systematic literature review prisma

The PRISMA 2020 statement: an updated guideline for reporting systematic reviews

Affiliations.

• 1 School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia [email protected].
• 2 School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.
• 3 Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, Netherlands.
• 4 Université de Paris, Centre of Epidemiology and Statistics (CRESS), Inserm, F 75004 Paris, France.
• 5 Institute for Evidence-Based Healthcare, Faculty of Health Sciences and Medicine, Bond University, Gold Coast, Australia.
• 6 University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA; Annals of Internal Medicine.
• 7 Knowledge Translation Program, Li Ka Shing Knowledge Institute, Toronto, Canada; School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, Canada.
• 8 Evidence Partners, Ottawa, Canada.
• 9 Clinical Research Institute, American University of Beirut, Beirut, Lebanon; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.
• 10 Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon, USA.
• 11 York Health Economics Consortium (YHEC Ltd), University of York, York, UK.
• 12 Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada; School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada; Department of Medicine, University of Ottawa, Ottawa, Canada.
• 13 Centre for Evidence-Based Medicine Odense (CEBMO) and Cochrane Denmark, Department of Clinical Research, University of Southern Denmark, Odense, Denmark; Open Patient data Exploratory Network (OPEN), Odense University Hospital, Odense, Denmark.
• 14 Department of Anesthesiology and Pain Medicine, The Ottawa Hospital, Ottawa, Canada; Clinical Epidemiology Program, Blueprint Translational Research Group, Ottawa Hospital Research Institute, Ottawa, Canada; Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada.
• 15 Department of Ophthalmology, School of Medicine, University of Colorado Denver, Denver, Colorado, United States; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
• 16 Division of Headache, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Head of Research, The BMJ, London, UK.
• 17 Department of Epidemiology and Biostatistics, Indiana University School of Public Health-Bloomington, Bloomington, Indiana, USA.
• 18 Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
• 19 Centre for Reviews and Dissemination, University of York, York, UK.
• 20 EPPI-Centre, UCL Social Research Institute, University College London, London, UK.
• 21 Li Ka Shing Knowledge Institute of St. Michael's Hospital, Unity Health Toronto, Toronto, Canada; Epidemiology Division of the Dalla Lana School of Public Health and the Institute of Health Management, Policy, and Evaluation, University of Toronto, Toronto, Canada; Queen's Collaboration for Health Care Quality Joanna Briggs Institute Centre of Excellence, Queen's University, Kingston, Canada.
• 22 Methods Centre, Bruyère Research Institute, Ottawa, Ontario, Canada; School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, Canada.
• 23 Centre for Journalology, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada; School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, Canada.
• PMID: 33782057
• PMCID: PMC8005924
• DOI: 10.1136/bmj.n71

The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, published in 2009, was designed to help systematic reviewers transparently report why the review was done, what the authors did, and what they found. Over the past decade, advances in systematic review methodology and terminology have necessitated an update to the guideline. The PRISMA 2020 statement replaces the 2009 statement and includes new reporting guidance that reflects advances in methods to identify, select, appraise, and synthesise studies. The structure and presentation of the items have been modified to facilitate implementation. In this article, we present the PRISMA 2020 27-item checklist, an expanded checklist that details reporting recommendations for each item, the PRISMA 2020 abstract checklist, and the revised flow diagrams for original and updated reviews.

Publication types

• Research Support, N.I.H., Extramural
• Research Support, Non-U.S. Gov't
• Medical Writing / standards
• Meta-Analysis as Topic
• Practice Guidelines as Topic
• Quality Control
• Research Design / standards*
• Statistics as Topic
• Systematic Reviews as Topic* / methods
• Systematic Reviews as Topic* / standards
• Terminology as Topic

Grants and funding

• UG1 EY020522/EY/NEI NIH HHS/United States

Literature Reviews: systematic searching at various levels

• for assignments
• for dissertations / theses
• Search strategy and searching
• Boolean Operators
• Search strategy template
• Screening & critiquing
• Citation Searching
• Google Scholar (with Lean Library)
• Resources for literature reviews
• Adding a referencing style to EndNote
• Exporting from different databases

PRISMA Flow Diagram

• Grey Literature
• What is the PRISMA Flow Diagram?
• How should I use it?
• When should I use it?
• PRISMA Links

The PRISMA Flow Diagram is a tool that can be used to record different stages of the literature search process--across multiple resources--and clearly show how a researcher went from, 'These are the databases I searched for my terms', to, 'These are the papers I'm going to talk about'.

PRISMA is not inflexible; it can be modified to suit the research needs of different people and, indeed, if you did a Google images search for the flow diagram you would see many different versions of the diagram being used. It's a good idea to have a look at a couple of those examples, and also to have a look at a couple of the articles on the PRISMA website to see how it has--and can--be used.

The PRISMA 2020 Statement was published in 2021. It consists of a  checklist  and a  flow diagram , and is intended to be accompanied by the PRISMA 2020 Explanation and Elaboration document.

In order to encourage dissemination of the PRISMA 2020 Statement, it has been published in several journals.

• How to use the PRISMA Flow Diagram for literature reviews A PDF [3.81MB] of the PowerPoint used to create the video. Each slide that has notes has a callout icon on the top right of the page which can be toggled on or off to make the notes visible.

There is also a PowerPoint version of the document but the file size is too large to upload here.

If you would like a copy, please email the Academic Librarians' mailbox from your university account to ask for it to be sent to you.

This is an example of how you  could  fill in the PRISMA flow diagram when conducting a new review. It is not a hard and fast rule but it should give you an idea of how you can use it.

For more detailed information, please have a look at this article:

Page, M.J., McKenzie, J.E., Bossuyt, P.M., Boutron, I., Hoffmann, T.C., Mulrow, C.D., Shamseer, L., Tetzlaff, J.M., Akl, E.A., Brennan, S.E., Chou, R., Glanville, J., Grimshaw, J.M., Hróbjartsson, A., Lalu, M.M., Li, T., Loder, E.W., Mayo-Wilson, E., McDonald, S., McGuinness, L.A., Stewart, L.A., Thomas, J., Tricco, A.C., Welch, V.A., Whiting,P. & Moher, D. (2021) 'The PRISMA 2020 statement: an updated guideline for reporting systematic reviews',  BMJ 372:(71). doi: 10.1136/bmj.n71 .

• Example of PRISMA 2020 diagram This is an example of *one* of the PRISMA 2020 flow diagrams you can use when reporting on your research process. There is more than one form that you can use so for other forms and advice please look at the PRISMA website for full details.

Start using the flow diagram as you start searching the databases you've decided upon. 

Make sure that you record the number of results that you found per database (before removing any duplicates) as per the filled in example. You can also do a Google images search for the PRISMA flow diagram to see the different ways in which people have used them to express their search processes.

• Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) PRISMA is an evidence-based minimum set of items for reporting in systematic reviews and meta-analyses. PRISMA focuses on the reporting of reviews evaluating randomized trials, but can also be used as a basis for reporting systematic reviews of other types of research, particularly evaluations of interventions.
• Prisma Flow Diagram This link will take you to downloadable Word and PDF copies of the flow diagram. These are modifiable and act as a starting point for you to record the process you engaged in from first search to the papers you ultimately discuss in your work. more... less... Do an image search on the internet for the flow diagram and you will be able to see all the different ways that people have modified the diagram to suit their personal research needs.

You can access the various checklists via the Equator website and the articles explaining PRISMA and its various extensions are available via PubMed.

Page, M.J., McKenzie, J.E., Bossuyt, P.M., Boutron, I., Hoffmann, T.C., Mulrow, C.D., Shamseer, L., Tetzlaff, J.M., Akl, E.A., Brennan, S.E., Chou, R., Glanville, J., Grimshaw, J.M., Hróbjartsson, A., Lalu, M.M., Li, T., Loder, E.W., Mayo-Wilson, E., McDonald, S., McGuinness, L.A., Stewart, L.A., Thomas, J., Tricco, A.C., Welch, V.A., Whiting, P., & Moher, D. (2021) ' The PRISMA 2020 statement: an updated guideline for reporting systematic reviews,'  BMJ .  Mar 29; 372:n71. doi: 10.1136/bmj.n71 .

Page, M.J., Moher, D., Bossuyt, P.M., Boutron, I., Hoffmann, T.C., Mulrow, C.D., Shamseer, L., Tetzlaff, J.M., Akl, E.A., Brennan, S.E., Chou, R., Glanville, J., Grimshaw, J.M., Hróbjartsson, A., Lalu, M.M., Li, T., Loder, E.W., Mayo-Wilson, E., McDonald, S., McGuinness, L.A., Stewart, L.A., Thomas, J., Tricco, A.C., Welch, V.A., Whiting, P., & McKenzie, J.E. (2021)  'PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews',  BMJ, Mar 29; 372:n160. doi: 10.1136/bmj.n160 .

Page, M.J., McKenzie, J.E., Bossuyt, P.M., Boutron, I., Hoffmann, T.C., Mulrow, C.D., Shamseer, L., Tetzlaff, J.M., Akl, E.A., Brennan, S.E., Chou, R., Glanville, J., Grimshaw, J.M., Hróbjartsson, A., Lalu, M.M., Li, T., Loder, E.W., Mayo-Wilson, E., McDonald, S., McGuinness, L.A., Stewart, L.A., Thomas, J., Tricco, A.C., Welch, V.A., Whiting, P., & Moher, D. (2021) ' The PRISMA 2020 statement: An updated guideline for reporting systematic reviews,'  Journal of Clinical Epidemiology, June; 134:178-189. doi: 10.1016/j.jclinepi.2021.03.001 . 

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• UNC Libraries
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• Systematic Reviews
• Step 8: Write the Review

Systematic Reviews: Step 8: Write the Review

Created by health science librarians.

• Step 1: Complete Pre-Review Tasks
• Step 2: Develop a Protocol
• Step 3: Conduct Literature Searches
• Step 4: Manage Citations
• Step 5: Screen Citations
• Step 6: Assess Quality of Included Studies
• Step 7: Extract Data from Included Studies

About Step 8: Write the Review

Write your review, report your review with prisma, review sections, plain language summaries for systematic reviews, writing the review- webinars.

• Writing the Review FAQs

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In Step 8, you will write an article or a paper about your systematic review.  It will likely have five sections: introduction, methods, results, discussion, and conclusion.  You will: 

• Review the reporting standards you will use, such as PRISMA. 
• Gather your completed data tables and PRISMA chart. 
• Write the Introduction to the topic and your study, Methods of your research, Results of your research, and Discussion of your results.
• Write an Abstract describing your study and a Conclusion summarizing your paper. 
• Cite the studies included in your systematic review and any other articles you may have used in your paper. 
• If you wish to publish your work, choose a target journal for your article.

The PRISMA Checklist will help you report the details of your systematic review. Your paper will also include a PRISMA chart that is an image of your research process. 

Click an item below to see how it applies to Step 8: Write the Review.

Reporting your review with PRISMA

To write your review, you will need the data from your PRISMA flow diagram .  Review the PRISMA checklist to see which items you should report in your methods section.

Managing your review with Covidence

When you screen in Covidence, it will record the numbers you need for your PRISMA flow diagram from duplicate removal through inclusion of studies.  You may need to add additional information, such as the number of references from each database, citations you find through grey literature or other searching methods, or the number of studies found in your previous work if you are updating a systematic review.

How a librarian can help with Step 8

A librarian can advise you on the process of organizing and writing up your systematic review, including: 

• Applying the PRISMA reporting templates and the level of detail to include for each element
• How to report a systematic review search strategy and your review methodology in the completed review
• How to use prior published reviews to guide you in organizing your manuscript 

Reporting standards & guidelines

Be sure to reference reporting standards when writing your review. This helps ensure that you communicate essential components of your methods, results, and conclusions. There are a number of tools that can be used to ensure compliance with reporting guidelines. A few review-writing resources are listed below.

• Cochrane Handbook - Chapter 15: Interpreting results and drawing conclusions
• JBI Manual for Evidence Synthesis - Chapter 12.3 The systematic review
• PRISMA 2020 (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) The aim of the PRISMA Statement is to help authors improve the reporting of systematic reviews and meta-analyses.

Tools for writing your review

• RevMan (Cochrane Training)
• Methods Wizard (Systematic Review Accelerator) The Methods Wizard is part of the Systematic Review Accelerator created by Bond University and the Institute for Evidence-Based Healthcare.
• UNC HSL Systematic Review Manuscript Template Systematic review manuscript template(.doc) adapted from the PRISMA 2020 checklist. This document provides authors with template for writing about their systematic review. Each table contains a PRISMA checklist item that should be written about in that section, the matching PRISMA Item number, and a box where authors can indicate if an item has been completed. Once text has been added, delete any remaining instructions and the PRISMA checklist tables from the end of each section.
• The PRISMA 2020 statement: an updated guideline for reporting systematic reviews The PRISMA 2020 statement replaces the 2009 statement and includes new reporting guidance that reflects advances in methods to identify, select, appraise, and synthesise studies.
• PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews This document is intended to enhance the use, understanding and dissemination of the PRISMA 2020 Statement. Through examples and explanations, the meaning and rationale for each checklist item are presented.

The PRISMA checklist

The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) is a 27-item checklist used to improve transparency in systematic reviews. These items cover all aspects of the manuscript, including title, abstract, introduction, methods, results, discussion, and funding. The PRISMA checklist can be downloaded in PDF or Word files.

• PRISMA 2020 Checklists Download the 2020 PRISMA Checklists in Word or PDF formats or download the expanded checklist (PDF).

The PRISMA flow diagram

The PRISMA Flow Diagram visually depicts the flow of studies through each phase of the review process. The PRISMA Flow Diagram can be downloaded in Word files.

• PRISMA 2020 Flow Diagrams The flow diagram depicts the flow of information through the different phases of a systematic review. It maps out the number of records identified, included and excluded, and the reasons for exclusions. Different templates are available depending on the type of review (new or updated) and sources used to identify studies.

Documenting grey literature and/or hand searches

If you have also searched additional sources, such as professional organization websites, cited or citing references, etc., document your grey literature search using the flow diagram template version 1 PRISMA 2020 flow diagram for new systematic reviews which included searches of databases, registers and other sources or the version 2 PRISMA 2020 flow diagram for updated systematic reviews which included searches of databases, registers and other sources . 

Complete the boxes documenting your database searches,  Identification of studies via databases and registers, according to the PRISMA flow diagram instructions.  Complete the boxes documenting your grey literature and/or hand searches on the right side of the template, Identification of studies via other methods, using the steps below.

Need help completing the PRISMA flow diagram?

There are different PRISMA flow diagram templates for new and updated reviews, as well as different templates for reviews with and without grey literature searches. Be sure you download the correct template to match your review methods, then follow the steps below for each portion of the diagram you have available.

View the step-by-step explanation of the PRISMA flow diagram

Step 1: Preparation Download the flow diagram template version 1 PRISMA 2020 flow diagram for new systematic reviews which included searches of databases and registers only or the version 2 PRISMA 2020 flow diagram for updated systematic reviews which included searches of databases and registers only . 

View the step-by-step explanation of the grey literature & hand searching portion of the PRISMA flow diagram

Step 1: Preparation Download the flow diagram template version 1 PRISMA 2020 flow diagram for new systematic reviews which included searches of databases, registers and other sources or the version 2 PRISMA 2020 flow diagram for updated systematic reviews which included searches of databases, registers and other sources . 

View the step-by-step explanation of review update portion of the PRISMA flow diagram

Step 1: Preparation Download the flow diagram template version 2 PRISMA 2020 flow diagram for updated systematic reviews which included searches of databases and registers only or the version 2 PRISMA 2020 flow diagram for updated systematic reviews which included searches of databases, registers and other sources . 

For more information about updating your systematic review, see the box Updating Your Review? on the Step 3: Conduct Literature Searches page of the guide.

Sections of a Scientific Manuscript

Scientific articles often follow the IMRaD format: Introduction, Methods, Results, and Discussion.  You will also need a title and an abstract to summarize your research.

You can read more about scientific writing through the library guides below.

• Structure of Scholarly Articles & Peer Review • Explains the standard parts of a medical research article • Compares scholarly journals, professional trade journals, and magazines • Explains peer review and how to find peer reviewed articles and journals
• Writing in the Health Sciences (For Students and Instructors)
• Citing & Writing Tools & Guides Includes links to guides for popular citation managers such as EndNote, Sciwheel, Zotero; copyright basics; APA & AMA Style guides; Plagiarism & Citing Sources; Citing & Writing: How to Write Scientific Papers

Sections of a Systematic Review Manuscript

Systematic reviews follow the same structure as original research articles, but you will need to report on your search instead of on details like the participants or sampling. Sections of your manuscript are shown as bold headings in the PRISMA checklist.

Refer to the PRISMA checklist for more information.

Consider including a Plain Language Summary (PLS) when you publish your systematic review. Like an abstract, a PLS gives an overview of your study, but is specifically written and formatted to be easy for non-experts to understand. 

Tips for writing a PLS:

• Use clear headings e.g. "why did we do this study?"; "what did we do?"; "what did we find?"
• Use active voice e.g. "we searched for articles in 5 databases instead of "5 databases were searched"
• Consider need-to-know vs. nice-to-know: what is most important for readers to understand about your study? Be sure to provide the most important points without misrepresenting your study or misleading the reader. 
• Keep it short: Many journals recommend keeping your plain language summary less than 250 words. 
• Check journal guidelines: Your journal may have specific guidelines about the format of your plain language summary and when you can publish it. Look at journal guidelines before submitting your article. 

Learn more about Plain Language Summaries: 

• Rosenberg, A., Baróniková, S., & Feighery, L. (2021). Open Pharma recommendations for plain language summaries of peer-reviewed medical journal publications. Current Medical Research and Opinion, 37(11), 2015–2016.  https://doi.org/10.1080/03007995.2021.1971185
• Lobban, D., Gardner, J., & Matheis, R. (2021). Plain language summaries of publications of company-sponsored medical research: what key questions do we need to address? Current Medical Research and Opinion, 1–12. https://doi.org/10.1080/03007995.2021.1997221
• Cochrane Community. (2022, March 21). Updated template and guidance for writing Plain Language Summaries in Cochrane Reviews now available. https://community.cochrane.org/news/updated-template-and-guidance-writing-plain-language-summaries-cochrane-reviews-now-available
• You can also look at our Health Literacy LibGuide:  https://guides.lib.unc.edu/healthliteracy 

How to Approach Writing a Background Section

What Makes a Good Discussion Section

Writing Up Risk of Bias

Developing Your Implications for Research Section

• << Previous: Step 7: Extract Data from Included Studies
• Next: FAQs >>
• Last Updated: May 16, 2024 3:24 PM
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• v.372; 2021

The PRISMA 2020 statement: an updated guideline for reporting systematic reviews

Matthew j page.

1 School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia

Joanne E McKenzie

Patrick m bossuyt.

2 Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, Netherlands

Isabelle Boutron

3 Université de Paris, Centre of Epidemiology and Statistics (CRESS), Inserm, F 75004 Paris, France

Tammy C Hoffmann

4 Institute for Evidence-Based Healthcare, Faculty of Health Sciences and Medicine, Bond University, Gold Coast, Australia

Cynthia D Mulrow

5 University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA; Annals of Internal Medicine

Larissa Shamseer

6 Knowledge Translation Program, Li Ka Shing Knowledge Institute, Toronto, Canada; School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, Canada

Jennifer M Tetzlaff

7 Evidence Partners, Ottawa, Canada

8 Clinical Research Institute, American University of Beirut, Beirut, Lebanon; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada

Sue E Brennan

9 Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon, USA

Julie Glanville

10 York Health Economics Consortium (YHEC Ltd), University of York, York, UK

Jeremy M Grimshaw

11 Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada; School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada; Department of Medicine, University of Ottawa, Ottawa, Canada

Asbjørn Hróbjartsson

12 Centre for Evidence-Based Medicine Odense (CEBMO) and Cochrane Denmark, Department of Clinical Research, University of Southern Denmark, Odense, Denmark; Open Patient data Exploratory Network (OPEN), Odense University Hospital, Odense, Denmark

Manoj M Lalu

13 Department of Anesthesiology and Pain Medicine, The Ottawa Hospital, Ottawa, Canada; Clinical Epidemiology Program, Blueprint Translational Research Group, Ottawa Hospital Research Institute, Ottawa, Canada; Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada

Tianjing Li

14 Department of Ophthalmology, School of Medicine, University of Colorado Denver, Denver, Colorado, United States; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA

Elizabeth W Loder

15 Division of Headache, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Head of Research, The BMJ , London, UK

Evan Mayo-Wilson

16 Department of Epidemiology and Biostatistics, Indiana University School of Public Health-Bloomington, Bloomington, Indiana, USA

Steve McDonald

Luke a mcguinness.

17 Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK

Lesley A Stewart

18 Centre for Reviews and Dissemination, University of York, York, UK

James Thomas

19 EPPI-Centre, UCL Social Research Institute, University College London, London, UK

Andrea C Tricco

20 Li Ka Shing Knowledge Institute of St. Michael's Hospital, Unity Health Toronto, Toronto, Canada; Epidemiology Division of the Dalla Lana School of Public Health and the Institute of Health Management, Policy, and Evaluation, University of Toronto, Toronto, Canada; Queen's Collaboration for Health Care Quality Joanna Briggs Institute Centre of Excellence, Queen's University, Kingston, Canada

Vivian A Welch

21 Methods Centre, Bruyère Research Institute, Ottawa, Ontario, Canada; School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, Canada

Penny Whiting

David moher.

22 Centre for Journalology, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada; School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, Canada

Associated Data

The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, published in 2009, was designed to help systematic reviewers transparently report why the review was done, what the authors did, and what they found. Over the past decade, advances in systematic review methodology and terminology have necessitated an update to the guideline. The PRISMA 2020 statement replaces the 2009 statement and includes new reporting guidance that reflects advances in methods to identify, select, appraise, and synthesise studies. The structure and presentation of the items have been modified to facilitate implementation. In this article, we present the PRISMA 2020 27-item checklist, an expanded checklist that details reporting recommendations for each item, the PRISMA 2020 abstract checklist, and the revised flow diagrams for original and updated reviews.

Systematic reviews serve many critical roles. They can provide syntheses of the state of knowledge in a field, from which future research priorities can be identified; they can address questions that otherwise could not be answered by individual studies; they can identify problems in primary research that should be rectified in future studies; and they can generate or evaluate theories about how or why phenomena occur. Systematic reviews therefore generate various types of knowledge for different users of reviews (such as patients, healthcare providers, researchers, and policy makers). 1 2 To ensure a systematic review is valuable to users, authors should prepare a transparent, complete, and accurate account of why the review was done, what they did (such as how studies were identified and selected) and what they found (such as characteristics of contributing studies and results of meta-analyses). Up-to-date reporting guidance facilitates authors achieving this. 3

The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement published in 2009 (hereafter referred to as PRISMA 2009) 4 5 6 7 8 9 10 is a reporting guideline designed to address poor reporting of systematic reviews. 11 The PRISMA 2009 statement comprised a checklist of 27 items recommended for reporting in systematic reviews and an “explanation and elaboration” paper 12 13 14 15 16 providing additional reporting guidance for each item, along with exemplars of reporting. The recommendations have been widely endorsed and adopted, as evidenced by its co-publication in multiple journals, citation in over 60 000 reports (Scopus, August 2020), endorsement from almost 200 journals and systematic review organisations, and adoption in various disciplines. Evidence from observational studies suggests that use of the PRISMA 2009 statement is associated with more complete reporting of systematic reviews, 17 18 19 20 although more could be done to improve adherence to the guideline. 21

Many innovations in the conduct of systematic reviews have occurred since publication of the PRISMA 2009 statement. For example, technological advances have enabled the use of natural language processing and machine learning to identify relevant evidence, 22 23 24 methods have been proposed to synthesise and present findings when meta-analysis is not possible or appropriate, 25 26 27 and new methods have been developed to assess the risk of bias in results of included studies. 28 29 Evidence on sources of bias in systematic reviews has accrued, culminating in the development of new tools to appraise the conduct of systematic reviews. 30 31 Terminology used to describe particular review processes has also evolved, as in the shift from assessing “quality” to assessing “certainty” in the body of evidence. 32 In addition, the publishing landscape has transformed, with multiple avenues now available for registering and disseminating systematic review protocols, 33 34 disseminating reports of systematic reviews, and sharing data and materials, such as preprint servers and publicly accessible repositories. To capture these advances in the reporting of systematic reviews necessitated an update to the PRISMA 2009 statement.

Summary points

• To ensure a systematic review is valuable to users, authors should prepare a transparent, complete, and accurate account of why the review was done, what they did, and what they found
• The PRISMA 2020 statement provides updated reporting guidance for systematic reviews that reflects advances in methods to identify, select, appraise, and synthesise studies
• The PRISMA 2020 statement consists of a 27-item checklist, an expanded checklist that details reporting recommendations for each item, the PRISMA 2020 abstract checklist, and revised flow diagrams for original and updated reviews
• We anticipate that the PRISMA 2020 statement will benefit authors, editors, and peer reviewers of systematic reviews, and different users of reviews, including guideline developers, policy makers, healthcare providers, patients, and other stakeholders

Development of PRISMA 2020

A complete description of the methods used to develop PRISMA 2020 is available elsewhere. 35 We identified PRISMA 2009 items that were often reported incompletely by examining the results of studies investigating the transparency of reporting of published reviews. 17 21 36 37 We identified possible modifications to the PRISMA 2009 statement by reviewing 60 documents providing reporting guidance for systematic reviews (including reporting guidelines, handbooks, tools, and meta-research studies). 38 These reviews of the literature were used to inform the content of a survey with suggested possible modifications to the 27 items in PRISMA 2009 and possible additional items. Respondents were asked whether they believed we should keep each PRISMA 2009 item as is, modify it, or remove it, and whether we should add each additional item. Systematic review methodologists and journal editors were invited to complete the online survey (110 of 220 invited responded). We discussed proposed content and wording of the PRISMA 2020 statement, as informed by the review and survey results, at a 21-member, two-day, in-person meeting in September 2018 in Edinburgh, Scotland. Throughout 2019 and 2020, we circulated an initial draft and five revisions of the checklist and explanation and elaboration paper to co-authors for feedback. In April 2020, we invited 22 systematic reviewers who had expressed interest in providing feedback on the PRISMA 2020 checklist to share their views (via an online survey) on the layout and terminology used in a preliminary version of the checklist. Feedback was received from 15 individuals and considered by the first author, and any revisions deemed necessary were incorporated before the final version was approved and endorsed by all co-authors.

The PRISMA 2020 statement

Scope of the guideline.

The PRISMA 2020 statement has been designed primarily for systematic reviews of studies that evaluate the effects of health interventions, irrespective of the design of the included studies. However, the checklist items are applicable to reports of systematic reviews evaluating other interventions (such as social or educational interventions), and many items are applicable to systematic reviews with objectives other than evaluating interventions (such as evaluating aetiology, prevalence, or prognosis). PRISMA 2020 is intended for use in systematic reviews that include synthesis (such as pairwise meta-analysis or other statistical synthesis methods) or do not include synthesis (for example, because only one eligible study is identified). The PRISMA 2020 items are relevant for mixed-methods systematic reviews (which include quantitative and qualitative studies), but reporting guidelines addressing the presentation and synthesis of qualitative data should also be consulted. 39 40 PRISMA 2020 can be used for original systematic reviews, updated systematic reviews, or continually updated (“living”) systematic reviews. However, for updated and living systematic reviews, there may be some additional considerations that need to be addressed. Where there is relevant content from other reporting guidelines, we reference these guidelines within the items in the explanation and elaboration paper 41 (such as PRISMA-Search 42 in items 6 and 7, Synthesis without meta-analysis (SWiM) reporting guideline 27 in item 13d). Box 1 includes a glossary of terms used throughout the PRISMA 2020 statement.

