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How to Write a Literature Review | Guide, Examples, & Templates

How to Write a Literature Review | Guide, Examples, & Templates

Published on January 2, 2023 by Shona McCombes . Revised on September 11, 2023.

What is a literature review? A literature review is a survey of scholarly sources on a specific topic. It provides an overview of current knowledge, allowing you to identify relevant theories, methods, and gaps in the existing research that you can later apply to your paper, thesis, or dissertation topic .

There are five key steps to writing a literature review:

Search for relevant literature
Evaluate sources
Identify themes, debates, and gaps
Outline the structure
Write your literature review

A good literature review doesn’t just summarize sources—it analyzes, synthesizes , and critically evaluates to give a clear picture of the state of knowledge on the subject.

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What is the purpose of a literature review, examples of literature reviews, step 1 – search for relevant literature, step 2 – evaluate and select sources, step 3 – identify themes, debates, and gaps, step 4 – outline your literature review’s structure, step 5 – write your literature review, free lecture slides, other interesting articles, frequently asked questions, introduction.

Quick Run-through
Step 1 & 2

When you write a thesis , dissertation , or research paper , you will likely have to conduct a literature review to situate your research within existing knowledge. The literature review gives you a chance to:

Demonstrate your familiarity with the topic and its scholarly context
Develop a theoretical framework and methodology for your research
Position your work in relation to other researchers and theorists
Show how your research addresses a gap or contributes to a debate
Evaluate the current state of research and demonstrate your knowledge of the scholarly debates around your topic.

Writing literature reviews is a particularly important skill if you want to apply for graduate school or pursue a career in research. We’ve written a step-by-step guide that you can follow below.

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Writing literature reviews can be quite challenging! A good starting point could be to look at some examples, depending on what kind of literature review you’d like to write.

Example literature review #1: “Why Do People Migrate? A Review of the Theoretical Literature” ( Theoretical literature review about the development of economic migration theory from the 1950s to today.)
Example literature review #2: “Literature review as a research methodology: An overview and guidelines” ( Methodological literature review about interdisciplinary knowledge acquisition and production.)
Example literature review #3: “The Use of Technology in English Language Learning: A Literature Review” ( Thematic literature review about the effects of technology on language acquisition.)
Example literature review #4: “Learners’ Listening Comprehension Difficulties in English Language Learning: A Literature Review” ( Chronological literature review about how the concept of listening skills has changed over time.)

You can also check out our templates with literature review examples and sample outlines at the links below.

Download Word doc Download Google doc

Before you begin searching for literature, you need a clearly defined topic .

If you are writing the literature review section of a dissertation or research paper, you will search for literature related to your research problem and questions .

Make a list of keywords

Start by creating a list of keywords related to your research question. Include each of the key concepts or variables you’re interested in, and list any synonyms and related terms. You can add to this list as you discover new keywords in the process of your literature search.

Social media, Facebook, Instagram, Twitter, Snapchat, TikTok
Body image, self-perception, self-esteem, mental health
Generation Z, teenagers, adolescents, youth

Search for relevant sources

Use your keywords to begin searching for sources. Some useful databases to search for journals and articles include:

Your university’s library catalogue
Google Scholar
Project Muse (humanities and social sciences)
Medline (life sciences and biomedicine)
EconLit (economics)
Inspec (physics, engineering and computer science)

You can also use boolean operators to help narrow down your search.

Make sure to read the abstract to find out whether an article is relevant to your question. When you find a useful book or article, you can check the bibliography to find other relevant sources.

You likely won’t be able to read absolutely everything that has been written on your topic, so it will be necessary to evaluate which sources are most relevant to your research question.

For each publication, ask yourself:

What question or problem is the author addressing?
What are the key concepts and how are they defined?
What are the key theories, models, and methods?
Does the research use established frameworks or take an innovative approach?
What are the results and conclusions of the study?
How does the publication relate to other literature in the field? Does it confirm, add to, or challenge established knowledge?
What are the strengths and weaknesses of the research?

Make sure the sources you use are credible , and make sure you read any landmark studies and major theories in your field of research.

You can use our template to summarize and evaluate sources you’re thinking about using. Click on either button below to download.

Take notes and cite your sources

As you read, you should also begin the writing process. Take notes that you can later incorporate into the text of your literature review.

It is important to keep track of your sources with citations to avoid plagiarism . It can be helpful to make an annotated bibliography , where you compile full citation information and write a paragraph of summary and analysis for each source. This helps you remember what you read and saves time later in the process.

Prevent plagiarism. Run a free check.

To begin organizing your literature review’s argument and structure, be sure you understand the connections and relationships between the sources you’ve read. Based on your reading and notes, you can look for:

Trends and patterns (in theory, method or results): do certain approaches become more or less popular over time?
Themes: what questions or concepts recur across the literature?
Debates, conflicts and contradictions: where do sources disagree?
Pivotal publications: are there any influential theories or studies that changed the direction of the field?
Gaps: what is missing from the literature? Are there weaknesses that need to be addressed?

This step will help you work out the structure of your literature review and (if applicable) show how your own research will contribute to existing knowledge.

Most research has focused on young women.
There is an increasing interest in the visual aspects of social media.
But there is still a lack of robust research on highly visual platforms like Instagram and Snapchat—this is a gap that you could address in your own research.

There are various approaches to organizing the body of a literature review. Depending on the length of your literature review, you can combine several of these strategies (for example, your overall structure might be thematic, but each theme is discussed chronologically).

Chronological

The simplest approach is to trace the development of the topic over time. However, if you choose this strategy, be careful to avoid simply listing and summarizing sources in order.

Try to analyze patterns, turning points and key debates that have shaped the direction of the field. Give your interpretation of how and why certain developments occurred.

If you have found some recurring central themes, you can organize your literature review into subsections that address different aspects of the topic.

For example, if you are reviewing literature about inequalities in migrant health outcomes, key themes might include healthcare policy, language barriers, cultural attitudes, legal status, and economic access.

Methodological

If you draw your sources from different disciplines or fields that use a variety of research methods , you might want to compare the results and conclusions that emerge from different approaches. For example:

Look at what results have emerged in qualitative versus quantitative research
Discuss how the topic has been approached by empirical versus theoretical scholarship
Divide the literature into sociological, historical, and cultural sources

Theoretical

A literature review is often the foundation for a theoretical framework . You can use it to discuss various theories, models, and definitions of key concepts.

You might argue for the relevance of a specific theoretical approach, or combine various theoretical concepts to create a framework for your research.

Like any other academic text , your literature review should have an introduction , a main body, and a conclusion . What you include in each depends on the objective of your literature review.

The introduction should clearly establish the focus and purpose of the literature review.

Depending on the length of your literature review, you might want to divide the body into subsections. You can use a subheading for each theme, time period, or methodological approach.

As you write, you can follow these tips:

Summarize and synthesize: give an overview of the main points of each source and combine them into a coherent whole
Analyze and interpret: don’t just paraphrase other researchers — add your own interpretations where possible, discussing the significance of findings in relation to the literature as a whole
Critically evaluate: mention the strengths and weaknesses of your sources
Write in well-structured paragraphs: use transition words and topic sentences to draw connections, comparisons and contrasts

In the conclusion, you should summarize the key findings you have taken from the literature and emphasize their significance.

When you’ve finished writing and revising your literature review, don’t forget to proofread thoroughly before submitting. Not a language expert? Check out Scribbr’s professional proofreading services !

This article has been adapted into lecture slides that you can use to teach your students about writing a literature review.

Scribbr slides are free to use, customize, and distribute for educational purposes.

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

Sampling methods
Simple random sampling
Stratified sampling
Cluster sampling
Likert scales
Reproducibility

Statistics

Null hypothesis
Statistical power
Probability distribution
Effect size
Poisson distribution

Research bias

Optimism bias
Cognitive bias
Implicit bias
Hawthorne effect
Anchoring bias
Explicit bias

A literature review is a survey of scholarly sources (such as books, journal articles, and theses) related to a specific topic or research question .

It is often written as part of a thesis, dissertation , or research paper , in order to situate your work in relation to existing knowledge.

There are several reasons to conduct a literature review at the beginning of a research project:

To familiarize yourself with the current state of knowledge on your topic
To ensure that you’re not just repeating what others have already done
To identify gaps in knowledge and unresolved problems that your research can address
To develop your theoretical framework and methodology
To provide an overview of the key findings and debates on the topic

Writing the literature review shows your reader how your work relates to existing research and what new insights it will contribute.

The literature review usually comes near the beginning of your thesis or dissertation . After the introduction , it grounds your research in a scholarly field and leads directly to your theoretical framework or methodology .

A literature review is a survey of credible sources on a topic, often used in dissertations , theses, and research papers . Literature reviews give an overview of knowledge on a subject, helping you identify relevant theories and methods, as well as gaps in existing research. Literature reviews are set up similarly to other academic texts , with an introduction , a main body, and a conclusion .

An annotated bibliography is a list of source references that has a short description (called an annotation ) for each of the sources. It is often assigned as part of the research process for a paper .

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UConn Library
Literature Review: The What, Why and How-to Guide
Introduction

Literature Review: The What, Why and How-to Guide — Introduction

Getting Started
How to Pick a Topic
Strategies to Find Sources
Evaluating Sources & Lit. Reviews
Tips for Writing Literature Reviews
Writing Literature Review: Useful Sites
Citation Resources
Other Academic Writings

What are Literature Reviews?

So, what is a literature review? "A literature review is an account of what has been published on a topic by accredited scholars and researchers. In writing the literature review, your purpose is to convey to your reader what knowledge and ideas have been established on a topic, and what their strengths and weaknesses are. As a piece of writing, the literature review must be defined by a guiding concept (e.g., your research objective, the problem or issue you are discussing, or your argumentative thesis). It is not just a descriptive list of the material available, or a set of summaries." Taylor, D. The literature review: A few tips on conducting it . University of Toronto Health Sciences Writing Centre.

Goals of Literature Reviews

What are the goals of creating a Literature Review? A literature could be written to accomplish different aims:

To develop a theory or evaluate an existing theory
To summarize the historical or existing state of a research topic
Identify a problem in a field of research

Baumeister, R. F., & Leary, M. R. (1997). Writing narrative literature reviews . Review of General Psychology , 1 (3), 311-320.

What kinds of sources require a Literature Review?

A research paper assigned in a course
A thesis or dissertation
A grant proposal
An article intended for publication in a journal

All these instances require you to collect what has been written about your research topic so that you can demonstrate how your own research sheds new light on the topic.

Types of Literature Reviews

What kinds of literature reviews are written?

Narrative review: The purpose of this type of review is to describe the current state of the research on a specific topic/research and to offer a critical analysis of the literature reviewed. Studies are grouped by research/theoretical categories, and themes and trends, strengths and weakness, and gaps are identified. The review ends with a conclusion section which summarizes the findings regarding the state of the research of the specific study, the gaps identify and if applicable, explains how the author's research will address gaps identify in the review and expand the knowledge on the topic reviewed.

Example : Predictors and Outcomes of U.S. Quality Maternity Leave: A Review and Conceptual Framework: 10.1177/08948453211037398

Systematic review : "The authors of a systematic review use a specific procedure to search the research literature, select the studies to include in their review, and critically evaluate the studies they find." (p. 139). Nelson, L. K. (2013). Research in Communication Sciences and Disorders . Plural Publishing.

Example : The effect of leave policies on increasing fertility: a systematic review: 10.1057/s41599-022-01270-w

Meta-analysis : "Meta-analysis is a method of reviewing research findings in a quantitative fashion by transforming the data from individual studies into what is called an effect size and then pooling and analyzing this information. The basic goal in meta-analysis is to explain why different outcomes have occurred in different studies." (p. 197). Roberts, M. C., & Ilardi, S. S. (2003). Handbook of Research Methods in Clinical Psychology . Blackwell Publishing.

Example : Employment Instability and Fertility in Europe: A Meta-Analysis: 10.1215/00703370-9164737

Meta-synthesis : "Qualitative meta-synthesis is a type of qualitative study that uses as data the findings from other qualitative studies linked by the same or related topic." (p.312). Zimmer, L. (2006). Qualitative meta-synthesis: A question of dialoguing with texts . Journal of Advanced Nursing , 53 (3), 311-318.

Example : Women’s perspectives on career successes and barriers: A qualitative meta-synthesis: 10.1177/05390184221113735

Literature Reviews in the Health Sciences

UConn Health subject guide on systematic reviews Explanation of the different review types used in health sciences literature as well as tools to help you find the right review type
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Next: How to Pick a Topic >>
Last Updated: Sep 21, 2022 2:16 PM
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YSN Doctoral Programs: Steps in Conducting a Literature Review

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Steps in Conducting a Literature Review

What is a literature review?

A literature review is an integrated analysis -- not just a summary-- of scholarly writings and other relevant evidence related directly to your research question. That is, it represents a synthesis of the evidence that provides background information on your topic and shows a association between the evidence and your research question.

A literature review may be a stand alone work or the introduction to a larger research paper, depending on the assignment. Rely heavily on the guidelines your instructor has given you.

Why is it important?

A literature review is important because it:

Explains the background of research on a topic.
Demonstrates why a topic is significant to a subject area.
Discovers relationships between research studies/ideas.
Identifies major themes, concepts, and researchers on a topic.
Identifies critical gaps and points of disagreement.
Discusses further research questions that logically come out of the previous studies.

APA7 Style resources

APA Style Blog - for those harder to find answers

1. Choose a topic. Define your research question.

Your literature review should be guided by your central research question. The literature represents background and research developments related to a specific research question, interpreted and analyzed by you in a synthesized way.

Make sure your research question is not too broad or too narrow. Is it manageable?
Begin writing down terms that are related to your question. These will be useful for searches later.
If you have the opportunity, discuss your topic with your professor and your class mates.

2. Decide on the scope of your review

How many studies do you need to look at? How comprehensive should it be? How many years should it cover?

This may depend on your assignment. How many sources does the assignment require?

3. Select the databases you will use to conduct your searches.

Make a list of the databases you will search.

Where to find databases:

use the tabs on this guide
Find other databases in the Nursing Information Resources web page
More on the Medical Library web page
... and more on the Yale University Library web page

4. Conduct your searches to find the evidence. Keep track of your searches.

Use the key words in your question, as well as synonyms for those words, as terms in your search. Use the database tutorials for help.
Save the searches in the databases. This saves time when you want to redo, or modify, the searches. It is also helpful to use as a guide is the searches are not finding any useful results.
Review the abstracts of research studies carefully. This will save you time.
Use the bibliographies and references of research studies you find to locate others.
Check with your professor, or a subject expert in the field, if you are missing any key works in the field.
Ask your librarian for help at any time.
Use a citation manager, such as EndNote as the repository for your citations. See the EndNote tutorials for help.

Review the literature

Some questions to help you analyze the research:

What was the research question of the study you are reviewing? What were the authors trying to discover?
Was the research funded by a source that could influence the findings?
What were the research methodologies? Analyze its literature review, the samples and variables used, the results, and the conclusions.
Does the research seem to be complete? Could it have been conducted more soundly? What further questions does it raise?
If there are conflicting studies, why do you think that is?
How are the authors viewed in the field? Has this study been cited? If so, how has it been analyzed?

Tips:

Review the abstracts carefully.
Keep careful notes so that you may track your thought processes during the research process.
Create a matrix of the studies for easy analysis, and synthesis, across all of the studies.
<< Previous: Recommended Books
Last Updated: Jun 20, 2024 9:08 AM
URL: https://guides.library.yale.edu/YSNDoctoral

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Writing a Literature Review

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A literature review is a document or section of a document that collects key sources on a topic and discusses those sources in conversation with each other (also called synthesis ). The lit review is an important genre in many disciplines, not just literature (i.e., the study of works of literature such as novels and plays). When we say “literature review” or refer to “the literature,” we are talking about the research ( scholarship ) in a given field. You will often see the terms “the research,” “the scholarship,” and “the literature” used mostly interchangeably.

Where, when, and why would I write a lit review?

There are a number of different situations where you might write a literature review, each with slightly different expectations; different disciplines, too, have field-specific expectations for what a literature review is and does. For instance, in the humanities, authors might include more overt argumentation and interpretation of source material in their literature reviews, whereas in the sciences, authors are more likely to report study designs and results in their literature reviews; these differences reflect these disciplines’ purposes and conventions in scholarship. You should always look at examples from your own discipline and talk to professors or mentors in your field to be sure you understand your discipline’s conventions, for literature reviews as well as for any other genre.

A literature review can be a part of a research paper or scholarly article, usually falling after the introduction and before the research methods sections. In these cases, the lit review just needs to cover scholarship that is important to the issue you are writing about; sometimes it will also cover key sources that informed your research methodology.

Lit reviews can also be standalone pieces, either as assignments in a class or as publications. In a class, a lit review may be assigned to help students familiarize themselves with a topic and with scholarship in their field, get an idea of the other researchers working on the topic they’re interested in, find gaps in existing research in order to propose new projects, and/or develop a theoretical framework and methodology for later research. As a publication, a lit review usually is meant to help make other scholars’ lives easier by collecting and summarizing, synthesizing, and analyzing existing research on a topic. This can be especially helpful for students or scholars getting into a new research area, or for directing an entire community of scholars toward questions that have not yet been answered.

What are the parts of a lit review?

Most lit reviews use a basic introduction-body-conclusion structure; if your lit review is part of a larger paper, the introduction and conclusion pieces may be just a few sentences while you focus most of your attention on the body. If your lit review is a standalone piece, the introduction and conclusion take up more space and give you a place to discuss your goals, research methods, and conclusions separately from where you discuss the literature itself.

Introduction:

An introductory paragraph that explains what your working topic and thesis is
A forecast of key topics or texts that will appear in the review
Potentially, a description of how you found sources and how you analyzed them for inclusion and discussion in the review (more often found in published, standalone literature reviews than in lit review sections in an article or research paper)
Summarize and synthesize: Give an overview of the main points of each source and combine them into a coherent whole
Analyze and interpret: Don’t just paraphrase other researchers – add your own interpretations where possible, discussing the significance of findings in relation to the literature as a whole
Critically Evaluate: Mention the strengths and weaknesses of your sources
Write in well-structured paragraphs: Use transition words and topic sentence to draw connections, comparisons, and contrasts.

Conclusion:

Summarize the key findings you have taken from the literature and emphasize their significance
Connect it back to your primary research question

How should I organize my lit review?

Lit reviews can take many different organizational patterns depending on what you are trying to accomplish with the review. Here are some examples:

Chronological : The simplest approach is to trace the development of the topic over time, which helps familiarize the audience with the topic (for instance if you are introducing something that is not commonly known in your field). If you choose this strategy, be careful to avoid simply listing and summarizing sources in order. Try to analyze the patterns, turning points, and key debates that have shaped the direction of the field. Give your interpretation of how and why certain developments occurred (as mentioned previously, this may not be appropriate in your discipline — check with a teacher or mentor if you’re unsure).
Thematic : If you have found some recurring central themes that you will continue working with throughout your piece, you can organize your literature review into subsections that address different aspects of the topic. For example, if you are reviewing literature about women and religion, key themes can include the role of women in churches and the religious attitude towards women.
Qualitative versus quantitative research
Empirical versus theoretical scholarship
Divide the research by sociological, historical, or cultural sources
Theoretical : In many humanities articles, the literature review is the foundation for the theoretical framework. You can use it to discuss various theories, models, and definitions of key concepts. You can argue for the relevance of a specific theoretical approach or combine various theorical concepts to create a framework for your research.

What are some strategies or tips I can use while writing my lit review?

Any lit review is only as good as the research it discusses; make sure your sources are well-chosen and your research is thorough. Don’t be afraid to do more research if you discover a new thread as you’re writing. More info on the research process is available in our "Conducting Research" resources .

As you’re doing your research, create an annotated bibliography ( see our page on the this type of document ). Much of the information used in an annotated bibliography can be used also in a literature review, so you’ll be not only partially drafting your lit review as you research, but also developing your sense of the larger conversation going on among scholars, professionals, and any other stakeholders in your topic.

Usually you will need to synthesize research rather than just summarizing it. This means drawing connections between sources to create a picture of the scholarly conversation on a topic over time. Many student writers struggle to synthesize because they feel they don’t have anything to add to the scholars they are citing; here are some strategies to help you:

It often helps to remember that the point of these kinds of syntheses is to show your readers how you understand your research, to help them read the rest of your paper.
Writing teachers often say synthesis is like hosting a dinner party: imagine all your sources are together in a room, discussing your topic. What are they saying to each other?
Look at the in-text citations in each paragraph. Are you citing just one source for each paragraph? This usually indicates summary only. When you have multiple sources cited in a paragraph, you are more likely to be synthesizing them (not always, but often
Read more about synthesis here.

The most interesting literature reviews are often written as arguments (again, as mentioned at the beginning of the page, this is discipline-specific and doesn’t work for all situations). Often, the literature review is where you can establish your research as filling a particular gap or as relevant in a particular way. You have some chance to do this in your introduction in an article, but the literature review section gives a more extended opportunity to establish the conversation in the way you would like your readers to see it. You can choose the intellectual lineage you would like to be part of and whose definitions matter most to your thinking (mostly humanities-specific, but this goes for sciences as well). In addressing these points, you argue for your place in the conversation, which tends to make the lit review more compelling than a simple reporting of other sources.

Methodological Approaches to Literature Review

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First Online: 09 May 2023
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Dennis Thomas 2 ,
Elida Zairina 3 &
Johnson George 4

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The literature review can serve various functions in the contexts of education and research. It aids in identifying knowledge gaps, informing research methodology, and developing a theoretical framework during the planning stages of a research study or project, as well as reporting of review findings in the context of the existing literature. This chapter discusses the methodological approaches to conducting a literature review and offers an overview of different types of reviews. There are various types of reviews, including narrative reviews, scoping reviews, and systematic reviews with reporting strategies such as meta-analysis and meta-synthesis. Review authors should consider the scope of the literature review when selecting a type and method. Being focused is essential for a successful review; however, this must be balanced against the relevance of the review to a broad audience.

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Reviewing Literature for and as Research

Discussion and Conclusion

Systematic Reviews in Educational Research: Methodology, Perspectives and Application

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Thomas, D., Zairina, E., George, J. (2023). Methodological Approaches to Literature Review. In: Encyclopedia of Evidence in Pharmaceutical Public Health and Health Services Research in Pharmacy. Springer, Cham. https://doi.org/10.1007/978-3-030-50247-8_57-1

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What is a Literature Review? | Guide, Template, & Examples

What is a Literature Review? | Guide, Template, & Examples

Published on 22 February 2022 by Shona McCombes . Revised on 7 June 2022.

There are five key steps to writing a literature review:

Search for relevant literature
Evaluate sources
Identify themes, debates and gaps
Outline the structure
Write your literature review

A good literature review doesn’t just summarise sources – it analyses, synthesises, and critically evaluates to give a clear picture of the state of knowledge on the subject.

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Why write a literature review, examples of literature reviews, step 1: search for relevant literature, step 2: evaluate and select sources, step 3: identify themes, debates and gaps, step 4: outline your literature review’s structure, step 5: write your literature review, frequently asked questions about literature reviews, introduction.

Quick Run-through
Step 1 & 2

When you write a dissertation or thesis, you will have to conduct a literature review to situate your research within existing knowledge. The literature review gives you a chance to:

Demonstrate your familiarity with the topic and scholarly context
Develop a theoretical framework and methodology for your research
Position yourself in relation to other researchers and theorists
Show how your dissertation addresses a gap or contributes to a debate

You might also have to write a literature review as a stand-alone assignment. In this case, the purpose is to evaluate the current state of research and demonstrate your knowledge of scholarly debates around a topic.

The content will look slightly different in each case, but the process of conducting a literature review follows the same steps. We’ve written a step-by-step guide that you can follow below.

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Writing literature reviews can be quite challenging! A good starting point could be to look at some examples, depending on what kind of literature review you’d like to write.

Example literature review #1: “Why Do People Migrate? A Review of the Theoretical Literature” ( Theoretical literature review about the development of economic migration theory from the 1950s to today.)
Example literature review #2: “Literature review as a research methodology: An overview and guidelines” ( Methodological literature review about interdisciplinary knowledge acquisition and production.)
Example literature review #3: “The Use of Technology in English Language Learning: A Literature Review” ( Thematic literature review about the effects of technology on language acquisition.)
Example literature review #4: “Learners’ Listening Comprehension Difficulties in English Language Learning: A Literature Review” ( Chronological literature review about how the concept of listening skills has changed over time.)

You can also check out our templates with literature review examples and sample outlines at the links below.

Download Word doc Download Google doc

Before you begin searching for literature, you need a clearly defined topic .

