A systematic scoping review on quality criteria for clinical practice guidelines for rare diseases

A systematic scoping review on quality criteria for clinical practice guidelines for rare diseases | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A systematic scoping review on quality criteria for clinical practice guidelines for rare diseases Iméze Hieltjes, Mirthe Klein Haneveld, Ingeborg Van Dusseldorp, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6693080/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background Rare diseases impose substantial challenges on affected individuals and healthcare systems. While clinical practice guidelines (CPGs) are crucial for standardizing care, tools to assess their trustworthiness are limited, particularly for rare diseases. There is a need for minimum quality criteria to ensure CPG reliability and utility. Objective This systematic scoping review aims to identify a set of criteria that can be used for evaluating and endorsing CPGs for rare diseases. Methods A systematic scoping review was conducted using four databases (Ovid/Medline, Embase.com, Scopus, and Google Scholar) from inception to April 9, 2024. The search, developed by a medical information specialist. Titles and abstracts were independently screened by two reviewers, with disagreements resolved through discussion or a third reviewer. Articles were included if they addressed quality criteria for guidelines on rare diseases in general, excluding disease-specific guidelines. Results From 9587 unique titles, only one study met the inclusion criteria. The included study, published by Hilton-Boon et al. (2015), summarized an international workshop on the applicability of AGREE II criteria for rare disease guidelines. Conclusion Our systematic review identified a single report detailing an international workshop that evaluated the utility of the AGREE II instrument for assessing two guidelines focused on rare diseases. This limited finding highlights a significant gap in methodologies tailored to the specific complexities of rare disease guidelines. The findings underscore the need for a tailored, streamlined set of criteria to address the unique challenges of rare disease guidelines, supporting their development, evaluation, and endorsement in clinical practice. Figures Figure 1 What is new? Key findings Despite a sensitive search in this systematic review, we did not find a set of quality criteria for the specific context of rare disease guidelines. We only identified a single report describing an international workshop that examined the applicability of the AGREE II instrument for evaluating two guidelines for one rare disease. What this adds to what is known? This shows the significant lack of quality criteria tailored to the specific complexities of rare disease guidelines. What is the implication and what should change now? Guidelines for rare diseases may benefit from a tailored, streamlined set of criteria to address the unique challenges of the rare disease field, supporting the development, evaluation, and endorsement of these guidelines. Introduction In Europe, a disease is considered rare if it affects no more than 1 in 2000 persons ( 1 , 2 ). Around six to seven thousand rare diseases have been discovered, and new diseases are identified regularly ( 3 ). Although rare diseases individually affect a small number of people, collectively they have a considerable impact on the population ( 1 ). Due to limited knowledge and less robust evidence on diagnosis and interventions the quality of care may be lower compared to more prevalent diseases ( 4 ). In 2009 the European Commission recommended establishing and implementing national plans and strategies to ensure that patients with rare diseases have access to high-quality care( 5 ). Clinical practice guidelines (CPGs) are systematically developed statements or recommendations that assist healthcare providers in making informed decisions about the care of patients. These CPGs are based on a thorough review of the best available evidence from clinical research and expert opinion (including both clinical and patient expertise). They aim to standardize and improve patient care by providing clear, evidence-based recommendations for diagnosing, managing, and treating specific medical conditions or diseases ( 6 ). Additionally, CPGs serve as a valuable resource for ensuring consistency in healthcare, reducing practice variability, and supporting shared decision-making between patients and providers. However, developing CPGs for rare diseases poses several challenges( 7 – 12 ). First, it is difficult to decide which topics to address in a rare disease CPG given the limited resources and evidence. For many rare diseases, there are still considerable knowledge gaps with regard to the best way to diagnose, manage, and treat patients. When resources are scarce, it is challenging to decide for which rare disease a CPG should be developed and which clinical questions for this disease need to be addressed most urgently. Another challenge is that the existing literature on rare diseases often consists of case studies or non-comparative observational designs, resulting in very low certainty of evidence. Due to limited resources guideline development panels may refrain from performing a systematic review since they do not expect considerable high-level evidence, and in this way make methodological shortcuts ( 13 – 15 ). Also, guideline development panels in rare diseases are not always aware of existing methodologies for guideline development in our experience as methodologists. Not only the number of patients is low in rare diseases; also, the number of medical professionals and patient representatives may be limited, which may lead to insufficient representation of stakeholders when developing a CPG. In a small group, the influence of an individual (either patient expert or clinical expert) may be out of proportion and may not always align with the interests of all stakeholders. Personal differences are of more influence in small expert groups. This issue is less salient in