Glossary of terms

• Systematic review —A review that uses explicit, systematic methods to collate and synthesise findings of studies that address a clearly formulated question 43
• Statistical synthesis —The combination of quantitative results of two or more studies. This encompasses meta-analysis of effect estimates (described below) and other methods, such as combining P values, calculating the range and distribution of observed effects, and vote counting based on the direction of effect (see McKenzie and Brennan 25 for a description of each method)
• Meta-analysis of effect estimates —A statistical technique used to synthesise results when study effect estimates and their variances are available, yielding a quantitative summary of results 25
• Outcome —An event or measurement collected for participants in a study (such as quality of life, mortality)
• Result —The combination of a point estimate (such as a mean difference, risk ratio, or proportion) and a measure of its precision (such as a confidence/credible interval) for a particular outcome
• Report —A document (paper or electronic) supplying information about a particular study. It could be a journal article, preprint, conference abstract, study register entry, clinical study report, dissertation, unpublished manuscript, government report, or any other document providing relevant information
• Record —The title or abstract (or both) of a report indexed in a database or website (such as a title or abstract for an article indexed in Medline). Records that refer to the same report (such as the same journal article) are “duplicates”; however, records that refer to reports that are merely similar (such as a similar abstract submitted to two different conferences) should be considered unique.
• Study —An investigation, such as a clinical trial, that includes a defined group of participants and one or more interventions and outcomes. A “study” might have multiple reports. For example, reports could include the protocol, statistical analysis plan, baseline characteristics, results for the primary outcome, results for harms, results for secondary outcomes, and results for additional mediator and moderator analyses

PRISMA 2020 is not intended to guide systematic review conduct, for which comprehensive resources are available. 43 44 45 46 However, familiarity with PRISMA 2020 is useful when planning and conducting systematic reviews to ensure that all recommended information is captured. PRISMA 2020 should not be used to assess the conduct or methodological quality of systematic reviews; other tools exist for this purpose. 30 31 Furthermore, PRISMA 2020 is not intended to inform the reporting of systematic review protocols, for which a separate statement is available (PRISMA for Protocols (PRISMA-P) 2015 statement 47 48 ). Finally, extensions to the PRISMA 2009 statement have been developed to guide reporting of network meta-analyses, 49 meta-analyses of individual participant data, 50 systematic reviews of harms, 51 systematic reviews of diagnostic test accuracy studies, 52 and scoping reviews 53 ; for these types of reviews we recommend authors report their review in accordance with the recommendations in PRISMA 2020 along with the guidance specific to the extension.

How to use PRISMA 2020

The PRISMA 2020 statement (including the checklists, explanation and elaboration, and flow diagram) replaces the PRISMA 2009 statement, which should no longer be used. Box 2 summarises noteworthy changes from the PRISMA 2009 statement. The PRISMA 2020 checklist includes seven sections with 27 items, some of which include sub-items ( table 1 ). A checklist for journal and conference abstracts for systematic reviews is included in PRISMA 2020. This abstract checklist is an update of the 2013 PRISMA for Abstracts statement, 54 reflecting new and modified content in PRISMA 2020 ( table 2 ). A template PRISMA flow diagram is provided, which can be modified depending on whether the systematic review is original or updated ( fig 1 ).

Noteworthy changes to the PRISMA 2009 statement

• Inclusion of the abstract reporting checklist within PRISMA 2020 (see item #2 and table 2 ).
• Movement of the ‘Protocol and registration’ item from the start of the Methods section of the checklist to a new Other section, with addition of a sub-item recommending authors describe amendments to information provided at registration or in the protocol (see item #24a-24c).
• Modification of the ‘Search’ item to recommend authors present full search strategies for all databases, registers and websites searched, not just at least one database (see item #7).
• Modification of the ‘Study selection’ item in the Methods section to emphasise the reporting of how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process (see item #8).
• Addition of a sub-item to the ‘Data items’ item recommending authors report how outcomes were defined, which results were sought, and methods for selecting a subset of results from included studies (see item #10a).
• Splitting of the ‘Synthesis of results’ item in the Methods section into six sub-items recommending authors describe: the processes used to decide which studies were eligible for each synthesis; any methods required to prepare the data for synthesis; any methods used to tabulate or visually display results of individual studies and syntheses; any methods used to synthesise results; any methods used to explore possible causes of heterogeneity among study results (such as subgroup analysis, meta-regression); and any sensitivity analyses used to assess robustness of the synthesised results (see item #13a-13f).
• Addition of a sub-item to the ‘Study selection’ item in the Results section recommending authors cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded (see item #16b).
• Splitting of the ‘Synthesis of results’ item in the Results section into four sub-items recommending authors: briefly summarise the characteristics and risk of bias among studies contributing to the synthesis; present results of all statistical syntheses conducted; present results of any investigations of possible causes of heterogeneity among study results; and present results of any sensitivity analyses (see item #20a-20d).
• Addition of new items recommending authors report methods for and results of an assessment of certainty (or confidence) in the body of evidence for an outcome (see items #15 and #22).
• Addition of a new item recommending authors declare any competing interests (see item #26).
• Addition of a new item recommending authors indicate whether data, analytic code and other materials used in the review are publicly available and if so, where they can be found (see item #27).

PRISMA 2020 item checklist

PRISMA 2020 for Abstracts checklist*

PRISMA 2020 flow diagram template for systematic reviews. The new design is adapted from flow diagrams proposed by Boers, 55 Mayo-Wilson et al. 56 and Stovold et al. 57 The boxes in grey should only be completed if applicable; otherwise they should be removed from the flow diagram. Note that a “report” could be a journal article, preprint, conference abstract, study register entry, clinical study report, dissertation, unpublished manuscript, government report or any other document providing relevant information.

We recommend authors refer to PRISMA 2020 early in the writing process, because prospective consideration of the items may help to ensure that all the items are addressed. To help keep track of which items have been reported, the PRISMA statement website ( http://www.prisma-statement.org/ ) includes fillable templates of the checklists to download and complete (also available in the data supplement on bmj.com). We have also created a web application that allows users to complete the checklist via a user-friendly interface 58 (available at https://prisma.shinyapps.io/checklist/ and adapted from the Transparency Checklist app 59 ). The completed checklist can be exported to Word or PDF. Editable templates of the flow diagram can also be downloaded from the PRISMA statement website.

We have prepared an updated explanation and elaboration paper, in which we explain why reporting of each item is recommended and present bullet points that detail the reporting recommendations (which we refer to as elements). 41 The bullet-point structure is new to PRISMA 2020 and has been adopted to facilitate implementation of the guidance. 60 61 An expanded checklist, which comprises an abridged version of the elements presented in the explanation and elaboration paper, with references and some examples removed, is available in the data supplement on bmj.com. Consulting the explanation and elaboration paper is recommended if further clarity or information is required.

Journals and publishers might impose word and section limits, and limits on the number of tables and figures allowed in the main report. In such cases, if the relevant information for some items already appears in a publicly accessible review protocol, referring to the protocol may suffice. Alternatively, placing detailed descriptions of the methods used or additional results (such as for less critical outcomes) in supplementary files is recommended. Ideally, supplementary files should be deposited to a general-purpose or institutional open-access repository that provides free and permanent access to the material (such as Open Science Framework, Dryad, figshare). A reference or link to the additional information should be included in the main report. Finally, although PRISMA 2020 provides a template for where information might be located, the suggested location should not be seen as prescriptive; the guiding principle is to ensure the information is reported.

Use of PRISMA 2020 has the potential to benefit many stakeholders. Complete reporting allows readers to assess the appropriateness of the methods, and therefore the trustworthiness of the findings. Presenting and summarising characteristics of studies contributing to a synthesis allows healthcare providers and policy makers to evaluate the applicability of the findings to their setting. Describing the certainty in the body of evidence for an outcome and the implications of findings should help policy makers, managers, and other decision makers formulate appropriate recommendations for practice or policy. Complete reporting of all PRISMA 2020 items also facilitates replication and review updates, as well as inclusion of systematic reviews in overviews (of systematic reviews) and guidelines, so teams can leverage work that is already done and decrease research waste. 36 62 63

We updated the PRISMA 2009 statement by adapting the EQUATOR Network’s guidance for developing health research reporting guidelines. 64 We evaluated the reporting completeness of published systematic reviews, 17 21 36 37 reviewed the items included in other documents providing guidance for systematic reviews, 38 surveyed systematic review methodologists and journal editors for their views on how to revise the original PRISMA statement, 35 discussed the findings at an in-person meeting, and prepared this document through an iterative process. Our recommendations are informed by the reviews and survey conducted before the in-person meeting, theoretical considerations about which items facilitate replication and help users assess the risk of bias and applicability of systematic reviews, and co-authors’ experience with authoring and using systematic reviews.

Various strategies to increase the use of reporting guidelines and improve reporting have been proposed. They include educators introducing reporting guidelines into graduate curricula to promote good reporting habits of early career scientists 65 ; journal editors and regulators endorsing use of reporting guidelines 18 ; peer reviewers evaluating adherence to reporting guidelines 61 66 ; journals requiring authors to indicate where in their manuscript they have adhered to each reporting item 67 ; and authors using online writing tools that prompt complete reporting at the writing stage. 60 Multi-pronged interventions, where more than one of these strategies are combined, may be more effective (such as completion of checklists coupled with editorial checks). 68 However, of 31 interventions proposed to increase adherence to reporting guidelines, the effects of only 11 have been evaluated, mostly in observational studies at high risk of bias due to confounding. 69 It is therefore unclear which strategies should be used. Future research might explore barriers and facilitators to the use of PRISMA 2020 by authors, editors, and peer reviewers, designing interventions that address the identified barriers, and evaluating those interventions using randomised trials. To inform possible revisions to the guideline, it would also be valuable to conduct think-aloud studies 70 to understand how systematic reviewers interpret the items, and reliability studies to identify items where there is varied interpretation of the items.

We encourage readers to submit evidence that informs any of the recommendations in PRISMA 2020 (via the PRISMA statement website: http://www.prisma-statement.org/ ). To enhance accessibility of PRISMA 2020, several translations of the guideline are under way (see available translations at the PRISMA statement website). We encourage journal editors and publishers to raise awareness of PRISMA 2020 (for example, by referring to it in journal “Instructions to authors”), endorsing its use, advising editors and peer reviewers to evaluate submitted systematic reviews against the PRISMA 2020 checklists, and making changes to journal policies to accommodate the new reporting recommendations. We recommend existing PRISMA extensions 47 49 50 51 52 53 71 72 be updated to reflect PRISMA 2020 and advise developers of new PRISMA extensions to use PRISMA 2020 as the foundation document.

We anticipate that the PRISMA 2020 statement will benefit authors, editors, and peer reviewers of systematic reviews, and different users of reviews, including guideline developers, policy makers, healthcare providers, patients, and other stakeholders. Ultimately, we hope that uptake of the guideline will lead to more transparent, complete, and accurate reporting of systematic reviews, thus facilitating evidence based decision making.

Acknowledgments

We dedicate this paper to the late Douglas G Altman and Alessandro Liberati, whose contributions were fundamental to the development and implementation of the original PRISMA statement.

We thank the following contributors who completed the survey to inform discussions at the development meeting: Xavier Armoiry, Edoardo Aromataris, Ana Patricia Ayala, Ethan M Balk, Virginia Barbour, Elaine Beller, Jesse A Berlin, Lisa Bero, Zhao-Xiang Bian, Jean Joel Bigna, Ferrán Catalá-López, Anna Chaimani, Mike Clarke, Tammy Clifford, Ioana A Cristea, Miranda Cumpston, Sofia Dias, Corinna Dressler, Ivan D Florez, Joel J Gagnier, Chantelle Garritty, Long Ge, Davina Ghersi, Sean Grant, Gordon Guyatt, Neal R Haddaway, Julian PT Higgins, Sally Hopewell, Brian Hutton, Jamie J Kirkham, Jos Kleijnen, Julia Koricheva, Joey SW Kwong, Toby J Lasserson, Julia H Littell, Yoon K Loke, Malcolm R Macleod, Chris G Maher, Ana Marušic, Dimitris Mavridis, Jessie McGowan, Matthew DF McInnes, Philippa Middleton, Karel G Moons, Zachary Munn, Jane Noyes, Barbara Nußbaumer-Streit, Donald L Patrick, Tatiana Pereira-Cenci, Ba’ Pham, Bob Phillips, Dawid Pieper, Michelle Pollock, Daniel S Quintana, Drummond Rennie, Melissa L Rethlefsen, Hannah R Rothstein, Maroeska M Rovers, Rebecca Ryan, Georgia Salanti, Ian J Saldanha, Margaret Sampson, Nancy Santesso, Rafael Sarkis-Onofre, Jelena Savović, Christopher H Schmid, Kenneth F Schulz, Guido Schwarzer, Beverley J Shea, Paul G Shekelle, Farhad Shokraneh, Mark Simmonds, Nicole Skoetz, Sharon E Straus, Anneliese Synnot, Emily E Tanner-Smith, Brett D Thombs, Hilary Thomson, Alexander Tsertsvadze, Peter Tugwell, Tari Turner, Lesley Uttley, Jeffrey C Valentine, Matt Vassar, Areti Angeliki Veroniki, Meera Viswanathan, Cole Wayant, Paul Whaley, and Kehu Yang. We thank the following contributors who provided feedback on a preliminary version of the PRISMA 2020 checklist: Jo Abbott, Fionn Büttner, Patricia Correia-Santos, Victoria Freeman, Emily A Hennessy, Rakibul Islam, Amalia (Emily) Karahalios, Kasper Krommes, Andreas Lundh, Dafne Port Nascimento, Davina Robson, Catherine Schenck-Yglesias, Mary M Scott, Sarah Tanveer and Pavel Zhelnov. We thank Abigail H Goben, Melissa L Rethlefsen, Tanja Rombey, Anna Scott, and Farhad Shokraneh for their helpful comments on the preprints of the PRISMA 2020 papers. We thank Edoardo Aromataris, Stephanie Chang, Toby Lasserson and David Schriger for their helpful peer review comments on the PRISMA 2020 papers.

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PRISMA 2020 checklist

PRISMA 2020 expanded checklist

Contributors: JEM and DM are joint senior authors. MJP, JEM, PMB, IB, TCH, CDM, LS, and DM conceived this paper and designed the literature review and survey conducted to inform the guideline content. MJP conducted the literature review, administered the survey and analysed the data for both. MJP prepared all materials for the development meeting. MJP and JEM presented proposals at the development meeting. All authors except for TCH, JMT, EAA, SEB, and LAM attended the development meeting. MJP and JEM took and consolidated notes from the development meeting. MJP and JEM led the drafting and editing of the article. JEM, PMB, IB, TCH, LS, JMT, EAA, SEB, RC, JG, AH, TL, EMW, SM, LAM, LAS, JT, ACT, PW, and DM drafted particular sections of the article. All authors were involved in revising the article critically for important intellectual content. All authors approved the final version of the article. MJP is the guarantor of this work. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Funding: There was no direct funding for this research. MJP is supported by an Australian Research Council Discovery Early Career Researcher Award (DE200101618) and was previously supported by an Australian National Health and Medical Research Council (NHMRC) Early Career Fellowship (1088535) during the conduct of this research. JEM is supported by an Australian NHMRC Career Development Fellowship (1143429). TCH is supported by an Australian NHMRC Senior Research Fellowship (1154607). JMT is supported by Evidence Partners Inc. JMG is supported by a Tier 1 Canada Research Chair in Health Knowledge Transfer and Uptake. MML is supported by The Ottawa Hospital Anaesthesia Alternate Funds Association and a Faculty of Medicine Junior Research Chair. TL is supported by funding from the National Eye Institute (UG1EY020522), National Institutes of Health, United States. LAM is supported by a National Institute for Health Research Doctoral Research Fellowship (DRF-2018-11-ST2-048). ACT is supported by a Tier 2 Canada Research Chair in Knowledge Synthesis. DM is supported in part by a University Research Chair, University of Ottawa. The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication.

Competing interests: All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/conflicts-of-interest/ and declare: EL is head of research for the BMJ ; MJP is an editorial board member for PLOS Medicine ; ACT is an associate editor and MJP, TL, EMW, and DM are editorial board members for the Journal of Clinical Epidemiology ; DM and LAS were editors in chief, LS, JMT, and ACT are associate editors, and JG is an editorial board member for Systematic Reviews . None of these authors were involved in the peer review process or decision to publish. TCH has received personal fees from Elsevier outside the submitted work. EMW has received personal fees from the American Journal for Public Health , for which he is the editor for systematic reviews. VW is editor in chief of the Campbell Collaboration, which produces systematic reviews, and co-convenor of the Campbell and Cochrane equity methods group. DM is chair of the EQUATOR Network, IB is adjunct director of the French EQUATOR Centre and TCH is co-director of the Australasian EQUATOR Centre, which advocates for the use of reporting guidelines to improve the quality of reporting in research articles. JMT received salary from Evidence Partners, creator of DistillerSR software for systematic reviews; Evidence Partners was not involved in the design or outcomes of the statement, and the views expressed solely represent those of the author.

Provenance and peer review: Not commissioned; externally peer reviewed.

Patient and public involvement: Patients and the public were not involved in this methodological research. We plan to disseminate the research widely, including to community participants in evidence synthesis organisations.

• Open access
• Published: 26 January 2021

PRISMA-S: an extension to the PRISMA Statement for Reporting Literature Searches in Systematic Reviews

• Melissa L. Rethlefsen   ORCID: orcid.org/0000-0001-5322-9368 1 ,
• Shona Kirtley   ORCID: orcid.org/0000-0002-7801-5777 2 ,
• Siw Waffenschmidt   ORCID: orcid.org/0000-0001-6860-6699 3 ,
• Ana Patricia Ayala   ORCID: orcid.org/0000-0002-3613-2270 4 ,
• David Moher   ORCID: orcid.org/0000-0003-2434-4206 5 ,
• Matthew J. Page   ORCID: orcid.org/0000-0002-4242-7526 6 ,
• Jonathan B. Koffel   ORCID: orcid.org/0000-0003-1723-5087 7 &

PRISMA-S Group

Systematic Reviews volume  10 , Article number:  39 ( 2021 ) Cite this article

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Literature searches underlie the foundations of systematic reviews and related review types. Yet, the literature searching component of systematic reviews and related review types is often poorly reported. Guidance for literature search reporting has been diverse, and, in many cases, does not offer enough detail to authors who need more specific information about reporting search methods and information sources in a clear, reproducible way. This document presents the PRISMA-S (Preferred Reporting Items for Systematic reviews and Meta-Analyses literature search extension) checklist, and explanation and elaboration.

The checklist was developed using a 3-stage Delphi survey process, followed by a consensus conference and public review process.

The final checklist includes 16 reporting items, each of which is detailed with exemplar reporting and rationale.

Conclusions

The intent of PRISMA-S is to complement the PRISMA Statement and its extensions by providing a checklist that could be used by interdisciplinary authors, editors, and peer reviewers to verify that each component of a search is completely reported and therefore reproducible.

Peer Review reports

Introduction

One crucial component of a systematic review is the literature search. The literature search, or information retrieval process, not only informs the results of a systematic review; it is the underlying process that establishes the data available for analysis. Additional components of the systematic review process such as screening, data extraction, and qualitative or quantitative synthesis procedures are dependent on the identification of eligible studies. As such, the literature search must be designed to be both robust and reproducible to ensure the minimization of bias.

Guidelines exist for both the conduct of literature searches (Table 2 ) for systematic reviews and their reporting [ 2 , 3 , 4 , 5 , 6 , 7 ]. Problematically, however, the many guidelines for reporting systematic review searches share few common reporting elements. In fact, Sampson et al. discovered that of the eleven instruments designed to help authors report literature searches well, only one item appeared in all eleven instruments [ 8 ]. Though Sampson et al.’s study was conducted in 2007, the problem has only been compounded as new checklists and tools have continued to be developed. The most commonly used reporting guidance for systematic reviews, which covers the literature search component, is the Preferred Reporting Items for Systematic reviews and Meta-Analyses Statement, or PRISMA Statement [ 9 ]. The 2009 PRISMA Statement checklist included three items related to literature search reporting, items 7, 8, and 17:

Item 7: Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

Item 8: Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

Item 17: Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.

Despite wide usage of the PRISMA Statement [ 10 ], compliance with its items regarding literature search reporting is low [ 11 , 12 , 13 , 14 ]. Even for those studies which explicitly reference PRISMA, there is only slight, statistically non-significant evidence of improved reporting, as found by Page et al. [ 15 ]. Part of the challenge may be the multifactorial nature of each of the PRISMA items relating to searches; authors may feel if they completed one of the components of the item that they can check off that item altogether. Another part of the challenge may be that many systematic reviews do not include librarians or information specialists as members of the systematic review team or as authors on the final manuscript [ 11 , 16 , 17 , 18 ]. Preliminary research suggests that librarian or information specialist involvement is correlated with reproducibility of searches [ 16 , 17 , 18 ], likely due to their expertise surrounding search development and documentation. However, reviews where librarians are authors still include reproducible searches only 64% of the time [ 17 ].

A larger issue may be that, even amongst librarians and information specialists, debate exists as to what constitutes a reproducible search and how best to report the details of the search. Researchers assessing the reproducibility of the search have used varying methods to determine what constitutes a reproducible search [ 11 , 17 , 19 , 20 ]. Post-publication peer review of search methods, even amongst Cochrane reviews, which generally have superior reporting compared to non-Cochrane reviews [ 15 ], has shown that reporting that appears complete may still pose challenges for those wishing to reproduce searches [ 20 , 21 , 22 , 23 , 24 ]. Furthermore, little guidance on how to report searches using information sources or methods other than literature databases, such as searching web sites or study registries, exists [ 25 , 26 ].

Incomplete reporting of the literature search methods can introduce doubt and diminish trust in the final systematic review conclusions. If researchers are unable to understand or reproduce how information was gathered for a systematic review, they may suspect the authors of having introduced bias into their review by not conducting a thorough or pre-specified literature search. After observing the high number of systematic reviews with poorly reported literature searches, we sought to create an extension to the PRISMA statement. Our aims were four-fold:

To provide extensive guidance on reporting the literature search components of a systematic review.

To create a checklist that could be used by authors, editors, and peer reviewers to verify that each component of a search was completely reported and therefore reproducible.

To develop an interdisciplinary checklist applicable to all method-driven literature searches for evidence synthesis.

To complement the PRISMA Statement and its extensions.

Because we intend the checklist to be used in all fields and disciplines, we use “systematic reviews” throughout this document as a representative name for the entire family of evidence syntheses [ 27 ]. This includes, but is not limited to, scoping reviews, rapid reviews, realist reviews, metanarrative reviews, mixed methods reviews, umbrella reviews, and evidence maps [ 28 ]. We use the term “literature search” or “search” throughout to encompass the full range of possible search methods and information sources.

Part 1: Developing the Checklist

After consultation with members of the PRISMA Statement steering group (D.M. and D.G.A.), we formed an executive committee (M.L.R, J.K., S.K.) and developed a protocol [ 29 ] according to the steps outlined in the “Guidance for Developers of Health Research Reporting Guidelines [ 30 ].” The protocol was registered on the EQUATOR Network [ 29 ]. We identified 405 potential items relevant to reporting searches in systematic reviews from 61 sources (see Additional file 1 ) located through a search of MEDLINE via Ovid, Embase via Embase.com , and LISTA via EBSCOhost, in addition to reviewing all of the sources identified by the EQUATOR Network relating to systematic reviews. We also searched our personal files and examined references of included documents for additional sources. Details of the search are available in Additional file 1 . Sources included both explicit reporting guidelines and studies assessing reproducibility of search strategies. The 405 items were reviewed for overlap and consolidated into 123 remaining items for potential inclusion in a checklist.

To narrow the list into a usable checklist, we then used a three-step Delphi survey process [ 31 ]. The first survey included the initially identified 123 items and asked respondents to rate each item on a 4-point Likert-type scale. Items that 70% of experts rated as 3 or 4 (4 being “essential” and 1 “not important”) and that received a mean score of at least 3.25 were retained for rating in the second round of the Delphi process. Respondents to the first survey were invited to participate in the second and third rounds. The second round asked respondents to pick the 25 most essential items out of the remaining 53 potential items; the third round was identical, except respondents also selected the most appropriate location for reporting their selected items (e.g., in the main text, or a supplementary file). The items were ranked and categorized by general theme for discussion at an in-person consensus conference.

We created a list of one hundred and sixty-three international experts, including librarian and information specialists with expertise in systematic reviews, researchers who had written about systematic review reporting, journal editors, and systematic review methodologists, to whom we sent our initial Delphi survey. The list of experts was created using a combination of publications, mailing lists, conference proceedings, and knowledge of the authors to represent research groups and experts in 23 countries. We received 52 responses (32% response rate) to the first survey, and of these, 35 (67% response rate) completed both surveys two and three. This study was declared exempt by the University of Utah Institutional Review Board (IRB_00088425).

The results of the Delphi process were reported at a consensus conference meeting that took place in May 2016 concurrently with Mosaic ‘16, the joint meeting of the Medical Library Association, Canadian Health Libraries Association/Association des bibliothèques de la santé du Canada, and the International Clinical Librarian Conference (ICLC). 38 individuals attended the consensus conference, 14 (37%) of whom had participated in the Delphi surveys. At the consensus conference, the grouped and ranked remaining items were distributed to small groups who were asked to discuss, consolidate, remove, or add missing critical items under the guidance of a group leader. After two rounds of discussion, the group leaders presented the discussion and proposed list items from their small groups for consideration by the whole group of experts.

Upon completion of the consensus conference, 30 items remained from those identified during the Delphi process, with an additional three items that had been excluded during the Delphi process added back to the draft checklist because meeting attendees considered them critical to the guideline. The list was then consolidated and reviewed by executive committee members, including two new information specialist members (S.W. and A.P.A). The draft checklist and explanation and elaboration document was released to the public on March 20, 2019, along with all data and study materials [ 32 ]. All participants in the Delphi process and/or consensus conference were contacted via email with instructions on how to provide feedback on the draft checklist items and/or elaboration and explanation document by commenting directly on the explanation and elaboration draft using a private commenting system, Hypothesis [ 33 ], or if preferred, via email. Comments from other interested individuals were solicited via Twitter, conference presentations, and personal contacts. Comments were collected from the private Hypothesis group, the public Hypothesis comments, and via email. All comments were combined into a single document. Executive committee members reviewed each comment in duplicate to indicate what type of feedback was received (i.e., linguistic, major substantive, minor substantive, or unclear) and, for substantive comments, whether change was recommended or required further discussion.

During the draft and revision process (March 20–June 15, 2019), 358 separate comments were received from 22 individuals and organizations. Based upon the extensive feedback received, the executive team revised the checklist and developed the next iteration, which was released on December 6, 2019, to coincide with the 2019 Virtual Cochrane Colloquium Santiago. Additional feedback from this release was incorporated into the final checklist. Throughout the draft and revision process, several teleconferences were held with the lead of the PRISMA 2020 statement (M.J.P), as an update of the 2009 PRISMA statement was in development, to ensure that the content on search methods was consistent between the PRISMA 2020 and PRISMA-S guidelines [ 34 , 35 ].

Part 2: Checklist

PRISMA-S is a 16-item checklist that covers multiple aspects of the search process for systematic reviews. It is intended to guide reporting, not conduct, of the search. The checklist should be read in conjunction with the Explanation and Elaboration (Part 3), which provides more detail about each item. We also include two boxes, one a glossary of terms (see Table 2 ) and the other, guidance on depositing search data and method descriptions in online repositories (see Table 3 ).