If you are writing the literature review section of a dissertation or research paper, you will search for literature related to your research objectives and questions .

If you are writing a literature review as a stand-alone assignment, you will have to choose a focus and develop a central question to direct your search. Unlike a dissertation research question, this question has to be answerable without collecting original data. You should be able to answer it based only on a review of existing publications.

Make a list of keywords

Start by creating a list of keywords related to your research topic. Include each of the key concepts or variables you’re interested in, and list any synonyms and related terms. You can add to this list if you discover new keywords in the process of your literature search.

Social media, Facebook, Instagram, Twitter, Snapchat, TikTok
Body image, self-perception, self-esteem, mental health
Generation Z, teenagers, adolescents, youth

Search for relevant sources

Use your keywords to begin searching for sources. Some databases to search for journals and articles include:

Your university’s library catalogue
Google Scholar
Project Muse (humanities and social sciences)
Medline (life sciences and biomedicine)
EconLit (economics)
Inspec (physics, engineering and computer science)

You can use boolean operators to help narrow down your search:

Read the abstract to find out whether an article is relevant to your question. When you find a useful book or article, you can check the bibliography to find other relevant sources.

To identify the most important publications on your topic, take note of recurring citations. If the same authors, books or articles keep appearing in your reading, make sure to seek them out.

You probably won’t be able to read absolutely everything that has been written on the topic – you’ll have to evaluate which sources are most relevant to your questions.

For each publication, ask yourself:

What question or problem is the author addressing?
What are the key concepts and how are they defined?
What are the key theories, models and methods? Does the research use established frameworks or take an innovative approach?
What are the results and conclusions of the study?
How does the publication relate to other literature in the field? Does it confirm, add to, or challenge established knowledge?
How does the publication contribute to your understanding of the topic? What are its key insights and arguments?
What are the strengths and weaknesses of the research?

Make sure the sources you use are credible, and make sure you read any landmark studies and major theories in your field of research.

You can find out how many times an article has been cited on Google Scholar – a high citation count means the article has been influential in the field, and should certainly be included in your literature review.

The scope of your review will depend on your topic and discipline: in the sciences you usually only review recent literature, but in the humanities you might take a long historical perspective (for example, to trace how a concept has changed in meaning over time).

Remember that you can use our template to summarise and evaluate sources you’re thinking about using!

Take notes and cite your sources

As you read, you should also begin the writing process. Take notes that you can later incorporate into the text of your literature review.

It’s important to keep track of your sources with references to avoid plagiarism . It can be helpful to make an annotated bibliography, where you compile full reference information and write a paragraph of summary and analysis for each source. This helps you remember what you read and saves time later in the process.

You can use our free APA Reference Generator for quick, correct, consistent citations.

To begin organising your literature review’s argument and structure, you need to understand the connections and relationships between the sources you’ve read. Based on your reading and notes, you can look for:

Trends and patterns (in theory, method or results): do certain approaches become more or less popular over time?
Themes: what questions or concepts recur across the literature?
Debates, conflicts and contradictions: where do sources disagree?
Pivotal publications: are there any influential theories or studies that changed the direction of the field?
Gaps: what is missing from the literature? Are there weaknesses that need to be addressed?

This step will help you work out the structure of your literature review and (if applicable) show how your own research will contribute to existing knowledge.

Most research has focused on young women.
There is an increasing interest in the visual aspects of social media.
But there is still a lack of robust research on highly-visual platforms like Instagram and Snapchat – this is a gap that you could address in your own research.

There are various approaches to organising the body of a literature review. You should have a rough idea of your strategy before you start writing.

Depending on the length of your literature review, you can combine several of these strategies (for example, your overall structure might be thematic, but each theme is discussed chronologically).

Chronological

The simplest approach is to trace the development of the topic over time. However, if you choose this strategy, be careful to avoid simply listing and summarising sources in order.

Try to analyse patterns, turning points and key debates that have shaped the direction of the field. Give your interpretation of how and why certain developments occurred.

If you have found some recurring central themes, you can organise your literature review into subsections that address different aspects of the topic.

Methodological

Look at what results have emerged in qualitative versus quantitative research
Discuss how the topic has been approached by empirical versus theoretical scholarship
Divide the literature into sociological, historical, and cultural sources

Theoretical

A literature review is often the foundation for a theoretical framework . You can use it to discuss various theories, models, and definitions of key concepts.

You might argue for the relevance of a specific theoretical approach, or combine various theoretical concepts to create a framework for your research.

Like any other academic text, your literature review should have an introduction , a main body, and a conclusion . What you include in each depends on the objective of your literature review.

The introduction should clearly establish the focus and purpose of the literature review.

If you are writing the literature review as part of your dissertation or thesis, reiterate your central problem or research question and give a brief summary of the scholarly context. You can emphasise the timeliness of the topic (“many recent studies have focused on the problem of x”) or highlight a gap in the literature (“while there has been much research on x, few researchers have taken y into consideration”).

Depending on the length of your literature review, you might want to divide the body into subsections. You can use a subheading for each theme, time period, or methodological approach.

As you write, make sure to follow these tips:

Summarise and synthesise: give an overview of the main points of each source and combine them into a coherent whole.
Analyse and interpret: don’t just paraphrase other researchers – add your own interpretations, discussing the significance of findings in relation to the literature as a whole.
Critically evaluate: mention the strengths and weaknesses of your sources.
Write in well-structured paragraphs: use transitions and topic sentences to draw connections, comparisons and contrasts.

In the conclusion, you should summarise the key findings you have taken from the literature and emphasise their significance.

If the literature review is part of your dissertation or thesis, reiterate how your research addresses gaps and contributes new knowledge, or discuss how you have drawn on existing theories and methods to build a framework for your research. This can lead directly into your methodology section.

A literature review is a survey of scholarly sources (such as books, journal articles, and theses) related to a specific topic or research question .

It is often written as part of a dissertation , thesis, research paper , or proposal .

There are several reasons to conduct a literature review at the beginning of a research project:

To familiarise yourself with the current state of knowledge on your topic
To ensure that you’re not just repeating what others have already done
To identify gaps in knowledge and unresolved problems that your research can address
To develop your theoretical framework and methodology
To provide an overview of the key findings and debates on the topic

Writing the literature review shows your reader how your work relates to existing research and what new insights it will contribute.

The literature review usually comes near the beginning of your dissertation . After the introduction , it grounds your research in a scholarly field and leads directly to your theoretical framework or methodology .

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Home » Literature Review – Types Writing Guide and Examples

Literature Review – Types Writing Guide and Examples

Table of Contents

Literature Review

Definition:

A literature review is a comprehensive and critical analysis of the existing literature on a particular topic or research question. It involves identifying, evaluating, and synthesizing relevant literature, including scholarly articles, books, and other sources, to provide a summary and critical assessment of what is known about the topic.

Types of Literature Review

Types of Literature Review are as follows:

Narrative literature review : This type of review involves a comprehensive summary and critical analysis of the available literature on a particular topic or research question. It is often used as an introductory section of a research paper.
Systematic literature review: This is a rigorous and structured review that follows a pre-defined protocol to identify, evaluate, and synthesize all relevant studies on a specific research question. It is often used in evidence-based practice and systematic reviews.
Meta-analysis: This is a quantitative review that uses statistical methods to combine data from multiple studies to derive a summary effect size. It provides a more precise estimate of the overall effect than any individual study.
Scoping review: This is a preliminary review that aims to map the existing literature on a broad topic area to identify research gaps and areas for further investigation.
Critical literature review : This type of review evaluates the strengths and weaknesses of the existing literature on a particular topic or research question. It aims to provide a critical analysis of the literature and identify areas where further research is needed.
Conceptual literature review: This review synthesizes and integrates theories and concepts from multiple sources to provide a new perspective on a particular topic. It aims to provide a theoretical framework for understanding a particular research question.
Rapid literature review: This is a quick review that provides a snapshot of the current state of knowledge on a specific research question or topic. It is often used when time and resources are limited.
Thematic literature review : This review identifies and analyzes common themes and patterns across a body of literature on a particular topic. It aims to provide a comprehensive overview of the literature and identify key themes and concepts.
Realist literature review: This review is often used in social science research and aims to identify how and why certain interventions work in certain contexts. It takes into account the context and complexities of real-world situations.
State-of-the-art literature review : This type of review provides an overview of the current state of knowledge in a particular field, highlighting the most recent and relevant research. It is often used in fields where knowledge is rapidly evolving, such as technology or medicine.
Integrative literature review: This type of review synthesizes and integrates findings from multiple studies on a particular topic to identify patterns, themes, and gaps in the literature. It aims to provide a comprehensive understanding of the current state of knowledge on a particular topic.
Umbrella literature review : This review is used to provide a broad overview of a large and diverse body of literature on a particular topic. It aims to identify common themes and patterns across different areas of research.
Historical literature review: This type of review examines the historical development of research on a particular topic or research question. It aims to provide a historical context for understanding the current state of knowledge on a particular topic.
Problem-oriented literature review : This review focuses on a specific problem or issue and examines the literature to identify potential solutions or interventions. It aims to provide practical recommendations for addressing a particular problem or issue.
Mixed-methods literature review : This type of review combines quantitative and qualitative methods to synthesize and analyze the available literature on a particular topic. It aims to provide a more comprehensive understanding of the research question by combining different types of evidence.

Parts of Literature Review

Parts of a literature review are as follows:

Introduction

The introduction of a literature review typically provides background information on the research topic and why it is important. It outlines the objectives of the review, the research question or hypothesis, and the scope of the review.

Literature Search

This section outlines the search strategy and databases used to identify relevant literature. The search terms used, inclusion and exclusion criteria, and any limitations of the search are described.

Literature Analysis

The literature analysis is the main body of the literature review. This section summarizes and synthesizes the literature that is relevant to the research question or hypothesis. The review should be organized thematically, chronologically, or by methodology, depending on the research objectives.

Critical Evaluation

Critical evaluation involves assessing the quality and validity of the literature. This includes evaluating the reliability and validity of the studies reviewed, the methodology used, and the strength of the evidence.

The conclusion of the literature review should summarize the main findings, identify any gaps in the literature, and suggest areas for future research. It should also reiterate the importance of the research question or hypothesis and the contribution of the literature review to the overall research project.

The references list includes all the sources cited in the literature review, and follows a specific referencing style (e.g., APA, MLA, Harvard).

How to write Literature Review

Here are some steps to follow when writing a literature review:

Define your research question or topic : Before starting your literature review, it is essential to define your research question or topic. This will help you identify relevant literature and determine the scope of your review.
Conduct a comprehensive search: Use databases and search engines to find relevant literature. Look for peer-reviewed articles, books, and other academic sources that are relevant to your research question or topic.
Evaluate the sources: Once you have found potential sources, evaluate them critically to determine their relevance, credibility, and quality. Look for recent publications, reputable authors, and reliable sources of data and evidence.
Organize your sources: Group the sources by theme, method, or research question. This will help you identify similarities and differences among the literature, and provide a structure for your literature review.
Analyze and synthesize the literature : Analyze each source in depth, identifying the key findings, methodologies, and conclusions. Then, synthesize the information from the sources, identifying patterns and themes in the literature.
Write the literature review : Start with an introduction that provides an overview of the topic and the purpose of the literature review. Then, organize the literature according to your chosen structure, and analyze and synthesize the sources. Finally, provide a conclusion that summarizes the key findings of the literature review, identifies gaps in knowledge, and suggests areas for future research.
Edit and proofread: Once you have written your literature review, edit and proofread it carefully to ensure that it is well-organized, clear, and concise.

Examples of Literature Review

Here’s an example of how a literature review can be conducted for a thesis on the topic of “ The Impact of Social Media on Teenagers’ Mental Health”:

Start by identifying the key terms related to your research topic. In this case, the key terms are “social media,” “teenagers,” and “mental health.”
Use academic databases like Google Scholar, JSTOR, or PubMed to search for relevant articles, books, and other publications. Use these keywords in your search to narrow down your results.
Evaluate the sources you find to determine if they are relevant to your research question. You may want to consider the publication date, author’s credentials, and the journal or book publisher.
Begin reading and taking notes on each source, paying attention to key findings, methodologies used, and any gaps in the research.
Organize your findings into themes or categories. For example, you might categorize your sources into those that examine the impact of social media on self-esteem, those that explore the effects of cyberbullying, and those that investigate the relationship between social media use and depression.
Synthesize your findings by summarizing the key themes and highlighting any gaps or inconsistencies in the research. Identify areas where further research is needed.
Use your literature review to inform your research questions and hypotheses for your thesis.

For example, after conducting a literature review on the impact of social media on teenagers’ mental health, a thesis might look like this:

“Using a mixed-methods approach, this study aims to investigate the relationship between social media use and mental health outcomes in teenagers. Specifically, the study will examine the effects of cyberbullying, social comparison, and excessive social media use on self-esteem, anxiety, and depression. Through an analysis of survey data and qualitative interviews with teenagers, the study will provide insight into the complex relationship between social media use and mental health outcomes, and identify strategies for promoting positive mental health outcomes in young people.”

Reference: Smith, J., Jones, M., & Lee, S. (2019). The effects of social media use on adolescent mental health: A systematic review. Journal of Adolescent Health, 65(2), 154-165. doi:10.1016/j.jadohealth.2019.03.024

Reference Example: Author, A. A., Author, B. B., & Author, C. C. (Year). Title of article. Title of Journal, volume number(issue number), page range. doi:0000000/000000000000 or URL

Applications of Literature Review

some applications of literature review in different fields:

Social Sciences: In social sciences, literature reviews are used to identify gaps in existing research, to develop research questions, and to provide a theoretical framework for research. Literature reviews are commonly used in fields such as sociology, psychology, anthropology, and political science.
Natural Sciences: In natural sciences, literature reviews are used to summarize and evaluate the current state of knowledge in a particular field or subfield. Literature reviews can help researchers identify areas where more research is needed and provide insights into the latest developments in a particular field. Fields such as biology, chemistry, and physics commonly use literature reviews.
Health Sciences: In health sciences, literature reviews are used to evaluate the effectiveness of treatments, identify best practices, and determine areas where more research is needed. Literature reviews are commonly used in fields such as medicine, nursing, and public health.
Humanities: In humanities, literature reviews are used to identify gaps in existing knowledge, develop new interpretations of texts or cultural artifacts, and provide a theoretical framework for research. Literature reviews are commonly used in fields such as history, literary studies, and philosophy.

Role of Literature Review in Research

Here are some applications of literature review in research:

Identifying Research Gaps : Literature review helps researchers identify gaps in existing research and literature related to their research question. This allows them to develop new research questions and hypotheses to fill those gaps.
Developing Theoretical Framework: Literature review helps researchers develop a theoretical framework for their research. By analyzing and synthesizing existing literature, researchers can identify the key concepts, theories, and models that are relevant to their research.
Selecting Research Methods : Literature review helps researchers select appropriate research methods and techniques based on previous research. It also helps researchers to identify potential biases or limitations of certain methods and techniques.
Data Collection and Analysis: Literature review helps researchers in data collection and analysis by providing a foundation for the development of data collection instruments and methods. It also helps researchers to identify relevant data sources and identify potential data analysis techniques.
Communicating Results: Literature review helps researchers to communicate their results effectively by providing a context for their research. It also helps to justify the significance of their findings in relation to existing research and literature.

Purpose of Literature Review

Some of the specific purposes of a literature review are as follows:

To provide context: A literature review helps to provide context for your research by situating it within the broader body of literature on the topic.
To identify gaps and inconsistencies: A literature review helps to identify areas where further research is needed or where there are inconsistencies in the existing literature.
To synthesize information: A literature review helps to synthesize the information from multiple sources and present a coherent and comprehensive picture of the current state of knowledge on the topic.
To identify key concepts and theories : A literature review helps to identify key concepts and theories that are relevant to your research question and provide a theoretical framework for your study.
To inform research design: A literature review can inform the design of your research study by identifying appropriate research methods, data sources, and research questions.

Characteristics of Literature Review

Some Characteristics of Literature Review are as follows:

Identifying gaps in knowledge: A literature review helps to identify gaps in the existing knowledge and research on a specific topic or research question. By analyzing and synthesizing the literature, you can identify areas where further research is needed and where new insights can be gained.
Establishing the significance of your research: A literature review helps to establish the significance of your own research by placing it in the context of existing research. By demonstrating the relevance of your research to the existing literature, you can establish its importance and value.
Informing research design and methodology : A literature review helps to inform research design and methodology by identifying the most appropriate research methods, techniques, and instruments. By reviewing the literature, you can identify the strengths and limitations of different research methods and techniques, and select the most appropriate ones for your own research.
Supporting arguments and claims: A literature review provides evidence to support arguments and claims made in academic writing. By citing and analyzing the literature, you can provide a solid foundation for your own arguments and claims.
I dentifying potential collaborators and mentors: A literature review can help identify potential collaborators and mentors by identifying researchers and practitioners who are working on related topics or using similar methods. By building relationships with these individuals, you can gain valuable insights and support for your own research and practice.
Keeping up-to-date with the latest research : A literature review helps to keep you up-to-date with the latest research on a specific topic or research question. By regularly reviewing the literature, you can stay informed about the latest findings and developments in your field.

Advantages of Literature Review

There are several advantages to conducting a literature review as part of a research project, including:

Establishing the significance of the research : A literature review helps to establish the significance of the research by demonstrating the gap or problem in the existing literature that the study aims to address.
Identifying key concepts and theories: A literature review can help to identify key concepts and theories that are relevant to the research question, and provide a theoretical framework for the study.
Supporting the research methodology : A literature review can inform the research methodology by identifying appropriate research methods, data sources, and research questions.
Providing a comprehensive overview of the literature : A literature review provides a comprehensive overview of the current state of knowledge on a topic, allowing the researcher to identify key themes, debates, and areas of agreement or disagreement.
Identifying potential research questions: A literature review can help to identify potential research questions and areas for further investigation.
Avoiding duplication of research: A literature review can help to avoid duplication of research by identifying what has already been done on a topic, and what remains to be done.
Enhancing the credibility of the research : A literature review helps to enhance the credibility of the research by demonstrating the researcher’s knowledge of the existing literature and their ability to situate their research within a broader context.

Limitations of Literature Review

Limitations of Literature Review are as follows:

Limited scope : Literature reviews can only cover the existing literature on a particular topic, which may be limited in scope or depth.
Publication bias : Literature reviews may be influenced by publication bias, which occurs when researchers are more likely to publish positive results than negative ones. This can lead to an incomplete or biased picture of the literature.
Quality of sources : The quality of the literature reviewed can vary widely, and not all sources may be reliable or valid.
Time-limited: Literature reviews can become quickly outdated as new research is published, making it difficult to keep up with the latest developments in a field.
Subjective interpretation : Literature reviews can be subjective, and the interpretation of the findings can vary depending on the researcher’s perspective or bias.
Lack of original data : Literature reviews do not generate new data, but rather rely on the analysis of existing studies.
Risk of plagiarism: It is important to ensure that literature reviews do not inadvertently contain plagiarism, which can occur when researchers use the work of others without proper attribution.

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Lau F, Kuziemsky C, editors. Handbook of eHealth Evaluation: An Evidence-based Approach [Internet]. Victoria (BC): University of Victoria; 2017 Feb 27.

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Handbook of eHealth Evaluation: An Evidence-based Approach [Internet].

Chapter 9 methods for literature reviews.

Guy Paré and Spyros Kitsiou .

9.1. Introduction

Literature reviews play a critical role in scholarship because science remains, first and foremost, a cumulative endeavour ( vom Brocke et al., 2009 ). As in any academic discipline, rigorous knowledge syntheses are becoming indispensable in keeping up with an exponentially growing eHealth literature, assisting practitioners, academics, and graduate students in finding, evaluating, and synthesizing the contents of many empirical and conceptual papers. Among other methods, literature reviews are essential for: (a) identifying what has been written on a subject or topic; (b) determining the extent to which a specific research area reveals any interpretable trends or patterns; (c) aggregating empirical findings related to a narrow research question to support evidence-based practice; (d) generating new frameworks and theories; and (e) identifying topics or questions requiring more investigation ( Paré, Trudel, Jaana, & Kitsiou, 2015 ).

Literature reviews can take two major forms. The most prevalent one is the “literature review” or “background” section within a journal paper or a chapter in a graduate thesis. This section synthesizes the extant literature and usually identifies the gaps in knowledge that the empirical study addresses ( Sylvester, Tate, & Johnstone, 2013 ). It may also provide a theoretical foundation for the proposed study, substantiate the presence of the research problem, justify the research as one that contributes something new to the cumulated knowledge, or validate the methods and approaches for the proposed study ( Hart, 1998 ; Levy & Ellis, 2006 ).

The second form of literature review, which is the focus of this chapter, constitutes an original and valuable work of research in and of itself ( Paré et al., 2015 ). Rather than providing a base for a researcher’s own work, it creates a solid starting point for all members of the community interested in a particular area or topic ( Mulrow, 1987 ). The so-called “review article” is a journal-length paper which has an overarching purpose to synthesize the literature in a field, without collecting or analyzing any primary data ( Green, Johnson, & Adams, 2006 ).

When appropriately conducted, review articles represent powerful information sources for practitioners looking for state-of-the art evidence to guide their decision-making and work practices ( Paré et al., 2015 ). Further, high-quality reviews become frequently cited pieces of work which researchers seek out as a first clear outline of the literature when undertaking empirical studies ( Cooper, 1988 ; Rowe, 2014 ). Scholars who track and gauge the impact of articles have found that review papers are cited and downloaded more often than any other type of published article ( Cronin, Ryan, & Coughlan, 2008 ; Montori, Wilczynski, Morgan, Haynes, & Hedges, 2003 ; Patsopoulos, Analatos, & Ioannidis, 2005 ). The reason for their popularity may be the fact that reading the review enables one to have an overview, if not a detailed knowledge of the area in question, as well as references to the most useful primary sources ( Cronin et al., 2008 ). Although they are not easy to conduct, the commitment to complete a review article provides a tremendous service to one’s academic community ( Paré et al., 2015 ; Petticrew & Roberts, 2006 ). Most, if not all, peer-reviewed journals in the fields of medical informatics publish review articles of some type.

The main objectives of this chapter are fourfold: (a) to provide an overview of the major steps and activities involved in conducting a stand-alone literature review; (b) to describe and contrast the different types of review articles that can contribute to the eHealth knowledge base; (c) to illustrate each review type with one or two examples from the eHealth literature; and (d) to provide a series of recommendations for prospective authors of review articles in this domain.

9.2. Overview of the Literature Review Process and Steps

As explained in Templier and Paré (2015) , there are six generic steps involved in conducting a review article:

formulating the research question(s) and objective(s),
searching the extant literature,
screening for inclusion,
assessing the quality of primary studies,
extracting data, and
analyzing data.

Although these steps are presented here in sequential order, one must keep in mind that the review process can be iterative and that many activities can be initiated during the planning stage and later refined during subsequent phases ( Finfgeld-Connett & Johnson, 2013 ; Kitchenham & Charters, 2007 ).

