypothesis is supported by evidence indicating that the accumulation of phosphatidylinositol (18:0/20:3) not only affects cellular membrane fluidity but also influences the activity of the PI3K signaling pathway [ 39 , 40 , 41 , 42 ]. In previous studies, higher levels of phosphatidylinositol (16:0/18:1) were found in the epithelial region compared to the stromal area, and its distribution in malignant BC tissues was significantly higher than in benign breast tumors [ 38 ]. In our study, we observed that phosphatidylinositol (16:0/18:1) exhibited a significant protective effect on overall BC and ER + BC. This discrepancy underscores a potentially multifaceted role of phosphatidylinositol (16:0/18:1) in BC, suggesting that its impact may not be uniformly pro-tumorigenic and could vary depending on the context or subtype of BC. Notably, phosphatidylinositol (18:0/18:2), which showed no significant difference in distribution within the stroma and epithelial tissues according to previous literature, did not demonstrate any significant differences between BC and benign tumors [ 38 ]. However, in our study, phosphatidylinositol (18:0/18:2) displayed a significant protective effect among overall BC, ER + BC, and ER − BC. Regarding phosphatidylethanolamine(O-18:2/18:2), it played a protective role in overall BC, while in ER − BC, specific subtypes (O-16:1/20:4, O-18:1/20:4, and O-18:2/20:4) exerted clear promoting effects. Phosphatidylethanolamine, an essential component for ferroptosis, has been found to play an important role in the heterogeneity of tumors in triple-negative BC (TNBC) [ 43 , 44 ], which might an essential breakthrough for further investigation to explore the potential dual effects of phosphatidylethanolamine on BC. Additionally, the downregulation of RARRES2, which regulates lipid metabolism reprogramming and mediates the development of brain metastasis in TNBC, has been found to lead to an increase in phosphatidylethanolamine and phosphatidylcholine levels. This highlights the significance of investigating the role of RARRES2 and its impact on phosphatidylethanolamine in BC [ 45 ]. Our findings shed light on the distinct effects of different phospholipid subtypes, such as phosphatidylinositol and phosphatidylethanolamine, on BC. The observed protective effects of certain phospholipids in specific BC subtypes provide valuable insights into the underlying mechanisms and potential therapeutic targets. The relationship between lipid metabolism and BC progression, merits further investigation. One noteworthy example is the inconsistent effects observed with phosphatidylcholine, as different structural forms of phosphatidylcholine exert entirely opposing roles. Further research is warranted to unravel the molecular mechanisms involved and to explore the clinical implications of these findings.

The randomized results from Mendelian randomization have also presented us with some questions and challenges. In our traditional understanding, diacylglycerols and triglycerides increase the risk of various diseases, with a steady state existing between monoglycerides, diacylglycerols, and triglycerides synthesis. Previous cohort studies have indicated an increased risk of BC with elevated triglyceride levels [ 46 ]. However, evidence from evidence-based medicine suggests that high triglyceride levels do not lead to an increased risk of BC [ 47 , 48 ]. Our research findings suggest that triglycerides may be a protective factor for ER + BC, but this phenomenon is not clearly evident in ER − BC. This seemingly novel perspective is supported by existing evidence as well. Similarly, other Mendelian randomization studies focusing on lipid metabolism and tumor risk also indicate triglycerides as a protective factor for BC, particularly ER + BC [ 49 , 50 , 51 , 52 , 53 , 54 ], aligning with our research results. However, as with most complex diseases, common variants identified in GWAS can only explain a small portion of the total heritability of the disease, especially in the case of cancer. Rare variants throughout the genome may also play a significant role in disease development. Therefore, a combination of basic and clinical research is needed to further clarify causal relationships [ 55 ]. Some scholars have suggested that these intriguing findings may indicate a complex relationship between lipid metabolism, estrogen, and BC [ 51 ]. The consistency of these results across multiple studies from different data sources further enhances our confidence in the reliability of our findings. High mammographic breast density (MBD) has been widely recognized as a strong risk factor for the development of BC. Volumetric percent density (VPD) has emerged as a quantitative standard for assessing MBD. Previous study revealed that lipid species inversely associated with VPD predominantly belonged to the triacylglycerol ( N  = 43) and diacylglycerol ( N  = 7) sub-pathways [ 56 ]. These lipid species align with the protective effects observed in our research. Furthermore, investigations into the lipid profiles of plasma-derived extracellular vesicles revealed a higher concentration of triglycerides in TNBC [ 57 ], which is consistent with the low prominence of triglycerides as protective factors in our findings for ER-BC. However, it is worth noting that triglycerides and diglycerides exhibit diverse structural variations. Previous studies have predominantly explored triglycerides as a whole without specific subdivisions based on their structural forms. Hence, further research is warranted to identify which specific structural forms of triglycerides can exert preventive effects [ 56 ]. Our study highlights the potential importance of triglyceride subtypes in modulating BC risk, particularly in different molecular subtypes. These findings underscore the complexity of lipid metabolism in BC aetiology, and further investigation is essential to unravel the precise mechanisms involved.

Strengths and limitations

This study has several strengths. Firstly, we are the first to utilize the TSMR approach to thoroughly investigate the association between lipidomes and BC. This study encompasses a collection of genetic data and minimizes potential confounding factors to the greatest extent possible. Secondly, we applied the BMA-MR method to replicate our results, enhancing the accuracy of our findings. Thirdly, we conducted analyses based on different ER statuses to examine overall BC and specific subgroups, allowing us to apply our conclusions to the population more precisely.

However, there are certain limitations to our study. Firstly, during screening SNPs of lipidomes, a less stringent threshold of P  < 5*10 –6 was utilized instead of the conventional threshold of 5*10 –8 to acquire enough SNPs. Secondly, the majority of participants in this study were of European descent, which restricts the generalizability of our findings to other populations.Thirdly, due to the challenge of securing sufficiently high-confidence and quality SNPs necessary for multivariable Mendelian randomization analysis (MVMR), our study does not currently present MVMR results at present. We aim to refine our algorithms in future research to achieve these outcomes. Meanwhile, MR analysis assumes that the impact of genetic variants on the outcome is entirely mediated by the exposure [ 58 ]. Further, the inconsistency in significance assessment between TSMR and BMA-MR could be attributed to the differing algorithms used by the two analysis methods. TSMR typically employs frequentist statistical methods, whereas BMA-MR utilizes Bayesian methods. Bayesian methods estimate parameters by introducing prior distributions and calculating posterior distributions, offering unique advantages in handling uncertainty and integrating external information. However, this may also result in associations that are significant in frequentist analyses becoming non-significant in Bayesian analyses [ 59 , 60 ]. BMA-MR analysis may be more stringent than traditional frequentist methods in some cases, requiring stronger evidence to support causal inference. This means that results deemed significant in TSMR analysis may not remain significant in MR-BMA analysis when the data support is insufficient. Therefore, MR techniques can only assess causal relationships and cannot provide deeper insights into the underlying mechanisms of how lipidomes contribute to breast cancer prevention. Therefore, further research is needed to elucidate the potential processes underlying the novel insights generated by our study.

Our study provide significant insights into the association between specific lipidomes and the risk of BC. The findings indicate thatphosphatidylinositol and triglycerides would decrease the incidence of BC, suggesting their potential protective role. Furthermore, the study highlights the complexity of lipid metabolism in BC by uncovering the diverse structural variations of lipidomes and their potential differential effects in different molecular subtypes. These findings contribute to our understanding of the role of lipidomes, such as phosphatidylinositol and triglycerides, in modulating BC risk and emphasize the need for further research to elucidate the underlying mechanisms.

Availability of data and materials

No datasets were generated or analysed during the current study.

Abbreviations

• Breast cancer

Estrogen receptor-positive BC

Estrogen receptor-negative BC

• Mendelian randomization

Randomized controlled trials

Single nucleotide polymorphisms

Instrumental variables

Two-Sample Mendelian randomization

False Discovery Rate

Bayesian model averaging multivariate mendelian randomization

Genome-Wide Association Study

Breast Cancer Association Consortium

Linkage disequilibrium

MR Pleiotropy RESidual Sum and Outlier

Inverse variance weighting

Nolan E, Lindeman GJ, Visvader JE. Deciphering breast cancer: from biology to the clinic. Cell. 2023;186:1708–28.

CAS   PubMed   Google Scholar  

Akram M, Iqbal M, Daniyal M, Khan AU. Awareness and current knowledge of breast cancer. Biol Res. 2017;50:33.

PubMed   PubMed Central   Google Scholar  

Anastasiadi Z, Lianos GD, Ignatiadou E, Harissis HV, Mitsis M. Breast cancer in young women: an overview. Updates Surg. 2017;69:313–7.

PubMed   Google Scholar  

DeSantis C, Ma J, Bryan L, Jemal A. Breast cancer statistics. CA Cancer J Clin. 2013;64(2014):52–62.

H Zhong, G Zeng, and L He, Overexpression of the lncRNA AC012213.3 Promotes Proliferation, Migration and Invasion of Breast Cancer via RAD54B/PI3K/AKT Axis and is Associated with Worse Patient Prognosis. Cancer Manag Res 2021;13:7213–7223.

M.P. Coleman, M. Quaresma, F. Berrino, J.M. Lutz, R. De Angelis, R. Capocaccia, P. Baili, B. Rachet, G. Gatta, T. Hakulinen, A. Micheli, M. Sant, H.K. Weir, J.M. Elwood, H. Tsukuma, S. Koifman, E.S. GA, S. Francisci, M. Santaquilani, A. Verdecchia, H.H. Storm, J.L. Young, and C.W. Group, Cancer survival in five continents: a worldwide population-based study (CONCORD). Lancet Oncol 2008;9:730–56.

Lin Y, Zhang Y, Wang S, Yang Q. Elucidating the relationship between metabolites and breast cancer: A Mendelian randomization study. Toxicol Appl Pharmacol. 2024;484: 116855.

Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics. CA Cancer J Clin. 2023;73(2023):17–48.

Liu G, Hou S, Tong P, Li J. Liposomes: Preparation, Characteristics, and Application Strategies in Analytical Chemistry. Crit Rev Anal Chem. 2022;52:392–412.

Shah S, Dhawan V, Holm R, Nagarsenker MS, Perrie Y. Liposomes: Advancements and innovation in the manufacturing process. Adv Drug Deliv Rev. 2020;154–155:102–22.

Guimaraes D, Cavaco-Paulo A, Nogueira E. Design of liposomes as drug delivery system for therapeutic applications. Int J Pharm. 2021;601: 120571.

Shah SM, Goel PN, Jain AS, Pathak PO, Padhye SG, Govindarajan S, Ghosh SS, Chaudhari PR, Gude RP, Gopal V, Nagarsenker MS. Liposomes for targeting hepatocellular carcinoma: use of conjugated arabinogalactan as targeting ligand. Int J Pharm. 2014;477:128–39.

Shah SM, Pathak PO, Jain AS, Barhate CR, Nagarsenker MS. Synthesis, characterization, and in vitro evaluation of palmitoylated arabinogalactan with potential for liver targeting. Carbohydr Res. 2013;367:41–7.

Dutta R, Mahato RI. Recent advances in hepatocellular carcinoma therapy. Pharmacol Ther. 2017;173:106–17.

CAS   PubMed   PubMed Central   Google Scholar  

Yu B, Zhao X, Lee LJ, Lee RJ. Targeted delivery systems for oligonucleotide therapeutics. AAPS J. 2009;11:195–203.

Eloy JO, Petrilli R, Trevizan LNF, Chorilli M. Immunoliposomes: A review on functionalization strategies and targets for drug delivery. Colloids Surf B Biointerfaces. 2017;159:454–67.

Chavda VP, Vihol D, Mehta B, Shah D, Patel M, Vora LK, Pereira-Silva M, Paiva-Santos AC. Phytochemical-loaded liposomes for anticancer therapy: an updated review. Nanomedicine (Lond). 2022;17:547–68.

Jain AS, Goel PN, Shah SM, Dhawan VV, Nikam Y, Gude RP, Nagarsenker MS. Tamoxifen guided liposomes for targeting encapsulated anticancer agent to estrogen receptor positive breast cancer cells: in vitro and in vivo evaluation. Biomed Pharmacother. 2014;68:429–38.

G.Y.W. Tseu, and K.A. Kamaruzaman, A Review of Different Types of Liposomes and Their Advancements as a Form of Gene Therapy Treatment for Breast Cancer. Mole.  20232;28.

SY Shin, EB Fauman, AK Petersen, J Krumsiek, R Santos, J Huang, M Arnold, I Erte, V Forgetta, TP Yang, K Walter, C Menni, L Chen, L Vasquez, AM Valdes, CL Hyde, V Wang, D Ziemek, P Roberts, L Xi, E Grundberg, C. Multiple Tissue Human Expression Resource, M. Waldenberger, JB Richards, RP Mohney, MV Milburn, SL John, J Trimmer, FJ Theis, JP  Overington, K Suhre, MJ Brosnan, C Gieger, G Kastenmuller, TD Spector, and N Soranzo, An atlas of genetic influences on human blood metabolites. Nat Genet 2014;46:543–550.

Murphy N, Knuppel A, Papadimitriou N, Martin RM, Tsilidis KK, Smith-Byrne K, Fensom G, Perez-Cornago A, Travis RC, Key TJ, Gunter MJ. Insulin-like growth factor-1, insulin-like growth factor-binding protein-3, and breast cancer risk: observational and Mendelian randomization analyses with approximately 430 000 women. Ann Oncol. 2020;31:641–9.

N. Seyed Khoei, R. Carreras-Torres, N. Murphy, M.J. Gunter, P. Brennan, K. Smith-Byrne, D. Mariosa, J. McKay, T.A. O'Mara, R. Jarrett, H. Hjalgrim, K.E. Smedby, W. Cozen, K. Onel, A. Diepstra, K.H. Wagner, and H. Freisling, Genetically Raised Circulating Bilirubin Levels and Risk of Ten Cancers: A Mendelian Randomization Study. Cells 2021:10.

NM Davies, MV Holmes, and G Davey Smith, Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ. 2018;362:k601.

L Ottensmann, R Tabassum, SE Ruotsalainen, MJ Gerl, C Klose, E Widen, FinnGen, K  Simons, S Ripatti, and M Pirinen, Genome-wide association analysis of plasma lipidome identifies 495 genetic associations. Nat Commun 2023;14:6934.

K Michailidou, S Lindstrom, J Dennis, J Beesley, S Hui, S Kar, A Lemacon, P Soucy, D Glubb, A Rostamianfar, MK Bolla, Q Wang, J Tyrer, E Dicks, A Lee, Z Wang, J Allen, R Keeman, U Eilber, JD French, X Qing Chen, L Fachal, K McCue, AE McCart Reed, M Ghoussaini, JS Carroll, X Jiang, H Finucane, M Adams, MA Adank, H Ahsan, K Aittomaki, H Anton-Culver, NN Antonenkova, V Arndt, KJ Aronson, B Arun, PL Auer, F Bacot, M Barrdahl, C Baynes, MW Beckmann, S Behrens, J Benitez, M Bermisheva, L Bernstein, C Blomqvist, NV Bogdanova, SE Bojesen, B Bonanni, AL Borresen-Dale, JS Brand, H Brauch, P Brennan, H Brenner, L Brinton, P Broberg, IW Brock, A Broeks, A Brooks-Wilson, SY Brucker, T Bruning, B Burwinkel, K Butterbach, Q Cai, H Cai, T Caldes, F Canzian, A Carracedo, BD Carter, JE Castelao, TL Chan, TY David Cheng, K Seng Chia, JY Choi, H Christiansen, CL Clarke, N Collaborators, M Collee, DM Conroy, E Cordina-Duverger, S Cornelissen, DG Cox, A Cox, SS Cross, JM Cunningham, K Czene, MB Daly, P Devilee, KF Doheny, T Dork, I Dos-Santos-Silva, M Dumont, L Durcan, M Dwek, DM Eccles, AB Ekici, AH Eliassen, C Ellberg, M Elvira, et al., Association analysis identifies 65 new breast cancer risk loci. Nature 2017;551:92–94.

Verbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018;50:693–8.

DA Lawlor, RM Harbord, JA Sterne, N Timpson, and G Davey Smith. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med 2008;27:1133–63.

Zuber V, Colijn JM, Klaver C, Burgess S. Selecting likely causal risk factors from high-throughput experiments using multivariable Mendelian randomization. Nat Commun. 2020;11:29.

J Bowden, G Davey Smith, and S Burgess. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol 2015;44:512–25.

Burgess S, Zuber V, Valdes-Marquez E, Sun BB, Hopewell JC. Mendelian randomization with fine-mapped genetic data: Choosing from large numbers of correlated instrumental variables. Genet Epidemiol. 2017;41:714–25.

van Meer G, de Kroon AI. Lipid map of the mammalian cell. J Cell Sci. 2011;124:5–8.

Cantley LC. The phosphoinositide 3-kinase pathway. Science. 2002;296:1655–7.

N. Cancer Genome Atlas, Comprehensive molecular portraits of human breast tumours. Nature 2012;490:61–70.

Miller TW, Balko JM, Arteaga CL. Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J Clin Oncol. 2011;29:4452–61.

Holub BJ, Kuksis A. Structural and metabolic interrelationships among glycerophosphatides of rat liver in vivo. Can J Biochem. 1971;49:1347–56.

Baker RR, Thompson W. Positional distribution and turnover of fatty acids in phosphatidic acid, phosphinositides, phosphatidylcholine and phosphatidylethanolamine in rat brain in vivo. Biochim Biophys Acta. 1972;270:489–503.

Lee HC, Kubo T, Kono N, Kage-Nakadai E, Gengyo-Ando K, Mitani S, Inoue T, Arai H. Depletion of mboa-7, an enzyme that incorporates polyunsaturated fatty acids into phosphatidylinositol (PI), impairs PI 3-phosphate signaling in Caenorhabditis elegans. Genes Cells. 2012;17:748–57.

Kawashima M, Iwamoto N, Kawaguchi-Sakita N, Sugimoto M, Ueno T, Mikami Y, Terasawa K, Sato TA, Tanaka K, Shimizu K, Toi M. High-resolution imaging mass spectrometry reveals detailed spatial distribution of phosphatidylinositols in human breast cancer. Cancer Sci. 2013;104:1372–9.

Dirat B, Bochet L, Dabek M, Daviaud D, Dauvillier S, Majed B, Wang YY, Meulle A, Salles B, Le Gonidec S, Garrido I, Escourrou G, Valet P, Muller C. Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res. 2011;71:2455–65.

Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell-Gutbrod R, Zillhardt MR, Romero IL, Carey MS, Mills GB, Hotamisligil GS, Yamada SD, Peter ME, Gwin K, Lengyel E. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med. 2011;17:1498–503.

D Hoshino, J Jourquin, SW Emmons, T Miller, M Goldgof, K Costello, DR Tyson, B Brown, Y Lu, NK Prasad, B Zhang, GB Mills, WG Yarbrough, V Quaranta, M Seiki, and AM Weaver, Network analysis of the focal adhesion to invadopodia transition identifies a PI3K-PKCalpha invasive signaling axis. Sci Signal 2012;5:ra66.

Wander SA, Zhao D, Besser AH, Hong F, Wei J, Ince TA, Milikowski C, Bishopric NH, Minn AJ, Creighton CJ, Slingerland JM. PI3K/mTOR inhibition can impair tumor invasion and metastasis in vivo despite a lack of antiproliferative action in vitro: implications for targeted therapy. Breast Cancer Res Treat. 2013;138:369–81.

F Yang, Y Xiao, JH Ding, X Jin, D Ma, DQ Li, JX Shi, W Huang, YP Wang, YZ Jiang, and ZM Shao, Ferroptosis heterogeneity in triple-negative breast cancer reveals an innovative immunotherapy combination strategy. Cell Metab 2023;35:84–100 e8.

GH Su, Y Xiao, C You, RC Zheng, S Zhao, SY Sun, JY Zhou, LY Lin, H Wang, ZM Shao, YJ Gu, and YZ Jiang, Radiogenomic-based multiomic analysis reveals imaging intratumor heterogeneity phenotypes and therapeutic targets. Sci Adv 2023;9:eadf0837.

Li YQ, Sun FZ, Li CX, Mo HN, Zhou YT, Lv D, Zhai JT, Qian HL, Ma F. RARRES2 regulates lipid metabolic reprogramming to mediate the development of brain metastasis in triple negative breast cancer. Mil Med Res. 2023;10:34.

Berrino F, Villarini A, Traina A, Bonanni B, Panico S, Mano MP, Mercandino A, Galasso R, Barbero M, Simeoni M, Bassi MC, Consolaro E, Johansson H, Zarcone M, Bruno E, Gargano G, Venturelli E, Pasanisi P. Metabolic syndrome and breast cancer prognosis. Breast Cancer Res Treat. 2014;147:159–65.

Esposito K, Chiodini P, Capuano A, Bellastella G, Maiorino MI, Rafaniello C, Giugliano D. Metabolic syndrome and postmenopausal breast cancer: systematic review and meta-analysis. Menopause. 2013;20:1301–9.

Narii N, Zha L, Komatsu M, Kitamura T, Sobue T, Ogawa T. Cholesterol and breast cancer risk: a cohort study using health insurance claims and health checkup databases. Breast Cancer Res Treat. 2023;199:315–22.

Chen K, Li J, Ouyang Y, Liu G, Xie Y, Xu G, Peng W, Liu Y, He H, Huang R. Blood Lipid Metabolic Profiles and Causal Links to Site-Specific Cancer Risks: A Mendelian Randomization Study. Nutr Cancer. 2024;76:175–86.

Zhou M, Henricks M, Loch V, Zhang G, Lu Y, Li X. Mendelian randomization analysis revealed potential metabolic causal factors for breast cancer. Sci Rep. 2023;13:14290.

Xiao J, Hao Y, Wu X, Zhao X, Xu B, Xiao C, Zhang W, Zhang L, Cui H, Yang C, Yan P, Tang M, Wang Y, Chen L, Liu Y, Zou Y, Yang C, Yao Y, Li J, Jiang X, Zhang B. Nuclear magnetic resonance-determined lipoprotein profile and risk of breast cancer: a Mendelian randomization study. Breast Cancer Res Treat. 2023;200:115–26.

Johnson KE, Siewert KM, Klarin D, Damrauer SM, Program VAMV, Chang KM, Tsao PS, Assimes TL, Maxwell KN, Voight BF. The relationship between circulating lipids and breast cancer risk: A Mendelian randomization study. PLoS Med. 2020;17: e1003302.

Tan VY, Bull CJ, Biernacka KM, Teumer A, Richardson TG, Sanderson E, Corbin LJ, Dudding T, Qi Q, Kaplan RC, Rotter JI, Friedrich N, Volker U, Mayerle J, Perks CM, Holly JMP, Timpson NJ. Investigation of the Interplay between Circulating Lipids and IGF-I and Relevance to Breast Cancer Risk: An Observational and Mendelian Randomization Study. Cancer Epidemiol Biomarkers Prev. 2021;30:2207–16.

Beeghly-Fadiel A, Khankari NK, Delahanty RJ, Shu XO, Lu Y, Schmidt MK, Bolla MK, Michailidou K, Wang Q, Dennis J, Yannoukakos D, Dunning AM, Pharoah PDP, Chenevix-Trench G, Milne RL, Hunter DJ, Per H, Kraft P, Simard J, Easton DF, Zheng W. A Mendelian randomization analysis of circulating lipid traits and breast cancer risk. Int J Epidemiol. 2020;49:1117–31.

Z Zhang, H Li, H Weng, G Zhou, H Chen, G Yang, P Zhang, X Zhang, Y Ji, K Ying, B Liu, Q Xu, Y  Tang, G Zhu, Z Liu, S Xia, X Yang, L Dong, L Zhu, M Zeng, Y Yuan, Y Yang, N Zhang, X Xu, W Pang, M Zhang, Y Zhang, K Zhen, D Wang, J Lei, S Wu, S Shu, Y Zhang, S Zhang, Q Gao, Q Huang, C Deng, X Fu, G Chen, W Duan, J Wan, W Xie, P Zhang, S Wang, P Yang, X Zuo, Z Zhai, C Wang, and R Si. China pUlmonary Thromboembolism, Genome-wide association analyses identified novel susceptibility loci for pulmonary embolism among Han Chinese population. BMC Med 2023;21:153.

Getz KR, Jeon MS, Luo C, Luo J, Toriola AT. Lipidome of mammographic breast density in premenopausal women. Breast Cancer Res. 2023;25:121.

Liu L, Kawashima M, Sugimoto M, Sonomura K, Pu F, Li W, Takeda M, Goto T, Kawaguchi K, Sato TA, Toi M. Discovery of lipid profiles in plasma-derived extracellular vesicles as biomarkers for breast cancer diagnosis. Cancer Sci. 2023;114:4020–31.

Weng H, Li H, Zhang Z, Zhang Y, Xi L, Zhang D, Deng C, Wang D, Chen R, Chen G, Tang S, Zuo X, Yang P, Zhai Z, Wang C. Association between uric acid and risk of venous thromboembolism in East Asian populations: a cohort and Mendelian randomization study. Lancet Reg Health West Pac. 2023;39: 100848.

J.K. Kruschke, Doing Bayesian data analysis: A tutorial with R and BUGS. Brain 2010:1.

A. Gelman, J.B. Carlin, H.S. Stern, D.B. Dunson, and D.B. Rubin, Bayesian data analysis, third edition. J Am Stat Assoc 2003;45.

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This research was supported by Capital's funds for Health Improvement and Research (2024–1-4041), CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2020-I2M-C&T-B-082) and Institute funding (No. YS202016) to Dr. Chunjun Liu.

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Chunjun Liu and Yuchen Cao conceived the study. Yuchen Cao was the major contributor to the research and the writing of the manuscript. Meichen Ai summarized the literature, typeset the articles and embellished the language. Chunjun Liu critically reviewed the intellectual content of the manuscript, and made substantive revisions to the crucial contents of the manuscript. All authors contributed to the article and approved the submitted version.

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Promotion of self-directed learning abilities among Chinese medical students through preparing for career calling and enhancing teaching competencies in medical education: a cross-sectional study

• Chen-xi Zhao 1   na1 ,
• Zi-jiao Wang 2   na1 ,
• Xiao-jing Yang 2 ,
• Xing Ma 3 ,
• Ying Cui 1 ,
• Yan-xin Zhang 1 ,
• Xin-hui Cheng 1 ,
• Shu-e Zhang 2   na2 ,
• Qing-feng Guo 1   na2 &
• De-pin Cao 2   na2  

BMC Medical Education volume  24 , Article number:  386 ( 2024 ) Cite this article

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Medical students face a heavy burden as they are tasked with acquiring a vast amount of medical knowledge within a limited time frame. Self-directed learning (SDL) has become crucial for efficient and ongoing learning among medical students. However, effective ways to foster SDL ability among Chinese medical students are lacking, and limited studies have identified factors that impact the SDL ability of medical students. This makes it challenging for educators to develop targeted strategies to improve students’ SDL ability. This study aims to assess SDL ability among Chinese medical students and examine the effects of career calling and teaching competencies on SDL ability, as well as the possible mechanisms linking them.

Data were collected from 3614 respondents (effective response rate = 60.11%) using cross-sectional online questionnaires and analyzed using IBM SPSS Statistics 22.0. The questionnaire comprised a Demographic Characteristics Questionnaire, Self-directed Learning Ability Scale (Cronbach’s alpha = 0.962), Teaching Competencies Scale, and Career Calling Scale.

The average SDL ability score of Chinese medical students was 3.68 ± 0.56, indicating a moderate level of SDL ability. The six factors of the Self-directed Learning Ability Scale—self-reflection, ability to use learning methods, ability to set study plans, ability to set studying objectives, ability to adjust psychological state, and willpower in studying—accounted for 12.90%, 12.89%, 12.39%, 11.94%, 11.34%, and 8.67% of the variance, respectively. Furthermore, career calling was positively associated with SDL learning ability ( β  = 0.295, p  < 0.001), and SDL learning ability was positively associated with teaching competencies ( β  = 0.191, p  < 0.01). Simple slope analysis showed that when the level of teaching competencies was higher, the influence of career calling on SDL ability was stronger.

Conclusions

Chinese medical students’ SDL ability has room for improvement. Medical students could strengthen their willpower in studying by setting milestones goals with rewards, which could inspire their motivation for the next goals. Teachers should guide students to learn experience to improve students’ reflective ability. Educators play a crucial role in bridging the gap between career calling education and SDL ability enhancement, highlighting the significance of optimal teaching competencies. Colleges should focus on strengthening teachers’ sense of career calling and teaching competencies.

Peer Review reports

Medical education functions in a highly dynamic environment [ 1 ]. Both during their time in college and in their future professional careers, medical students need to continually update their medical knowledge to maintain their clinical skills [ 2 ]. They are required to acquire more information than students of other subjects and expected to develop a lifelong learning ability [ 3 ]. However, the overwhelming volume of medical information [ 4 ], extensive literature [ 5 ], and limited time [ 6 ] impose a huge burden on medical students. In the face of these challenges and the evolving nature of medical education, it has become an urgent challenge for educators to help develop efficient and ongoing self-directed learning (SDL) abilities among medical students.

After Malcolm Knowles first introduced the concept of SDL, several scholars understood that SDL would significantly advance medical students’ careers [ 5 , 6 , 7 , 8 ]. Since then, educators have increasingly focused on medical students’ abilities to effectively plan their time and acquire the necessary professional skills for their future careers. Holec deeply studied the concept of SDL ability, considering it the capability to take responsibility for one’s learning [ 9 ], including setting learning objectives, deciding on learning content and pace, choosing learning methods and technologies, monitoring learning progress, and evaluating learning outcomes. SDL has gradually become an indispensable competency for medical students [ 10 ], helping them stay abreast of the latest medical advancements [ 11 ]. Without a sense of SDL for academic learning, medical students may struggle to meet professional demands in the present and future [ 12 ]. Therefore, it is critical to integrate a sense of SDL into daily life to adequately prepare medical students for their careers.

Nevertheless, many medical students struggle with effective time management [ 13 ]. Due to the traditional exam-oriented education system in China, some Chinese medical students, accustomed to acquiring knowledge from teachers, remain passive learners with limited learning activity [ 14 , 15 ]. These students may not have the ability to learn independently when faced with problems [ 16 ] and may lack a sense of learning consciousness [ 17 ], ultimately lagging behind the pace of medical development. This is a significant problem that could affect the quality of medical services in China in the coming years. To become outstanding medical practitioners, Chinese medical students must urgently enhance their SDL ability. Fostering an adaptive and sustainable SDL ability among Chinese medical students is an imminent requirement that medical educators must address.

