systematic review research protocol

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Systematic reviews.

• Should I do a systematic review?
• Writing the Protocol
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• Where to Search
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How do I write a protocol?

The protocol serves as a roadmap for your review and specifies the objectives, methods, and outcomes of primary interest of the systematic review. Having a protocol promotes transparency and can be helpful for project management. Some journals require you to submit your protocol along with your manuscript. 

A good way to familiarize yourself with research protocols is to take a look at those registered on PROSPERO. PROSPERO's registration form includes 22 mandatory fields and 18 optional fields which will help you to explain every aspect of your research plan. 

• PROSPERO - International prospective register of systematic reviews

A protocol ideally includes the following:

• Databases to be searched and additional sources (particularly for grey literature)
• Keywords to be used in the search strategy
• Limits applied to the search
• Screening process
• Data to be extracted
• Summary of data to be reported

Once you have written your protocol, it is advisable to register it. Registering your protocol is a good way to announce that you are working on a review, so that others do not start working on it.

The University of Warwick's protocol template is available below and is a great tool for planning your protocol. 

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• Last Updated: May 1, 2024 1:01 PM
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Systematic Review Service

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• Step 1: Form Your Team
• Step 2: Define Your Research Question
• Step 3: Write and Register Your Protocol
• Step 4: Search for Evidence
• Step 5: Screen Your Results
• Step 6: Assess the Quality
• Step 7: Collect the Data
• Step 8: Write and Publish the Review
• Additional Resources

You Need a Systematic Review Protocol

When completed early in your review process, the protocol:

• Streamlines the process for all team members.
• Improves the quality of the resulting review.
• Saves time, as you have your plans outlined before you start.
• Increases your chances of publication, as some journals require pre-registered protocols.

The Protocol Process

• Write Your Protocol
• Register Your Protocol
• Publish Your Protocol

The  PRISMA for Systematic Review Protocols (PRISMA-P) extension  lays out everything your team needs to include in a protocol. Protocol registries follow similar, if not identical, requirements.

You have several choices as to where to register a review protocol:

• Download a  PDF of the PROSPERO Registration Form .
• Download the registration form as a  Word document . More detailed instructions are in the PDF and on the PROSPERO website.
• You must  register your protocol in PROSPERO  before beginning the data extraction phase of your review.  
• If you are performing a scoping review , your protocol is not eligible for registration on PROSPERO. Open Science Framework (OSF) Registries  is a go-to alternative.  Find out more here.   
• Research Registry's Registry of Systematic Reviews/Meta-Analyses 
• The International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY)
• Protocols.io

It is an option, but not a requirement, to publish your review protocol. Here is a selection of journals that accept them. Note that all of these journals charge article processing fees .

• BMJ Open  
• JBI Evidence Synthesis  
• JMIR Research Protocols  
• Medicine (Baltimore)  
• PLOS One   
• Systematic Reviews  

How the MSK Library Can Help

Drafts of protocols are enormously helpful to MSK librarians as they build searches that accurately reflect your topic. 

Moreover, PRISMA-P , the PRISMA extension for protocols, requires a list of information sources to be searched in your review, along with a draft of a search strategy. Your MSK librarian will work with your team to determine the sources to search and build the search, and can send this information to your team once it is ready.

Your MSK librarian can also work with you to determine the review requirements of your target journal(s), which may impact the plans for your review as reflected in your protocol.

• << Previous: Step 2: Define Your Research Question
• Next: Step 4: Search for Evidence >>
• Last Updated: Apr 18, 2024 9:23 AM
• URL: https://libguides.mskcc.org/systematic-review-service

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Living Systematic Review

Carole Mitnick, Molly Franke, Celia Fung, Andrew Lindeborg. Clinical Outcomes of Individuals with COVID-19 and Tuberculosis Disease: a Living Systematic Review . PROSPERO 2020 CRD42020187349 

Systematic Review and Meta-Analysis

Brindle ME, Roberts DJ, Daodu O, Haynes AB, Cauley C, Dixon E, La Flamme C, Bain P, Berry W. Deriving literature-based benchmarks for surgical complications in high-income countries: a protocol for a systematic review and meta-analysis. BMJ Open. 2017 May 9. PMID: 28487456

We require a completed protocol before we will carry out final searches on any knowledge synthesis project.

We encourage you to use this template, which is based on the PRISMA-P checklist (Moher D, et al. Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4(1):1. PMID: 25554246 .)

• Countway Protocol Template

Why a Protocol

From the Cochrane Handbook :

“The protocol sets out the context in which the review is being conducted. It presents an opportunity to develop ideas that are foundational for the review.” “Preparing a systematic review is complex and involves many judgements. To minimize the potential for bias in the review process, these judgements should be made as far as possible in ways that do not depend on the findings of the studies included in the review.” “Publication of a protocol for a review that is written without knowledge of the available studies reduces the impact of review authors’ biases, promotes transparency of methods and processes, reduces the potential for duplication, allows peer review of the planned methods before they have been completed, and offers an opportunity for the review team to plan resources and logistics for undertaking the review itself.”

Lasserson TJ, Thomas J, Higgins JPT. Chapter 1: Starting a review. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.4 (updated August 2023). Cochrane, 2023. Available from www.training.cochrane.org/handbook.

A protocol is your plan for carrying out your knowledge synthesis. It presents the rationale for carrying out the project and clearly states the aims of the work. The protocol describes the process for selecting research for inclusion, including the provision of explicit criteria for assessing reports for inclusion and for analyzing the included reports. Hence, it is an internal document that helps team members work together more smoothly. But it also is a hedge against bias by clearly stating the rules of the game before any work has begun. A protocol makes it more difficult to alter selection patterns based on perceived results. Beyond acting as a roadmap for your research, protocols, when registered or published in some way, allow others to see your research plan, establishing priority and reducing the risk of duplicate research.

Protocol Reporting Guidelines

• PRISMA (Preferred Reporting Items for Systematic Reviews) PRISMA-P was published in 2015 aiming to facilitate the development and reporting of systematic review protocols.
• MECIR (Methodological Expectations of Cochrane Intervention Reviews) Standards for the conduct of new Cochrane Intervention Reviews, and the planning and conduct of updates

Protocol Registries

• PROSPERO International prospective register of systematic reviews
• OSF (Open Science Framework) OSF is a free, open platform to support your research and enable collaboration.
• Cochrane If planning a Cochrane Review, you must publish your protocol with them after your proposal has been accepted.

Additional Resources

• Writing a review protocol - good practice and common errors This is a two part webinar provided by Cochrane Training intended to provide up to date guidance for review authors wishing to learn more about developing their own protocol.
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• Next: Databases and Sources >>
• Last Updated: Feb 26, 2024 3:17 PM
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Article Contents

Introduction, contents of a systematic review/meta-analysis protocol, conflict of interest statement.

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How to write a systematic review or meta-analysis protocol

• Article contents
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Julien Al Shakarchi, How to write a systematic review or meta-analysis protocol, Journal of Surgical Protocols and Research Methodologies , Volume 2022, Issue 3, July 2022, snac015, https://doi.org/10.1093/jsprm/snac015

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A protocol is an important document that specifies the research plan for a systematic review/meta analysis. In this paper, we have explained a simple and clear approach to writing a research study protocol for a systematic review or meta-analysis.

A study protocol is an essential part of any research project. It sets out in detail the research methodology to be used for the systematic review or meta-analysis. It assists the research team to stay focused on the question to be answered by the study. Prospero, from the Centre for Reviews and Dissemination at the University of York, is an international prospective register of systematic reviews and authors should consider registering their research to reduce the potential for duplication of work. In this paper, we will explain how to write a research protocol by describing what needs to be included.

Introduction

This section sets out the need for the planned research and the context of the current evidence. It should be supported by an extensive background to the topic with appropriate references to the literature. This should be followed by a brief description of the condition and the target population. A clear explanation for the rationale and objective of the project is also expected to justify the need of the study.

Methods and analysis

A detailed search strategy is necessary to be described in the protocol. It should set out which databases are to be included as well as the specific keywords be searched and publication timeframe. The inclusion/exclusion criteria should be described for the type of studies, participants and interventions. The population, intervention, comparator and outcome (PICO) framework is a useful tool to consider for this section.

The methodology of the data extraction should be detailed in this section and should include how many reviewers will be involved and how any disagreement will be resolved. The methodology to be used for quality and bias assessment of included studies should also be described in this section. Data analysis including statistical methodology needs to be established clearly in this section of the protocol. Finally details of any planned subgroup analyses should also be included.

Ethics and dissemination

Any competing interests of the researchers should also be stated in this section. The authorship of any publication should have a clear and fair criterion which should be described in this section of the protocol. By doing so, it will resolve any issues arising at the publication stage.

Funding statement

It is important to explain who are the sponsors and funders of the study. It should clearly clarify the involvement and potential influence of any party. The protocol should explicitly outline the roles and responsibilities of any funder(s) in study design, data analysis and interpretation, manuscript writing and dissemination of results.

A protocol is an important document that specifies the research plan for a systematic review or meta-analysis. It should be written in detail and researchers should aim to publish their study protocols. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement provides a useful checklist on what should be included in a systematic review [ 1 ]. In this paper, we have explained a simple and clear approach to writing a research study protocol for a systematic review or meta-analysis.

None declared.

Page   MJ , McKenzie   JE , Bossuyt   PM , Boutron   I , Hoffmann   TC , Mulrow   CD , et al.    The PRISMA 2020 statement: an updated guideline for reporting systematic reviews . BMJ   2021 ; 372 : n71 .

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Cochrane Cochrane Interactive Learning

Cochrane interactive learning, module 2: writing the review protocol, about this module.

Part of the Cochrane Interactive Learning course on Conducting an Intervention Review, this module explains why a review protocol is a crucial step in planning and delivering a systematic review. This module teaches you about the components of a protocol, and how to define eligibility criteria using the PICO format.

45-60 minutes

What you can expect to learn (learning outcomes).

This module will teach you to:

• Recognize the importance of Cochrane Protocols
• Identify the eligibility criteria for studies to be included in a Cochrane Review
• Identify the information that should be included in the background of a Cochrane Review
• Recognize the key components of a well-written objective
• Recognize the structure of a protocol

Authors, contributors, and how to cite this module

Module 2 has been written and compiled by Dario Sambunjak, Miranda Cumpston and Chris Watts,  Cochrane Central Executive Team .

A full list of acknowledgements, including our expert advisors from across Cochrane, is available at the end of each module page.

This module should be cited as: Sambunjak D, Cumpston M, Watts C. Module 2: Writing the review protocol. In: Cochrane Interactive Learning: Conducting an intervention review. Cochrane, 2017. Available from https://training.cochrane.org/interactivelearning/module-2-writing-review-protocol .

Update and feedback

The module was last updated on September 2022.

We're pleased to hear your thoughts. If you have any questions, comments or feedback about the content of this module, please contact us .

• UNC Libraries
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• Systematic Reviews
• Step 2: Develop a Protocol

Systematic Reviews: Step 2: Develop a Protocol

Created by health science librarians.

• Step 1: Complete Pre-Review Tasks

Do I need to write a protocol?

Writing a protocol, make your protocol visible.

• Protocol FAQs
• 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
• Step 8: Write the Review

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About Step 2: Develop a Protocol

In Step 2, you will write your systematic review protocol. This is a detailed work plan for your systematic review. You will:

• Define the criteria you will use to screen literature.
• Decide where and how you will search for literature.
• Choose quality assessment tools to evaluate the literature.
• Decide how you will extract data from the articles you include.
• Upload your protocol to a website or registry to make it available to the public.

This page has checklists and templates to help you write your protocol. Librarians can help you refine your protocol based on systematic review best-practices.

Click an item below to see how it applies to Step 2: Develop a Protocol.

Reporting your review with PRISMA

For PRISMA, there are specific items you will want to report in your protocol.  For this step, review the PRISMA-P standards and the explanation document.

• PRISMA-P for Protocols
• PRISMA-P Explanation & Elaboration document
• PRISMA-P Checklist

Managing your review with Covidence

Covidence is a tool that can be used for screening, quality assessment, and data extraction. Decisions made in this stage will inform the logistics and completion of future review steps. Specify the use of Covidence in the protocol, if applicable, and note team member roles for these tasks.

How a librarian can help with Step 2

When writing your protocol, a librarian can help you :

• Develop and refine your research plan according to systematic review best practices 
• Advise on your literature searching methods documentation 
• Determine if/where to publish or share your completed protocol

What is a protocol? 

A protocol is a detailed work plan that describes how and why you are doing a systematic review. It includes your rationale and objectives, how you will search for literature, and how you will screen and synthesize what you find. It is best practice to develop a protocol and make it publicly available before starting a systematic review. 

Why should you write a protocol?

Your protocol will help your team navigate the systematic review process. It will also show readers how your completed systematic review might be different from your plan. This can help them understand whether there is any bias in your review results and conclusions. 

Uploading your protocol

You can upload a review protocol to a website or registry and make it accessible so researchers can know what reviews are planned or in process. While not an inclusive list, several options of places to upload or deposit your protocol can be found in our Protocol FAQ .  

Writing a Review Protocol: Good Practice and Common Errors

                            HSL Protocol Template                     

What to Include

Many  elements of a systematic review will need to be detailed in advance in the protocol. An example of items included in the protocol are:

• Team members
• Rationale and objectives of the review
• Eligibility criteria (also referred to as inclusion and exclusion criteria)
• Databases and key terms of the literature search (ideally, a full search strategy for at least one database)
• Process and tools for study selection (screening) , quality assessment , and data extraction
• Data items that will be extracted
• Methods of data synthesis

Use PRISMA to write your protocol

PRISMA is a set of standards about what to include in your systematic review. PRISMA 2015 has a special extension specifically for the best protocol reporting methods. The documents linked below (PRISMA-P Statement, E&E, and PRISMA-P Checklist) provide detailed instructions about how to write a good protocol.