Formulating the research question(s) and objective(s): As a first step, members of the review team must appropriately justify the need for the review itself ( Petticrew & Roberts, 2006 ), identify the review’s main objective(s) ( Okoli & Schabram, 2010 ), and define the concepts or variables at the heart of their synthesis ( Cooper & Hedges, 2009 ; Webster & Watson, 2002 ). Importantly, they also need to articulate the research question(s) they propose to investigate ( Kitchenham & Charters, 2007 ). In this regard, we concur with Jesson, Matheson, and Lacey (2011) that clearly articulated research questions are key ingredients that guide the entire review methodology; they underscore the type of information that is needed, inform the search for and selection of relevant literature, and guide or orient the subsequent analysis. Searching the extant literature: The next step consists of searching the literature and making decisions about the suitability of material to be considered in the review ( Cooper, 1988 ). There exist three main coverage strategies. First, exhaustive coverage means an effort is made to be as comprehensive as possible in order to ensure that all relevant studies, published and unpublished, are included in the review and, thus, conclusions are based on this all-inclusive knowledge base. The second type of coverage consists of presenting materials that are representative of most other works in a given field or area. Often authors who adopt this strategy will search for relevant articles in a small number of top-tier journals in a field ( Paré et al., 2015 ). In the third strategy, the review team concentrates on prior works that have been central or pivotal to a particular topic. This may include empirical studies or conceptual papers that initiated a line of investigation, changed how problems or questions were framed, introduced new methods or concepts, or engendered important debate ( Cooper, 1988 ). Screening for inclusion: The following step consists of evaluating the applicability of the material identified in the preceding step ( Levy & Ellis, 2006 ; vom Brocke et al., 2009 ). Once a group of potential studies has been identified, members of the review team must screen them to determine their relevance ( Petticrew & Roberts, 2006 ). A set of predetermined rules provides a basis for including or excluding certain studies. This exercise requires a significant investment on the part of researchers, who must ensure enhanced objectivity and avoid biases or mistakes. As discussed later in this chapter, for certain types of reviews there must be at least two independent reviewers involved in the screening process and a procedure to resolve disagreements must also be in place ( Liberati et al., 2009 ; Shea et al., 2009 ). Assessing the quality of primary studies: In addition to screening material for inclusion, members of the review team may need to assess the scientific quality of the selected studies, that is, appraise the rigour of the research design and methods. Such formal assessment, which is usually conducted independently by at least two coders, helps members of the review team refine which studies to include in the final sample, determine whether or not the differences in quality may affect their conclusions, or guide how they analyze the data and interpret the findings ( Petticrew & Roberts, 2006 ). Ascribing quality scores to each primary study or considering through domain-based evaluations which study components have or have not been designed and executed appropriately makes it possible to reflect on the extent to which the selected study addresses possible biases and maximizes validity ( Shea et al., 2009 ). Extracting data: The following step involves gathering or extracting applicable information from each primary study included in the sample and deciding what is relevant to the problem of interest ( Cooper & Hedges, 2009 ). Indeed, the type of data that should be recorded mainly depends on the initial research questions ( Okoli & Schabram, 2010 ). However, important information may also be gathered about how, when, where and by whom the primary study was conducted, the research design and methods, or qualitative/quantitative results ( Cooper & Hedges, 2009 ). Analyzing and synthesizing data : As a final step, members of the review team must collate, summarize, aggregate, organize, and compare the evidence extracted from the included studies. The extracted data must be presented in a meaningful way that suggests a new contribution to the extant literature ( Jesson et al., 2011 ). Webster and Watson (2002) warn researchers that literature reviews should be much more than lists of papers and should provide a coherent lens to make sense of extant knowledge on a given topic. There exist several methods and techniques for synthesizing quantitative (e.g., frequency analysis, meta-analysis) and qualitative (e.g., grounded theory, narrative analysis, meta-ethnography) evidence ( Dixon-Woods, Agarwal, Jones, Young, & Sutton, 2005 ; Thomas & Harden, 2008 ).

9.3. Types of Review Articles and Brief Illustrations

EHealth researchers have at their disposal a number of approaches and methods for making sense out of existing literature, all with the purpose of casting current research findings into historical contexts or explaining contradictions that might exist among a set of primary research studies conducted on a particular topic. Our classification scheme is largely inspired from Paré and colleagues’ (2015) typology. Below we present and illustrate those review types that we feel are central to the growth and development of the eHealth domain.

9.3.1. Narrative Reviews

The narrative review is the “traditional” way of reviewing the extant literature and is skewed towards a qualitative interpretation of prior knowledge ( Sylvester et al., 2013 ). Put simply, a narrative review attempts to summarize or synthesize what has been written on a particular topic but does not seek generalization or cumulative knowledge from what is reviewed ( Davies, 2000 ; Green et al., 2006 ). Instead, the review team often undertakes the task of accumulating and synthesizing the literature to demonstrate the value of a particular point of view ( Baumeister & Leary, 1997 ). As such, reviewers may selectively ignore or limit the attention paid to certain studies in order to make a point. In this rather unsystematic approach, the selection of information from primary articles is subjective, lacks explicit criteria for inclusion and can lead to biased interpretations or inferences ( Green et al., 2006 ). There are several narrative reviews in the particular eHealth domain, as in all fields, which follow such an unstructured approach ( Silva et al., 2015 ; Paul et al., 2015 ).

Despite these criticisms, this type of review can be very useful in gathering together a volume of literature in a specific subject area and synthesizing it. As mentioned above, its primary purpose is to provide the reader with a comprehensive background for understanding current knowledge and highlighting the significance of new research ( Cronin et al., 2008 ). Faculty like to use narrative reviews in the classroom because they are often more up to date than textbooks, provide a single source for students to reference, and expose students to peer-reviewed literature ( Green et al., 2006 ). For researchers, narrative reviews can inspire research ideas by identifying gaps or inconsistencies in a body of knowledge, thus helping researchers to determine research questions or formulate hypotheses. Importantly, narrative reviews can also be used as educational articles to bring practitioners up to date with certain topics of issues ( Green et al., 2006 ).

Recently, there have been several efforts to introduce more rigour in narrative reviews that will elucidate common pitfalls and bring changes into their publication standards. Information systems researchers, among others, have contributed to advancing knowledge on how to structure a “traditional” review. For instance, Levy and Ellis (2006) proposed a generic framework for conducting such reviews. Their model follows the systematic data processing approach comprised of three steps, namely: (a) literature search and screening; (b) data extraction and analysis; and (c) writing the literature review. They provide detailed and very helpful instructions on how to conduct each step of the review process. As another methodological contribution, vom Brocke et al. (2009) offered a series of guidelines for conducting literature reviews, with a particular focus on how to search and extract the relevant body of knowledge. Last, Bandara, Miskon, and Fielt (2011) proposed a structured, predefined and tool-supported method to identify primary studies within a feasible scope, extract relevant content from identified articles, synthesize and analyze the findings, and effectively write and present the results of the literature review. We highly recommend that prospective authors of narrative reviews consult these useful sources before embarking on their work.

Darlow and Wen (2015) provide a good example of a highly structured narrative review in the eHealth field. These authors synthesized published articles that describe the development process of mobile health ( m-health ) interventions for patients’ cancer care self-management. As in most narrative reviews, the scope of the research questions being investigated is broad: (a) how development of these systems are carried out; (b) which methods are used to investigate these systems; and (c) what conclusions can be drawn as a result of the development of these systems. To provide clear answers to these questions, a literature search was conducted on six electronic databases and Google Scholar . The search was performed using several terms and free text words, combining them in an appropriate manner. Four inclusion and three exclusion criteria were utilized during the screening process. Both authors independently reviewed each of the identified articles to determine eligibility and extract study information. A flow diagram shows the number of studies identified, screened, and included or excluded at each stage of study selection. In terms of contributions, this review provides a series of practical recommendations for m-health intervention development.

9.3.2. Descriptive or Mapping Reviews

The primary goal of a descriptive review is to determine the extent to which a body of knowledge in a particular research topic reveals any interpretable pattern or trend with respect to pre-existing propositions, theories, methodologies or findings ( King & He, 2005 ; Paré et al., 2015 ). In contrast with narrative reviews, descriptive reviews follow a systematic and transparent procedure, including searching, screening and classifying studies ( Petersen, Vakkalanka, & Kuzniarz, 2015 ). Indeed, structured search methods are used to form a representative sample of a larger group of published works ( Paré et al., 2015 ). Further, authors of descriptive reviews extract from each study certain characteristics of interest, such as publication year, research methods, data collection techniques, and direction or strength of research outcomes (e.g., positive, negative, or non-significant) in the form of frequency analysis to produce quantitative results ( Sylvester et al., 2013 ). In essence, each study included in a descriptive review is treated as the unit of analysis and the published literature as a whole provides a database from which the authors attempt to identify any interpretable trends or draw overall conclusions about the merits of existing conceptualizations, propositions, methods or findings ( Paré et al., 2015 ). In doing so, a descriptive review may claim that its findings represent the state of the art in a particular domain ( King & He, 2005 ).

In the fields of health sciences and medical informatics, reviews that focus on examining the range, nature and evolution of a topic area are described by Anderson, Allen, Peckham, and Goodwin (2008) as mapping reviews . Like descriptive reviews, the research questions are generic and usually relate to publication patterns and trends. There is no preconceived plan to systematically review all of the literature although this can be done. Instead, researchers often present studies that are representative of most works published in a particular area and they consider a specific time frame to be mapped.

An example of this approach in the eHealth domain is offered by DeShazo, Lavallie, and Wolf (2009). The purpose of this descriptive or mapping review was to characterize publication trends in the medical informatics literature over a 20-year period (1987 to 2006). To achieve this ambitious objective, the authors performed a bibliometric analysis of medical informatics citations indexed in medline using publication trends, journal frequencies, impact factors, Medical Subject Headings (MeSH) term frequencies, and characteristics of citations. Findings revealed that there were over 77,000 medical informatics articles published during the covered period in numerous journals and that the average annual growth rate was 12%. The MeSH term analysis also suggested a strong interdisciplinary trend. Finally, average impact scores increased over time with two notable growth periods. Overall, patterns in research outputs that seem to characterize the historic trends and current components of the field of medical informatics suggest it may be a maturing discipline (DeShazo et al., 2009).

9.3.3. Scoping Reviews

Scoping reviews attempt to provide an initial indication of the potential size and nature of the extant literature on an emergent topic (Arksey & O’Malley, 2005; Daudt, van Mossel, & Scott, 2013 ; Levac, Colquhoun, & O’Brien, 2010). A scoping review may be conducted to examine the extent, range and nature of research activities in a particular area, determine the value of undertaking a full systematic review (discussed next), or identify research gaps in the extant literature ( Paré et al., 2015 ). In line with their main objective, scoping reviews usually conclude with the presentation of a detailed research agenda for future works along with potential implications for both practice and research.

Unlike narrative and descriptive reviews, the whole point of scoping the field is to be as comprehensive as possible, including grey literature (Arksey & O’Malley, 2005). Inclusion and exclusion criteria must be established to help researchers eliminate studies that are not aligned with the research questions. It is also recommended that at least two independent coders review abstracts yielded from the search strategy and then the full articles for study selection ( Daudt et al., 2013 ). The synthesized evidence from content or thematic analysis is relatively easy to present in tabular form (Arksey & O’Malley, 2005; Thomas & Harden, 2008 ).

One of the most highly cited scoping reviews in the eHealth domain was published by Archer, Fevrier-Thomas, Lokker, McKibbon, and Straus (2011) . These authors reviewed the existing literature on personal health record ( phr ) systems including design, functionality, implementation, applications, outcomes, and benefits. Seven databases were searched from 1985 to March 2010. Several search terms relating to phr s were used during this process. Two authors independently screened titles and abstracts to determine inclusion status. A second screen of full-text articles, again by two independent members of the research team, ensured that the studies described phr s. All in all, 130 articles met the criteria and their data were extracted manually into a database. The authors concluded that although there is a large amount of survey, observational, cohort/panel, and anecdotal evidence of phr benefits and satisfaction for patients, more research is needed to evaluate the results of phr implementations. Their in-depth analysis of the literature signalled that there is little solid evidence from randomized controlled trials or other studies through the use of phr s. Hence, they suggested that more research is needed that addresses the current lack of understanding of optimal functionality and usability of these systems, and how they can play a beneficial role in supporting patient self-management ( Archer et al., 2011 ).

9.3.4. Forms of Aggregative Reviews

Healthcare providers, practitioners, and policy-makers are nowadays overwhelmed with large volumes of information, including research-based evidence from numerous clinical trials and evaluation studies, assessing the effectiveness of health information technologies and interventions ( Ammenwerth & de Keizer, 2004 ; Deshazo et al., 2009 ). It is unrealistic to expect that all these disparate actors will have the time, skills, and necessary resources to identify the available evidence in the area of their expertise and consider it when making decisions. Systematic reviews that involve the rigorous application of scientific strategies aimed at limiting subjectivity and bias (i.e., systematic and random errors) can respond to this challenge.

Systematic reviews attempt to aggregate, appraise, and synthesize in a single source all empirical evidence that meet a set of previously specified eligibility criteria in order to answer a clearly formulated and often narrow research question on a particular topic of interest to support evidence-based practice ( Liberati et al., 2009 ). They adhere closely to explicit scientific principles ( Liberati et al., 2009 ) and rigorous methodological guidelines (Higgins & Green, 2008) aimed at reducing random and systematic errors that can lead to deviations from the truth in results or inferences. The use of explicit methods allows systematic reviews to aggregate a large body of research evidence, assess whether effects or relationships are in the same direction and of the same general magnitude, explain possible inconsistencies between study results, and determine the strength of the overall evidence for every outcome of interest based on the quality of included studies and the general consistency among them ( Cook, Mulrow, & Haynes, 1997 ). The main procedures of a systematic review involve:

Formulating a review question and developing a search strategy based on explicit inclusion criteria for the identification of eligible studies (usually described in the context of a detailed review protocol).
Searching for eligible studies using multiple databases and information sources, including grey literature sources, without any language restrictions.
Selecting studies, extracting data, and assessing risk of bias in a duplicate manner using two independent reviewers to avoid random or systematic errors in the process.
Analyzing data using quantitative or qualitative methods.
Presenting results in summary of findings tables.
Interpreting results and drawing conclusions.

Many systematic reviews, but not all, use statistical methods to combine the results of independent studies into a single quantitative estimate or summary effect size. Known as meta-analyses , these reviews use specific data extraction and statistical techniques (e.g., network, frequentist, or Bayesian meta-analyses) to calculate from each study by outcome of interest an effect size along with a confidence interval that reflects the degree of uncertainty behind the point estimate of effect ( Borenstein, Hedges, Higgins, & Rothstein, 2009 ; Deeks, Higgins, & Altman, 2008 ). Subsequently, they use fixed or random-effects analysis models to combine the results of the included studies, assess statistical heterogeneity, and calculate a weighted average of the effect estimates from the different studies, taking into account their sample sizes. The summary effect size is a value that reflects the average magnitude of the intervention effect for a particular outcome of interest or, more generally, the strength of a relationship between two variables across all studies included in the systematic review. By statistically combining data from multiple studies, meta-analyses can create more precise and reliable estimates of intervention effects than those derived from individual studies alone, when these are examined independently as discrete sources of information.

The review by Gurol-Urganci, de Jongh, Vodopivec-Jamsek, Atun, and Car (2013) on the effects of mobile phone messaging reminders for attendance at healthcare appointments is an illustrative example of a high-quality systematic review with meta-analysis. Missed appointments are a major cause of inefficiency in healthcare delivery with substantial monetary costs to health systems. These authors sought to assess whether mobile phone-based appointment reminders delivered through Short Message Service ( sms ) or Multimedia Messaging Service ( mms ) are effective in improving rates of patient attendance and reducing overall costs. To this end, they conducted a comprehensive search on multiple databases using highly sensitive search strategies without language or publication-type restrictions to identify all rct s that are eligible for inclusion. In order to minimize the risk of omitting eligible studies not captured by the original search, they supplemented all electronic searches with manual screening of trial registers and references contained in the included studies. Study selection, data extraction, and risk of bias assessments were performed independently by two coders using standardized methods to ensure consistency and to eliminate potential errors. Findings from eight rct s involving 6,615 participants were pooled into meta-analyses to calculate the magnitude of effects that mobile text message reminders have on the rate of attendance at healthcare appointments compared to no reminders and phone call reminders.

Meta-analyses are regarded as powerful tools for deriving meaningful conclusions. However, there are situations in which it is neither reasonable nor appropriate to pool studies together using meta-analytic methods simply because there is extensive clinical heterogeneity between the included studies or variation in measurement tools, comparisons, or outcomes of interest. In these cases, systematic reviews can use qualitative synthesis methods such as vote counting, content analysis, classification schemes and tabulations, as an alternative approach to narratively synthesize the results of the independent studies included in the review. This form of review is known as qualitative systematic review.

A rigorous example of one such review in the eHealth domain is presented by Mickan, Atherton, Roberts, Heneghan, and Tilson (2014) on the use of handheld computers by healthcare professionals and their impact on access to information and clinical decision-making. In line with the methodological guidelines for systematic reviews, these authors: (a) developed and registered with prospero ( www.crd.york.ac.uk/ prospero / ) an a priori review protocol; (b) conducted comprehensive searches for eligible studies using multiple databases and other supplementary strategies (e.g., forward searches); and (c) subsequently carried out study selection, data extraction, and risk of bias assessments in a duplicate manner to eliminate potential errors in the review process. Heterogeneity between the included studies in terms of reported outcomes and measures precluded the use of meta-analytic methods. To this end, the authors resorted to using narrative analysis and synthesis to describe the effectiveness of handheld computers on accessing information for clinical knowledge, adherence to safety and clinical quality guidelines, and diagnostic decision-making.

In recent years, the number of systematic reviews in the field of health informatics has increased considerably. Systematic reviews with discordant findings can cause great confusion and make it difficult for decision-makers to interpret the review-level evidence ( Moher, 2013 ). Therefore, there is a growing need for appraisal and synthesis of prior systematic reviews to ensure that decision-making is constantly informed by the best available accumulated evidence. Umbrella reviews , also known as overviews of systematic reviews, are tertiary types of evidence synthesis that aim to accomplish this; that is, they aim to compare and contrast findings from multiple systematic reviews and meta-analyses ( Becker & Oxman, 2008 ). Umbrella reviews generally adhere to the same principles and rigorous methodological guidelines used in systematic reviews. However, the unit of analysis in umbrella reviews is the systematic review rather than the primary study ( Becker & Oxman, 2008 ). Unlike systematic reviews that have a narrow focus of inquiry, umbrella reviews focus on broader research topics for which there are several potential interventions ( Smith, Devane, Begley, & Clarke, 2011 ). A recent umbrella review on the effects of home telemonitoring interventions for patients with heart failure critically appraised, compared, and synthesized evidence from 15 systematic reviews to investigate which types of home telemonitoring technologies and forms of interventions are more effective in reducing mortality and hospital admissions ( Kitsiou, Paré, & Jaana, 2015 ).

9.3.5. Realist Reviews

Realist reviews are theory-driven interpretative reviews developed to inform, enhance, or supplement conventional systematic reviews by making sense of heterogeneous evidence about complex interventions applied in diverse contexts in a way that informs policy decision-making ( Greenhalgh, Wong, Westhorp, & Pawson, 2011 ). They originated from criticisms of positivist systematic reviews which centre on their “simplistic” underlying assumptions ( Oates, 2011 ). As explained above, systematic reviews seek to identify causation. Such logic is appropriate for fields like medicine and education where findings of randomized controlled trials can be aggregated to see whether a new treatment or intervention does improve outcomes. However, many argue that it is not possible to establish such direct causal links between interventions and outcomes in fields such as social policy, management, and information systems where for any intervention there is unlikely to be a regular or consistent outcome ( Oates, 2011 ; Pawson, 2006 ; Rousseau, Manning, & Denyer, 2008 ).

To circumvent these limitations, Pawson, Greenhalgh, Harvey, and Walshe (2005) have proposed a new approach for synthesizing knowledge that seeks to unpack the mechanism of how “complex interventions” work in particular contexts. The basic research question — what works? — which is usually associated with systematic reviews changes to: what is it about this intervention that works, for whom, in what circumstances, in what respects and why? Realist reviews have no particular preference for either quantitative or qualitative evidence. As a theory-building approach, a realist review usually starts by articulating likely underlying mechanisms and then scrutinizes available evidence to find out whether and where these mechanisms are applicable ( Shepperd et al., 2009 ). Primary studies found in the extant literature are viewed as case studies which can test and modify the initial theories ( Rousseau et al., 2008 ).

The main objective pursued in the realist review conducted by Otte-Trojel, de Bont, Rundall, and van de Klundert (2014) was to examine how patient portals contribute to health service delivery and patient outcomes. The specific goals were to investigate how outcomes are produced and, most importantly, how variations in outcomes can be explained. The research team started with an exploratory review of background documents and research studies to identify ways in which patient portals may contribute to health service delivery and patient outcomes. The authors identified six main ways which represent “educated guesses” to be tested against the data in the evaluation studies. These studies were identified through a formal and systematic search in four databases between 2003 and 2013. Two members of the research team selected the articles using a pre-established list of inclusion and exclusion criteria and following a two-step procedure. The authors then extracted data from the selected articles and created several tables, one for each outcome category. They organized information to bring forward those mechanisms where patient portals contribute to outcomes and the variation in outcomes across different contexts.

9.3.6. Critical Reviews

Lastly, critical reviews aim to provide a critical evaluation and interpretive analysis of existing literature on a particular topic of interest to reveal strengths, weaknesses, contradictions, controversies, inconsistencies, and/or other important issues with respect to theories, hypotheses, research methods or results ( Baumeister & Leary, 1997 ; Kirkevold, 1997 ). Unlike other review types, critical reviews attempt to take a reflective account of the research that has been done in a particular area of interest, and assess its credibility by using appraisal instruments or critical interpretive methods. In this way, critical reviews attempt to constructively inform other scholars about the weaknesses of prior research and strengthen knowledge development by giving focus and direction to studies for further improvement ( Kirkevold, 1997 ).

Kitsiou, Paré, and Jaana (2013) provide an example of a critical review that assessed the methodological quality of prior systematic reviews of home telemonitoring studies for chronic patients. The authors conducted a comprehensive search on multiple databases to identify eligible reviews and subsequently used a validated instrument to conduct an in-depth quality appraisal. Results indicate that the majority of systematic reviews in this particular area suffer from important methodological flaws and biases that impair their internal validity and limit their usefulness for clinical and decision-making purposes. To this end, they provide a number of recommendations to strengthen knowledge development towards improving the design and execution of future reviews on home telemonitoring.

9.4. Summary

Table 9.1 outlines the main types of literature reviews that were described in the previous sub-sections and summarizes the main characteristics that distinguish one review type from another. It also includes key references to methodological guidelines and useful sources that can be used by eHealth scholars and researchers for planning and developing reviews.

Typology of Literature Reviews (adapted from Paré et al., 2015).

As shown in Table 9.1 , each review type addresses different kinds of research questions or objectives, which subsequently define and dictate the methods and approaches that need to be used to achieve the overarching goal(s) of the review. For example, in the case of narrative reviews, there is greater flexibility in searching and synthesizing articles ( Green et al., 2006 ). Researchers are often relatively free to use a diversity of approaches to search, identify, and select relevant scientific articles, describe their operational characteristics, present how the individual studies fit together, and formulate conclusions. On the other hand, systematic reviews are characterized by their high level of systematicity, rigour, and use of explicit methods, based on an “a priori” review plan that aims to minimize bias in the analysis and synthesis process (Higgins & Green, 2008). Some reviews are exploratory in nature (e.g., scoping/mapping reviews), whereas others may be conducted to discover patterns (e.g., descriptive reviews) or involve a synthesis approach that may include the critical analysis of prior research ( Paré et al., 2015 ). Hence, in order to select the most appropriate type of review, it is critical to know before embarking on a review project, why the research synthesis is conducted and what type of methods are best aligned with the pursued goals.

9.5. Concluding Remarks

In light of the increased use of evidence-based practice and research generating stronger evidence ( Grady et al., 2011 ; Lyden et al., 2013 ), review articles have become essential tools for summarizing, synthesizing, integrating or critically appraising prior knowledge in the eHealth field. As mentioned earlier, when rigorously conducted review articles represent powerful information sources for eHealth scholars and practitioners looking for state-of-the-art evidence. The typology of literature reviews we used herein will allow eHealth researchers, graduate students and practitioners to gain a better understanding of the similarities and differences between review types.

We must stress that this classification scheme does not privilege any specific type of review as being of higher quality than another ( Paré et al., 2015 ). As explained above, each type of review has its own strengths and limitations. Having said that, we realize that the methodological rigour of any review — be it qualitative, quantitative or mixed — is a critical aspect that should be considered seriously by prospective authors. In the present context, the notion of rigour refers to the reliability and validity of the review process described in section 9.2. For one thing, reliability is related to the reproducibility of the review process and steps, which is facilitated by a comprehensive documentation of the literature search process, extraction, coding and analysis performed in the review. Whether the search is comprehensive or not, whether it involves a methodical approach for data extraction and synthesis or not, it is important that the review documents in an explicit and transparent manner the steps and approach that were used in the process of its development. Next, validity characterizes the degree to which the review process was conducted appropriately. It goes beyond documentation and reflects decisions related to the selection of the sources, the search terms used, the period of time covered, the articles selected in the search, and the application of backward and forward searches ( vom Brocke et al., 2009 ). In short, the rigour of any review article is reflected by the explicitness of its methods (i.e., transparency) and the soundness of the approach used. We refer those interested in the concepts of rigour and quality to the work of Templier and Paré (2015) which offers a detailed set of methodological guidelines for conducting and evaluating various types of review articles.

To conclude, our main objective in this chapter was to demystify the various types of literature reviews that are central to the continuous development of the eHealth field. It is our hope that our descriptive account will serve as a valuable source for those conducting, evaluating or using reviews in this important and growing domain.