Before proposing appropriate strategies to enhance this ability, it is imperative to evaluate the current SDL ability of Chinese medical students. However, after reviewing the literature, we found minimal research on measuring the current level of SDL ability among medical students. Therefore, we required a suitable tool to assess the current SDL ability of Chinese medical students and identify effective strategies to enhance it. Based on previous literature, this study explored two factors that may have a significant influence on Chinese medical students: career calling [ 18 , 19 ], and teaching competencies [ 20 , 21 ].

In recent years, there has been an increasing focus on medical practitioners’ career calling. Scholars have defined career calling as a subjective experience in which individuals are determined to work voluntarily and positively [ 22 ], indicating a passion or drive toward working in a particular field [ 23 ]. Bunderson noted that when individuals strongly identify with their jobs, they tend to focus all their attention on work [ 24 ]. Moreover, a high level of career calling is related to positive emotions [ 25 ], and this active feeling can lead to proactive behaviors [ 26 ]. In essence, career calling can maintain the passion of medical students for learning, encouraging them to actively plan and conduct their studies [ 27 ]. Can it be extrapolated that the higher the career calling of a Chinese medical student, the better their SDL ability? Based on these predictions, career calling may serve as a protective factor in fostering SDL ability. Therefore, this study aimed to explore the relationship between career calling and SDL ability, along with constructive factors to mobilize SDL ability.

Teaching philosophy reflects an individual’s beliefs and values about teaching and learning. It discusses the self-identity of teachers and how they educate others [ 28 ]. Thus, teachers can play the role of a bridge between career calling education and medical students’ learning. Teachers with strong beliefs and values related to career calling may influence students in a subtle way. Thus, it is important to focus on teachers’ teaching capacity. Studies have defined teaching competencies as comprising teachers’ personal characteristics, knowledge, skills, and attitudes required in various teaching environments [ 29 ]. Teachers with appropriate characteristics that align with educational requirements can benefit students’ academic achievements [ 30 ]. Deep subject knowledge can also improve students’ grades [ 31 ], while good teaching skills can direct students’ focus toward learning [ 32 ]. Additionally, positive attitudes toward teaching can promote students’ positive attitudes [ 33 ]. Overall, teachers’ teaching competencies influence students’ learning and academic achievements and are highly significant for nurturing future talents. Therefore, this study posits that teaching competencies play a positive moderating role between Chinese medical students’ career calling and SDL ability. In practical teaching, teachers’ teaching competencies directly impact students, who observe and judge these competencies more objectively and comprehensively. To better evaluate teaching competencies, this study used “students’ perception of their teachers’ competencies in teaching” as an evaluation method.

This study aimed to measure Chinese students’ SDL ability level and explore the correlations among career calling, teaching competencies, and SDL ability. To accomplish these aims, we proposed the following two hypotheses:

Hypothesis 1

Career calling is positively associated with SDL ability among Chinese medical students.

Hypothesis 2

Teaching competencies positively moderate the relationship between career calling and SDL ability among Chinese medical students.

Ethics statement

The procedures of this study adhered to the guidelines of the Declaration of Helsinki and were reviewed and approved by the Ethics Committee of the Institutional Review Board of Harbin Medical University(ECHMU: HMU202072). Each participant provided written online informed consent before participating in this study. All data collected from the participants were kept anonymous and confidential to protect their privacy.

Survey design and data collection

Initially, according to the calculation method and standard requirements for the cross-sectional sample size based on Zhou et al. [ 34 ], the minimum sample size for this study was calculated to be 1824. Considering a minimum response rate of approximately 40% based on previous online survey experience, the sample size was expanded to 4560. To further ensure data quality, we determined the final number of respondents to be 6000.

After determining the sample size, six medical universities were selected based on their size, academic programs, research performance, admission scores, and number of students. Different specialties and grades were then randomly selected in each university. These universities are located in Nanjing, Guangzhou, Dalian, Harbin, Mudanjiang, and Daqing.

To ensure the cost-effectiveness, time-effectiveness, and accessibility of the study [ 35 ], a cross-sectional anonymous online survey was conducted using a multistage stratified convenient sampling method to collect data from medical students from July to September 2021. Based on the characteristics of medical students, we used a multi-staged stratified convenient sampling method, with quotas allocated by the division of students’ years and majors. First, we grouped medical students according to their majors. Next, we further divided these groups into smaller groups based on their years. Finally, we distributed questionnaires and received responses in accordance with the predetermined quantity. The survey was conducted through the online survey platform “Questionnaire Star.” The researchers monitored the collected questionnaires in real-time through the platform and used it to effectively manage the data.

Data quality control

Data quality is key to ensuring the reliability and validity of a study. In this study, a data quality control process was implemented in three stages: questionnaire design, survey administration, and data processing.

Questionnaire design

The questionnaire included three “seriousness test questions” placed at the beginning, middle, and end. These questions prompted respondents to select specific answers to test their seriousness [ 36 ]. Additionally, a “self-evaluation question of answer quality” was included at the end of the questionnaire for respondents to evaluate the quality of the questionnaire. Each participant was allowed to respond only once.

Survey administration

One or two research leaders were selected from each university to conduct an “accurate survey” of the target participants. This ensured that all the questionnaires were completed by the target groups.

Data processing

During data processing, strict data screening criteria were applied. Responses with incorrect selections to any of the “seriousness test questions” were deleted. Respondents who took less than three hundred seconds to complete the questionnaire were considered “speeders,” and their questionnaires were deleted. Questionnaires that participants suggested deleting were also excluded. Finally, each remaining questionnaire was reviewed by the authors, and those with an irregular distribution of answers were deleted.

Study instruments

A Demographic Characteristics Questionnaire, Self-directed Learning Ability Scale, Teaching Competencies Scale, and Career Calling Scale were used. Permissions were obtained for using the Teaching Competencies Scale and the Career Calling Scale.

Measurement of demographic characteristics

Eight demographic information was collected using a self-designed questionnaire: gender, grade, major, experience of leadership, hometown, monthly living expenses, parenting style, and education level of parents. Student grade was collected as a continuous variable ranging from 1 to 5. The majors of students were categorized into eight groups: “basic medical science,” “clinical medicine,” “stomatology,” “public health,” “pharmacy,” “medical technology,” “nursing,” and “others.” Leadership experience was divided into “student leaders” and “ordinary students.” Students’ hometowns were categorized as “rural” or “urban.” The monthly living expenses of students were categorized into four groups: RMB “0  ∼  1000”, “1000  ∼  1500”, “1500  ∼  2000,” and “2000 and above”. Parenting style was divided into four categories: “neglecting,” “permissive,” “authoritarian,” and “authoritative.” The education level of parents was categorized as “primary school or below,” “junior middle school,” “high school,” “junior college,” or “bachelor’s degree or above.”

Measurement of SDL ability

According to the definition of SDL ability in previous studies [ 37 , 38 ], SDL ability was divided into six dimensions: ability to set studying objectives, willpower in studying, ability to set study plans, ability to use learning methods, ability to adjust psychological state, and ability to self-reflect. A 28-item instrument designed by the authors was used to measure SDL ability level. In a previously published article, the self-designed SDL ability scale was tested and implemented [ 39 ]. To ensure the applicability of the scale, a pre-survey was conducted with 454 students, which showed good reliability and validity. Items were scored on a 5-point Likert scale ranging from 1 “totally inconsistent” to 5 “totally consistent,” with higher scores representing a higher degree of SDL ability.

Measurement of teaching competencies

The teaching competencies of the teachers were assessed using a 5-item Teaching Competencies Scale, a questionnaire developed for German students by Thomas and Müller [ 40 ]. Items were scored on a 5-point Likert scale ranging from 1 “totally not in line with” to 5 “fully in line with,” with higher scores indicating a higher level of teachers’ teaching competencies. The cross-cultural adaptation of the scale into Chinese included performing forward and backward translations, with an assessment of its cultural equivalence and clarity. High reliability was demonstrated in the reliability analysis, with a Cronbach’s α-coefficient of 0.943 for the scale in this study.

Measurement of career calling

Medical students’ career calling level was assessed using the 4-item Career Calling Scale revised by Dik et al. [ 41 ]. The scale has been cross-culturally adapted and verified in other studies in China [ 42 , 43 ]. Items were scored on a 5-point Likert scale ranging from 1 “never” to 5 “every day,” with higher scores indicating a higher degree of career calling. Cronbach’s α-coefficient for the Career Calling Scale in this study was 0.843.

Statistical analysis

This study utilized Amos version 24.0 software and SPSS version 22.0 for statistical analysis, and a two-tailed p  < 0.05 was considered statistically significant. We assessed the suitability of the data for factor analysis by conducting the Kaiser–Meyer–Olkin (KMO) measure of sampling adequacy and Bartlett’s χ [ 2 ] test of sphericity. Subsequently, exploratory factor analysis (EFA) was conducted to explore the causal structure. We employed the principal component analysis (PCA) and varimax-rotation method to extract six factors, removing items with factor loadings lower than 0.4.

Confirmatory factor analysis (CFA) with maximum likelihood was used to validate the factor structure of the Self-directed Learning Ability Scale. Various indexes were used to assess model fit, including root mean square error of approximation (RMSEA), goodness-of-fit index (GFI), adjusted goodness-of-fit index (AGFI), and normed fit index (NFI), among others. The normed chi-square ( χ [ 2 ]) and goodness-of-fit test ( χ 2 /df ) were used to evaluate the null hypothesis that the model fits the data. However, achieving this in large sample sizes can be challenging, so we utilized the aforementioned indexes as criteria for our analysis. Cronbach’s alpha coefficient was used to measure the reliability of our instrument.

We used descriptive statistics and frequencies to analyze the demographic variables and total scores of the three scales. SDL ability scores across different demographic categories were examined using independent samples t -test or one-way ANOVA. In cases where one-way ANOVAs were found to be significant, we conducted least-significant-difference (LSD) tests for multiple comparisons. Pearson correlation analysis was used to examine correlations among SDL ability, teaching competencies, and career calling. Hierarchical multiple regression analysis was employed to test the moderating effect of teaching competencies on the relationship between career calling and SDL ability. All variables related to SDL ability in univariate analysis ( p  < 0.05) were included in the hierarchical multiple regression model. We performed the model estimation using PROCESS, a convenient, free, and easy-to-use computational add-on for SPSS documented by Hayes [ 44 ]. Before conducting the regression analysis for moderating effects, we employed mean centering (subtracting raw scores from the mean) to mitigate multicollinearity.

Results of EFA, CFA, and reliability

A total of 6012 students were invited to participate in this study. Of these, 3614 questionnaires were completed and passed the quality control procedure, yielding a response rate of 60.11%. Results from both KMO and Bartlett’s tests demonstrated that the samples met the criteria for factor analysis criteria, with a KMO measure of sampling adequacy of 0.975.

The six-factor model explained 70.12% of the variance, with each factor contributing as follows: ability to self-reflect (12.90%), ability to use learning methods (12.89%), ability to set study plans (12.39%), ability to set studying objectives (11.94%), ability to adjust psychological state (11.34%), and willpower in studying (8.67%). The pattern and structures of the rotated common factors are shown in Table  1 .

The results of the CFA are presented in Table  2 . The model fit the data reasonably well, with GFI, AGFI, NFI, and RMSEA all indicating a good fit. While the χ 2 /df was slightly higher than ideal, it is considered acceptable in large sample sizes [ 45 ]. The path diagram with standardized parameter estimates is shown in Fig.  1 .

Path diagram for the model with standardized parameter estimates

In this study, Cronbach’s alpha coefficients were used to assess the internal reliability of the instrument. The Cronbach’s alpha coefficient for the total score was 0.962. The alphas for the sub-scales of ability to set studying objectives, willpower in studying, ability to set study plans, ability to use learning methods, ability to adjust psychological state, and ability to self-reflect were 0.88, 0.84, 0.89, 0.87, 0.90, and 0.89, respectively.

Current SDL ability level among Chinese medical students

The results indicated that the SDL ability among Chinese medical students was at a moderate level ( M  = 3.68, SD  = 0.56). The scores for specific aspects of SDL ability, from highest to lowest, included the ability to set studying objectives ( M  = 3.88, SD  = 0.68), ability to use learning methods ( M  = 3.81, SD  = 0.61), ability to set study plans ( M  = 3.71, SD  = 0.65), ability to adjust psychological state ( M  = 3.61, SD  = 0.70), willpower in studying ( M  = 3.56, SD  = 0.65), and ability to self-reflect ( M  = 3.52, SD  = 0.70), as presented in Table  3 ; Fig.  2 .

Radar chart of SDL ability among chinese medical students

Difference in SDL ability based on participant characteristics

Significant differences were observed in SDL ability scores depending on students’ demographics, including gender, grade, major, experience of leadership, hometown, monthly living expenses, parenting style, and education level of parents. Details of the scores under different demographic characteristics and LSD test results are detailed in Table  4 . The demographic breakdown of participants indicated that 74.41% were women and 25.59% were men. Regarding grades, the majority were freshmen (56.79%), followed by sophomores (18.26%). In terms of majors, 4.10% were in basic medicine, 34.26% in clinical medicine, 6.34% in stomatology, 4.73% in public health and preventive medicine, 15.55% in pharmacy, 11.73% in medical technology, 14.78% in nursing, and 8.52% in other majors. Over half of the participants (53.90%) had experience as student leaders. Regarding hometowns, 55.76% were registered as urban residents, while the rest were from rural areas. In addition, 45.63% of students reported monthly living expenses between 1000  ∼  1500 RMB. Regarding parenting types, the majority of students (61.23%) reported experiencing permissive parenting. Finally, the education levels of the participants’ parents varied as follows: primary school or below (5.67%), junior middle school (32.57%), high school (28.17%), junior college (12.04%), and bachelor’s degree or above (21.56%).

Correlations among continuous variables

Table  5 presents the correlations among SDL ability, teaching competencies, and career calling. The three variables were found to be significantly correlated with each other. The level of SDL ability was positively correlated with career calling and teaching competencies. Career calling was positively correlated with teaching competencies. Therefore, Hypothesis 1 was supported.

Career calling, Teaching competencies, and SDL ability

Following the suggestions by Aiken and West [ 46 ], the data were centered (by subtracting the average value), indicating that teaching competencies significantly moderated the association between career calling and SDL ability, as shown in Table  6 ; Fig.  3 . Therefore, Hypothesis 2 was confirmed, suggesting that teaching competencies positively moderated the relationship between career calling and SDL ability among Chinese medical students.

Moderated effect of teaching competencies on the association between career calling and SDL ability

SDL ability among Chinese medical students

This study investigated the level of SDL ability in Chinese medical students. The results derived from this study indicate that the instrument measuring SDL ability had high reliability and validity, with Cronbach’s α exceeding 0.90 and the designed six-factor structure confirmed by CFA. The standardized factor loading coefficient of the items and the cumulative variance contribution rate also confirmed the reliability and validity of the instrument. In summary, the instrument appears to be appropriate for the assessment of SDL ability among Chinese medical students.

