<?xml version="1.0" encoding="UTF-8"?><!DOCTYPE article PUBLIC "-//NLM//DTD Journal Publishing DTD v2.0 20040830//EN" "journalpublishing.dtd"><article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" dtd-version="2.0" xml:lang="en" article-type="review-article"><front><journal-meta><journal-id journal-id-type="nlm-ta">J Med Internet Res</journal-id><journal-id journal-id-type="publisher-id">jmir</journal-id><journal-id journal-id-type="index">1</journal-id><journal-title>Journal of Medical Internet Research</journal-title><abbrev-journal-title>J Med Internet Res</abbrev-journal-title><issn pub-type="epub">1438-8871</issn><publisher><publisher-name>JMIR Publications</publisher-name><publisher-loc>Toronto, Canada</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="publisher-id">v28i1e87804</article-id><article-id pub-id-type="doi">10.2196/87804</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review</subject></subj-group></article-categories><title-group><article-title>Concerns of Using Large Language Models in Health Care Research and Practice: Umbrella Review</article-title></title-group><contrib-group><contrib contrib-type="author"><name name-style="western"><surname>Yarar</surname><given-names>Feyza</given-names></name><degrees>MPH</degrees><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name name-style="western"><surname>Addis</surname><given-names>Pauline</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="fn" rid="equal-contrib1">*</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name name-style="western"><surname>Fairweather</surname><given-names>Megan</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="fn" rid="equal-contrib1">*</xref></contrib><contrib contrib-type="author"><name name-style="western"><surname>Craig</surname><given-names>Dawn</given-names></name><degrees>MSc</degrees><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author" corresp="yes"><name name-style="western"><surname>O'Keefe</surname><given-names>Hannah</given-names></name><degrees>MSci</degrees><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref></contrib></contrib-group><aff id="aff1"><institution>Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University</institution><addr-line>Framlington Place</addr-line><addr-line>Newcastle-Upon-Tyne</addr-line><addr-line>England</addr-line><country>United Kingdom</country></aff><aff id="aff2"><institution>NIHR (National Institute of Health and Care Research) Innovation Observatory, Newcastle University</institution><addr-line>Newcastle-Upon-Tyne</addr-line><addr-line>England</addr-line><country>United Kingdom</country></aff><contrib-group><contrib contrib-type="editor"><name name-style="western"><surname>Brini</surname><given-names>Stefano</given-names></name></contrib></contrib-group><contrib-group><contrib contrib-type="reviewer"><name name-style="western"><surname>Biswas</surname><given-names>Al Amin</given-names></name></contrib><contrib contrib-type="reviewer"><name name-style="western"><surname>Sengupta</surname><given-names>Saurav</given-names></name></contrib></contrib-group><author-notes><corresp>Correspondence to Hannah O'Keefe, MSci, Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle-Upon-Tyne, England, NE2 4HH, United Kingdom, 44 7826034122; <email>nho11@newcastle.ac.uk</email></corresp><fn fn-type="equal" id="equal-contrib1"><label>*</label><p>these authors contributed equally</p></fn></author-notes><pub-date pub-type="collection"><year>2026</year></pub-date><pub-date pub-type="epub"><day>15</day><month>5</month><year>2026</year></pub-date><volume>28</volume><elocation-id>e87804</elocation-id><history><date date-type="received"><day>14</day><month>11</month><year>2025</year></date><date date-type="rev-recd"><day>08</day><month>04</month><year>2026</year></date><date date-type="accepted"><day>09</day><month>04</month><year>2026</year></date></history><copyright-statement>&#x00A9; Feyza Yarar, Pauline Addis, Megan Fairweather, Dawn Craig, Hannah O'Keefe. Originally published in the Journal of Medical Internet Research (<ext-link ext-link-type="uri" xlink:href="https://www.jmir.org">https://www.jmir.org</ext-link>), 15.5.2026. </copyright-statement><copyright-year>2026</copyright-year><license license-type="open-access" xlink:href="https://creativecommons.org/licenses/by/4.0/"><p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (<ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by/4.0/">https://creativecommons.org/licenses/by/4.0/</ext-link>), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in the Journal of Medical Internet Research (ISSN 1438-8871), is properly cited. The complete bibliographic information, a link to the original publication on <ext-link ext-link-type="uri" xlink:href="https://www.jmir.org/">https://www.jmir.org/</ext-link>, as well as this copyright and license information must be included.</p></license><self-uri xlink:type="simple" xlink:href="https://www.jmir.org/2026/1/e87804"/><abstract><sec><title>Background</title><p>Large language models (LLMs), such as ChatGPT (OpenAI), are rapidly evolving, and their applications in health care are increasing. There is a growing demand for automation of routine tasks and a drive to use LLMs or similar to support research.</p></sec><sec><title>Objective</title><p>This umbrella review examines concerns of health care professionals and researchers related to the use of LLMs in health care research and practice. We aimed to identify common issues raised and the implications for patient care, policy, and practice.