The Explanation and Elaboration also includes examples of good reporting for each item. Each exemplar is drawn from published systematic reviews. For clarity, some exemplars are edited to match the style of this document, including any original citations, and abbreviations are spelled out to aid comprehension. Any other edits to the text are noted with square brackets. A description of the rationale behind the item is explained, followed by additional suggestions for clear reporting and a suggested location(s) for reporting the item.

Not every systematic review will make use of all of the items in the Information Sources and Methods section of the checklist, depending on the research question and the methods chosen by the authors. The checklist provides a framework for the current most common and recommended types of information sources and methods for systematic reviews, but authors should use and report those items relevant and appropriate to their review. The checklist may also be used for systematic review protocols to fully document the planned search, in conjunction with the PRISMA-P reporting guideline [ 36 ] (Table 1 ).

Part 3: Explanation and Elaboration

Item 1. database name.

Name each individual database searched, stating the platform for each.

“The following electronic databases were searched: MEDLINE (Ovid), CINAHL (EBSCOhost), PsycINFO (Ovid), Cochrane Central Register of Controlled Trials (Ovid), SPORTDiscus (EBSCOhost), EMBASE (Ovid) and ProQuest Dissertations and Theses Global (ProQuest).” [ 38 ]

Explanation

Databases are the most commonly used tool to locate studies to include in systematic reviews and meta-analyses [ 6 , 39 ]. There is no single database that is able to provide a complete and accurate list of all studies that meet systematic review criteria due to the differences in the articles included and the indexing methods used between databases (Table 2 ). These differences have led to recommendations that systematic review teams search multiple databases to maximize the likelihood of finding relevant studies [ 6 , 39 , 40 ]. This may include using broad disciplinary databases (e.g., MEDLINE [ 41 ], Embase [ 42 ], Scopus [ 43 ]), specialized databases (e.g., PsycINFO [ 44 ] or EconLit [ 45 ]), or regional databases (e.g., LILACS [ 46 ] or African Index Medicus [ 47 ]).

Many of these literature databases are available through multiple different search platforms (Table 2 ). For example, the MEDLINE database is available through at least 10 different platforms, including Ovid, EBSCOhost, Web of Science, and PubMed. Each platform offers different ways of searching the databases, such as platform-specific field codes (Table 2 ), phrase searching, truncation, or searching full-text versus abstract and keyword only [ 48 ]. Different platforms may contain additional data that are not available in the original database, such as times cited, social media impact, or additional keywords. These differences between the platforms can have a meaningful impact on the results provided [ 48 , 49 , 50 ].

Authors should identify which specific literature databases were searched to locate studies included in the systematic review. It is important that authors indicate not only the database, but the platform through which the database was searched. This helps readers to evaluate the quality and comprehensiveness of the search and supports reproducibility and updating (Table 2 ) in the future by allowing the strategy to be copied and pasted as recommended in Item 8, below.

The distinctions between database and platform may not always be clear to authors, especially when the database is the only one available through a platform (e.g., Scopus [ 43 ]). In these cases, authors may choose to include the web address of the database in the text or the bibliography to provide clarity for their readers.

Suggested location for reporting

Report each database name and platform in the methods section and any supplementary materials (Table 2 ). If space permits, report key database names in the abstract.

Item 2. Multi-database searching

If databases were searched simultaneously on a single platform, state the name of the platform, listing all of the databases searched.

“The MEDLINE and Embase strategies were run simultaneously as a multi-file search in Ovid and the results de-duplicated using the Ovid de-duplication tool.” [ 51 ]

“A systematic literature search was performed in Web of Knowledge™ (including KCI Korean Journal Database, MEDLINE, Russian Science Citation Index, and SciELO Citation Index)….” [ 52 ]

Authors may choose to search multiple databases at once through a single search platform to increase efficiency. Along with the name of the platform, it is necessary to list the names of each of the individual databases included as part of the search. Including information about using this approach in the text of the manuscript helps readers immediately understand how the search was constructed and executed. This helps readers determine how effective the search strategy (Table 2 ) will be for each database [ 1 ].

Report any multi-database search (Table 2 ) in the methods section and any supplementary materials. If space permits, report key individual database names in the abstract, even if run through a multi-database search.

Item 3. Study registries

List any study registries searched.

“[We] searched several clinical trial registries ( ClinicalTrials.gov , Current Controlled Trials ( www.controlled-trials.com ), Australian New Zealand Clinical Trials Registry ( www.actr.org.au ), and University Hospital Medical Information Network Clinical Trials Registry ( www.umin.ac.jp/ctr )) to identify ongoing trials.” [ 53 ]

Study registries are a key source of information for systematic reviews and meta-analyses in the health sciences and increasingly in other disciplines. In the health sciences, study registries (Table 2 ) allow researchers to locate ongoing clinical trials and studies that may have gone unpublished [ 54 , 55 , 56 ]. Some funders, including the National Institutes of Health, require principal investigators to share their data on study registries within a certain time frame after grant completion [ 57 ]. This data may not have been published in any other location, making study registries a critical component of an information strategy, though timely reporting remains a challenge [ 58 , 59 ]. Different countries have their own study registries, as do many pharmaceutical companies.

Outside the health sciences, study registries are becoming increasingly important as many disciplines adopt study pre-registration as a tactic for improving the rigor of research. Though not yet as established as in the health sciences, these study registries are continually expanding and will serve as key sources for finding unpublished studies in fields in the social sciences and beyond.

To fully describe the study registries searched, list the name of each study registry searched, and include a citation or link to the study registry.

Report any study registries searched in the methods section and any supplementary materials.

Item 4. Online resources and browsing

Describe any online or print source purposefully searched or browsed (e.g., tables of contents, print conference proceedings, web sites), and how this was done.

“ We also searched the grey literature using the search string: “public attitudes” AND “sharing” AND “health data” on Google (in June 2017). The first 20 results were selected and screened.” [ 60 ]

“The grey literature search was conducted in October 2015 and included targeted, iterative hand searching of 22 government and/or research organization websites that were suggested during the expert consultation and are listed in S1 Protocol. Twenty two additional citations were added to the review from the grey literature search.” [ 61 ]

“To locate unpublished studies, we searched Embase [via Embase.com ] for conference proceedings since 2000 and hand-searched meeting abstracts of the Canadian Conference on Physician Health and the International Conference on Physician Health (2012 to 2016).” [ 62 ]

Systematic reviews were developed to remove as much bias as possible from the literature review process. One of the most important ways they achieve this reduction in bias is by searching beyond literature databases, which are skewed towards English-language publications with positive results [ 63 , 64 ]. To achieve a fuller picture of what the research on a specific topic looks like, systematic reviewers could seek out research that may be in progress and research that was never published [ 6 ]. Using other methods of finding research also helps identify research that may have been indexed in literature databases, but went undiscovered when searching those sources [ 40 ]. Seeking out this research often involves a complex strategy, drawing on a wealth of online and print resources as well as personal contacts.

Web search engines and specific web sites

Searching general internet search engines and searching the contents of specific websites is a key component of many systematic reviews [ 26 , 65 ]. Government, non-profit organization, and pharmaceutical company websites, for example, contain a wealth of information not published elsewhere [ 6 , 66 ]. Though searching a general search engine like Google or using a general search engine to search a specific website may introduce some bias into the search methodology through the personalization algorithms inherent in many of these tools [ 67 , 68 ], it is still important to fully document how web searches were conducted [ 65 ].

Authors should list all websites searched, along with their corresponding web address. Readers should be able to clearly understand if researchers used a website’s native search interface or advanced search techniques within a general search engine. If authors used a general search engine, authors should declare whether steps were taken to reduce personalization bias (e.g., using “incognito” mode in a browser). Authors may choose whether to detail the websites searched within the text (i.e., Google ( http://www.google.com )), by citing the websites in the bibliography, or by listing the website with corresponding web address in supplementary material, as shown in the examples above.

Review teams may occasionally set an artificial limit to the number of items they will screen from a given search or source [ 65 ]. This is because searching web search engines and individual websites will often lead to an unmanageable number of results, the search engine itself may only display a restricted number of results (e.g., Google will only display 1000 results), or the team has a finite budget or timeline to complete the review. Thus, many systematic review teams utilizing web search engines will often pre-designate a limit to the number of results they review. If review teams choose to review a limited set of results, it should be noted in the text, along with the rationale.

Conference proceedings

Studies show that large percentages of research presented as papers and posters at conferences never make their way into the published literature, particularly if the study’s results were statistically negative [ 63 , 69 ]. Conference proceedings are often the only way to locate these studies. Including conference proceedings in a systematic review search helps minimize bias [ 70 ]. The introduction of online conference proceedings has been a boon to researchers and reduced the need to review printed abstract books. Additionally, some databases either include conference proceedings along with journal articles (i.e., Embase [ 42 ]) or contain only conference proceedings (i.e., ProceedingsFirst [ 71 ] or Directory of Published Papers [ 72 ]). Some conferences have made their abstracts available in a single database (i.e., International AIDS Society’s Abstract Archive [ 73 ]). When using these types of databases to search conference proceedings, authors can treat them as above in Item 1.

Individual conferences’ online proceedings may be password-protected for association members or conference attendees [ 74 ]. When reporting on conference proceedings searched or browsed (Table 2 ) via a conference or association’s online or print proceedings, authors must specify the conference names, the dates of conferences included, and the method used to search the proceedings (i.e., browsing print abstract books or using an online source). If the conference proceedings are searched online, authors should specify the web address(es) for the conference proceedings and the date(s) of the conferences. If the conference proceedings are published in a journal, the authors should cite the journal. If the proceedings are a standalone publication, authors may choose to cite them using the same methods used to cite a book or by providing the full information about the conference (name, location, dates, etc.) in a supplementary file.

General browsing

Authors also commonly browse print or online tables of contents, full contents of journals, or other sources that are the most likely to contain research on the topic sought. When purposefully browsing, describe any method used, the name of the journal or other source, and the time frame covered by the search, if applicable.

Report online information sources (Table 2 ) searched or browsed in the methods section and in any supplementary materials. Systematic reviews using several of these methods, or using multiple information sources for each method, may need to report their methods briefly in the methods section, but should fully report all necessary information to describe their approaches in supplementary materials.

Item 5. Citation searching

Indicate whether cited references or citing references were examined, and describe any methods used for locating cited/citing references (e.g., browsing reference lists, using a citation index, setting up email alerts for references citing included studies).

“Reference lists of included articles were manually screened to identify additional studies.” [ 75 ]

“[W]e used all shared decision making measurement instruments that were identified in Gärtner et al’s recent systematic review (Appendix A). We then performed a systematic citation search, collecting all articles that cited the original papers reporting on the development, validation, or translation of any the observational and/or self-reported shared decision making measurement instruments identified in that review. An experienced librarian (P.J.E.) searched Web of Science [Science Citation Index] and Scopus for articles published between January 2012 and February 2018.” [ 76 ]

“We [conducted] citation tracking of included studies in Web of Science Core Collection on an ongoing basis, using citation alerts in Web of Science Core Collection.” [ 77 ]

One of the most common search methods is reviewing the references or bibliographies of included studies [ 11 , 17 ]. This type of citation searching (looking for cited references) can be additive to other cited reference searching methods, such as examining bibliographies of relevant systematic reviews. In addition, researchers may choose to look for articles that cite specified studies [ 78 ]. This may include looking beyond one level forwards and backwards (e.g., examining the bibliographies of articles cited by specified articles) [ 78 ]. Looking at bibliographies of included articles or other specified articles is often conducted by examining full-text articles, but it can also be accomplished using online tools called citation indexes (Table 2 ).

The use of these methods can be complicated to describe, but the explanation should clearly state the database used, if applicable (i.e., Scopus, Google Scholar, Science Citation Index) and describe any other methods used. Authors also must cite the “base” article(s) that citation searching was performed upon, either for examining cited or citing articles (Table 2 ). If the same database is used for both a topical search as well as citation searching, describe each use separately. For manually checking the reference lists for included articles, a simple statement as in the first example is sufficient.

Report citation searching details in the methods section and in any supplementary materials.

Item 6. Contacts

Indicate whether additional studies or data were sought by contacting authors, experts, manufacturers, or others.

“We contacted representatives from the manufacturers of erythropoietin-receptor agonists (Amgen, Ortho-Biotech, Roche), corresponding or first authors of all included trials and subject-area experts for information about ongoing studies.” [ 79 ]

“We also sought data via expert requests. We requested data on the epidemiology of injecting drug use and blood-borne viruses in October, 2016, via an email distribution process and social media. This process consisted of initial emails sent to more than 2000 key experts and organisations, including contacts in the global, regional, and country offices of WHO, UNAIDS, Global Fund, and UNODC (appendix p 61). Staff in those agencies also forwarded the request to their colleagues and other relevant contacts. One member of the research team (SL) posted a request for data on Twitter, which was delivered to 5525 individual feeds (appendix p 62).” [ 80 ]

Contacting manufacturers (e.g., pharmaceutical companies), or reaching out to authors or experts directly or through organizations, is a key method to locate unpublished and ongoing studies [ 6 ]. Contacting authors or manufacturers may also be necessary when publications, conference proceedings, or clinical trials registry records do not provide the complete information needed [ 63 , 81 ]. Contacting manufacturers or regulating agencies might be required to acquire complete trial data from the clinical study reports [ 82 , 83 ]. More broad calls for evidence may also be conducted when no specific groups or individuals are targeted.

Contact methods may vary widely, depending on the context, and may include personal contact, web forms, email mailing lists, mailed letters, social media contacts, or other methods. As these strategies are inherently difficult to reproduce, researchers should attempt to give as much detail as possible on what data or information was sought, who or what group(s) provided data or information, and how the individuals or groups were identified.

Report information about contacts to solicit additional information in the methods section and in any supplementary materials. Systematic reviews using elaborate calls for evidence or making extensive use of contacts as an information source may need to report their methods briefly in the methods section, but should fully report all necessary information to describe their approaches in supplementary materials.

Item 7. Other methods

Describe any additional information sources or search methods used.

“We also searched… our personal files.” [ 84 ]

“PubMed’s related articles search was performed on all included articles.” [ 85 ]

A thorough systematic review may utilize many additional methods of locating studies beyond database searching, many of which may not be reproducible methods. A key example is searching personal files. Another is using databases’ built in tools, such as PubMed’s Related Articles feature [ 86 ] or Clarivate Analytics’ Web of Science’s Related Records feature [ 87 ], to locate relevant articles based on commonalities with a starting article. Because these tools are often proprietary and their algorithms opaque, researchers may not be able to replicate the exact results at a later date. To attempt to be as transparent as possible, researchers should both note the tool that was used and cite any articles these operations were run upon. For all “other” methods, it is still important to declare that the method was used, even if it may not be fully replicable.

Report information about any other additional information sources or search methods used in the methods section and in any supplementary materials.

Item 8. Full search strategies

Include the search strategies for each database and information source, copied and pasted exactly as run.

Database search. Methods section description . “The reproducible searches for all databases are available at DOI:10.7302/Z2VH5M1H.” [ 88 ]

Database search. One of the full search strategies from supplemental materials in online repository . “ Embase.com (692 on Jan 19, 2017) 1. 'social media'/exp OR (social NEAR/2 (media* OR medium* OR network*)):ti OR twitter:ti OR youtube:ti OR facebook:ti OR linkedin:ti OR pinterest:ti OR microblog*:ti OR blog:ti OR blogging:ti OR tweeting:ti OR 'web 2.0':ti 2. 'professionalism'/exp OR 'ethics'/exp OR 'professional standard'/de OR 'professional misconduct'/de OR ethic*:ab,ti OR unprofessional*:ab,ti OR professionalism:ab,ti OR (professional* NEAR/3 (standard* OR misconduct)):ab,ti OR ((professional OR responsib*) NEAR/3 (behavi* OR act OR conduct*)):ab,ti 3. #1 AND #2 AND [english]/lim NOT ('conference abstract':it OR 'conference paper':it) [ 88 ]

Online resources and browsing. Methods section description . “The approach to study identification from this systematic review is transparently reported in the Electronic Supplementary Material Appendix S1.” [ 89 ]

Online resources and browsing. One of the full online resource search strategies reported in supplement . “Date: 12/01/16. Portal/URL: Google. https://www.google.co.uk/webhp?hl=en . Search terms: ((Physical training) and (man or men or male or males) and (female or females or women or woman) and (military)). Notes: First 5 pages screened on title (n=50 records).” [ 89 ]

Systematic reviews and related review types rely on thorough and complex search strategies to identify literature on a given topic. The search strategies used to conduct this data gathering are essential to the transparency and reproducibility of any systematic review. Without being able to assess the quality of the search strategies used, readers are unable to assess the quality of the systematic review [ 9 , 11 , 17 ].

When space was at a premium in publications, complete reporting of search strategies was a challenge. Because it was necessary to balance the need for transparency with publication restrictions, previous PRISMA guidelines recommended including the complete search strategy from a minimum of one database searched [ 9 ]. Many systematic reviews therefore reported only the minimum necessary. However, reporting only selected search strategies can contribute to the observed irreproducibility of many systematic reviews [ 11 , 17 ].

The prior versions of PRISMA did not elaborate on methods for reporting search strategies outside of literature databases. Subsequent to its publication, many groups have begun identifying the challenges of fully documenting other types of search methods [ 90 , 91 ]. Now recommended is the explicit documentation of all of the details of all search strategies undertaken [ 91 , 92 ]. These should be reported to ensure transparency and maximum reproducibility, including searches and purposeful browsing activities undertaken in web search engines, websites, conference proceeding databases, electronic journals, and study registries.

Journal restrictions vary, but many journals now allow authors to publish supplementary materials with their manuscripts. At minimum, all search strategies, including search strategies for web search engines, websites, conference proceedings databases, electronic journals, and study registries, should be submitted as a supplement for publication. Though most supplements are appropriately accessible on journal publishers’ web sites as submitted, supplements may disappear [ 17 ]. In addition, many supplements are only available to journal subscribers [ 93 ]. Similarly, manuscripts available on public access systems like PubMed Central [ 94 ] may not have the corresponding supplemental materials properly linked. For optimal accessibility, authors should upload complete documentation to a data repository (Table 2 ), an institutional repository, or other secure and permanent online archive instead of relying on journal publication (see Table 3 for additional information).

It is important to document and report the search strategy exactly as run, typically by copying and pasting the search strategy directly as entered into the search platform. This is to ensure that information such as the fields searched, term truncation, and combinations of terms (i.e., Boolean logic or phrases) are accurately recorded. Many times, the copied and pasted version of a search strategy will also include key information such as limits (see Item 9; Table 2 ) used, databases searched within a multi-database search, and other database-specific detail that will enable more accurate reporting and greater reproducibility. This documentation must also repeat the database or resource name, database platform or web address, and other details necessary to clearly describe the resource.

Report the full search strategy in supplementary materials as described above. Describe and link to the location of the supplementary materials in the methods section.

Item 9: Limits and restrictions

Specify that no limits were used, or describe any limits or restrictions applied to a search (e.g., date or time period, language, study design) and provide justification for their use.

No limits . “We imposed no language or other restrictions on any of the searches.” [ 95 ]

Limits described without justification . “The search was limited to the English language and to human studies.” [ 96 ]

“The following search limits were then applied: randomized clinical trials (RCTs) of humans 18 years or older, systematic reviews, and meta-analyses.” [ 97 ]

Limits described with justification . “The search was limited to publications from 2000 to 2018 given that more contemporary studies included patient cohorts that are most reflective of current co-morbidities and patient characteristics as a result of the evolving obesity epidemic.” [ 98 ]

Limits described, one with justification . “Excluded publication types were comments, editorials, patient education handouts, newspaper articles, biographies, autobiographies, and case reports. All languages were included in the search result; non-English results were removed during the review process…. To improve specificity, the updated search was limited to human participants.” [ 99 ]

Many databases have features that allow searchers to quickly restrict a search using limits. What limits are available in a database are unique to both the database and the platform used to search it. Limits are dependent on the accuracy of the indexer, the timeliness of indexing, and the quality of any publisher-supplied data. For instance, using database limits to restrict searches to randomized controlled trials will only find records identified by the indexer as randomized controlled trials. Since the indexing may take 6 months or more to complete for any given article, searchers risk missing new articles when using database limits.

Using database-provided limit features should not be confused with using filters (see Item 10; Table 2 ) or inclusion criteria for the systematic review. For example, systematic review teams may choose to only include English-language randomized controlled trials. This can be done using limits, a combination of a filter (see Item 10) and screening, or screening alone. It should be clear to the reader which approach is used. For instance, in the “ Limits described, with one justification ” example above, the authors used database limits to restrict their search by publication type, but they did not use database limits to restrict by language, even though that was a component of their eligibility criteria. They also used database limits to restrict to human participants in their search update.

It is important for transparency and reproducibility that any database limits applied when running the search are reported accurately, as their use has high potential for introducing bias into a search [ 1 , 64 , 100 , 101 ]. Database limits are not recommended for use in systematic reviews, due to their fallibility [ 39 , 100 ]. If used, review teams should include a statement of justification for each use of a database limit in the methods section, the limitations section, or both [ 102 , 103 ]. In the examples above, only the last two examples provide some justification in the methods section (“to improve specificity” [ 99 ] and “contemporary studies included patient cohorts that are most reflective of current co-morbidities and patient characteristics as a result of the evolving obesity epidemic” [ 98 ]).

Report any limits or restrictions used or that no limits were used in the abstract, methods section, and in any supplementary materials, including the full search strategies (Item 8). Report the justification for any limits used within the methods section and/or in the limitations section.

Item 10. Search filters

Indicate whether published search filters were used (as originally designed or modified), and if so, cite the filter(s) used.

“For our MEDLINE search we added a highly sensitive filter for identifying randomised trials developed by the Cochrane Collaboration [38]. For Embase we used the filter for randomised trials proposed by the Scottish Intercollegiate Guidelines Network [ 104 ].” [ 105 ]

Filters are a predefined combination of search terms developed to identify references with a specific content, such as a particular type of study design (e.g., randomized controlled trials) [ 106 ], populations (e.g., the elderly), or a topic (e.g., heart failure) [ 107 ]. They often consist of a combination of subject headings, free-text terms, and publication types [ 107 ]. For systematic reviews, filters are generally recommended for use instead of limits built into databases, as discussed in Item 9, because they provide the much higher sensitivity (Table 2 ) required for a comprehensive search [ 108 ].

Any filters used as part of the search strategy should be cited, whether published in a journal article or other source. This enables readers to assess the quality of the filter(s) used, as most published search filters are validated and/or peer reviewed [ 106 , 107 ]. Many commonly used filters are published on the InterTASC Information Specialists’ Sub-Group [ 109 ], in the Cochrane Handbook [ 4 , 39 ], and through the Health Information Research Unit of McMaster University [ 110 ].

Cite any search filter used in the methods section and describe adaptations made to any filter. Include the copied and pasted details of any search filter used or adapted for use as part of the full search strategy (Item 8).

Item 11. Prior work

Indicate when search strategies from other literature reviews were adapted or reused for a substantive part or all of the search, citing the previous review(s).

“We included [search strategies] used in other systematic reviews for research design [ 111 ], setting [ 112 , 113 ], physical activity and healthy eating [ 114 , 115 , 116 ], obesity [ 111 ], tobacco use prevention [ 117 ], and alcohol misuse [ 118 ]. We also used a search [strategy] for intervention (implementation strategies) that had been employed in previous Cochrane Reviews [ 119 , 120 ], and which was originally developed based on common terms in implementation and dissemination research.” [ 121 ]

Many authors may also examine previously published search strategies to develop the search strategies for their review. Sometimes, authors adapt or reuse these searches for different systematic reviews [ 122 ]. When basing a new search strategy on a published search strategy, it is appropriate to cite the original publication(s) consulted.

Search strategies differ from filters (Item 10) because search strategies are often developed for a specific project, not necessarily designed to be repeatedly used. Filters, on the other hand, are developed with the express purpose of reuse. Filters are often objectively derived, tested, and validated, whereas most search strategies published as part of systematic review or other evidence synthesis are “best guess,” relying on the expertise of the searcher and review team [ 107 ].

As in the example above, researchers may rely on multiple prior published searches to construct a new search for a novel review. Many times, researchers will use the same searches from a published systematic review to update the existing systematic review. In either case, it is helpful to the readers to understand whether major portions of a search are being adapted or reused.

Report any prior work consulted, adapted, or reused in the methods section. Include the copied and pasted search strategies used, including portions or the entirety of any prior work used or adapted for use, in the full search strategy (Item 8).

Item 12. Updates

Report the methods used to update the search(es) (e.g., rerunning searches, email alerts).

“Ovid Auto Alerts were set up to provide weekly updates of new literature until July 09, 2012.” [ 123 ]

“ Two consecutive searches were conducted and limited by publication type and by date, first from January 1, 1990, to November 30, 2012, and again from December 1, 2012, to July 31, 2015, in an updated search…. The original search strategy was used to model the updated search from December 1, 2012, to July 31, 2015. The updated search strategy was consistent with the original search; however, changes were required in the ERIC database search because of a change in the ERIC search algorithm. Excluded publication types were identical to the initial search. To improve specificity, the updated search was limited to human participants.” [ 99 ]

The literature search is usually conducted at the initial stage of the production of a systematic review. As a consequence, the results of a search may be outdated before the review is published [ 124 , 125 , 126 ]. The last search in a review should be conducted ideally less than 6 months before publication [ 90 , 92 , 125 ]. For this reason, authors often update searches by rerunning (Table 2 ) the same search(es) or otherwise updating searches before the planned publication date. Updating searches differs from updating a systematic review, i.e., when the same or different authors or groups decide to redo a published systematic review to bring its findings up to date. If authors are updating a published systematic review, either authored by the same review team or another, Item 11 contains relevant guidance.

When reporting search updates, the extent of reporting depends on methods used and any changes that were made while updating the searches. If there are no changes in information sources and/or search syntax (Table 2 ), it is sufficient to indicate the date the last search was run in the methods section and in the supplementary materials. If there are any changes in information sources and/or search syntax, the changes should be indicated (e.g., different set of databases, changes in search syntax, date restrictions) in the methods section. Authors should explain why these changes were made. When there were changes in the search strategy syntax, the original and the updated searches should both be reported as described in Item 8.

If authors use email alerts or other methods to update searches, these methods can be briefly described by indicating the method used, the frequency of any updates, the name of the database(s) used, or other relevant information that will help readers understand how the authors conducted search updates. If deduplication methods are used as part of the search update process, these methods can be described using guidance in Item 16.

Report the methods used to update the searches in the methods section and the supplementary materials, as described above.

Item 13. Dates of searches

For each search strategy, provide the date when the last search occurred.

“A comprehensive literature search was initially run on 26 February 2017 and then rerun on 5 February 2018….” [ 127 ]

Most literature databases are regularly updated with new citations as articles are published. Citations already in the database may also be updated once new information (such as indexing terms or citing articles) is available. As an example, MEDLINE added over 900,000 indexed citations (Table 2 ) in fiscal year 2018 [ 41 ]. In addition, the information gathered by databases (such as author affiliations in MEDLINE) can change over time. Because new citations are regularly being added, systematic review guidelines recommend updating searches throughout the writing process to ensure that all relevant articles are retrieved [ 6 , 92 ].

It is necessary for authors to document the date when searches were executed, either the date the initial search was conducted, if only searched once, or the most recent date the search was rerun. This allows readers to evaluate the currency of each search and understand what literature the search could have potentially identified [ 125 ]. In addition, it supports reproducibility and updating by allowing other researchers to use date limits to view the same “slice” of the database that the original authors used or to update a systematic review by searching from the last time point searched.