non-rare diseases, where there is a larger group of stakeholders to choose from. Finally, related to the former issue, it is not always possible to maintain editorial independence in the development of rare diseases CPGs. The limited number of experts in rare diseases makes it particularly difficult to find guideline panel members without competing interests. Due to these challenges, not all documents that are called guidelines or CPGs for rare diseases are developed according to the standard methodology ( 10 ). However, clinicians still use such documents to make informed decisions on the management and treatment of their patients. Therefore, clinicians are helped when they know how to distinguish trustworthy from untrustworthy CPGs ( 16 ). Lima et al., 2023 ( 16 ) give guidance to clinicians for the distinction of trustworthy and untrustworthy guidelines in general, not limited to rare diseases. However, the eight domains they propose as a conceptual framework for evaluating the trustworthiness of guidelines are intended as a flexible guide rather than a set of criteria. Endorsement by official organizations such as European Reference Networks (ERNs) or medical specialist scientific associations may be instrumental to distinguish trustworthy documents from less trustworthy documents. These organizations need ways to appraise the quality of CPGs or other quality documents for rare diseases that are offered to them for endorsement and official publication on the organization’s website. The AGREE II instrument was designed to assess the methodological quality and transparency of CPGs ( 17 ). It contains 23 items in six domains. Several studies that have used the AGREE II instrument to appraise CPGs for rare diseases ( 7 – 12 ) show considerable variation in quality and highlight the lack of methodological rigor of CPGs for rare diseases. While the AGREE II checklist represents a comprehensive standard, achieving high scores on all 23 quality items has its challenges for CPGs for rare diseases as shown before. Therefore, the development and appraisal of CPGs for rare diseases may need a specific set of criteria for rare disease CPGs, to enhance the feasibility of developing and endorsing such documents in the context of rare diseases. These criteria should ensure that CPGs meet essential quality benchmarks without necessitating perfection, thus providing a minimum level of reliability and utility for healthcare providers of rare diseases. This systematic scoping review aims to identify a set of criteria that can be used for evaluating and endorsing CPGs for rare diseases. Methods For this scoping review, a systematic sensitive literature search was performed to identify as many relevant articles as possible. The search strategy was set up by a medical information specialist (I.v.D.) of the Knowledge Institute of the Dutch Association of Medical Specialists, using the following bibliographic databases: Ovid/Medline, Embase.com, Scopus and Google Scholar. The literature was searched from inception until 9-4-2024. The systematic search was completed using a combination of controlled vocabulary wherever available, and natural language title, abstract and keywords. The overall search strategy was derived from three primary search concepts: “rare diseases” and “quality criteria” and “guidelines/standards”. Duplicates were removed using EndNote software. The detailed search strategy can be found in Appendix 1. Study selection: Titles and abstracts were independently screened by two reviewers (I.H. and M.K.). If considered potentially relevant, the full texts were independently assessed by two authors (I.H. and M.K). Disagreements between reviewers were discussed until consensus. If necessary, a third reviewer (C.G.) was consulted. The following inclusion criteria were used: 1. Articles about rare diseases in general and not about a specific disease 2. Articles presenting quality criteria for guidelines, standards or quality documents for rare diseases The exclusion criteria were: 1. Articles in other languages than English or Dutch 2. Posters or conference abstracts 3. Guidelines for specific (rare) diseases 4. Articles about quality documents for a non-rare disease Data analysis plan We planned to use the information in the included articles to make an overview of all available sets of criteria and how these criteria were developed. We intended to compare different sets of criteria to identify criteria that were common to all sets of criteria, and to critically assess criteria that were not included in more than one set of criteria. Results Our comprehensive search yielded 9587 unique titles. Thirty-eight full-text articles were assessed, but only one article met the inclusion criteria (Fig. 1 ). Most articles were excluded during the title and abstract screening because they did not report quality criteria or because they concerned a specific rare disease. We found several articles that were guidelines for developing CPGs for rare diseases ( 18 , 19 ). The one article that met our inclusion criteria was published by Hilton-Boon et al. (2015), reporting on an international workshop aimed at evaluating the applicability of the AGREE II criteria for appraising CPGs related to rare diseases. During this workshop, participants completed the AGREE II online tutorial and then worked in small groups to assess two guidelines about Huntington’s disease. The two guidelines had been selected because they ‘provided sufficient information to support informed judgment on most if not all AGREE items’ ( 20 ). Therefore, it was not surprising that the attendees concluded that the AGREE II instrument could be used to appraise rare disease CPGs. Based on the discussions, about the challenges and disagreements encountered when applying AGREE II to these two guidelines, several points to consider when using the instrument for the appraisal of rare disease CPGs were proposed as an addition to the manual of the AGREE II instrument. Discussion This systematic scoping review aimed to identify a minimum set of criteria that can be used for evaluating and endorsing