</p></sec><sec sec-type="methods"><title>Methods</title><p>A protocol was registered on PROSPERO (CRD420250640997). Searches were conducted in 7 databases (Ovid MEDLINE, Ovid Embase, Scopus, Web of Science, JBI Database of Systematic Reviews and Implementation Reports, Cochrane Database of Systematic Reviews, and Epistemonikos) in February 2025 and updated in February 2026. Screening was conducted in 2 stages, with independent screening by 2 reviewers. Studies published in the English language after January 2017 with at least one outcome expressing concerns of LLM or generative artificial intelligence use in health care research were included. The included studies were quality appraised for risk of bias and certainty of the evidence using AMSTAR-2 (A Measurement Tool to Assess Systematic Reviews) and GRADE (Grading of Recommendations Assessment, Development, and Evaluation), respectively. Data was extracted using a piloted form and narratively synthesized following SWiM guidelines and the PRIOR (Preferred Reporting Items for Overviews of Reviews) checklist.</p></sec><sec sec-type="results"><title>Results</title><p>The search retrieved 448 systematic reviews, of which 42 met the inclusion criteria. Further, 12 distinct populations were identified, including researchers and clinicians in various medical specialties. The included reviews were assessed to be of very poor quality, and the level of overlap between primary studies could not be determined. Additionally, 15 reviews focused on ChatGPT, a further 15 on two or more LLMs, and 12 on generic artificial intelligence. Thus, 3 main themes emerged from the narrative synthesis. In order of most to least frequently discussed: (1) technical capability; (2) ethical, legal, and societal; and (3) costs.</p></sec><sec sec-type="conclusions"><title>Conclusions</title><p>To our knowledge, this is the first umbrella review to address the concerns of LLMs in health care research and practice. Thematic analyses provided insight into the complexity of different perspectives, and by using a whole population approach, it demonstrates common narratives. However, the poor quality of the included studies and potential overlap of results are substantial limitations. Data quality is at the heart of these concerns, and combative action must ensure health care professionals and researchers have the resources required to overcome these apprehensions. Ethical, legal, and societal implications of artificial intelligence use were also commonly raised. As technology accelerates and demands on health care increase, we must adapt and embrace change with equity, diversity, inclusion, and safety at the core.</p></sec><sec><title>Trial Registration</title><p>PROSPERO CRD420250640997; https://www.crd.york.ac.uk/PROSPERO/view/CRD420250640997</p></sec></abstract><kwd-group><kwd>artificial intelligence</kwd><kwd>umbrella review</kwd><kwd>concerns</kwd><kwd>health and social care</kwd><kwd>life sciences</kwd></kwd-group></article-meta></front><body><sec id="s1" sec-type="intro"><title>Introduction</title><sec id="s1-1"><title>Background</title><p>Currently, we live in an era where an abundance of data is being produced worldwide. While the term &#x201C;big data&#x201D; is generally used for predictive analytics, health care data can be considered &#x201C;big data&#x201D; by definition, as it is high in volume, velocity, variety, and veracity [<xref ref-type="bibr" rid="ref1">1</xref>]. Big data is more suited to computational analysis, rather than traditional manual methods, and automating this analysis is an attractive proposition. The growing need to handle large datasets in the field of health care has led researchers to seek to leverage artificial intelligence (AI) as a means of automation [<xref ref-type="bibr" rid="ref2">2</xref>]. The recent development of generative artificial intelligence (GenAI), particularly large language models (LLMs), has opened new frontiers in data handling [<xref ref-type="bibr" rid="ref3">3</xref>]. In brief, GenAI uses advanced architectures, model context, and user prompts to recognize patterns in extensive data sets and generate original outputs. In the case of LLMs, this is done via transformer architectures, advanced neural networks designed to deliver next-token prediction [<xref ref-type="bibr" rid="ref4">4</xref>].</p><p>LLMs are a versatile tool with the potential to transform health care research, but they also pose distinct challenges. As with other health care innovations, the risks and benefits of using LLMs should be weighed before implementation. Increasingly, there is a growing effort to develop strategies for the responsible use of AI. For example, leading journals do not accept papers with AI as an author, and NICE (National Institute of Health and Care Excellence) has guidelines on the use of AI in evidence generation [<xref ref-type="bibr" rid="ref5">5</xref>,<xref ref-type="bibr" rid="ref6">6</xref>]. Internationally, the European Union is expected to create the first AI law to be enforced in 2026, stratifying AI systems by risk level and regulating them accordingly [<xref ref-type="bibr" rid="ref7">7</xref>]. Canada has also drafted legislation on AI [<xref ref-type="bibr" rid="ref8">8</xref>]. Most laws focus on AI companies rather than individuals and have not yet taken effect. In addition to specific laws surrounding AI, it is crucial to comply with current unrelated but relevant laws, such as the General Data Protection Regulation (GDPR), in the interest of safety [<xref ref-type="bibr" rid="ref9">9</xref>,<xref ref-type="bibr" rid="ref10">10</xref>]. This will involve enhancing data security and clearly defining accountability [<xref ref-type="bibr" rid="ref11">11</xref>,<xref ref-type="bibr" rid="ref12">12</xref>].