Report the date of the last search of the primary information sources used in the abstract for optimal clarity for readers [ 128 ]. Report the time frame during which searches were conducted, the initial search date(s), and/or the last update search date(s) in the methods section. Report the initial and/or last update search date with each complete search strategy in the supplementary materials, as in the examples for Item 8.

Item 14. Peer review

Describe any search peer review process.

“The strategies were peer reviewed by another senior information specialist prior to execution using the PRESS Checklist [ 1 ].” [ 129 ]

Peer reviewing search strategies is an increasingly valued component of search strategy development for systematic reviews. Expert guidance recommends taking this step to help increase the robustness of the search strategy [ 6 , 74 ]. Peer reviewing (Table 2 ) searches is useful to help to guide and improve electronic search strategies. One of peer review’s main benefits is the reduction of errors [ 23 , 130 ]. Peer review may also increase the number of relevant records found for inclusion in reviews, thus improving the overall quality of the systematic review [ 131 ].

Authors should consider using the Peer Review of Electronic Search Strategies (PRESS) Guideline statement, a practice guideline for literature search peer review outlining the major components important to review and the benefits of peer reviewing searches [ 1 ]. Authors should strongly consider having the search strategy peer reviewed by an experienced searcher, information specialist, or librarian [ 1 , 131 ]. Though peer review may be conducted generally with publication of a protocol, for example, this item is designed to document search-specific peer review.

Describe the use of peer review in the methods section.

Item 15. Total records

Document the total number of records identified from each database and other information sources.

Methods section . “A total of 3251 citations were retrieved from the six databases and four grey literature websites.” [ 133 ] Flow diagram . Fig. 1 . Fig. 1 “Figure 1. PRISMA 2009 flow diagram” [ 132 ] Full size image

Recording the flow of citations through the systematic review process is a key component of the PRISMA Statement [ 9 , 35 ]. It is helpful to identify how many records (Table 2 ) were identified within each database and additional source. Readers can use this information to see whether databases or expert contacts constituted the majority of the records reviewed, for example. Knowing the number of records from each source also helps with reproducibility. If a reader tries to duplicate a search from a systematic review, one would expect to retrieve nearly the same results when limiting to the timeframe in the original review. If instead, the searcher locates a drastically different number of results than reported in the original review, this can be indicative of errors in the published search [ 23 ] or major changes to a database, both of which might be reasons to update a systematic review or view the systematic review’s results with skepticism.

Report the total number of references retrieved from all sources, including updates, in the results section. Report the total number of references from each database and information source in the supplementary materials. If space permits, report the total number of references from each database in the PRISMA flow diagram [ 35 ].

Item 16. Deduplication

Describe the processes and any software used to deduplicate records from multiple database searches and other information sources.

“Duplicates were removed by the librarians (LP, PJE), using EndNote's duplicate identification strategy and then manually.” [ 134 ]

Databases contain significant overlap in content. When searching in multiple databases and additional information sources, as is necessary for a systematic review, authors often employ a variety of techniques to reduce the number of duplicates within their results prior to screening [ 135 , 136 , 137 , 138 ]. Techniques vary in their efficacy, sensitivity, and specificity (Table 2 ) [ 136 , 138 ]. Knowing which method is used enables readers to evaluate the process and understand to what extent these techniques may have removed false positive duplicates [ 138 ]. Authors should describe and cite any software or technique used, when applicable. If duplicates were removed manually, authors should include a description.

Report any deduplication method used in the methods section. The total number of references after deduplication should be reported in the PRISMA flow diagram [ 35 ].

Part 5. Discussion and conclusions

The PRISMA-S extension is designed to be used in conjunction with PRISMA 2020 [ 35 ] and PRISMA extensions including PRISMA-P for protocols [ 36 ], PRISMA-ScR for scoping reviews [ 139 ], the PRISMA Network Meta-analyses statement [ 140 ], and PRISMA-IPD for systematic reviews using individual patient data [ 141 ]. It may also be used with other reporting guidelines that relate to systematic reviews and related review types, such as RepOrting standards for Systematic Evidence Syntheses (ROSES) [ 142 ]. It provides additional guidance for systematic review teams, information specialists, librarians, and other researchers whose work contains a literature search as a component of the research methods. Though its origins are in the biomedical fields, PRISMA-S is flexible enough to be applied in all disciplines that use method-driven literature searching. Ultimately, PRISMA-S attempts to give systematic review teams a framework that helps ensure transparency and maximum reproducibility of the search component of their review.

PRISMA-S is intended to capture and provide specific guidance for reporting the most common methods used in systematic reviews today. As new methods and information sources are adopted, authors may need to adjust their reporting methods to accommodate new processes. Currently, PRISMA-S does not address using text mining or text analysis methods to create the search, for example, though this is an increasingly common way for information specialists to develop robust and objective search strategies [ 143 , 144 , 145 ]. Likewise, PRISMA-S does not require that decisions about the rationale behind choices in search terms and search construction be recorded, though this provides readers a great deal of insight. In the future, methods and rationales used to create search strategies may become more important for reproducibility.

PRISMA-S offers extensive guidance for many different types of information source and methods, many of them not described in detail in other reporting guidelines relating to literature searching. This includes detailed information on reporting study registry searches, web searches, multi-database searches, and updates. PRISMA-S can help authors report all components of their search, hopefully making the reporting process easier. As a note, PRISMA-S provides guidance on transparent reporting to authors and is not intended as a tool to either guide conduct of a systematic review or to evaluate the quality of a search or a systematic review.

The PRISMA-S checklist is available for download in Word and PDF formats from the PRISMA Statement web site [ 37 ]. The checklist should be used together with its Explanation & Elaboration documentation to provide authors with guidance for the complexities of different types of information sources and methods.

We intend to work with systematic review and information specialist organizations to broadly disseminate PRISMA-S and encourage its adoption by journals. In addition, we plan to host a series of webinars discussing how to use PRISMA-S most effectively. These webinars will also be available for later viewing and will serve as a community resource.

We hope that journal editors will recommend authors of systematic reviews and other related reviews to use PRISMA-S and submit a PRISMA-S checklist with their manuscripts. We also hope that journal editors will encourage more stringent peer review of systematic review searches to ensure greater transparency and reproducibility within the review literature.

Availability of data and materials

All data is available via the PRISMA-S PRISMA Search Reporting Extension OSF site ( https://doi.org/10.17605/OSF.IO/YGN9W ) [ 32 ]. This includes all data relating to item development, survey instruments, data from the Delphi surveys, and consent documents.

Abbreviations

Digital object identifier

Peer Review of Electronic Search Strategies

Preferred Reporting Items for Systematic reviews and Meta-Analyses

PRISMA for individual patient data

PRISMA for systematic review protocols

PRISMA for scoping reviews

RepOrting standards for Systematic Evidence Syntheses

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Acknowledgements

We would like to thank all of the members of the PRISMA-S Group, which is comprised of participants in the Delphi process, consensus conference, or both. PRISMA-S Group members include Heather Blunt (Dartmouth College), Tara Brigham (Mayo Clinic in Florida), Steven Chang (La Trobe University), Justin Clark (Bond University), Aislinn Conway (BORN Ontario and CHEO Research Institute), Rachel Couban (McMaster University), Shelley de Kock (Kleijnen Systematic Reviews Ltd), Kelly Farrah (Canadian Agency for Drugs and Technologies in Health (CADTH)), Paul Fehrmann (Kent State University), Margaret Foster (Texas A & M University), Susan A. Fowler (Washington University in St. Louis), Julie Glanville (University of York), Elizabeth Harris (La Trobe University), Lilian Hoffecker (University of Colorado Denver), Jaana Isojarvi (Tampere University), David Kaunelis (Canadian Agency for Drugs and Technologies in Health (CADTH)), Hans Ket (VU Amsterdam), Paul Levay (National Institute for Health and Care Excellence (NICE)), Jennifer Lyon, Jessie McGowan (uOttawa), M. Hassan Murad (Mayo Clinic), Joey Nicholson (NYU Langone Health), Virginia Pannabecker (Virginia Tech), Robin Paynter (VA Portland Health Care System), Rachel Pinotti (Icahn School of Medicine at Mount Sinai), Amanda Ross-White (Queens University), Margaret Sampson (CHEO), Tracy Shields (Naval Medical Center Portsmouth), Adrienne Stevens (Ottawa Hospital Research Institute), Anthea Sutton (University of Sheffield), Elizabeth Weinfurter (University of Minnesota), Kath Wright (University of York), and Sarah Young (Carnegie Mellon University). We would also like to thank Kate Nyhan (Yale University), Katharina Gronostay (IQWiG), the many others who contributed to the PRISMA-S project anonymously or as draft reviewers, and our peer reviewers. We would like to give special thanks to the late Douglas G. Altman (D.G.A.; University of Oxford) for his support and guidance, and the co-chairs of the Medical Library Association’s Systematic Reviews SIG in 2016, Margaret Foster (Texas A & M University) and Susan Fowler (Washington University in St. Louis), for allowing us to use one of their meeting times for the consensus conference.

Melissa Rethlefsen was funded in part by the University of Utah’s Center for Clinical and Translational Science under the National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1TR002538 in 2017–2018 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Shona Kirtley was funded by the Cancer Research UK (grant C49297/A27294). The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The views expressed are those of the authors and not necessarily those of the Cancer Research UK.

Matthew Page is supported by an Australian Research Council Discovery Early Career Researcher Award (DE200101618).

David Moher is supported by a University Research Chair, University of Ottawa, Ottawa, Canada.

The consensus conference was sponsored by the Systematic Reviews SIG of the Medical Library Association. There was no specific funding associated with this event.

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• Heather Blunt
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M.L.R. conceived and designed the study, conducted the thematic and quantitative analyses, curated the data, drafted the manuscript, and reviewed and edited the manuscript. M.L.R. is the guarantor. J.B.K. and S.K. contributed to the design of the study, developed the literature search strategies, contributed to the thematic content analyses, drafted a portion of the Elaboration & Explanation, and reviewed and edited the manuscript. J.B.K. developed the survey instrument. M.L.R., J.B.K., and S.K. hosted and organized the consensus conference. S.W. and A.P.A. contributed to the thematic content analysis, drafted a portion of the Elaboration & Explanation, and reviewed and edited the manuscript. S.W. supervised the draft revision documentation. D.M. helped conceive and design the study. M.J.P. provided substantive review and editing of the checklist, Explanation & Elaboration, and final manuscript. The author (s) read and approved the final manuscript.

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Correspondence to Melissa L. Rethlefsen .

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Rethlefsen, M.L., Kirtley, S., Waffenschmidt, S. et al. PRISMA-S: an extension to the PRISMA Statement for Reporting Literature Searches in Systematic Reviews. Syst Rev 10 , 39 (2021). https://doi.org/10.1186/s13643-020-01542-z

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Systematic literature review of real-world evidence for treatments in HR+/HER2- second-line LABC/mBC after first-line treatment with CDK4/6i

• Veronique Lambert   ORCID: orcid.org/0000-0002-6984-0038 1 ,
• Sarah Kane   ORCID: orcid.org/0009-0006-9341-4836 2   na1 ,
• Belal Howidi   ORCID: orcid.org/0000-0002-1166-7631 2   na1 ,
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• David Chandiwana   ORCID: orcid.org/0009-0002-3499-2565 3 ,
• Yan Wu   ORCID: orcid.org/0009-0008-3348-9232 1 ,
• Michelle Edwards   ORCID: orcid.org/0009-0001-4292-3140 3 &
• Imtiaz A. Samjoo   ORCID: orcid.org/0000-0003-1415-8055 2   na1  

BMC Cancer volume  24 , Article number:  631 ( 2024 ) Cite this article

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Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) are currently recommended by the National Comprehensive Cancer Network (NCCN) guidelines and the European Society for Medical Oncology (ESMO) guidelines as the first-line (1 L) treatment for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, locally advanced/metastatic breast cancer (HR+/HER2- LABC/mBC). Although there are many treatment options, there is no clear standard of care for patients following 1 L CDK4/6i. Understanding the real-world effectiveness of subsequent therapies may help to identify an unmet need in this patient population. This systematic literature review qualitatively synthesized effectiveness and safety outcomes for treatments received in the real-world setting after 1 L CDK4/6i therapy in patients with HR+/ HER2- LABC/mBC.

MEDLINE®, Embase, and Cochrane were searched using the Ovid® platform for real-world evidence studies published between 2015 and 2022. Grey literature was searched to identify relevant conference abstracts published from 2019 to 2022. The review was conducted in accordance with PRISMA guidelines (PROSPERO registration: CRD42023383914). Data were qualitatively synthesized and weighted average median real-world progression-free survival (rwPFS) was calculated for NCCN/ESMO-recommended post-1 L CDK4/6i treatment regimens.

Twenty records (9 full-text articles and 11 conference abstracts) encompassing 18 unique studies met the eligibility criteria and reported outcomes for second-line (2 L) treatments after 1 L CDK4/6i; no studies reported disaggregated outcomes in the third-line setting or beyond. Sixteen studies included NCCN/ESMO guideline-recommended treatments with the majority evaluating endocrine-based therapy; five studies on single-agent ET, six studies on mammalian target of rapamycin inhibitors (mTORi) ± ET, and three studies with a mix of ET and/or mTORi. Chemotherapy outcomes were reported in 11 studies. The most assessed outcome was median rwPFS; the weighted average median rwPFS was calculated as 3.9 months (3.3-6.0 months) for single-agent ET, 3.6 months (2.5–4.9 months) for mTORi ± ET, 3.7 months for a mix of ET and/or mTORi (3.0–4.0 months), and 6.1 months (3.7–9.7 months) for chemotherapy. Very few studies reported other effectiveness outcomes and only two studies reported safety outcomes. Most studies had heterogeneity in patient- and disease-related characteristics.

Conclusions

The real-world effectiveness of current 2 L treatments post-1 L CDK4/6i are suboptimal, highlighting an unmet need for this patient population.

Peer Review reports

Introduction

Breast cancer (BC) is the most diagnosed form of cancer in women with an estimated 2.3 million new cases diagnosed worldwide each year [ 1 ]. BC is the second leading cause of cancer death, accounting for 685,000 deaths worldwide per year [ 2 ]. By 2040, the global burden associated with BC is expected to surpass three million new cases and one million deaths annually (due to population growth and aging) [ 3 ]. Numerous factors contribute to global disparities in BC-related mortality rates, including delayed diagnosis, resulting in a high number of BC cases that have progressed to locally advanced BC (LABC) or metastatic BC (mBC) [ 4 , 5 , 6 ]. In the United States (US), the five-year survival rate for patients who progress to mBC is three times lower (31%) than the overall five-year survival rate for all stages (91%) [ 6 , 7 ].

Hormone receptor (HR) positive (i.e., estrogen receptor and/or progesterone receptor positive) coupled with negative human epidermal growth factor 2 (HER2) expression is the most common subtype of BC, accounting for ∼ 60–70% of all BC cases [ 8 , 9 ]. Historically, endocrine therapy (ET) through estrogen receptor modulation and/or estrogen deprivation has been the standard of care for first-line (1 L) treatment of HR-positive/HER2-negative (HR+/HER2-) mBC [ 10 ]. However, with the approval of the cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) palbociclib in combination with the aromatase inhibitor (AI) letrozole in 2015 by the US Food and Drug Administration (FDA), 1 L treatment practice patterns have evolved such that CDK4/6i (either in combination with AIs or with fulvestrant) are currently considered the standard of care [ 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. Other CDK4/6i (ribociclib and abemaciclib) in combination with ET are approved for the treatment of HR+/HER2- LABC/mBC; 1 L use of ribociclib in combination with an AI was granted FDA approval in March 2017 for postmenopausal women (with expanded approval in July 2018 for pre/perimenopausal women and for use in 1 L with fulvestrant for patients with disease progression on ET as well as for postmenopausal women), and abemaciclib in combination with fulvestrant was granted FDA approval in September 2017 for patients with disease progression following ET and as monotherapy in cases where disease progression occurs following ET and prior chemotherapy in mBC (with expanded approval in February 2018 for use in 1 L in combination with an AI for postmenopausal women) [ 18 , 19 , 20 , 21 ].

Clinical trials investigating the addition of CDK4/6i to ET have demonstrated significant improvement in progression-free survival (PFS) and significant (ribociclib) or numerical (palbociclib and abemaciclib) improvement in overall survival (OS) compared to ET alone in patients with HR+/HER2- advanced or mBC, making this combination treatment the recommended option in the 1 L setting [ 22 , 23 , 24 , 25 , 26 , 27 ]. However, disease progression occurs in a significant portion of patients after 1 L CDK4/6i treatment [ 28 ] and the optimal treatment sequence after progression on CDK4/6i remains unclear [ 29 ]. At the time of this review (literature search conducted December 14, 2022), guidelines by the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO) recommend various options for the treatment of HR+/HER2- advanced BC in the second-line (2 L) setting, including fulvestrant monotherapy, mammalian target of rapamycin inhibitors (mTORi; e.g., everolimus) ± ET, alpelisib + fulvestrant (if phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha mutation positive [PIK3CA-m+]), poly-ADP ribose polymerase inhibitors (PARPi) including olaparib or talazoparib (if breast cancer gene/partner and localizer of BRCA2 positive [BRCA/PALB2m+]), and chemotherapy (in cases when a visceral crisis is present) [ 15 , 16 ]. CDK4/6i can also be used in 2 L [ 16 , 30 ]; however, limited data are available to support CDK4/6i rechallenge after its use in the 1 L setting [ 15 ]. Depending on treatments used in the 1 L and 2 L settings, treatment in the third-line setting is individualized based on the patient’s response to prior treatments, tumor load, duration of response, and patient preference [ 9 , 15 ]. Understanding subsequent treatments after 1 L CDK4/6i, and their associated effectiveness, is an important focus in BC research.

Treatment options for HR+/HER2- LABC/mBC continue to evolve, with ongoing research in both clinical trials and in the real-world setting. Real-world evidence (RWE) offers important insights into novel therapeutic regimens and the effectiveness of treatments for HR+/HER2- LABC/mBC. The effectiveness of the current treatment options following 1 L CDK4/6i therapy in the real-world setting highlights the unmet need in this patient population and may help to drive further research and drug development. In this study, we conducted a systematic literature review (SLR) to qualitatively summarize the effectiveness and safety of treatment regimens in the real-world setting after 1 L treatment with CDK4/6i in patients with HR+/HER2- LABC/mBC.

Literature search

An SLR was performed in accordance with the Cochrane Handbook for Systematic Reviews of Interventions [ 31 ] and reported in alignment with the Preferred Reporting Items for Systematic Literature Reviews and Meta-Analyses (PRISMA) statement [ 32 ] to identify all RWE studies assessing the effectiveness and safety of treatments used for patients with HR+/HER2- LABC/mBC following 1 L CDK4/6i therapy and received subsequent treatment in 2 L and beyond (2 L+). The Ovid® platform was used to search MEDLINE® (including Epub Ahead of Print and In-Process, In-Data-Review & Other Non-Indexed Citations), Ovid MEDLINE® Daily, Embase, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews by an experienced medical information specialist. The MEDLINE® search strategy was peer-reviewed independently by a senior medical information specialist before execution using the Peer Review of Electronic Search Strategies (PRESS) checklist [ 33 ]. Searches were conducted on December 14, 2022. The review protocol was developed a priori and registered with the International Prospective Register of Systematic Review (PROSPERO; CRD42023383914) which outlined the population, intervention, comparator, outcome, and study design (PICOS) criteria and methodology used to conduct the review (Table  1 ).

Search strategies utilized a combination of controlled vocabulary (e.g., “HER2 Breast Cancer” or “HR Breast Cancer”) and keywords (e.g., “Retrospective studies”). Vocabulary and syntax were adjusted across databases. Published and validated filters were used to select for study design and were supplemented using additional medical subject headings (MeSH) terms and keywords to select for RWE and nonrandomized studies [ 34 ]. No language restrictions were included in the search strategy. Animal-only and opinion pieces were removed from the results. The search was limited to studies published between January 2015 and December 2022 to reflect the time at which FDA approval was granted for the first CDK4/6i agent (palbociclib) in combination with AI for the treatment of LABC/mBC [ 35 ]. Further search details are presented in Supplementary Material 1 .

Grey literature sources were also searched to identify relevant abstracts and posters published from January 2019 to December 2022 for prespecified relevant conferences including ESMO, San Antonio Breast Cancer Symposium (SABCS), American Society of Clinical Oncology (ASCO), the International Society for Pharmacoeconomics and Outcomes Research (ISPOR US), and the American Association for Cancer Research (AACR). A search of ClinicalTrials.gov was conducted to validate the findings from the database and grey literature searches.

Study selection, data extraction & weighted average calculation

Studies were screened for inclusion using DistillerSR Version 2.35 and 2.41 (DistillerSR Inc. 2021, Ottawa, Canada) by two independent reviewers based on the prespecified PICOS criteria (Table  1 ). A third reviewer was consulted to resolve any discrepancies during the screening process. Studies were included if they reported RWE on patients aged ≥ 18 years with HR+/HER2- LABC/mBC who received 1 L CDK4/6i treatment and received subsequent treatment in 2 L+. Studies were excluded if they reported the results of clinical trials (i.e., non-RWE), were published in any language other than English, and/or were published prior to 2015 (or prior to 2019 for conference abstracts and posters). For studies that met the eligibility criteria, data relating to study design and methodology, details of interventions, patient eligibility criteria and baseline characteristics, and outcome measures such as efficacy, safety, tolerability, and patient-reported outcomes (PROs), were extracted (as available) using a Microsoft Excel®-based data extraction form (Microsoft Corporation, WA, USA). Data extraction was performed by a single reviewer and was confirmed by a second reviewer. Multiple publications identified for the same RWE study, patient population, and setting that reported data for the same intervention were linked and extracted as a single publication. Weighted average median real-world progression-free survival (rwPFS) values were calculated by considering the contribution to the median rwPFS of each study proportional to its respective sample size. These weighted values were then used to compute the overall median rwPFS estimate.

Quality assessment

The Newcastle-Ottawa scale (NOS) for nonrandomized (cohort) studies was used to assess the risk of bias for published, full-text studies [ 36 ]. The NOS allocates a maximum of nine points for the least risk of bias across three domains: (1) Formation of study groups (four points), (2) Comparability between study groups (two points), (3) Outcome ascertainment (three points). NOS scores can be categorized in three groups: very high risk of bias (0 to 3 points), high risk of bias (4 to 6), and low risk of bias (7 to 9) [ 37 ]. Risk of bias assessment was performed by one reviewer and validated by a second independent reviewer to verify accuracy. Due to limited methodological data by which to assess study quality, risk of bias assessment was not performed on conference abstracts or posters. An amendment to the PROSPERO record (CRD42023383914) for this study was submitted in relation to the quality assessment method (specifying usage of the NOS).

The database search identified 3,377 records; after removal of duplicates, 2,759 were screened at the title and abstract stage of which 2,553 were excluded. Out of the 206 reports retrieved and assessed for eligibility, an additional 187 records were excluded after full-text review; most of these studies were excluded for having patients with mixed lines of CDK4/6i treatment (i.e., did not receive CDK4/6i exclusively in 1 L) (Fig.  1 and Table S1 ). The grey literature search identified 753 records which were assessed for eligibility; of which 752 were excluded mainly due to the population not meeting the eligibility criteria (Fig.  1 ). In total, the literature searches identified 20 records (9 published full-text articles and 11 conference abstracts/posters) representing 18 unique RWE studies that met the inclusion criteria. The NOS quality scores for the included full-text articles are provided in Table S2 . The scores ranged from four to six points (out of a total score of nine) and the median score was five, indicating that all the studies suffered from a high risk of bias [ 37 ].

Most studies were retrospective analyses of chart reviews or medical registries, and all studies were published between 2017 and 2022 (Table S3 ). Nearly half of the RWE studies (8 out of 18 studies) were conducted in the US [ 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ], while the remaining studies included sites in Canada, China, Germany, Italy, Japan, and the United Kingdom [ 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ]. Sample sizes ranged from as few as 4 to as many as 839 patients across included studies, with patient age ranging from 26 to 86 years old.

Although treatment characteristics in the 1 L setting were not the focus of the present review, these details are captured in Table S3 . Briefly, several RWE studies reported 1 L CDK4/6i use in combination with ET (8 out of 18 studies) or as monotherapy (2 out of 18 studies) (Table S3 ). Treatments used in combination with 1 L CDK4/6i included letrozole, fulvestrant, exemestane, and anastrozole. Where reported (4 out of 18 studies), palbociclib was the most common 1 L CDK4/6i treatment. Many studies (8 out of 18 studies) did not report which specific CDK4/6i treatment(s) were used in 1 L or if its administration was in combination or monotherapy.

Characteristics of treatments after 1 L CDK4/6i therapy

Across all studies included in this review, effectiveness and safety data were only available for treatments administered in the 2 L setting after 1 L CDK4/6i treatment. No studies were identified that reported outcomes for patients treated in the third-line setting or beyond after 1 L CDK4/6i treatment. All 18 studies reported effectiveness outcomes in 2 L, with only two of these studies also describing 2 L safety outcomes. The distribution of outcomes reported in these studies is provided in Table S4 . Studies varied in their reporting of outcomes for 2 L treatments; some studies reported outcomes for a group of 2 L treatments while others described independent outcomes for specific 2 L treatments (i.e., everolimus, fulvestrant, or chemotherapy agents such as eribulin mesylate) [ 42 , 45 , 50 , 54 , 55 ]. Due to the heterogeneity in treatment classes reported in these studies, this data was categorized (as described below) to align with the guidelines provided by NCCN and ESMO [ 15 , 16 ]. The treatment class categorizations for the purpose of this review are: single-agent ET (patients who exclusively received a single-agent ET after 1 L CDK4/6i treatment), mTORi ± ET (patients who exclusively received an mTORi with or without ET after 1 L CDK4/6i treatment), mix of ET and/or mTORi (patients who may have received only ET, only mTORi, and/or both treatments but the studies in this group lacked sufficient information to categorize these patients in the “single-agent ET” or “mTOR ± ET” categories), and chemotherapy (patients who exclusively received chemotherapy after 1 L CDK4/6i treatment). Despite ESMO and NCCN guidelines indicating that limited evidence exists to support rechallenge with CDK4/6i after 1 L CDK4/6i treatment [ 15 , 16 ], two studies reported outcomes for this treatment approach. Data for such patients were categorized as “ CDK4/6i ± ET ” as it was unclear how many patients receiving CDK4/6i rechallenge received concurrent ET. All other patient groups that lacked sufficient information or did not report outcome/safety data independently (i.e., grouped patients with mixed treatments) to categorize as one of the treatment classes described above were grouped as “ other ”.

The majority of studies reported effectiveness outcomes for endocrine-based therapy after 1 L CDK4/6i treatment; five studies for single-agent ET, six studies for mTORi ± ET, and three studies for a mix of ET and/or mTORi (Fig.  2 ). Eleven studies reported effectiveness outcomes for chemotherapy after 1 L CDK4/6i treatment, and only two studies reported effectiveness outcomes for CDK4/6i rechallenge ± ET. Eight studies that described effectiveness outcomes were grouped into the “other” category. Safety data was only reported in two studies: one study evaluating the chemotherapy agent eribulin mesylate and one evaluating the mTORi everolimus.

Effectiveness outcomes

Real-world progression-free survival

Median rwPFS was described in 13 studies (Tables  2 and Table S5 ). Across the 13 studies, the median rwPFS ranged from 2.5 months [ 49 ] to 17.3 months [ 39 ]. Out of the 13 studies reporting median rwPFS, 10 studies reported median rwPFS for a 2 L treatment recommended by ESMO and NCCN guidelines, which ranged from 2.5 months [ 49 ] to 9.7 months [ 45 ].