• PRISMA-P 2015 Statement PRISMA reporting guideline for systematic review protocols.
• PRISMA-P 2015 E&E PRISMA-P Elaboration & Explanation document of the 2015 Statement (includes examples).
• PRISMA-P 2015 Checklist Choose between PDF and Word versions of the PRISMA-P 2015 Checklist
• UNC HSL Systematic Review Protocol Template Word document protocol template for systematic review protocols adapted from the PRISMA-P checklist
• Review Protocol Template by Sarah Vistintini A downloadable Word document that can be used to draft a systematic review protocol
• Evidence Synthesis Protocol Template A downloadable Word document that can be used to create a systematic review protocol
• PROSPERO Protocol Registration Form A PDF of the PROSPERO registration form
• Open Science Framework (OSF) Systematic Review Protocol Open Science Framework's (OSF) protocol template for preregistering systematic reviews, scoping reviews, and meta-analyses

You can upload your protocol to a website or registry and make it available to others. There are several places to upload or deposit your protocol listed below.  Alternatively, some journals publish systematic review protocols. If you plan to publish your protocol in a journal, make sure to check the protocol requirements on the journal website before submitting.

Compare protocol registries to see which tool might meet your needs.

• PROSPERO International prospective register of systematic reviews. Free.
• Open Science Framework (OSF) Open repository for scientific research. Free.
• Carolina Digital Repository Long-term storage and access for scholarly works, datasets, research materials and records produced by the UNC-CH community (free). Choose "Other Deposits" and then select "Poster, Presentation, Protocol, or Paper".
• Research Registry Register all types of research studies, from ‘first in man’ case reports to observational/interventional studies to systematic reviews and meta-analyses. Not free.
• INPLASY- The International Platform of Registered Systematic Review and Meta-analysis Protocols An international database created to help researchers around the world to register their systematic review protocols. Not free.
• Protocols.io A secure platform for developing and sharing reproducible methods. Create a protocol, collaborate with your team, then run as a checklist. Free.
• << Previous: Step 1: Complete Pre-Review Tasks
• Next: Step 3: Conduct Literature Searches >>
• Last Updated: Apr 24, 2024 2:00 PM
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• The PRISMA 2020...

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

PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews

• Related content
• Peer review
• Matthew J Page , senior research fellow 1 ,
• Joanne E McKenzie , associate professor 1 ,
• Patrick M Bossuyt , professor 2 ,
• Isabelle Boutron , professor 3 ,
• Tammy C Hoffmann , professor 4 ,
• Cynthia D Mulrow , professor 5 ,
• Larissa Shamseer , doctoral student 6 ,
• Jennifer M Tetzlaff , research product specialist 7 ,
• Elie A Akl , professor 8 ,
• Sue E Brennan , senior research fellow 1 ,
• Roger Chou , professor 9 ,
• Julie Glanville , associate director 10 ,
• Jeremy M Grimshaw , professor 11 ,
• Asbjørn Hróbjartsson , professor 12 ,
• Manoj M Lalu , associate scientist and assistant professor 13 ,
• Tianjing Li , associate professor 14 ,
• Elizabeth W Loder , professor 15 ,
• Evan Mayo-Wilson , associate professor 16 ,
• Steve McDonald , senior research fellow 1 ,
• Luke A McGuinness , research associate 17 ,
• Lesley A Stewart , professor and director 18 ,
• James Thomas , professor 19 ,
• Andrea C Tricco , scientist and associate professor 20 ,
• Vivian A Welch , associate professor 21 ,
• Penny Whiting , associate professor 17 ,
• David Moher , director and professor 22
• 1 School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
• 2 Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, Netherlands
• 3 Université de Paris, Centre of Epidemiology and Statistics (CRESS), Inserm, F 75004 Paris, France
• 4 Institute for Evidence-Based Healthcare, Faculty of Health Sciences and Medicine, Bond University, Gold Coast, Australia
• 5 University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA; Annals of Internal Medicine
• 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
• 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
• 9 Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon, USA
• 10 York Health Economics Consortium (YHEC Ltd), University of York, York, UK
• 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
• 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
• 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
• 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
• 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
• 16 Department of Epidemiology and Biostatistics, Indiana University School of Public Health-Bloomington, Bloomington, Indiana, USA
• 17 Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
• 18 Centre for Reviews and Dissemination, University of York, York, UK
• 19 EPPI-Centre, UCL Social Research Institute, University College London, London, UK
• 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
• 21 Methods Centre, Bruyère Research Institute, Ottawa, Ontario, Canada; School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, Canada
• 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
• Correspondence to: M J Page matthew.page{at}monash.edu
• Accepted 4 January 2021

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

• View inline

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.

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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.

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.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/ .

• Gurevitch J ,
• Koricheva J ,
• Nakagawa S ,
• Liberati A ,
• Tetzlaff J ,
• Altman DG ,
• PRISMA Group
• Tricco AC ,
• Sampson M ,
• Shamseer L ,
• Leoncini E ,
• de Belvis G ,
• Ricciardi W ,
• Fowler AJ ,
• Leclercq V ,
• Beaudart C ,
• Ajamieh S ,
• Rabenda V ,
• Tirelli E ,
• O’Mara-Eves A ,
• McNaught J ,
• Ananiadou S
• Marshall IJ ,
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• Chandler J ,
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• Reeves BC ,
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• ROBIS group
• Hultcrantz M ,
• Stewart L ,
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• Flemming K ,
• McInnes E ,
• France EF ,
• Cunningham M ,
• Rethlefsen ML ,
• Kirtley S ,
• Waffenschmidt S ,
• PRISMA-S Group
• ↵ Higgins JPT, Thomas J, Chandler J, et al, eds. Cochrane Handbook for Systematic Reviews of Interventions : Version 6.0. Cochrane, 2019. Available from https://training.cochrane.org/handbook .
• Dekkers OM ,
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• IOM (Institute of Medicine)
• PRISMA-P Group
• Salanti G ,
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• PRISMA-IPD Development Group
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• Ioannidis JP ,
• PRISMAHarms Group
• McInnes MDF ,
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• and the PRISMA-DTA Group
• Beller EM ,
• Glasziou PP ,
• PRISMA for Abstracts Group
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• MUDS investigators
• Stovold E ,
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• Noel-Storr A
• McGuinness LA
• Sarafoglou A ,
• Boutron I ,
• Giraudeau B ,
• Porcher R ,
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Systematic Review Protocols and Protocol Registries

Systematic review protocols.

• a good systematic review can start with a protocol - it can serve as a road map for your review
• a protocol specifies the objectives, methods, and outcomes of primary interest of the systematic review
• a protocol promotes transparency of methods
• allows your peers to review how you will extract information to quantitavely summarize your outcome data

About Systematic Review Protocol Registries

• Various protocol registries exists
• Anyone can register their protocol
• Registering your protocol is helpful to establish that your group is doing this review
• Registering increases potential communication with interested researchers
• Registering may reduce the risk of multiple reviews addressing the same question
• Registering may provide greater transparency when updating a systematic review

Protocol Reporting Guidelines

• MECIR (Methodological Expectations for Cochrane Intervention Reviews) Manual  - guidelines on reporting protocols for Cochrane Intervention reviews
• PRISMA-P  - (PRISMA (Preferred Reporting Items for Systematic Reviews) for systematic review protocols

Systematic Review/Protocol Registries

• Campbell Collaboration  - produces systematic reviews of the effects of social interventions
• Cochrane Collaboration  - international organization, produces and disseminates systematic reviews of health care interventions
• PROSPERO  -international prospective register of systematic reviews

Introduction to Systematic Reviews

In this guide.

• Introduction
• Lane Research Services
• Types of Reviews
• Systematic Review Process
• Protocols & Guidelines
• Data Extraction and Screening
• Resources & Tools
• Systematic Review Online Course

Is there already a systematic review on your topic?

Have a topic in mind? Before deciding on a research question for a systematic review, it is best to see if there is a systematic review on that topic already. You can broadly search across the databases and registries below for current and past systematic reviews.

• PROSPERO An international database of health research protocols for systematic reviews, rapid reviews, and umbrella reviews that have been registered but not yet published.
• Cochrane Database of Systematic Reviews Full-text access to systematic reviews conducted by the Cochrane Collaboration and includes review protocols in development.
• PubMed Clinical Queries Locates published systematic reviews indexed in MEDLINE.
• Joanna Briggs Institute Systematic Review Register A registry of systematic review titles by JBI review authors that are currently in development or underway.
• Epistemonikos A database of systematic reviews and other types of scientific evidence. It connects systematic reviews and its included studies to allow clustering of systematic reviews based on the primary studies they have in common.

Registering A Protocol

It is important to register your research protocol in a publicly accessible way. This will help you avoid other researchers completing a review on your topic. Similarly, before you begin a systematic review, it's worth checking different registries and systematic review databases to determine what projects are already completed or is currently underway on the same topic. The following lists some resources to register and prepare a protocol.

• Open Science Framework
• Joanna Briggs Institute Systematic Review Register
• Cochrane Reviews 

Systematic Review Guidelines

• Cochrane Handbook for Systematic Reviews of Interventions (V6.1, 2020) The Cochrane Collaboration produces systematic reviews of primary research in human health care and health policy.
• Joanna Briggs Institute (JBI) Manual for Evidence Synthesis (2020)
• Institute of Medicine (IOM) Standards for Systematic Reviews (2011)
• Center for Reviews Dissemination (CRD) Systematic Reviews (2009) The Center for Reviews Dissemination is a research department at the University of York, UK that specializes in developing evidence synthesis methods and facilitating the use of research evidence in decision-making, economic evaluations, and policies.
• Campbell Collaboration The Campbell Collaboration is an international social science research network that produces systematic reviews on the effects of social interventions in Crime & Justice, Education, International Development, and Social Welfare.

Reporting Standards

The EQUATOR Network is an international initiative that seeks to improve the reliability and value of published health research literature by promoting transparent and accurate reporting and wider use of robust reporting guidelines. The EQUATOR Library rovides an up-to-date collection of guidelines and policy documents related to health research reporting. These are aimed mainly at authors of research articles, journal editors, peer reviewers and reporting guideline developers. There are over 400 guidelines in the library's collection.

Reporting guidelines for common study types:

• PRISMA (systematic reviews)
• CONSORT (randomized control trials)
• MOOSE (observational studies)
• SQUIRE (quality improvement studies)
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• Last Updated: Apr 29, 2024 10:50 AM
• URL: https://laneguides.stanford.edu/systematicreviews

Doing a systematic review

Creating a protocol, pico framework for structuring your research, alternative frameworks.

• Step 2: choosing where to search
• Step 3: developing a search strategy
• Step 4: running & recording your search
• Step 5: managing your search results
• Step 6: screening & evaluating
• Step 7: synthesis and writing it up (including PRISMA flow diagrams)

Finding reviews in progress and examples

Use the PROSPERO database to find examples of protocols and details of reviews in progress. If you are planning to publish your review check PROSPERO to make sure someone isn't already investigating that area. It is also a good idea to register your own review here once you've established its uniqueness.

• PROSPERO This international database covers prospectively registered systematic reviews in health and social care, welfare, public health, education, crime, justice, and international development, where there is a health related outcome.

Software for managing your review

• RevMan Review Manager (RevMan) is Cochrane's software for preparing and maintaining Cochrane reviews, although it can be used for non-Cochrane reviews too. If you are doing a professional systematic review leading to publication you may wish to consider using it to help manage the process. RevMan facilitates preparation of protocols and full reviews, including text, characteristics of studies, comparison tables, and study data. It can perform meta-analysis of the data entered, and present results graphically.

• research question and aims
• criteria for inclusion and exclusion
• search strategy
• selecting studies for inclusion
• quality assessment
• data extraction & analysis
• synthesis of results
• dissemination
• time frame.

You may wish to do some scoping searches of relevant databases to find out how much has been written, and what limits you should apply.

• Systematic review protocol template Use this Word document to help you plan your review and develop your protocol
• Systematic review protocol example An example of using the protocol template to plan a systematic review.
• The review protocol Produced by the Centre for Reviews and Dissemination this detailed guidance covers elements to consider when creating a review protocol.
• Watch our video introductions to doing a systematic review Watch video 2 in our series of videos on doing a systematic review for brief guidance on creating your protocol.

There are several different frameworks you can use to help structure your research and ensure you have clear parameters for your search. The most commonly used one used for health-related reviews is the PICO framework:

• Population This could be the general population, or a specific group defined by: age (e.g. infants, children, adolescents, elderly); socioeconomic status (e.g. low-income, homeless); risk status; location (rural or urban)
• Intervention Refers to the therapy, test, strategy to be investigated (e.g. drug, behavioural change, environmental factors, counselling)
• Comparator A measure you will use to compare results against (e.g. no treatment, alternative treatment/exposure, standard/routine interventions)
• Outcome What outcome is significant to your population or issue? This may be different from the outcome measures used in the studies.

PICO example

This example is extracted from: PROSPERO 2018 CRD42018100888 .

Further information

• Developing an efficient search strategy using PICO A tool created by Health Evidence which can be used to: develop a clear, answerable question that can be used to generate a search strategy; identify key search terms to facilitate a more efficient search; and to document search strategies/terms for future search updates, either in the same or similar topics.

Another framework may be more suitable depending on your review topic. Here are some other options:

• PECO – Population | Environment | Comparison | Outcome Very similar to PICO but looking at the effect of exposure to something e.g. smoky atmosphere
• SPICE - Setting | Population | Intervention | Comparison | Evaluation Another variant of PICO but this time including the setting (where? in what context?)
• CIMO - Context | Intervention | Mechanisms | Outcome A variant of PICO suitable for management and organisation studies
• ECLIPSE - Expectation | Client group | Location | Impact | Professionals | SErvice Recommended for health policy/management searches
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Unlocking the Potential: A Systematic Review of Master Protocol in Pediatrics

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• Published: 23 April 2024

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• Yimei Li   ORCID: orcid.org/0000-0001-9067-6992 1 , 2 , 3 ,
• Robert Nelson 4 ,
• Rima Izem 5 ,
• Kristine Broglio 6 ,
• Rajiv Mundayat 7 ,
• Margaret Gamalo 7 ,
• Yansong Wen 3 ,
• Haitao Pan 8 ,
• Hengrui Sun 9 &
• Jingjing Ye 10  

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The use of master protocols allows for innovative approaches to clinical trial designs, potentially enabling new approaches to operations and analytics and creating value for patients and drug developers. Pediatric research has been conducted for many decades, but the use of novel designs such as master protocols in pediatric research is not well understood. This study aims to provide a systematic review on the utilization of master protocols in pediatric drug development. A search was performed in September 2022 using two data sources (PubMed and ClinicalTrials.gov) and included studies conducted in the past10 years. General study information was extracted such as study type, study status, therapeutic area, and clinical trial phase. Study characteristics that are specific to pediatric studies (such as age of the participants and pediatric drug dosing) and important study design elements (such as number of test drug arms and whether randomization and/or concurrent control was used) were also collected. Our results suggest that master protocol studies are being used in pediatrics, with platform and basket trials more common than umbrella trials. Most of this experience is in oncology and early phase studies. There is a rise in the use starting in 2020, largely in oncology and COVID-19 trials. However, adoption of master protocols in pediatric clinical research is still on a small scale and could be substantially expanded. Work is required to further understand the barriers in implementing pediatric master protocols, from setting up infrastructure to interpreting study findings.