CPGs for rare diseases. The extensive review only revealed one report concluding that the AGREE II ( 17 ) criteria could be employed to evaluate the quality of CPGs for rare diseases according to an international workshop with members of the RARE best practices consortium ( 20 ). The report of this workshop by Hilton Boon et al., 2015, proposed additions to the AGREE II manual for the appraisal of CPGs for rare diseases. Despite a thorough search, no other set of criteria beyond AGREE II was identified. While the AGREE II checklist offers a comprehensive and widely recognized standard, achieving high scores across all 23 quality items presents significant challenges, particularly for CPGs addressing rare diseases. These challenges are related to the uncertainty of evidence, limited resources, insufficient representation of stakeholders, lack of editorial independence, and lack of awareness of existing guideline development methodology in rare disease experts, as argued in the introduction. One of the strengths of our systematic scoping review was the extensive and rigorous search strategy, with well-defined inclusion and exclusion criteria. This approach ensured a thorough examination of the existing literature on the topic. However, only a single article met our criteria, suggesting a significant gap in the available research. Variations in the definitions of guidelines or quality documents related to rare diseases may have led to the failure to discover relevant articles that used alternative but conceptually similar terminology; furthermore, restricting our search to English-language publications may have introduced a language bias, potentially leading to the omission of relevant studies published in other languages. However, we are convinced that if a set of criteria specifically aimed to appraise CPGs for rare diseases were to exist, this sensitive search would have found it. Based on these results the AGREE II instrument is the only set of criteria that is recommended to evaluate the quality of rare disease CPGs, supplemented by the guidance provided by Hilton Boon et al., 2015 ( 20 ). However, since the AGREE II set may be overly ambitious in the context of rare diseases, we strongly recommend the development of a set of criteria that is more tailored to the context of rare diseases. Conclusion We did not find a set of criteria specifically designed for evaluating and endorsing CPGs for rare diseases. Our comprehensive literature search yielded one report of a workshop in which international experts discussed the utility of the AGREE II instrument for the appraisal of two guidelines about one rare disease. AGREE II may be overly ambitious to evaluate CPGs in the context of rare diseases, this highlights the need to develop a leaner set of criteria tailored to the specific challenges of rare diseases, which will better support the evaluation and endorsement of CPGs in this field. Declarations a. Ethics approval and consent to participate – Not applicable b. Consent for publication – All authors have given consent for publication. c. Availability of data and material - Data sharing not applicable to this article as no datasets were generated or analysed during the current study d. Competing interests - None of the authors have a competing interest to disclose. e. Funding - This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. f. Authors' contributions – IH: Conceptualization, Formal analysis, Writing – original draft. MKH: Formal analysis, Writing – review & editing. ID: Methodology – search strategy support. CG: Conceptualization, Writing – review & editing. JH: Conceptualization, Writing – review & editing. g. Acknowledgements – Not applicable h. Authors' information (optional) – Iméze Hieltjes, [email protected] References Schieppati A, Henter JI, Daina E, Aperia A. Why rare diseases are an important medical and social issue. Lancet. 2008;371(9629):2039–41. Richter T, Nestler-Parr S, Babela R, Khan ZM, Tesoro T, Molsen E, et al. Rare Disease Terminology and Definitions-A Systematic Global Review: Report of the ISPOR Rare Disease Special Interest Group. Value Health. 2015;18(6):906–14. Nguengang Wakap S, Lambert DM, Olry A, Rodwell C, Gueydan C, Lanneau V, et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet. 2020;28(2):165–73. Wastfelt M, Fadeel B, Henter JI. A journey of hope: lessons learned from studies on rare diseases and orphan drugs. J Intern Med. 2006;260(1):1–10. commission E. Rare Diseases [Web page]. 2023 [Official website of the European Union]. Available from: https://health.ec.europa.eu/non-communicable-diseases/expert-group-public-health/rare-diseases_en#documents Lugtenberg M, Burgers JS, Westert GP. Effects of evidence-based clinical practice guidelines on quality of care: a systematic review. Qual Saf Health Care. 2009;18(5):385–92. Pai M, Yeung CHT, Akl EA, Darzi A, Hillis C, Legault K, et al. Strategies for eliciting and synthesizing evidence for guidelines in rare diseases. BMC Med Res Methodol. 2019;19(1):67. Fritz C, De Ravin E, Suresh N, Romeo D, Shah M, Rajasekaran K. Clinical practice guidelines for management of medullary thyroid carcinoma: An AGREE II appraisal. Am J Otolaryngol. 2022;43(6):103606. Uchida T, Takahashi Y, Yamashita H, Nakaoku Y, Ohura T, Okura T, et al. Evaluation of Clinical Practice Guidelines for Rare Diseases in Japan. JMA J. 2022;5(4):460–70. Klein Haneveld MJ, Hieltjes IJ, Langendam MW, Cornel MC, Gaasterland CMW, Van Eeghen AM. Improving care for rare genetic neurodevelopmental disorders: a systematic review and critical appraisal of clinical practice guidelines using AGREE II. Genet Sci. 2024. Schoenmaker NJ, Tromp WF, van der Lee JH, Offringa M, Craig JC, Groothoff JW. Quality and consistency of clinical practice guidelines for the management of children on chronic dialysis. Nephrol Dial Transpl. 