Weighted average median rwPFS was calculated for 2 L treatments recommended by both ESMO and NCCN guidelines (Fig.  3 ). The weighted average median rwPFS for single-agent ET was 3.9 months ( n  = 92 total patients) and was derived using data from two studies reporting median rwPFS values of 3.3 months ( n  = 70) [ 38 ] and 6.0 months ( n  = 22) [ 40 ]. For one study ( n  = 7) that reported outcomes for single agent ET, median rwPFS was not reached during the follow-up period; as such, this study was excluded from the weighted average median rwPFS calculation [ 49 ].

The weighted average median rwPFS for mTORi ± ET was 3.6 months ( n  = 128 total patients) and was derived based on data from 3 studies with median rwPFS ranging from 2.5 months ( n  = 4) [ 49 ] to 4.9 months ( n  = 25) [ 54 ] (Fig.  3 ). For patients who received a mix of ET and/or mTORi but could not be classified into the single-agent ET or mTORi ± ET treatment classes, the weighted average median rwPFS was calculated to be 3.7 months ( n  = 17 total patients). This was calculated based on data from two studies reporting median rwPFS values of 3.0 months ( n  = 5) [ 46 ] and 4.0 months ( n  = 12) [ 49 ]. Notably, one study of patients receiving ET and/or everolimus reported a median rwPFS duration of 3.0 months; however, this study was excluded from the weighted average median rwPFS calculation for the ET and/or mTORi class as the sample size was not reported [ 53 ].

The weighted average median rwPFS for chemotherapy was 6.1 months ( n  = 499 total patients), calculated using data from 7 studies reporting median rwPFS values ranging from 3.7 months ( n  = 249) [ 38 ] to 9.7 months ( n  = 121) [ 45 ] (Fig.  3 ). One study with a median rwPFS duration of 5.6 months was not included in the weighted average median rwPFS calculation as the study did not report the sample size [ 53 ]. A second study was excluded from the calculation since the reported median rwPFS was not reached during the study period ( n  = 7) [ 41 ].

Although 2 L CDK4/6i ± ET rechallenge lacks sufficient information to support recommendation by ESMO and NCCN guidelines, the limited data currently available for this treatment have shown promising results. Briefly, two studies reported median rwPFS for CDK4/6i ± ET with values of 8.3 months ( n  = 302) [ 38 ] and 17.3 months ( n  = 165) (Table  2 ) [ 39 ]. The remaining median rwPFS studies reported data for patients classified as “Other” (Table S5 ). The “Other” category included median rwPFS outcomes from seven studies, and included a myriad of treatments (e.g., ET, mTOR + ET, chemotherapy, CDK4/6i + ET, alpelisib + fulvestrant, chidamide + ET) for which disaggregated median rwPFS values were not reported.

Overall survival

Median OS for 2 L treatment was reported in only three studies (Table  2 ) [ 38 , 42 , 43 ]. Across the three studies, the 2 L median OS ranged from 5.2 months ( n  = 3) [ 43 ] to 35.7 months ( n  = 302) [ 38 ]. Due to the lack of OS data in most of the studies, weighted averages could not be calculated. No median OS data was reported for the single-agent ET treatment class whereas two studies reported median OS for the mTORi ± ET treatment class, ranging from 5.2 months ( n  = 3) [ 43 ] to 21.8 months ( n  = 54) [ 42 ]. One study reported 2 L median OS of 24.8 months for a single patient treated with chemotherapy [ 43 ]. The median OS data in the CDK4/6i ± ET rechallenge group was 35.7 months ( n  = 302) [ 38 ].

Patient mortality was reported in three studies [ 43 , 44 , 45 ]. No studies reported mortality for the single-agent ET treatment class and only one study reported this outcome for the mTORi ± ET treatment class, where 100% of patients died ( n  = 3) as a result of rapid disease progression [ 43 ]. For the chemotherapy class, one study reported mortality for one patient receiving 2 L capecitabine [ 43 ]. An additional study reported eight deaths (21.7%) following 1 L CDK4/6i treatment; however, this study did not disclose the 2 L treatments administered to these patients [ 44 ].

Other clinical endpoints

The studies included limited information on additional clinical endpoints; two studies reported on time-to-discontinuation (TTD), two reported on duration of response (DOR), and one each on time-to-next-treatment (TTNT), time-to-progression (TTP), objective response rate (ORR), clinical benefit rate (CBR), and stable disease (Tables  2 and Table S5 ).

Safety, tolerability, and patient-reported outcomes

Safety and tolerability data were reported in two studies [ 40 , 45 ]. One study investigating 2 L administration of the chemotherapy agent eribulin mesylate reported 27 patients (22.3%) with neutropenia, 3 patients (2.5%) with febrile neutropenia, 10 patients (8.3%) with peripheral neuropathy, and 14 patients (11.6%) with diarrhea [ 45 ]. Of these, neutropenia of grade 3–4 severity occurred in 9 patients (33.3%) [ 45 ]. A total of 55 patients (45.5%) discontinued eribulin mesylate treatment; 1 patient (0.83%) discontinued treatment due to adverse events [ 45 ]. Another study reported that 5 out of the 22 patients receiving the mTORi everolimus combined with ET in 2 L (22.7%) discontinued treatment due to toxicity [ 40 ]. PROs were not reported in any of the studies included in the SLR.

The objective of this study was to summarize the existing RWE on the effectiveness and safety of therapies for patients with HR+/HER2- LABC/mBC after 1 L CDK4/6i treatment. We identified 18 unique studies reporting specifically on 2 L treatment regimens after 1 L CDK4/6i treatment. The weighted average median rwPFS for NCCN- and ESMO- guideline recommended 2 L treatments ranged from 3.6 to 3.9 months for ET-based treatments and was 6.1 months when including chemotherapy-based regimens. Treatment selection following 1 L CDK4/6i therapy remains challenging primarily due to the suboptimal effectiveness or significant toxicities (e.g., chemotherapy) associated with currently available options [ 56 ]. These results highlight that currently available 2 L treatments for patients with HR+/HER2- LABC/mBC who have received 1 L CDK4/6i are suboptimal, as evidenced by the brief median rwPFS duration associated with ET-based treatments, or notable side effects and toxicity linked to chemotherapy. This conclusion is aligned with a recent review highlighting the limited effectiveness of treatment options for HR+/HER2- LABC/mBC patients post-CDK4/6i treatment [ 56 , 57 ]. Registrational trials which have also shed light on the short median PFS of 2–3 months achieved by ET (i.e., fulvestrant) after 1 L CDK4/6i therapy emphasize the need to develop improved treatment strategies aimed at prolonging the duration of effective ET-based treatment [ 56 ].

The results of this review reveal a paucity of additional real-world effectiveness and safety evidence after 1 L CDK4/6i treatment in HR+/HER2- LABC/mBC. OS and DOR were only reported in two studies while other clinical endpoints (i.e., TTD, TTNT, TTP, ORR, CBR, and stable disease) were only reported in one study each. Similarly, safety and tolerability data were only reported in two studies each, and PROs were not reported in any study. This hindered our ability to provide a comprehensive assessment of real-world treatment effectiveness and safety following 1 L CDK4/6i treatment. The limited evidence may be due to the relatively short period of time that has elapsed since CDK4/6i first received US FDA approval for 1 L treatment of HR+/HER2- LABC/mBC (2015) [ 35 ]. As such, almost half of our evidence was informed by conference abstracts. Similarly, no real-world studies were identified in our review that reported outcomes for treatments in the third- or later-lines of therapy after 1 L CDK4/6i treatment. The lack of data in this patient population highlights a significant gap which limits our understanding of the effectiveness and safety for patients receiving later lines of therapy. As more patients receive CDK4/6i therapy in the 1 L setting, the number of patients requiring subsequent lines of therapy will continue to grow. Addressing this data gap over time will be critical to improve outcomes for patients with HR+/HER2- LABC/mBC following 1 L CDK4/6i therapy.

There are several strengths of this study, including adherence to the guidelines outlined in the Cochrane Handbook to ensure a standardized and reliable approach to the SLR [ 58 ] and reporting of the SLR following PRISMA guidelines to ensure transparency and reproducibility [ 59 ]. Furthermore, the inclusion of only RWE studies allowed us to assess the effectiveness of current standard of care treatments outside of a controlled environment and enabled us to identify an unmet need in this patient population.

This study had some notable limitations, including the lack of safety and additional effectiveness outcomes reported. In addition, the dearth of studies reporting PROs is a limitation, as PROs provide valuable insight into the patient experience and are an important aspect of assessing the impact of 2 L treatments on patients’ quality of life. The studies included in this review also lacked consistent reporting of clinical characteristics (e.g., menopausal status, sites of metastasis, prior surgery) making it challenging to draw comprehensive conclusions or comparisons based on these factors across the studies. Taken together, there exists an important gap in our understanding of the long-term management of patients with HR+/HER2- LABC/mBC. Additionally, the effectiveness results reported in our evidence base were informed by small sample sizes; many of the included studies reported median rwPFS based on less than 30 patients [ 39 , 40 , 41 , 46 , 49 , 51 , 60 ], with two studies not reporting the sample size at all [ 47 , 53 ]. This may impact the generalizability and robustness of the results. Relatedly, the SLR database search was conducted in December 2022; as such, novel agents (e.g., elacestrant and capivasertib + fulvestrant) that have since received FDA approval for the treatment of HR+/HER2- LABC/mBC may impact current 2 L rwPFS outcomes [ 61 , 62 ]. Finally, relative to the number of peer-reviewed full-text articles, this SLR identified eight abstracts and one poster presentation, comprising half (50%) of the included unique studies. As conference abstracts are inherently limited by how much content that can be described due to word limit constraints, this likely had implications on the present synthesis whereby we identified a dearth of real-world effectiveness outcomes in patients with HR+/HER2- LABC/mBC treated with 1 L CDK4/6i therapy.

Future research in this area should aim to address the limitations of the current literature and provide a more comprehensive understanding of optimal sequencing of effective and safe treatment for patients following 1 L CDK4/6i therapy. Specifically, future studies should strive to report robust data related to effectiveness, safety, and PROs for patients receiving 2 L treatment after 1 L CDK4/6i therapy. Future studies should also aim to understand the mechanism underlying CDK4/6i resistance. Addressing these gaps in knowledge may improve the long-term real-world management of patients with HR+/HER2- LABC/mBC. A future update of this synthesis may serve to capture a wider breadth of full-text, peer-reviewed articles to gain a more robust understanding of the safety, effectiveness, and real-world treatment patterns for patients with HR+/HER2- LABC/mBC. This SLR underscores the necessity for ongoing investigation and the development of innovative therapeutic approaches to address these gaps and improve patient outcomes.

This SLR qualitatively summarized the existing real-world effectiveness data for patients with HR+/HER2- LABC/mBC after 1 L CDK4/6i treatment. Results of this study highlight the limited available data and the suboptimal effectiveness of treatments employed in the 2 L setting and underscore the unmet need in this patient population. Additional studies reporting effectiveness and safety outcomes, in addition to PROs, for this patient population are necessary and should be the focus of future research.

PRISMA flow diagram. *Two included conference abstracts reported the same information as already included full-text reports, hence both conference abstracts were not identified as unique. Abbreviations: 1 L = first-line; AACR = American Association of Cancer Research; ASCO = American Society of Clinical Oncology; CDK4/6i = cyclin-dependent kinase 4/6 inhibitor; ESMO = European Society for Medical Oncology; ISPOR = Professional Society for Health Economics and Outcomes Research; n = number of studies; NMA = network meta-analysis; pts = participants; SABCS = San Antonio Breast Cancer Symposium; SLR = systematic literature review.

Number of studies reporting effectiveness outcomes exclusively for each treatment class. *Studies that lack sufficient information on effectiveness outcomes to classify based on the treatment classes outlined in the legend above. Abbreviations: CDK4/6i = cyclin-dependent kinase 4/6 inhibitor; ET = endocrine therapy; mTORi = mammalian target of rapamycin inhibitor.

Weighted average median rwPFS for 2 L treatments (recommended in ESMO/NCCN guidelines) after 1 L CDK4/6i treatment. Circular dot represents weighted average median across studies. Horizontal bars represent the range of values reported in these studies. Abbreviations: CDK4/6i = cyclin-dependent kinase 4/6 inhibitor; ESMO = European Society for Medical Oncology; ET = endocrine therapy, mTORi = mammalian target of rapamycin inhibitor; n = number of patients; NCCN = National Comprehensive Cancer Network; rwPFS = real-world progression-free survival.

Data availability

All data generated or analyzed during this study are included in this published article [and its supplementary information files]. This study is registered with PROSPERO (CRD42023383914).

Abbreviations

Second-line

Second-line treatment setting and beyond

American Association of Cancer Research

Aromatase inhibitor

American Society of Clinical Oncology

• Breast cancer

breast cancer gene/partner and localizer of BRCA2 positive

Clinical benefit rate

Cyclin-dependent kinase 4/6 inhibitor

Complete response

Duration of response

European Society for Medical Oncology

Food and Drug Administration

Human epidermal growth factor receptor 2

Human epidermal growth factor receptor 2 negative

Hormone receptor

Hormone receptor positive

Professional Society for Health Economics and Outcomes Research

Locally advanced breast cancer

Metastatic breast cancer

Medical Literature Analysis and Retrieval System Online

Medical subject headings

Mammalian target of rapamycin inhibitor

National Comprehensive Cancer Network

Newcastle Ottawa Scale

Objective response rate

Poly-ADP ribose polymerase inhibitor

Progression-free survival

Population, Intervention, Comparator, Outcome, Study Design

Partial response

Preferred Reporting Items for Systematic Literature Reviews and Meta-Analyses

Patient-reported outcomes

• Real-world evidence

San Antonio Breast Cancer Symposium

• Systematic literature review

Time-to-discontinuation

Time-to-next-treatment

Time-to-progression

United States

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Acknowledgements

The authors would like to acknowledge Joanna Bielecki who developed, conducted, and documented the database searches.

This study was funded by Pfizer Inc. (New York, NY, USA) and Arvinas (New Haven, CT, USA).

Author information

Sarah Kane, Belal Howidi, Bao-Ngoc Nguyen and Imtiaz A. Samjoo contributed equally to this work.

Authors and Affiliations

Pfizer, 10017, New York, NY, USA

Veronique Lambert & Yan Wu

EVERSANA, Burlington, ON, Canada

Sarah Kane, Belal Howidi, Bao-Ngoc Nguyen & Imtiaz A. Samjoo

Arvinas, 06511, New Haven, CT, USA

David Chandiwana & Michelle Edwards

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VL, IAS, SK, BH, BN, DC, YW, and ME participated in the conception and design of the study. IAS, SK, BH and BN contributed to the literature review, data collection, analysis, and interpretation of the data. VL, IAS, SK, BH, BN, DC, YW, and ME contributed to the interpretation of the data and critically reviewed for the importance of intellectual content for the work. VL, IAS, SK, BH, BN, DC, YW, and ME were responsible for drafting or reviewing the manuscript and for providing final approval. VL, IAS, SK, BH, BN, DC, YW, and ME meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work, and have given their approval for this version to be published.

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The authors of this manuscript declare that the research presented was funded by Pfizer Inc. and Arvinas. While the support from Pfizer Inc. and Arvinas was instrumental in facilitating this research, the authors affirm that their interpretation of the data and the content of this manuscript were conducted independently and without bias to maintain the transparency and integrity of the research. IAS, SK, BH, and BN are employees of EVERSANA, Canada, which was a paid consultant to Pfizer in connection with the development of this manuscript.

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Lambert, V., Kane, S., Howidi, B. et al. Systematic literature review of real-world evidence for treatments in HR+/HER2- second-line LABC/mBC after first-line treatment with CDK4/6i. BMC Cancer 24 , 631 (2024). https://doi.org/10.1186/s12885-024-12269-8

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Guidelines and Guidance

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PRISMA for Abstracts: Reporting Systematic Reviews in Journal and Conference Abstracts

* E-mail: [email protected]

Affiliation Centre for Research in Evidence-Based Practice, Bond University, Gold Coast, Australia

Affiliation Centre for Statistics in Medicine, University of Oxford, Oxford, United Kingdom

Affiliations Centre for Statistics in Medicine, University of Oxford, Oxford, United Kingdom, INSERM, Paris, France

Affiliation National Center for Biotechnology Information, National Library of Medicine, Washington DC, United States of America

Affiliation James Lind Initiative, Oxford, United Kingdom

Affiliation Nordic Cochrane Centre, Copenhagen, Denmark

Affiliation Cochrane Editorial Unit, London, United Kingdom

¶ Membership of the PRISMA for Abstracts Group is provided in the Acknowledgments.

• Elaine M. Beller, 
• Paul P. Glasziou, 
• Douglas G. Altman, 
• Sally Hopewell, 
• Hilda Bastian, 
• Iain Chalmers, 
• Peter C. Gøtzsche, 
• Toby Lasserson, 
• David Tovey, 
• for the PRISMA for Abstracts Group

Published: April 9, 2013

• https://doi.org/10.1371/journal.pmed.1001419
• Reader Comments

Citation: Beller EM, Glasziou PP, Altman DG, Hopewell S, Bastian H, Chalmers I, et al. (2013) PRISMA for Abstracts: Reporting Systematic Reviews in Journal and Conference Abstracts. PLoS Med 10(4): e1001419. https://doi.org/10.1371/journal.pmed.1001419

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Funding: This research was supported (in part) by the Intramural Research Program of the NIH, National Center for Biotechnology Information (National Library of Medicine). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: TL is employed by The Cochrane Collaboration. TL is an editor (unpaid) for the Cochrane Airways Group. The authors have declared that no other competing interests exist.

Abbreviations: PICOS, participants, interventions, comparators, outcomes, and study designs

Provenance: Not commissioned; externally peer reviewed.

Summary Points

• The abstract of a systematic review should provide a structured summary that enables a quick assessment of the review's validity and applicability, and easy identification in electronic searching.
• Despite published guidance on writing the abstract in the PRISMA Statement guiding the reporting of systematic reviews in general and elsewhere, evaluations show that reporting of systematic reviews in journal and conference abstracts is poor.
• We developed consensus-based reporting guidelines as an extension to the PRISMA Statement on good reporting of systematic reviews and meta-analyses in abstracts.
• The PRISMA for Abstracts checklist gives authors a framework for condensing their systematic review into the essentials for an abstract that will meet the needs of many readers.

Introduction

When readers screen the title of an article, and parts of its abstract, they try to determine whether or not to devote their scarce time to reading on. Some may be screening literature to identify the articles that are systematic reviews. Thus, the main function of an abstract of a systematic review should be to signal its systematic methodology. For most readers, the findings described in the abstract will also be key, either as the sole part of an article that will be read, or to determine whether reading the full text is required. Abstracts of systematic reviews are very important, as some readers cannot access the full paper, such that abstracts may be the only option for gleaning research results. This can be because of a pay wall, low Internet download capacity, or if the full article is only available in a language not understood by the reader. Readers in countries where English is not the primary language may have access to an abstract translated to their own language, but not to a translated full text. Conversely, a large proportion of systematic reviews are published by health technology agencies in non-English speaking countries [1] , many of which provide only the abstract in English.

The predominance of the abstract in biomedical literature use is clear. Within queries to PubMed, most readers look only at titles; only half of searches result in any clicks on content [2] . The average number of titles clicked on to obtain the abstract or full text, even after retrieving several searches in a row, is less than five. Of those clicks, abstracts will be represented about 2.5 times more often than full texts of articles [2] . Even people going straight to a PDF or full text are likely to start, and perhaps end, with reading the abstract. The frequency of viewing full texts is somewhat higher among people searching the Cochrane Database of Systematic Reviews [3] , but the same pattern is clear. After the title, the abstract is the most read part of a biomedical article.

Abstracts can be useful for screening by study type [4] ; facilitating quick assessment of validity [4] , [5] ; enabling efficient perusal of electronic search results [4] , [6] ; clarifying to which patients and settings the results apply [4] , [5] ; providing readers and peer reviewers with explicit summaries of results [5] ; facilitating the pre-publication peer review process [7] ; and increasing precision of computerised searches [6] , [7] .

Structured abstracts were introduced in the medical literature about 25 years ago [4] – [6] . They provide readers with a series of headings, generally about the purpose, methods, results, and conclusions of the report, and have been adopted by many journals and conferences. They act as a prompt to the writer to give more complete information, and facilitate the finding of information by the reader.

Despite the adoption of structured abstracts, studies of the quality of abstracts of clinical trials have demonstrated that improvement is needed [8] , [9] , and a study of systematic review abstracts demonstrated that the direction of the effect or association could not be determined in one in four abstracts from the general and specialty medical literature [10] . The PRISMA Statement [11] gives some guidance for abstracts, closely linked to commonly used headings in structured abstracts. After observing that the quality of abstracts of systematic reviews is still poor [10] , we decided to develop an extension to the PRISMA Statement to provide guidance on writing abstracts for systematic reviews. We also wanted to provide a checklist enabling the items suggested to fit into any set of headings mandated by a journal or conference submission.

Methods for Development of the Checklist

We established a steering committee (EMB, PPG, SH, DGA). In collaboration with the steering group of the PRISMA Statement [11] , we used the Statement to inform our selection of potential items for the checklist of essential items that authors should consider when reporting the primary results of a systematic review in a journal or conference abstract. The committee generated a list of items from PRISMA and other sources of guidance and information on structured abstracts and abstract composition and reporting [7] , [11] , [12] , which were found using a thorough search of the literature.

In preparation for a consensus meeting, we used a modified Delphi consensus survey method [13] to select and reduce the number of possible checklist items. Each item was rated by survey participants as “omit”, “possible”, “desirable”, or “essential” to include in the final checklist. From the first round of the survey, the ranked items were divided into three lists for the second round. The first list contained the items with the highest rankings, and participants for the second round were instructed that these would be contained in the checklist unless they received low rankings in the second round. The second list contained the items with moderate rankings, and participants were instructed that these items were likely to be removed from the checklist unless they received high rankings in the second round. The third list contained the items with low rankings, and participants were instructed that these items would be removed unless they received very high rankings in the second round.

For the third round of the Delphi survey, a draft checklist was presented, which included only the items ranked highest in rounds one and two. The five next highest-ranked items were then presented, giving participants an opportunity to choose to include these in the checklist as well.

One hundred and forty-seven participants, who were authors of research on abstracts, established authors of systematic reviews, methodologists or statisticians related to systematic reviews, and journal editors, were invited by email to complete the three rounds of the web-based survey. The response rate was 68% ( n  = 100) for the first round. Only those who completed round one were invited to participate in rounds two and three. The response rate for round two was 80% ( n  = 80) and for round three 88% ( n  = 88).

The results of the survey were reported at a two-day consensus-style meeting on 13–14 October 2011, in Oxford, United Kingdom. Fifteen invited experts attended, most of whom had participated in the survey. The meeting began with a review of the literature about abstract structure and content, followed by a review of the checklist items as proposed by the survey respondents. Meeting participants discussed the items and agreed whether they should be included and how each item should be worded.

Following the meeting, the checklist was distributed to the participants to ensure it reflected the decisions made. This explanatory document was drafted and circulated through several iterations among members of the writing subcommittee who had all participated in the meeting. We developed this document using the template for the PRISMA Statement [11] , which in turn was based on the methods of the CONSORT Group [14] , [15] .

Scope of PRISMA for Abstracts

The PRISMA for Abstracts checklist focuses on truthful representation of a systematic review in an abstract. We developed the checklist to help authors report all types of systematic reviews, but recognise that the emphasis is on systematic reviews of evaluations of interventions where one or more meta-analyses are conducted. Authors who address questions on aetiology, diagnostic test accuracy, or prognosis may need to modify items or include other items in their abstract to reflect the essentials of the full report.

The PRISMA for Abstracts Checklist

The checklist is shown in Table 1 . An explanation for each item is given below. Citations for the examples of good reporting are in Table 2 .

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https://doi.org/10.1371/journal.pmed.1001419.t001

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Section 1: TITLE

Item 1: Title.

Identify the report as a systematic review, meta-analysis, or both.

Examples: 1a. “Systematic review and meta-analysis of the diagnostic and therapeutic role of water-soluble contrast agent in adhesive small bowel obstruction.”

1b. “Inhaled corticosteroids vs placebo for preventing COPD [chronic obstructive pulmonary disease] exacerbations: a systematic review and metaregression of randomized controlled trials.”

Explanation: The abstract should make it clear that the report is a systematic review, meta-analysis, or both (examples 1a and 1b). Search filters have been developed to identify systematic reviews [16] , but inclusion of the words “systematic review” or “meta-analysis” in the title may improve indexing and electronic searching.

We also suggest using informative titles that incorporate the PICOS approach (participants, interventions, comparators, outcomes, and study designs). This provides key information about the scope of the systematic review. As including all elements of the PICOS approach may make the title unwieldy, we suggest including the most important of these elements in the title. These might be the elements that make this review unusual, or that assist readers in searching for the review.

Section 2: BACKGROUND

Item 2: Objectives.

The research question including components such as participants, interventions, comparators, and outcomes.

Examples: 2a. “To assess the effect on survival of supportive care and chemotherapy versus supportive care alone in advanced NSCLC [non-small cell lung cancer].”

2b. “To evaluate the risk of serious asthma-related events among patients treated with formoterol.”

2c. “The objective of this study was to investigate the predictive value of C-reactive protein in critically ill patients.”

Explanation: Irrespective of the strength and nature of the results reported in the abstract, readers should be able to assess the questions that the review intended to address. The objectives in an abstract should convey succinctly the broad aims of the systematic review. Objectives should reflect what the review intended to evaluate, such as benefit (example 2a), harms (example 2b), association, predictive value (example 2c), of the intervention or exposure of interest and the population or context in which this is being studied.

Section 3: METHODS

Item 3: Eligibility criteria.

Study and report characteristics used as criteria for inclusion.

Examples – study characteristics: 3a. “We included randomised controlled trials testing the combination of long-acting ß 2 - agonists in combination with inhaled corticosteroids (ICS) versus the same or an increased dose of ICS for a minimum of at least 28 days in children and adolescents with asthma.”

3b. “… randomized trials of compression stockings versus no stockings in passengers on flights lasting at least four hours. Trials in which passengers wore a stocking on one leg but not the other, or those comparing stockings and another intervention were also eligible.”

Examples – report characteristics: 3c. “… studies published in English, French, Spanish, Italian and German between 1966 and July, 2008 [were included].”

3d. “We performed a literature search of trials using MEDLINE (January 1966–December 2001) … we retrieved English- and non-English-language articles for review… we searched for both published and unpublished trials…”

Explanation: One of the key features distinguishing a systematic review from a narrative review is the pre-specification of eligibility criteria for including and excluding studies. A clear description of these allows the readers to assess the applicability of the systematic review findings [11] . Study eligibility characteristics are likely to include the study questions (PICOS)—types of participants included in the studies (often based on a common clinical diagnosis), the intervention of prime interest and possibly the specific comparison intervention, the main outcome(s) being assessed—and acceptable study designs (examples 3a and 3b).

Eligibility criteria for reports may also include the language of publication, the publication status (e.g., whether to include unpublished materials and abstracts) and the year of publication (example 3d). This is important as inclusion, or not, of studies published in languages other than English (examples 3c and 3d), unpublished data, or older data can influence the estimates of effect or association in meta-analyses [17] , [18] .

Item 4: Information sources.

Key databases searched and date of last search.

Examples: 4a. “PubMed, ERIC and Cochrane Reviews databases from January 1980 to November 2007 were searched for studies…”

4b. “We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), other trial registries and product information sheets through June 2008.”