The mean score of SDL ability among surveyed medical students was 3.68 ± 0.56 (Mean  ±  SD ). Similar results were found by Yang et al. [ 47 ], suggesting that the SDL ability of Chinese medical students is at a moderate level. Among demographic characteristics, gender, grade, major, experience of leadership, hometown, monthly living expenses, parenting style, and education level of parents were found to have an impact on the SDL ability of Chinese medical students.

The results of the scoring order of SDL ability in each dimension indicate that Chinese medical students can actively set studying objectives and plans, and are able to use learning methods correctly. However, in the process of SDL, the ability to adjust psychological state, willpower in studying, and ability to self-reflect were relatively low. This indicates that students’ executive ability and reflective ability were poor, affecting the effectiveness of SDL, or even making the study plan formalistic. Scholars have found that students may be disturbed by minor distractions before fully engaging in the learning process, leading to potential disruptions in their ability to execute their learning goals, even when they have meticulously planned their studying routines in advance [ 48 ]. Medical students could add milestones achievement rewards to their study plans. The sense of achievement gained from completing small milestones of learning goals could inspire medical students to move on to the next goal, and thus enhance their willpower to learn. Additionally, studies have pointed out that students may face challenges in describing the influence without drawing lessons from experience [ 49 ]; such reflection may be ineffective. In this context, teachers could guide medical students to delve deeply into their experiences hidden behind various events, thereby improving their reflective ability.

Career calling and its positive association with SDL ability among Chinese medical students

The findings of this study confirm that career calling can positively affect SDL ability among Chinese medical students. This result is similar to Lang’s findings, which suggest that students with a strong career calling or a steadfast commitment to their professions tend to have higher levels of energy and a greater sense of control over their professional success [ 50 ]. For medical students, a stronger sense of career calling is associated with a greater SDL ability. Chinese medical students’ societal value is closely tied to their academic skills. Additionally, the medical industry requires its workers to cultivate the capacity for lifelong learning to keep up with the latest developments [ 51 ]. In essence, Chinese medical students must continue learning on the job to maintain their societal value and status. Therefore, Chinese medical students are encouraged to develop SDL abilities during their undergraduate education to become qualified medical practitioners and smoothly transition into formal work.

It is therefore crucial for medical universities to devote sufficient effort to developing medical students’ sense of career calling during higher education. Chinese medical universities could implement a series of curriculum changes focused on the missions of the medical profession, aiming to enhance students’ sense of responsibility and morality, which in turn would promote self-regulation in learning. By using real-life cases to highlight the responsibilities that medical practitioners bear concerning human life, Chinese medical universities can help students cultivate a noble sense of career calling. This can motivate students to invest more energy and time in academic learning, leading to higher academic achievements through enhanced SDL abilities.

Moderating role of teaching competencies in the positive association between career calling and SDL ability among Chinese medical students

This study provides evidence that teaching competencies can play a positive moderating role between Chinese medical students’ career calling and SDL ability. Strong teaching competencies can capture students’ attention during lectures. For instance, medical teachers can use engaging teaching techniques to make the transfer of seemingly dull knowledge interesting and memorable. Teaching competencies, such as a passionate teaching attitude, can inspire students to unlock their learning potential [ 52 ]. Accordingly, when students’ learning potential is unleashed, teachers’ strong teaching competencies, coupled with a broad knowledge base, can cater to students’ academic curiosities. This mutual relationship can stimulate students’ interest, leading them to immerse themselves in learning and create a virtuous cycle. As a result, Chinese medical students may recognize the significance of SDL and proactively improve their SDL ability.

The path to a medical professional learning career is undoubtedly challenging and lengthy, but it should not lack academic assistance and motivation. Properly combining extrinsic teaching competencies with intrinsic career calling can provide the physical and psychological energy needed for medical students to advance further. Therefore, from the perspective of medical colleges, addressing how to improve medical teachers’ teaching competencies seems to be an urgent issue. Medical colleges could design questionnaires to evaluate existing teaching competencies and gather feedback from students to target improvements in teachers’ teaching competencies. Moreover, colleges could invite teachers from other disciplines to deliver lectures and provide training for medical teachers, as few medical teachers have received systematic educational training and may lack knowledge in educational theory and practice [ 53 ]. Enhancing teaching competencies is an ongoing endeavor, but it can greatly assist Chinese medical students in improving their SDL abilities and optimizing the quality of education.

Limitations

Although the present study reveals important findings, it has some limitations. First, the data collected are cross-sectional, indicating that establishing causal relationships among the factors was not possible. Second, considering that each medical college has its own unique circumstances and our sample did not include all medical students in China, the generalizability of the results may be limited. Third, the questionnaires were collected online, which may have introduced response bias and made it challenging to control data quality. In future studies, scholars could consider researching a wider and more diverse sample through face-to-face investigations to address these limitations.

This study displayed the research and development process of the SDL ability and verified the reliability and validity of the SDL ability scale for 6 factor 28 items once again. We found that Chinese medical students’ SDL ability is at a moderate level, suggesting room for improvement. We also identified eight demographic factors that influence Chinese medical students’ SDL ability and explored the relationships among career calling, teaching competencies, and SDL ability. Both career calling and teaching competencies were found to be effective factors that can strengthen Chinese medical students’ SDL ability.

Data availability

The datasets used and/or analyzed during this study are available from the corresponding authors on reasonable request [email protected].

Abbreviations

Self-directed learning

Kaiser–Meyer–Olkin

Exploratory factor analysis

Principal component analysis

Confirmatory factor analysis

Root mean square error of approximation

Goodness-of-fit index

Adjusted goodness-of-fit index

Normed fit index

Least-significant-difference

van Woezik TE, Koksma JJ-J, Reuzel RP, et al. There is more than ‘I’in self-directed learning: an exploration of self-directed learning in teams of undergraduate students. Med Teach. 2021;43(5):590–98. https://doi.org/10.1080/0142159X.2021.1885637 .

Article   Google Scholar  

Hill M, Peters M, Salvaggio M, et al. Implementation and evaluation of a self-directed learning activity for first-year medical students. Med Educ Online. 2020;25(1):1717780. https://doi.org/10.1080/10872981.2020.1717780 .

Ramamurthy S, Er HM, Devi Nadarajah V, et al. Medical students’ orientation toward lifelong learning in an outcome-based curriculum and the lessons learnt. Med Teach. 2021;43(sup1):S6–11. https://doi.org/10.1080/0142159X.2019.1646894 .

Sohail N. Stress and academic performance among medical students. J Coll Physicians Surg Pak. 2013;23(1):67–71.

Google Scholar  

Murad MH, Varkey P. Self-directed learning in health professions education. Annals Acad Med Singap. 2008;37(7):580.

Karakose T. The relationship between medical students’ time management skills and academic achievement. Stud Ethno-Medicine. 2015;9(1):19–24.

Liu T-H, Sullivan AM. A story half told: a qualitative study of medical students’ self-directed learning in the clinical setting. BMC Med Educ. 2021;21(1):1–11. https://doi.org/10.1186/s12909-021-02913-3 .

Greveson G, Spencer J. Self-directed learning–the importance of concepts and contexts. Wiley Online Library; 2005. pp. 348–49.

Holek H. Autonomy and foreign language learning. xford. 1981.

Ricotta DN, Richards JB, Atkins KM, et al. Self-directed learning in medical education: training for a lifetime of discovery. Teach Learn Med. 2022;34(5):530–40. https://doi.org/10.1080/10401334.2021.1938074 .

Morris TH. Self-directed learning: a fundamental competence in a rapidly changing world. Int Rev Educ. 2019;65(4):633–53. https://doi.org/10.1007/s11159-019-09793-2 .

Kemp K, Baxa D, Cortes C. Exploration of a collaborative self-directed learning model in medical education. Med Sci Educ. 2022;32(1):195–207. https://doi.org/10.1007/s40670-021-01493-7 .

Tewari S. Exploring the Time Management skills among First-Year Medical undergraduates: an early sensitization. Int J Life Sci Biotechnol Pharma Res 2023.

chunyan W, Jingwei C, Fei W, et al. Discussion on Teaching Mode of cultivating critical thinking of medical students. China Continuing Med Educ. 2023;15(10):37–41.

Current situation on exam-oriented education in. China and the outlook for quality-oriented education. 2021 3rd International Conference on Literature, Art and Human Development (ICLAHD 2021); 2021. Atlantis Press.

An overview on the impact of the exam-oriented education in China. SHS Web of Conferences. 2023. EDP Sciences.

Comparative Analysis on Contemporary Exam-oriented Education in Colleges and Universities in China and Western Liberal Educational Model. 2016 4th International Education, Economics, Social Science, Arts, Sports and Management Engineering Conference (IEESASM 2016); 2016. Atlantis Press.

Chen J, Zhang X. The impact of career calling on higher vocational nursing students’ learning engagement: the mediating roles of career adaptability and career commitment. Front Psychol. 2023;14:1111842. https://doi.org/10.3389/fpsyg.2023.1111842 .

Wang Y, Zhou Y, Li T, et al. A cross-sectional study in college‐based nursing education: the influence of core self‐evaluation and career calling on study engagement in nursing undergraduates. Nurs Open. 2023;10(6):3561–69. https://doi.org/10.1002/nop2.1598 .

Analysis on Teaching Competence of Clinical Teachers in Applied Undergraduate Medical Colleges. 2019 International Conference on Advanced Education, Service and Management; 2019. The Academy of Engineering and Education.

Ren R, Chen G, Yan J, et al. Development and validation of a core competence instrument for clinical nursing teachers: a mixed-methods study. Nurse Educ Today. 2024;132:106011. https://doi.org/10.1016/j.nedt.2023.106011 .

Yang C, Chen A. The double-edged sword effects of career calling on occupational embeddedness: mediating roles of work–family conflict and career adaptability. Asian Nurs Res. 2020;14(5):338–44. https://doi.org/10.1016/j.anr.2020.09.005 .

Dobrow SR, Tosti-Kharas J, Calling. The development of a scale measure. Pers Psychol. 2011;64(4):1001–49. https://doi.org/10.1111/j.1744-6570.2011.01234.x .

Bunderson JS, Thompson JA. The call of the wild: zookeepers, callings, and the double-edged sword of deeply meaningful work. Adm Sci Q. 2009;54(1):32–57. https://doi.org/10.2189/asqu.2009.54.1.32 .

Duffy RD, Dik BJ, Douglass RP, et al. Work as a calling: a theoretical model. J Couns Psychol. 2018;65(4):423. https://doi.org/10.1037/cou0000276 .

Den Hartog DN, Belschak FD. Personal initiative, commitment and affect at work. J Occup Organizational Psychol. 2007;80(4):601–22. https://doi.org/10.1348/096317906X171442 .

Bonvin S, Stiefel F, Gholam M, et al. Calling situated: a survey among medical students supplemented by a qualitative study and a comparison with a surveyed sample of physicians. BMC Med Educ. 2022;22(1):619. https://doi.org/10.1186/s12909-022-03642-x .

Bowne M. Developing a teaching philosophy. J Effective Teach. 2017;17(3):59–63.

Tigelaar DE, Dolmans DH, Wolfhagen IH, et al. The development and validation of a framework for teaching competencies in higher education. High Educ. 2004;48:253–68. https://doi.org/10.1023/B:HIGH.0000034318.74275.e4 .

Armstrong P. Teacher characteristics and student performance: an analysis using hierarchical linear modelling. South Afr J Child Educ. 2015;5(2):123–45.

Metzler J, Woessmann L. The impact of teacher subject knowledge on student achievement: evidence from within-teacher within-student variation. J Dev Econ. 2012;99(2):486–96. https://doi.org/10.1016/j.jdeveco.2012.06.002 .

Gultom S, Hutauruk AF, Ginting AM. Teaching skills of teacher in increasing student learning interest. Budapest Int Res Critics Inst (BIRCI-Journal): Humanit Social Sci. 2020;3(3):1564–69. https://doi.org/10.33258/BIRCI.V3I3.1086 .

Mensah J, Okyere M, Kuranchie A. Student attitude towards mathematics and performance: does the teacher attitude matter. J Educ Pract. 2013;4(3):132–39.

Zhou X, Liao X, Spiegelman D. Cross-sectional stepped wedge designs always reduce the required sample size when there is no time effect. J Clin Epidemiol. 2017;83:108–09. https://doi.org/10.1016/j.jclinepi.2016.12.011 .

Chang T-ZD, Vowles N. Strategies for improving data reliability for online surveys: a case study. Int J Electron Commer Stud. 2013;4(1):121–30. https://doi.org/10.7903/ijecs.1121 .

Yu F, Hu H, Du S. A study of data quality control in web-based questionnaires. Statistics and decision-making 2019;35(16):10–14. https://doi.org/10.13546/j.cnki.tjyjc.2019.16.002 .

Zimmerman BJ. A social cognitive view of self-regulated academic learning. J Educ Psychol. 1989;81(3):329. https://doi.org/10.1037/0022-0663.81.3.329 .

Weiguo P. On students’ independent learning. J East China Normal Univ (Education Sci Edition). 2001;0278–83. https://doi.org/10.16382/j.cnki.1000-5560.2001.02.009 .

Zhang H, Zhao C, Zhang S, et al. A quantitative study of influencing factors of self-directed learning ability in medical undergraduates in China. Chin J Med Educ. 2023;43(12):902–06. https://doi.org/10.3760/cma.j.cn115259-20221130-01504 .

Thomas AE, Müller FH. Skalen Zur Motivationalen Regulation Beim Lernen Von Schülerinnen Und Schülern. Wissenschaftliche Beiträge aus dem Inst für Unterrichts-und Schulentwicklung (IUS) 2011;5.

Dik BJ, Eldridge BM, Steger MF, et al. Development and validation of the calling and vocation questionnaire (CVQ) and brief calling scale (BCS). J Career Assess. 2012;20(3):242–63. https://doi.org/10.1177/1069072711434410 .

Duan W, Tang X, Li Y, et al. Perceived organizational support and employee creativity: the mediation role of calling. Creativity Res J. 2020;32(4):403–11. https://doi.org/10.1080/10400419.2020.1821563 .

Zhang Z, Zhang Y, Jia M. Does a sense of calling facilitate sustainability? Research on the influence of calling on employee green behavior. Bus Strategy Environ. 2021;30(7):3145–59. https://doi.org/10.1002/bse.2795 .

Hayes AF. Introduction to mediation, moderation, and conditional process analysis: A regression-based approach: Guilford publications 2017.

Zhonglin Wen J, Hou M. Structural equation model testing: cutoff criteria for goodness of fit indices and Chi-square test. Psychol Dly 2004(02):186–94.

Aiken L. Multiple regression: testing and interpreting interactions. Sage Publications Google Schola. 1991;2:513–31.

Yang C, Zhu Y, Jiang H, et al. Influencing factors of self-directed learning abilities of medical students of mainland China: a cross-sectional study. BMJ open. 2021;11(10):e051590. https://doi.org/10.1136/bmjopen-2021-051590 .

Rabin LA, Fogel J, Nutter-Upham KE. Academic procrastination in college students: the role of self-reported executive function. J Clin Exp Neuropsychol. 2011;33(3):344–57. https://doi.org/10.1080/13803395.2010.518597 .

Su Y. An investigation into the contents and aspects of college students’ reflective thoughts during field experience. Innovations Educ Teach Int. 2015;52(3):322–34. https://doi.org/10.1080/14703297.2014.880364 .