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Introduction

A master protocol is a novel clinical trial design that attempts to evaluate multiple experimental therapies in one or multiple indications, under one overarching protocol [ 1 ]. The definitions of a master protocol and its subtypes vary considerably in the medical literature [ 2 ]; however, it is reasonable to adopt the definitions proposed by the Food & Drug Administration (FDA) whereby there are three types of master protocols: umbrella, basket, and platform [ 3 ]. An umbrella trial evaluates multiple drugs or drug regimens for a single disease. A basket trial evaluates a single drug or drug regimen for multiple diseases. A platform trial studies multiple drugs for a single disease but allows drugs to enter or leave the platform based on a decision algorithm [ 1 ]. As such, a platform trial can be understood as an adaptive umbrella trial where substudies involving either treatment arms or study populations can be added or dropped during the trial [ 4 , 5 ].

The use of a master protocol holds the promise of increasing efficiency and enabling new approaches to operations and analytics [ 6 ]. Pediatric drug development poses many challenges, some of which could be addressed by using master protocols. For example, sponsors are required to conduct pediatric studies (absent a waiver) for assets being developed for adult diseases. Thus multiple sponsors may need to conduct similar pediatric studies in the same, relatively small population. In this context, pediatric development requires prior agreement with health authorities regarding a plan that will result in pediatric labeling– a requirement that adds further complexity to achieving alignment if more than one sponsor is involved. Multiple sponsors enrolling pediatric patients into separate trials of drugs in the same disease or with the same mechanism of action is not efficient, while master protocols may be a good alternative design to improve efficiency [ 7 ]. For example, the NCI-COG Pediatric MATCH trial [ 8 ] aims to evaluate molecular-targeted therapies in biomarker-selected cohorts of pediatric patients with refractory cancers by screening tumors for actionable alterations. Because the diseases are rare, and the incidence of some genetic mutations targeted by a given therapy is low (e.g., less than 3% of patients with the disease), conducting a separate trial for each concurrently developed therapy will slow down recruitment and thus slow down access to potentially life-saving therapies for all patients. Conversely, a master protocol under a shared infrastructure/platform alleviates this issue by including many new therapies under one study so that more patients could receive appropriate treatment after molecular screening. In the NCI-COG Pediatric MATCH trial, actionable mutations were detected in 31.5% of the first 1000 tumors screened, and 13% of the screened patients were enrolled in a treatment arm [ 9 ].

Pediatric studies also pose ethical challenges, such as enrolling the minimum number of participants necessary to answer the scientific question [ 10 , 11 ], and minimizing or avoiding exposure to placebo (e.g., some pediatric cancers, rare progressive genetic diseases, pediatric inflammatory bowel diseases) [ 12 , 13 ]. In addition, there are many barriers to enrolling children in clinical trials, including technical limitations on blood draws and procedures, parental hesitance to permit their child to participate, and off-label prescribing of the investigational treatment outside of a clinical trial once it is approved in adults [ 14 , 15 ]. With master protocols, more specifically platform trials, a shared concurrent control group is often used to compare with multiple experimental therapies under investigation. Thus, there may be a lower chance of a participant being randomized to the control arm (compared to a traditional study design with one control and one experimental therapy arm), which may reduce the reluctance of participation from the patient/parent perspective. From the trial conduct perspective, this leads to a smaller overall sample size (while achieving the same statistical power) which aligns with the ethical preference of enrolling as few pediatric patients as possible [ 16 , 17 ]. Examples of platform trials in adult research include I-SPY2 in breast cancer [ 18 , 19 ] and DIAN-TU in Alzheimer’s disease [ 20 ].

Although there are some successful examples of master protocols in adult studies [ 21 ], the use of master protocols in pediatric research is lagging behind, with the experience largely in the field of oncology [ 22 ]. As summarized by Khan and colleagues (2019), master protocols are primarily used in early phase trials focused on dose finding, safety, and an estimate of pharmacologic activity with the goal of carrying selected candidates forward in more definitive Phase III trials [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. The experience outside of pediatric oncology is more limited. This systematic review was undertaken with the goal of updating the available information about and to stimulate the use of master protocols in pediatric drug development.

This systematic review aimed to identify pediatric clinical trials that used master protocols and was based on searching two data sources: PubMed and ClinicalTrials.gov (Supplemental Table 1 ). The PubMed search was conducted on September 9th, 2022, and included articles published in the past 10 years that have terms ‘master protocol’ or ‘basket trial’ or ‘platform trial’ or ‘umbrella’ in the title or abstract. The articles were filtered to restrict to article type ‘Clinical Trial’, article language ‘English’, and species ‘Humans’. These articles’ abstract and title were screened by two authors (YL, HP) to include clinical trials only, and remove statistical methodology papers, cases series, and biomarker studies (Supplemental Fig.  1 ). Full texts of the remaining articles were further reviewed by the two authors to identify the studies that included pediatric participants (age < 18) in the trial.

The ClinicalTrials.gov search was conducted on September 30th, 2022, and included studies that were ‘First Posted’ by that date. The studies were filtered with terms ‘master protocol’ or ‘basket’ or ‘platform trial’ or ‘umbrella’ and inclusion of ‘Child’ in the study (Supplemental Table 1 ). The remaining studies were reviewed by two authors (JY, KB) to include interventional trials only and exclude observational studies and patient registries (Supplemental Fig.  1 ). Non-relevant studies were also removed, such as digital platform, behavioral and exercise studies. The study lists identified from PubMed and ClinicalTrials.gov were then cross compared to remove duplicates.

For the studies that have been included in this systematic review, data were extracted from the information on ClinicalTrials.gov, and the full text manuscript and their supplemental materials, if available, using a standardized form. General study information was extracted, including study type, study status, trial sponsor, therapeutic area, study start year (based on ‘Actual Study Start Date’ on ClinicalTrials.gov), clinical trial phase, estimated trial duration (estimated using the study start date and completion date or estimated completion date if the study was still ongoing), whether the drugs used in the trial were from single or multiple organizations, whether used for drug repurposing (considered ‘Yes’ if all drugs used in the trial had been approved for adult indication), and whether used to support registration. For study status, the categories include ‘registered/proposed’ (but not started yet), ‘ongoing’, ‘completed’, and ‘terminated’. For therapeutic area, oncology is a combined category, while other categories indicate a specific disease (e.g., COVID). This was chosen because oncology has been the primary area of application of master protocols, and it is of interest to understand if studies of any other diseases are starting to use master protocols.

Study characteristics that are specific to pediatric studies were also extracted, including the minimum and maximum age of the study participants, whether the study was part of a master protocol that also included adult patients, whether the pediatric drug dosing was the same as adults (considered ‘Yes’ if all the drugs included in the study used adult dosing), the type of pediatric dosing if any of the drugs were dosed differently from adults (e.g., weight-based, body surface area [BSA]-based), and whether the pediatric drug formulation was the same as adult. Based on the minimum age of the study participants, flags were created to indicate if the trial included participants that were younger than 16, 12, 6, or 2 years old, which aligns with ICH E11(R1) age categories [ 34 ]. Another flag was also created to indicate if the trial included only adolescent or older patients (age > = 12).

Lastly, important study design elements of the master protocol were collected, including number of test drug arms at the start-up of the trial, whether randomization was used, whether a concurrent control was implemented, the type of control arm (e.g., placebo only, standard of care [SOC], active [defined as having been approved by FDA]), type of randomization (adaptive or fixed) and randomization ratio. All the data were first extracted by one reviewer and then independently validated by another reviewer. Discrepancies between reviewers were discussed and resolved based on consensus.

As mentioned in the Introduction, we specifically define the study types as follows [ 3 ]:

Basket trial , which is defined as a trial/study testing a single investigational drug or drug combination in multiple disease populations, defined by disease stage, histology, number of prior therapies, genetic or other biomarkers, or demographic characteristics (e.g., AMETHIST, TRAM-01).

Umbrella trial , which is defined as a trial/study evaluating multiple investigational drugs administered as single drugs or as drug combinations in a single disease population, where all investigational drugs (or combinations) are enrolled at the same time and with no rolling arm option [ 1 ] (e.g., PRAM-2, Pegathor Lymphoma 205).

Platform trial , which allows flexibility to add new treatment arms in the future (e.g., ALLTogether1; hybrid of different disease indications and different treatments or treatment combinations in the same trial, such as NCI-COG Pediatric MATCH).

As this review does not synthesize the results of included clinical trials and only considers their study designs, formal bias assessment is not applicable. All analyses are descriptive, and no hypothesis tests are conducted. Summary of design elements are reported as frequencies and proportions for categorical variables, and mean, standard deviation (SD), median, range, and interquartile range (IQR) for continuous variables. These statistics are calculated overall, by study type, by sponsor type, and by therapeutic indication (grouped into oncology, covid, and other). All analyses have been performed using R 4.2.1.

One hundred and eighty-seven studies from the PubMed search were screened and assessed for eligibility. After applying the inclusion and exclusion criteria, 11 pediatric master protocol studies were identified (Supplemental Fig.  1 ). In the ClinicalTrial.gov search, 399 studies were screened, and 38 studies were selected. Cross comparison between the two lists revealed that all 11 publications in PubMed appeared in the ClinicalTrial.gov list so the final analysis included 38 pediatric studies.

Figure  1 shows the distribution of study type, study status, trial sponsor, and therapeutic area. Among the 38 studies, 16 (42%) are platform trials, 15 (39%) are basket trials and 7 (18%) are umbrella studies. Most of the studies (79%) are still ongoing and 5 (13%) studies have been completed. The trial sponsor type is almost evenly distributed between company (52%) and non-company (45%), with one study sponsored by both a company and non-company. Oncology (58%) is the largest therapeutic area for the included studies, followed by infectious diseases treating COVID (18%) and HIV (8%). Among the 6 COVID studies, 3 are therapeutic and 3 are vaccine trials.

Summary of study type, study status, trial sponsor, and therapeutic area. N  = 38

General study characteristics are summarized in Table  1 , overall and by study type. The earliest pediatric trial that used a master protocol started in 1997, with a few (1 to 3) studies having started every year subsequently. The use of master protocols in pediatrics suddenly increased in 2020, with 10 studies starting in 2020 and another 10 studies starting in 2021 (the number in 2022 is underestimated because the search was conducted in September 2022). This rise was seen in both company and non-company sponsored trials (Supplemental Table 2 ), and mostly in the Oncology disease area (Supplemental Table 3 ). This increase in the past few years explains the observation that most studies are still ongoing. In terms of phases, the majority are early phase studies, with 60% Phase I or Phase I/II or Phase II studies. Most studies (61%) are not for drug repurposing and 47% trials use drugs from multiple organizations. Overall mean estimated trial duration for pediatric master protocols is 5.7 years, with a longer duration for platform trials (mean 7.3 years) compared to basket (mean 5.0 years) or umbrella trials (mean 3.7 years).

Pediatric specific characteristics are summarized in Table  2 , overall and by study type. The minimum age of the study participants has a median of 2 with IQR 0.6 to 12. Among the 38 studies, 33 (87%) include participants younger than 16 years old, 26 (68%) include participants younger than 12 years old, 20 (53%) include participants younger than 6 years old, 15 (39%) include participants younger than 2 years old, and 12 (32%) include only adolescent or older participants. Interestingly, among the 6 COVID trials, 4 (3 therapeutic and 1 vaccine trials) include participants younger than 2 years old (Fig.  2 ). The minimum age of the study participants differs by study type, with a lower median for platform trials (1 year old) than basket (6 years old) or umbrella trials (12 years old). Twenty-six (68%) of the 38 pediatric studies are part of a master protocol that also included adult patients, and among them 12 studies (46%) include only adolescent or older patients. Twelve (32%) studies use the same dosing as adult, and 9 of these 12 studies include only adolescent or older patients. The most common type of pediatric dosing is weight-based dosing (46%), followed by BSA-based dosing (15%), and a combination of weight-based and BSA-based dosing (12%, e.g., weight-based dosing for one study drug and BSA-based dosing for another study drug).

Number of trials that included patients younger than 16, 12, 6 or 2 years old, by therapeutic area

Table  3 summarizes certain elements related to the study design, overall and by study type. For basket trials, most of them (12 out of 15, 80%) have only 1 test drug arm (a combination therapy is considered as 1 test drug arm). For platform trials, only 13% (2 out of 16) have 1 test drug arm (with the plan to add more arms) and 44% (7 out 16) have 5 or more test drug arms at the start-up of the trial with potential to expand. Overall, 17 studies (45%) used randomization. Among the 17 studies that used randomization, the majority (13 out of 17, 76%) use a concurrent control, but the type of control arm varies, with 6 studies (35%) using a placebo control, 6 studies (35%) using an active control, and 3 studies (18%) using SOC. Of note, among the 6 trials that use a placebo control, only 1 study is an adolescent study. Among the studies that have provided information on the details of randomization, no study used adaptive randomization and most studies used 1:1 randomization ratio (11 out of 17, 65%).

All the study characteristics are also summarized by sponsor type (Supplemental Table 2 ) and by therapeutic area (Supplemental Table 3 ). A few characteristics vary by sponsor type; for example, trials sponsored by a company are more likely to include drugs from a single (rather than more than one) organization and are more likely to use a placebo (rather than an active) control arm, compared to the trials sponsored by a non-company. For comparison by therapeutic area, oncology trials are more likely in early phases, more likely to have one (rather than more than one) test drug arm, and less likely to use randomization, compared to trials for other indications.