Explanation: The abstract should briefly indicate how thorough and up-to-date the search was by listing key databases searched, and the date range (example 4a) or date of last search (example 4b). We recommend that if there are three or fewer databases, list them all; otherwise list the three that provided the majority of included studies.

Item 5: Risk of bias assessment.

Methods for assessing risk of bias.

Example: 5a. “Risk of bias was assessed regarding randomisation, allocation sequence concealment, blinding, incomplete outcome data, selective outcome reporting, and other biases.”

Explanation: Problems in the design and conduct of individual studies can raise questions about the validity of their findings [19] . For example, reports of randomised trials with inadequate allocation sequence concealment are more likely to show exaggerated treatment effects [20] . And non-blinded assessors of subjective outcomes generate substantially biased effect estimates [21] , [22] . It is therefore an important part of a systematic review to assess the validity of individual studies, and the risk that they will overestimate the true intervention effect. Authors should describe any methods they used to assess the risk of bias in the included studies (example 5a).

Many tools exist for assessing the overall risk of bias in included studies, including scales, checklists and individual components [23] . Most tools are scales in which various components of quality are scored and combined to give a summary score. This approach can be seriously misleading, however, and should be discouraged. A preferred approach requires authors to specify which individual methodological components they will assess and to provide a description and judgment for each component for each of the studies assessed [19] . For randomised trials, common components include: appropriate generation of the allocation sequence [24] , concealment of the allocation sequence [20] , blinding of participant and health care providers, blinding of outcome assessors [22] , assessment of incomplete outcome data [25] , and selective outcome reporting [26] .

Section 4: RESULTS

Item 6: Included studies.

Number and type of included studies and participants, and relevant characteristics of studies.

Examples: 6a. “We included 22 trials involving 101 507 participants: 11 trials reported on presumptive pneumococcal pneumonia, 19 on all-cause pneumonia and 12 on all-cause mortality. The current 23-valent vaccine was used in 8 trials.”

6b. “Eight studies included in this review (n = 586 patients, median PEDro score = 8.0/10) evaluated various parameters, including the duration of patients' symptoms (0–12 months), duty cycle (20% and 100%), intensity (0.1–2.0 W/cm2), treatment time per session (4.5–15.8 minutes), number of treatments (6–39), and total energy applied per treatment (181–8,152 J).”

Explanation: The number of studies, number of participants, and characteristics of the included studies (examples 6a and 6b) enable readers to gauge the validity and applicability of the systematic review's results. These characteristics might include descriptors of the participants (e.g., age, severity of disease), range of interventions used (e.g., dose and frequency of drug administration), and measurement of outcomes (e.g., follow-up times).

Item 7: Synthesis of results.

Results for main outcomes (benefits and harms), preferably indicating the number of studies and participants for each. If meta-analysis was done, include summary measures and confidence intervals.

Examples: 7a. “… CRT [cardiac resynchonization therapy] reduced all-cause mortality (6 trials, 4572 participants; risk ratio [RR], 0.83 [95% CI, 0.72 to 0.96]) and heart failure hospitalizations (4 trials, 4349 participants; RR, 0.71 [CI, 0.57 to 0.87]) without improving functional outcomes or quality of life.”

7b. “Six studies reported on maternal mortality and our meta-analysis showed a non-significant reduction (three randomised trials, relative risk 0.79, 0.53 to 1.05, P = 0.12; three non-randomised studies, 0.80, 0.44 to 1.15, P = 0.26).”

7c. “Eight studies presented adjusted odds ratios, ranging from 0.3 to 0.9, suggesting a reduced likelihood of self-reported sharing of non-N/S [non-needle/syringe] injecting paraphernalia associated with use of NSP [needle and syringe exchange programmes] or SIF [safer injection facilities].”

Explanation: The results for the main outcomes should be given in the abstract. If meta-analyses have been done, include for each the summary measure (estimated effect) and confidence interval. If the intention had been to perform meta-analysis, but no meta-analysis was done for one or more main outcomes, the reasons should be stated (e.g., heterogeneity too great).

The abstract should make clear the protocol-defined, pre-specified importance of each outcome reported, and should not report only those outcomes that have statistically significant or clinically important results.

Where possible, given space limitations, the number of studies and participants for each main outcome should be stated, particularly if only a small proportion of the total number of studies or patients in the systematic review contributed information on a particular outcome.

If there are no summary measures, some numerical data may still be given (example 7c), although authors should be wary of making this in the form of “vote counting” where the number of “positive” and “negative” studies is given. Vote counting takes no account of weighting of studies according to the amount of information they contain [27] .

Item 8: Description of effect.

Direction of the effect (i.e., which group is favoured) and size of the effect in terms meaningful to patients and clinicians.

Examples: 8a. “Radial access reduced major bleeding by 73% compared to femoral access (0.05% vs 2.3%, OR 0.27 [95% CI 0.16, 0.45], P<0.001).”

8b. “Length of hospital and critical care unit stay were both modestly reduced in the tested group compared with the control group, with a mean difference of −1.22 day (CI, −2.31 to −0.14 day) and −0.56 day (CI, −1.06 to −0.05 day), respectively.”

8c. “A small difference was found between acupuncture and placebo acupuncture: standardised mean difference −0.17 (95% confidence interval −0.26 to −0.08)… [in favour of acupuncture]…, corresponding to 4 mm (2 mm to 6 mm) on a 100 mm visual analogue scale.”

Explanation: The results should summarise the main outcomes in words and numbers. The wording should indicate the direction of the effect (e.g., lower, fewer, reduced; greater, more, increased) and the size of the effect using familiar units such as percentages, days, or kilograms. Example 8a makes clear the size of the effect even for readers who have difficulty interpreting relative risks and confidence intervals. When a percentage is used, the baseline risk should also be shown, which allows the reader to see what the absolute benefit or harm is, and calculate whichever measures they choose (example 8a). Authors should take care to make it clear whether the reported measure is an absolute or a relative one (e.g., where percentage is used as the units of measurement). Where possible, continuous outcome measures should be expressed in familiar units (example 8b), particularly when the standardised mean difference is used (example 8c).

Section 5: DISCUSSION

Item 9: Strengths and limitations of evidence.

Brief summary of strength and limitations of evidence (e.g., inconsistency, imprecision, indirectness, or risk of bias, other supporting or conflicting evidence).

Examples: 9a. “Four potentially eligible trials were not included in the meta-analysis because mortality data by age group were not available.”

9b. “All trials were open label, which may introduce bias. Most of the trials were of 24 weeks' duration or less, limiting assessment of long-term safety.”

9c. “Meta-analyses for some outcomes had large statistical heterogeneity or evidence for publication bias. Only 11 trials followed outcomes beyond 12 months.”

9d. “Meta-regression showed that small, poor-quality studies that assessed outcomes soon after radiocontrast administration were more likely to suggest benefit (P<0.05 for all).”

Explanation: The abstract should briefly describe the strengths and limitations of the evidence across studies [28] . Limitations may include: risk of bias common to many or all studies, such as lack of blinding for subjective outcomes (example 9b) or unavailability of data (example 9a); inconsistency of effect or association, as demonstrated by high heterogeneity (examples 9c and 9d); imprecision, e.g., due to few events or small sample sizes; indirectness of the evidence, such as the use of an intermediate or short-term outcome (examples 9b and 9c); and likely publication bias (example 9c). Potential strengths of the overall body of evidence that might apply for a particular outcome of a systematic review include: a large effect (example 8a); demonstration of a dose-response relationship (example 10a, below); and that all biases would be likely to reduce the effect rather than increase it. One or more of these strengths and limitations may apply to each of the outcomes of the systematic review being described in the abstract. Some of this information may be combined with item 6, above, when describing the included studies, however a summary of the overall strengths and limitations of the evidence might also be helpful.

Item 10: Interpretation.

General interpretation of the results and important implications.

Examples: 10a. “Travel is associated with a nearly 3-fold higher risk for VTE [venous thromoboembolism], with a dose-response relationship of 18% higher risk for each 2-hour increase in travel duration.”

10b. “Housing improvements, especially warmth improvements, can generate health improvements; there is little evidence of detrimental health impacts. The potential for health benefits may depend on baseline housing conditions and careful targeting of the intervention. Investigation of socioeconomic impacts associated with housing improvement is needed to investigate the potential for longer-term health impacts.”

10c. “The cumulative evidence is now conclusive that the addition of cardiac resynchronization to optimal medical therapy or defibrillator therapy significantly reduces mortality among patients with heart failure.”

Explanation: Remembering that some readers may struggle with interpreting the statistical results, an overall summary of the main effects—positive or negative—should be given (example 10a). This could include an indication of what is clear (example 10c), what important uncertainties remain (example 10b), and whether there is ongoing research addressing these.

If there is insufficient evidence from well-conducted studies to answer the review's question, this should be made clear to the reader. When the results are not statistically significant, authors should distinguish between those where there is insufficient evidence to rule out a difference between treatments (wide confidence interval), and those which have sufficient evidence that an important difference is unlikely (narrow confidence interval).

If the conclusions of the review differ substantially from previous systematic reviews, then some explanation might also be provided. Reference could be made to known ongoing studies that have the potential to change the result of the review. Possible implications for policy and practice should be stated.

Section 6: OTHER

Item 11: Funding.

Primary source of funding for the review.

Examples: 11a. “This work was supported, in part, by the Program in Reproductive and Adult Endocrinology, NICHD, NIH, Bethesda, MD. The authors have no competing interests to declare.”

11b. “Funding: National Institute for Health Research Programme Grant for Applied Research.”

Explanation: Studies of the relationship between pharmaceutical company funding and results of clinical trials have shown that sponsored studies are more likely to have outcomes favouring the sponsor [29] , [30] . This is also the case for systematic reviews [31] . Therefore, the abstract should indicate whether the sponsor of the research or the researchers might have a conflict of interest in respect of the findings of the systematic review, for example, as the manufacturer of the intervention being evaluated (examples 11a and 11b). The abstract should include the main source of funding for the systematic review, whether from host institutions or from external bodies.

Item 12: Registration.

Registration number and registry name.

Examples: 12a. “PROSPERO registration: CRD42011001243.”

12b. “PROSPERO 2011:CRD42011001329.”

Explanation: Registration of systematic reviews provides a record of reviews that have been initiated, even if they have not been published. It is therefore a means of alerting researchers to systematic reviews that are in progress, and serves as a public record of the proposed systematic review. It also helps to detect reporting bias by enabling better identification of unpublished systematic reviews, and also to compare the methods or outcomes reported in published reviews with those originally proposed in registered protocols [32] . The abstract should record the name of the database with which the review is registered, and the registration number. Cochrane reviews are an exception to this requirement, as they are preceded by a peer reviewed protocol that is published in the Cochrane Library and can be downloaded from there.

The title of a systematic review is its first signal of its relevance to potential readers. Few titles will entice a reader to invest additional time, but when they do, they ordinarily start—and quite often end—with the abstract. The first impression is therefore crucial.

We strongly recommend the use of structured abstracts for reporting systematic reviews, as does the PRISMA Statement [11] . We recognise that journals have developed their own set of headings that are considered appropriate for reporting systematic reviews, and it is not our intention to suggest changes to these headings, but to recommend what should be reported under them. The order of items and the headings are therefore flexible. For example, the strengths and limitations may be stated at the end of the Results, under a separate heading, or with the Discussion or Conclusions, depending on journal requirements. It may also be possible to combine items from the checklist into one sentence. For example, limitations may be combined with a description of the included studies (i.e., items 6 and 9 from the checklist).

We have suggested reporting a minimum set of items. We do not advocate that abstracts replace full articles in informing decision making, but we recognise that for many time-pressed readers, or for those with limited access to the full texts of reports, it is important that abstracts contain as much information as is feasible within the word limit of abstracts. Indeed, for readers who do not understand the language of publication of the article, the translated abstract may have far more relevance than the full-text article.

A checklist is not sufficient to ensure good abstract writing. For example, the abstract should clearly and truthfully reflect the full report, and not selectively report results that are statistically significant while not referring to those that were not. Similarly, the abstract should only draw conclusions that are substantiated by data from the full report and analyzed as described in the protocol, rather than selectively emphasising interesting results that were a minor or ad hoc component of the analysis. In brief, the abstract should be an unbiased representation of the full report. We also suggest that peer and editorial review processes related to the abstract should explicitly check this.

A particularly difficult area is the Discussion section of an abstract. The checklist includes two items with several elements. We suggest that authors let the reader know whether they feel their question has been answered, or whether there is still uncertainty before presenting practice and policy implications. These statements should be clearly backed by the results given in the abstract, and by presentation of the strengths and limitations of the evidence in the review.

We encourage journals and conference organisers to endorse the use of PRISMA for Abstracts, in a similar way to CONSORT for Abstracts [33] . This may be done by modifying their instructions to authors and including a link to the checklist on their website. It has been demonstrated that the number of checklist items reported is improved in journals that require checklist completion as part of the submission process [34] .

Abstracts should not replace full articles in informing decision making, but for time-pressed readers and those with limited access to full text reports, the abstract must stand alone in presenting a clear and truthful account of the research. The PRISMA for Abstracts checklist will guide authors in presenting an abstract that facilitates a quick assessment of review validity, an explicit summary of results, facilitates pre-publication or conference selection peer review, and enables efficient perusal of electronic search results.

Acknowledgments

We dedicate this paper to the memory of Alessandro Liberati who, among many important achievements, was instrumental in the development and implementation of the PRISMA Statement, and had many thoughtful insights to offer at the PRISMA for Abstracts consensus meeting.

Contributors

We are grateful to the other participants of the consensus meeting for their time and interest: Martin Burton, UK Cochrane Centre, UK; Trish Groves, BMJ, UK; Alessandro Liberati, Italian Cochrane Centre, Italy; Cynthia Mulrow, Annals of Internal Medicine , USA; Melissa Norton, PLOS Medicine , UK; Elizabeth Wager, Sideview, UK; and to everyone who responded to the PRISMA for Abstracts survey.

Author Contributions

Analyzed the data: EMB. Wrote the first draft of the manuscript: EMB. Contributed to the writing of the manuscript: EMB PPG DGA SH HB IC PCG TL DT. ICMJE criteria for authorship read and met: EMB PPG DGA SH HB IC PCG TL DT. Agree with manuscript results and conclusions: EMB PPG DGA SH HB IC PCG TL DT.

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From economic wealth to well-being: exploring the importance of happiness economy for sustainable development through systematic literature review

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• Published: 23 May 2024

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• Shruti Agrawal   ORCID: orcid.org/0000-0002-1620-9429 1 , 5 ,
• Nidhi Sharma 1 , 5 ,
• Karambir Singh Dhayal   ORCID: orcid.org/0000-0002-0000-4330 2 &
• Luca Esposito   ORCID: orcid.org/0000-0001-5983-6898 3 , 4  

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The pursuit of happiness has been an essential goal of individuals and countries throughout history. In the past few years, researchers and academicians have developed a huge interest in the notion of a ‘happiness economy’ that aims to prioritize subjective well-being and life satisfaction over traditional economic indicators such as Gross Domestic Product (GDP). Over the past few years, many countries have adopted a happiness and well-being-oriented framework to re-design the welfare policies and assess environmental, social, economic, and sustainable progress. Such a policy framework focuses on human and planetary well-being instead of material growth and income. The present study offers a comprehensive summary of the existing studies on the subject, exploring how a happiness economy framework can help achieve sustainable development. For this purpose, a systematic literature review (SLR) summarised 257 research publications from 1995 to 2023. The review yielded five major thematic clusters, namely- (i) Going beyond GDP: Transition towards happiness economy, (ii) Rethinking growth for sustainability and ecological regeneration, (iii) Beyond money and happiness policy, (iv) Health, human capital and wellbeing and (v) Policy push for happiness economy. Furthermore, the study proposes future research directions to help researchers and policymakers build a happiness economy framework.

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1 Introduction

Happiness is considered the ultimate goal of human beings (Ikeda, 2010 ; Lama, 2012 ). All economic, social, environmental and political human activities are aligned towards achieving this goal. This fundamental pursuit of human life introduces a new scope of research, namely the ‘happiness economy’ (Agrawal and Sharma 2023 ). The happiness economy is an emerging economic domain wherein many countries are working to envision and implement a happiness-oriented framework by expanding how they measure economic success, which includes wellbeing and sustainability (Cook and Davíðsdóttir 2021 ; Forgeard et al., 2011 ). The investigation of happiness, life-satisfaction and subjective well-being has witnessed increasing research interest across the disciplines- from psychology, philosophy, psychiatry, and cognitive neuroscience to sociology, economics and management (Diener 1984 ; Hallberg and Kullenberg, 2019 ).

In the post-Covid era, the world seeks an enormous transformation shift in the public system (Costanza 2020 ). However, public authorities need more time to realize such needs. To experience the ‘policy transformation’ within the coming few years, we require a paradigm shift that helps warm peoples’ hearts and minds. The new economic paradigm can penetrate the policy processes in advanced economies and every part of the world affected by the epidemic with the support of intellectuals, researchers, entrepreneurs and professionals.

OECD ( 2016 ) proposed a well-being economy framework to measure living conditions and people’s well-being. In 2020, developed countries like Finland, New Zealand, Iceland, Scotland and Wales have become members of the Wellbeing Economy Government (WEGo) (Abrar 2021 ). Since then, the network of government and international authorities across the globe has gained a quick momentum concerning an increasing tendency about a growing tendency to concentrate governmental decisions around human well-being rather than wealth and economic growth (Coscieme et al. 2019 ; Costanza et al. 2020 ).

In light of these circumstances, the purpose of this article is to describe the concept of a “happiness economy” or one that seeks to give everyone fair possibilities for growth, a sense of social inclusion, and stability that can support human resilience (Coyne and Boettke 2006 ). It provides a promising route towards improved social well-being and environmental health and is oriented towards serving individuals and communities (Skul’skaya & Shirokova, 2010 ). Moreover, the happiness economy paradigm is a transition from material production and consumption of commodities and services as the only means to economic development towards embracing a considerable variety of economic, social, environmental and subjective well-being dynamics that are considered fundamental contributors to human happiness (Atkinson et al., 2012 ; King et al., 2014 ; Agrawal and Sharma 2023 ). In following so, it reflects the ‘beyond growth’ approach that empathizes with the revised concept of growth, which is not centred around an increase in income or material production; instead it is grounded in the philosophy of achieving greater happiness for more people (Fioramonti et al. 2019a ).

Whereas the other critiques of economic growth emphasize contraction, frugality and deprivation, the happiness economy relies on a cumulative approach of humanity, hope and well-being, with a perceptive to build a ‘forward-looking’ narrative of ways for humans to live a happy and motivated life by inspiring the cumulative actions and encouraging policy-reforms in the measuring growth of an economy (Stucke 2013 ). Agrawal et al. ( 2023a , b ) explore the domain of happiness economics through a review of the various trends coupled with the future directions and highlight why it needs to be supported for a well-managed economic system and a happy society.

In this paper, we define a “happiness economy as an economy that aims to achieve the well-being of individuals in a nation, promoting human happiness, environmental up-gradation, and sustainability. Alternatively, as an economy where the wellbeing of people counts more than the goals of production and income”. Moreover, we have examined the existing body of research on the happiness economy and analyzed the emerging research themes related to rethinking the conventional approach to economic growth. We conclude by discussing how the happiness economy concept has been accepted so far and realizing its importance by triggering policy reforms at the societal level, by outlining potential future directions that might be included into the current national post-growth policies.

Various researchers and experts in the field of happiness economy support the idea that there is a lack of thorough studies related to the concept, definitions, and themes of the happiness economy model in the nations. This gap has motivated us to conduct a SLR in order to identify the evolution in the domain of happiness economy and to identify the emerging themes in this context. Therefore, this present study seeks to offer a holistic outline of the emerging research area of the happiness economy and helps to understand how the happiness economy can accelerate sustainable development. With the following research questions, this study seeks to give an all-encompassing review of this subject.

What is the annual publication trend in this domain and the most contributing authors, journals, countries etc?

Which themes and upcoming research areas are present in this field?

What directions will the happiness economics study field go in the future?

The SCOPUS database was used to achieve the above research objectives. We have selected 257 articles for examination by hand-selecting the pertinent keywords and going over each one. In the methods section, a thorough explanation of the procedures for gathering, reviewing, and selecting documents is provided.

The remainder of this paper is structured as follows; A thorough survey of the literature on the happiness economy is provided in Sect.  2 . The research approach employed in the study is presented in Sect.  3 . A thorough data analysis of the research findings is given in Sect.  4 . After discussing the results in Sect.  5 , Sect.  6 suggests areas for further research in this field. The study is summarised with a conclusion in Sect.  7 . Section  8 outlines the study’s limitation.

2 Literature review

The supporters of conventional economic growth proclaim that the material production of goods and services and consumption is vital to enhancing one’s living standards. The statement is true to some degree, mainly in countries of enormous deprivation. Some studies have found significantly less correlation between growth and happiness after fulfilling minimum threshold needs (Easterlin 1995 ; Kahneman and Krueger, 2006 ; Inglehart et al., 2008 ). These studies recommend that rather than concentrating solely on economic growth, governmental policy should give priority to non-economic aspects of human existence above a particular income level. According to some researchers, it is challenging to distinguish between the use and emissions of natural resources and economic growth (absolute decoupling) because of the interdependence between socioeconomic conditions and their biophysical basis (Wiedenhofer et al. 2020 ; Wang and Su, 2019 ; Wu et al., 2018 ). However, a shred of increasing evidence shows that it could be possible for humans to maintain a quality of life and a decent standard of living inside the ecological frontier of the environment, given that a contemporary perspective on the production and use of materials are adopted in conjunction with more fair wealth distribution (Millward-Hopkins et al. 2020 ; Bengtsson et al., 2018 ; Ni et al., 2022 ).

The scholarly discourse and institutional framework on the relationship between happiness and economic progress are synthesised in the happiness economy (Frey and Gallus 2012 ; Sohn, 2010 ; Clark et al., 2016 ; Easterlin, 2015 ; Su et al., 2022 ). From a happiness economy perspective, extreme materialism is unsustainable as it significantly impacts natural resources and hinders social coherence and individuals psychological and physical well-being (Fioramonti et al. 2022a ). Additionally, inequalities within countries have grown, while psychological suffering has increased, especially during accelerated growth (Vicente 2020 ; Galbraith, 2009 ). The modern world is witnessing anxiety, depression, wars, reduction of empathy, climate change, pandemics, loss of social bonds and other psychological disorders (Brahmi et al., 2022 ; Santini et al., 2015 ).

It has been scientifically proven that cordial human relations, care-based activity, voluntary activities and the living environment immensely impact a person’s health and societal well-being (Bowler et al. 2010 ; Keniger et al., 2013 ). Ecological economists demonstrated that free ecosystem services have enhanced human well-being (Fang et al. 2022 ). Social epidemiologists have long argued that an increase in inequalities has a negative influence on society while providing equality tends to improve significant objective ways of well-being, from healthier communities to happier communities, declining hate and crime and enhancing social cohesion, productivity, unity and mutual trust (Aiyar and Ebeke 2020 ; Ferriss, 2010 ).

From moving beyond materialistic growth, the happiness economy promotes, appreciates, and protects the environmental, societal, and human capital contributions that lead to cummalative well-being. In a happiness economy framework, a multidimensional approach is needed to evaluate the level of development based on the environmental parameters, health outcomes, as well as public trust, hope, value-creating education and social bonds (Agrawal and Sharma 2023 ; Bayani et al. 2023 ; Lavrov, 2010 ). Such factors have consistently been excluded from any traditional concept or assessment of economic growth. As a result, countries have promoted more industrial activities that deteriorate the authentic ways of human well-being and, hence, the foundations of economic progress.

An excess of production can create a detrimental effect on climate and people’s health, thereby creating a negative externality for society (Fioramonti et al. 2022b ). Moderation of output may be more efficient and desirable than hyper/over-production, as the former can reduce negative environmental externalities (e.g. waste, climate change) and create positive externalities (e.g. employment of the local resources and community) (Kim et al. 2019 ; Kinman and Jones, 2008 ). Moreover, people can also be productive in other contexts outside of the workplace, such as as volunteers, business owners, artists, friends, or members of the community (Fioramonti et al. 2022a ).

Various scholars and scientific research have established that the essential contributions to happiness in one’s life are made by natural surroundings, green and blue spaces, eco-friendly environment, healthy social relations, spirituality, good health, responsible consumption and value-creating education (Helliwell et al. 2021 ; Francart et al., 2018 ; Armstrong et al., 2016 ; Gilead, 2016 ; Giannetti et al., 2015 ). Unfortunately, existing conventional growth theories have ignored all these significant contributions. For example, GDP considers natural ecosystems as economically helpful only up until they are mined and their products are traded (Carrero et al. 2020 ). The non-market benefits they generate, such as natural fertilization, soil regeneration, climate regulation, clean air and maintenance of biodiversity, are entirely ignored (Boyd 2007 ; Hirschauer et al., 2014). The quality time people spend with their families and communities for leisure, educating future generations and making a healthy communal harmony is regarded meaningless, even in the event that they are important to enhance people’s well-being and, hence, to assist any dimension of economic engagement (Griep et al. 2015 ; Agrawal et al., 2020 ). Similarly, if an economy is focusing on people’s healthy lifestyle (for example, by providing comfortable working hours, improving work-life balance, emphasizing mental health, focusing on healthy food, reducing pollution, and promoting sustainable consumption), it is not considered in sync with the growth paradigm (Roy 2021 ; Scrieciu et al., 2013; Shrivastava and Zsolnai 2022 ; Lauzon et al., 2023 ).

Among the latest reviews, Bayani et al. ( 2023 ) highlight that the economics of happiness helps reduce the country’s financial crime by providing a livelihood that reduces financial delinquency. Chen ( 2023 ) highlights that smart city performance enhances urban happiness by adopting green spaces, reusing and recycling products, and controlling pollution. The study by (Agrawal and Sharma 2023 ) proposed a conceptual framework for a happiness economy to achieve sustainability by going beyond GDP. Similarly, Fioramonti et al. ( 2019b ) explored going beyond GDP for a transition towards a happy and well-being economy. The article by Laurent et al. ( 2022 ) has intensively reviewed the well-being indicators in Rome and proposed a conceptual framework for it.

Table  1 provides a thorough summary of the prior review studies about the happiness economy and its contribution to public policy and sustainable development.

3 Research methodology

In the current study, we have adopted an integrative review approach of SLR and bibliometric analysis of the academic literature to get a detailed knowledge of the study, which could also help propose future research avenues. The existing scientific production’s qualitative and quantitative context must be incorporated for a conclusive decision. The study by Meredith ( 1993 ) defines that SLR enables an “integrating several different works on the same topic, summarising the common elements, contrasting the differences, and extending the work in some fashion”. In the present study, the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) is applied to perform the SLR to follow systematic and transparent steps for the research methodology, as shown in Fig.  1 . The PRISMA technique includes the identification, screening, eligibility, and exclusion criteria parts of the review process.

Additionally, examples of the data abstraction and analysis processes are provided (Mengist et al. 2020 ; Moher et al., 2015 ). The four main phases of the PRISMA process are eligibility, identification, screening, and data abstraction and analysis. Because the PRISMA technique employs sequential steps to accomplish the study’s purpose, it benefits SLR research. Moreover, the bibliometric analysis helps summarise the existing literature’s bibliographic data and determine the emerging condition of the intellectual structure and developing tendencies in the specified research domain (Dervis 2019 ).

3.1 Identification

The step to conduct the PRISMA is the identification of the relevant keywords to initiate the search for material. Next, search strings for the digital library’s search services are created using the selected keywords. The basic search query is for digital library article titles, keywords, and abstracts. Next, a Boolean AND or OR operator is used to generate the search string (Boolean combinations of the operators may also be used).