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Cite this Page Paré G, Kitsiou S. Chapter 9 Methods for Literature Reviews. In: Lau F, Kuziemsky C, editors. Handbook of eHealth Evaluation: An Evidence-based Approach [Internet]. Victoria (BC): University of Victoria; 2017 Feb 27.
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Introduction
Overview of the Literature Review Process and Steps
Types of Review Articles and Brief Illustrations
Concluding Remarks

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What is a Literature Review? How to Write It (with Examples)

A literature review is a critical analysis and synthesis of existing research on a particular topic. It provides an overview of the current state of knowledge, identifies gaps, and highlights key findings in the literature. 1 The purpose of a literature review is to situate your own research within the context of existing scholarship, demonstrating your understanding of the topic and showing how your work contributes to the ongoing conversation in the field. Learning how to write a literature review is a critical tool for successful research. Your ability to summarize and synthesize prior research pertaining to a certain topic demonstrates your grasp on the topic of study, and assists in the learning process.

What is the purpose of literature review?
a. Habitat Loss and Species Extinction:
b. Range Shifts and Phenological Changes:
c. Ocean Acidification and Coral Reefs:
d. Adaptive Strategies and Conservation Efforts:

How to write a good literature review

Choose a Topic and Define the Research Question:
Decide on the Scope of Your Review:
Select Databases for Searches:
Conduct Searches and Keep Track:
Review the Literature:
Organize and Write Your Literature Review:
How to write a literature review faster with Paperpal?
Frequently asked questions

What is a literature review?

A well-conducted literature review demonstrates the researcher’s familiarity with the existing literature, establishes the context for their own research, and contributes to scholarly conversations on the topic. One of the purposes of a literature review is also to help researchers avoid duplicating previous work and ensure that their research is informed by and builds upon the existing body of knowledge.

What is the purpose of literature review?

A literature review serves several important purposes within academic and research contexts. Here are some key objectives and functions of a literature review: 2

1. Contextualizing the Research Problem: The literature review provides a background and context for the research problem under investigation. It helps to situate the study within the existing body of knowledge.

2. Identifying Gaps in Knowledge: By identifying gaps, contradictions, or areas requiring further research, the researcher can shape the research question and justify the significance of the study. This is crucial for ensuring that the new research contributes something novel to the field.

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3. Understanding Theoretical and Conceptual Frameworks: Literature reviews help researchers gain an understanding of the theoretical and conceptual frameworks used in previous studies. This aids in the development of a theoretical framework for the current research.

4. Providing Methodological Insights: Another purpose of literature reviews is that it allows researchers to learn about the methodologies employed in previous studies. This can help in choosing appropriate research methods for the current study and avoiding pitfalls that others may have encountered.

5. Establishing Credibility: A well-conducted literature review demonstrates the researcher’s familiarity with existing scholarship, establishing their credibility and expertise in the field. It also helps in building a solid foundation for the new research.

6. Informing Hypotheses or Research Questions: The literature review guides the formulation of hypotheses or research questions by highlighting relevant findings and areas of uncertainty in existing literature.

Literature review example

Let’s delve deeper with a literature review example: Let’s say your literature review is about the impact of climate change on biodiversity. You might format your literature review into sections such as the effects of climate change on habitat loss and species extinction, phenological changes, and marine biodiversity. Each section would then summarize and analyze relevant studies in those areas, highlighting key findings and identifying gaps in the research. The review would conclude by emphasizing the need for further research on specific aspects of the relationship between climate change and biodiversity. The following literature review template provides a glimpse into the recommended literature review structure and content, demonstrating how research findings are organized around specific themes within a broader topic.

Literature Review on Climate Change Impacts on Biodiversity:

Climate change is a global phenomenon with far-reaching consequences, including significant impacts on biodiversity. This literature review synthesizes key findings from various studies:

a. Habitat Loss and Species Extinction:

Climate change-induced alterations in temperature and precipitation patterns contribute to habitat loss, affecting numerous species (Thomas et al., 2004). The review discusses how these changes increase the risk of extinction, particularly for species with specific habitat requirements.

b. Range Shifts and Phenological Changes:

Observations of range shifts and changes in the timing of biological events (phenology) are documented in response to changing climatic conditions (Parmesan & Yohe, 2003). These shifts affect ecosystems and may lead to mismatches between species and their resources.

c. Ocean Acidification and Coral Reefs:

The review explores the impact of climate change on marine biodiversity, emphasizing ocean acidification’s threat to coral reefs (Hoegh-Guldberg et al., 2007). Changes in pH levels negatively affect coral calcification, disrupting the delicate balance of marine ecosystems.

d. Adaptive Strategies and Conservation Efforts:

Recognizing the urgency of the situation, the literature review discusses various adaptive strategies adopted by species and conservation efforts aimed at mitigating the impacts of climate change on biodiversity (Hannah et al., 2007). It emphasizes the importance of interdisciplinary approaches for effective conservation planning.

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Writing a literature review involves summarizing and synthesizing existing research on a particular topic. A good literature review format should include the following elements.

Introduction: The introduction sets the stage for your literature review, providing context and introducing the main focus of your review.

Opening Statement: Begin with a general statement about the broader topic and its significance in the field.
Scope and Purpose: Clearly define the scope of your literature review. Explain the specific research question or objective you aim to address.
Organizational Framework: Briefly outline the structure of your literature review, indicating how you will categorize and discuss the existing research.
Significance of the Study: Highlight why your literature review is important and how it contributes to the understanding of the chosen topic.
Thesis Statement: Conclude the introduction with a concise thesis statement that outlines the main argument or perspective you will develop in the body of the literature review.

Body: The body of the literature review is where you provide a comprehensive analysis of existing literature, grouping studies based on themes, methodologies, or other relevant criteria.

Organize by Theme or Concept: Group studies that share common themes, concepts, or methodologies. Discuss each theme or concept in detail, summarizing key findings and identifying gaps or areas of disagreement.
Critical Analysis: Evaluate the strengths and weaknesses of each study. Discuss the methodologies used, the quality of evidence, and the overall contribution of each work to the understanding of the topic.
Synthesis of Findings: Synthesize the information from different studies to highlight trends, patterns, or areas of consensus in the literature.
Identification of Gaps: Discuss any gaps or limitations in the existing research and explain how your review contributes to filling these gaps.
Transition between Sections: Provide smooth transitions between different themes or concepts to maintain the flow of your literature review.

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Conclusion: The conclusion of your literature review should summarize the main findings, highlight the contributions of the review, and suggest avenues for future research.

Summary of Key Findings: Recap the main findings from the literature and restate how they contribute to your research question or objective.
Contributions to the Field: Discuss the overall contribution of your literature review to the existing knowledge in the field.
Implications and Applications: Explore the practical implications of the findings and suggest how they might impact future research or practice.
Recommendations for Future Research: Identify areas that require further investigation and propose potential directions for future research in the field.
Final Thoughts: Conclude with a final reflection on the importance of your literature review and its relevance to the broader academic community.

Conducting a literature review

Conducting a literature review is an essential step in research that involves reviewing and analyzing existing literature on a specific topic. It’s important to know how to do a literature review effectively, so here are the steps to follow: 1

Choose a Topic and Define the Research Question:

Select a topic that is relevant to your field of study.
Clearly define your research question or objective. Determine what specific aspect of the topic do you want to explore?

Decide on the Scope of Your Review:

Determine the timeframe for your literature review. Are you focusing on recent developments, or do you want a historical overview?
Consider the geographical scope. Is your review global, or are you focusing on a specific region?
Define the inclusion and exclusion criteria. What types of sources will you include? Are there specific types of studies or publications you will exclude?

Select Databases for Searches:

Identify relevant databases for your field. Examples include PubMed, IEEE Xplore, Scopus, Web of Science, and Google Scholar.
Consider searching in library catalogs, institutional repositories, and specialized databases related to your topic.

Conduct Searches and Keep Track:

Develop a systematic search strategy using keywords, Boolean operators (AND, OR, NOT), and other search techniques.
Record and document your search strategy for transparency and replicability.
Keep track of the articles, including publication details, abstracts, and links. Use citation management tools like EndNote, Zotero, or Mendeley to organize your references.

Review the Literature:

Evaluate the relevance and quality of each source. Consider the methodology, sample size, and results of studies.
Organize the literature by themes or key concepts. Identify patterns, trends, and gaps in the existing research.
Summarize key findings and arguments from each source. Compare and contrast different perspectives.
Identify areas where there is a consensus in the literature and where there are conflicting opinions.
Provide critical analysis and synthesis of the literature. What are the strengths and weaknesses of existing research?

Organize and Write Your Literature Review:

Literature review outline should be based on themes, chronological order, or methodological approaches.
Write a clear and coherent narrative that synthesizes the information gathered.
Use proper citations for each source and ensure consistency in your citation style (APA, MLA, Chicago, etc.).
Conclude your literature review by summarizing key findings, identifying gaps, and suggesting areas for future research.

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Frequently asked questions

A literature review is a critical and comprehensive analysis of existing literature (published and unpublished works) on a specific topic or research question and provides a synthesis of the current state of knowledge in a particular field. A well-conducted literature review is crucial for researchers to build upon existing knowledge, avoid duplication of efforts, and contribute to the advancement of their field. It also helps researchers situate their work within a broader context and facilitates the development of a sound theoretical and conceptual framework for their studies.

Literature review is a crucial component of research writing, providing a solid background for a research paper’s investigation. The aim is to keep professionals up to date by providing an understanding of ongoing developments within a specific field, including research methods, and experimental techniques used in that field, and present that knowledge in the form of a written report. Also, the depth and breadth of the literature review emphasizes the credibility of the scholar in his or her field.

Before writing a literature review, it’s essential to undertake several preparatory steps to ensure that your review is well-researched, organized, and focused. This includes choosing a topic of general interest to you and doing exploratory research on that topic, writing an annotated bibliography, and noting major points, especially those that relate to the position you have taken on the topic.

Literature reviews and academic research papers are essential components of scholarly work but serve different purposes within the academic realm. 3 A literature review aims to provide a foundation for understanding the current state of research on a particular topic, identify gaps or controversies, and lay the groundwork for future research. Therefore, it draws heavily from existing academic sources, including books, journal articles, and other scholarly publications. In contrast, an academic research paper aims to present new knowledge, contribute to the academic discourse, and advance the understanding of a specific research question. Therefore, it involves a mix of existing literature (in the introduction and literature review sections) and original data or findings obtained through research methods.

Literature reviews are essential components of academic and research papers, and various strategies can be employed to conduct them effectively. If you want to know how to write a literature review for a research paper, here are four common approaches that are often used by researchers. Chronological Review: This strategy involves organizing the literature based on the chronological order of publication. It helps to trace the development of a topic over time, showing how ideas, theories, and research have evolved. Thematic Review: Thematic reviews focus on identifying and analyzing themes or topics that cut across different studies. Instead of organizing the literature chronologically, it is grouped by key themes or concepts, allowing for a comprehensive exploration of various aspects of the topic. Methodological Review: This strategy involves organizing the literature based on the research methods employed in different studies. It helps to highlight the strengths and weaknesses of various methodologies and allows the reader to evaluate the reliability and validity of the research findings. Theoretical Review: A theoretical review examines the literature based on the theoretical frameworks used in different studies. This approach helps to identify the key theories that have been applied to the topic and assess their contributions to the understanding of the subject. It’s important to note that these strategies are not mutually exclusive, and a literature review may combine elements of more than one approach. The choice of strategy depends on the research question, the nature of the literature available, and the goals of the review. Additionally, other strategies, such as integrative reviews or systematic reviews, may be employed depending on the specific requirements of the research.

The literature review format can vary depending on the specific publication guidelines. However, there are some common elements and structures that are often followed. Here is a general guideline for the format of a literature review: Introduction: Provide an overview of the topic. Define the scope and purpose of the literature review. State the research question or objective. Body: Organize the literature by themes, concepts, or chronology. Critically analyze and evaluate each source. Discuss the strengths and weaknesses of the studies. Highlight any methodological limitations or biases. Identify patterns, connections, or contradictions in the existing research. Conclusion: Summarize the key points discussed in the literature review. Highlight the research gap. Address the research question or objective stated in the introduction. Highlight the contributions of the review and suggest directions for future research.

Both annotated bibliographies and literature reviews involve the examination of scholarly sources. While annotated bibliographies focus on individual sources with brief annotations, literature reviews provide a more in-depth, integrated, and comprehensive analysis of existing literature on a specific topic. The key differences are as follows:

	Annotated Bibliography	Literature Review
Purpose	List of citations of books, articles, and other sources with a brief description (annotation) of each source.	Comprehensive and critical analysis of existing literature on a specific topic.
Focus	Summary and evaluation of each source, including its relevance, methodology, and key findings.	Provides an overview of the current state of knowledge on a particular subject and identifies gaps, trends, and patterns in existing literature.
Structure	Each citation is followed by a concise paragraph (annotation) that describes the source’s content, methodology, and its contribution to the topic.	The literature review is organized thematically or chronologically and involves a synthesis of the findings from different sources to build a narrative or argument.
Length	Typically 100-200 words	Length of literature review ranges from a few pages to several chapters
Independence	Each source is treated separately, with less emphasis on synthesizing the information across sources.	The writer synthesizes information from multiple sources to present a cohesive overview of the topic.

References

Denney, A. S., & Tewksbury, R. (2013). How to write a literature review.  Journal of criminal justice education ,  24 (2), 218-234.
Pan, M. L. (2016).  Preparing literature reviews: Qualitative and quantitative approaches . Taylor & Francis.
Cantero, C. (2019). How to write a literature review.  San José State University Writing Center .

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6 Tips for Post-Doc Researchers to Take Their Career to the Next Level

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How to Do a Systematic Review: A Best Practice Guide for Conducting and Reporting Narrative Reviews, Meta-Analyses, and Meta-Syntheses

Affiliations.

1 Behavioural Science Centre, Stirling Management School, University of Stirling, Stirling FK9 4LA, United Kingdom; email: [email protected].
2 Department of Psychological and Behavioural Science, London School of Economics and Political Science, London WC2A 2AE, United Kingdom.
3 Department of Statistics, Northwestern University, Evanston, Illinois 60208, USA; email: [email protected].
PMID: 30089228
DOI: 10.1146/annurev-psych-010418-102803

Systematic reviews are characterized by a methodical and replicable methodology and presentation. They involve a comprehensive search to locate all relevant published and unpublished work on a subject; a systematic integration of search results; and a critique of the extent, nature, and quality of evidence in relation to a particular research question. The best reviews synthesize studies to draw broad theoretical conclusions about what a literature means, linking theory to evidence and evidence to theory. This guide describes how to plan, conduct, organize, and present a systematic review of quantitative (meta-analysis) or qualitative (narrative review, meta-synthesis) information. We outline core standards and principles and describe commonly encountered problems. Although this guide targets psychological scientists, its high level of abstraction makes it potentially relevant to any subject area or discipline. We argue that systematic reviews are a key methodology for clarifying whether and how research findings replicate and for explaining possible inconsistencies, and we call for researchers to conduct systematic reviews to help elucidate whether there is a replication crisis.

Keywords: evidence; guide; meta-analysis; meta-synthesis; narrative; systematic review; theory.

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Literature reviews, what is a literature review, learning more about how to do a literature review.

Planning the Review
The Research Question
Choosing Where to Search
Organizing the Review
Writing the Review

A literature review is a review and synthesis of existing research on a topic or research question. A literature review is meant to analyze the scholarly literature, make connections across writings and identify strengths, weaknesses, trends, and missing conversations. A literature review should address different aspects of a topic as it relates to your research question. A literature review goes beyond a description or summary of the literature you have read.

Sage Research Methods Core Collection This link opens in a new window SAGE Research Methods supports research at all levels by providing material to guide users through every step of the research process. SAGE Research Methods is the ultimate methods library with more than 1000 books, reference works, journal articles, and instructional videos by world-leading academics from across the social sciences, including the largest collection of qualitative methods books available online from any scholarly publisher. – Publisher

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Last Updated: May 2, 2024 10:39 AM
URL: https://libguides.northwestern.edu/literaturereviews

Research Methods

Getting Started
Literature Review Research
Research Design
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Literature Review

What is a Literature Review?
What is NOT a Literature Review?
Purposes of a Literature Review
Types of Literature Reviews
Literature Reviews vs. Systematic Reviews
Systematic vs. Meta-Analysis

Literature Review is a comprehensive survey of the works published in a particular field of study or line of research, usually over a specific period of time, in the form of an in-depth, critical bibliographic essay or annotated list in which attention is drawn to the most significant works.

Also, we can define a literature review as the collected body of scholarly works related to a topic:

Summarizes and analyzes previous research relevant to a topic
Includes scholarly books and articles published in academic journals
Can be an specific scholarly paper or a section in a research paper

The objective of a Literature Review is to find previous published scholarly works relevant to an specific topic

Help gather ideas or information
Keep up to date in current trends and findings
Help develop new questions

A literature review is important because it:

Explains the background of research on a topic.
Demonstrates why a topic is significant to a subject area.
Helps focus your own research questions or problems
Discovers relationships between research studies/ideas.
Suggests unexplored ideas or populations
Identifies major themes, concepts, and researchers on a topic.
Tests assumptions; may help counter preconceived ideas and remove unconscious bias.
Identifies critical gaps, points of disagreement, or potentially flawed methodology or theoretical approaches.
Indicates potential directions for future research.

All content in this section is from Literature Review Research from Old Dominion University

Keep in mind the following, a literature review is NOT:

Not an essay

Not an annotated bibliography in which you summarize each article that you have reviewed. A literature review goes beyond basic summarizing to focus on the critical analysis of the reviewed works and their relationship to your research question.

Not a research paper where you select resources to support one side of an issue versus another. A lit review should explain and consider all sides of an argument in order to avoid bias, and areas of agreement and disagreement should be highlighted.

A literature review serves several purposes. For example, it

provides thorough knowledge of previous studies; introduces seminal works.
helps focus one’s own research topic.
identifies a conceptual framework for one’s own research questions or problems; indicates potential directions for future research.
suggests previously unused or underused methodologies, designs, quantitative and qualitative strategies.
identifies gaps in previous studies; identifies flawed methodologies and/or theoretical approaches; avoids replication of mistakes.
helps the researcher avoid repetition of earlier research.
suggests unexplored populations.
determines whether past studies agree or disagree; identifies controversy in the literature.
tests assumptions; may help counter preconceived ideas and remove unconscious bias.

As Kennedy (2007) notes*, it is important to think of knowledge in a given field as consisting of three layers. First, there are the primary studies that researchers conduct and publish. Second are the reviews of those studies that summarize and offer new interpretations built from and often extending beyond the original studies. Third, there are the perceptions, conclusions, opinion, and interpretations that are shared informally that become part of the lore of field. In composing a literature review, it is important to note that it is often this third layer of knowledge that is cited as "true" even though it often has only a loose relationship to the primary studies and secondary literature reviews.

Given this, while literature reviews are designed to provide an overview and synthesis of pertinent sources you have explored, there are several approaches to how they can be done, depending upon the type of analysis underpinning your study. Listed below are definitions of types of literature reviews:

Argumentative Review This form examines literature selectively in order to support or refute an argument, deeply imbedded assumption, or philosophical problem already established in the literature. The purpose is to develop a body of literature that establishes a contrarian viewpoint. Given the value-laden nature of some social science research [e.g., educational reform; immigration control], argumentative approaches to analyzing the literature can be a legitimate and important form of discourse. However, note that they can also introduce problems of bias when they are used to to make summary claims of the sort found in systematic reviews.

Integrative Review Considered a form of research that reviews, critiques, and synthesizes representative literature on a topic in an integrated way such that new frameworks and perspectives on the topic are generated. The body of literature includes all studies that address related or identical hypotheses. A well-done integrative review meets the same standards as primary research in regard to clarity, rigor, and replication.

Historical Review Few things rest in isolation from historical precedent. Historical reviews are focused on examining research throughout a period of time, often starting with the first time an issue, concept, theory, phenomena emerged in the literature, then tracing its evolution within the scholarship of a discipline. The purpose is to place research in a historical context to show familiarity with state-of-the-art developments and to identify the likely directions for future research.

Methodological Review A review does not always focus on what someone said [content], but how they said it [method of analysis]. This approach provides a framework of understanding at different levels (i.e. those of theory, substantive fields, research approaches and data collection and analysis techniques), enables researchers to draw on a wide variety of knowledge ranging from the conceptual level to practical documents for use in fieldwork in the areas of ontological and epistemological consideration, quantitative and qualitative integration, sampling, interviewing, data collection and data analysis, and helps highlight many ethical issues which we should be aware of and consider as we go through our study.

Systematic Review This form consists of an overview of existing evidence pertinent to a clearly formulated research question, which uses pre-specified and standardized methods to identify and critically appraise relevant research, and to collect, report, and analyse data from the studies that are included in the review. Typically it focuses on a very specific empirical question, often posed in a cause-and-effect form, such as "To what extent does A contribute to B?"

Theoretical Review The purpose of this form is to concretely examine the corpus of theory that has accumulated in regard to an issue, concept, theory, phenomena. The theoretical literature review help establish what theories already exist, the relationships between them, to what degree the existing theories have been investigated, and to develop new hypotheses to be tested. Often this form is used to help establish a lack of appropriate theories or reveal that current theories are inadequate for explaining new or emerging research problems. The unit of analysis can focus on a theoretical concept or a whole theory or framework.

* Kennedy, Mary M. "Defining a Literature." Educational Researcher 36 (April 2007): 139-147.

All content in this section is from The Literature Review created by Dr. Robert Larabee USC

Robinson, P. and Lowe, J. (2015), Literature reviews vs systematic reviews. Australian and New Zealand Journal of Public Health, 39: 103-103. doi: 10.1111/1753-6405.12393

What's in the name? The difference between a Systematic Review and a Literature Review, and why it matters . By Lynn Kysh from University of Southern California

Systematic review or meta-analysis?

A systematic review answers a defined research question by collecting and summarizing all empirical evidence that fits pre-specified eligibility criteria.

A meta-analysis is the use of statistical methods to summarize the results of these studies.

Systematic reviews, just like other research articles, can be of varying quality. They are a significant piece of work (the Centre for Reviews and Dissemination at York estimates that a team will take 9-24 months), and to be useful to other researchers and practitioners they should have:

clearly stated objectives with pre-defined eligibility criteria for studies
explicit, reproducible methodology
a systematic search that attempts to identify all studies
assessment of the validity of the findings of the included studies (e.g. risk of bias)
systematic presentation, and synthesis, of the characteristics and findings of the included studies

Not all systematic reviews contain meta-analysis.

Meta-analysis is the use of statistical methods to summarize the results of independent studies. By combining information from all relevant studies, meta-analysis can provide more precise estimates of the effects of health care than those derived from the individual studies included within a review. More information on meta-analyses can be found in Cochrane Handbook, Chapter 9 .

A meta-analysis goes beyond critique and integration and conducts secondary statistical analysis on the outcomes of similar studies. It is a systematic review that uses quantitative methods to synthesize and summarize the results.

An advantage of a meta-analysis is the ability to be completely objective in evaluating research findings. Not all topics, however, have sufficient research evidence to allow a meta-analysis to be conducted. In that case, an integrative review is an appropriate strategy.

Some of the content in this section is from Systematic reviews and meta-analyses: step by step guide created by Kate McAllister.

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Last Updated: Aug 21, 2023 4:07 PM
URL: https://guides.lib.udel.edu/researchmethods

Research Methods: Literature Reviews

Annotated Bibliographies
Literature Reviews
Scoping Reviews
Systematic Reviews
Scholarship of Teaching and Learning
Persuasive Arguments
Subject Specific Methodology

A literature review involves researching, reading, analyzing, evaluating, and summarizing scholarly literature (typically journals and articles) about a specific topic. The results of a literature review may be an entire report or article OR may be part of a article, thesis, dissertation, or grant proposal. A literature review helps the author learn about the history and nature of their topic, and identify research gaps and problems.

Steps & Elements

Problem formulation

Determine your topic and its components by asking a question
Research: locate literature related to your topic to identify the gap(s) that can be addressed
Read: read the articles or other sources of information
Analyze: assess the findings for relevancy
Evaluating: determine how the article are relevant to your research and what are the key findings
Synthesis: write about the key findings and how it is relevant to your research

Elements of a Literature Review

Summarize subject, issue or theory under consideration, along with objectives of the review
Divide works under review into categories (e.g. those in support of a particular position, those against, those offering alternative theories entirely)
Explain how each work is similar to and how it varies from the others
Conclude which pieces are best considered in their argument, are most convincing of their opinions, and make the greatest contribution to the understanding and development of an area of research

Writing a Literature Review Resources

How to Write a Literature Review From the Wesleyan University Library
Write a Literature Review From the University of California Santa Cruz Library. A Brief overview of a literature review, includes a list of stages for writing a lit review.
Literature Reviews From the University of North Carolina Writing Center. Detailed information about writing a literature review.
Undertaking a literature review: a step-by-step approach Cronin, P., Ryan, F., & Coughan, M. (2008). Undertaking a literature review: A step-by-step approach. British Journal of Nursing, 17(1), p.38-43

Literature Review Tutorial

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Last Updated: Feb 29, 2024 12:00 PM
URL: https://guides.auraria.edu/researchmethods

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Teaching and Research guides

Literature reviews.