2013;28(12):3052–61. Irvine WFE, Spivack OKC, Ista E. Moving toward the Development and Effective Implementation of High-Quality Guidelines in Pediatric Surgery: A Review of the Literature. Eur J Pediatr Surg. 2024;34(2):115–27. Dingemann C, Eaton S, Aksnes G, Bagolan P, Cross KM, De Coppi P et al. ERNICA Consensus Conference on the Management of Patients with Long-Gap Esophageal Atresia: Perioperative, Surgical, and Long-Term Management. Eur J Pediatr Surg. 2021;31(3):214 – 25. Govaerts K, Lurvink RJ, De Hingh I, Van der Speeten K, Villeneuve L, Kusamura S, et al. Appendiceal tumours and pseudomyxoma peritonei: Literature review with PSOGI/EURACAN clinical practice guidelines for diagnosis and treatment. Eur J Surg Oncol. 2021;47(1):11–35. Ray-Coquard I, Morice P, Lorusso D, Prat J, Oaknin A, Pautier P, et al. Non-epithelial ovarian cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(Suppl 4):iv1–18. Lima JP, Tangamornsuksan W, Guyatt GH. Trustworthy evidence-based versus untrustworthy guidelines: detecting the difference. Fam Med Community Health. 2023;11(4). Brouwers MC, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, et al. AGREE II: advancing guideline development, reporting and evaluation in health care. CMAJ. 2010;182(18):E839–42. Pai M, Santesso N, Yeung CH, Lane SJ, Schunemann HJ, Iorio A. Methodology for the development of the NHF-McMaster Guideline on Care Models for Haemophilia Management. Haemophilia. 2016;22(Suppl 3):17–22. Aleksovska K, Kobulashvili T, Costa J, Zimmermann G, Ritchie K, Reinhard C, et al. European Academy of Neurology guidance for developing and reporting clinical practice guidelines on rare neurological diseases. Eur J Neurol. 2022;29(6):1571–86. Boon MH. Report of an international workshop to explore the utility of the AGREE II instrument for appraisal of rare disease guidelines. Rare Diseases and Orphan Drugs Journal. 2015;2:11 – 5. Supplementary Files Appendix1.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Minor revision 08 Apr, 2026 Reviewers agreed at journal 19 Mar, 2026 Reviewers invited by journal 18 Mar, 2026 Editor assigned by journal 11 Jun, 2025 First submitted to journal 28 May, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6693080","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":608087994,"identity":"591e3bfc-a04b-4838-bd81-8f81d20c85cc","order_by":0,"name":"Iméze Hieltjes","email":"data:image/png;base64,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","orcid":"https://orcid.org/0009-0008-6090-7284","institution":"Knowledge Institute of Medical Specialists: Kennisinstituut van Medisch Specialisten","correspondingAuthor":true,"prefix":"","firstName":"Iméze","middleName":"","lastName":"Hieltjes","suffix":""},{"id":608087997,"identity":"22e96a20-9f59-4f0a-8386-b3412b0c83c2","order_by":1,"name":"Mirthe Klein Haneveld","email":"","orcid":"","institution":"Amsterdam UMC - Locatie AMC: Amsterdam UMC Locatie AMC","correspondingAuthor":false,"prefix":"","firstName":"Mirthe","middleName":"Klein","lastName":"Haneveld","suffix":""},{"id":608087999,"identity":"937fa411-3f30-41c5-aa0b-3122ed9bd609","order_by":2,"name":"Ingeborg Van Dusseldorp","email":"","orcid":"","institution":"Knowledge Institute of Medical Specialists: Kennisinstituut van Medisch Specialisten","correspondingAuthor":false,"prefix":"","firstName":"Ingeborg","middleName":"Van","lastName":"Dusseldorp","suffix":""},{"id":608088003,"identity":"b18f86d2-75ff-4892-a539-96237c17dd3c","order_by":3,"name":"Charlotte Gaasterland","email":"","orcid":"","institution":"Knowledge Institute of Medical Specialists: Kennisinstituut van Medisch Specialisten","correspondingAuthor":false,"prefix":"","firstName":"Charlotte","middleName":"","lastName":"Gaasterland","suffix":""},{"id":608088004,"identity":"86178103-188f-4933-9e04-d28f2b959c13","order_by":4,"name":"Johanna Van der Lee","email":"","orcid":"","institution":"Knowledge Institute of Medical Specialists: Kennisinstituut van Medisch Specialisten","correspondingAuthor":false,"prefix":"","firstName":"Johanna","middleName":"Van der","lastName":"Lee","suffix":""}],"badges":[],"createdAt":"2025-05-18 17:36:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6693080/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6693080/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105064138,"identity":"2b4345bc-1308-472e-913a-61d389330d57","added_by":"auto","created_at":"2026-03-20 13:38:05","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":263050,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u0026nbsp;\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6693080/v1/148bb4c4778c7ffef1fe426b.png"},{"id":105568973,"identity":"e8e90096-ea54-4d21-b4e3-15c54eedf555","added_by":"auto","created_at":"2026-03-27 13:10:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":530358,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6693080/v1/a15bba37-768d-4746-a95d-bec5ee27dc42.pdf"},{"id":105563093,"identity":"667d4ba3-aa37-434b-8dc0-88bc106c2c8c","added_by":"auto","created_at":"2026-03-27 12:45:55","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":30250,"visible":true,"origin":"","legend":"","description":"","filename":"Appendix1.docx","url":"https://assets-eu.researchsquare.com/files/rs-6693080/v1/022894650d971332c3ebd95c.docx"}],"financialInterests":"","formattedTitle":"A systematic scoping review on quality criteria for clinical practice guidelines for rare diseases","fulltext":[{"header":"What is new?","content":"\u003cp\u003eKey findings\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003eDespite a sensitive search in this systematic review, we did not find a set of quality criteria for the specific context of rare disease guidelines. We only identified a single report describing an international workshop that examined the applicability of the AGREE II instrument for evaluating two guidelines for one rare disease. \u003c/li\u003e\n\u003c/ul\u003e\n\n\u003cp\u003eWhat this adds to what is known?\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003eThis shows the significant lack of quality criteria tailored to the specific complexities of rare disease guidelines. \u003c/li\u003e\n\u003c/ul\u003e\n\n\u003cp\u003eWhat is the implication and what should change now?