There are different search databases to conduct the review studies, such as Scopus, Sage, Web of Science, IEEE, and Google Scholar. Among all the available search databases, we have used the Scopus database to identify the articles; since 84% of the material on Web of Science (WoS) overlaps with Scopus, very few authors have addressed the benefits of adopting Scopus over WoS (Mongeon and Paul-Hus 2016 ). Scopus is widely used by academicians and researchers for quantitative analysis (Donthu et al. 2021 ). It is the biggest database of scientific research and contains citations and abstracts from peer-reviewed publications consisting of journal research articles, books and conference articles (Farooque et al., 2019 ; Dhayal et al., 2022 ; Brahmi et al., 2022 ). The following search term was used: (TITLE-ABS-KEY (“happiness economy” OR “economics of happiness” OR “happiness in economy” OR “economy of happiness” OR “economy of wellbeing” OR “wellbeing economy” OR “wellbeing in economy” OR “beyond growth”). This process yields 380 artciles in the initial phase.

3.2 Screening

The second phase is completed by all identified articles from the Scopus database obtained from the search string in the identification phase. The publications are either included or excluded throughout the screening process based on the standards established by the authors and with the aid of particular databases. Exclusion and inclusion criteria are shown during the screening phase to identify pertinent articles for the systematic review procedure. The timeline of this study’s selected articles is from 1995 to 2023. The first article related to the research domain was published in 1995. The second criterion for the inclusion includes the types of documents. In the present research, the authors have regarded only peer-reviewed journals and review articles. Other types of articles, such as books, book chapters, conference articles, notes, and editorials, are excluded to maintain the quality of the review. The third inclusion and exclusion criterion is based on language. All the non-English language documents are excluded to avoid translation confusion; hence, only the English language articles are considered for the final review. After the screening process, 297 articles are obtained.

3.3 Eligibility

Articles are manually selected or excluded depending on specific criteria specified by the authors during the eligibility process. During the elimination process, the authors excluded the articles that did not fit into the scope of review after manual screening of the articles. Two hundred fifty-seven articles were selected after the eligibility procedure. These selected articles are carefully reviewed for the study by reviewing the titles, abstracts, and standards from earlier screening processes.

3.4 Data abstraction and analysis

Analysis and abstraction of data are part of the fourth step. Finally, 257 papers were taken into account for final review. After that, the studies are culled to identify pertinent themes and subthemes for the current investigation by thoroughly reviewing each article’s text. An integrative review is a form of study that combines mixed, qualitative, and quantitative research procedures. It is carried out as shown in Fig.  1 . R-studio Bibliometrix and VOSviewer version 1.6.18 were used to evaluate the final study dataset corpus of 257 articles. Since the Bibliometrix software package is a free-source tool programmed in the R language. It is proficient of conducting comprehensive scientific mapping. It also contains several graphical and statistical features with flexible and frequent updates (Agrawal et al. 2023a , b ).

Extraction of articles and selection process

This section provides an answer to the first research question, RQ1, by indicating the main information of corpus data, research publication trends, influential prolific authors, journals, countries and most used keywords, etc. (Refer to Tables  2 , 3 and 4 ) and (Refer to Figs.  2 , 3 , 4 , 5 and 6 ).

4.1 Bibliometric analysis

Table  2 shows the relevant information gathered from the publication-related details. It presents the cognitive knowledge of the research area, for instance, details about authors, annual average publication, average citations and collaboration index. By observing the rate of document publishing, the study illustrates how much has already been done and how much remains to be investigated.

The annual publication trend is shown in Fig.  2 . It is reflected that the first article related to happiness in an economy was released in the year 1995 when (Bowling 1995 ) published the article “What things are important in people’s lives? A survey of the public’s judgements to inform scales of health related quality of life” where the article discussed “quality of life” and “happiness” as an essential component of a healthy life. Oswald ( 1997 ) brought the concept of happiness and economics together and raised questions such as “Does money buy happiness?” or “Do you think your children’s lives will be better than your own?”. Eventually, the gross national product of the past year and the coming year’s exchange rate was no longer the concern; instead, happiness as the sublime moment became more accurate (Schyns 1998 ; Easterlin, 2001; Frey and Stutzer, 2005 ). Post-2013, we can see exponential growth in the publication trend, and the reason behind the growth is the report published by the “ Stiglitz-Sen-Fitoussi” Commission, which has identified limitations of GDP and questioned the metric of wealth, economic and societal progress. The affirmed questions have gained the attention of researchers and organizations, and thus, they have explored the alternatives to GDP. As a result, the “Organization for Economic Co-operation and Development” (OECD) have proposed a wellbeing framework. Some research work has significantly impacted that time, contributing to the immense growth in this research area (Sangha et al. 2015 ; Spruk and Kešeljević, 2015 ; Nunes et al., 2016 ).

Publication trend

Table  3 shows the top prolific journals concerning the topmost publications in the domain of happiness economy for the corpus of 257 articles, namely “International Journal of Environmental Research and Public Health”, “Ecological Economics”, “Ecological Indicators”, “Sustainability” and “Journal of Cleaner Production” with 5, 4, 4,4 and 4 articles respectively (Refer to Table  4 ). Moreover, the most influential journals with maximum citations are “Nature Human Behavior”, “Quality of Life Research”, “Journal of Applied Behavior Analysis”, “Journal of Cleaner Production” and “Ecological Economics”, with 219, 205, 186, 154 and 142 citations, respectively. “Journal of Cleaner Production” and “Ecological Economics” are highly prolific and the most influential journals in the happiness economy research domain.

Table  4 shows the most influential authors. Baños, R.M. and Botella, C. are the two most contributing authors with maximum publications. For the maximum number of citations, Zheng G. and Coscieme L. are the topmost authors for their research work. The nations were sorted according to the quantity of publications, and Fig.  3 showed where the top ten countries with the highest number of publications are listed originated. It can be seen from the figure that the United Stated has contributed the maximum publications, 66, followed by the United Kingdom with 41 articles, followed by Germany with 32 articles. It is worth noting that emerging nation such as India and China have also made significant contributions.

Top ten contributing countries

Figure  4 shows semantic network analysis in which the relationships between words in individual texts are performed. In the present study, we have identified word frequency distributions and the co-occurrences of the authors’ keywords in this study. We employed co-word analysis to find repeated keywords or terms in the title, abstract, or body of a text. In Fig.  5 , the circle’s colour represents a particular cluster, and the circle’s radius indicates how frequently the words occur. The size of a keyword’s node indicates how frequently that keyword appears. The arcs connecting the nodes represent their co-occurrence in the same publication. The greater the distance between two nodes, the more often the two terms co-occur. It can be seen that “happiness” is linked with “growth” and “life satisfaction”. The nodes of “green economy”, “ecological economics”, and “climate change” are in a separate cluster that shows they are emerging areas, and future studies can explore the relationship between happiness economy with these keywords.

Co-ocurrance of author’s keyword (Author’s compilation)

4.2 Thematic map analysis through R studio

The thematic analysis map, as shown in Fig.  5 , displays, beneath the author’s keywords, the visualisation of four distinct topic typologies produced via a biblioshiny interface. The thematic map shows nine themes/clusters under four quadrants segregated in “Callon’s centrality” and “density value”. The degree of interconnectedness between networks is determined by Callon’s centrality, while Callon’s density determines the internal strength of networks. (Chen et al. 2019 ). The rectangular boxes in Fig.  5 represent the subthemes under each topic or cluster that are either directly or indirectly connected to the major themes, based on the available research. In the upper-right quadrant, four themes have appeared, namely “circular economy”, “well-being economy”, “depression”, and “sustainable development”, they fall under the category of motor themes since they are extremely pertinent to the research field, highly repetitious, and well-developed. When compared to other issues with internal linkages but few exterior relations, “urban population” in the upper-left quadrant is seen as a niche concern since it is not as significant. This cluster may have affected the urban population’s happiness (Knickel et al. 2021 ). “Social innovation” is categorised as an emerging or declining subject with low centrality and density, meaning it is peripheral and undeveloped. It is positioned in the lower-left quadrant. Last but not least, the transversal and fundamental themes “happiness economy”, “subjective well-being”, and “climate change” in the lower-right quadrant are seen to be crucial to the happiness economy study field but are still in the early stages of development. As a result, future research must place greater emphasis on the quantitative and qualitative growth of the study area in light of the key themes that have been identified.

Thematic map analysis

4.3 Science mapping through cluster analysis

In the study, science mapping was conducted to examine the interrelationship between the research domains that could be intellectual (Aria and Cuccurullo 2017 ; Donthu et al. 2021 ). It includes various techniques, such as co-authorship analysis, co-occurrence analysis, bibliographic coupling, etc. We have used R-Studio for the study’s temporal analysis by cluster analysis. To answer RQ2, the authors have performed a qualitative examination of the emerging cluster themes through the science mapping of the existing research corpus of 257 articles by performing bibliographic coupling of documents. Bibliographic coupling analysis helps identify clusters reflecting the most recent research themes in the happiness economy field to illuminate the field’s current areas of interest.

The visual presentation of science mapping relied on VoSviewer version 1.6.18 (refer to Fig.  6 ). Five significant clusters emerged in this research domain (refer to Table  5 ). Going beyond GDP: Transition towards happiness economy, rethinking growth for sustainability and ecological regeneration, beyond money and happiness policy, health, human capital and wellbeing and Policy-Push for happiness economy. A thorough examination identified cluster analyzes has also assists us in identifying potential future research proposals. (Franceschet 2009 )

4.4 Cluster 1: Going beyond GDP: transition towards happiness economy

It depicts from the green colour circles and nodes, where seven research articles were identified with a common theme of beyond GDP that can be seen in Fig.  6 . Cook and Davíðsdóttir ( 2021 ) investigated the linkages between the alternative measure of the beyond growth approach such as a well-being economy prespective and the SDGs. They proposed a conceptual model of a well-being economy consisting of four capital assets interrelated with SDGs that promote well-being goals and domains. To extend the concept of going beyond GDP, various economic well-being indicators are being aligned with the different economic, environmental, and social dimensions to target the set goals of SDG. It is found that the “Genuine Progress Indicator” (GPI) is consider as the most extensive method that covers the fourteen targets among the seventeen’s SDG’s. Cook et al. ( 2022 ) consider SDGs to represent the classical, neoclassical and growth-based economy model and as an emerging paradigm for a well-being economy. The significance of GDP is more recognized within the goals of sustainable development.

GPI is considered an alternative indicator of economic well-being. On this basis, excess consumption of high-quality energy will expand macro-economic activity, which GDP measures. For such, a conceptual exploration of the study is conducted on how pursuing “Sustainable Energy Development” (SED) that can increase the GPI results. As the study’s outcome, according to the GPI, SED will have a significant advantage in implementing energy and environment policy and will also contribute to the advancement of social and economic well-being. Coscieme et al. ( 2020a ) explored the connection between the unconditional growth of GDP and SDG. The author considered that policy coherence for sustainable development should lessen the damaging effects of cyclic manufacturing on the ecosystem. Thus, the services considered free of charge in the GDP model should be valued as a component of society. Generally, such services include ecosystem services and a myriad of “economic” functions like rainfall and carbon sequestration. To work for SDG 8, defined by the “United Nations Sustainable Development Goals” (UNSDGs), a higher GDP growth rate would eventually make it more difficult to achieve environmental targets and lessen inequality. Various guidelines were proposed to select alternative variables for SDG-8 to enhance coherence among all the SDG and other policies for sustainability.

Fioramonti et al. ( 2019a ) state their focus is to go beyond GDP toward a well-being economy rather than material output with the help of convergence reforms in policies and economic shifts. To achieve the SDG through protecting the environment, promoting equality, equitable development and sharing economy. The authors have developed the Sustainable Well-Being Index (SWBI) to consolidate the “Beyond GDP” streams as a metric of well-being matched with the objectives to achieve SDG. The indicators of well-being for an economy have enough possibility to connect current transformations in the economic policies and the economy that, generally, GDP is unable to capture.

Fioramonti et al. ( 2022a ) investigate the critical features of the Wellbeing Economy (WE), including its various parameters like work, technology, and productivity. Posting a WE framework that works for mainstream post-growth policy at the national and international levels was the study’s primary goal. The authors have focused on building a society that promotes well-being that should be empowering, adaptable, and integrative. A well-being economic model should develop new tools and indicators to monitor all ecological and human well-being contributors. A multidimensional approach including critical components for a well-being economy was proposed that creates value to re-focus on economic, societal, personal, and natural aspects. Rubio-Mozos et al. ( 2019 ) conducted in-depth interviews with Fourth Sector business leaders, entrepreneurs, and academicians to investigate the function of small and medium-sized businesses and the pressing need to update the economic model using a new measure in line with UN2030. They have proposed a network from “limits to growth” to a “sustainable well-being economy”.

4.5 Cluster 2: Rethinking growth for sustainability and ecological regeneration

Figure  6 depicts it from blue circles and nodes, wherein four papers were identified. Knickel et al. ( 2021 ) proposed an analytical approach by collecting the data from 11 European areas to examine the existing conditions, difficulties, and anticipated routes forward. The goal of the study is to define the many ideas of a sustainable well-being economy and territorial development plans that adhere to the fundamental characteristics of a well-being economy. A transition from a conventional economic viewpoint to a broader view of sustainable well-being is centred on regional development plans and shifting rural-urban interactions.

Pillay ( 2020 ) investigates the new theories of de-growth, ecosocialism, well-being and happiness economy to break the barriers of traditional economic debates by investigating ways to commercialise and subjugate the state to a society in line with non-human nature. The significant indicator of Gross National Happiness (GNH) is an alternative working indicator of development; thus, the Chinese wall between Buddha and Marx has been built. They questioned the perspective of Buddha and Marx, whether they were harmonized or became a counter-hegemonic movement. In order to determine if the happiness principle is grounded in spiritual values and aligns with the counter-hegemonic ecosocialist movement, the author examined the ecosocialist perspective. Shrivastava and Zsolnai ( 2022 ) have investigated the theoretical and practical ramifications of creative organisations for well-being rooted in the drive for a well-being economy. Wellbeing and happiness-focused economic frameworks are emerging primarily in developed countries. This new policy framework also abolishes GDP-based economic growth and prioritizes individual well-being and ecological regeneration. To understand its application and interpretation, Van Niekerk ( 2019 ) develops a conceptual framework and theoretical analysis of inclusive economics. It contributes to developing a new paradigm for economic growth, both theoretically and practically.

4.6 Cluster 3: ‘Beyond money’ and happiness policy

It depicts pink circles and nodes, wherein five articles were identified, as shown in Fig.  6 . According to Diener and Seligman ( 2004a ) economic indicators are critical in the early phases of economic growth when meeting basic requirements is the primary focus. However, as society becomes wealthier, an individual’s well-being becomes less dependent on money and more on social interactions and job satisfaction. Individuals reporting high well-being outperform those reporting low well-being in terms of income and performance. A national well-being index is required to evaluate well-being variables and shape policies systematically. Diener and Seligman ( 2018 ) propounded the ‘Beyond Money’ concept in 2004. In response to the shortcomings of GDP and economic measures, other quality-of-life indicators, such as health and education, have been created. The national account of well-being has been proposed as a common path to provide societies with an overall quality of life metric. While measuring the subjective well-being of people, the authors reasoned a societal indicator of the quality of life. In this article, the authors have proposed an economy of well-being model by combining subjective and objective measures to convince policymakers and academicians to enact policies that enhance human welfare. The well-being economy includes quality of life indicators and life satisfaction, subjective well-being and happiness.

Frey and Stutzer ( 2000 ) perceived the microeconomic well-being variables in countries. In the study, survey data was used from 6000 individuals in Switzerland and showed that the individuals are happier in developed democracies and institutions (government federalization). They analyzed the reported subjective well-being data to determine the function of federal and democratic institutions on an individual’s satisfaction with life. The study found a negative relationship between income and unemployment. Three criteria have been employed in the study to determine happiness: demographic and psychological traits, macro- and microeconomic factors, and constitutional circumstances. Thus, a new pair of determinants reflects happiness’s effect on individuals’ income, unemployment, inflation and income growth.

Happiness policy, according to Frey and Gallus ( 2013b ), is an intrinsic aspect of the democratic process in which various opinions are collected and examined. “Happiness policy” is far more critical than continuing a goal such as increasing national income and instead considered an official policy goal. The article focuses on how politicians behave differently when they believe that achieving happiness is the primary objective of policy. Frey et al. ( 2014 ) explored the three critical areas of happiness, which are positive and negative shocks on happiness, choice of comparison and its extent to derive the theoretical propositions that can be investigated in future research. It discussed the areas where a more novel and comprehensive theoretical framework is needed: comparison, adaptation, and happiness policy. Wolfgramm et al. ( 2020 ) derived a value-driven transformation framework in Māori economics of wellbeing. It contributes to a multilevel and comprehensive review of Māori economics and well-being. The framework is adopted to advance the policies and implement economies of well-being.

4.7 Cluster 4: Health, human capital and wellbeing

It is depicted as a red colour circle and nodes in Fig.  6 , and only three papers on empirical investigations were found. Laurent et al. ( 2022 ) investigated the Health-Environment Nexus report published by the “Wellbeing Economy Alliance”. In place of increased production and consumption, they suggested a comprehensive framework for human health and the environment that includes six essential paths. The six key pathways are well-being energy, sustainable food, health care, education, social cooperation and health-environment nexus. The proposed variables yield the co-benefits for the climate, health and sustainable economy. Steer clear of the false perception of trade-offs, such as balancing the economy against the environment or the need to save lives. McKinnon and Kennedy ( 2021 ) focuses on community economics of well-being that benefits entrepreneurs and employees. They investigated the interactions of four social enterprises that work for their employees inside and within the broader community. Cylus et al. ( 2020 ) proposed the opportunities and challenges in adopting the model of happiness or well-being in an economy as an alternative measure of GDP. Orekhov et al. ( 2020 ) proposed the derivation of happiness from the World Happiness Index (WHI) data to estimate the regression model for developed countries.

4.8 Cluster 5: Policy-push for happiness economy

It is depicted as an orange circle and nodes in Fig.  6 , and only five papers on empirical and review investigations were found. Oehler-Șincai et al. ( 2023 ) proposed the conceptual and practical perspective of household-income-labour dynamics for policy formulation. It discusses the measurement of well-being as a representation of various policies focusing on health, productivity, and longevity. It focuses on the role of policy in building the subjective and objective dimensions of well-being, defines the correlation between well-being, employment policies, and governance, is inclined to the well-being performance of various countries, and underscores present risks that jeopardize well-being. Musa et al. ( 2018 ) have developed a “community happiness index” by incorporating the four aspects of sustainability—economic, social, environmental, and urban governance—as well as the other sustainability domains, such as human well-being and eco-environmental well-being. From then onwards, community happiness and sustainable urban development emerged. Chernyahivska et al. ( 2020 ) developed strategies to raise the standard of living for people in countries undergoing economic transition by using the quality of life index. The methods uncovered are enhancing employment opportunities and uplifting the international labour market in urban and rural areas, prioritizing human capital, eliminating gender inequality, focusing on improving the individual’s health, and enhancing social protection. Zheng et al. ( 2019 ) investigated the livelihood and well-being index of the population that makes liveable conditions and city construction in society based on people’s happiness index. The structure of a liveable city should be emphasised on sustainable development. The growth strategy in urban areas is an essential aspect of building a liveable city. Frey and Gallus ( 2013a ) criticised the National Happiness Index as a policy goal in a country because it cannot be measured and thus fails to measure the true happiness of people. To measure real happiness, the government should establish living conditions that enable individuals to become happy. The rule of law and human rights must support the process.

The structure of a liveable city should be emphasized in sustainable development. The growth strategy in urban areas is an essential aspect of building a liveable city. Frey and Gallus ( 2013a ) criticized the National Happiness Index as a policy goal in a country because it cannot be measured and thus fails to identify the true individuals happiness. To measure real happiness, the government should establish living conditions that enable individuals to be happy. The process needs to be supported by human rights and the rule of law.

Visualization of cluster analysis

5 Discussion of findings

Concerns like the improved quality-of-life and a decent standard of living within the ecological frontier of the environment have various effects on individuals overall well-being and life satisfaction. The ‘beyond growth’ approach empathized with the revised concept of growth, which is based on the idea of maximising happiness for a larger number of people rather than being driven by a desire for financial wealth or production. In that aspect, the notion of happiness economy is designed that prioritizes serving both people and the environment over the other. This present article has focused on the beyond growth approach and towards a new economic paradigm by doing bibliometric and visual analysis on the dataset that was obtained from Scopus, helping to determine which nations, publications, and authors were most significant in this field of study.

In this field of study, developed nations have made significant contributions as compared to the developing nations. In total, 59 countries have made the substantial contribution to the beyond growth approach literature an some of them have proposed their respective national well-being economy framwework. Among 59 countries the United States and the United Kingdom have been crucial to the publishing. With the exception of five of the top 10 nations, Europe contributes the most to scientific research. The existing research shows the inclination of developed and developing countries to build a new economic paradigm that goes beyond growth by prioritizing the happiness level at individual as well as at collective level.

The most prolific journals in this research domain are the “International Journal of Environmental Research” and “Public Health” with the total publication of 5 and 4. The top two cited journals were the “ Nature Human Behavior” with 219 citations and the “Quality of Life Research” with 205 citations. Due to various economic and non-economic factors, these journals struggled to strike a balance between scientific accuracy and timeliness, and it became vital to spread accurate and logical knowledge. For, example, discussing the relationship between inequality and well-being, exploring the challenges and opportunites of happiness economy in different countries, assessing the role of health in all policies to support the transition to the well-being economy. Visualization of semantic network analysis of co-ocurrance of authors keywords from the VOSviewer showed the future research scope to explore the association between happiness economy along with green economy, climate change, spirituality and sustainability. However, in the thematic mapping, the motor themes denotes the themes that are well-developed and repetative in research, such as, well-being economy, depression, sustainable development and circular economy. The basic themes depicts the developing and transveral themes such as happiness economy, subjective well-being and climate condition. As a result, future research must place greater emphasis on the theoretical and practical expansion of the research field in view of the determined major subjects.

The present study have performed the cluster analysis to identify the emerging research themes in this domain through VOSviewer that helps to analyze the network of published documents. Based on published papers, the author can analyse the interconnected network structure with the use of cluster analysis. We have identified the top five clusters from the study. Each cluster denote the specific and defined theme of the research in this domain. In cluster 1, the majorly of the authors are working in the area of going beyond GDP and transition towards happiness economy, which consists of empirical and review studies. Cluster 2 represents that authors are exploring the relationship between rethinking growth for sustainability and ecological regeneration to evaluate the transition from a conventional economic thought to a broader view of sustainable well-being which is centred on regional development plans and shifting rural-urban interactions. In cluster 3, the authors are exploring the beyond money and happiness policy themes and identified the shortcomings of GDP and economic measures, other quality-of-life indicators, such as health and education. They have proposed the well-being index to evaluate the well-being variables and shape socio-economic policies systematically. The authors have proposed an economy of well-being model by combining subjective and objective measures to convince policymakers and academicians to enact policies that enhance human welfare. The well-being economy includes quality of life indicators and life satisfaction, subjective well-being and happiness. In cluster 4, the authors are working of related theme of Health, human capital and wellbeing, whereby they have put up a comprehensive framework for health and the environment that includes several important avenues for prioritising human and ecological well-being over increased production and consumption. In cluster 5, the authors have suggested the policy-push for happiness economy in which they have identified the conceptual and practical perspective of household-income-labour dynamics for policy formulation. Majorly of the authors in this clutster have focused on the role of policy in building the subjective and objective dimensions of well-being, defines the correlation between well-being, employment policies, and governance, is inclined to the well-being performance of various countries, and underscores present risks that jeopardize well-being. Hence, the present study will give academics, researchers, and policymakers a thorough understanding of the productivity, features, key factors, and research outcomes in this field of study.

6 Scope for future research avenues

The emergence of a happiness economy will transform society’s traditional welfare measure. Such changes will generate more reliable and practical means to measure the well-being or welfare of an economy. After a rigorous analysis of the existing literature, we have proposed the scope for future research in Table  6 .

7 Conclusion

In 2015, the United Nations proposed the pathbreaking and ambitious seventeen “Sustainable Development Goals” (SDGs) for countries to steer their policies toward achieving them by 2030. In reality, economic growth remains central to the agenda for SDGs, demonstrating the absence of a ground-breaking and inspirational vision that might genuinely place people and their happiness at the core of a new paradigm for development. As this research has reflect, there are various evidence that the happiness economy strategy is well-suited to permeate policies geared towards sustainable development. In this context, ‘happiness’ may be a strong concept that ensures the post-2030 growth will resonate with the socioeconomic and environmental traits of everyone around the world while motivating public policies for happiness.

The current research has emphasized the many dynamics of the happiness economy by using a bibliometric analytic study of 257 articles. We have concluded that the happiness economy is an emerging area that includes different dimensions of happiness, such as ecological regeneration, circular economy, sustainability, sustainable well-being, economic well-being, subjective well-being, and well-being economy. In addition to taking into consideration the advantages and disadvantages of human participation in the market, a happiness-based economic system would offer new metrics to assess all contributions to human and planetary well-being. In terms of theoretical ramifications, we suggest that future scholars concentrate on fusing the welfare and happiness theory with economic policy. As countries are predisposed to generate disharmony and imbalance, maximizing societal well-being now entails expanding sustainable development. Since the happiness economy is still a relatively novel field, it offers numerous potential research opportunities.

8 Limitations

Similar to every other research, this one has significant restrictions as well. We are primarily concerned that all our data were extracted from the Scopus database. Furthermore, future research can utilize other software like BibExcel and Gephi to expound novel variables and linkages. Given the research limitations, this article still provides insightful and relevant direction to policymakers, scholars, and those intrigued by the idea of happiness and well-being in mainstream economics.

The study offers scope for future research in connecting the happiness economy framework with different SDGs. Future studies can also carry empirical research towards creating a universally acceptable ‘happiness economy index’ with human and planetary well-being at its core.

Data availability

Data not used in this article.