This systematic review showed that master protocol studies are being used in pediatrics, with platform and basket trials more common than umbrella trials. As expected, most experience with the use of master protocols is in oncology, with early phase studies more common than late phase. There has been a rise in the number of pediatric master protocols starting in 2020, again largely in oncology. It is speculated that the rise is a result of increasing awareness of master protocols. In particular, oncology is an opportune area to apply pediatric master protocols, given the previous success with adult oncology master protocols [ 18 , 19 , 35 , 36 , 37 , 38 ]. The application of master protocols has also emerged in COVID-19 therapeutic and vaccine trials, and FDA has published specific guidelines for COVID-19 master protocols [ 39 ], in addition to guidelines for oncology [ 3 ]. The COVID-19 pandemic has led to many examples of advances in clinical trial designs such as master protocols to deliver critical data to inform patient management [ 40 , 41 , 42 , 43 , 44 ]. However, the FDA assessment has been that the vast number of these global clinical trials were not randomized or adequately powered. As a result, the majority of these innovative designs were unable to generate actionable data of sufficient quality [ 45 ].

Our results show that many of the pediatric studies are in the same master protocols as adults, and they include both adolescent studies and pediatric studies with younger age groups. This suggests that the master protocol studies need not be solely pediatric unless perhaps when the indication itself is primarily for a pediatric group (e.g., rare disorders). Conceptually, the relatively easy way to incorporate pediatric participants in every therapeutic area, especially adolescents, may be to broaden the inclusion criteria in the same adult protocol and adjust the treatment and/or outcome for the pediatric age groups. This approach could potentially leverage adult information for pediatrics and allow for generalization across entire study populations [ 46 ]. Additionally, we also found that about one third of the pediatric master protocols use the same dosing as adults (a flat dose), and the majority of these studies are adolescent trials.

As expected, and confirmed by our review, platform and umbrella trials include multiple test drug arms, or plan to add more arms if starting with only one arm. Basket trials mostly have one test drug arm, although occasionally include multiple arms. The involvement of multiple drugs requires access to these drugs, either all from a single organization leading the trial or a collaboration among multiple organizations agreeing to participate in the trial. Not surprisingly, we found that trials sponsored by a company are more likely to include drugs from a single rather than multiple organizations, compared to the trials sponsored by a non-company.

For pediatric master protocols with randomization, no study in our review has been identified as using adaptive randomization. This may be due to the reluctance of adding another layer of complexity to an already complicated master protocol study design. When evaluating the type of control arms in randomized studies, we observed that the use of SOC is infrequent, although this was recommended by FDA guidance [ 3 ]. Interestingly, a few studies use placebo as a control arm, and most of these studies are not adolescent only trials. In general, there have been concerns as to whether a placebo arm is feasible in pediatric studies [ 47 ], but our results suggest that pediatric master protocols are able to recruit patients into placebo-controlled studies.

Our study has a few limitations. First, our review included studies that had inclusion/exclusion criteria allowing adolescent as well as pediatric participants. The studies cover diseases that are solely diagnosed in pediatric patients, as well as diseases are in both adult and pediatric patients. Further work is needed to understand the reasons why some master protocols did not include younger age groups. Second, we were unable to collect key drivers as to why an organization adopted a master protocol design in the first place rather than conduct a more traditional clinical trial. One example is whether the master protocol study results would be used to support registration, which is difficult to determine using public information.

The use of master protocols in pediatric research could potentially improve trial efficiency and reduce the costs of drug development; for example, by including pediatric patients in adult master protocols. Another opportunity would be the use of a master protocol by a single sponsor, for example, when multiple products in the pipeline are being developed for the same indication. What is aspirational and would require more efforts is building collaborations across several sponsors, including pediatric (or rare disease) registries to facilitate master protocols. The development of cross-sponsor collaborations and a shared trial infrastructure may impose logistical difficulties with coordinating and communicating across multiple companies and raise issue about ownership of the trial. However, once agreement is reached and the infrastructure established, it will make evaluation of new therapies easier and faster and provide assurance that necessary and sufficient data in pediatrics will be collected. Hopefully, there will be a paradigm shift from a single entity conducting a pediatric trial to multiple entities collaborating together. EU-PEARL (EU Patient-cEntric clinnicAl tRial pLatforms) serves as a good example of partnership [ 48 ], which offers a useful model for pediatric platform trials.

Master protocols offer the potential for improved pediatric studies by creating efficiencies in clinical operations and possibly using shared control groups. Our review shows that master protocols are starting to be adopted in pediatric clinical research, but on a small scale that could be substantially expanded. Work is required to further understand the barriers in implementing pediatric master protocols, from setting up shared infrastructure to interpreting study findings. The ultimate goal would be to reduce the delay in pediatric marketing approvals to allow timely access to safe and effective therapies for children.

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Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, USA

Division of Oncology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

Yimei Li & Yansong Wen

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Robert Nelson

Statistical Methodology, Novartis Pharma AG, Basel, Switzerland

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Kristine Broglio

Pfizer, New York, NY, USA

Rajiv Mundayat & Margaret Gamalo

Department of Biostatistics, St. Jude Children’s Hospital, Memphis, TN, USA

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Hengrui Sun

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Jingjing Ye

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Li, Y., Nelson, R., Izem, R. et al. Unlocking the Potential: A Systematic Review of Master Protocol in Pediatrics. Ther Innov Regul Sci (2024). https://doi.org/10.1007/s43441-024-00656-z

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• Volume 14, Issue 4
• Self-directed digital interventions for the improvement of emotion regulation—effectiveness for mental health and functioning in adolescents: protocol for a systematic review
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• http://orcid.org/0000-0001-5322-8488 Abigail Thomson 1 ,
• Erin G Lawrence 1 ,
• Bonamy R Oliver 2 ,
• Ben Wright 3 , 4 ,
• Georgina M Hosang 1
• 1 Centre for Psychiatry and Mental Health, Wolfson Institute of Population Health , Queen Mary University of London , London , UK
• 2 UCL Institute of Education , University College London , London , UK
• 3 East London NHS Foundation Trust , London , UK
• 4 City University of London , London , UK
• Correspondence to Abigail Thomson; a.c.thomson{at}qmul.ac.uk

Introduction Research suggests that problems with emotion regulation, that is, how a person manages and responds to an emotional experience, are related to a range of psychological disorders (eg, bipolar disorder, anxiety and depression). Interventions targeting emotion regulation have been shown to improve mental health in adults, but evidence on related interventions for adolescents is still emerging. Increasingly, self-directed digital interventions (eg, mobile apps) are being developed to target emotion regulation in this population, but questions remain about their effectiveness. This systematic review aimed to synthesise evidence on current self-directed digital interventions available to adolescents (aged 11–18 years) and their effectiveness in addressing emotion regulation, psychopathology and functioning (eg, academic achievement).

Methods and analysis Several electronic databases will be searched (eg, MEDLINE, PsycINFO, ACM Digital Library) to identify all studies published any time after January 2010 examining self-directed digital interventions for adolescents, which include an emotion regulation component. This search will be updated periodically to identify any new relevant research from the selected databases. Data on the study characteristics (eg, author(s)) and methodology, participant characteristics (eg, age) and the digital interventions used to address emotion (dys-)regulation (eg, name, focus) will be extracted. A narrative synthesis of all studies will be presented. If feasible, the effectiveness data will be synthesised using appropriate statistical techniques. The methodological quality of the included studies will be assessed with the Effective Public Health Practice Project quality assessment tool.

Ethics and dissemination Ethical approval is not required for this study. Findings will be disseminated widely via peer-reviewed publications and presentations at conferences related to this field.

Registration details PROSPERO CRD42022385547.

• Adolescents
• MENTAL HEALTH

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:  https://creativecommons.org/licenses/by/4.0/ .

https://doi.org/10.1136/bmjopen-2023-081556

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STRENGTHS AND LIMITATIONS OF THIS STUDY

This Preferred Reporting Items for Systematic Review and Meta-Analysis-guided review applies a systematic methodology that includes a comprehensive search strategy and well-defined eligibility criteria for screening.

We follow a dual-review process; a second independent researcher is employed throughout the screening and data extraction process.

This review uses the Effective Public Health Practice Project quality assessment tool—a tool validated for reviews of intervention effectiveness—to assess the methodological quality of included studies and comment on the strength of the existing evidence.

The heterogeneity of the interventions and tools used to measure emotion regulation may not allow for direct comparisons between studies as part of a planned meta-analysis.

Introduction

Approximately 75% of mental health problems begin in adolescence. 1 In the UK, one in six adolescents (aged 11–16 years) has been identified as having a probable mental health problem—a figure that has steadily increased since 2004. 2 Current attempts to support this population are designed to target specific conditions (eg, depression). However, 60% of those adolescents with one diagnosable mental health problem have one or more additional conditions. 3

Mental health comorbidity—the presence of two or more mental illnesses in an individual—is the rule, rather than the exception, and has been associated with greater clinical severity and a greater detriment to overall quality of life. 4 There is also significant overlap in the aetiological origins of different psychopathologies, including evidence of major overlap in both genetic and environmental contributors between most disorders (eg, major depressive disorder, bipolar disorder and schizophrenia). 5 Further complexity emerges from evidence linking non-specific risk factors (such as adverse childhood experiences: ACEs) with the onset of psychopathology. 6 ACEs (eg, abuse and domestic violence) are a robust predictor of various mental and physical disorders and symptoms. 7 8 While the mechanisms underpinning the aetiology and development of different psychopathologies are complex, associations have been found across a range of different conditions, including mood disorders, anxiety disorders and substance use disorders. 6

A transdiagnostic approach

Given this, researchers have highlighted the need to understand and develop interventions that are directly effective across several disorders, or which alter psychopathological processes common to multiple conditions; these transdiagnostic strategies would offer broader, more effective support for adolescents struggling with their mental health. 9 The Unified Protocol (UP) for the transdiagnostic treatment of emotional disorders is one such strategy that targets the emotional processes (eg, emotional reactivity, emotional responding) underlying multiple different disorders. The UP is a transdiagnostic, emotion-focused cognitive-behavioural therapy (CBT) designed to treat all anxiety and unipolar mood disorders, as well as other disorders with strong emotional components (eg, dissociative and somatoform disorders 10 ). Preliminary evidence has found it an effective treatment for adolescents with emotional disorders, 11 12 demonstrating the possible utility of transdiagnostic approaches in adolescent mental health.

Emerging evidence suggests the transdiagnostic approach could be effective in targeting a range of psychopathologies in young people and can activate a range of related, beneficial developmental cascades, including improvement in social and academic outcomes in adolescence, as well as improved sleeping patterns. 13 A transdiagnostic approach to treatment is also thought to be time-effective and cost-effective compared with disorder-specific strategies and may offer a more sustainable alternative to treatments currently available to this population. 4

Emotion regulation—a transdiagnostic target?

Emotion regulation has received increased attention in recent years as a transdiagnostic mechanism and clinical target in psychological treatment. 14 Emotion regulation is a multidimensional process wherein an individual monitors, evaluates and shapes their emotions, when they have them, and how they experience or express them. This process is typically understood to be goal-directed, helping individuals to meet the demands of their environment and achieve their ambitions (eg, remaining calm to resolve a conflict). 15 Gross provides a well-defined ‘Process model of emotion regulation’ 16 17 of specific relevance for research and practice, whereby an individual recognises an emotion regulation goal, selects and, finally, implements specific emotion regulation strategies. 18 Gross defined a set of five distinct emotion regulation strategies occurring at different points in an emotional experience: situation selection, situation modification, attentional deployment, cognitive change and response modulation. 18 Situation selection can be understood as an individual’s efforts to alter the likelihood of being in an emotion-evoking situation. Situation modification involves modifying a situation at the time to change its emotional impact. Attentional deployment involves directing attention towards or away from an emotion or its causes. Cognitive change enables reappraising a situation to change its emotional significance. Response modulation includes any efforts to modify the behavioural, experiential and physiological elements of an emotional response. Each of these strategies can be understood to influence an individual’s emotional response in a way that can be interpreted as adaptive (eg, problem-solving, acceptance) or maladaptive (eg, withdrawal, suppression), 17 depending on the context.

Maladaptive patterns of emotional experience or expression that interfere with goal-directed activity are typically understood as emotion dysregulation and have physiological, cognitive and social consequences. 17 18 Emotion dysregulation can also be understood to represent problematic emotion dynamics: persistence, lability and intensity of emotions. 19 Evidence demonstrates emotion dysregulation is present across a range of psychopathologies, including internalising (eg, generalised anxiety disorder, major depressive disorder, dysthymia) and externalising disorders (eg, attention-deficit/hyperactivity disorder, conduct disorder, oppositional defiant disorder). 20 For example, generalised anxiety disorder has been associated with a lack of understanding of emotions and an increased reliance on emotion regulation strategies that could be understood as maladaptive, such as withdrawal. 20 Similarly, attention-deficit/hyperactivity disorder is characterised by individuals’ emotion regulation deficits and emotion reactivity. 21

Most evidence on the impact of emotion regulation on psychopathology has been derived from adult populations. 22 However, recent findings are beginning to show a close association between emotion regulation and psychopathology in adolescence. 23 Evidence indicates a significant shift in emotion regulation between the ages of 13 and 15 (eg, access to strategies, use of adaptive vs maladaptive strategies), suggesting that adolescence is a particularly vulnerable period in the development of emotion regulation. 24 Therefore, interventions targeting emotion regulation as a transdiagnostic construct central to developing and maintaining psychopathology may reduce the risk and severity of adolescent mental health problems.