Lang A. Analysis of burnout and career calling in undergraduate pre-medical students. J Interdisciplinary Undergrad Res. 2019;11(1):1.

Berkhout JJ, Helmich E, Teunissen PW, et al. Context matters when striving to promote active and lifelong learning in medical education. Med Educ. 2018;52(1):34–44. https://doi.org/10.1111/medu.13463 .

Mart CT. A passionate teacher: teacher commitment and dedication to student learning. Int J Acad Res Progressive Educ Dev. 2013;2(1):437–42.

Oliveira Td M, RLSFMd, Pires MPB, et al. Pedagogical Preparation for Physicians and their performance in the Medical Course. Revista Brasileira De Educação Médica. 2018;42:171–77. https://doi.org/10.1590/1981-52712015v42n3RB2017066.r2ING .

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Acknowledgements

The authors sincerely thank all participants who contributed to this study, particularly those who helped in collecting data, distributing questionnaires, and participating in our research. We would like to thank Editage ( www.editage.cn ) for English language editing.

This study was supported as the key commissioned project of the Higher Education Teaching Reform of Heilongjiang Province in 2022 (SJGZ20220070). The study was also part of a project of Chinese Medical Education on the mechanisms of influence of medical students’ professional cognition on learning motivation research (2023B088).

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Chen-xi Zhao and Zi-jiao Wang have contributed equally to this work.

Shu-e Zhang, Qing-feng Guo and De-pin Cao have contributed equally to this work.

Authors and Affiliations

Academic Affairs Office, First Affiliated Hospital of Harbin Medical University, 150001, Harbin, China

Chen-xi Zhao, Ying Cui, Yan-xin Zhang, Xin-hui Cheng & Qing-feng Guo

Department of Health Management, School of Health Management, Harbin Medical University, 150081, Harbin, China

Zi-jiao Wang, Xiao-jing Yang, Shu-e Zhang & De-pin Cao

Center for the Evaluation of Higher Education Teaching and Learning of Harbin Medical University, 150081, Harbin, China

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Conceptualization, Shu-e Zhang, Qing-feng Guo and De-pin Cao; Data curation, Xing Ma; Formal analysis, Ying Cui; Funding acquisition, Qing-feng Guo; Investigation, Chen-xi Zhao, Zi-jiao Wang, Xiao-jing Yang and Yan-xin Zhang; Methodology, Chen-xi Zhao and Zi-jiao Wang; Project administration, Xiao-jing Yang; Resources, Chen-xi Zhao; Software, Xin-hui Cheng; Supervision, De-pin Cao and Shu-e Zhang; Visualization, Chen-xi Zhao and Zi-jiao Wang; Writing– original draft, Chen-xi Zhao, Zi-jiao Wang and Xiao-jing Yang; Writing– review & editing, Xing Ma, Ying Cui, Yan-xin Zhang, Xin-hui Cheng.

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Correspondence to Shu-e Zhang , Qing-feng Guo or De-pin Cao .

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This study adhered to the guidelines of the Declaration of Helsinki and was reviewed and approved by the Ethics Committee of the Institutional Review Board of Harbin Medical University(ECHMU: HMU202072). Due to the online survey approach, the written informed consent could not be received. Therefore, verbal informed consent for survey was approved by the Ethics Committee of the Institutional Review Board of Harbin Medical University and obtained from each participate.

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Zhao, Cx., Wang, Zj., Yang, Xj. et al. Promotion of self-directed learning abilities among Chinese medical students through preparing for career calling and enhancing teaching competencies in medical education: a cross-sectional study. BMC Med Educ 24 , 386 (2024). https://doi.org/10.1186/s12909-024-05330-4

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• Self-directed learning ability
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Post-industrial countries with high rates of female labour force participation have generally had low fertility rates, but recent studies demonstrate that this is no longer the case. This has generated increased attention to how greater gender equality in the private sphere of the household may contribute to a positive relationship between women’s employment rates and fertility. Building on recent scholarship demonstrating the multidimensionality of gender-role attitudes, we argue that conversely, the prevalence of a gender-role ideology that supports women’s employment but places greater priority on their role as caregivers may depress the higher-order fertility intentions of working mothers. Using data from 25 European countries, we find that this type of gender-role ideology (egalitarian familism) moderates the relationship between mothers’ full-time employment and their intention to have a second child. This holds even after accounting for key features of the policy environment that are likely to mitigate work–family conflict. The analysis suggests that conflicting normative expectations for women’s work and family roles tend to dampen working mothers’ second-order fertility intentions, independent of work–family reconciliation policies.

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Investigating the role of VDR gene variants in multiple sclerosis susceptibility: a case–control study in Egypt

• Hala Ashraf Hosni   ORCID: orcid.org/0009-0008-3550-9313 1 ,
• Amr Mohamed Fouad 2 ,
• Noha Wael Ibrahim 1 &
• Sahar Abd El-Atty Sharaf 1  

The Egyptian Journal of Neurology, Psychiatry and Neurosurgery volume  60 , Article number:  51 ( 2024 ) Cite this article

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Multiple sclerosis (MS) is a chronic inflammatory disorder. Vitamin D has a major role in preventing inflammatory disorders as well as its role in the pathophysiology of MS. Vitamin D initiates its biological responses by binding to the nuclear vitamin D receptor (VDR). Several studies have been conducted over the last decade to investigate the relationship between VDR gene variants and the risk of MS, but the results have been inconsistent and inconclusive. The objective of this study is to investigate the association between the VDR gene variants (c.1025-49C>A) and (c.1056A>G) and MS susceptibility in a sample of the Egyptian population, and to shed light on its potential role in preventing inflammatory disorders and its impact on clinical outcomes and treatment using TaqMan Real-Time Polymerase Chain Reaction (PCR). This case-control study was conducted on 100 participants, categorized into two groups. The first group included 50 patients diagnosed with relapsing-remitting multiple sclerosis (RRMS) based on the Revised McDonald MS criteria, and the second group included 50 matched healthy participants. After collecting the blood samples, deoxyribonucleic acid (DNA) was extracted and detection of the VDR: c.1025-49C>A and VDR: c.1056A>G gene variants was done using TaqMan Real-Time PCR on all involved individuals.

The distribution of the genotypes and alleles of VDR gene variants (c.1025- 49C>A) and (c.1056A>G) did not differ significantly between MS patients and healthy participants (P>0.05 in both).

Here we show in this study that there was no association between the risk of MS and the VDR gene variants (c.1025-49C>A) and (c.1056A>G) in a group of the Egyptian population which may have impact on MS therapy and outcome.

Multiple sclerosis (MS) is an autoimmune disease that often affects young and middle-aged adults. It is characterized by demyelination of the central nervous system (CNS) matter, both grey and white leading to disorganization of the nervous system conduction. MS is one of the most common causes of non-traumatic disability among young and middle-aged adults [ 1 ].

The etiology of MS is still unsettled, but it is assumed that environmental, geographical, and genetic factors may have a role in its etiology and progression [ 2 ].

MS is still an incurable disease that affects an estimated 2.8 million people globally. It most commonly happens during one of the most productive times of life, namely young adulthood, making the condition responsible for lowering the quality of life not only for those affected but also for society as a whole [ 3 ].

The diagnosis of MS is made according to the revised McDonald criteria, which is based on neurological symptoms and signs, as well as evidence of dissemination of CNS lesions in space and time. Modern revolutionary techniques such as immunohistochemistry and MRI allow the recognition of multiple sclerosis lesions. These lesions appear throughout the CNS matter as focal areas of demyelination, inflammation, and glial reaction. It is denoted by fully or partially reversible incidents of neurological disability, usually lasting days to weeks [ 4 ].

Clinical researchers in the last decade have drawn attention to vitamin D deficiency and its role in MS pathophysiology. Vitamin D has broad regulatory effects on cells of the adaptive and innate immune system, such as reducing T cell proliferation and shifting the balance of T cell differentiation from the Th1 and Th17 pathways to the Th2 and regulatory T cell (Treg) pathways [ 5 ].

The effect of vitamin D is dependent on the nuclear vitamin D receptor (VDR), so any changes in vitamin D can be influenced by mutations in the VDR gene, such as single nucleotide variants (SNVs) [ 6 ].

The risk of developing MS has associated with certain class I and class II alleles of the major histocompatibility complex (MHC), particularly the HLA-DRB1 locus . The presence of a vitamin D response element (VDRE) located in the promoter region of many but not all HLA-DRB1 alleles suggests that environmental differences in vitamin D might interact with HLA-DRB1 to influence the risk of MS. The VDRE enhances gene expression when stimulated by vitamin D. However, other factors related to HLA variation may have more impact on MS risk than vitamin D regulation of HLA-DR expression [ 3 ]. Mounting evidence suggests that the risk of MS is associated with multiple genes related to vitamin D metabolic pathway of modest effect (such as, DHCR7, NADSYN1, CYP2R1, CYP27A1, CYP3A4, CYP24A1, VDBP ) and genes related to the mechanism of action ( VDR, RXR, and MARRS) [ 7 ] .

The vitamin D receptor gene is located on chromosome 12q13.1 and is approximately 100 kb in size and is divided into 8 introns and 9 exons. The first exon contains the gene promoter, exon 2–3 code for the DNA binding domain, and exon 6–9 for the ligand-binding domain [ 8 ].

The 1,25(OH) 2 D 3 binds to VDR with high affinity and selectivity as it exerts its effect through a series of cell-signaling reactions. To exert the genomic effect, 1,25(OH) 2 D 3 dissociates from vitamin D-binding protein and then diffuses across the plasma membrane migrating towards the nucleus. The interaction of 1,25(OH) 2 D 3 hormone with VDR initiates a complex cascade of molecular events that activates a range of biological functions or mediates the suppression of gene transcriptions [ 9 , 10 ].

Gene variants can be defined as subtle sequence variations transpiring in at least 1% of the population. Variants alter gene expression, thereby affecting protein levels of the VDR gene, leading to functional changes. Despite over 30 variants discovered within the VDR gene, four SNVs have been studied as the major variants involved in autoimmune diseases such as MS, including rs2228570 ( VDR :c.2 T > C), rs1544410 ( VDR: c.1024 + 283G > T), rs7975232 ( VDR: c.1025-49C > A) and rs731236 ( VDR: c.1056A > G) [ 8 ].

Some well-known VDR gene variants are rs2228570 (VDR: c.2 T > C), rs1544410 (VDR: c.1024 + 283G > T), rs7975232 (VDR: c.1025-49C > A), and rs731236 (VDR: c.1056A > G). In general, the majority of variants in the VDR gene are found to be in regulatory areas such as the 5’ promoter area and the 3’ UTR region rather than in coding exons [ 6 ].

The rs2228570 ( VDR :c.2 T > C) variant is located in the translation initiation site in exon 2 (alteration in the start codon) causing shortened VDR protein. The rs1544410 ( VDR :c.1024 + 283G > T) and rs7975232 ( VDR :c.1025-49C > A) variants are located in the intron between exon 8–9 at the 3′ end. The rs731236 ( VDR :c.1056A > G) is located in exon 9 at the 3′ end. These variants do not affect VDR protein but are involved in the regulation of the stability of VDR mRNA. Regarding their functional effect, they could generate an alteration in the splice sites for mRNA transcription or a change in the intron regulatory elements of VDR [ 11 , 12 ] .

The rs731236 ( VDR: c.1056A > G) gene variant (which was known as TaqI, referred to the used, Thermus aquaticus restriction enzyme) is a transition substitution. It results from a T (thymine) replacement by a C (cytosine) nucleotide, where the AT T  codon transitions to AT C generating a silent mutation, as both encode the amino acid isoleucine. Nonetheless, this SNV may alter some functional characteristics of the protein as it is involved in the regulation of mRNA stability and correlates with transcriptional activity [ 13 , 14 ] .

While rs7975232 ( VDR: c.1025-49C > A) gene variant, was defined using the Acetobacter pasteurianus restriction enzyme, therefore was known as ApaI, is a transversion substitution. It presents a change of A (alanine) instead of C (cytosine) nucleotide but there is no change in the amino acid sequence of the VDR protein [ 15 ].

There are many discrepancies in the study results regarding these variants; while some studies have established an association between VDR gene variants and vitamin D levels, other studies have not found any such association [ 1 , 16 , 17 , 18 , 19 , 20 ].

The aim of this study was to investigate the association between the VDR gene variants c.1025-49C > A and c.1056A > G and MS susceptibility in a sample of the Egyptian population, and to study its effect on clinical outcomes using TaqMan Real-Time PCR. The findings of the study could have implications for the treatment and prevention of multiple sclerosis in Egypt.

This case–control study was conducted on two groups: Group I, consisting of relapsing–remitting multiple sclerosis (RRMS) patients recruited from Multiple Sclerosis unit of Kasr el Ainy, Cairo University  between March 2021 and March 2022, and Group II, consisting of healthy control individuals of matching age and sex.

Sample size calculation was done using the comparison of the prevalence of VDR: c.1056A > G (rs731236) and VDR: c.1025-49C > A (rs7975232) genotypes between Egyptian patients with multiple sclerosis (MS) and matched healthy controls, as reported in previous publications [ 21 , 22 ].

Inclusion criteria included patients diagnosed with RRMS based on the Revised McDonald MS criteria of 2017 [ 23 ]. Both sexes were included with an age range between 18 and 52 years. Exclusion criteria included patients with neurological, inflammatory, and autoimmune diseases other than MS, as well as smokers.

All patients were subjected to the following history taking, clinical, and neurological examination including the Expanded Disability Status Scale (EDSS) [ 23 ].

Blood samples were taken for molecular analysis of VDR gene variants: c.1056A > G (rs731236) and c.1025-49C > A (rs7975232) using TaqMan Real-Time polymerase chain reaction in the Molecular Research and Diagnosis Unit at the Chemical Pathology Department of Kasr el Ainy, Cairo University.

Regarding collection of samples, Peripheral venous blood samples were taken and dispensed into 3 mL tubes containing 5.4 mg of ethylene diamine tetra acetic acid (EDTA), then they were stored at – 20 °C for DNA extraction.

The test was done in two main steps, DNA extraction in which Genomic DNA was extracted from EDTA-anticoagulated peripheral blood leucocytes according to the manufacturer’s instructions using QIAamp DNA Extraction Mini Kit provided by Thermo Fisher Scientific. The extracted DNA was stored at – 20 °C for further use. The purity and concentration of the DNA was detected by measuring the absorbance at 260 nm (A260) to the absorbance at 280 nm (A280) By Nanodrop. Then Detection of the VDR c.1056A > G (rs731236) and c.1025-49C > A (rs7975232) gene variants was performed using the Real-Time PCR System (Applied Biosystems, USA). Vitamin D receptor SNVs (rs731236, rs7975232) were genotyped by fluorogenic TaqMan SNV technology from a ready to use assays library (Applied Biosystems, Foster City, CA, USA) with the TaqMan Genotyping Master Mix (Applied Biosystems, Foster City, CA, USA) in a 20 µl reaction volume. The final concentration of genomic DNA for all samples in the experiment sample was 10 ng/µl [ 25 , 26 , 27 , 28 , 29 ].