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All authors contributed to the study conception and design. Shruti Agrawal: Conceptualization, Material preparation, Data Collection, Formal analysis, Methodology, Writing - Original Draft, Review and Editing. Nidhi Sharma: Validation, Project Administration, Supervision, and Writing - Review & Editing. Karambir Singh Dhayal: Validation, Formal analysis, Methodology, Writing - Review and Editing. Luca Esposito: Validation, Writing - Review and Editing. The first draft of the manuscript was written by Shruti Agrawal and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript

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Agrawal, S., Sharma, N., Dhayal, K.S. et al. From economic wealth to well-being: exploring the importance of happiness economy for sustainable development through systematic literature review. Qual Quant (2024). https://doi.org/10.1007/s11135-024-01892-z

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Size of box indicates number of estimates.

eTable 1. Search Strategy

eTable 2. Risk of Bias Assessment Using the Joanna Briggs Institute Critical Appraisal Checklist Tool

eTable 3. Time From Symptom Presentation to Diagnosis Measurement Across Studies

eFigure 1. Forest Plots of Proportions of Presenting Signs and Symptoms for EOCRC, by Sign or Symptom

eFigure 2. Pooled Proportions of Presenting Signs and Symptoms for EOCRC by Geography

eFigure 3. Pooled Proportions of Presenting Signs and Symptoms for EOCRC; Stratified Analysis by Age Group

eFigure 4. Pooled Proportions of Presenting Signs and Symptoms for EOCRC, Stratified Analysis by Risk of Bias

eFigure 5. Pooled Proportions of Presenting Signs and Symptoms for EOCRC, Stratified Analysis by Data Source

eFigure 6. Histograms of Mean and Median Diagnosis Stratified by Data Source

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Demb J , Kolb JM , Dounel J, et al. Red Flag Signs and Symptoms for Patients With Early-Onset Colorectal Cancer : A Systematic Review and Meta-Analysis . JAMA Netw Open. 2024;7(5):e2413157. doi:10.1001/jamanetworkopen.2024.13157

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Red Flag Signs and Symptoms for Patients With Early-Onset Colorectal Cancer : A Systematic Review and Meta-Analysis

• 1 Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla
• 2 Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at UCLA, VA Greater Los Angeles Healthcare System, Los Angeles, California
• 3 Department of Medicine, University of California San Diego, La Jolla
• 4 Division of Gastroenterology, Washington University in St Louis, St Louis, Missouri
• 5 Department of Internal Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York
• 6 Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, Missouri
• 7 UC San Diego Library, University of California San Diego, La Jolla
• 8 University of Colorado Cancer Center, Colorado School of Public Health, Aurora
• 9 Molecular Medicine Unit, Department of Medicine, Biomedical Research Institute of Salamanca, University of Salamanca, Salamanca, Spain
• 10 Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Vanderbilt University School of Medicine, Nashville, Tennessee
• 11 Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus, Aurora
• 12 Division of Biomedical Informatics, Department of Medicine, University of California San Diego, La Jolla
• 13 Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
• 14 Jennifer Moreno Veteran Affairs San Diego Healthcare System, San Diego, California
• 15 Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri
• 16 Alvin J. Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri
• 17 Surgery Department, Vithas Arturo Soria University Hospital, Madrid, Spain

Question   In patients with early-onset colorectal cancer (EOCRC), what are the most common presenting signs and symptoms, what is their association with EOCRC risk, and what is the time from presentation to diagnosis?

Findings   In this systematic review and meta-analysis including 81 studies and more than 24.9 million patients, nearly half of individuals with EOCRC presented with hematochezia and abdominal pain and one-quarter presented with altered bowel habits. Delays in diagnosis of 4 to 6 months from time of initial presentation were common.

Meaning   These findings underscore the need to identify signs and symptoms concerning for EOCRC and complete timely diagnostic workup for individuals without an alternative diagnosis or sign or symptom resolution.

Importance   Early-onset colorectal cancer (EOCRC), defined as a diagnosis at younger than age 50 years, is increasing, and so-called red flag signs and symptoms among these individuals are often missed, leading to diagnostic delays. Improved recognition of presenting signs and symptoms associated with EOCRC could facilitate more timely diagnosis and impact clinical outcomes.

Objective   To report the frequency of presenting red flag signs and symptoms among individuals with EOCRC, to examine their association with EOCRC risk, and to measure variation in time to diagnosis from sign or symptom presentation.

Data Sources   PubMed/MEDLINE, Embase, CINAHL, and Web of Science were searched from database inception through May 2023.

Study Selection   Studies that reported on sign and symptom presentation or time from sign and symptom presentation to diagnosis for patients younger than age 50 years diagnosed with nonhereditary CRC were included.

Data Extraction and Synthesis   Data extraction and quality assessment were performed independently in duplicate for all included studies using Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guidelines. Joanna Briggs Institute Critical Appraisal tools were used to measure risk of bias. Data on frequency of signs and symptoms were pooled using a random-effects model.

Main Outcomes and Measures   Outcomes of interest were pooled proportions of signs and symptoms in patients with EOCRC, estimates for association of signs and symptoms with EOCRC risk, and time from sign or symptom presentation to EOCRC diagnosis.

Results   Of the 12 859 unique articles initially retrieved, 81 studies with 24 908 126 patients younger than 50 years were included. The most common presenting signs and symptoms, reported by 78 included studies, were hematochezia (pooled prevalence, 45% [95% CI, 40%-50%]), abdominal pain (pooled prevalence, 40% [95% CI, 35%-45%]), and altered bowel habits (pooled prevalence, 27% [95% CI, 22%-33%]). Hematochezia (estimate range, 5.2-54.0), abdominal pain (estimate range, 1.3-6.0), and anemia (estimate range, 2.1-10.8) were associated with higher EOCRC likelihood. Time from signs and symptoms presentation to EOCRC diagnosis was a mean (range) of 6.4 (1.8-13.7) months (23 studies) and a median (range) of 4 (2.0-8.7) months (16 studies).

Conclusions and Relevance   In this systematic review and meta-analysis of patients with EOCRC, nearly half of individuals presented with hematochezia and abdominal pain and one-quarter with altered bowel habits. Hematochezia was associated with at least 5-fold increased EOCRC risk. Delays in diagnosis of 4 to 6 months were common. These findings highlight the need to identify concerning EOCRC signs and symptoms and complete timely diagnostic workup, particularly for individuals without an alternative diagnosis or sign or symptom resolution.

The incidence of early-onset colorectal cancer (EOCRC), defined as a diagnosis at younger than age 50 years, has been increasing at an alarming rate, in contrast to the decreasing CRC rate among older individuals. 1 These trends have been observed globally, 2 - 9 and EOCRC rates in the US are projected to increase by at least 140% by 2030. 10 These worrisome epidemiologic findings prompted an update in US CRC screening guidelines to begin screening among individuals at average risk at age 45 years. 11

Outside of screening, early detection of symptomatic EOCRC remains a priority. Delayed diagnosis may be a result of late patient presentation and lack of clinician knowledge of common CRC symptoms, such as hematochezia or abdominal and pelvic pain, and signs, such as iron deficiency anemia. Patients and clinicians alike may downplay symptom severity and fail to recognize key red flags and clinical cues that should trigger suspicion of CRC. 12 - 15 Furthermore, diagnostic algorithms in adults younger than 50 years often favor a less invasive and more conservative watchful waiting strategy, which could result in missed opportunities for intervention. 16 Therefore, defining the prevalence of these common signs and symptoms and their associated EOCRC risk is a critical first step to inform care pathways.

Additionally, delays in diagnostic workup after sign or symptom presentation are up to 40% longer in younger compared with older individuals with CRC, which may contribute to greater proportion of late stage diagnosis (58%-89% vs 30%-63%) and increasing EOCRC mortality rates in the US (1.3% per year from 2008-2017). 17 - 20 Mitigation strategies to expedite timely diagnoses may help decrease EOCRC morbidity and mortality. To address these gaps and pressing clinical issues, we performed a systematic review and meta-analysis to quantify the prevalence of signs and symptoms at EOCRC presentation, their association with EOCRC risk, and time to diagnosis.

We conducted a systematic review and meta-analysis to answer 3 questions. First, which signs and symptoms are most commonly present in individuals diagnosed with EOCRC? Second, what is the association between EOCRC sign or symptom exposure and EOCRC risk? Third, what is the time from sign or symptom presentation to diagnosis of EOCRC? This study is registered on Prospero (identifier: CRD42020181296 ). We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses ( PRISMA ) reporting guideline.

A comprehensive literature search was performed in PubMed/MEDLINE, Embase, CINAHL, and Web of Science Core Collection from inception through May 2023 to identify candidate studies for inclusion (eTable 1 in Supplement 1 ). Results were exported and deduplicated in EndNote (Clarivate) using the Bramer method. 21

Study review and data extraction were performed in Covidence (Veritas Health Innovation). Two independent reviewers (among J. Demb, J.M.K, J. Dounel, C.D.L.F., S.M.A. and F.E.R.V.) screened titles and abstracts for eligibility and reviewed the full text of all designated articles, with a third reviewer (S.G.) providing consensus if needed. Studies that reported on sign or symptom presentation or time to diagnosis for patients younger than age 50 years diagnosed with nonhereditary CRC were included. Studies with fewer than 15 eligible patients, most patients younger than age 18 years, or published before 1996 or in which more than half of the study period occurred before 1996—the year when EOCRC incidence rates began increasing, notably among adults aged 40 to 49 years—were excluded. 22 Meeting abstracts, reviews, non-English articles, and nonoriginal research were excluded.

Two reviewers (J. Demb and J.M.K.) extracted relevant data from articles meeting inclusion criteria, including study characteristics (time period, design, country, and population composition), the proportion of patients with EOCRC presenting with each sign and symptom, relative estimates for association of signs and symptoms with EOCRC risk, and time from symptom presentation to diagnosis, as defined by either patient report of onset of symptoms or medical record capture of symptom presentation. Risk of bias assessment was performed using the Joanna Briggs Institute (JBI) Critical Appraisal tools for cohort studies, cross-sectional studies, and case-control studies. 23 These tools include questions characterizing a study’s sources of bias and internal validity, measurement of exposures, outcomes and follow-up, and potential risk of selection or information bias. Risk of bias was graded and separated into 3 categories: low risk, 75% to 100% of checklist items included; moderate risk, 50% to 75% of checklist items; and high risk, less than 50% of checklist items.

For the assessment of signs and symptoms among patients with EOCRC, sign and symptom proportions were pooled individually across studies and proportions were compared using forest plots. Pooled prevalence estimates were calculated via random-effects meta-analysis using the Hartung and Knapp method, which has been found to perform well when between-study heterogeneity is high and study sample sizes are similar. 24 , 25 Stratified analyses were performed to measure pooled estimates based on specific study characteristics to assess potential variations in estimates, including geographic study location (US vs non-US), study age groups (≤40 years and ≤50 years), risk of bias (low, moderate, high), and data source type (claims or medical record, patient-reported, not well defined). Meta-regression was also performed adjusting for percentage of male study participants and the year of study publication.

We assessed heterogeneity between study-specific estimates using the inconsistency index ( I 2 ), and used cutoffs of 0% to 30%, 30% to 60%, 60% to 90%, and 90% to 100% to suggest minimal, moderate, substantial, and considerable heterogeneity, respectively. Between-study sources of heterogeneity were investigated using subgroup analyses by stratifying original estimates according to study characteristics. In this analysis, P  < .10 differences between subgroups was considered statistically significant (ie, a value of P  < .10 suggests that stratifying based on that particular study characteristic partly explained the heterogeneity observed in the analysis).

Signs and symptoms with estimates of EOCRC risk across at least 3 studies were described using forest plots. Due to significant heterogeneity across studies, particularly the composition of the analytic samples, we were unable to conduct meta-analysis of signs and symptoms and their association with EOCRC risk. Time to diagnosis was defined as the date of sign or symptom presentation to the date of diagnosis and stratified according to the data source type, since this was measured differently across studies. These data were aggregated based on whether the estimate was a mean or median, and the distributions of mean and median times to diagnosis were evaluated.

P values were 2-sided, and statistical significance was set at P  < .10. All analyses were performed using R statistical software version 4.1.3 (R Project for Statistical Computing), with plots and statistical analyses calculated using the suite of functions and commands within the meta package and the ggplot2 package, with R code provided in the eMethods in Supplement 1 . 26 Data were analyzed from August 2022 and April 2024.

Of the 12 859 unique articles retrieved, 699 full texts were reviewed, and 81 studies 12 , 13 , 18 , 27 - 104 were included ( Figure 1 and Table ). There were 76 cross-sectional studies, 12 , 13 , 18 , 27 - 35 , 37 - 43 , 45 , 46 , 48 - 92 , 94 , 96 - 104 4 case-control studies, 44 , 47 , 93 , 95 and 1 cohort study. 36 Studies were performed in Africa (5 studies), 31 , 41 , 54 , 65 , 84 Asia or the Middle East (26 studies), 18 , 35 , 37 , 42 , 48 , 49 , 51 - 53 , 56 , 62 , 66 , 67 , 71 , 77 , 78 , 80 , 82 , 85 , 96 , 99 - 104 Europe (19 studies), 28 , 29 , 40 , 43 , 45 , 46 , 50 , 55 , 57 , 58 , 60 , 63 , 64 , 72 , 73 , 75 , 87 , 91 , 93 North America (23 studies), 12 , 27 , 32 - 34 , 36 , 39 , 44 , 47 , 59 , 61 , 68 - 70 , 74 , 81 , 86 , 88 , 92 , 94 , 95 , 97 , 98 South America (5 studies), 30 , 38 , 83 , 89 , 90 and Oceania (2 studies). 76 , 79 There were 67 studies 12 , 13 , 27 , 28 , 30 , 32 - 34 , 36 , 38 - 40 , 44 , 45 , 47 , 48 , 51 - 77 , 79 , 81 , 83 , 84 , 86 - 102 , 104 deemed to have low risk of bias, 10 studies 18 , 29 , 31 , 35 , 37 , 46 , 50 , 80 , 85 , 103 with moderate risk of bias, and 4 studies 41 , 49 , 78 , 82 with high risk of bias, based on JBI checklists. Notable sources of bias included using patient-reported or inadequately defined measures of signs or symptoms and time to diagnosis (eTable 2 in Supplement 1 ).

There were 78 studies 12 , 13 , 18 , 31 - 92 , 94 - 108 that reported on 17 signs and symptoms at presentation, based on claims or medical records (66 studies), 12 , 13 , 27 , 28 , 30 , 32 - 34 , 38 - 40 , 42 - 45 , 47 , 48 , 51 - 77 , 79 , 81 , 83 , 84 , 86 - 92 , 94 - 104 patient report (6 studies), 18 , 29 , 37 , 46 , 80 , 82 or other (7 studies). 31 , 35 , 41 , 49 , 50 , 78 , 85 ( Figure 2 ; eFigure 1 in Supplement 1 ). In adults with EOCRC, the 3 most common presenting signs and symptoms were hematochezia (pooled prevalence, 45% [95% CI, 40%-50%]; 76 studies), 12 , 13 , 18 , 27 - 31 , 33 - 35 , 37 - 63 , 65 - 92 , 94 - 102 , 104 abdominal pain (pooled prevalence, 40% [95% CI, 35%-45%]; 73 studies), 12 , 13 , 18 , 27 - 31 , 33 - 35 , 37 - 40 , 42 - 67 , 70 - 85 , 87 - 92 , 94 - 102 , 104 and altered bowel habits, which included constipation, diarrhea, alternating bowel habits, or alternating diarrhea or constipation (pooled prevalence, 27% [95% CI, 22%-33%]; 63 studies). 12 , 18 , 28 - 31 , 33 - 35 , 37 - 39 , 43 - 68 , 70 - 72 , 74 - 80 , 83 - 85 , 87 , 88 , 90 , 92 , 94 - 96 , 98 - 100 , 102 , 104

When evaluating patterns by geography, the 3 most common presenting signs and symptoms were the same in both the US (20 studies) 12 , 33 , 34 , 39 , 44 , 47 , 59 , 61 , 68 - 70 , 74 , 81 , 86 , 88 , 92 , 94 , 95 , 97 , 98 and non-US (58 studies) 13 , 27 - 29 , 35 , 37 , 38 , 40 - 43 , 45 , 46 , 48 - 58 , 60 , 62 - 67 , 71 - 73 , 75 - 80 , 82 - 85 , 87 , 89 - 91 , 96 , 99 - 102 , 104 studies (eFigure 2 in Supplement 1 ). When stratifying by age of study population, there were 42 studies 12 , 18 , 28 - 30 , 32 - 34 , 38 - 40 , 42 , 44 , 45 , 48 , 50 , 54 , 61 , 62 , 67 , 69 - 71 , 74 , 75 , 78 , 80 , 82 , 86 - 92 , 94 - 100 including adults aged 50 years or younger and 25 studies 31 , 35 , 37 , 41 , 43 , 46 , 47 , 49 , 51 , 53 , 55 , 56 , 59 , 60 , 63 - 66 , 68 , 72 , 77 , 81 , 83 - 85 including adults aged 40 years and younger. In both groups, the top 3 presenting signs and symptoms were consistent with the primary results (eFigure 3 in Supplement 1 ). Primary results were unchanged in studies with low risk of bias; although in studies with moderate risk of bias, the 3 most common presenting signs and symptoms varied: hematochezia (pooled prevalence, 43% [95% CI, 34%-53%]; 9 studies), abdominal pain (pooled prevalence, 36% [95% CI, 26%-48%]; 9 studies) and obstruction (pooled prevalence, 24% [95% CI. 16%-33%]; 2 studies) (eFigure 4 in Supplement 1 ). When examining data source used to ascertain presenting sign or symptom, only studies with a poorly defined data source showed alternative most common presenting symptoms: loss of appetite (pooled prevalence, 58% [95% CI, 40%-74%]; 2 studies), hematochezia (pooled prevalence, 57% [95% CI, 37%-75%]; 7 studies), and abdominal pain (pooled prevalence, 54% [95% CI, 36%-71%]; 6 studies) (eFigure 5 in Supplement 1 ). Meta-regression analyses by percentage of male study participants or year of study publication across the 17 signs and symptoms for CRC were not found to account for a significant amount of between-study heterogeneity.

There were 5 studies 36 , 44 , 47 , 93 , 95 examining the association of EOCRC risk with abdominal pain, anemia, constipation, diarrhea, hematochezia, and nausea or vomiting ( Figure 3 ). Hematochezia (relative estimate range, 5.2-54.0; 5 studies), 36 , 44 , 47 , 93 , 95 abdominal pain (relative estimate range, 1.3-6.0; 4 studies), 44 , 47 , 93 , 95 and anemia (relative estimate range, 2.1-10.8; 3 studies) 36 , 44 , 47 were associated with higher likelihood of CRC compared with no CRC.

There were 34 studies 18 , 28 , 29 , 31 - 34 , 37 , 38 , 41 , 43 , 44 , 50 , 52 - 54 , 56 - 58 , 61 , 62 , 71 , 75 , 80 , 81 , 83 - 86 , 88 , 90 , 94 , 96 , 104 that reported a continuous measure of time from sign or symptom presentation to diagnosis, with 23 studies providing a mean result and 16 studies providing a median result (eTable 3 in Supplement 1 ). The time from symptom onset to EOCRC diagnosis was reported as a mean (range) of 6.4 (1.8-13.7) months and a median (range) of 4.1 (2.0-8.7) months ( Figure 4 ). When classifying time from sign or symptom onset to diagnosis by measurement type (medical record, patient reported, not well defined), there was considerable heterogeneity. When excluding studies with inadequately defined data sources, the time from symptom onset to EOCRC diagnosis was a mean (range) of 6.6 (3.0-13.7) months and median (range) of 3.8 (2.0-8.7) months (eFigure 6 in Supplement 1 ).

In this systematic review and meta-analysis, nearly half of individuals diagnosed with EOCRC presented with hematochezia and abdominal pain, which were associated with 5- to 54-fold and 1.3- to 6-fold increased likelihood of CRC, respectively. An interval of 4 to 6 months from symptom onset to EOCRC diagnosis was common. These findings underscore the need for clinicians to consider EOCRC as part of the differential diagnosis for patients presenting with potential red flag signs and symptoms, and to follow up through either confirmation of diagnosis and sign or symptom resolution when a benign cause is suspected, or colonoscopy referral to rule out CRC based on sign or symptom severity or absence of diagnosis or sign or symptom resolution after initial workup and management for a suspected benign cause.

Our finding that 45% of individuals with EOCRC presented with hematochezia aligns with current clinical paradigms—hematochezia (or rectal bleeding) is often cited as a common presenting symptom among patients with CRC. 105 In addition, the 5 studies 36 , 44 , 47 , 93 , 95 that measured the association between hematochezia and EOCRC risk found estimates between 5.1 and 54.0, underscoring the urgent need for these patients to undergo comprehensive diagnostic evaluation. A full colonoscopy should be pursued when individuals younger than 50 years present with hematochezia, according to guidelines from the American Society for Gastrointestinal Endoscopy and European Panel on the Appropriateness of Gastrointestinal Endoscopy. 106 , 107 A high index of suspicion for CRC in younger patients with hematochezia may be particularly useful to identify patients with high risk, given the high frequency and association with CRC.

Our review also found that nearly half of individuals with EOCRC reported abdominal pain, based on evidence from 73 studies 12 , 13 , 18 , 27 - 31 , 33 - 35 , 37 - 40 , 42 - 67 , 70 - 85 , 87 - 92 , 94 - 102 , 104 and a 1.3- to 6-fold positive association with EOCRC risk across 4 studies. 44 , 47 , 93 , 95 Given its association with a myriad of gastrointestinal conditions, the American Academy of Family Physicians recommends computed tomography for evaluating patients with acute right or left lower quadrant abdominal pain and ultrasonography for right upper quadrant pain, though the guidelines also recommend identifying associated symptoms to better focus a differential diagnosis. 108 It may be inefficient and unrealistic to perform colonoscopy for all adults younger than 45 years with isolated abdominal pain, given the low diagnostic yield 109 and insufficient capacity across the US to accommodate this group. Nevertheless, the fact that 40% of patients with EOCRC presented with abdominal pain and 27% presented with altered bowel habits reinforces that any new symptom should be comprehensively evaluated by a clinician. Our findings suggest that EOCRC should be part of the initial differential diagnosis, and that a plan for follow-up should be in place, such as a 30- to 60-day follow-up visit to confirm whether the original working diagnosis was correct, the red flag sign or symptom has resolved, or to refer for colonoscopy to exclude EOCRC if these criteria are not met. 110 We postulate that all benign causes of red flag signs or symptoms either can be diagnostically confirmed or should resolve with initial treatment. When an alternative diagnosis is not confirmed or signs or symptoms fail to resolve, a colonoscopy to rule out EOCRC should be pursued. Abdominal pain could serve as a marker to prompt further patient-clinician discussion about additional medical history, which could help determine whether further diagnostic work-up is warranted.

Globally and in the US, hematochezia, abdominal pain, and altered bowel habits were the 3 most common signs and symptoms. The fourth most common symptom differed based on geographic location—diarrhea among US studies and loss of appetite in non-US studies. The findings highlight how nonspecific symptoms are frequently present at EOCRC diagnosis and emphasize the need for medical professionals to be aware of the symptoms most associated with EOCRC, to refine clinical practice pathways and minimize late EOCRC detection.

The mean time from sign or symptom onset to EOCRC diagnosis was found to be 6.4 months (median, 4 months). A recent study using administrative claims data in Canada from 2003 to 2018 reported the greatest delay occurring between the first investigation and diagnosis (78 days) with short turnaround times between presentation and first investigation (5 days) or diagnosis and treatment start (23 days). Date of first presentation was defined by the physician visit related to the diagnostic examination (endoscopy, surgery, or imaging). 111 The data are mixed on whether decreasing time to diagnosis would improve outcomes, but it is well established that risk for progression to more advanced-stage disease increases over time. Another claims-based study from Canada found that young individuals with CRC had longer diagnostic intervals compared with middle-aged patients, although young patients with metastatic EOCRC had a short diagnostic interval, likely due to more noticeable or concerning symptoms. 32 Other studies found that differences between older and younger patients with CRC in stage at presentation were not just associated with delayed diagnosis, but could be associated with additional biological and genetic factors. 33

Nevertheless, it is prudent to address potential physician and patient barriers to timely workup. Younger patients may experience ongoing signs and symptoms and delay seeking medical attention. 88 Potential reasons for these delays include a patient believing they are too young to worry about cancer or a lack of access to primary care or health insurance. 88 , 110 Clarifying how these signs and symptoms are associated with EOCRC could give patients greater urgency to report these symptoms sooner, leading to quicker diagnostic workup and resolution. For clinicians, particularly those in primary care, recognition of clues and appropriate diagnostic workup for concerning signs and symptoms is paramount to early EOCRC detection. However, prior studies found that clinicians often dismiss these signs and symptoms or misattribute them to more benign conditions, such as attributing rectal bleeding to hemorrhoids, without conducting further diagnostic evaluation. 15 , 112 This can leave a potentially concerning sign or symptom unresolved for an extended period of time, and for some patients, delay EOCRC diagnosis. To avoid missing an EOCRC diagnosis, clinicians should work with patients to ensure concerning signs and symptoms undergo diagnostic evaluation to identify and resolve the underlying cause.

Our study has several strengths. Our approach distilled a tremendous amount of global data over several decades into clear and practical information that is immediately useful to clinicians. We applied strict study selection criteria to capture only individuals younger than 50 years with nonhereditary CRC to represent an individual with average risk diagnosed with EOCRC beginning in 1996, when EOCRC rates started to increase. The meta-analysis adjusted for or stratified by potential contributors to study heterogeneity, including study quality, age of study population, country of study origin, percentage of male study participants, and year of publication.

Our study has some limitations. There was significant heterogeneity across studies, which impacted our ability to meta-analyze some of our results. This was most significant in assessment of the associations of signs and symptoms with EOCRC, where a lack of a consistent comparator group hindered our ability to pool estimates for the associations. Additionally, we were unable to compare EOCRC risk against other potential outcomes, which might have better contextualized the relative risk. In our measurement of association of signs and symptoms with EOCRC, studies did not measure the potential likelihood of reverse causation—whether EOCRC was associated with sign or symptom presentation. We were unable to evaluate the impact of time to diagnosis on CRC outcomes due to a limited number of studies answering this question. In addition, sign- and symptom-based data extracted from studies used in this review were often extracted cross-sectionally to characterize patients with EOCRC at study baseline, limiting our access to stratified or more granular results by age, sex, race and ethnicity, or genetic ancestry, which could have better contextualized the burden of signs and symptoms and relevant EOCRC risk. We were unable to examine the constellation of signs and symptoms since we lacked individual-level data from each study and could not provide a positive predictive value for symptoms. However, we anticipate patients may have presented with multiple signs and symptoms and encourage clinicians to consider the full list of common presenting signs and symptoms and their prevalence to aid in EOCRC risk assessment.

This systematic review and meta-analysis of studies examining sign and symptom presentation of EOCRC found that hematochezia, abdominal pain, altered bowel habits, and unexplained weight loss were the most common presenting signs and symptoms in patients diagnosed with EOCRC. Markedly increased EOCRC risk was seen in adults with hematochezia and abdominal pain. Furthermore, time from sign or symptom presentation to EOCRC diagnosis was often between 4 and 6 months. These findings and the increasing risk of CRC in individuals younger than 50 years highlight the urgent need to educate clinicians and patients about these signs and symptoms to ensure that diagnostic workup and resolution are not delayed. Adapting current clinical practice to identify and address these signs and symptoms through careful clinical triage and follow-up could help limit morbidity and mortality associated with EOCRC.

Accepted for Publication: March 19, 2024.

Published: May 24, 2024. doi:10.1001/jamanetworkopen.2024.13157

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2024 Demb J et al. JAMA Network Open .

Corresponding Author: Joshua Demb, PhD, MPH, Division of Gastroenterology, Department of Medicine, University of California, San Diego, 3350 La Jolla Village Dr, Bldg 13, San Diego, CA 92126 ( [email protected] ).

Author Contributions: Drs Demb and Kolb had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Demb and Kolb are co–first authors.

Concept and design: Demb, Kolb, Fritz, Advani, Cao, Dwyer, Heskett, Lieu, Singh, Vuik, Gupta.

Acquisition, analysis, or interpretation of data: Demb, Kolb, Dounel, Fritz, Cao, Coppernoll-Blach, Perea, Heskett, Holowatyj, Lieu, Singh, Spaander, Gupta.

Drafting of the manuscript: Demb, Kolb, Dounel, Fritz, Advani, Dwyer, Heskett, Lieu.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Demb, Singh.

Administrative, technical, or material support: Dwyer, Heskett, Gupta.

Supervision: Demb, Kolb, Advani, Perea, Spaander, Gupta.

Conflict of Interest Disclosures: Dr Holowatyj reported receiving grants from National Institutes of Health, American Cancer Society, Pfizer, Dalton Family Foundation, and ACPMP Research Foundation and personal fees from MJH Life Sciences outside the submitted work. Dr Gupta reported receiving personal fees from Guardant Health, Universal Diagnostics, Geneoscopy, and InterVenn Biosciences and owning stock in CellMax Life outside the submitted work. No other disclosures were reported.

Data Sharing Statement: See Supplement 2 .

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