Emotion regulation interventions

Existing psychological interventions adopt different approaches to improving emotional regulation. Some focus on reducing the use of maladaptive strategies such as rumination (eg, rumination-focused cognitive behavioural therapy 25 ), while others focus on increasing the use of adaptive strategies such as acceptance (eg, Acceptance and Commitment Therapy 26 ). Both the adult and adolescent literature indicate that such interventions improve emotion regulation and mediate decreases in psychopathological symptoms within certain diagnoses (eg, anxiety). 23 27 However, the effectiveness of these interventions in improving multiple mental health and functional outcomes, rather than specific and individual symptom groups, is largely unknown. 28

Further, much of the research to date has focused on the delivery of such interventions in person despite a growing number of digital solutions for adolescent emotion regulation and psychopathology. 23 Previous research examining the effectiveness of several different digital interventions targeting emotion regulation in adolescents found that, in general, such interventions (eg, digital games and biofeedback) can be effective in improving emotion regulation. 29 Digital interventions also have a greater capacity for innovation and engagement with adolescents 30 and the potential to extend effective care cost-effectively and sustainably, 31 but less is known about how such interventions can be applied at scale to support this population.

A self-directed, digital approach

An increasing number of innovative self-directed digital interventions are being developed, which target emotion regulation and related processes (eg, emotional self-awareness). 32 33 Such interventions (eg, mobile apps) are led by the service user, with little to no support from anyone else (eg, therapist, parent/carer), and aim to widen access to support for adolescents. Despite a growing number of self-directed digital interventions made available to adolescents, the effectiveness of interventions delivered in this self-directed and digital format for improving emotion regulation and psychopathology is, as yet, unclear. Further, more evidence is needed to determine the ‘active ingredients’ of self-directed digital interventions that improve emotion regulation the most and reduce psychopathology in adolescents. 34 As the prevalence of adolescent mental health problems increases, innovative digital solutions could help to ensure that a broad range of adolescents can access and engage in support for their mental health.

Review objectives

To address some of these issues, the proposed systematic review will synthesise evidence on current self-directed digital interventions available to adolescents (aged 11–18 years) to investigate their effectiveness in addressing emotion (dys-)regulation, psychopathology and functioning (eg, academic achievement).

Despite an increase in the number of available self-directed digital interventions for emotion regulation, evidence about their effectiveness among adolescent populations has yet to be synthesised. This review provides an important extension to existing work which has thus far demonstrated the effectiveness of in-person or therapist-supported emotion regulation interventions available for young people (aged 6–24 years), 20 as well as the utility of a broad spectrum of digital emotion regulation interventions for adolescents. 29 This review takes a more specific focus to develop evidence on a burgeoning number of self-directed , scalable, digital mental health interventions available to adolescents with or without diagnosed psychopathology. Specifically, we will seek to answer the following research questions:

Are current self-directed digital interventions that target emotion regulation effective in improving emotion (dys-)regulation in adolescents?

Are these interventions effective in treating psychopathology and improving function (eg, academic achievement)?

What are the specific components (eg, mood monitoring) of these interventions that most improve emotion (dys-)regulation and/or psychopathology and functioning in adolescents?

Methods and analysis

Protocol and registration.

This protocol is written in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines. 35 The completed PRISMA-P checklist is provided in online supplemental file 1 . The systematic review has been registered in PROSPERO, the International Prospective Register of Systematic Reviews (CRD42022385547). Important amendments to this protocol will be reported and published with the review results.

Supplemental material

Eligibility criteria.

The following criteria ( table 1 ) are set out to screen identified studies using a Population, Intervention, Comparison, Outcomes and Study (PICOS) framework. 36

• View inline

Inclusion and exclusion criteria

Information sources

10 electronic databases will be searched for studies published any time from January 2010: MEDLINE, PsycINFO; Global Health: Scopus; Web of Science Core Collection; EBSCO CINAHL; EBSCO ERIC; OVID Embase; The Cochrane Central Register of Controlled Trials (CENTRAL) and ACM Digital Library. Grey literature such as preprints and theses are also included in this review (databases: HMIC, EThOS, Psyarxiv, Trip, ClinicalTrials.gov). This search will be updated periodically to identify any new relevant research from the selected databases before the results are finalised (most recent search in August 2023).

Search strategy

The search strategy ( online supplemental file 1 ) is designed to identify all studies examining one or more self-directed digital mental health interventions for adolescents, which include an emotion (dys-)regulation component. It will search for synonyms for the following three concepts: adolescents, emotion (dys-)regulation and self-directed digital interventions . The search will be limited to English language studies conducted with a human population.

Study selection

All identified studies will be exported to Endnote 20, and any duplicates will be removed following a specified method 37 before being imported into Rayyan 38 for further deduplication and screening. Abstracts and titles will be screened based on the inclusion and exclusion criteria ( table 1 ). Those studies that meet these criteria will enter the full-text screening stage for further checks against the eligibility criteria. The full-text screening will allow for the identification of those interventions that do not address emotion (dys-)regulation directly. A second researcher (EGL) will be assigned a random 10% of the identified studies for screening at the title and abstract stage. Discrepancies throughout the study selection process will be resolved through consensus between AT and EGL. If discrepancies cannot be resolved through discussion, a third reviewer will be consulted to adjudicate.

Data extraction and management

Data will be extracted and collated by two independent reviewers (AT and EGL) and tracked in Microsoft Excel using a structured coding form and associated coding manual. The form will be piloted on a sample of included studies and refined before extraction begins. Information relating to study characteristics (eg, author(s), publication date), participant characteristics (eg, age, gender), digital intervention characteristics (eg, name, focus), and relevant clinical and emotion dysregulation outcomes will be extracted from each study. Information to determine any study bias will also be collated. Study investigators will be contacted for missing/unreported data or additional details. If we are not able to obtain sufficient details/raw data using this approach, we will exclude the respective studies.

The primary outcome of this review is the change in emotion (dys-)regulation, psychopathology and functioning (eg, academic achievement) occurring as a result of participation in a self-directed digital intervention that addresses emotion (dys-)regulation. Emotion (dys-)regulation must be assessed, and where possible, using a valid and appropriate item, scale or measure (eg, Child Social Behaviour Questionnaire), 39 including through clinical interviews or self-reported measures. An existing review of emotion (dys-)regulation assessment 40 and similar reviews 22 41 will be used as guidance to decide on a measure’s eligibility. Symptoms of psychopathology will be assessed by any available valid and appropriate measure, including through clinical interview or self-reported measures.

Quality and risk of bias assessment

Two researchers (AT and EGL) will independently assess the methodological quality of the included studies using the Effective Public Health Practice Project Quality Assessment tool (EPHPP). The EPHPP is applicable to a range of quantitative study designs (eg, case-control studies) and has been judged to be particularly suitable for systematic reviews on the effectiveness of interventions/treatments. 42 Evidence has shown the EPHPP has good content and construct validity. 42 43 The AACODS Checklist will be used to assess the quality and content of any included grey literature (ie, theses and reports). It has been designed as a critical appraisal tool specifically for use with grey literature sources.

If sufficient data is available, potential reporting bias will be assessed visually using a funnel plot and commented on in the review. An asymmetrical plot suggests a publication bias. 44 If asymmetry in the funnel plot is detected, the studies will be reviewed to assess whether this asymmetry was likely due to publication bias or other factors such as methodological or clinical heterogeneity.

Data synthesis

Information from the included studies will be synthesised in line with guidance from Popay. 45 A narrative overview of the study characteristics and methodology, participant characteristics and the digital interventions used to address emotion (dys-)regulation will be included. A summary of any observed changes in emotion dysregulation and/or psychopathology occurring as a result of the intervention will be provided. Additionally, any general improvements in functioning (eg, social or academic) that occur as a result of participation in the intervention will also be described if reported in the included papers.

Given the findings of preliminary searches and previous reviews, 23 it is anticipated that there will be high heterogeneity across studies. However, a meta-analysis will be conducted if (a) there are a minimum of two papers included in the review and (b) the available data within the included studies are sufficiently homogenous (Q statistic is non-significant and/or I² < 25%). Studies judged to be of low quality will be excluded from the meta-analysis. Two meta-analyses are planned: one with psychopathology as the primary outcome and one with emotion dysregulation as the primary outcome. Outcomes will be pooled using a random-effects model, in line with the current recommendations for meta-analysis models in psychology. 46

Subgroup analyses will be completed if sufficient data are available to explore the efficacy of different intervention components (ie, mood monitoring, psychoeducation) in improving emotion dysregulation and psychopathology in adolescents. Subgroup analyses will also be conducted to identify whether there are differences in effect size or heterogeneity due to study-level factors (ie, quality). These analyses will be conducted when I² < 50% and there are 10 or more studies (n>10) to evaluate differences by specific a priori subgroups.

All analyses will be conducted in RStudio V.2023.06.0+421 for macOS Sonoma 14.1.2 (meta, metasen, metafor packages).

Ethics statements

Patient consent for publication.

Not applicable.

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Supplementary materials

Supplementary data.

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

• Data supplement 1

X @AbiThomson9

Contributors AT is the guarantor. AT, GMH and BRO conceived the initial idea for the systematic review and design of the protocol. AT drafted the manuscript, and GMH and BRO provided critical insight. AT, GH, BRO, EGL and BW contributed to the revision of the manuscript and approved the final version.

Funding This work is funded by the UK Research and Innovation, Economic and Social Research Council (grant number: ES/P000703/1).

Competing interests None declared.

Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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• Published: 02 May 2024

Risk factors and long-term outcomes of oropharyngeal dysphagia in persons with multiple sclerosis: a systematic review protocol

• Zahra Sadeghi 1 ,
• Mohamadreza Afshar 2 ,
• Asefeh Memarian 3 &
• Heather L. Flowers   ORCID: orcid.org/0000-0001-6742-9459 3  

Systematic Reviews volume  13 , Article number:  121 ( 2024 ) Cite this article

Metrics details

Oropharyngeal dysphagia (OPD) can be functionally debilitating in persons with multiple sclerosis (pwMS). OPD induces alterations in safety and efficiency of food and/or liquid ingestion and may incur negative sequalae such as aspiration pneumonia or malnutrition/dehydration. Early detection and timely management of OPD in pwMS could prevent such complications and reduce mortality rates. Identifying risk factors of OPD relative to its onset or repeat manifestation will enable the development of care pathways that target early assessment and sustained management. The aims of this systematic review are to compile, evaluate, and summarize the existing literature reporting potential risk factors and associated long-term outcomes (e.g., aspiration pneumonia, malnutrition, dehydration, and/or death) of OPD in pwMS.

We will undertake a systematic review to identify studies that describe patterns and complications of OPD in pwMS. Variables of interest include predictors of OPD along with long-term outcomes. We will search MEDLINE, Embase, CINAHL, AMED, the Cochrane Library, Web of Science, and Scopus. We will consider studies for inclusion if they involve at least 30 adult participants with MS and report risk factors for OPD and/or its long-term outcomes. Studies will be excluded if they refer to esophageal or oropharyngeal dysphagia induced by causes other than multiple sclerosis. Study selection and data extraction will be performed by two independent assessors for abstract and full article review. We will present study characteristics in tables and document research findings for dysphagia-related risk factors or its complications via a narrative format or meta-analysis if warranted (e.g., mean difference and/or risk ratio measurements). All included studies will undergo risk-of-bias assessment conducted independently by two authors with consensus on quality ratings.

There is a lacune for systematic reviews involving risk factors and long-term outcomes of dysphagia in pwMS to date. Our systematic review will provide the means to develop accurate and efficient management protocols for careful monitoring and evaluation of dysphagia in pwMS. The results of this systematic review will be published in a peer-reviewed journal.

Systematic review registration

PROSPERO CRD42022340625.

Peer Review reports

Oropharyngeal dysphagia (OPD) is common in multiple sclerosis (MS) [ 1 ] due to injury to the corticobulbar tracts, potentially involving the brainstem, the cerebellum [ 2 , 3 ], and the cortex [ 4 ]. There may be a differing clinical course across types of MS, classified based on disease onset and progression over time [ 5 ]. The most frequent includes relapsing–remitting MS (RRMS), usually beginning with acute exacerbation and detrimental impacts that recover fully or partially over time. The other forms of MS are all defined as progressive, including secondary progressive MS (SPMS), primary progressive MS (PPMS), and progressive relapsing MS (PRMS). Patients with RRMS develop SPMS within 10 years of the onset of RRMS. PPMS is the least frequent type of MS and is characterized by deteriorating neurological function from disease onset coupled with a lack of remittance. Nevertheless, superimposed relapses are also evidenced in this type. Overall, the course of MS is unpredictable, and depending on the severity, the diversity of anatomic impacts, and the onset of associated lesions, its clinical manifestations are also heterogeneous.

Symptoms of OPD in MS may include coughing and/or choking on saliva or other liquid and food boluses, feelings of bolus sticking in the throat, the need to swallow multiple times per bolus, difficulty initiating a swallow (accompanied by drooling), and alterations to usual eating patterns (such as viscosity or texture changes) [ 3 , 4 , 6 ]. Oropharyngeal dysphagia may incur severe and multifaceted poor outcomes, such as aspiration pneumonia, malnutrition/dehydration [ 3 , 4 , 6 ], increased psychosocial comorbidities [ 7 , 8 ], and even death during periods of medical instability [ 9 ]. Identifying risk factors for OPD in pwMS will provide the means to develop accurate and efficient management protocols for careful monitoring and evaluation by dysphagia experts. By extension, sustained management will permit timely and comprehensive care to mitigate potential serious complications.

In two recent systematic reviews, the authors provided an estimate of the pooled frequency of dysphagia in pwMS based on a range of evaluation methods, whether screening, clinical, or instrumental examination [ 1 , 10 ]. Guan et al. [ 1 ] reported a pooled frequency estimate of 36% based on subjective screenings or cursory evaluations (such as the Dysphagia in Multiple Sclerosis Questionnaire, the water swallowing test, and various dysphagia checklists from individual clinical swallowing centers) and 81% based on objective measurements (such as videofluoroscopy or fiber-optic nasoendoscopy). More specifically, the frequency of dysphagia was 46% in pwMS when Expanded Disability Status Scale (EDSS) scores were stratified as 4.5 or higher and 40% for those below 3.0. Similarly, patients with longer disease duration (over 10 years) were more likely to have dysphagia symptoms compared with shorter disease duration.