\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003eGuidelines for rare diseases may benefit from a tailored, streamlined set of criteria to address the unique challenges of the rare disease field, supporting the development, evaluation, and endorsement of these guidelines.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Introduction","content":"\u003cp\u003eIn Europe, a disease is considered rare if it affects no more than 1 in 2000 persons (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e). Around six to seven thousand rare diseases have been discovered, and new diseases are identified regularly (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e). Although rare diseases individually affect a small number of people, collectively they have a considerable impact on the population (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e). Due to limited knowledge and less robust evidence on diagnosis and interventions the quality of care may be lower compared to more prevalent diseases (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e). In 2009 the European Commission recommended establishing and implementing national plans and strategies to ensure that patients with rare diseases have access to high-quality care(\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eClinical practice guidelines (CPGs) are systematically developed statements or recommendations that assist healthcare providers in making informed decisions about the care of patients. These CPGs are based on a thorough review of the best available evidence from clinical research and expert opinion (including both clinical and patient expertise). They aim to standardize and improve patient care by providing clear, evidence-based recommendations for diagnosing, managing, and treating specific medical conditions or diseases (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e). Additionally, CPGs serve as a valuable resource for ensuring consistency in healthcare, reducing practice variability, and supporting shared decision-making between patients and providers. However, developing CPGs for rare diseases poses several challenges(\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e–\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFirst, it is difficult to decide which topics to address in a rare disease CPG given the limited resources and evidence. For many rare diseases, there are still considerable knowledge gaps with regard to the best way to diagnose, manage, and treat patients. When resources are scarce, it is challenging to decide for which rare disease a CPG should be developed and which clinical questions for this disease need to be addressed most urgently.\u003c/p\u003e \u003cp\u003eAnother challenge is that the existing literature on rare diseases often consists of case studies or non-comparative observational designs, resulting in very low certainty of evidence. Due to limited resources guideline development panels may refrain from performing a systematic review since they do not expect considerable high-level evidence, and in this way make methodological shortcuts (\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e–\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e). Also, guideline development panels in rare diseases are not always aware of existing methodologies for guideline development in our experience as methodologists.\u003c/p\u003e \u003cp\u003eNot only the number of patients is low in rare diseases; also, the number of medical professionals and patient representatives may be limited, which may lead to insufficient representation of stakeholders when developing a CPG. In a small group, the influence of an individual (either patient expert or clinical expert) may be out of proportion and may not always align with the interests of all stakeholders. Personal differences are of more influence in small expert groups. This issue is less salient in non-rare diseases, where there is a larger group of stakeholders to choose from.\u003c/p\u003e \u003cp\u003eFinally, related to the former issue, it is not always possible to maintain editorial independence in the development of rare diseases CPGs. The limited number of experts in rare diseases makes it particularly difficult to find guideline panel members without competing interests.\u003c/p\u003e \u003cp\u003eDue to these challenges, not all documents that are called guidelines or CPGs for rare diseases are developed according to the standard methodology (\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e). However, clinicians still use such documents to make informed decisions on the management and treatment of their patients. Therefore, clinicians are helped when they know how to distinguish trustworthy from untrustworthy CPGs (\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e). Lima et al., 2023 (\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e) give guidance to clinicians for the distinction of trustworthy and untrustworthy guidelines in general, not limited to rare diseases. However, the eight domains they propose as a conceptual framework for evaluating the trustworthiness of guidelines are intended as a flexible guide rather than a set of criteria.\u003c/p\u003e \u003cp\u003eEndorsement by official organizations such as European Reference Networks (ERNs) or medical specialist scientific associations may be instrumental to distinguish trustworthy documents from less trustworthy documents. These organizations need ways to appraise the quality of CPGs or other quality documents for rare diseases that are offered to them for endorsement and official publication on the organization’s website. The AGREE II instrument was designed to assess the methodological quality and transparency of CPGs (\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e). It contains 23 items in six domains. Several studies that have used the AGREE II instrument to appraise CPGs for rare diseases (\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e–\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e) show considerable variation in quality and highlight the lack of methodological rigor of CPGs for rare diseases. While the AGREE II checklist represents a comprehensive standard, achieving high scores on all 23 quality items has its challenges for CPGs for rare diseases as shown before. Therefore, the development and appraisal of CPGs for rare diseases may need a specific set of criteria for rare disease CPGs, to enhance the feasibility of developing and endorsing such documents in the context of rare diseases. These criteria should ensure that CPGs meet essential quality benchmarks without necessitating perfection, thus providing a minimum level of reliability and utility for healthcare providers of rare diseases.