IBM SPSS ® Statistics version 22 (IBM ® Corp., Armonk, NY, USA) was used for statistical analysis. Numerical data were expressed as mean and standard deviation, or median and range, as appropriate. Qualitative data were expressed as frequency and percentage. Pearson’s Chi-square test or Fisher’s exact test was used to examine the relationship between qualitative variables. For normally distributed quantitative data, a comparison between two groups was done using the Student’s t-test, while a comparison between more than two groups was done using ANOVA test. For not normally distributed quantitative data, a comparison between three groups was done using the Kruskal–Wallis test (non-parametric ANOVA). All tests were two-tailed, and a P -value < 0.05 was considered statistically significant. Odds ratios were used to present the strength of association between risk factors and outcomes.

The study was approved by the Institutional Review Board of the Faculty of Medicine (IRB No. MS-279-2021) and was conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent were obtained from all participants before they enrolled to participate in the study.

This study included 50 patients with RRMS and 50 healthy, age- and sex-matched controls showing demographic data in Table  1 .

Regarding the VDR c.1056A > G (rs731236) genotype analysis and alleles distributions for all studied subjects by real-time PCR (Table  2 , Fig.  1 ).

Genotype distribution of VDR c.1056A > G (rs731236) variant among study groups

Regarding the genotype analysis and alleles distribution of VDR c.1025-49C > A (rs7975232) by TaqMan Real-Time PCR (Table  3 , Fig.  2 ).

Genotype distribution of VDR c.1025-49C > A (rs7975232) variant among study groups

No statistically significant difference was found when comparing different VDR c.1056A > G gene variants regarding the main clinical parameters in MS patients; the same was reported regarding VDR c.1025-49C > A gene variants, as shown in Table  4 .

The haplotyping between VDR c.1056A > G and VDR c.1025-49C > A gene variants was done, as shown in Table  5 .

In summary, our findings demonstrated an increase in the G allele in the MS group, which is thought to be the hazardous allele; however, this difference was not statistically significant in VDR:c.1056A > G (rs731236). However, in the VDR:c.1025-49C > A (rs7975232) variant allelic distribution A hazardous allele was found to be more prevalent in the MS group, although it did not achieve statistical significance. In both variations, haplotype analysis and genotype distribution demonstrate a non-significant relationship to MS etiology.

Multiple sclerosis is a demyelinating neurodegenerative autoimmune illness. Motor dysfunction, autonomic symptoms, and psychbehavioral aspects of MS include gait difficulties, paresthesia, visual issues, vertigo, incontinence, sexual problems, pain, cognitive dysfunctions, emotional disturbances, and depression. MS biomarkers and gene variants certainly may be able to help identify various stages of MS and build personalized treatment plan [ 30 , 31 ].

This study aimed to investigate the association between the VDR c.1056A > G and c.1025-49C > A SNVs and susceptibility to MS in a group of Egyptian population which is an important point provides insights into the potential role of vitamin D in preventing inflammatory disorders and its impact on clinical outcomes. The findings of the study could have implications for the treatment and prevention of MS in Egypt. Our results revealed that there was an increase in the G allele in the MS group, which was suggested to be the risky allele; however, this difference did not reach statistical significance in VDR c.1056A > G (rs731236). On the other hand, in VDR c.1025-49C > A (rs7975232), the variant allelic distribution of the A allele, which was supposed to be the risky allele, was increased in the MS group but did not reach statistical significance. The genotype distribution in both variants showed no significant relation to MS pathogenesis. Most of the published work agreed with part of our data and disagreed with others.

Regarding the VDR c.1056A > G genotype distribution analysis, in agreement with our results, Mazrouei-Arani et al. (2022) conducted a study on 101 MS patients and 101 healthy subjects in the Iranian population, and Moosavi et al. (2021) conducted a study on 160 MS patients and 162 healthy personnel and found that the genotype frequency of VDRc.1056A > G did not differ between the patients and controls ( P  = 0.348 and P  = 0.092, respectively) [ 1 , 18 ]. Additionally, Hassab et al. (2019) and Zayed et al. (2019) (in which 50 and 63 Egyptian MS patients were recruited, respectively) revealed no statistically significant association between MS and VDRc.1056A > G ( P  = 0.945 and P  = 0.845, respectively) [ 22 , 32 ].

In other studies, conducted on the Turkish population, there was nostatistically significant difference between 167 MS patients and 146 healthy controls, and between 70 MS patients and 70 healthy controls, respectively [ 33 , 34 ]. Additionally, Zhang et al. (2018) conducted a meta-analysis which included 24 case–control studies with a total of 4013 cases and 4218 controls and found that the association between the VDRc.1056A > G variant and MS was not significant under dominant, recessive genotypes, and allele contrast ( P  = 0.078, P  = 0.314, and P  = 0.127, respectively) in overall populations [ 35 ]. Similarly, Imani et al. (2019) conducted a meta-analysis with a total of 30 case–control studies and detected no significant association across different genotype models [ 18 ].

In contrast to our findings, Al-Temaimi et al. (2015) found that the genotype distribution of Kuwaiti VDR c.1056A > G in 50 MS patients was significantly different from that of 50 healthy controls ( P  = 0.0008) [ 21 ].

In addition, Mohammadi et al. (2020) discovered a statistically significant negative relationship between the VDR c.1056A > G variant and risk of MS in the homozygote A/A genetic model (OR = 0.28, 95% CI: 0.08–0.9; P  = 0.04) [ 36 ]. Additionally, Abdollahzadeh et al. (2018) found that the homozygote G/G genotype carriers for the VDR c.1056A > G variant have a predisposition to MS (OR = 2.18, 95% CI = 1.05–4.52) [ 37 ]. Furthermore, Zhang et al. (2019) conducted a meta-analysis, which included 27 case–control studies with 4879 MS patients and 5402 controls and observed that the G/G genotype is associated with the risk of MS (OR = 0.76, 95% CI = 0.62–0.94) [ 38 ].

Concerning the allelic distribution, similar to our findings, Mohammadi et al. (2020) conducted a meta-analysis which showed that in allelic comparison, no statistical association between allele G and risk of MS was found in 1206 Iranian patients ( P  = 0.07) [ 36 ].

However, Moosavi et al. (2021) found that the G allele was more prominent in 160 MS patients than in the 162 control individuals, increasing the risk of disease susceptibility by 1.6 times (OR = 1.6, P  = 0.0232) [ 1 ]. According to Abdollahzadeh et al. (2018), the G allele had a positive correlation with MS (OR = 1.98, 95% CI = 1.36–2.87; P  = 0.003), while the A allele had a negative association (OR = 0.51, 95% CI = 0.39–0.73; P  = 0.003) [ 36 ]. Additionally, Al-Temaimi et al. (2015) demonstrated that the G allele was associated with MS risk (OR = 1.7, 95% CI = 1.2–2.4; P  = 0.003) [ 21 ].

Regarding the VDR c.1025-49C > A genotype distribution analysis, in agreement with our results, many studies and meta-analyses done on Turkish and Iranian populations have agreed with our results, showing no evidence of an association between VDR c.1025-49C > A and MS risk [ 17 , 35 , 37 , 38 ].

In contrast to our findings, a statistical analysis of a study done by Mazrouei-Arani et al. (2022) revealed a significant association between VDR c.1025-49C > A genotypes and MS disease ( P  = 0.05), showing that MS patients had an A/A genotype 2.54 times higher than the CC genotype (OR = 2.54, P  = 0.029) [ 18 ].

Upon evaluating the genotypes by Cetinel et al. (2021), a statistically significant correlation was found with VDRc.1025-49C > A A/A, C/C, and A/C ( P  < 0.01, 0.01, and P  < 0.01, respectively) in the SPMS group and with VDR:c.1025-49C > A A/A and A/C genotypes ( P  = 0.01 and 0.04, respectively) in the PPMS group, but no significant difference was found in the genotypes within the RRMS group [ 16 ].

In a meta-analysis study conducted on 1206 cases and 1402 controls, a statistically significant association was also found between the VDR c.1025-49C > A homozygote genetic model of A/A and G/G and the risk of MS (OR = 3.48, 95% CI = 1.7–6.9; P  = 0.00) [ 36 ]. Additionally, Zhang et al. (2019) performed a meta-analysis revealed a significant association between the VDRc.1025-49C > A variant and MS risk in Asians in the recessive model C/C genotype (OR = 0.66, 95% CI = 0.53–0.82; P  = 0.0002) [ 37 ].

Regarding the allelic distribution, like our findings, Imani et al. (2019) meta-analysis showed no statistically significant difference in allelic discrimination [ 17 ].

However, Mohammadi et al. (2020) meta-analysis showed a statistically significant relationship between the A allele and decreased risk of MS in Iran (OR = 0.54, 95% CI = 0.37–0.79, P  = 0.00) [ 36 ]. Additionally, Hassab et al. (2019) study detected a statistically significant association between the A allele and MS cases (OR = 2.47, 95% CI = 1.25–4.88, P  = 0.008) [ 22 ]. Furthermore Zhang et al. (2018) conducted a meta-analysis which observed that the A allele was associated with MS risk in Asian populations (OR = 1.267, 95% CI = 1.074–1.496; P  = 0.005) [ 35 ].

The contradictory results of the studies may be because; small sample sizes, differences in ethnicities, extensive geographic variation, interactions with other genetic or environmental factors, and/or clinical heterogeneity.

The significance of this manuscript is that it presents a research study that looks into the relationship between VDR gene variants and MS in the Egyptian population. The study analyzes genetic data using TaqMan Real-Time Polymerase Chain Reaction (PCR) which is accurate method and provides insights into the potential role of vitamin D in preventing inflammatory disorders and its impact on clinical outcomes. The findings of the study could have implications for the treatment and prevention of MS in Egypt. The research adds to the body of knowledge on the subject and may help guide future research and clinical practice. It is recommended that the results obtained by this study be studied on a wider scale with a larger sample size, taking into consideration the presence of different ethnicities. It is also advised that other single nucleotide variants (SNVs) of the vitamin D receptor (VDR) affecting multiple sclerosis (MS) should be studied. This will help in clarifying the genetic role in the development of MS and achieving more accurate results.

Vitamin D receptor gene variants had been studied in many studies to assess its relationship with MS, but the results are contradictory. Data from this study suggested that there was no association between the risk of MS and the VDR gene variants regarding VDR c.1025-49C > A and VDR c.1056A > G in a group of Egyptian population.

Availability of data and materials

The datasets generated during the current study are not publicly available due to the hospital policy and because the data will be used in future multi-center research to generate a nationwide statistic. However, these datasets are available from the corresponding author (Hala Ashraf) on reasonable request.

Abbreviations

Multiple sclerosis

Vitamin D receptor

Deoxyribonucleic acid

Relapsing–remitting multiple sclerosis

Polymerase chain reaction

Central nervous system

Magnetic resonance imaging

Regulatory T cells

Single nucleotide variants

Research Ethics Committee

Expanded Disability Status Scale

Ethylene diamine tetra acetic acid

Moosavi E, Rafiei A, Yazdani Y, Eslami M, Saeedi M. Association of serum levels and receptor genes BsmI, TaqI and FokI polymorphisms of vitamin D with the severity of multiple sclerosis. J Clin Neurosci. 2021;84:75–81.

Article   CAS   PubMed   Google Scholar  

Vaughn CB, Jakimovski D, Kavak KS, Ramanathan M, Benedict RH, Zivadinov R, et al. Epidemiology and treatment of multiple sclerosis in elderly populations. Nat Rev Neurol. 2019;15(6):329–42.

Article   PubMed   Google Scholar  

Polyák H, Galla Z, Nánási N, Cseh EK, Rajda C, Veres G, et al. The tryptophan-kynurenine metabolic system is suppressed in cuprizone-induced model of demyelination simulating progressive multiple sclerosis. Biomed. 2023;11(3):945.

Google Scholar  

Brownlee WJ, Hardy TA, Fazekas F, Miller DH. Diagnosis of multiple sclerosis: progress and challenges. Lancet. 2017;389(10076):1336–46.

Bikle DD. Vitamin D regulation of immune function. Vitam Horm. 2011;1(86):1–21.

Lu M, McComish BJ, Burdon KP, Taylor BV, Körner H. The association between vitamin D and multiple sclerosis risk: 1, 25 (OH) 2D3 induces super-enhancers bound by VDR. Front Immunol. 2019;19(10):488.

Article   Google Scholar  

Ortiz GG, Torres-Mendoza BM, Ramírez-Jirano J, Marquez-Pedroza J, Hernández-Cruz JJ, Mireles-Ramirez MA, et al. Genetic basis of inflammatory demyelinating diseases of the central nervous system: multiple sclerosis and neuromyelitis optica spectrum. Genes. 2023;14(7):1319.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Mohammadi A, Azarnezhad A, Khanbabaei H, Izadpanah E, Abdollahzadeh R, Barreto GE, et al. Vitamin D receptor genetic polymorphisms and the risk of multiple sclerosis: a systematic review and meta-analysis. Steroids. 2020;158: 108615.

Pike JW, Meyer MB. Fundamentals of vitamin D hormone-regulated gene expression. J Steroid Biochem. 2014;144:5–11.

Article   CAS   Google Scholar  

Sirajudeen S, Shah I, Al MA. A narrative role of vitamin D and its receptor: with current evidence on the gastric tissues. Int J Mol Sci. 2019;20(15):3832.

Article   PubMed   PubMed Central   Google Scholar  

Köstner KI, Denzer N, Mueller CS, Klein R, Tilgen W, Reichrath J. The relevance of vitamin D receptor (VDR) gene polymorphisms for cancer: a review of the literature. Anticancer Res. 2009;29(9):3511–36.

PubMed   Google Scholar  

Triantos C, Aggeletopoulou I, Kalafateli M, Spantidea PI, Vourli G, Diamantopoulou G, et al. Prognostic significance of vitamin D receptor (VDR) gene polymorphisms in liver cirrhosis. Sci Rep. 2018;8(1):14065.

Morrison NA, Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen TV, et al. Prediction of bone density from vitamin D receptor alleles. Nature. 1994;367(6460):284–7.

de Souza Freitas R, Fratelli CF, de Souza Silva CM, de Lima LR, Stival MM, da Silva IC, Funghetto SS. Association of Vitamin D with the TaqI Polymorphism of the VDR gene in older women attending the basic health unit of the Federal District, DF (Brazil). J Aging Res. 2020;2020.

Ruiz-Ballesteros AI, Meza-Meza MR, Vizmanos-Lamotte B, Parra-Rojas I, de la Cruz-Mosso U. Association of vitamin D metabolism gene polymorphisms with autoimmunity: evidence in population genetic studies. Int J Mol Sci. 2020;21(24):9626.

Cetinel TT, Gokce SF, Yildirim ME, Bolayir A. Effects of ApaI, FokI, and BsmI gene polymorphisms of the vitamin D receptor on serum vitamin D level in Turkish MS patients with different types and severities of the disease. Ann Med Res. 2019;28:11.

Imani D, Razi B, Motallebnezhad M, Rezaei R. Association between vitamin D receptor (VDR) polymorphisms and the risk of multiple sclerosis (MS): an updated meta-analysis. BMC Neurol. 2019;19:1–7.

Mazrouei-Arani N, Zargar M, Nikoueinejad H. Association between ApaI and TaqI polymorphisms of the vitamin D receptor gene and the multiple sclerosis. Gene Rep. 2022;1(27): 101584.

Gaebler AJ, Finner-Prével M, Sudar FP, Langer FH, Keskin F, Gebel A, et al. The interplay between vitamin D, exposure of anticholinergic antipsychotics and cognition in schizophrenia. Biomed. 2022;10(5):1096.