Various individual studies have also shown a higher frequency of dysphagia with greater disability [ 11 , 12 , 13 , 14 , 15 ] and/or disease duration [ 15 , 16 ]. Nevertheless, a few studies have reported that pwMS with low EDSS scores still had dysphagia [ 15 , 17 , 18 ]. To illustrate, Abraham et al. [ 18 ] reported that 43% of pwMS in their sample had dysphagia including 17% with low levels of disability (EDSS score lower than 2.5). Aghaz et al. [ 10 ] estimated the pooled frequency of dysphagia as 37% based on subjective evaluations or cursory checklists versus 47% for objective instrumental evaluations respectively. In contrast to the findings of Abraham et al. [ 18 ], they failed to demonstrate associations for the presence of dysphagia according to EDSS-based disease severity, duration of disease, or MS stage.

Taken together, reported frequencies of dysphagia hover around one-third of pwMS at a given point in time [ 1 , 10 ], whereby varied frequencies relate primarily to evaluation methods, whether screening, clinical assessment, or instrumental evaluation. The most common patient-report tool used to identify dysphagia in pwMS is the Dysphagia in Multiple Sclerosis Questionnaire (DYMUS) [ 1 , 10 , 19 ], involving 10 items with very good reliability and internal consistency. However, frequencies of reported dysphagia based on questionnaires are lower than those based on standardized tools or instrumental evaluations [ 1 ]. In general, instrumental assessment remains the gold standard for dysphagia and aspiration detection, whether by videofluoroscopy or fiber-optic nasoendoscopy rather than various types of screening tools, bedside evaluations, or patient-reported questionnaires. Some pwMS may underestimate their dysphagia severity due to altered sensory appreciation of symptoms, despite instrumental evidence to the contrary.

In addition to our poor understanding of the frequency of dysphagia in pwMS, gaps exist regarding patterns of associations between disease severity, duration, or stage. Notwithstanding, certain predictive factors may well routinely accompany the expression of dysphagia in pwMS. Elucidating such information would require a comprehensive profile of patient groups with known disease severity, duration, and stage alongside MS type, neuroanatomical impacts, and concomitant deficits or disorders. For example, dysphagia may be precipitated by coexisting psychological or cognitive impairments [ 11 , 18 , 20 ]. Therefore, continual monitoring for risk of dysphagia in pwMS who also experience negative mental health symptoms or cognitive disorders [ 4 , 20 ] is warranted. Furthermore, speech impairments (e.g., dysarthria) may provide good and readily identifiable clinical indicators for the presence of dysphagia in persons with neuromuscular diseases [ 21 ]. A systematic appraisal of the literature is required to identify the best available evidence for risk factors of dysphagia along with ensuing long-term sequelae in pwMS.

A systematic review constitutes the highest level of research evidence, especially if there is a quality evaluation and meta-analysis. Therefore, a comprehensive systematic review, aimed at establishing the predictors of dysphagia in pwMS, ideally identified with gold standard evaluation methods (such as instrumental assessment), could facilitate the development of new tools for screening or assessing dysphagia and inform practice guidelines. In addition, a close consideration of associated outcomes over the long term (e.g., pneumonia, poor social participation, death) could contribute to our understanding of prognostic indicators for particular patient groups. Consequently, our purpose is to search the existing literature to systematically identify the risk factors and associated outcomes of oropharyngeal dysphagia over the long term in persons with pwMS.

The protocol of this systematic review has been registered in PROSPERO (registration number: CRD42022340625). We have applied PRISMA-P guidelines to develop this review protocol further. It served to direct our search strategy of databases and the gray literature as well as our data extraction and compilation methods. We will document our article selection results using the PRISMA flow diagram to delineate reasons for abstract and article exclusion until the final set of articles is identified. Our investigation of risk factors is in keeping with recommendations from the Cochrane Prognostic Methods Group ( https://methods.cochrane.org/prognosis/ ) [ 22 ]. We are submitting the protocol prior to undertaking the full search or any subsequent processes such as abstract screening and full article evaluation.

Operational definitions

Oropharyngeal dysphagia is defined as body and structure impairment [ 23 ] in swallowing physiology evidenced by expert clinical or instrumental assessment of function from the anterior aspect of the lips to inferior aspect of the upper esophageal sphincter. Diagnosis of multiple sclerosis is based on accepted criteria for both definite and probable MS, according to a classification scheme that involves expert clinical and objective evaluations (such as neuroimaging) [ 24 ].

Data sources

We will conduct an electronic search in the following databases for abstracts in languages that the co-authors can read (English, French, German, Persian, Portuguese, Spanish, and Turkish). No publication date or study design restrictions will be imposed. Relevant databases will include MEDLINE, Embase, CINAHL, AMED, the Cochrane Library (CENTRAL), Web of Science, and Scopus. The MeSH and search terms used in the search strategy were developed a priori (Table  1 ). A research librarian will consult to enable valid adaptations of the MEDLINE terms into the other databases. Our MEDLNE search was conducted in OVID, revealing 189 citations (April 2023). We will also search international gray literature sources (e.g., OpenGrey and Dissertation Abstracts) and review the bibliographies and citations for all included articles in a reiterative manner until no further possible references are identified.

Eligibility criteria

Studies will be considered for inclusion if they have observational intent and involve retrospective or prospective consecutive or randomly selected sampling (either from a particular cohort or population). Study designs may include case series, cross-sectional, longitudinal, case–control, and/or other observational investigations as well as the control arm (i.e., participants who are not receiving trial-related interventions for MS or dysphagia) of randomized controlled trials. We will consider studies with at least 30 adults (18 years or older) with MS. Studies must include an aim to identify risk factors (e.g., MS subtype, disease duration, EDSS score, age, gender, smoking or alcohol use, psychological symptoms, cognitive impairments, and/or dysarthria) that may precipitate oropharyngeal dysphagia (OPD). We have chosen not to prespecify all possible risk factors as we seek to identify new potential risk factors. The body of evidence is small, and risk factors are likely underrepresented at present. Any potential new risk factors will provide a path for future researchers to investigate them in a comprehensive way and thus extend the literature and knowledge base in this respect.

Corresponding studies that include follow-up time points will contribute to our interest in long-term outcomes (e.g., detrimental medical, activity/participation, or quality-of-life outcomes). Ideally, such studies would have comparable follow-up periods (e.g., yearly) that span the course of the disease and document the outcomes relative to the absence/presence and/or severity classifications of OPD. However, we will not exclude any studies based on their follow-up points or overall time horizon.

During our review of abstracts and full articles, we will apply pre-defined exclusion criteria. That is, we will exclude studies involving convenience samples, those without extractable data (e.g., studies involving aggregate results for multiple etiologies rather than pwMS alone) for our outcomes of interest, and those reporting duplicate data. Any abstracts without corresponding full study publications will be excluded. We will also exclude articles without a clear sample of at least 30 pwMS and corresponding OPD (for at least a declared portion of the sample), identified by clinical or instrumental swallowing assessments. Finally, articles will be excluded if they do not conform to our operational definitions of OPD and MS or if they refer to oropharyngeal dysphagia induced by causes other than multiple sclerosis. We will contact authors when we cannot find full articles or when we wish to elucidate study characteristics such as method of dysphagia assessment. Our full systematic review reporting will conform to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist [ 27 ].

Data collection

Study selection from primary articles will be performed in two stages:

Initial screening and coding of titles and abstracts whereby relevant abstracts (stage 1) will undergo full article review (stage 2) (Table  2 )

Evaluation and coding of full articles for inclusion in the final sample (Table  2 )

The review process will be conducted by two independent reviewers (blind to each other’s coding) across the two stages. Any discrepancies will be resolved by consensus discussion between the two reviewers, and, when agreement is not possible, a third reviewer (also a member of the research team) will read the abstract or article independently and contribute to a decision. All references for the excluded articles will be retained for documentation purposes.

One data extractor will identify pertinent information from the final set of included articles and compile it into a table or spreadsheet. Extracted data will be verified by a second independent reviewer to ensure the accuracy of information from the following categories:

Study characteristics: First author’s name, year of publication, country in which the study was conducted, study design, and size of the sample

Study population and participant characteristics: Age, gender, MS type, disease duration, and EDSS score

Diagnostic assessments for MS and dysphagia

Risk factors for dysphagia whether related to MS (e.g., MS type, disease duration, and EDSS score), to patient characteristics (e.g., age, gender, and smoking or alcohol abuse), and/or to comorbidities (e.g., psychological symptoms, cognitive impairments, or dysarthria)

Follow-up assessments of dysphagia in terms of type and timing

Frequency and impact (e.g., severity) of detrimental medical (e.g., aspiration pneumonia, dehydration, malnutrition, institutionalization, and mortality), activity/participation (e.g., fewer social engagements around meals), or quality-of-life outcomes.

Risk of bias in individual studies

We will apply appropriate risk-of-bias evaluations [ 22 , 28 ] such as the Newcastle–Ottawa scale (NOS) [ 29 ] as a quality evaluation of included obserervational studies. To illustrate, the NOS contains grading for categories of selection (e.g., sample representativeness), comparability (e.g., evaluation of confounders), and outcome (adequacy of follow-up period). Further, if warranted, the Cochrane Collaboration’s risk-of-bias tool will be used for randomized controlled trials, based on the domains: sequence generation, blinding of participants, blinding of outcome measurement, allocation sequence concealment, missing data, selective outcome reporting, and other biases such as sources of funding and conflicts of interest [ 30 ]. Additionally, the Quality in Prognosis Studies (QUIPS) tool will facilitate assessment for the risk factor studies [ 22 ]. For any type of quality appraisal (observational study quality scale, Cochrane’s risk-of-bias tool, or QUIPS), two authors will independently review the included studies and resolve discrepancies by discussion and consensus agreement within the review team.

Data analysis

We will provide a descriptive synthesis of the findings from the included studies, structured around target population characteristics, type of assessments, and outcomes of interest. We will consider meta-analyses if there is an adequate number of studies and homogeneity of study populations and assessment methods. Otherwise, we will present a narrative synthesis of the results. We anticipate that there will be restricted scope for meta-analysis due to differing study populations and/or assessment methods along with a paucity of existing literature. Where studies have similar sample characteristics (including potential comparison groups), assessment methods, and corresponding outcomes, we will pool the results and apply various types of meta-analyses such as mean difference, standard mean difference, or Cox regression for continuous outcomes and risk ratio measurement or logistic regression for categorical outcomes depicted in forest plots along with their 95% confidence intervals (CIs). Finally, we will evaluate the overall strength of the evidence based on discussion among authors through application of a tool such as GRADE.

Assessment of heterogeneity

If there is reason to consider meta-analysis, analyses will be performed using Cochrane’s Review Manager tool (Review Manager: RevMan [computer program]. The Cochrane Collaboration, 2024). We plan to assess study features such as participant age and sex, MS subtype, time course for follow-up, and primary outcome measures as the basis for determining if data pooling for meta-analysis is warranted. Subsequently, if meta-analysis is undertaken, we will apply and interpret the I 2 statistic [ 30 ] as an indictor of heterogeneity relative to the number of studies and direction of effect using the following guide: mild (between 0 and < 25%), moderate (between 25 and < 50%), severe (between 50 and < 75%), and highly severe (between 75 and 100%). If there is moderate heterogeneity, we will present a supplementary qualitative synthesis of the findings.

Analysis of subgroups or subsets

If sufficient data are available, subgroup analyses may be conducted for different OPD assessment methods (e.g., clinical bedside evaluation, fiber-optic nasoendoscopic evaluation, and/or videofluoroscopic evaluation) relative to MS type and risk factors. Similarly, long-term outcomes based on dysphagia status or severity levels will be analyzed according to follow-up periods or comparable overall time horizon.

Assessment of publication bias

Publication bias will be evaluated using a funnel plot (i.e., plots of study results against precision) and Begg’s [ 31 ] and Egger’s [ 32 ] tests if an adequate number of studies (≥ 10) are identified. Additionally, we will incorporate Deek’s asymmetry test [ 33 ] to mitigate overestimation of effects when predictive modeling with odds ratios is applied for the determination of OPD across studies that involve low event proportions. However, if meta-analysis is not possible, publication bias will be assessed descriptively and involve documentation of direction of results across risk factors (whether significant or not) as well as potential follow-up time lags across studies.

Our search strategy is extensive compared to other recent systematic reviews in the field of multiple sclerosis [ 1 , 34 ] given the inclusion of numerous sources and comprehensive search terms. We believe that it will yield a broad capture of abstracts internationally, but that many articles will derive from western or developed countries. This may be an important limitation because many underrepresented countries, such as Iran, have a high and increasing prevalence of pwMS in certain regions [ 35 , 36 ].

Other systematic reviews have undertaken different lines of inquiry such as investigating the prevalence of dysphagia in pwMS without considering risk factors [ 1 ] or long-term outcomes [ 1 , 10 ]. Thus, we will extend the knowledge base in a new content area (involving predictors and long-term outcomes of dysphagia in pwMS). Our identification of literature in the field of MS will provide new insights into the repercussions of dysphagia and offer direction for the development of screening protocols, assessment methods, and improved therapeutic management in pwMS. In the event that our findings elucidate multiple predictors (e.g., related to MS, patient characteristics, and/or comorbidities) and varied outcomes (e.g., medical, activity/participation, or quality of life), they may warrant publication in multiple peer-reviewed papers.

We anticipate that various limitations will result during our search of the literature. First, studies may not report the timeframe between dysphagia onset, assessments, and associated outcomes. Second, dysphagia identification in specific studies might be based on cursory screenings, patient self-report (and potentially non-standardized) questionnaires, and/or subjective clinical assessments rather than on instrumental reference tests such as videofluoroscopy and fiber-optic nasoendoscopy. Finally, it may be difficult to pool results from the existing literature for some of the risk factors or outcomes if investigations restrict enrolment to particular types of pwMS, involving subsamples of larger studies, or if they fail to incorporate shared definitions and research methods in the field of multiple sclerosis [ 36 ].

Although the frequency of dysphagia in pwMS has been a topic of inquiry within the past two decades [ 1 , 10 ], a poor understanding of associations to disease-related risk factors and negative outcomes remains. Our proposed systematic review will address such a gap in the literature, as we will attempt to elucidate risk factors of dysphagia and long-term outcomes from observational studies reporting frequencies of dysphagia over the long term. Where relevant, we will pool results across studies or extract individual-level data that may permit us to model risk factors of dysphagia and/or its associated long-term outcomes in pwMS. Our inquiry will offer the means to inform best practices in the early detection of dysphagia and provide information that can be incorporated into guidelines and clinical practice initiatives for the management of dysphagia in pwMS.