Introduction
Plan your search
Where to search
Refine and update your search
Finding grey literature
Writing the review
Referencing

Research methods overview

Finding literature on research methodologies, sage research methods online.

Get material not at RMIT
Further help

What are research methods?

Research methodology is the specific strategies, processes, or techniques utilised in the collection of information that is created and analysed.

The methodology section of a research paper, or thesis, enables the reader to critically evaluate the study’s validity and reliability by addressing how the data was collected or generated, and how it was analysed.

Types of research methods

There are three main types of research methods which use different designs for data collection.

(1) Qualitative research

Qualitative research gathers data about lived experiences, emotions or behaviours, and the meanings individuals attach to them. It assists in enabling researchers to gain a better understanding of complex concepts, social interactions or cultural phenomena. This type of research is useful in the exploration of how or why things have occurred, interpreting events and describing actions.

Examples of qualitative research designs include:

focus groups
observations
document analysis
oral history or life stories

(2) Quantitative research

Quantitative research gathers numerical data which can be ranked, measured or categorised through statistical analysis. It assists with uncovering patterns or relationships, and for making generalisations. This type of research is useful for finding out how many, how much, how often, or to what extent.

Examples of quantitative research designs include:

surveys or questionnaires
observation
document screening
experiments

(3) Mixed method research

Mixed Methods research integrates both Qualitative research and Quantitative research. It provides a holistic approach combining and analysing the statistical data with deeper contextualised insights. Using Mixed Methods also enables triangulation, or verification, of the data from two or more sources.

Sometimes in your literature review, you might need to discuss and evaluate relevant research methodologies in order to justify your own choice of research methodology.

When searching for literature on research methodologies it is important to search across a range of sources. No single information source will supply all that you need. Selecting appropriate sources will depend upon your research topic.

Developing a robust search strategy will help reduce irrelevant results. It is good practice to plan a strategy before you start to search.

Search tips

(1) free text keywords.

Free text searching is the use of natural language words to conduct your search. Use selective free text keywords such as: phenomenological, "lived experience", "grounded theory", "life experiences", "focus groups", interview, quantitative, survey, validity, variance, correlation and statistical.

To locate books on your desired methodology, try LibrarySearch . Remember to use refine options such as books, ebooks, subject, and publication date.

(2) Subject headings in Databases

Databases categorise their records using subject terms, or a controlled vocabulary (thesaurus). These subject headings may be useful to use, in addition to utilising free text keywords in a database search.

Subject headings will differ across databases, for example, the PubMed database uses 'Qualitative Research' whilst the CINHAL database uses 'Qualitative Studies.'

(3) Limiting search results

Databases enable sets of results to be limited or filtered by specific fields, look for options such as Publication Type, Article Type, etc. and apply them to your search.

(4) Browse the Library shelves

To find books on research methods browse the Library shelves at call number 001.42

SAGE Research Methods Online SAGE Research Methods Online (SRMO) is a research tool supported by a newly devised taxonomy that links content and methods terms. It provides the most comprehensive picture available today of research methods (quantitative, qualitative and mixed methods) across the social and behavioural sciences.

SAGE Research Methods Overview (2:07 min) by SAGE Publishing ( YouTube )

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Last Updated: Jun 27, 2024 2:49 PM
URL: https://rmit.libguides.com/literature-review

Which review is that? A guide to review types

Which review is that?
Review Comparison Chart
Decision Tool
Critical Review
Integrative Review
Narrative Review
State of the Art Review
Narrative Summary
Systematic Review
Meta-analysis
Comparative Effectiveness Review
Diagnostic Systematic Review
Network Meta-analysis
Prognostic Review
Psychometric Review
Review of Economic Evaluations
Systematic Review of Epidemiology Studies
Living Systematic Reviews
Umbrella Review
Review of Reviews
Rapid Review
Rapid Evidence Assessment
Rapid Realist Review
Qualitative Evidence Synthesis
Qualitative Interpretive Meta-synthesis
Qualitative Meta-synthesis
Qualitative Research Synthesis
Framework Synthesis - Best-fit Framework Synthesis
Meta-aggregation
Meta-ethnography
Meta-interpretation
Meta-narrative Review
Meta-summary
Thematic Synthesis
Mixed Methods Synthesis
Narrative Synthesis
Bayesian Meta-analysis
EPPI-Centre Review
Critical Interpretive Synthesis
Realist Synthesis - Realist Review
Scoping Review
Mapping Review
Systematised Review
Concept Synthesis
Expert Opinion - Policy Review
Technology Assessment Review

Methodological Review

Systematic Search and Review

A methodological review is a type of systematic secondary research (i.e., research synthesis) which focuses on summarising the state-of-the-art methodological practices of research in a substantive field or topic" (Chong et al, 2021).

Methodological reviews "can be performed to examine any methodological issues relating to the design, conduct and review of research studies and also evidence syntheses". Munn et al, 2018)

Physical Therapy

Critical Appraisal
Getting Started with Research
Reference Resources
Evidence Summaries and Clinical Guidelines
Health Data and Statistics
Patient/Consumer Facing Materials
Images and Streaming Video
Database Tutorials and Search Guidance
Crafting a Search
Narrowing/Filtering the Search
Expanding the Search
Find Grey Literature
Save Your Searches
Cite and Manage Sources
What are Literature Reviews?
Conducting & Reporting Systematic Reviews
Finding Systematic Reviews
Tutorials & Tools for Literature Reviews

Types of Literature Reviews

Literature reviews are comprehensive summaries and syntheses of the previous research on a given topic.

The review purpose, methods used, and the results produced vary among different kinds of literature reviews. Some of the common types of literature review are detailed below.

Common Types of Literature Reviews 1

Narrative (literature) review.

A broad term referring to reviews with a wide scope and non-standardized methodology
Search strategies, comprehensiveness of literature search, time range covered and method of synthesis will vary and do not follow an established protocol

Integrative Review

A type of literature review based on a systematic, structured literature search
Often has a broadly defined purpose or review question
Seeks to generate or refine and theory or hypothesis and/or develop a holistic understanding of a topic of interest
Relies on diverse sources of data (e.g. empirical, theoretical or methodological literature; qualitative or quantitative studies)

Systematic Review

Systematically and transparently collects and categorize existing evidence on a question of scientific, policy or management importance
Follows a research protocol that is established a priori
Some sub-types of systematic reviews include: SRs of intervention effectiveness, diagnosis, prognosis, etiology, qualitative evidence, economic evidence, and more.
Time-intensive and often takes months to a year or more to complete
The most commonly referred to type of evidence synthesis; sometimes confused as a blanket term for other types of reviews

Meta-Analysis

Statistical technique for combining the findings from disparate quantitative studies
Uses statistical methods to objectively evaluate, synthesize, and summarize results
Often conducted as part of a systematic review

Scoping Review

Systematically and transparently collects and categorizes existing evidence on a broad question of scientific, policy or management importance
Seeks to identify research gaps, identify key concepts and characteristics of the literature and/or examine how research is conducted on a topic of interest
Useful when the complexity or heterogeneity of the body of literature does not lend itself to a precise systematic review
Useful if authors do not have a single, precise review question
May critically evaluate existing evidence, but does not attempt to synthesize the results in the way a systematic review would
May take longer than a systematic review

Rapid Review

Applies a systematic review methodology within a time-constrained setting
Employs methodological "shortcuts" (e.g., limiting search terms and the scope of the literature search), at the risk of introducing bias
Useful for addressing issues requiring quick decisions, such as developing policy recommendations

Umbrella Review

Reviews other systematic reviews on a topic
Often defines a broader question than is typical of a traditional systematic review
Most useful when there are competing interventions to consider

1. Adapted from:

Eldermire, E. (2021, November 15). A guide to evidence synthesis: Types of evidence synthesis. Cornell University LibGuides. https://guides.library.cornell.edu/evidence-synthesis/types

Nolfi, D. (2021, October 6). Integrative Review: Systematic vs. Scoping vs. Integrative. Duquesne University LibGuides. https://guides.library.duq.edu/c.php?g=1055475&p=7725920

Delaney, L. (2021, November 24). Systematic reviews: Other review types. UniSA LibGuides. https://guides.library.unisa.edu.au/SystematicReviews/OtherReviewTypes

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Published: 01 July 2024

Time of sample collection is critical for the replicability of microbiome analyses

Celeste Allaband ORCID: orcid.org/0000-0003-1832-4858 1 , 2 , 3 ,
Amulya Lingaraju 2 ,
Stephany Flores Ramos ORCID: orcid.org/0000-0002-1918-9769 1 , 2 , 3 ,
Tanya Kumar 4 ,
Haniyeh Javaheri 2 ,
Maria D. Tiu 2 ,
Ana Carolina Dantas Machado 2 ,
R. Alexander Richter 2 ,
Emmanuel Elijah 5 , 6 ,
Gabriel G. Haddad 3 , 7 , 8 ,
Vanessa A. Leone 9 ,
Pieter C. Dorrestein ORCID: orcid.org/0000-0002-3003-1030 3 , 5 , 6 , 10 ,
Rob Knight ORCID: orcid.org/0000-0002-0975-9019 3 , 6 , 11 , 12 , 13 &
Amir Zarrinpar ORCID: orcid.org/0000-0001-6423-5982 2 , 6 , 13 , 14 , 15

Nature Metabolism ( 2024 ) Cite this article

Metrics details

Animal disease models
Circadian regulation
Research management

As the microbiome field moves from descriptive and associative research to mechanistic and interventional studies, being able to account for all confounding variables in the experimental design, which includes the maternal effect 1 , cage effect 2 , facility differences 3 , as well as laboratory and sample handling protocols 4 , is critical for interpretability of results. Despite significant procedural and bioinformatic improvements, unexplained variability and lack of replicability still occur. One underexplored factor is that the microbiome is dynamic and exhibits diurnal oscillations that can change microbiome composition 5 , 6 , 7 . In this retrospective analysis of 16S amplicon sequencing studies in male mice, we show that sample collection time affects the conclusions drawn from microbiome studies and its effect size is larger than those of a daily experimental intervention or dietary changes. The timing of divergence of the microbiome composition between experimental and control groups is unique to each experiment. Sample collection times as short as only 4 hours apart can lead to vastly different conclusions. Lack of consistency in the time of sample collection may explain poor cross-study replicability in microbiome research. The impact of diurnal rhythms on the outcomes and study design of other fields is unknown but likely significant.

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Data availability

Literature review data are at https://github.com/knightlab-analyses/dynamics/data/ . Figure 1 , mock data are at https://github.com/knightlab-analyses/dynamics/data/MockData . Figure 2 (Allaband/Zarrinpar 2021) data are under EBI accession ERP110592 . Figure 3 data (longitudinal IHC) are under EBI accession ERP110592 and (longitudinal circadian TRF) EBI accession ERP123226 . Figure 4 data (Zarrinpar/Panda 2014) are in the Supplementary Excel file attached to the source paper 13 ; (Leone/Chang 2015) figshare for the 16S amplicon sequence data are at https://doi.org/10.6084/m9.figshare.882928 (ref. 63 ). Extended Data Fig. 2 data (Caporaso/Knight 2011) are at MG-RAST project mgp93 (IDs mgm4457768.3 and mgm4459735.3). Extended Data Fig. 3 data (Wu/Chen 2018) are under ENA accession PRJEB22049 . Extended Data Fig. 4 data (Tuganbaev/Elinav 2021) are under ENA accession PRJEB38869 .

Code availability

All relevant code notebooks are on GitHub at https://github.com/knightlab-analyses/dynamics/notebooks .

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Acknowledgements

C.A. was supported by NIH T32 OD017863. S.F.R. is supported by the Soros Foundation. A.L. is supported by the AHA Postdoctoral Fellowship grant. T.K. is supported by NIH T32 GM719876. A.C.D.M. is supported by R01 HL148801-02S1. G.G.H. and A.Z. are supported by NIH R01 HL157445. A.Z. is further supported by the VA Merit BLR&D Award I01 BX005707 and NIH grants R01 AI163483, R01 HL148801, R01 EB030134 and U01 CA265719. All authors receive institutional support from NIH P30 DK120515, P30 DK063491, P30 CA014195, P50 AA011999 and UL1 TR001442.

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Contributions

C.A. and A.Z. conceptualized the work. C.A., E.E., P.C.D., R.K. and A.Z. determined the methodology. C.A., A.L., S.F.R., T.K., H.J., M.D.T., A.C.D.M. and R.A.R. were involved in data investigation. C.A., S.F.R., T.K., H.J., M.D.T., A.C.D.M. and R.A.R. created visualizations. A.Z. acquired funding and was the project administrator. R.K. and A.Z. supervised the work. G.G.H. and V.A.L. provided resources. C.A., A.L., S.F.R., T.K., H.J., M.D.T. and A.Z. wrote the first draft. All authors contributed to the review and editing of the manuscript.

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A.Z. is a co-founder and a chief medical officer, and holds equity in Endure Biotherapeutics. P.C.D. is an advisor to Cybele and co-founder and advisor to Ometa and Enveda with previous approval from the University of California, San Diego. All other authors declare no competing interests.

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Extended data

Extended data fig. 1 microbiome literature review..

A ) 2019 Literature Review Summary. Of the 586 articles containing microbiome (16 S or metagenomic) data, found as described in the methods section, the percentage of microbiome articles from each of the publication groups. B ) The percentage of microbiome articles belonging to each individual journal in 2019. Because the numerous individual journals from Science represented low percentages individually, they were grouped together. C ) The percentage articles where collection time was explicitly stated (yes: 8 AM, ZT4, etc.), implicitly stated (relative: ‘before surgery’, ‘in the morning’, etc.), or unstated (not provided: ‘daily’, ‘once a week’, etc.). D ) Meta-Analysis Inclusion Criteria Flow Chart. Literature review resulting in the five previously published datasets for meta-analysis 11 , 13 , 28 , 29 , 30 .

Extended Data Fig. 2 Single Time Point (Non-Circadian) Example.

A ) Weighted UniFrac PCoA Plot - modified example from Moving Pictures Qiime2 tutorial data [ https://docs.qiime2.org/2022.11/tutorials/moving-pictures/ ]. Each point is a sample. Points were coloured by body site of origin. There are 8 gut, 8 left palm, 9 right palm, and 9 tongue samples. B ) Within-Condition Distances (WCD) boxplot/stripplot for each body site (n = 8–9 mouse per group per time point). C ) Between Condition Distances (BCD) boxplot/stripplot for each unique body site comparison (n = 8–9 mouse per group per time point). D ) All pairwise grouping comparisons, both WCD and BCD, are shown in the boxplots/stripplots (n = 8–9 mouse per group per time point). Only WCD to BCD statistical differences are shown. Boxplot centre line indicates median, edges of boxes are quartiles, error bars are min and max values. Significance was determined using a paired Mann-Whitney-Wilcoxon test two-sided with Bonferroni correction. Notation: ns (not significant) = p > 0.05, * = p < 0.05; ** = p < 0.01; *** = p < 0.001, **** = p < 0.00001.

Extended Data Fig. 3 Additional Analysis of Apoe-/- Mice Exposed to IHC Conditions.

A ) Weighted UniFrac PCoA stacked view (same as Fig. 2b but different orientation). Good for assessing overall similarity not broken down by time point. Significance determined by PERMANOVA (p = 0.005). B ) Weighted UniFrac PCoA of only axis 1 over time. C ) Boxplot/scatterplot of within-group weighted UniFrac distance values for the control group (Air, n = 3–4 samples per time point). Unique non-zero values in the matrix were kept. Dotted line indicates the mean of all values presented. No significant differences (p > 0.05) found. D ) Boxplot/scatterplot of within-group weighted UniFrac distance values for the experimental group (IHC, n = 3–4 samples per time point)). Unique non-zero values in the matrix were kept. Dotted line indicates the mean of all values presented. No significant differences (p > 0.05) found. E ) Boxplot/scatterplot of within-group weighted UniFrac distance values for both control (Air) and experimental (IHC) groups [n = 3–4 samples per group per time point]. Mann-Whitney-Wilcoxon test with Bonferroni correction used to determine significant differences between groups. Boxplot centre line indicates median, edges of boxes are quartiles, error bars are min and max values. Notation: ns = not significant, p > 0.05; * = p < 0.05; ** = p < 0.01; *** = p < 0.001.

Extended Data Fig. 4 Irregular differences in diurnal rhythm patterns leads to generally minor shifts in BCD when comparing LD vs DD mice.

A ) Experimental design. Balb/c mice were fed NCD ad libitum under 0:24 L:D (24 hr darkness, DD) experimental conditions and compared to 12:12 L:D (LD) control conditions. After 2 weeks, mice from each group were euthanized every 4 hours for 24 hours (N = 4–5 mice/condition) and samples were collected from the proximal small intestine (‘jejunum’) and distal small intestine (‘ileum’) contents. B ) BCD for luminal contents of proximal small intestine samples comparing LD to DD mice (N = 4–5 mice/condition). Dotted line is the average of all shown weighted UniFrac distances. Significance was determined using a paired Mann-Whitney-Wilcoxon test two-sided with Bonferroni correction; notation: **** = p < 0.00001. C ) BCD for luminal contents of distal small intestine samples comparing LD to DD mice (N = 4–5 mice/condition). Dotted line is the average of all shown weighted UniFrac distances. Boxplot centre line indicates median, edges of boxes are quartiles, error bars are min and max values.

Extended Data Fig. 5 Localized changes in BCD between luminal and mucosal contents.

A ) Experimental design and sample collection for a local site study. Small intestinal samples were collected every 4 hours for 24 hours (N = 4–5 mice/condition, skipping ZT8). Mice were fed ad libitum on the same diet (NCD) for 4 weeks before samples were taken. B ) BCD for luminal vs mucosal conditions (N = 4–5 mice/condition). The dotted line is the average of all shown weighted UniFrac distances. Significance is determined using the Mann-Whitney-Wilcoxon test two-sided with Bonferroni correction. C ) Heatmap of mean BCD distances comparing luminal and mucosal by time point (N = 4–5 mice/condition). Highest value highlighted in navy, lowest value highlighted in gold. Boxplot centre line indicates median, edges of boxes are quartiles, error bars are min and max values. Significance was determined using a paired Mann-Whitney-Wilcoxon test two-sided with Bonferroni correction. Notation: * = p < 0.05; ** = p < 0.01; *** = p < 0.001, **** = p < 0.00001. D ) Experimentally relevant log ratio, highlighting the changes seen at ZT20 (N = 4–5 mice/condition). Boxplot center line indicates median, edges of boxes are quartiles, error bars are min and max values. Significance was determined using a paired Mann-Whitney-Wilcoxon test two-sided with Bonferroni correction. Notation: * = p < 0.05; ** = p < 0.01; *** = p < 0.001, **** = p < 0.00001.

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Allaband, C., Lingaraju, A., Flores Ramos, S. et al. Time of sample collection is critical for the replicability of microbiome analyses. Nat Metab (2024). https://doi.org/10.1038/s42255-024-01064-1

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Published: 26 June 2024

iPSCs chondrogenic differentiation for personalized regenerative medicine: a literature review

Eltahir Abdelrazig Mohamed Ali 1 , 2 na1 ,
Rana Smaida 3 na1 ,
Morgane Meyer 2 , 3 na1 ,
Wenxin Ou 2 , 6 , 7 na1 ,
Zongjin Li 4 ,
Zhongchao Han 5 ,
Nadia Benkirane-Jessel 1 , 2 , 3 ,
Jacques Eric Gottenberg 2 , 6 &
Guoqiang Hua ORCID: orcid.org/0000-0001-7639-5908 1 , 2

Stem Cell Research & Therapy volume 15 , Article number: 185 ( 2024 ) Cite this article

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Metrics details

Cartilage, an important connective tissue, provides structural support to other body tissues, and serves as a cushion against impacts throughout the body. Found at the end of the bones, cartilage decreases friction and averts bone-on-bone contact during joint movement. Therefore, defects of cartilage can result from natural wear and tear, or from traumatic events, such as injuries or sudden changes in direction during sports activities. Overtime, these cartilage defects which do not always produce immediate symptoms, could lead to severe clinical pathologies. The emergence of induced pluripotent stem cells (iPSCs) has revolutionized the field of regenerative medicine, providing a promising platform for generating various cell types for therapeutic applications. Thus, chondrocytes differentiated from iPSCs become a promising avenue for non-invasive clinical interventions for cartilage injuries and diseases. In this review, we aim to highlight the current strategies used for in vitro chondrogenic differentiation of iPSCs and to explore their multifaceted applications in disease modeling, drug screening, and personalized regenerative medicine. Achieving abundant functional iPSC-derived chondrocytes requires optimization of culture conditions, incorporating specific growth factors, and precise temporal control. Continual improvements in differentiation methods and integration of emerging genome editing, organoids, and 3D bioprinting technologies will enhance the translational applications of iPSC-derived chondrocytes. Finally, to unlock the benefits for patients suffering from cartilage diseases through iPSCs-derived technologies in chondrogenesis, automatic cell therapy manufacturing systems will not only reduce human intervention and ensure sterile processes within isolator-like platforms to minimize contamination risks, but also provide customized production processes with enhanced scalability and efficiency.

Graphical abstract

Cartilage is a semi-rigid, load-bearing, avascular connective tissue, formed solely by cells known as chondrocytes. These cells are loosely embedded in an extracellular matrix (ECM) composed predominantly of collagens and, in some cases, elastic fibers, hyaluronan and proteoglycans [ 1 ]. Cartilage formation, also known as chondrogenesis, is a dynamic cellular process of a condensed mesenchyme tissue derived from the mesoderm germ layer during embryogenesis. Cartilage represents the fetal precursor tissue for skeletal development. In adults, it persists at almost all joints between bones and in structures that must be deformable as well as strong such as in the respiratory system. Based on the structure and composition of their ECMs, chondrocytes form three different types of cartilage; namely, hyaline cartilage, fibrocartilage and elastic cartilage [ 2 ].

Cartilage exhibits diverse clinical aspects and relevance to various medical disciplines, including orthopedics, rheumatology, and respiratory medicine. Cartilage defects are associated with various clinical conditions such as osteoarthritis (OA), rheumatoid arthritis, and cartilage dysplasias [ 1 ]. Understanding the clinical significance of cartilage is critical for the development of effective therapeutics and interventions in various healthcare settings. Orthopedic surgeries such as joint arthroplasty and cartilage transplantation are the most commonly used therapeutic interventions for cartilage repair or replacement [ 3 ]. However, these surgical interventions are invasive or minimally invasive, and their ability to restore normal joint function, alleviate pain, and improve the quality of life for individuals with cartilage-related issues is limited.

Therefore, it is crucial to develop other non-invasive therapeutic approaches with high safety and efficacy. Theoretically and due to their ability to repair injured tissues, adult stem cells can be a good source for developing therapies for a large number of diseases [ 4 ]. Mesenchymal stem cells (MSCs) which can be derived from various tissues such as bone marrow, adipose tissu, placenta, umbilical cord blood, and multiple dental tissues, are multipotent cells that have the potential to differentiate into the mesenchymal lineages including osteocytes, chondrocytes, and adipocytes, as well as other non-mesenchymal lineages, such as cardiomyocytes, astrocytes, neural cells, and endothelial cells [ 5 , 6 ]. Therefore, extensive efforts have been spent to develop MSCs-based cell therapies for a broad spectrum of diseases, encompassing cartilage and bone diseases, hematological diseases, inflammatory diseases, and graft-versus-host disease [ 7 ]. It is important to note that different transcription factors regulate the differentiation of MSCs to different lineages. Chondrogenic differentiation is determined by members the SOX (sex determining region Y (SRY)-related HMG-box) family of transcription factors SOX9, SOX5, and SOX6 while regulation of osteoblast differentiation involve the transcription factors runt-related transcription factor 2 (RUNX2), osterix, and β-catenin [ 8 , 9 ]. Among the different sources of MSCs, bone marrow-derived MSCs (BM-MSCs) are the most commonly used MSCs in regenerative medicine, particularly for cartilage and bone regeneration [ 10 ]. Although significant strides have been taken to improve the chondrogenic differentiation from BM-MSCs and other cell sources, several obstacles persist complicating the achievement of consistent and effective chondrocytes required for clinical application [ 11 ]. Several factors may lead to the failure of utilizing BM-MSCs for efficient treatment of cartilage diseases including but not limited to the restricted proliferation capabilities in cultures [ 12 ], donor variations, and immunogenicity triggered during culture and cryopreservation [ 13 ].