\u003c/p\u003e \u003cp\u003eThis systematic scoping review aims to identify a set of criteria that can be used for evaluating and endorsing CPGs for rare diseases.\u003c/p\u003e "},{"header":"Methods","content":"\u003cp\u003eFor this scoping review, a systematic sensitive literature search was performed to identify as many relevant articles as possible. The search strategy was set up by a medical information specialist (I.v.D.) of the Knowledge Institute of the Dutch Association of Medical Specialists, using the following bibliographic databases: Ovid/Medline, Embase.com, Scopus and Google Scholar. The literature was searched from inception until 9-4-2024. The systematic search was completed using a combination of controlled vocabulary wherever available, and natural language title, abstract and keywords. The overall search strategy was derived from three primary search concepts: “rare diseases” and “quality criteria” and “guidelines/standards”. Duplicates were removed using EndNote software. The detailed search strategy can be found in Appendix 1.\u003c/p\u003e\u003cp\u003eStudy selection:\u003c/p\u003e\u003cp\u003eTitles and abstracts were independently screened by two reviewers (I.H. and M.K.). If considered potentially relevant, the full texts were independently assessed by two authors (I.H. and M.K).\u003c/p\u003e\u003cp\u003eDisagreements between reviewers were discussed until consensus. If necessary, a third reviewer (C.G.) was consulted. The following inclusion criteria were used:\u003c/p\u003e\u003cp\u003e1. Articles about rare diseases in general and not about a specific disease\u003c/p\u003e\u003cp\u003e2. Articles presenting quality criteria for guidelines, standards or quality documents for rare diseases\u003c/p\u003e\u003cp\u003eThe exclusion criteria were:\u003c/p\u003e\u003cp\u003e1. Articles in other languages than English or Dutch\u003c/p\u003e\u003cp\u003e2. Posters or conference abstracts\u003c/p\u003e\u003cp\u003e3. Guidelines for specific (rare) diseases\u003c/p\u003e\u003cp\u003e4. Articles about quality documents for a non-rare disease\u003c/p\u003e\u003cp\u003eData analysis plan\u003c/p\u003e\u003cp\u003eWe planned to use the information in the included articles to make an overview of all available sets of criteria and how these criteria were developed. We intended to compare different sets of criteria to identify criteria that were common to all sets of criteria, and to critically assess criteria that were not included in more than one set of criteria.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eOur comprehensive search yielded 9587 unique titles. Thirty-eight full-text articles were assessed, but only one article met the inclusion criteria (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Most articles were excluded during the title and abstract screening because they did not report quality criteria or because they concerned a specific rare disease. We found several articles that were guidelines for developing CPGs for rare diseases (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe one article that met our inclusion criteria was published by Hilton-Boon et al. (2015), reporting on an international workshop aimed at evaluating the applicability of the AGREE II criteria for appraising CPGs related to rare diseases. During this workshop, participants completed the AGREE II online tutorial and then worked in small groups to assess two guidelines about Huntington\u0026rsquo;s disease. The two guidelines had been selected because they \u0026lsquo;provided sufficient information to support informed judgment on most if not all AGREE items\u0026rsquo; (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Therefore, it was not surprising that the attendees concluded that the AGREE II instrument could be used to appraise rare disease CPGs. Based on the discussions, about the challenges and disagreements encountered when applying AGREE II to these two guidelines, several points to consider when using the instrument for the appraisal of rare disease CPGs were proposed as an addition to the manual of the AGREE II instrument.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis systematic scoping review aimed to identify a minimum set of criteria that can be used for evaluating and endorsing CPGs for rare diseases.\u003c/p\u003e \u003cp\u003eThe extensive review only revealed one report concluding that the AGREE II (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) criteria could be employed to evaluate the quality of CPGs for rare diseases according to an international workshop with members of the RARE best practices consortium (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). The report of this workshop by Hilton Boon et al., 2015, proposed additions to the AGREE II manual for the appraisal of CPGs for rare diseases. Despite a thorough search, no other set of criteria beyond AGREE II was identified. While the AGREE II checklist offers a comprehensive and widely recognized standard, achieving high scores across all 23 quality items presents significant challenges, particularly for CPGs addressing rare diseases. These challenges are related to the uncertainty of evidence, limited resources, insufficient representation of stakeholders, lack of editorial independence, and lack of awareness of existing guideline development methodology in rare disease experts, as argued in the introduction.