Availability of data and materials

Not applicable.

Abbreviations

• Oropharyngeal dysphagia

Persons with multiple sclerosis

• Multiple sclerosis

Expanded Disability Status Scale

Dysphagia in Multiple Sclerosis Questionnaire

Strengthening the Reporting of Observational Studies in Epidemiology

Newcastle-Ottawa scale

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Department of Speech Therapy, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran

Zahra Sadeghi

Department of Speech Therapy, School of Rehabilitation, Tehran University of Medical Sciences, Tehran, Iran

Mohamadreza Afshar

School of Rehabilitation Sciences, Faculty of Health Sciences, University of Ottawa, 200 Lees Avenue, Ottawa, ON, K1S 5S9, Canada

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ZS conceptualized, designed, and wrote much manuscript. HF conceptualized, designed, wrote, and edited the manuscript. MA conceptualized, designed, and wrote parts of the manuscript. AM developed the search terms and wrote parts of the manuscript.

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Sadeghi, Z., Afshar, M., Memarian, A. et al. Risk factors and long-term outcomes of oropharyngeal dysphagia in persons with multiple sclerosis: a systematic review protocol. Syst Rev 13 , 121 (2024). https://doi.org/10.1186/s13643-024-02530-3

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Study Protocol

Social networking older adults with mild cognitive impairment: Systematic review protocol on their use of information and communication technology

Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Validation, Visualization, Writing – original draft

* E-mail: [email protected]

Affiliation Department of Rehabilitation and Health Services, University of North Texas, Denton, Texas, United States of America

Roles Methodology, Project administration, Resources, Supervision, Validation, Writing – review & editing

Affiliations Department of Rehabilitation and Health Services, University of North Texas, Denton, Texas, United States of America, School of Health Sciences, University of Sydney, Camperdown, Australia, Department of Educational Psychology, University of Johannesburg, Johannesburg, South Africa

Roles Supervision, Writing – review & editing

• Rongfang Zhan, 
• Elias Mpofu, 
• Gayle Prybutok, 
• Stan Ingman

• Published: May 2, 2024
• https://doi.org/10.1371/journal.pone.0302138
• Reader Comments

This systematic review will identify and synthesize the emerging evidence on older adults with Mild Cognitive Impairment (MCI) utilizing Information and Communication Technology (ICT) to maintain, restore, or augment social networks. The systematic review will consider the evidence on contextual and personal factors of older adults with MCI and their ICT use for social connectedness. The evidence searches will be implemented in PsycINFO, Academic Search Complete, Medline, PubMed, and manual searches. We shall review articles that were published between January 2010 and October 2023 in English and on Information and Communication Technology utility in social networking among older adults with MCI. The process of article selection will be conducted through title screening, abstract screening; and full article screening, following the Population, Intervention, Control, Outcomes (PICO) criteria. Given that all the studies included in this review are publicly accessible and have already obtained ethical approval from their respective institutions, there is no obligation for us to seek additional ethical clearance for our systematic review. We plan to share the outcomes of the systematic review through online presentations and dissemination within the research community. The findings from this review will identify the extent of empirical evidence on older adults with MCI utilizing ICTs to maintain, restore or augment their social networks. This review will provide evidence for contextual and personal factors in older adults with MCI for the social networks with ICT use. This review will propose practical implications for the effective utilization of ICT by older adults with MCI.

Citation: Zhan R, Mpofu E, Prybutok G, Ingman S (2024) Social networking older adults with mild cognitive impairment: Systematic review protocol on their use of information and communication technology. PLoS ONE 19(5): e0302138. https://doi.org/10.1371/journal.pone.0302138

Editor: Tamlyn Julie Watermeyer, University of Northumbria at Newcastle: Northumbria University, UNITED KINGDOM

Received: December 26, 2023; Accepted: March 25, 2024; Published: May 2, 2024

Copyright: © 2024 Zhan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: No datasets were generated or analysed during the current study. All relevant data from this study will be made available upon study completion.

Funding: The author(s) received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

Introduction

As people age, they tend to lose their social networks, placing them at disproportionate risk for developing cognitive decline and impairment [ 1 , 2 ]. For those aging with or into Mild cognitive impairment (MCI), they are at higher risk for loss of social networks [ 3 , 4 ], perhaps due to lack of social stimulation from interactions with others resulting in social isolation and/or loneliness [ 5 ]. Social isolation refers to an objective social reality that lacks connections with social relationships [ 6 , 7 ]. Loneliness refers to the subjective feeling of aloneness or disconnectedness from discrepancy between one’s desire for social connections and their real-life social interactions [ 8 , 9 ].

Mild Cognitive Impairment (MCI) is an intermediate clinical state of cognitive deterioration between normal aging and Alzheimer’s disease [ 10 – 12 ]. Individuals with mild cognitive impairment experience a decline in everyday life cognitive abilities such as memory, thinking, language expression at a higher level than expected for age [ 13 , 14 ], and which may harm their social engagement or social networking. Social networks provide older adults with connections to other people, such as family, friends, acquaintances, and neighbors, through meaningful social interaction [ 15 ]. Limited social networks could potentially exacerbate cognitive decline [ 16 – 19 ]. Social networks are beneficial to health functioning in both personal and physical connectivity utilizing information and communication technology tools [ 20 ].

Information and Communication Technology (ICT) is fast becoming an everyday tool for usage by older adults, with the historical digital divide diminishing [ 21 , 22 ]. ICT usage encompasses various digital tools and platforms such as computers, smartphones, social media, web-based sites, email, telehealth and so on [ 23 , 24 ]. Use of ICT may assist older adults with MCI to age successfully by maintaining, restoring, and augmenting their social networks. Using information and communication technology, older adults foster positive social relationships, thereby mitigating loneliness and social isolation, and alleviating cognitive decline during the COVID-19 pandemic [ 25 ]. Successful aging is being able to maintain physical and mental well-being, social engagement, and overall life satisfaction at older age [ 26 ]. For instance, the ownership of smartphones among older adults has experienced a significant surge, increasing from 18% in 2013 to 61% for those aged 65 and above in the year 2021 [ 27 ]. Yet, while there exists extensive literature on ICTs usage by older adults, the evidence remains unclear regarding their utilization specifically for social networking purposes, particularly among those with MCI who are at a high-risk population for social isolation and loneliness.

However, within the current digital age, social networks supported by ICT have transcended physical boundaries and seamlessly expanded their influence to encompass the dynamic interactions unfolding on online social sites [ 28 ]. But this may vary in unknown ways based on the older adult’s life situations (e.g., living arrangement, geographical area, neighborhood) and personal factors of age, health status, gender et cetera. There is a need to synthesize the evidence of the ICT utility supporting social networking of older adults with MCI for trends that would inform related studies. Our systematic review will synthesize the emerging evidence on Information and Communication Technology utility in social networking among older adults with Mild Cognitive Impairment.

The systematic review we propose will address the following questions:

• To what extent do older adults with MCI utilize ICTs to maintain, restore or augment their social networks?
• What is the evidence for contextual and personal factors of older adults with MCI use of ICT for their social networking?

Research design

The systematic review will follow the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analysis 2020 [ 29 ]. We will use the PRISMA 2020 checklist [ 29 ] to ensure a transparent and reliable approach in conducting our systematic review. This protocol is registered on PROSPERO (international prospective register of systematic reviews) (registration number CRD42023469950).

Eligibility criteria

We will specify the inclusion and exclusion criteria for the review, with reference to the study characteristics including Population, Intervention, Control, Outcomes (PICO), study design, setting, time frame, and the report characteristics such as the years considered, publication status, and language ( Table 1 ).

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https://doi.org/10.1371/journal.pone.0302138.t001

Population.

We will include for the systematic review studies on older adults who are 65 years or older with MCI and exclude populations with severe memory functions such as dementia and Alzheimer’s disease. Rubinow [ 30 ] defined that “age 65 is generally set at the threshold of old age since it is at the period of life that the rates for sickness and death begin to show a marked increase over those of the earlier years.”

Types of ICT usage.

The systemic review will examine the evidence from studies that specify the use of ICT in social networks. ICT usage includes any form of communication with at least one other person. Due to the concentration of the review on the implementations of ICT, other types of technologies such as daily assistive technology will be excluded.

Types of control and comparison.

Control and comparison refer to the study elements on ICT usage for social lives by older adults. The comparator will include three scopes based on the feature of each included study: 1) ICT usage and no ICT usage. We will compare the outcomes of social networks in older adults with MCI between how they use ICT and don’t use ICT; 2) ICT usage and traditional in-person social intervention. We will compare the evidence from studies using ICT and traditional methods such as only in-person social support groups in older adults with MCI; 3) different types of ICT usage. The review will compare the effectiveness of different types of ICT in included studies such as smartphone, tablets, and social media or technologically based cognitive training programs on social networks. Additionally, we also explore the effectiveness of various online platforms, such as social media platforms and other web-based applications, in facilitating social networks among older adults.

Types of outcome measures.

The outcome measures will assess the evidence on the level of social networks among older adults with MCI by their ICT usage. We will assess the evidence on usage to maintain existing social networks, to restore previous social networks, and/or to form new social networks. We also will examine the evidence from studies that utilized standardized cognitive assessment tools and self-reported assessments of cognitive functioning and social networks using ICT.

The systematic review will include studies on older adults in community living as well as those in assisted living and able to use Information and Communication Technology. Institutions such as assisted living, retirement homes, hospitals or nursing homes are included. We will exclude studies that are implemented in memory care facilities taking care of older adults with dementia and Alzheimer’s disease.

Types of study designs.

Eligible for the systematic review inclusion are peer reviewed studies, nonrandomized controlled trials, randomized controlled trials, case-control studies, and prospective controlled cohort studies.

For ICT intervention studies, we will include those that implemented a minimum duration of at least two months.

Date of search.

The inclusion of the date of the literature will start from January 2010 to October 2023.

Publication language.

The proposed systematic review will focus on English published studies. We will exclude the studies that are published in other languages.

Information sources

Studies will be systematically identified through structured searches from key databases: PsycINFO, Academic Search Complete, Medline, and PubMed. In addition, we will conduct manual searches by searching relevant studies in Google Scholar.

Search strategy

Included studies are those published between January 2010 and October 2023. Key concepts of the proposed systematic review will be ‘older adults’, ‘mild cognitive impairment’, and ‘information communication technology’, ‘social networks’, ‘usage status’ and we extend our search terms listed below ( Table 2 ).

https://doi.org/10.1371/journal.pone.0302138.t002

Selection process and data collection process

The process of article selection will be conducted through three consecutive steps: 1) title screening; 2) abstract screening; and 3) full article screening. All extracted articles will be stored in a RefWorks database. The duplication elimination procedure will be handled in RefWorks as well. The first author reviewer will employ text extraction techniques by using Python to retrieve all titles and abstracts saved in a PDF, and then two reviewers will independently review all titles and abstracts in the PDF to further identify each study for eligibility against our inclusion and exclusion criteria. After identifying the included titles and abstracts, we will retrieve and review the full text of selected titles. Two reviewers will independently review the full-text articles, with any discrepancies addressed until a unanimous agreement is reached.

The systematic review process will be illustrated visually in the PRISMA 2020 flow diagram that is a version for new systematic reviews which included searches of databases, registers, and other sources [ 29 ].

For ease of interpreting included studies, we will create data abstraction tables to classify extracted study information from each study. The tables will include the study characteristics (e.g., author, publication year), participant characteristics (e.g., age, gender, race, sample size), types of ICT usage, study conducted in the USA, methods, and findings. The first author and second author reviewer will independently review and verify the information included in the evidence tables for accuracy. Any discrepancies in the results will be resolved through discussion with a third reviewer, as necessary.

We will identify the types of ICT usage and present the setting, method, participant characteristics and findings of each included study.

Risk of bias assessment

Two independent reviewers will independently access the risk bias for data information extracted from the studies. Any discrepancy of information between two reviewers will be solved by discussing with third and fourth team members. To ensure the methodological quality of each included study, we will appraise the studies based on the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) tool. We will use the Cochrane Risk of Bias Tool (CRB) for appraisal of the randomized controlled trials and the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool for verifying nonrandomized studies.

Data synthesis

The proposed systematic review will incorporate a descriptive numerical summary for quantitative studies and a qualitative thematic synthesis for qualitative studies [ 31 ]. If we find comparisons of interest on included studies, we will conduct a descriptive numerical summary that will structure and present main characterizations of included studies including the types of ICT intervention, types of study design, year of publication, characteristics of the participants, settings where studies were conducted, and other features. For in-depth understanding, the topic of the proposed systematic review implements a qualitative thematic synthesis. The qualitative thematic synthesis will be conducted to identify the common themes or patterns of meaning across the included studies [ 31 ]. Further, we focus on social networking activity and participation for those suffering with MCI supported by ICT.

Ethics and dissemination

The ethical approval status of each included study will be appraised by two independent reviewers. Since all included studies are publicly available and approved by their initial studies, we are not required to provide ethical approval for our systematic review. The findings of the systematic review will be presented online and disseminated to the research community.

Synthesizing the evidence on older adults with MCI of ICT usage for social networking is critical for researchers, stakeholders, practitioners, and policymakers to improve ICT services for the social well-being of older adults with MCI. Finding may contribute to the further ICT innovations in older adults with MCI. We shall present the results in three tables: evidence trends across the total sample of all studies, contextual factors, and personal factors.

This systematic review protocol provides an outline and framework for further systematic review that fills the research gap in ICT utilization in social networks by older adults with MCI. To our knowledge, there is no previous review trending evidence on ICT utility for social networking by older adults with MCI. Particularly, we will provide a holistic framework for older adults with MCI’s use of ICT to maintain, restore and/or augment their social networks. We shall discuss the findings for trends in the evidence on ICT-supported social connectedness rapidly becoming the new normal for social interactions with MCI, important to older adults maintaining, restoring, and augmenting their social networking.