These challenges could be addressed by the induced pluripotent stem cell (iPSC) technology. iPSCs are pluripoent cells which have the capacity for self-renewal and differentiation into almost all cell types [ 14 ]. The concept of self-renewal is the ability of the cells to undergo infinite cell divisions without differentiation into other cell types, while pluripotency is the ability of the cells to produce specialized cells of the three embryonic layers: ectoderm, mesoderm, and endoderm [ 15 ]. iPSCs can be generated from any type of cells through non-integrating reprogramming method using specific transcription factors known as Yamanaka factors namely, Octamer binding transcription factor 3/4 (OCT3/4), SOX2, Krüppel-like factor 4 (KLF4), and Cellular-Myelocytomatosis c-MYC [ 15 ]. Simplicity and reproducibility are the attractive features of the iPSC technology and have attracted the biomedical scientists to generate and differentiate iPSCs from numerous normal and disease-specific cell types for disease modeling and drug screening applications [ 16 ]. Syngeneic non-integrated iPSCs and their derivatives have no or minimal immunogenic effect supporting the notion that these cells could be used for cellular therapy without causing harmful immune responses [ 17 ]. Therefore, generation of iPSC-derived chondrocytes has become indispensable to advance our understanding of the mechanisms of cartilage-related disorders and represents an important avenue in regenerative medicine. In the following section, we will summarize different strategies developed to differentiate iPSCs into chondrocytes aiming to recapitulate the in vivo microenvironment that support chondrogenesis, and to generate functional and stable iPSC-derived chondrocytes.

Generation of iPSC-derived chondrocytes

Chondrocytes can be differentiated from iPSCs though different intermediate stages, such as iPSC-derived MSCs (iPSC-MSCs), embryoid bodies (EBs) formation, induction of neural crest cells (NCCs), and primitive streak-mesendoderm and mesodermal lineage. iPSC-MSCs are morphologically highly similar to BM-MSCs and their gene expression profiling is also comparable to that of BM-MSCs [ 18 ], and exhibit traits that encompass features of both iPSCs and MSCs. iPSC-MSCs show reduced immunogenicity as compared to iPSCs [ 19 ], which renders them appropriate for allogeneic transplantation and enables development of off-the-shelf therapies. Moreover, patient-specific iPSC-MSCs open up the potential for developing personalized medicine for autologous transplantation, in vitro disease modeling, and drug screening [ 20 ]. These iPSC-MSCs were reported to differentiate into chondrocytes with growth factors, such as transforming growth factor-beta 3 (TGF-β3) (Fig. 1 A). Another commonly used approach to obtain chondrocytes from iPSCs in vitro is through formation of three-dimensional (3D) aggregates of pluripotent stem cells (PSCs) known as embryoid bodies (EBs) (Fig. 1 B). The EB has the capacity to generate ectodermal, mesodermal and endodermal cells due to its initiation of a process that resembles gastrulation-like events in embryonic development [ 21 ]. Several protocols have been developed under this category with slight variations in the number and concentration of growth factors used, the number of days required and whether an additional step such as differentiation of EBs to MSCs or paraxial mesoderm cells, is needed to differentiate iPSCs to chondrocytes [ 22 ]. NCCs are a multipotent group of transient embryonic cells in the vertebrate. They are derived from the ectoderm and differentiate to the peripheral nervous system cells and several non-neural cell types including pigment cells, and the cranio-facial cartilage and bones [ 23 ]. Taking the advantage of being multipotent, chondrogenic cells could be differentiated from the NCC-derived MSCs [ 24 ] (Fig. 1 C). Chondrocytes were also reported to be differentiated from human embryonic stem cells (hESCs) through primitive streak or mesendoderm to mesoderm [ 25 ]. Cheng et al. followed this method to differentiate iPSCs to chondrocyte in three short stages using different combination of growth factors in each stage [ 26 ] (Fig. 1 D). iPSCs can also be differentiated to chondrocytes by co-culture with primary chondrocytes (Fig. 1 D). This method is based on the fact that the primary chondrocytes secret paracrine factors which may induce chondrogenic differentiation of the stem cells by closely mimicking the in vivo tissue microenvironment for chondrogenesis [ 27 ]. Moreover, co-culture permits crosstalk between the stem cells and the primary chondrocytes influencing chondrocyte development. It facilitates physical contact between different cell types which stabilizes the cellular phenotype and allows for communication of molecular signals involved in chondrogenic differentiation [ 28 ].

Schematic representation of the current strategies for in vitro differentiation of iPSCs to chondrocytes. A Via iPSC-derived MSCs. B Via EBs formation. C Via induction of NCCs. D Via primitive streak-mesendoderm and mesodermal lineage. E Via co-culture with primary chondrocytes. BMP4: bone morphogenetic protein 4; BMP7: bone morphogenetic protein 7; CHIR99021: glycogen synthase kinase 3 (GSK-3) inhibitor; DM: dorsomorphin; EB: embryoid body; EGF: epidermal growth factor; FGF2: fibroblast growth factor 2; GDF5: growth/differentiation factor-5; hESC: human embryonic stem cell; iPSC: induced pluripotent stem cell; MSC: mesenchymal stem cell; NCC: neural crest cell; NT4: neurotrophin-4; PDGF: platelet-derived growth factor; PSC: pluripotent stem cell; SB431542: transforming growth factor-beta receptor inhibitor; TGF-β3: transforming growth factor-beta 3; Wnt3a: Wingless/Int1 family member 3A

The above-mentioned studies showed that cartilage cells differentiated from human iPSCs represent a promising tool for regenerative medicine to treat cartilage-related diseases, however some challenges remain. The variability in the quality and characteristics of different iPSC lines affects the efficiency and consistency of chondrogenic differentiation [ 29 ]. Since the suspension culture promotes the chondrogenic differentiation and enables removal of non-chondrocytic cells, Yamashita and colleagues reported that homogenous chondrogenic nodules derived from iPSCs cultivated in suspension culture has the potential to form scaffold-free hyaline cartilage in animal models [ 30 ]. How to generate homogenous cartilage cells without formation of hypertrophic chondrocytes which have the potential to trigger the process of initiating endochondral ossification in vivo remains the main challenge. Moreover, iPSCs have the potential to form teratomas, therefore it is crucial to ensure complete elimination of undifferentiated iPSCs from chondrogenic cultures to prevent teratoma formation upon transplantation [ 31 ]. Obtaining fully mature chondrocytes from iPSCs with a phenotype comparable to native chondrocytes, is challenging [ 32 ]. In addition, undesired development of chondrogenic hypertrophy and fibrocartilage in vitro may require modification of the growth factors cocktail used [ 33 ]. Due to bovine xenoproteins, use of fetal bovine serum (FBS) in cell culture may induce adverse response in transplant patient upon injection of MSCs [ 34 ]. Additionally, there is a risk of infection because of viral and prion contamination [ 35 ]. Interestingly, MSC induction in xeno-free conditions may tackle these problems and promote the safety and efficiency of iPSC-MSCs for clinical applications [ 36 ].

Genome-edited iPSC-derived chondrocytes

In the last decade, the clustered regularly interspaced short palindromic repeats (CRISPR-Cas9) approach has become an efficient and indispensable tool in biomedical research, and has been extensively explored in bone and cartilage research [ 37 , 38 ]. It has been used to edit genes associated with chondrogenic differentiation to enhance their expression [ 39 ] or to modify signaling pathways involved in chondrogenesis [ 40 ]. For example, chondrogenesis can be regulated by the expression of SOX9 and Stat3 [ 39 ]. Chondrogenic differentiation of MSCs can be promoted by knocking down the RUNX2 , a key transcription factor associated with osteoblast differentiation [ 41 ]. Genomic editing in iPSC-derived chondrocytes has been also reported in disease modeling. Efficient editing of cartilage related genes enables to investigate in depth the mechanisms underlying cartilage disorders and to identify potential therapeutic agents [ 42 ]. An interesting genome editing study showed simultaneous SOX9 activation and peroxisome proliferator-activated receptor gamma (PPAR-γ) repression in rat BM-MSCs, which promoted chondrocytes differentiation and regeneration of calvarial bone [ 43 ]. Various studies have investigated diverse targets for regeneration, paving the way for potential clinical trials in the near future. Genome editing has been employed to boost the regenerative potential of chondrocytes. This may involve editing genes related to ECM production, cell proliferation, or resistance to hypertrophy [ 41 , 44 , 45 ]. Although numerous studies have been reported on the application of genome-edited chondrocytes for in vivo cartilage repair, drug screening, and disease modeling [ 39 , 41 , 43 ], relatively few studies have been conducted specifically on iPSC-derived chondrocytes [ 40 , 46 , 47 ]. It was revealed that mutations in TRPV4 disrupted the bone morphogenetic protein (BMP) signaling pathway in iPSC-derived chondrocytes and blocked formation of hypertrophic chondrocytes providing potential targets for drug development for TRPV4-associated skeletal dysplasias [ 48 ]. The existing methods for chondrogenic differentiation from iPSCs may generate heterogeneous cell populations. To resolve this problem, a collagen, type II, alpha 1- green fluorescent protein (COL2A1-GFP) knock-in reporter allele generated by CRISPR-Cas9 system was used to purify the cells. The purified chondroprogenitors exhibited enhanced chondrogenic potential in comparison to unselected groups [ 40 ].

Transplantation of allogeneic human iPSC-derived cartilage have shown to be more effective than allogeneic BM-MSC-derived cartilage [ 49 ]. However, these cartilage cells can trigger immunological reactions [ 50 ]. To overcome this issue, it is necessary to reduce the immunological reactions. The β2 microglobulin, a component of MHC class I molecules, was knocked down in monkey iPSCs before their differentiation into chondrocytes. As expected, the allogeneic iPSC-derived cartilage transplanted in osteochondral defects in monkey knee joints showed increased proliferation of natural killer cells and leukocytes surrounding the knocked down PSC-derived cartilage. This indicates the intricate processes in the immune response of the transplanted allogeneic cartilage in osteochondral defects in vivo [ 47 ]. These studies highlight the tremendous advantages of the CRISPR-Cas9 system in understanding the pathogenesis, identification of promising drug targets, and development of feasible treatment interventions for cartilage diseases.

Cartilage organoids formed and differentiated from iPSCs

iPSC-derived cartilage organoids are 3D cell clusters that are created by differentiation of iPSCs in vitro. To support formation of cartilage organoids and their ability to self-renewal and self-organization, a number of biocompatible materials are used, such as Matrigel and synthetic hydrogels [ 51 ]. Cartilage organoid technology has been developed to facilitate drug screening through identification of important signaling pathways, recapitulate joint developmental events during embryogenesis and cartilage regeneration. Li and colleagues showed that long-term culturing of hiPSC-derived multi-tissue organoids (MTOs) in E8 medium results in a spontaneous emergence of hyaline cartilage tissues. Moreover, a transcriptome analysis indicated a strong association between the expression of chondrogenic markers in MTOs and fetal lower limb chondrocytes [ 52 ]. Another intriguing research demonstrated that subcutaneous implantation of iPSC-derived cartilage microtissues combined with pre-hypertrophic cartilage organoids in nude mice results in formation of both cartilaginous and bony regions [ 53 ]. Similarly, O’Connor and colleagues established osteochondral organoids using murine iPSCs through time-dependent sequential exposure of TGF-β3 and BMP2, to mimic natural bone development through the process of endochondral ossification. The generated organoids showed dual tissues consisting of cartilaginous and calcified bony regions [ 54 ]. A recent study showed a sequential differentiation process to produce matrix-rich cartilage spheroids from iPSC-MSCs by inducing NCCs in xeno-free environments. Efficient chondrogenic differentiation was induced by a thienoindazole derivative, TD-198946, a small molecule used to enhance differentiation of various human progenitor cells to chondrocytes. No hypertrophy, fibrotic cartilage formation, or dedifferentiation detected in vivo in the generated cartilage spheroids. These chondrogenic spheroids can serve as building blocks for biofabrication of engineered cartilage tissues, as they have the ability to fuse within a short timeframe of a few days [ 24 ]. It is worth mentioning that iPSC-derived cartilage organoids have also been reported to recruit osteogenic precursors for bone repair [ 55 ]. A recent study has revealed that allogeneic iPSC-derived cartilage organoids transplanted in the knee joints of a primate model of chondral defects integrated with articular cartilage of the host and prevented further degeneration of the surrounding cartilage [ 49 ]. These findings open new horizons for development of complex tissue engineered implants to promote zone-specific functionality by using pre-differentiated organoids as building blocks to establish articular cartilage grafts. Even though the research on iPSC-derived cartilage organoids is still in its infancy and creating fully functional cartilage organoids is still challenging, it is evident that they have demonstrated promising applications in drug screening, disease modeling, regeneration, and repair. It is of note that application of 3D bioprinting technology in development of iPSC-derived cartilage organoids can create more complex cartilage organoids and heighten their structural organization [ 56 ].

Therapeutic applications of iPSC-derived chondrocytes

Advanced disease modeling.

iPSC-derived chondrocytes have been utilized to recapitulate cartilage injuries and diseases in vitro (Table 1 ). The pluripotency and unlimited self-renewal capacity of the iPSCs make these cells vitally important for disease modeling, which permit us to investigate the mechanisms of various diseases, screen for potential treatment targets, and test therapeutic agents [ 57 ]. iPSC-derived disease models for both monogenic and complex cartilage diseases have been developed with more focus on single gene cartilage disorders [ 58 ]. Saitta et al. established an iPSC-based in vitro model of skeletal dysplasia to investigate the initial stages of abnormal cartilage formation. Mutations in the calcium channel gene TRPV4 lead to abnormal chondrogenesis during cartilage growth plate differentiation [ 59 ]. Isogenic iPSCs with wild-type or mutant NLRP3 have been generated from patients with neonatal-onset multisystem inflammatory disease. Both in vitro and in vivo chondrogenic differentiation were performed. Furthermore, immunodeficient mice that received mutant cartilaginous pellets in vivo experienced disordered endochondral ossification [ 60 ]. In vitro models of familial osteochondritis dissecans (FOCD) was developed using both patient BM-MSCs and iPSCs derived from patient fibroblasts to delineate the pathogenesis of this disease. The results showed that chondrogenic pellets with a high glycosaminoglycan (GAG) content but a poor structural integrity. Moreover, dysregulation of matrix production and assembly was evident. These findings show that how studying FOCD iPSC-derived chondrocytes can reveal insights into disease phenotype and pathogenesis offering a new in vitro model of OA and cartilage degeneration [ 61 ]. Esseltine et al. [ 62 ] converted fibroblasts from patient with oculodentodigital dysplasia (ODDD) into iPSCs, which provided a useful model for investigation of this disease. In this study, the iPSCs showed mutated Cx43 gene, decreased levels of Cx43 mRNA and protein, resulting in impaired channel function. Furthermore, the subcellular localization of Cx43 changed during the chondrogenic differentiation of ODDD-derived iPSCs. This altered localization may have contributed to the more compact cartilage pellet morphology observed in differentiated ODDD-derived iPSCs. Additionally, other research teams successfully developed iPSC-derived disease models for other genetic and complex multifactorial skeletal disorders including type II collagenopathy , fibrodysplasia ossificans progressive (FOP), OA, hand OA, and early-onset finger OA (efOA) [ 58 ]. Recently, a novel method was introduced to direct iPSC-derived sclerotome through a sequential transformation in a 3D pellet culture. The generated chondroprogenitors can further be differentiated into articular chondrocytes or, alternatively, transformed into hypertrophic chondrocytes capable of transitioning into osteoblasts. Moreover, distinctive gene expression signatures have been identified at critical developmental stages, highlighting the effectiveness of this system in modeling genetic disorders affecting cartilage and bone [ 63 ]. In general, these studies demonstrated that normal chondrogenesis can be recapitulated using an iPSC-derived model, and disease-specific iPSCs exhibit molecular evidence of aberrant chondrogenic developmental processes. These findings may be utilized to develop therapeutic strategies for cartilage-related disorders.

To overcome some limitations of scaffold-based 3D cell culture method, scaffold-free methods showed promising results as well. Nakumora et al. [ 64 ] reported efficient fabrication of unified, self-sufficient, and functional cartilaginous constructs by combining iPSCs and bio-3D printers using a Kenzan needle array technology. This approach may facilitate repairing of articular cartilage defects . Zhang et al. [ 65 ] established a rapid and efficient approach, employing a 3D rotary suspension culture system, to directly guide iPSC differentiation toward the chondrogenic mesoderm lineage. Subsequently, the research group introduced a tetracycline-controlled BMP4 gene regulation system for iPSCs, linking transcriptional activation of BMP4 with heightened chondrogenesis using the piggyBac (PB) transposon-based gene delivery system. Kotaka and associates used magnetically-labeled iPSCs and an external magnetic force to evaluate the safety and efficacy of magnetic field-mediated delivery of iPSCs for articular cartilage repair in nude rats. The results demonstrated the effectiveness and safety of this approach for in vivo cartilage repair [ 66 ] .

Drug screening

Surgical interventions are performed to prevent progressing of focal articular cartilage defects [ 29 ], however, no effective drugs are available for treatment of cartilage regeneration. Using human MSCs for screening of compounds that promote chondrogenesis has limitations due to limited expansion of MSC passages, variations between donors and the high cost [ 67 ]. The development of the iPSC technology and advancement in genome editing approaches provide crucial tools for drug screening by establishing iPSC-derived chondrocytes. Using human iPSCs, a 96-well screening platform was developed to identify chondrogenesis-inducing agents that can be used separately or combined with other techniques for cartilage regeneration and repair. Due to their ability to promote chondrogenesis in vitro and in vivo, AB235 and NB61, two chimeric ligands of Activin/BMP2, were used and tested separately at two different doses for validation of the 96-well chondrogenic screening format. Strikingly, elevated concentrations of each of these two agents resulted in improved chondrogenic differentiation [ 68 ]. Another OA drug screening study was conducted on iPSC-derived or native mouse cartilage samples. The inflammatory environment of OA was induced in these cells by interleukin-1α (IL-1α), and a 96-well plate format was used for screening of OA drug candidates. The high-throughput screening revealed that the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inhibitor SC514 was the most effective drug candidate to reduce cartilage loss induced by IL-1α [ 69 ]. Increased mineralization in the FOP-derived iPSCs has been detected, a phenomenon that could be mitigated by the use of the BMP inhibitor DMH1 [ 70 ]. It has been demonstrated that statins could effectively rectify the degraded cartilage observed in both chondrogenically differentiated thanatophoric dysplasia type 1 (TD1)- and achondroplasia (ACH)-specific iPSCs [ 71 ]. These studies illustrate the potential of iPSCs to provide a suitable platform to identify novel therapeutic agents for cartilage-related disorders and facilitate development of personalized regenerative medicine.

Preclinical studies

Chondrocytes derived from iPSCs have demonstrated great promise in a variety of regenerative medicine applications, especially in relation to cartilage regeneration and repair [ 49 , 64 , 72 ]. These cells offer regenerative treatments for diseases such as OA and cartilage injuries (Table 1 ). They can be combined with biomaterial scaffolds or scaffold-free methods to create engineered cartilage grafts for transplantation [ 73 ]. Generation of cartilage tissues from patient-specific iPSCs reduces the risk of immunological rejection, thus this personalized strategy has a potential for treating diseases such as OA [ 19 ]. Before their clinical application, preclinical studies of the iPSC-derived chondrocytes are crucial to assess their viability, functionality, and safety [ 74 ]. iPSC-MSCs were used to repair cartilage defects in a rabbit model. Macroscopic and histological assessment revealed more cartilage repair in the experimental group as compared to both the control and scaffold implantation group. Furthermore, no teratoma formation detected in all the three groups indicating the safety and potential of iPSC-MSCs for cartilage regeneration [ 75 ]. Ko et al. [ 76 ] implanted iPSC-derived chondrocytes in osteochondral defects in immunosuppressed rats. The defects exhibited a significantly higher quality of cartilage repair than in the control. In another study, homogenous cartilaginous particles derived from chondrocyte-specific reporter hiPSC lines were transplanted into joint surface defects in immunodeficient rat and immunosuppressed mini-pig models. The neocartilage survived and integrated into native cartilage, and no tumor formation was observed in all the animal models following the transplantation [ 30 ]. The potential of MSC-based therapies is attributed to the release of trophic factors via paracrine signaling, with small extracellular vesicles (sEVs) potentially playing a significant role [ 77 ]. Zhu et al. [ 78 ] investigated the therapeutic efficacy of exosomes derived from synovial membrane MSCs (SM-MSC-Exos) and iPSC-MSCs (iPSC-MSC-Exos) in treatment of OA. The injected exosomes in an OA mouse model showed that iPSC-MSC-Exos exhibit a stronger therapeutic impact on OA compared to SM-MSC-Exos. Similarly, iPSC-MSC-derived sEVs injected in degenerative discs of intervertebral disc degeneration (IVDD) rat models revealed significant improvement in IVDD and senescence of nucleus pulposus cells of the IVD [ 79 ]. Given the poliferative capacity of autologous iPSC-MSCs, these cells ensure a consistent and abundant source of therapeutic sEVs, which could introduce a new therapeutic strategy for OA and IVDD treatment [ 78 , 79 ]. As previousely mentioned, Nejadnik et al. developed an effective method to directly differentiate human iPSCs (hiPSCs) into MSCs and chondrocytes without the need for EBs formation. Transplantation of these cells in OA rat models successfully repaired the osteochondral defects [ 33 ]. However, the traces of fibrocartilage and hypertrophic cartilage detected in the generated chondrocytes in vitro and use of FBS in the chondrogenic medium may prevent their clinical application. Use of Xeno-free media and thorough characterization of hiPSC-derived MSCs and chondrocytes will be essential prior to transplantation [ 33 ]. An intriguing study has demonestrated that chondrogenic spheroids derived from iPSC-MSCs retain cartilage phenotype in vivo comparable to the chondrogenic-like tissues generated from the same cell spheroids in vitro. In contrast to spheroids obtained from iPSC-MSCs, distinct bone-like tissue formation was evident in BM-MSC spheroids. This may prove the capacity of iPSC-MSC-derived chondrogenic spheroids to form cartilage-like tissues without endochondral ossification for treatment of cartilage defects in vivo [ 24 ]. Additionally, due to the ability of chondrogenic spheroids to fuse rapidly within a short timeframe, they can serve as as building blocks for constructing larger cartilage tissues using techniques like the Kenzan bioprinting method [ 56 ]. Current focus tends to shift towards investigating immune reactions in the context of allogeneic cartilage transplantation. Abe and colleagues were the first to conduct allogeneic cartilage transplantation into a primate model using major histocompatibility complex (MHC)-mismatched iPSC-derived cartilage organoids without the need for immunosuppressive drugs [ 49 ]. Remarkably, the transplanted organoids exhibited successful engraftment into chondral defects on the knee joint surface of the primate model, demonstrating survival, integration, and remodeling similar to native cartilage, without any observed immune reactions [ 49 ]. The findings of these preclinical studies demonstrate effective and clinically translatable approaches for regenerating cartilage tissue using hiPSC-derived MSCs and chondrocytes, offering potential enhancements in cartilage regeneration outcomes in cartilage diseases.

Clinical studies

Over the past decade, iPSCs have shown significant advancements, offering new prospects for personalized cell therapy. Patient-derived iPSCs exhibit a lower risk of rejection compared to allogeneic iPSCs. Therefore, some challenges such as tumorigenicity or immunogenicity must be addressed before the iPSCs can be extensively utilized in clinical therapy. To date, 89 clinical trials referenced under “induced pluripotent stem cells” have been registered on the World Health Organization (WHO)-managed main databases ( https://clinicaltrials.gov/ , International Clinical Trials Registry Platform (ICTRP), https://trialsearch.who.int/ ). Several studies from the Japan Primary Registries Network ( https://rctportal.niph.go.jp/en ) can be added to the list since most of their 21 iPSCs trials are not cross-referenced with the WHO’s platforms. Among the total 110 identified clinical trials, 51 trials were registered as interventional and the remaining as observational. Despite the low rejection risk, slow shifting from autologous to allogenic iPSC-derived therapy approach has been crucial due to the time and cost required for characterization and safety testing of each cell line. Furthermore, allogeneic iPSCs approach allow more time for the testing process, and once an approved cell line is established, it can be used to treat multiple patients. Opting for allogeneic cell therapy would result in a readily accessible therapeutic product for interventions [ 80 ].