\u003c/p\u003e \u003cp\u003eOne of the strengths of our systematic scoping review was the extensive and rigorous search strategy, with well-defined inclusion and exclusion criteria. This approach ensured a thorough examination of the existing literature on the topic. However, only a single article met our criteria, suggesting a significant gap in the available research. Variations in the definitions of guidelines or quality documents related to rare diseases may have led to the failure to discover relevant articles that used alternative but conceptually similar terminology; furthermore, restricting our search to English-language publications may have introduced a language bias, potentially leading to the omission of relevant studies published in other languages.\u003c/p\u003e \u003cp\u003eHowever, we are convinced that if a set of criteria specifically aimed to appraise CPGs for rare diseases were to exist, this sensitive search would have found it.\u003c/p\u003e \u003cp\u003eBased on these results the AGREE II instrument is the only set of criteria that is recommended to evaluate the quality of rare disease CPGs, supplemented by the guidance provided by Hilton Boon et al., 2015 (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). However, since the AGREE II set may be overly ambitious in the context of rare diseases, we strongly recommend the development of a set of criteria that is more tailored to the context of rare diseases.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWe did not find a set of criteria specifically designed for evaluating and endorsing CPGs for rare diseases. Our comprehensive literature search yielded one report of a workshop in which international experts discussed the utility of the AGREE II instrument for the appraisal of two guidelines about one rare disease. AGREE II may be overly ambitious to evaluate CPGs in the context of rare diseases, this highlights the need to develop a leaner set of criteria tailored to the specific challenges of rare diseases, which will better support the evaluation and endorsement of CPGs in this field.\u003c/p\u003e"},{"header":"Declarations","content":"\n\n\n\n\u003cp\u003ea. Ethics approval and consent to participate – Not applicable\u003cbr\u003e b. Consent for publication – All authors have given consent for publication. \u003cbr\u003e c. Availability of data and material - Data sharing not applicable to this article as no datasets were generated or analysed during the current study\u003cbr\u003e d. Competing interests - None of the authors have a competing interest to disclose. \u003cbr\u003e e. Funding - This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003cbr\u003e f. Authors' contributions – \u003c/p\u003e\n\u003cp\u003eIH: Conceptualization, Formal analysis, Writing – original draft.\u003c/p\u003e\n\u003cp\u003eMKH: Formal analysis, Writing – review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003eID: Methodology – search strategy support.\u003c/p\u003e\n\u003cp\u003eCG: Conceptualization, Writing – review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003eJH: Conceptualization, Writing – review \u0026amp; editing.\u003cbr\u003e g. Acknowledgements – Not applicable\u003cbr\u003e h. Authors' information (optional) – Iméze Hieltjes, [email protected]\u003cbr clear=\"all\"\u003e \u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSchieppati A, Henter JI, Daina E, Aperia A. Why rare diseases are an important medical and social issue. Lancet. 2008;371(9629):2039\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRichter T, Nestler-Parr S, Babela R, Khan ZM, Tesoro T, Molsen E, et al. Rare Disease Terminology and Definitions-A Systematic Global Review: Report of the ISPOR Rare Disease Special Interest Group. Value Health. 2015;18(6):906\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNguengang Wakap S, Lambert DM, Olry A, Rodwell C, Gueydan C, Lanneau V, et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet. 2020;28(2):165\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWastfelt M, Fadeel B, Henter JI. A journey of hope: lessons learned from studies on rare diseases and orphan drugs. J Intern Med. 2006;260(1):1\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ecommission E. Rare Diseases [Web page]. 2023 [Official website of the European Union]. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://health.ec.europa.eu/non-communicable-diseases/expert-group-public-health/rare-diseases_en#documents\u003c/span\u003e\u003cspan address=\"https://health.ec.europa.eu/non-communicable-diseases/expert-group-public-health/rare-diseases_en#documents\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLugtenberg M, Burgers JS, Westert GP. Effects of evidence-based clinical practice guidelines on quality of care: a systematic review. Qual Saf Health Care. 2009;18(5):385\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePai M, Yeung CHT, Akl EA, Darzi A, Hillis C, Legault K, et al. Strategies for eliciting and synthesizing evidence for guidelines in rare diseases. BMC Med Res Methodol. 2019;19(1):67.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFritz C, De Ravin E, Suresh N, Romeo D, Shah M, Rajasekaran K. Clinical practice guidelines for management of medullary thyroid carcinoma: An AGREE II appraisal. Am J Otolaryngol. 2022;43(6):103606.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUchida T, Takahashi Y, Yamashita H, Nakaoku Y, Ohura T, Okura T, et al. Evaluation of Clinical Practice Guidelines for Rare Diseases in Japan. JMA J. 2022;5(4):460\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKlein Haneveld MJ, Hieltjes IJ, Langendam MW, Cornel MC, Gaasterland CMW, Van Eeghen AM. Improving care for rare genetic neurodevelopmental disorders: a systematic review and critical appraisal of clinical practice guidelines using AGREE II. Genet Sci. 2024.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchoenmaker NJ, Tromp WF, van der Lee JH, Offringa M, Craig JC, Groothoff JW. Quality and consistency of clinical practice guidelines for the management of children on chronic dialysis. Nephrol Dial Transpl. 2013;28(12):3052\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIrvine WFE, Spivack OKC, Ista E. Moving toward the Development and Effective Implementation of High-Quality Guidelines in Pediatric Surgery: A Review of the Literature. Eur J Pediatr Surg. 2024;34(2):115\u0026ndash;27.