Supporting information

S1 checklist. prisma-p (preferred reporting items for systematic review and meta-analysis protocols) 2015 checklist: recommended items to address in a systematic review protocol*..

https://doi.org/10.1371/journal.pone.0302138.s001

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This paper is in the following e-collection/theme issue:

Published on 23.4.2024 in Vol 13 (2024)

Impact of Digital Interventions on the Treatment Burden of Patients With Chronic Conditions: Protocol for a Systematic Review

Authors of this article:

• Manria Polus 1, 2 , MSc   ; 
• Pantea Keikhosrokiani 1, 2 , PhD   ; 
• Olli Korhonen 1 , PhD   ; 
• Woubshet Behutiye 1 , PhD   ; 
• Minna Isomursu 1, 2 , PhD  

1 Faculty of Information Technology and Electrical Engineering, University of Oulu, Oulu, Finland

2 Faculty of Medicine, University of Oulu, Oulu, Finland

Corresponding Author:

Manria Polus, MSc

Faculty of Information Technology and Electrical Engineering

University of Oulu

Pentti Kaiteran Katu 1

Oulu, 90570

Phone: 358 294 48 0000

Email: [email protected]

Background: There is great potential for delivering cost-effective, quality health care for patients with chronic conditions through digital interventions. Managing chronic conditions often includes a substantial workload required for adhering to the treatment regimen and negative consequences on the patient’s function and well-being. This treatment burden affects adherence to treatment and disease outcomes. Digital interventions can potentially exacerbate the burden but also alleviate it.

Objective: The objective of this review is to identify, summarize, and synthesize the evidence of how digital interventions impact the treatment burden of people with chronic conditions.

Methods: The search, selection, and data synthesis processes were designed according to the PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols) 2015. A systematic search was conducted on October 16, 2023, from databases PubMed, Scopus, Web of Science, ACM, PubMed Central, and CINAHL.

Results: Preliminary searches have been conducted, and screening has been started. The review is expected to be completed in October 2024.

Conclusions: As the number of patients with chronic conditions is increasing, it is essential to design new digital interventions for managing chronic conditions in a way that supports patients with their treatment burden. To the best of our knowledge, the proposed systematic review will be the first review that investigates the impact of digital interventions on the treatment burden of patients. The results of this review will contribute to the field of health informatics regarding knowledge of the treatment burden associated with digital interventions and practical implications for developing better digital health care for patients with chronic conditions.

Trial Registration: PROSPERO CRD42023477605; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=477605

International Registered Report Identifier (IRRID): DERR1-10.2196/54833

Introduction

Digital technologies are now commonly used in daily life, bringing many new possibilities for connecting people and providing services. The use of mobile- and web-based digital health care interventions has increased during the COVID-19 pandemic and has been found to have high efficacy, accessibility, and cost-effectiveness in the self-management of chronic diseases [ 1 - 3 ].

As the global population is growing, the prevalence of chronic diseases has increased significantly [ 4 ]. The World Health Organization [ 4 ] has estimated that if this trend continues, by 2050 chronic diseases will be the cause of 86% of the 90 million deaths each year. This means a 90% increase in absolute numbers since 2019. Therefore, there is a continuous need for new interventions for the management of chronic diseases.

Chronic diseases often require regular long-term management, which requires patients to not only cope with their symptoms but also navigate services, interact with health professionals, and adhere to treatments, creating a significant burden for many patients [ 5 ]. Treatment burden is defined as both the workload required for self-management of disease and the impact treatment regimens have on the patient’s function and well-being [ 5 ]. Treatment burden can affect many domains: burden of taking medications, traveling to appointments, financial burden, impact on social life and emotions, and burden of accessing health care services [ 6 , 7 ]. A high treatment burden has been associated with poor adherence and worse disease outcomes [ 6 ].

The variety of available digital interventions can be tailored to meet the diverse needs of patients. For example, telemedicine and remote visits can reduce the need for traveling to medical appointments [ 8 ]. Mobile health apps, wearable technologies, and remote monitoring systems can track patients’ health data and alert health care professionals (HCPs) if intervention is required [ 9 , 10 ]. Electronic health records offer a central repository for patients’ history to minimize the paperwork and speed up the adherence process [ 11 ], while electronic prescription management improves patient safety as well as the efficiency and costs of prescribing medications [ 12 ]. Furthermore, patients’ portals, web-based support groups, and forums provide emotional and social support for patients [ 13 ].

The World Health Organization Classification of Digital Interventions, Services and Applications in Health [ 14 ] highlights a variety of digital health technologies for different types of services. In this study, we will focus on the point of service category of digital interventions. The point of service category includes those digital interventions that facilitate and deliver health care services to the patients, making it easier to see the connection between the treatment burden of the patient and the digital intervention. This category includes communication systems, community-based information systems, decision support systems, diagnostics information systems, electronic medical record systems, laboratory information systems, personal health records, pharmacy information systems, and a variety of telehealth systems. These digital interventions can include many different components, such as monitoring tools, decision aids, behavior change support, communication with HCPs, and web-based peer support groups.

Digital interventions may affect the treatment burden in multiple ways. With limited resources, digital interventions may be used to reduce the burden on the health care system, and staff end up offloading the burden to patients [ 15 - 18 ]. Patients may also find digital systems inaccessible or difficult to use [ 19 ] and struggle with digital stress [ 20 ]. However, digital interventions can expedite and simplify health care processes in a way that patients may receive treatment more efficiently, reducing the treatment burden for patients. For example, they can reduce the need for medical appointments and travel to hospitals [ 8 ] and make self-management easier and more motivating for patients [ 21 , 22 ].

Many systematic reviews have been conducted to investigate the treatment burden on patients with chronic conditions [ 6 , 7 , 23 - 26 ]. These reviews have provided insights into the definition, prevention, and patient’s experience of treatment burden. In addition, recent systematic and umbrella reviews about digital interventions have found that most digital interventions in health care are mobile- or computer-based [ 27 - 29 ]. The findings of the recent research are mostly focused on effectiveness, and the largest targeted condition group is mental illnesses [ 27 , 29 ]. However, we have observed a gap in the literature regarding systematic reviews combining these 3 concepts: treatment burden, digital interventions, and chronic conditions.

The aim of this review is to identify gaps in the literature and summarize and synthesize currently available evidence of how digital interventions impact the treatment burden of people with chronic conditions. The impact can be a positive or negative effect on any domain of treatment burden. We aim to investigate if the results differ between chronic conditions with different levels of treatment burden or between interventions with different components.

Research Questions

We have two primary research questions: (1) How can digital interventions impact the treatment burden on people with chronic conditions? (2) What kind of support can digital interventions provide for people with chronic conditions with their treatment burden?

Ethical Considerations

We followed the University of Oulu ethics process as defined in the guidelines from the Ethics Committee of Human Sciences [ 30 ]. According to the guidelines, an ethics board review is not needed for this protocol.

Study Design

This protocol is reported according to the PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols) 2015 [ 31 ]. We registered the protocol on the International Prospective Register of Systematic Reviews (PROSPERO CRD42023477605).

The systematic review will use a convergent design for systematic mixed studies reviews [ 32 ]. The mixed method approach was selected because qualitative results can help us to understand the phenomenon of treatment burden in the context of digital health care, and quantitative results can be used to generalize the qualitative findings by measuring their magnitude, trends, causes, and effects [ 33 ]. The convergent design was most suitable for this review since the research questions can be answered by both qualitative and quantitative findings.

Information Sources and Search Strategy

A systematic search for papers published between January 1, 2013, and October 16, 2023, was conducted from bibliographical databases PubMed, Scopus, Web of Science, ACM, PubMed Central, and CINAHL. The following search string was used: (“Chronic illness” OR “chronic disease” OR “chronic diseases” OR “chronic illnesses” OR “chronically ill” OR “diabetes” OR “asthma” OR “cancer” OR “cystic fibrosis” OR “epilepsy” OR “rheumatoid arthritis” OR “HIV” OR “patient”) AND (“Digital” OR “Remote” OR “Mobile” OR “smartphone” OR “smartwatch” OR “smart ring” OR “smart device” OR “smart devices” OR “app” OR “mHealth” OR “eHealth” OR “web-based”) AND (“Treatment burden” OR “Burden of treatment” OR “Treatment impact” OR “Treatment workload” OR “Treatment inconvenience” OR “Treatment acceptability” OR “Illness burden” OR “Burden of illness” OR “Medication burden”). To identify relevant papers, a search strategy was conducted in an iterative way. The creation of the search strings for treatment burden was informed by previous systematic reviews on the topic [ 23 , 24 ]. Scoping searches were conducted in several potential databases focusing on health and biomedicine, information technology, nursing, psychology, or multiple disciplines (PubMed, Scopus, Web of Science, ACM, PubMed Central, CINAHL, IEEE, and APA PsycINFO). Scoping searches were conducted on October 15, 2023, in CINAHL and on October 12, 2023, in other databases. Searches conducted on IEEE and APA PsycINFO databases revealed no relevant results, so databases were excluded from the search strategy. Including only certain chronic conditions, for example, epilepsy or neurological conditions, was considered, but there was a limited number of studies found during the initial scoping searches. For example, in the scoping search for epilepsy conducted on October 12, 2023, only 3 relevant papers were identified. Therefore, we decided to keep the scope wide and include all chronic conditions in the search string.

The MeSH term “chronic disease” and search terms “coronary heart disease,” “heart disease,” “MS,” and “multiple sclerosis” were tested during a scoping search in PubMed, but they brought no new results and therefore were removed from the search terms. A supplementary search will be conducted from the citations contained in systematic literature reviews and scoping reviews that were found during the literature searches.

Inclusion Criteria

We have included original publications written in English and accepted in peer-reviewed journals or conference proceedings. Qualitative, quantitative, and mixed method studies are included. The studies can be clinical trials, nonrandomized controlled trials, cross-sectional studies, longitudinal studies, observational studies, case studies, and other types of qualitative studies. Study design will be classified based on the tool from Grimes and Schulz [ 34 ]. Conference proceedings are included, but reviews, protocols, and book chapters are excluded.

We limited our search to publications after 2013 to include the last 10 years of research. Although digital health technology has developed quickly in recent years, the use of digital interventions in health care for chronic conditions goes farther than 10 years [ 35 ]. To the best of our knowledge, there are no previous systematic reviews relating to both digital health and treatment burden. However, studies before 2013 referred mostly to apps created only for research purposes, which were not available to the public at that time. Therefore, we decided to include papers published after 2013 to cover all relevant publications.

The study population in the included publications must consist of patients who have a chronic condition, their caregivers, or HCPs treating patients with chronic conditions. All ages and ethnicities are included. Only studies with outcomes regarding treatment burden for the patients are included. Studies that do not specifically mention the phrase “treatment burden” or “burden of treatment” but still discuss the impact of health care on the workload and burden for patients are also included. Only studies regarding a digital intervention that facilitates and delivers health care services to patients with chronic conditions are included.

Selection of Studies

After the searches, all titles and abstracts from search results were uploaded to a web-based Covidence screening tool (Veritas Health Innovation), where duplicate records will be removed. All titles and abstracts were screened and selected for inclusion independently by 2 authors (MP and PK or OK). Full-text papers from the selected papers will also be screened and selected for inclusion independently by 2 authors (MP and PK or OK). Disagreements will be resolved by discussion.

Data Extraction

Data on population characteristics, study design, aims, intervention characteristics, measures, and main results will be extracted using a predefined data extraction form in Covidence. Study design will be classified based on the tool from Grimes and Schulz [ 34 ]. Before proceeding with data extraction, MP will pilot the data extraction form with 5 papers to identify possible adjustment needs. Data extraction will be performed independently by 2 reviewers (MP and PK or OK). Disagreements will be resolved by discussion.

Risk of Bias

The quality of the included studies will be assessed using Joanna Briggs Institute Critical Appraisal tools. Two reviewers (MP and PK or OK) will assess the quality of each included study independently. Based on the design of the eligible studies, we will use Joanna Briggs Institute checklists designed for randomized controlled trials, quasi-experimental studies, analytical cross-sectional studies, case-control studies, case series, and qualitative studies.

Data Synthesis

A convergent integrated approach to synthesis and integration will be used [ 32 ]. This involves converting quantitative data into qualitative data followed by integration of the qualitative and quantitative evidence [ 36 ].

Currently, we have performed searches in the 6 selected databases, and 241 studies have been identified. Screening based on title and abstract excluded 192 studies. Overall, 69 studies have been included in the second round of study selection, which is ongoing. The review is expected to be completed in 2024.

This systematic review is performed to investigate the impact of digital health care on the treatment burden of patients with chronic conditions. This review is important because the world is currently facing increasing amounts of chronic diseases, and digital solutions are needed to improve the management of chronic diseases, which pose a significant burden on both health care systems and the patients themselves. However, it is essential to design the digital interventions in a way that helps patients to deal with their existing treatment burden and avoids further increasing the treatment burden. To the best of our knowledge, this will be the first review that covers the impact of digital health care on the treatment burden of patients with chronic conditions. The outcomes are expected to cover the positive and negative impacts of digital interventions on treatment burden and the different types of support digital interventions can provide to people with chronic conditions struggling with treatment burden. We aim to categorize different types of interventions and their components and find potential differences between interventions with different components and chronic conditions with different levels of treatment burden.

For the limitations of this review, the findings will depend on the number of eligible studies we will be able to identify and the quality of these studies. In addition, the studies identified for this review may be heterogeneous in terms of design, interventions, participant groups, and outcomes. Furthermore, our search will be restricted to peer-reviewed studies published in English.

Authors' Contributions

MP developed the initial research questions; design of the review, search, and selection strategies; and drafted the paper. PK and OK contributed to the refining of the research questions; design of the review, search, and selection strategies; and writing and editing of the paper. WB and MI contributed to the editing and approved the final paper.

Conflicts of Interest

None declared.

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Abbreviations

Edited by A Mavragani; submitted 24.11.23; peer-reviewed by KL Mauco, C Baxter; comments to author 02.02.24; revised version received 20.02.24; accepted 13.03.24; published 23.04.24.

©Manria Polus, Pantea Keikhosrokiani, Olli Korhonen, Woubshet Behutiye, Minna Isomursu. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 23.04.2024.

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