CAS   Google Scholar  

Quirant-Sánchez B, Mansilla MJ, Navarro-Barriuso J, Presas-Rodríguez S, Teniente-Serra A, Fondelli F, et al. Combined therapy of vitamin D3-tolerogenic dendritic cells and interferon-β in a preclinical model of multiple sclerosis. Biomed. 2021;9(12):1758.

Al-Temaimi RA, Al-Enezi A, Al-Serri A, Al-Roughani R, Al-Mulla F. The association of vitamin D receptor polymorphisms with multiple sclerosis in a case-control study from Kuwait. PLoS ONE. 2015;10(11): e0142265.

Hassab AH, Deif AH, Elneely DA, Tawadros IM, Fayad AI. Protective association of VDR gene polymorphisms and haplotypes with multiple sclerosis patients in Egyptian population. Egypt J Med Hum Genet. 2019;20(1):1–9.

Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17(2):162–73.

Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33(11):1444.

Albahlol IA, Neamatallah M, Serria MS, El-Gilany AH, Setate YA, Alkasaby NM, et al. Vitamin D receptor gene polymorphism and polycystic ovary syndrome susceptibility. BMC Medical Genom. 2023;16(1):1–9.

Barut D, Akisu M, Koroglu OA, Terek D, Ergin F, Onay H, et al. The role of vitamin D receptor gene polymorphism in the development of necrotizing enterocolitis. Pediatr Res. 2023;3:1–5.

Usategui-Martín R, De Luis-Román DA, Fernández-Gómez JM, Ruiz-Mambrilla M, Pérez-Castrillón JL. Vitamin D receptor (VDR) gene polymorphisms modify the response to vitamin D supplementation: a systematic review and meta-analysis. Nutrients. 2022;14(2):360.

Pistono C, Osera C, Monti MC, Boiocchi C, Mallucci G, Cuccia M, Pascale A. Vitamin D receptor and its influence on multiple sclerosis risk and severity: from gene polymorphisms to protein expression. Immuno. 2022;2(3):469–81.

Guerini FR, Agliardi C, Oreni L, Groppo E, Bolognesi E, Zanzottera M, et al. Vitamin D receptor gene polymorphism predicts the outcome of multidisciplinary rehabilitation in multiple sclerosis patients. Int J Mol Sci. 2023;24(17):13379.

Tanaka M, Vécsei L. Editorial of special issue ‘dissecting neurological and neuropsychiatric diseases: neurodegeneration and neuroprotection.’ Int J Mol Sci. 2022;23(13):6991.

Török N, Tanaka M, Vécsei L. Searching for peripheral biomarkers in neurodegenerative diseases: the tryptophan-kynurenine metabolic pathway. Int J Mol Sci. 2020;21(24):9338.

Zayed AM, Shehata AE, Gouda TA, Abd Elnour HM. Association of vitamin D receptor, interleukin7 receptor alpha gene polymorphisms with the risk of multiple sclerosis. ZUMJ. 2021;27(1):122–31.

Cakina S, Ocak O, Ozkan A, Yucel S, Karaman HIO. Vitamin D receptor gene polymorphisms in multiple sclerosis disease: a case-control study. RJLabM. 2018;26(4):489–96.

Kamisli O, Acar C, Sozen M, Tecellioglu M, Yücel FE, Vaizoglu D, et al. The association between vitamin D receptor polymorphisms and multiple sclerosis in a Turkish population. Mult Scler Relat Disord. 2018;1(20):78–81.

Zhang YJ, Zhang L, Chen SY, Yang GJ, Huang XL, Duan Y, et al. Association between VDR polymorphisms and multiple sclerosis: systematic review and updated meta-analysis of case-control studies. J Neurol Sci. 2018;39:225–34.

Mohammadi A, Azarnezhad A, Khanbabaei H, Izadpanah E, Abdollahzadeh R, Barreto GE, et al. Vitamin D receptor genetic polymorphisms and the risk of multiple sclerosis: a systematic review and meta-analysis. Steroids. 2020;1(158): 108615.

Abdollahzadeh R, Moradi Pordanjani P, Rahmani F, Mashayekhi F, Azarnezhad A, Mansoori Y. Association of VDR gene polymorphisms with risk of relapsing-remitting multiple sclerosis in an Iranian Kurdish population. Int J Neurosci. 2018;128(6):505–11.

Zhang D, Wang L, Zhang R, Li S. Association of vitamin D receptor gene polymorphisms and the risk of multiple sclerosis: a meta analysis. Arch Med Res. 2019;50(6):350–61.

Dobson R, Giovannoni G. Multiple sclerosis–a review. Eur J Neurol. 2019;26(1):27–40.

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Acknowledgements

The authors would like to express their gratitude to the patients for their participation and cooperation in this study.

This research received no specific grant from any funding agency from commercial or not-for-profit sectors.

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Hala Ashraf Hosni, Noha Wael Ibrahim & Sahar Abd El-Atty Sharaf

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HAH was the idea founder, shared in the patient collection, and the supervisor in all the steps. AMF shared in the patient collection did the data analysis, wrote and revised the manuscript and is the submitting and corresponding author. NWI shared in the patient collection and did the laboratory work. SAS shared in the patient collection and supervision. All authors read and approved the final manuscript.

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Correspondence to Hala Ashraf Hosni .

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The study was approved by the Institutional Review Board of Faculty of Medicine, Cairo University (IRB No. MS-279-2021) and was performed in accordance with the principles of the Declaration of Helsinki. Written informed consents were obtained from all participants before the enrollment to participate in the study.

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Hosni, H.A., Fouad, A.M., Ibrahim, N.W. et al. Investigating the role of VDR gene variants in multiple sclerosis susceptibility: a case–control study in Egypt. Egypt J Neurol Psychiatry Neurosurg 60 , 51 (2024). https://doi.org/10.1186/s41983-024-00794-z

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DOI : https://doi.org/10.1186/s41983-024-00794-z

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The role of histological subtype and chemotherapy on prognosis of ureteral cancer

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• Published: 13 April 2024
• Volume 150 , article number  192 , ( 2024 )

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• Jincong Li 1   na1 ,
• Yuxuan Song 1   na1 ,
• Yun Peng 1 ,
• Jiaxing Lin 1 ,
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• Caipeng Qin 1 &

To date, there have been few studies examining the prognostic implications of histological subtypes in ureteral cancer. And chemotherapy plays a crucial role in the treatment of ureteral cancer, while many factors influence the efficacy of chemotherapy. This study aimed to utilize the Surveillance, Epidemiology and End Results database to assess the impact of histological type on ureteral cancer prognostic outcomes and discovered how histological type and T-stage influence the efficacy of chemotherapy.

Based on Surveillance, Epidemiology, and End Results Program, we reviewed 8915 records of patients with primary ureteral cancer from 18 centers between 2000 and 2018. We focused on the overall survival and cancer-specific survival of the records and used Kaplan‒Meier method to calculate survival curves.

In the comparison of prognostic outcomes, atypical subtypes exhibited a less favorable prognosis compared to typical ureteral carcinoma. Notably, patients diagnosed with papillary urothelial carcinoma demonstrated the most favorable overall survival (p = 0.005). Statistically significant benefits were observed in the prognosis of patients with non-papillary urothelial carcinoma who received chemotherapy (HR = 0.860, 95% CI 0.764–0.966, p = 0.011), while chemotherapy did not yield a statistically significant effect on the prognosis of patients with papillary urothelial carcinoma (HR = 1.055, 95% CI 0.906–1.228, p = 0.493). Chemotherapy had an adverse impact on the prognosis of patients with T1 ureteral cancer (HR = 1.235, 95% CI 1.016–1.502, p = 0.034), whereas it exhibited a positive prognostic effect for T3/T4 cases (HR = 0.739, 95% CI 0.654–0.835, p < 0.001).

Conclusions

Histological type affects the prognosis of ureteral cancer. And evaluation of cancer histological type and T stage in ureteral cancer patients prior to chemotherapy is mandatory.

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Introduction

Urothelial carcinomas are the sixth most common tumours in developed countries (Siegel et al. 2021 ). Per the European Association of Urology (EAU) guidelines (Rouprêt et al. 2018 ) and numerous clinical investigations, renal pelvic cancer (RPC) and ureteral cancer (UC) are considered an integral group and are collectively referred to as upper urinary tract urothelial carcinoma. Nevertheless, clinical and epigenetic disparities suggest that renal pelvic and ureteral tumors may represent distinct disease entities. Recent research indicates that patients diagnosed with ureteral tumors experience an unfavorable prognosis (Rouprêt et al. 2021 ). Fujii et al. ( 2021 ) conducted a comprehensive molecular study of upper urinary tract urothelial carcinoma using unbiased, multiplatform analyses and observed distinctions in the molecular characteristics between RPC and UC. Histological subtypes of tumors at certain sites were reported to be likely to affect the prognosis (Zhou et al. 2022 ; Beadsmoore and Screaton 2003 ; Davy et al. 2003 ). Zhou et al. ( 2022 ) reported that prostate cancer with neuroendocrine subtype had the worst survival among all the histological types of prostate cancer. Beadsmoore et al.’s study on lung cancer prognosis (Beadsmoore and Screaton 2003 ) revealed that patients with small cell subtype had the worst survival. Davy et al. ( 2003 ) investigated the prognosis of cervical cancer and noted that adenocarcinoma subtypes were associated with a less favorable prognosis compared to typical squamous cell carcinoma. We suspect that histological type might also affect the prognosis of UC. To date, there have been few studies examining the prognostic implications of histological subtypes in UC. Therefore this study aimed to utilize the Surveillance, Epidemiology, and End Results (SEER) database to assess the impact of histological type on UC prognostic outcomes. Additionally, we investigated the effects of chemotherapy on prognosis.

Data acquisition

Based on SEER, we reviewed 8915 records of patients with primary UC from 18 centers between 2000 and 2018. The records include age at diagnosis, sex, race, Histological Type ICD-O-3, tumor grade, TNM stages of the cancer, survival, data, surgery recode and chemotherapy recode. There are many histological types of UC including papillary urothelial carcinoma, non-papillary urothelial carcinoma, small cell carcinoma, adenocarcinoma, squamous cell carcinoma, papillary carcinoma, spindle cell carcinoma. Urothelial carcinoma is the predominant form of urinary tract cancer (Song et al. 2023 ). Therefore, we categorized papillary urothelial carcinoma and non-papillary urothelial carcinoma as “typical UC” and classified the remaining histological types as “atypical subtypes”. The quantities of records of some histological types of UC are too low (< = 20) and some histological types are not otherwise specified, so we categorized all of them as “other types of ureter carcinoma”, including large cell carcinoma, pleomorphic carcinoma, pseudosarcomatous carcinoma, combined small cell carcinoma, clear cell adenocarcinoma, renal cell carcinoma and granular cell carcinoma. The classification of all the histological types is shown in Supplementary Table 1.

Statistics analyses

This study focused on the overall survival (OS) and cancer-specific survival (CSS). OS is the time from diagnosis to death due to any cause, with censoring at the last visit date within SEER or the date of death due to any cause. CSS is the time from diagnosis to death from UC, with censoring at the last visit date within SEER or the date of death due to any other cause. Survival curves were calculated by the Kaplan‒Meier method. Log-rank test was used to compare different survival curves. A multivariable Cox regression analysis was used to identify independent prognostic factors for UC. The chi-square test was used for comparisons between groups. Statistical analyses were performed with IBM SPSS Statistics 26. P values < 0.05 were considered statistically significant.

Clinical characteristics of typical UC and atypical subtypes

In total, 8915 patients were enrolled, of which 8220 (92.2%) exhibited typical UC, while 695 (7.8%) presented as atypical subtypes. Clinical parameters of patients with typical carcinoma and atypical subtypes are detailed in Table  1 . N-stage and M-stage of atypical subtypes were higher than typical UC (all p < 0.001). Figure  1 presents the statistical data concerning histological types. Non-papillary urothelial carcinoma accounted for 53.30% of cases, while papillary urothelial carcinoma represented 46.70%. Among atypical subtypes, other types of ureter carcinoma was the most prevalent, accounting for 64.03%.

Summary of histological type and prognosis analysis of different groups of histological types. A Truncate histogram of histological type statistics B Pie chart of histological type statistics C Prognosis analysis of all patients D Prognosis analysis of patients with typical UC E Prognosis analysis of patients with atypical subtype

Effects of histological types on prognosis

Kaplan–Meier curves revealed that all atypical subtypes had worse CSS and OS than typical urothelial carcinoma (all p < 0.001; Fig.  1 C). In addition, we divided all patients into distinct histological type groups. Kaplan–Meier curves illustrated that papillary urothelial carcinoma had better CSS and OS than non-papillary urothelial carcinoma (all p < 0.001; Fig.  1 D). Among all the atypical subtypes, papillary carcinoma demonstrated the most favorable CSS and OS outcomes (CSS: p = 0.05, OS: p = 0.005; Fig.  1 E). Multivariate analysis showed histological subtype as an independent risk factor for an unfavorable prognosis (HR = 1.602, 95% CI 1.371–1.872, p < 0.001; Table  2 ).

Effects of chemotherapy on prognosis of different histological types

We divided all patients into chemotherapy and nonchemotherapy group. Kaplan–Meier curves demonstrated that the non-chemotherapy group exhibited superior OS and CSS (all p < 0.001; Fig.  2 A). However, multivariate analysis indicated that chemotherapy had no statistically significant impact on the prognosis of all patients (HR = 0.931, 95% CI 0.850–1.019, p = 0.121; Table  2 ).

Effects of chemotherapy on prognosis of different histological types A Effects of chemotherapy on all patients B Effects of chemotherapy on patients with T1 UC C Effects of chemotherapy on patients with T2 UC D Effects of chemotherapy on patients with T3/T4 UC

To investigate the impact of chemotherapy on various histological type of UC, we categorized the patients into distinct histological type groups. Records of papillary urothelial carcinoma and non-papillary urothelial carcinoma were sufficient for multivariate Cox analysis, while others (atypical subtypes) were of insufficient quantity. Therefore we divided all the rest of the patients with atypical UC into one group for multivariate Cox analysis. We also constructed Kaplan–Meier curves to evaluate the impact of chemotherapy within each group of atypical subtypes.

Multivariate Cox analysis revealed that chemotherapy had no statistically significant effect on the prognosis of patients with papillary urothelial carcinoma (HR = 1.055, 95% CI 0.906–1.228, p = 0.493; Supplementary Table 3). However, chemotherapy demonstrated a statistically significant positive impact on the prognosis of patients with non-papillary urothelial carcinoma (HR = 0.860, 95% CI 0.764–0.966, p = 0.011; Supplementary Table 2).

The multivariate Cox analysis on all patients with atypical UC indicated that chemotherapy had no statistically significant effect on the prognosis (HR = 0.997, 95% CI 0.675–1.473, p = 0.987; Supplementary Table 4). Chemotherapy group of patients with small cell carcinoma exhibited improved OS and CSS than non-chemotherapy group (OS: p = 0.003, CSS: p = 0.014; Supplementary Fig. 1B). However, Kaplan–Meier curves revealed that chemotherapy group had worse CSS than non-chemotherapy group among patients with squamous cell carcinoma or papillary carcinoma (Squamous cell carcinoma: p = 0.03; Papillary carcinoma: p = 0.002; Supplementary Fig. 1).