Until recently, pluripotent cell-derived MSCs were not a popular focus in clinical research, with only a small number of studies exploring this area, despite the wide variety of potential tissues that could be produced. Currently, only three clinical trials involving ESC-derived MSCs [ 81 , 82 , 83 ], and six iPSC-MSCs clinical trials have been reported (Table 2 ) [ 84 , 85 ]. It is important to note that from the six clinical trials, cartilage regeneration through iPSC-MSCs was only addressed in two studies. In 2020, the University of Sydney and Cynata Therapeutics conducted phase 1 clinical trial to evaluate the safety, efficacy, and cost-effectiveness of an allogenic MSCs therapy (Cymerus MSCs) for tibiofemoral knee OA [ 86 ]. Lately, Cynata Therapeutics has reported that 321 subjects were recruited for the phase 3 SCUlpTOR clinical trial which will start in 2024 for 24 months (Trial ID: ACTRN12620000870954). In the foreseeable future, the phase 1 clinical trial sponsored by the Chinese Nuwacell Biotechnology company will investigate the safety and efficacy of the NCR100 allogenic iPSC-MSCs intra-articular injection for treatment of knee OA (Trial ID: NCT06049342). This is the first Chinese iPSC-derived cell product approved to be used in phase 1 clinical trial following six years of research and development, ( https://en.nuwacell.com/news ). It is to be noted that a study tried to directly differentiate allogenic iPSCs into chondrocytes without intermediate MSCs differentiation, to treat knee OA as well (Trial ID: jRCTa050190104). The 2020 Japanese interventional trial from Kyoto University was followed by a second observational trial in 2020 for post-treatment evaluation on the subject’s knees (Trial ID: jRCT1050220051).

As a concluding remark, there have been no results regarding cartilage regeneration through iPSC-derived cell therapy in these trials so far. The scarcity of iPSC-MSCs and cartilage-oriented clinical trials indicates significant potential for further advancement and enhancement. Hopefully with the extensively growing iPSCs research, cartilage regeneration for condition such as OA will receive greater attention.

Limitations of iPSC-derived chondrocyte in vitro models

Throughout this review, numerous studies have demonstrated the tremendous advantages offered by iPSC-derived chondrocytes for cartilage research. However, there are some limitations associated with iPSC-derived chondrocyte in vitro models. The first limitation is that the iPSC-derived chondrocytes may show an immature phenotype, and it is still challenging to obtain iPSC-derived chondrocytes with full maturation and stability [ 87 ]. The second limitation is the possibility to generate diverse cell populations with variation in maturation stages. This heterogeneity might complicate result interpretation and compromise the validity and reproducibility of experimental results [ 22 ]. Due to the potential of iPSCs to form teratomas, residual undifferentiated iPSCs in iPSC-derived cartilage grafts may pose a risk of tumor formation in transplantation studies [ 88 ]. Another main challenge is the variability in the efficiency of chondrogenic differentiation among different iPSC lines and even among clones of the same line [ 31 ]. Moreover, the culture conditions for differentiation of iPSCs to chondrocytes may not fully replicate the complex microenvironment of native cartilage tissue. The artificial culture conditions can influence cellular behavior and might not fully capture the in vivo physiological and mechanical complexity of chondrocytes [ 18 , 24 ]. Even though patient-derived iPSCs can potentially reduce the immunological rejection [ 89 ], the in vitro differentiation and manipulation processes may introduce foreign antigens, raising concerns about the immunogenicity of the generated chondrocytes [ 19 ]. In addition, the ability of iPSC-derived chondrocytes to produce a mature and robust ECM may be limited. The structure and organization of the ECM are essential for the functionality and integrity of cartilage tissue. Therefore, ECM defects may affect the utility of in vitro models [ 90 ]. Last, but not the least, the robustness of cartilage in vitro models may be affected by the technical aspects of iPSC maintenance, differentiation, and characterization, which may introduce variability [ 32 ]. These limitations illuminate the challenges associated with iPSC-derived chondrocyte in vitro models. Improvement and optimization of chondrogenic differentiation protocols may overcome these limitations and ensure reliable and comparable results across various studies.

Scaling-up of iPSC-derived cells

The potential of iPSC-derived technologies in chondrogenesis, offering significant benefits for OA and other medical conditions, is evident. However, unlocking these benefits encounters hurdles such as limited process understanding, outdated manufacturing techniques, and insufficient automation. Manual manufacturing and quality control processes prove labor-intensive and error prone. To address the anticipated demand for iPSC-derived cells, scalable production methods must be developed to uphold clinical-grade yields and immunomodulatory properties. Moreover, research indicates that human iPSCs might present an epigenetic edge compared to adult stem cells in producing chondrocytes on a large scale without a tendency towards hypertrophy. Ko and his team showcased heightened expression of key chondrogenic markers such as SOX9, COL2A1, and aggrecan (ACAN), alongside decreased levels of hypertrophic markers like COL10A1 and RUNX2 in iPSC-derived chondrocytes when compared to BM-MSC pellets [ 76 ].

It is crucial to establish robust protocols for large-scale iPSC production to support tasks like cell banking. Thorough evaluations of iPSC-derived chondrocytes in large-scale production settings are essential for consistent quality outcomes and to tackle the challenge of spontaneous differentiation. Closing the gap between research and clinical application necessitates the development of scaled production technologies spanning from initial seeding to final fill-and-finish stages. Embracing full automation in iPSCs cell therapy manufacturing and quality control is paramount for enhancing both product quality and production efficiency in this rapidly evolving field [ 91 ]. A recent study developed hiPSC-derived limb bud mesenchymal cells (ExpLBM cells) with strong chondrogenic potential and stable proliferation. Using a stirred bioreactor, this method outperformed conventional culture plate methods by yielding significant cartilage tissue with just 1 × 10 6 cells. This produced significant amounts of cartilaginous particles, suggesting a scalable method for cartilage regeneration without immune rejection. This efficient approach requires minimal cell quantities and offers potential scalability through adjustments in medium volume and cell numbers [ 92 ]. Another recent study has introduced GelMA microcarriers developed via step emulsification microfluidic devices as a degradable platform for amplifying iPSC-MSCs in scalable bioreactors, while maintaining typical MSC traits and immune-modulatory capabilities. These GelMA microcarriers, manufactured with efficiency and reproducibility in mind, facilitate substantial expansion of iPSC-MSCs (up to 16 times within 8 days) in vertical wheel bioreactors, with a post-digestion viability exceeding 95%. When compared to monolayer culture, iPSC-MSCs expanded on GelMA microcarriers exhibit at least similar, if not superior, immune-modulatory potential. This approach marks a notable progression in producing immune-modulatory iPSC-MSCs, providing scalability, cost-efficiency, and simplified cell retrieval through direct dissolution of microcarriers, thereby minimizing cell wastage [ 93 ].

A novel, good manufacturing practice (GMP)-compliant scalable manufacturing procedure is introduced for the fabrication of iPSC-MSCs, tackling the aforementioned hurdles. By employing xenogeneic-, serum-, and feeder-free conditions, alongside chemically defined maintenance for iPSCs, the process eliminates the necessity for murine feeders and accomplishes mesoderm induction, resulting in heightened performance of MSCs in immunopotency assessments. The manufacturing process comprises three phases: iPSC banking, iPSC expansion and differentiation into MSCs, and MSC expansion and formulation of the final clinical product. Impressively, one vial of iPSCs can yield an average of 3.2 × 10 10 MSCs, and the complete iPSC bank has the potential to generate 2.9 × 10 15 MSCs, equating to 29 million clinical doses, each containing 1 × 10 8 MSCs. This method presents a promising resolution to the challenges of supply, scalability, and consistency in iPSC-MSC production, paving the way for their utilization in clinical applications with heightened efficacy and safety. This optimized manufacturing process for iPSC-MSCs has been applied in treating steroid-resistant acute graft versus host disease (SR-aGvHD) in a phase 1 clinical trial but could be similarly employed in the iPSC-MSCs-Chondrocyte approach for chondrogenesis [ 84 ].

The aim of automating cell therapy manufacturing is to reduce human intervention, ensuring sterile processes within isolator-like platforms to minimize contamination risks. Despite notable advancements, challenges persist, including difficulties in executing specific biological procedures with robotic assistance, prompting the need for exploring new solutions and standardization. Establishing an automated manufacturing platform requires precise definition of process parameters and configurations through validated standard operating procedures (SOPs). To address these needs, an advanced automated cell manufacturing platform was employed to produce both equine and human iPSC-MSCs via EBs [ 94 ]. These iPSC-MSCs were further demonstrated their ability to differentiate into adipogenic, osteogenic, and chondrogenic lineages proficiently. The main goal of this study was to develop a simplified and uniform procedure for isolating MSCs from peripheral blood under GMP conditions, ensuring their viability and purity. Compared to existing protocols documented in the literature, this approach offers simplicity, scalability and consistently delivering robust cell purity [ 94 ]. Recently, another automatic system was reported to produce iPSC-derived therapies, covering a range of cell types including iPSC-MSCs, iPSC-derived chondrocytes, and extracellular vesicles [ 95 ]. iPSC expansion and differentiation into MSCs and chondrocytes take place in plates, while expansion of iPSC-derived MSCs and production of extracellular vesicles utilize microcarriers within stirred tank bioreactors. The system is designed to oversee iPSC expansion, differentiation, and the fill and finish of the products. Furthermore, this platform including a range of quality control assays such as microscopy, cell counting, viability assessment, qPCR, and endotoxin assays, aims to address these challenges by establishing an automated platform for producing cell therapies specifically targeting OA, and serves as an example of how existing automation technology can be customized and improved to enhance scalability and efficiency.

Conclusions

Genomic abnormalities detected during the reprogramming and subsequent expansion of iPSCs raised serious safety concerns [ 96 ]. Therefore, several factors including starting cell source, method of delivery, reprogramming factor and cell passage, should be taken into consideration for the generation of iPSCs in order to reduce not only genomic instability [ 97 ], but also immunogenicity [ 98 , 99 ].

The field of iPSC-derived cartilages is rapidly evolving, and several approaches and perspectives have been explored to tackle limitations and enhance the potential applications of these cells in regenerative medicine. Development of new or optimization of the current differentiation protocols to improve the maturation and stability of iPSC-derived chondrocytes is critical [ 25 ]. This can be achieved by further research on signaling pathways, culture conditions, and other factors that facilitate the maturation of iPSC-derived chondrocytes. It is significantly important to implement cutting-edge 3D culture systems combined with ink-free bioprinting technique to more closely mimic the in vivo microenvironment of cartilage tissue [ 56 ]. Using bioreactors, biomimetic scaffolds, 3D bioprinting and other advanced technologies can improve the functional characteristics of iPSC-derived chondrocytes for cartilage repair. Generation of heterogeneous cell populations remains one of the major challenges in development of efficient cartilage grafts [ 100 ]. To eliminate undesired cells and promote the homogeneity of iPSC-derived chondrocyte populations, sustained development of precise genome editing tools is quite essential. Moreover, it is necessary to identify the sources of heterogeneity in iPSC-derived chondrocyte populations to reduce variability and improve reproducibility [ 101 ]. Tumorigenicity associated with residual undifferentiated iPSCs can be addressed by advancements in purification methods and genetic modifications to increase the safety of iPSC-derived chondrocytes for clinical applications [ 102 ]. Moreover, scalability and cost-effectiveness of the methods used for generation of iPSC-derived chondrocytes should be improved by simplifying the differentiation protocols, optimizing culture conditions, and utilizing automation technologies [ 95 ]. Additionally, it is very crucial to enhance the development of in vivo models to investigate the safety and efficacy of iPSC-derived chondrocytes in preclinical studies [ 103 ]. Successful preclinical studies should be followed by well-designed clinical trials in patients with cartilage-related disorders. Furthermore, for personalized regenerative medicine, the design of preclinical and clinical trials should focus on the integration of patient-specific iPSCs with advanced gene editing technologies and highly efficient chondrogenic differentiation protocols. These future perspectives reflect the continuous endeavors to harness the full potential of iPSC-derived chondrocytes, opening the door for innovative approaches in cartilage regeneration and repair. Since this field is advancing rapidly, interdisciplinary collaborations and advancement in technologies will play a vital role in shaping the future of iPSC-based cartilage regeneration research.

Abbreviations

Two dimentional

Three dimentional

Achondroplasia

Bone marrow-derived Mesenchymal stem cells

Bone morphogenetic protein 2

Bone morphogenetic protein 4

Umbilical cord blood mononuclear cell

Cellular-Myelocytomatosis

Collagen, type II, alpha 1

Collagen, type II, alpha 1-green fluorescent protein

Clustered regularly interspaced short palindromic repeats

Dorsomorphin homolog 1

Embryoid bodies

Extracellular matrix

Early-onset finger osteoarthritis

Fibrodysplasia ossficans progressive

Good manufacturing practice

Human embryonic stem cells

Human induced pluripotent stem cells

Hand osteoarthritis

Identification number

Induced pluripotent stem cells

Intervertebral disc degeneration

Krüppel-like factor 4

Knee osteoarthritis

Metaphyseal chondrodysplasia type Schmid

Multiple epiphyseal dysplasia

Mesenchymal stem cell

Not applicable

Neural crest cells

Kappa-light-chain-enhancer of activated B cells

Normal human epidermal keratinocytes

Osteoarthritis

Octamer binding transcription factor 3/4

Peripheral blood mononuclear cells

Pluripotent stem cells

Runt-related transcription factor 2

Small extracellular vesicles

Standard operating procedures

SRY-related high mobility group box

Sex determining region Y

Thanatophoric dysplasia type 1

Transforming growth factor-beta 3

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Acknowledgements

We thank the support of Institut national de la santé et de la recherche médicale (INSERM), Faculté de médecine et Faculté de chirurgie dentaire de Université de Strasbourg, and Lamina therapeutics. EAMA is financially supported by ANR ARTiTHERA, WO was supported by Chinese Scholarship Council (CSC N° 202309240005). We also thank Servier Medical ART for free medical images.

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Eltahir Abdelrazig Mohamed Ali, Rana Smaida, Morgane Meyer and Wenxin Ou have contributed equally to this work.

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Institut National de la Santé et de la Recherche Médicale (INSERM), UMR 1260, Regenerative NanoMedicine (RNM), 1 Rue Eugène Boeckel, 67000, Strasbourg, France

Eltahir Abdelrazig Mohamed Ali, Nadia Benkirane-Jessel & Guoqiang Hua

Université de Strasbourg, 67000, Strasbourg, France

Eltahir Abdelrazig Mohamed Ali, Morgane Meyer, Wenxin Ou, Nadia Benkirane-Jessel, Jacques Eric Gottenberg & Guoqiang Hua

Lamina Therapeutics, 1 Rue Eugène Boeckel, 67000, Strasbourg, France

Rana Smaida, Morgane Meyer & Nadia Benkirane-Jessel

Nankai University School of Medicine, Tianjin, 300071, China

Beijing Engineering Laboratory of Perinatal Stem Cells, Beijing Institute of Health and Stem Cells, Health & Biotech Co, Beijing, 100176, China

Zhongchao Han

Centre National de Référence des Maladies Auto-Immunes et Systémiques Rares, Est/Sud-Ouest (RESO), Service de Rhumatologie, Centre Hospitalier Universitaire de Strasbourg, 67000, Strasbourg, France

Wenxin Ou & Jacques Eric Gottenberg

Chongqing Medical University, 1 Yixueyuan Road, Yuzhong District, Chongqing, 400016, China

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EAMA, RS, MM and WO wrote the draft of the manuscript. ZL, ZH, NBJ, JEG and GH revised the manuscript. All authors reviewed and approved the final manuscript.

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Correspondence to Nadia Benkirane-Jessel , Jacques Eric Gottenberg or Guoqiang Hua .

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Ali, E.A.M., Smaida, R., Meyer, M. et al. iPSCs chondrogenic differentiation for personalized regenerative medicine: a literature review. Stem Cell Res Ther 15 , 185 (2024). https://doi.org/10.1186/s13287-024-03794-1

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GPT-4 performance on querying scientific publications: reproducibility, accuracy, and impact of an instruction sheet

Kaiming Tao 1 ,
Zachary A. Osman 1 ,
Philip L. Tzou 1 ,
Soo-Yon Rhee 1 ,
Vineet Ahluwalia 2 &
Robert W. Shafer 1

BMC Medical Research Methodology volume 24 , Article number: 139 ( 2024 ) Cite this article

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Large language models (LLMs) that can efficiently screen and identify studies meeting specific criteria would streamline literature reviews. Additionally, those capable of extracting data from publications would enhance knowledge discovery by reducing the burden on human reviewers.

We created an automated pipeline utilizing OpenAI GPT-4 32 K API version “2023–05-15” to evaluate the accuracy of the LLM GPT-4 responses to queries about published papers on HIV drug resistance (HIVDR) with and without an instruction sheet. The instruction sheet contained specialized knowledge designed to assist a person trying to answer questions about an HIVDR paper. We designed 60 questions pertaining to HIVDR and created markdown versions of 60 published HIVDR papers in PubMed. We presented the 60 papers to GPT-4 in four configurations: (1) all 60 questions simultaneously; (2) all 60 questions simultaneously with the instruction sheet; (3) each of the 60 questions individually; and (4) each of the 60 questions individually with the instruction sheet.

GPT-4 achieved a mean accuracy of 86.9% – 24.0% higher than when the answers to papers were permuted. The overall recall and precision were 72.5% and 87.4%, respectively. The standard deviation of three replicates for the 60 questions ranged from 0 to 5.3% with a median of 1.2%. The instruction sheet did not significantly increase GPT-4’s accuracy, recall, or precision. GPT-4 was more likely to provide false positive answers when the 60 questions were submitted individually compared to when they were submitted together.

Conclusions

GPT-4 reproducibly answered 3600 questions about 60 papers on HIVDR with moderately high accuracy, recall, and precision. The instruction sheet's failure to improve these metrics suggests that more sophisticated approaches are necessary. Either enhanced prompt engineering or finetuning an open-source model could further improve an LLM's ability to answer questions about highly specialized HIVDR papers.

Peer Review reports

The systematic review of data from multiple research studies is often required to answer many of the most significant biomedical questions. However, the literature searches required for a systematic review often suffer from low sensitivity (recall) and specificity (precision) in part as a result of the limitations of current search tools which rely on the Medical Subject Headings (MeSH) key words, the National Library of Medicine’s controlled vocabulary used for indexing articles [ 1 ]. Extracting data from relevant studies also requires painstaking review by highly trained human reviewers.

The use of automated software tools to assist in reviewing research papers has become a topic of increasing interest. Most such tools have used natural language processing (NLP) and machine learning (ML) algorithms primarily to screen the titles and abstracts of publications to determine whether they meet the search criteria for a systematic review [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. Several studies have also described the potential for using the representational language model Bidirectional Encoder Representations from Transformers (BERT) and the Generative Pre-trained Transformer (GPT) large language models (LLMs) for reviewing the full text of published studies [ 9 , 10 , 11 , 12 ]. LLMs have also been evaluated for their ability to summarize research studies [ 13 , 14 ].

We have extensive experience reviewing published studies on the topic of human immunodeficiency virus (HIV) drug resistance having maintained the Stanford HIV Drug Resistance Database (HIVDB; https://hivdb.stanford.edu ) and performed multiple systematic literature reviews [ 15 , 16 ]. In this study, we evaluated the ability of GPT-4 to correctly answer questions about publications on HIV drug resistance with and without an instruction sheet designed to provide GPT-4 with specialized HIV drug resistance knowledge. We evaluated publications considered for inclusion in a curated database. This database primarily links mutations in the genetic targets of HIV therapy to the antiviral treatments of the persons from whom the sequences were obtained and to the impact of these mutations on the i n vitro susceptibility to individual HIV drugs.

HIV drug resistance questions

We designed 60 questions pertaining to HIV drug resistance reflecting the type of information typically extracted from published papers evaluated for possible addition to HIVDB. Most of the questions dealt with linking HIV genetic sequence data to two other forms of data: (1) the antiviral treatments received by the patients from whom the sequenced viruses were obtained and (2) the effect of mutations in these viruses on their susceptibility to antiviral drugs. The questions were of three types: Boolean, requiring yes or no answers; numerical, where the correct response was an integer; and list-based, where a series of items constituted the correct answer. The complete list of questions can be found in Supplementary File 1.

Published papers

We selected 60 published papers on HIV drug resistance identified in recent PubMed searches and in recent GenBank database submissions including 19 published after September 2021, the cut-off date for the dataset used to train the GPT-4 model that was used. Nearly two-thirds of the papers reported HIV genotypic resistance data (e.g., genetic sequence data or lists of HIV drug-resistance mutations). Nearly one-half reported that their sequences had been submitted to GenBank, the standard public repository for sequence data, and provided GenBank accession numbers. The selected papers often reported the antiviral treatment histories of patients undergoing virus sequencing, the samples submitted for sequencing, the technology used for sequencing, and the results of in vitro susceptibility testing. Two authors reviewed each paper to determine the answers to the 60 questions. A third author designated the correct answer when there was a disagreement between the first two authors. The complete list of papers can be found in Supplementary File 2.

Instruction sheet

The instruction sheet contained 2002 words that provided background knowledge about HIV drug resistance and the type of information that a human curator would need to know to identify the relevant data for inclusion in HIVDB (Supplementary File 3). This document encapsulated fundamental antiviral therapy and HIV drug resistance concepts, alongside a description of frequently used terms and abbreviations within the field. The instruction sheet was not designed to be a comprehensive treatise on antiviral therapy and HIV drug resistance but rather to offer practical guidance to human curators with some background HIV knowledge. The instruction sheet contained information considered useful to answering many of the 60 questions. However, it was not designed specifically to answer each of the questions developed for this study.

Automated query pipeline

We designed an automated pipeline utilizing OpenAI GPT-4 32K API version “2023–05-15” (Microsoft Azure, accessed Sep 15th, 2023) (Fig. 1 ). A Python script was used to transform a published paper to a markdown format containing the text of the study methods, study results, tabular data, and figure legends. The abstract, introduction, discussion, and references were excluded from the markdown version of the paper. The median number of tokens in each markdown paper was 5338 (range:1282 to 13,861). On average, one token is about 0.75 words or about four English language characters. We chose to not submit the introduction, discussion, and references to GPT-4 because these parts of a paper often refer to the work of other studies.

Automated query pipeline work flow. The first step involved developing 60 questions relevant to HIV drug resistance, identifying 60 published papers, and developing an approximately 2000 word instruction sheet with HIV drug resistance information. Each paper was reviewed by two human reviewers and a markdown version of each paper’s full text was created. The second step involved querying GPT-4: building a prompt that included (1) the marked down version of each paper, (2) all 60 questions, and (3) the instruction sheet. The third step evaluated the GPT-4 answers to assess whether they were the same as the answers determined by the human curators. Three sample questions are shown including one for which the correct answer was Yes or No, another for which the correct answer was a list of items, and a third for which the correct answer was a number

Each GPT-4 query consisted of one markdown paper plus one of the following: (1) all 60 questions presented simultaneously; (2) all 60 questions presented simultaneously with the instruction sheet; (3) each of the 60 questions presented individually; and (4) each of the 60 questions presented individually with the instruction sheet.

We refer to the process of submitting the 60 questions simultaneously as the multiple-question mode and the process of submitting each question individually as the single-question mode. We refer to the process of presenting all questions without the instruction sheet as the base model. The single-question mode necessitated repeatedly submitting the same markdown paper with each question. It was therefore much more time consuming and expensive than the multiple-question mode.

If GPT-4 failed to answer all 60 questions for a paper or if a time-out error occurred when questions were presented in the multiple-question mode, the unanswered questions were resubmitted along with the paper.

Supplementary File 4 provides an example GPT-4 prompt. Supplementary File 5 provides the Python code used to generate the GPT-4 prompts.

Automated response evaluation pipeline

We evaluated the accuracy of GPT-4 responses using the following approach: (1) for Boolean questions, a script was used to determine if the response began with “yes” or “no”; (2) for numerical questions, a script was used to determine if the response contained a single number; (3) all other responses were evaluated manually. Accuracy was defined as concordance between the correct answer and the GPT-4 response for Boolean and numerical questions. For list questions, we considered the GPT-4 response to be accurate if it identified at least one element of the correct list. The response was considered inaccurate if it did not identify any element of the correct list or if it identified elements that were not part of the correct list. A manual review of half of the responses to the Boolean and numerical questions confirmed that the script used to determine whether the response began with “yes” or “no” or contained a single number accurately gauged GPT-4’s answers to these questions.