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDingemann C, Eaton S, Aksnes G, Bagolan P, Cross KM, De Coppi P et al. ERNICA Consensus Conference on the Management of Patients with Long-Gap Esophageal Atresia: Perioperative, Surgical, and Long-Term Management. Eur J Pediatr Surg. 2021;31(3):214\u0026thinsp;\u0026ndash;\u0026thinsp;25.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGovaerts K, Lurvink RJ, De Hingh I, Van der Speeten K, Villeneuve L, Kusamura S, et al. Appendiceal tumours and pseudomyxoma peritonei: Literature review with PSOGI/EURACAN clinical practice guidelines for diagnosis and treatment. Eur J Surg Oncol. 2021;47(1):11\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRay-Coquard I, Morice P, Lorusso D, Prat J, Oaknin A, Pautier P, et al. Non-epithelial ovarian cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(Suppl 4):iv1\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLima JP, Tangamornsuksan W, Guyatt GH. Trustworthy evidence-based versus untrustworthy guidelines: detecting the difference. Fam Med Community Health. 2023;11(4).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrouwers MC, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, et al. AGREE II: advancing guideline development, reporting and evaluation in health care. CMAJ. 2010;182(18):E839\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePai M, Santesso N, Yeung CH, Lane SJ, Schunemann HJ, Iorio A. Methodology for the development of the NHF-McMaster Guideline on Care Models for Haemophilia Management. Haemophilia. 2016;22(Suppl 3):17\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAleksovska K, Kobulashvili T, Costa J, Zimmermann G, Ritchie K, Reinhard C, et al. European Academy of Neurology guidance for developing and reporting clinical practice guidelines on rare neurological diseases. Eur J Neurol. 2022;29(6):1571\u0026ndash;86.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBoon MH. Report of an international workshop to explore the utility of the AGREE II instrument for appraisal of rare disease guidelines. Rare Diseases and Orphan Drugs Journal. 2015;2:11\u0026thinsp;\u0026ndash;\u0026thinsp;5.\u003c/span\u003e\u003c/li\u003e \u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"systematic-reviews","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sysr","sideBox":"Learn more about [Systematic Reviews](http://systematicreviewsjournal.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/sysr/default.aspx","title":"Systematic Reviews","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6693080/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6693080/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eRare diseases impose substantial challenges on affected individuals and healthcare systems. While clinical practice guidelines (CPGs) are crucial for standardizing care, tools to assess their trustworthiness are limited, particularly for rare diseases. There is a need for minimum quality criteria to ensure CPG reliability and utility.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eThis systematic scoping review aims to identify a set of criteria that can be used for evaluating and endorsing CPGs for rare diseases.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA systematic scoping review was conducted using four databases (Ovid/Medline, Embase.com, Scopus, and Google Scholar) from inception to April 9, 2024. The search, developed by a medical information specialist. Titles and abstracts were independently screened by two reviewers, with disagreements resolved through discussion or a third reviewer. Articles were included if they addressed quality criteria for guidelines on rare diseases in general, excluding disease-specific guidelines.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eFrom 9587 unique titles, only one study met the inclusion criteria. The included study, published by Hilton-Boon et al. (2015), summarized an international workshop on the applicability of AGREE II criteria for rare disease guidelines.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eOur systematic review identified a single report detailing an international workshop that evaluated the utility of the AGREE II instrument for assessing two guidelines focused on rare diseases. This limited finding highlights a significant gap in methodologies tailored to the specific complexities of rare disease guidelines. The findings underscore the need for a tailored, streamlined set of criteria to address the unique challenges of rare disease guidelines, supporting their development, evaluation, and endorsement in clinical practice.\u003c/p\u003e","manuscriptTitle":"A systematic scoping review on quality criteria for clinical practice guidelines for rare diseases","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-20 13:38:00","doi":"10.21203/rs.3.rs-6693080/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2026-04-09T03:31:29+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2026-03-20T02:20:48+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-18T08:07:40+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-12T03:52:49+00:00","index":"","fulltext":""},{"type":"submitted","content":"Systematic Reviews","date":"2025-05-28T09:45:56+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"systematic-reviews","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sysr","sideBox":"Learn more about [Systematic Reviews](http://systematicreviewsjournal.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/sysr/default.aspx","title":"Systematic Reviews","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"641f781f-2cbb-4f1d-93ab-eba11f2a05ce","owner":[],"postedDate":"March 20th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-18T03:09:34+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-20 13:38:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6693080","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6693080","identity":"rs-6693080","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}