Effects of chemotherapy on prognosis of different T stages

Stratified analysis of T1, T2, T3/T4 was performed for typical UC and atypical subtypes. Patients with lower T-stage were shown to have better prognosis (all p < 0.001; Fig.  3 A–C ). Kaplan–Meier curves revealed that all atypical subtypes had worse CSS and OS than typical urothelial carcinoma among patients with T1 UC, T2 UC, and T3/T4 UC (all p < 0.001; Fig.  3 D–F).

Stratified analysis of T-stage effects on prognosis of different histological types A Effects of T-stage on all patients B Effects of T-stage on patients with atypical subtypes C Effects of T-stage on patients with typical UC D Effects of histological types on patients with T1 UC E Effects of histological types on patients with T2 UC F Effects of histological types on patients with T3/T4 UC

Kaplan–Meier curves demonstrated that nonchemotherapy group of patients in T1 group had better OS and CSS (OS: p < 0.001, CSS: p < 0.001; Fig.  2 B), while nonchemotherapy group of patients in T3/T4 group exhibited poorer OS and CSS (OS: p < 0.001, CSS: p = 0.026; Fig.  2 D). In T2 group, nonchemotherapy group of patients had better CSS while chemotherapy had no statistically significant effect on OS (OS: p = 0.237, CSS: p < 0.001; Fig.  2 C).

The multivariate analysis on patients in T1 group revealed that chemotherapy had statistically significant negative effect on prognosis (HR = 1.235, 95% CI 1.016–1.502, p = 0.034; Supplementary Table 5). However, chemotherapy had no statistically significant effect on the prognosis of patients in T2 group (HR = 1.103, 95% CI 0.916–1.329, p = 0.3; Supplementary Table 6). Chemotherapy had statistically significant positive effect on the prognosis of patients in T3/T4 group (HR = 0.739, 95% CI 0.654–0.835, p < 0.001; Supplementary Table 7).

In this research, among all the histological type of UC, patients with typical urothelial carcinoma exhibited superior CSS and OS compared to those with atypical UC. Marina et al. (Deuker et al. 2021 ) concluded that disease stage at diagnosis is more advanced in upper urinary tract tumors with variant histology patients than pure upper urinary tract urothelial carcinoma. This could potentially result in inferior CSS and OS, aligning with our research findings. Song et al. ( 2023 ) reported that patients with upper tract variant histology were more likely to present at advanced stages and experience higher mortality rates when compared to pure UC, which is consistent with our findings.

Retrospective studies based in Korea (Lee et al. 2006 ) and Japan (Soga et al. 2008 ) did not identify a benefit from adjuvant chemotherapy. However, a phase 3 multicentre trial evaluating the benefit of four cycles of adjuvant gemcitabine-platinum combination chemotherapy initiated within 90 d after nephroureterectomy versus surveillance reported a significant improvement in disease-free survival (DFS) in patients with upper urinary tract tumors (Birtle et al. 2020 ). Leow et al. ( 2021 ) conducted a meta-analysis investigating neoadjuvant chemotherapy or adjuvant chemotherapy for upper urinary tract tumors and discovered that adjuvant chemotherapy provided a benefit in OS, CSS, and DFS compared with radical nephroureterectomy alone. According to European Association of Urology guidelines (Rouprêt et al. 2023 ), adjuvant chemotherapy should be contemplated for urothelial carcinoma. Nevertheless, according to Thomas et al ( 2013 ), a decline in renal function following radical nephroureterectomy reduces eligibility for cisplatin-based chemotherapy, thereby constraining the use of adjuvant chemotherapy.

While studies focusing on adjuvant chemotherapy have yielded conflicting outcomes, numerous research on neoadjuvant chemotherapy have demonstrated consistent results. Although the use of carboplatin in a neoadjuvant setting remains a subject of debate (Koie et al. 2014 ; Koie et al. 2013 ; Dogliotti et al. 2007 ; Ohyama et al. 2014 ; Park et al. 2013 ; Fukushi et al. 2017 ), cisplatin-based neoadjuvant chemotherapy for patients with UC was exhibited to be safe. And cisplatin-based neoadjuvant chemotherapy is often proposed in patients with metastatic or locally advanced UC (Audenet et al. 2013 ). Matin et al. ( 2010 ) evaluated the incidence of pathologic downstaging and complete remission in patients with high-grade upper urinary tract tumors who received neoadjuvant chemotherapy followed by surgery. And they discovered that neoadjuvant chemotherapy was associated with a 14% complete remission rate and a significant rate of downstaging. Hosogoe et al. ( 2018 ) discovered that platinum-based neoadjuvant chemotherapy for advanced upper urinary tract urothelial carcinoma potentially improves oncological outcomes.

Due to limitation of SEER, our research could not differentiate between adjuvant chemotherapy and neoadjuvant chemotherapy. However, our research demonstrated varying effects of chemotherapy on the prognosis of UC with different histological subtypes, which might explain the reason why studies focusing on adjuvant chemotherapy have yielded conflicting outcomes. Apart from histological subtypes, other factors were reported to influence the prognosis of UC. Dabi et al. ( 2018 ) found that higher BMI was associated with higher cancer-specific mortality in patients treated with radical nephroureterectomy for upper tract urothelial carcinoma. Van et al. (Osch et al. 2016 ) discovered that lifetime cigarette smokers were at increased risk for a more malignant type of urothelial carcinoma associated with a worse prognosis. According to Tai et al. ( 2015 ), diabetes mellitus with poor glycemic control increases bladder cancer recurrence risk in patients with upper urinary tract urothelial carcinoma. Raj et al. ( 2006 ) discovered that patients with involved ureters and/or ureteral anastomotic margins have a higher risk of upper tract recurrence. Inamoto et al. ( 2020 ) reported that Patients with lower ureteral tumors had a higher prevalence of deaths compared to patients with upper ureter tumors. Fibroblast growth factor receptor 3 mutation were reported to exacerbate the treatment of UC patients (Song, et al. 2023 ).

Shinohara et al. ( 1995 ) performed clinical investigation of 93 patients with upper urinary tract urothelial carcinoma. They observed that chemotherapy had no impact on survival across all stages compared to the non-chemotherapy group. However only for T3/T4 cases, cisplatin-based chemotherapy improved the prognosis compared with patients without chemotherapy, which is consistent with our findings.

UC is a clinically important disease that carries a particularly unfavorable prognosis. Among all the histological types, patients with papillary urothelial carcinoma exhibited the most favorable prognosis. Chemotherapy yielded diverse effects across various histological types of UC. Statistically, chemotherapy demonstrated a positive impact on the prognosis of patients with non-papillary urothelial carcinoma, whereas its effect on patients with papillary urothelial carcinoma lacked statistical significance. Different T stages exhibited varying benefits from chemotherapy, with T3/T4 cases potentially benefiting more, while T1/T2 cases may not derive benefits from chemotherapy. According to our results, evaluation of cancer histological type and T stage in UC patients prior to chemotherapy is mandatory.

Availability of data and materials

The dataset used in the present study could be accessed from SEER.

Audenet F et al (2013) The role of chemotherapy in the treatment of urothelial cell carcinoma of the upper urinary tract (UUT-UCC). Urol Oncol 31(4):407–413

Article   CAS   PubMed   Google Scholar  

Beadsmoore CJ, Screaton NJ (2003) Classification, staging and prognosis of lung cancer. Eur J Radiol 45(1):8–17

Birtle A et al (2020) Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial. Lancet 395(10232):1268–1277

Article   CAS   PubMed   PubMed Central   Google Scholar  

Dabi Y et al (2018) Impact of body mass index on the oncological outcomes of patients treated with radical nephroureterectomy for upper tract urothelial carcinoma. World J Urol 36(1):65–71

Article   PubMed   Google Scholar  

Davy ML et al (2003) Cervical cancer: effect of glandular cell type on prognosis, treatment, and survival. Obstet Gynecol 101(1):38–45

PubMed   Google Scholar  

Deuker M et al (2021) Upper urinary tract tumors: variant histology versus urothelial carcinoma. Clin Genitourin Cancer 19(2):117–124

Dogliotti L et al (2007) Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol 52(1):134–141

Fujii Y et al (2021) Molecular classification and diagnostics of upper urinary tract urothelial carcinoma. Cancer Cell 39(6):793-809.e8

Fukushi K et al (2017) Quality-of-life evaluation during platinum-based neoadjuvant chemotherapies for urothelial carcinoma. Int J Clin Oncol 22(2):366–372

Hosogoe S et al (2018) Platinum-based neoadjuvant chemotherapy improves oncological outcomes in patients with locally advanced upper tract urothelial carcinoma. Eur Urol Focus 4(6):946–953

Inamoto T et al (2020) Tumor location based segmentation in upper-tract urothelial carcinoma impacts on the urothelial recurrence-free survival: a multi-institutional database study. Curr Urol 14(4):183–190

Article   PubMed   PubMed Central   Google Scholar  

Koie T et al (2013) Efficacies and safety of neoadjuvant gemcitabine plus carboplatin followed by immediate cystectomy in patients with muscle-invasive bladder cancer, including those unfit for cisplatin: a prospective single-arm study. Int J Clin Oncol 18(4):724–730

Koie T et al (2014) Neoadjuvant gemcitabine and carboplatin followed by immediate cystectomy may be associated with a survival benefit in patients with clinical T2 bladder cancer. Med Oncol 31(5):949

Lee SE et al (2006) Adjuvant chemotherapy in the management of pT3N0M0 transitional cell carcinoma of the upper urinary tract. Urol Int 77(1):22–26

Leow JJ et al (2021) Neoadjuvant and adjuvant chemotherapy for upper tract urothelial carcinoma: a 2020 systematic review and meta-analysis, and future perspectives on systemic therapy. Eur Urol 79(5):635–654

Matin SF et al (2010) Incidence of downstaging and complete remission after neoadjuvant chemotherapy for high-risk upper tract transitional cell carcinoma. Cancer 116(13):3127–3134

Ohyama C et al (2014) Neoadjuvant chemotherapy with gemcitabine plus carboplatin followed by immediate radical cystectomy for muscle-invasive bladder cancer. Int J Urol 21(1):3–4

Park JH et al (2013) Combination of gemcitabine and carboplatin as first line treatment in elderly patients or those unfit for cisplatin-based chemotherapy with advanced transitional cell carcinoma of the urinary tract. Cancer Chemother Pharmacol 71(4):1033–1039

Raj GV et al (2006) Significance of intraoperative ureteral evaluation at radical cystectomy for urothelial cancer. Cancer 107(9):2167–2172

Rouprêt M et al (2018) European association of urology guidelines on upper urinary tract urothelial carcinoma: 2017 update. Eur Urol 73(1):111–122

Rouprêt M et al (2021) European association of urology guidelines on upper urinary tract urothelial carcinoma: 2020 update. Eur Urol 79(1):62–79

Rouprêt M et al (2023) European association of urology guidelines on upper urinary tract urothelial carcinoma: 2023 update. Eur Urol 84(1):49–64

Shinohara M et al (1995) Clinical investigation of renal pelvic and ureteral cancer with special reference to adjuvant chemotherapy. Nihon Hinyokika Gakkai Zasshi 86(8):1375–1382

CAS   PubMed   Google Scholar  

Siegel RL et al (2021) Cancer statistics, 2021. CA Cancer J Clin 71(1):7–33

Soga N, Arima K, Sugimura Y (2008) Adjuvant methotrexate, vinblastine, adriamycin, and cisplatin chemotherapy has potential to prevent recurrence of bladder tumors after surgical removal of upper urinary tract transitional cell carcinoma. Int J Urol 15(9):800–803

Song Y et al (2023) Fibroblast growth factor receptor 3 mutation attenuates response to immune checkpoint blockade in metastatic urothelial carcinoma by driving immunosuppressive microenvironment. J Immunother Cancer 11(9):e006643. https://doi.org/10.1136/jitc-2022-006643

Song E et al (2023) Variant histology in upper tract carcinomas: analysis of the national cancer database. Urol Oncol 41(4):206.e1-206.e9

Tai YS et al (2015) Diabetes mellitus with poor glycemic control increases bladder cancer recurrence risk in patients with upper urinary tract urothelial carcinoma. Diabetes Metab Res Rev 31(3):307–314

Thomas CY, Hemal AK (2013) Impact of renal function on eligibility for chemotherapy and survival in patients who have undergone radical nephro-ureterectomy. BJU Int 112(4):425–426

van Osch FH et al (2016) Significant role of lifetime cigarette smoking in worsening bladder cancer and upper tract urothelial carcinoma prognosis: a meta-analysis. J Urol 195(4 Pt 1):872–879

Zhou J, Ding J, Qi J (2022) Comparison of typical prostate adenocarcinoma and rare histological variant prostate cancer showed different characteristics and prognosis: a surveillance, epidemiology, and end results database analysis. Eur Urol 82(2):152–155

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Acknowledgements

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This research was supported by National Key Research and Development Program of China (2018YFA0902802), Beijing Municipal Science & Technology Commission (Z221100007422058), Peking University People’s Hospital Scientific Research Development Funds (RDGS2022-02), Natural science foundation of Beijing, China (7242150), National Natural Science Foundation of China (82271877), and National Natural Science Foundation of China (82071777).

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Jincong Li and Yuxuan Song are contributed equally to this work.

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Department of Urology, Peking University People’s Hospital, Beijing, 100044, China

Jincong Li, Yuxuan Song, Yun Peng, Jiaxing Lin, Yiqing Du, Caipeng Qin & Tao Xu

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JC-L: Data management, Data analysis, Manuscript writing, Project development. YX-S: Manuscript writing, Project development. TX: Project development, Conception and design. YP: Conception and design. JX-L: Conception and design. YQ-D: Conception and design. CP-Q: Conception and design.

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Supplementary file 1: Supplementary table 1. Classification of all the histological types. Supplementary table 2. Cox regression analysis evaluating variables associated with overall survival of patients with non-papillary urothelial carcinoma. Supplementary table 3. Cox regression analysis evaluating variables associated with overall survival of patients with papillary urothelial carcinoma. Supplementary table 4. Cox regression analysis evaluating variables associated with overall survival of patients with atypical UC. Supplementary table 5. Cox regression analysis evaluating variables associated with overall survival of patients with T1 UC. Supplementary table 6. Cox regression analysis evaluating variables associated with overall survival of patients with T2 UC. Supplementary table 7. Cox regression analysis evaluating variables associated with overall survival of patients with T3/T4 UC. Supplementary figure 1. Effects of chemotherapy on prognosis of different histological types (A) Effects of chemotherapy on patients with squamous cell carcinoma (B) Effects of chemotherapy on patients with small cell carcinoma (C) Effects of chemotherapy on patients with spindle cell carcinoma (D) Effects of chemotherapy on patients with adenocarcinoma (E)Effects of chemotherapy on patients with papillary carcinoma

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Li, J., Song, Y., Peng, Y. et al. The role of histological subtype and chemotherapy on prognosis of ureteral cancer. J Cancer Res Clin Oncol 150 , 192 (2024). https://doi.org/10.1007/s00432-024-05684-8

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Received : 02 February 2024

Accepted : 04 March 2024

Published : 13 April 2024

DOI : https://doi.org/10.1007/s00432-024-05684-8

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