Experimental design and analyses

To evaluate the performance of GPT-4 in answering questions about a paper, we designed a series of experiments: (1) We assessed the reproducibility of the base model in the multiple-question mode by performing each query in triplicate. (2) We calculated the recall, precision, and F1 score – the harmonic mean of precision and recall, calculated as 2 x (recall * precision) / (recall + precision) – for the base model in multiple-question mode. This analysis was performed on the median of the triplicate results and it was performed separately for results obtained with and without the instruction sheet. (3) We compared the accuracy – measured as the proportion of correct answers – of the base model in the multiple-question mode to its performance when the responses were from randomly permuted papers. In essence, we assessed the accuracy of GPT-4's responses to the submitted paper compared with its accuracy when the answers were drawn from ten randomly selected papers, distinct from the actual paper. (4) We compared the accuracy of the base model in the multiple-question mode to the accuracy with the instruction sheet in the multiple-question mode. (5) Finally, we compared the accuracy of the base model in the multiple-question mode with the accuracy of the base model in the single-question mode, also in triplicate.

Figure 2 displays triplicate determinations of the accuracy of GPT-4 on each of the 60 questions applied to each of the 60 papers in the multiple-question mode without the instruction sheet (i.e., base model). The median accuracy for the 60 questions over the three replicates was 91.8% (range: 50.7%-100%). The mean accuracy for the 60 questions over the three replicates was 86.9%. The mean accuracies were similar for Boolean (86.6%), numerical (84.7%), and list (90.2%) questions. The standard deviation (SD) of three replicates for the 60 questions ranged from 0 to 5.3% with a median SD of 1.2% across all questions. The coefficient of variation (CV) of three replicates for the 60 questions ranged from 0 to 0.068 with a median CV of 0.012. The maximum difference between any two of the three replicates was 6 for one question, 4 for two questions, and 3 for three questions.

Triplicate determinations of the accuracy of each of the 60 questions applied to each of the 60 papers in the multiple question mode (i.e., all 60 questions presented simultaneously) without the instruction sheet (i.e., base model). The Y-axis indicates the percentage of times in which the GPT4 response was accurate across the 60 papers. The X-axis shows the question ID in descending order of median accuracy. The three bars shown for each question ID indicate separate replicates. The median accuracy for the 60 questions over the three replicates was 91.8% (range: 50.7%-100%). The mean accuracy across all questions and all papers were 86.8%, 86.9%, and 87.1%. Different colors mean different replicates

Figure 3 compares the results of one of the three replicates for the base model in multiple-question mode with the results obtained when the answers to the 60 papers were permuted. The mean accuracy for 10 permutations of the papers was 62.9%. Therefore, the increased accuracy of GPT-4 on the actual papers was 24.0% higher than expected by chance on the permuted set of papers (95% CI: 18.6%-29.4%; p < 0.000001; paired Student’s t-test). The surprisingly high level of accuracy for permuted answers is explained by the uniformity of responses across many papers. Specifically, for Boolean questions, the answers were not infrequently always ‘yes’ or ‘no.’ Similarly, for numerical questions, the answer was often 0, and for list questions, the answer was often an empty list. Figure 3 demonstrates this in 10 questions where ≥ 90% of the Boolean answers were either ‘yes’ or ‘no’, in two numerical questions where the answer was usually 0, and in two list questions where the answer was usually an empty list.

Figure 4 shows the precision, recall, and F1 score with and without the instruction sheet separately for the Boolean, numerical, and list questions. Without the instruction sheet, GPT-4 demonstrated a recall of 68.1% and a precision of 84.6% on the 2280 Boolean questions (i.e., 48 questions × 60 papers); a recall of 61.6% and a precision of 88.1% on the 660 numerical questions (i.e., 11 questions × 60 papers); and a recall of 88.6% and a precision of 91.9% on the 660 list questions (i.e., 11 questions × 60 papers). Of the 296 true positive answers for list questions, 273 (92.2%) were identical to the manual answers whereas 23 (7.8%) contained a subset of the manual answers.

Recall and precision of GPT-4 at answering questions about HIV drug resistance papers: comparison with manual curators. The manual result (obtained by two human curators and a third to break ties) was considered to be the correct answer. Each entry in the six sections containing raw data represents the median of 3 repeats. *Includes questions for which GPT reported a number > 0 when the correct answer was 0 and questions for which GPT reported an incorrect number (i.e., one that differed from the manual review). **The results were considered to be false positives when GPT-4 identified items not identified by manual review. Additionally, 12 of 16 answers obtained without the instruction sheet and 14 of 18 answers obtained with the instruction sheet were considered to be false negatives because GPT-4 also failed to identify any of the items that were identified by manual review. Abbreviations: GPT (GPT-4), TP (true positive), TN (true negative), FP (false positive), FN (false negative), F1 score = 2 * (Recall * Precision) / (Recall + Precision)

Figure 5 displays the triplicate determinations of the accuracy of GPT-4 in the multiple-question mode with and without the instruction sheet. Across the 60 questions, the mean net change in accuracy was + 1.2% resulting in an overall accuracy of 88.1% across all questions and papers with the instruction sheet. On average, across the three replicates, the instruction sheet improved the accuracy of 3.2% ( n = 114) of questions that were initially answered incorrectly. Conversely, 2.0% ( n = 72) of questions initially answered correctly were incorrect with the instruction sheet. For all 60 questions combined, recall (76.2% vs. 72.5%; p = 0.08; Fisher Exact Test) and precision 87.4% vs. 87.1%; NS) were not significantly higher with the instruction sheet compared to without the instruction sheet (Fig. 4 ).

Triplicate determinations of the accuracy of GPT-4 in multiple-question mode with and without the instruction sheet. For each question, two histograms are shown. The left histogram shows the median of triplicate accuracy determinations without the instruction sheet. The right histogram shows the median of triplicate accuracy determinations with the instruction sheet. Increased accuracy associated with the instruction sheet is shown by coloring part of the right-sided histogram in blue while reductions in accuracy are shown by coloring part of the left-sided histogram in red. The sizes of the colored regions indicate the sizes of the increases or decreases in accuracy associated with the instruction sheet. The questions are shown in descending order of the increased accuracy associated with instruction sheet (i.e., the size of the blue histograms)

The instruction sheet significantly impacted three questions: one showed a net accuracy increase of 26.1%, resulting in 16 additional correct responses; another recorded an 8.3% improvement (5 papers); and the third saw a 6.7% increase (4 papers). The remaining questions displayed net changes in accuracy that were no greater or lower than three. The question “Does the paper report GenBank accession numbers for sequenced HIV isolates other than those for laboratory HIV isolates?" was the one associated with a net increased accuracy of 26.1%. The question “How many samples in the paper were reported to have undergone plasma virus sequencing?” was the one associated with a net increased accuracy of 8.3%.

In an attempt to edit the instruction sheet to increase GPT-4 accuracy for questions that were often answered incorrectly, we modified the query pipeline as follows. Rather than submitting each paper in multiple-question mode, we submitted each paper with just the one question that we were targeting for improvement (i.e., in single-question mode). After running several questions in both modes, we noticed marked differences in GPT-4 accuracy between the multiple-question and single-question modes. Figure 6 compares the accuracy of the multiple-question and single-question mode for all 60 questions without the instruction sheet. Each histogram represents the median of three replicates. Overall, the median and mean accuracy for the single-question mode were significantly lower than the multiple-question mode across all 60 questions: median (83.0% vs 91.8%, p = 0.0006; Wilcoxon signed-rank test) and mean (77.6% vs 86.9%, p = 0.0005; Wilcoxon signed-rank test).

Figure 6 groups the questions according to whether the accuracy was ≥ 10% lower in the single-question mode ( n = 21 questions), ≥ 10% higher in the single-question mode ( n = 3 questions), or less than 10% different between the multiple-question and single-question modes. The largest differences in accuracy between the two modes was for questions for which the answer was usually no for Boolean questions, 0 for numerical questions, and an empty list for list questions. We refer to these usually negative questions as No_0_Empty. Indeed, for the 21 questions that belonged to this category, the median accuracy was 91.0% in the multiple-question mode but only 60.8% in the single-question mode. There was also a strong correlation between the frequency of answers that were No_0_Empty and the reduced accuracy when questions were presented in the single-question mode ( r = 0.45; p = 0.0003).

The cost of using the GPT-4 API to obtain responses for 60 papers × 60 questions in the multiple-question mode without and with the instruction sheet was $240 and $300, respectively. The cost of obtaining responses for 60 papers × 60 questions in the single-question mode without and with the instruction sheet was $1500 and $2000, respectively. The overall cost of this study, considering that most experiments were performed in triplicate was $8120: $240 × 3 plus $300 × 3 plus $1500 × 3 plus $2000 × 1. After completing this study, OpenAI released a new model, GPT-4-turbo (gpt-4–1106-preview), on November 6, 2023. This model significantly reduced costs, decreasing from $0.06 to $0.01 per prompt and from $0.12 to $0.03 per completion. Consequently, the overall cost of this study would have been approximately five times lower.

We submitted the text of the methods, results, tables, and figure legends of 60 published papers on HIV drug resistance together with 60 questions related to HIV drug resistance with and without an instruction sheet to the GPT-4 API. We found that the accuracy of GPT-4 responses was approximately 87%, which was 24% greater than that obtained when the answers to the papers were permuted. With the exception of one question, the accuracy of GPT-4 was not improved with an approximately 2000 word instruction sheet. Notably, GPT-4 was also less likely to answer certain types of questions accurately when they were submitted individually (single-question mode) compared to when they were submitted together (multiple-question mode).

This study differs from most previous studies of automated software tools designed to assist with systematic reviews. First, we prompted the LLM GPT-4 to answer specific questions about entire papers whereas previous studies were often optimized for screening paper title and abstracts [ 5 , 6 , 7 , 8 ]. Second, we used GPT without providing training examples, whereas previous studies, were often interactive in that they combined NLP and ML algorithms with user feedback [ 5 , 6 , 9 , 10 , 11 ]. Finally, the results presented in this study were quantitative and transparent, whereas several previous studies, particularly those using LLMs, presented their results in a qualitative manner.

GPT-4 performs well at summarizing research papers because LLMs are adept at distilling and condensing information into simpler shorter formats [ 13 , 14 ]. However, answering specific questions can be challenging for LLMs because they only process a limited amount of text at once. This limitation hampers their ability to cross-reference details within longer documents effectively. Indeed, the questions that GPT-4 was likely to answer correctly were those for which the answer could be found in a single paragraph or sentence in a paper. In contrast, those questions that required reasoning about information found in different parts of a paper were less likely to be answered correctly. For example, the question “Does the paper provide complete ART history for all of the individuals in the study?” was answered correctly only about 50% of the time.

The instruction sheet contained information that would have been expected to be helpful for several questions such as “Does the paper report the results of HIV pol sequences?” and “Were the individuals in the study INSTI-naïve?”. Despite this, when GPT-4 was equipped with the information that 'pol' refers to the gene encoding the viral enzymes protease, reverse transcriptase, and integrase, 'INSTI' denotes integrase strand transfer inhibitors, and 'naïve' implies untreated, it still only correctly answered these questions 57% and 62% of the time, respectively.

After completing the experiments outlined in this study, we performed ten queries in an attempt to determine the extent of GPT-4’s HIV drug resistance knowledge. Supplementary File 6 lists each of the ten queries and the entire GPT-4 response (version last updated April 2023). The responses to these additional queries, demonstrated that GPT-4 possesses extensive information about HIV drug resistance. Although the experiments outlined in the results were performed using an earlier version of GPT-4 (last updated September 2021), all of the information included in the GPT-4 response had been publicly available prior to this earlier date. Given that GPT-4 already contained most of the information provided in the instruction sheet, enhancing its performance would likely hinge on providing prompts that demonstrate how to apply its knowledge to a published paper.

In an attempt to edit the instruction sheet to increase GPT-4 accuracy we modified the query pipeline by submitting each paper with just the one question that we were targeting for improvement. This modification led to the study’s second major new finding: when questions were presented individually, GPT-4 tended to provide incorrect affirmative answers to questions that generally warranted a negative response such as ‘no’, ‘0’, or an empty list. For instance, when the query "Which drugs were tested on phenotypic susceptibility in the paper?" was posed separately, there were 40 instances where GPT-4 erroneously referenced drugs that were administered to patients instead of those used in a susceptibility assay. This mistake was infrequent when all 60 questions were asked at once, indicating that presenting the full batch of questions improves GPT-4's understanding of each question's context. The enhanced accuracy observed when presenting multiple questions simultaneously may resemble automatic chain-of-thought prompting [ 17 ]. This technique, used in AI interactions, involves supplying step-by-step questions that guide the system through a logical thought sequence, thereby improving its comprehension of complex inquiries.

While enhancing the questions and instruction sheet was of interest, undertaking such revisions methodically would have required an open-ended approach beyond the scope of this study. Nonetheless, we observed that rephrasing two of the questions led to a significantly increased GPT-4 accuracy. For example, the question “Were sequences obtained from individuals with active HIV replication?” was true for 26 of the 60 papers. The median accuracy of GPT-4 on three replicates, with and without the instruction sheet, was 61%. However, the median accuracy of GPT-4 was 97% when we rephrased the question as follows: “Were sequences in the paper obtained from individuals with virological failure while receiving antiretroviral therapy?”. In contrast, the few changes we made to the instruction sheet did not yield substantial increases in GPT-4 accuracy for any of the questions.

GPT-4 possesses extensive knowledge about HIV drug resistance and it reproducibly answers Boolean, numerical, and list questions about HIV drug resistance papers. Its accuracy, recall, and precision of approximately 87%, 73%, and 87% without human feedback demonstrate its potential at performing this task. GPT-4 faced several challenges beginning with the specialized nature of the questions that were on topics that likely represented a small part of its training corpus [ 18 ]. In addition, addressing queries that necessitate making inferences, particularly when dealing with unsaid elements within the text, can be difficult. A more robust familiarity with the subject of HIV drug resistance would potentially have empowered GPT-4 to make better inferences. Finally, the instruction sheet was designed for human comprehension without the multiple examples usually necessary for optimizing a language model’s performance. The inability of GPT-4 to utilize the instruction sheet suggests that more sophisticated prompt engineering approaches or the finetuning of an open source model are likely required to improve accuracy when answering questions on highly specialized research papers.

Availability of data and materials

All data generated or analyzed during this study are included in this published article and its supplementary information files.

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R.W.S contributed to the design of the work, interpretation of the data, and drafting the manuscript; K.T contributed to the design of the work, acquisition, analysis, and interpretation of the data, and creation of the software used in the work; Z.A.O and P.L.T contributed to the acquisition of the data; S.Y.R contributed to the design of the work and acquisition of the data; V.A contributed to conception of the work and revision of the manuscript.

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Tao, K., Osman, Z.A., Tzou, P.L. et al. GPT-4 performance on querying scientific publications: reproducibility, accuracy, and impact of an instruction sheet. BMC Med Res Methodol 24 , 139 (2024). https://doi.org/10.1186/s12874-024-02253-y

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Alzheimer’s disease and epilepsy: exploring shared pathways and promising biomarkers for future treatments.

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Genetic: , PSEN2, APP and duplication of APP [ ] —R47H variant [ ], APOEε4 allele [ ] ]

Age [ , ]

Mild cognitive impairment [ ]

Vascular [ ]: ] , ]

History of brain traumatic injury [ ]

Blood–brain barrier dysfunction [ ]

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Kalyvas, A.-C.; Dimitriou, M.; Ioannidis, P.; Grigoriadis, N.; Afrantou, T. Alzheimer’s Disease and Epilepsy: Exploring Shared Pathways and Promising Biomarkers for Future Treatments. J. Clin. Med. 2024 , 13 , 3879. https://doi.org/10.3390/jcm13133879

Kalyvas A-C, Dimitriou M, Ioannidis P, Grigoriadis N, Afrantou T. Alzheimer’s Disease and Epilepsy: Exploring Shared Pathways and Promising Biomarkers for Future Treatments. Journal of Clinical Medicine . 2024; 13(13):3879. https://doi.org/10.3390/jcm13133879

Kalyvas, Athanasios-Christos, Maria Dimitriou, Panagiotis Ioannidis, Nikolaos Grigoriadis, and Theodora Afrantou. 2024. "Alzheimer’s Disease and Epilepsy: Exploring Shared Pathways and Promising Biomarkers for Future Treatments" Journal of Clinical Medicine 13, no. 13: 3879. https://doi.org/10.3390/jcm13133879

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The methodology of the systematic literature review. Four phases of the
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Review of Literature Presentation and Methodology DRAFT version 1
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Literature Review Research Methodology
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How to Write a Literature Review
A Review of the Theoretical Literature" (Theoretical literature review about the development of economic migration theory from the 1950s to today.) Example literature review #2: "Literature review as a research methodology: An overview and guidelines" ( Methodological literature review about interdisciplinary knowledge acquisition and ...
Literature review as a research methodology: An overview and guidelines
As mentioned previously, there are a number of existing guidelines for literature reviews. Depending on the methodology needed to achieve the purpose of the review, all types can be helpful and appropriate to reach a specific goal (for examples, please see Table 1).These approaches can be qualitative, quantitative, or have a mixed design depending on the phase of the review.
Literature Review: The What, Why and How-to Guide
Example: Predictors and Outcomes of U.S. Quality Maternity Leave: A Review and Conceptual Framework: 10.1177/08948453211037398 ; Systematic review: "The authors of a systematic review use a specific procedure to search the research literature, select the studies to include in their review, and critically evaluate the studies they find." (p. 139).
Steps in Conducting a Literature Review
A literature review is an integrated analysis-- not just a summary-- of scholarly writings and other relevant evidence related directly to your research question.That is, it represents a synthesis of the evidence that provides background information on your topic and shows a association between the evidence and your research question.
PDF METHODOLOGY OF THE LITERATURE REVIEW
In the field of research, the term method represents the specific approaches and procedures that the researcher systematically utilizes that are manifested in the research design, sampling design, data collec-tion, data analysis, data interpretation, and so forth. The literature review represents a method because the literature reviewer chooses ...
Writing a Literature Review
A literature review is a document or section of a document that collects key sources on a topic and discusses those sources in conversation with each other (also called synthesis ). The lit review is an important genre in many disciplines, not just literature (i.e., the study of works of literature such as novels and plays).
Guidance on Conducting a Systematic Literature Review
Literature reviews establish the foundation of academic inquires. However, in the planning field, we lack rigorous systematic reviews. In this article, through a systematic search on the methodology of literature review, we categorize a typology of literature reviews, discuss steps in conducting a systematic literature review, and provide suggestions on how to enhance rigor in literature ...
Methodological Approaches to Literature Review
The literature review can serve various functions in the contexts of education and research. It aids in identifying knowledge gaps, informing research methodology, and developing a theoretical framework during the planning stages of a research study or project, as well as reporting of review findings in the context of the existing literature.
How-to conduct a systematic literature review: A quick guide for
Overview. A Systematic Literature Review (SLR) is a research methodology to collect, identify, and critically analyze the available research studies (e.g., articles, conference proceedings, books, dissertations) through a systematic procedure .An SLR updates the reader with current literature about a subject .The goal is to review critical points of current knowledge on a topic about research ...
What is a Literature Review?
A literature review is a survey of scholarly sources on a specific topic. It provides an overview of current knowledge, allowing you to identify relevant theories, methods, and gaps in the existing research. There are five key steps to writing a literature review: Search for relevant literature. Evaluate sources. Identify themes, debates and gaps.
Literature Review
Types of Literature Review are as follows: Narrative literature review: This type of review involves a comprehensive summary and critical analysis of the available literature on a particular topic or research question. It is often used as an introductory section of a research paper. Systematic literature review: This is a rigorous and ...
Chapter 9 Methods for Literature Reviews
9.3. Types of Review Articles and Brief Illustrations. EHealth researchers have at their disposal a number of approaches and methods for making sense out of existing literature, all with the purpose of casting current research findings into historical contexts or explaining contradictions that might exist among a set of primary research studies conducted on a particular topic.
(PDF) Literature Review as a Research Methodology: An overview and
This paper draws input from a study that employed a systematic literature review as its main source of data. A systematic review can be explained as a research method and process for identifying ...
What is a Literature Review? How to Write It (with Examples)
A literature review is a critical analysis and synthesis of existing research on a particular topic. It provides an overview of the current state of knowledge, identifies gaps, and highlights key findings in the literature. 1 The purpose of a literature review is to situate your own research within the context of existing scholarship, demonstrating your understanding of the topic and showing ...
Writing a literature review
Writing a literature review requires a range of skills to gather, sort, evaluate and summarise peer-reviewed published data into a relevant and informative unbiased narrative. ... This may be due to differences in subjects, experimental materials, methodology or how the data were analysed. Remember to consider negative findings by consulting ...
(PDF) Literature review as a research methodology: An overview and
This. paper discusses literature review as a methodology for conducting research and o ﬀers an overview of diﬀerent. types of reviews, as well as some guidelines to how to both conduct and ...
How to Do a Systematic Review: A Best Practice Guide for ...
Systematic reviews are characterized by a methodical and replicable methodology and presentation. They involve a comprehensive search to locate all relevant published and unpublished work on a subject; a systematic integration of search results; and a critique of the extent, nature, and quality of evidence in relation to a particular research question.
What is a Literature Review?
A literature review is a review and synthesis of existing research on a topic or research question. A literature review is meant to analyze the scholarly literature, make connections across writings and identify strengths, weaknesses, trends, and missing conversations. A literature review should address different aspects of a topic as it ...
Literature Review Research
Literature Review is a comprehensive survey of the works published in a particular field of study or line of research, usually over a specific period of time, in the form of an in-depth, critical bibliographic essay or annotated list in which attention is drawn to the most significant works. Also, we can define a literature review as the ...
Research Methods: Literature Reviews
A literature review involves researching, reading, analyzing, evaluating, and summarizing scholarly literature (typically journals and articles) about a specific topic. The results of a literature review may be an entire report or article OR may be part of a article, thesis, dissertation, or grant proposal.
Reviewing research methodologies
Sometimes in your literature review, you might need to discuss and evaluate relevant research methodologies in order to justify your own choice of research methodology. When searching for literature on research methodologies it is important to search across a range of sources. No single information source will supply all that you need.
Which review is that? A guide to review types
Appendix A: Guide to the contents of a Cochrane Methodology protocol and review. Cochrane Handbook for systematic reviews of interventions. Full Text PDF. Aguinis, H., Ramani, R. S., & Alabduljader, N. (2023). Best-Practice Recommendations for Producers, Evaluators, and Users of Methodological Literature Reviews.
PDF Literature Reviews: Methods and Applications
Systematic reviews define a topic and identify, summarize, and evaluate the findings of all well-designed research for that topic that is reported in the literature. This review method uses strict criteria designed to limit bias and emphasize scientific validity with the aim to produce an impartial analysis. Systematic reviews are the preferred ...
A Guide to Writing the Dissertation Literature Review
reporting a literature review it is that the stages for conducting and reporting a literature review parallel the process for conducting primary research. With a few modifications, what one knows about conducting primary research applies to conducting secondary research (i.e., a literature review).
What are Literature Reviews?
The review purpose, methods used, and the results produced vary among different kinds of literature reviews. Some of the common types of literature review are detailed below. Common Types of Literature Reviews 1 Narrative (Literature) Review. A broad term referring to reviews with a wide scope and non-standardized methodology
Creativity-Fostering Teacher Behaviors in Higher Education: A
A systematic literature review requires a rigorous and structured qualitative research approach that results in reliable and validated conclusions, ... While many of the studies included in this review used a mixed-methods or quantitative design, most studies focused on qualitative data in which creativity was an assumed learning outcome. ...
Time of sample collection is critical for the replicability of ...
A) 2019 Literature Review Summary. Of the 586 articles containing microbiome (16 S or metagenomic) data, found as described in the methods section, the percentage of microbiome articles from each ...
iPSCs chondrogenic differentiation for personalized regenerative
To overcome some limitations of scaffold-based 3D cell culture method, scaffold-free methods showed promising results as well. Nakumora et al. [] reported efficient fabrication of unified, self-sufficient, and functional cartilaginous constructs by combining iPSCs and bio-3D printers using a Kenzan needle array technology.This approach may facilitate repairing of articular cartilage defects.
GPT-4 performance on querying scientific publications: reproducibility
Background Large language models (LLMs) that can efficiently screen and identify studies meeting specific criteria would streamline literature reviews. Additionally, those capable of extracting data from publications would enhance knowledge discovery by reducing the burden on human reviewers. Methods We created an automated pipeline utilizing OpenAI GPT-4 32 K API version "2023-05-15" to ...
JCM
Methods: A comprehensive literature search was conducted, identifying 128 relevant articles published between 2018 and 2024. Results: Findings underscore a bidirectional relationship between AD and epilepsy, indicating shared pathogenic pathways that extend beyond traditional amyloid-beta and Tau protein pathology. ... This review examines the ...

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