</p><p>The use of health care data is already bound by GDPR, and LLMs have been used in health care research applications ranging from the analysis of medical records and images to enhancing drug discovery and informing the formulation of new treatments [<xref ref-type="bibr" rid="ref13">13</xref>-<xref ref-type="bibr" rid="ref17">17</xref>]. Automated documentation could further assist clinical practice through use cases such as writing discharge summaries and personalized treatment or medication management plans [<xref ref-type="bibr" rid="ref18">18</xref>,<xref ref-type="bibr" rid="ref19">19</xref>]. This is particularly timely in the United Kingdom, where the government has pledged to embed AI throughout the National Health Service to support routine administration tasks [<xref ref-type="bibr" rid="ref20">20</xref>]. There has also been a push toward automation methodologies in health and care research to deliver timely insights. This is particularly true in the field of evidence synthesis. However, the conversation and movement toward automation in this field have been ongoing for 2 decades with little to no progress [<xref ref-type="bibr" rid="ref21">21</xref>-<xref ref-type="bibr" rid="ref23">23</xref>].</p><p>As the speed of technological improvements accelerates, this can often outpace our ability to understand, assess, and mitigate concerns regarding AI [<xref ref-type="bibr" rid="ref24">24</xref>]. Such concerns include reliability, accuracy, transparency, various ethical, security, and privacy concerns, as well as environmental concerns [<xref ref-type="bibr" rid="ref25">25</xref>-<xref ref-type="bibr" rid="ref27">27</xref>]. Such issues may be intrinsic to the LLM, reflecting its technical capabilities; extrinsic to the LLM, often relating to how it is used; or they may fall under both categories. When considering health care data, protection, security, and accuracy are paramount. As such, it is crucial to understand the views of individuals working in health care practice and research surrounding the use of LLMs. While research has been conducted to understand different population views, there has been no effort to cross-reference and triangulate these views. This is imperative to understand the landscape as a whole and promote multidisciplinary combative action. Thus, this umbrella review examines the concerns of health care professionals and researchers to identify areas for improvement and understand the implications for practice. It is anticipated that through the robust identification of issues, steps can be taken to mitigate concerns, instill confidence in users of AI, and that the use of AI will become more responsible.</p></sec><sec id="s1-2"><title>Aims and Objectives</title><p>We aimed to map the concerns associated with the use of LLMs in health care research and practice through the following objectives: (1) identify systematic reviews that report concerns of health care professionals and health care researchers, and (2) perform qualitative analysis of the findings using inductive and deductive thematic analysis.</p></sec></sec><sec id="s2" sec-type="methods"><title>Methods</title><sec id="s2-1"><title>Study Design</title><p>Following a scoping search that confirmed the feasibility of this study, a protocol for the systematic review was developed and registered with PROSPERO (CRD420250640997) on February 24, 2025. No amendments were made to the information provided in the protocol. The umbrella review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and the synthesis without meta-analysis guidelines, and reported using the PRIOR (Preferred Reporting Items for Overviews of Reviews) checklist, PRISMA-S (Preferred Reporting Items for Systematic Reviews and Meta-Analyses - Search), and PRISMA 2020 Abstract checklist (<xref ref-type="supplementary-material" rid="app4">Checklists 1</xref><xref ref-type="supplementary-material" rid="app5"/>-<xref ref-type="supplementary-material" rid="app6">3</xref>) [<xref ref-type="bibr" rid="ref28">28</xref>-<xref ref-type="bibr" rid="ref31">31</xref>].</p></sec><sec id="s2-2"><title>Eligibility Criteria</title><p>The SPIDER (Sample, Phenomenon of Interest, Design, Evaluation, Research Type) framework was used to outline the inclusion criteria as follows:</p><list list-type="bullet"><list-item><p>Sample: health care professionals and researchers.</p></list-item><list-item><p>Phenomenon of interest: LLMs or GenAI.</p></list-item><list-item><p>Design: systematic reviews.</p></list-item><list-item><p>Evaluation measures: reporting of concerns.</p></list-item><list-item><p>Research type: qualitative research.</p></list-item></list><p>We included systematic reviews published since January 2017 (the year before the first LLMs being introduced publicly to ensure robust coverage of dates), where an outcome of the review was concerns surrounding the use of GenAIs or LLMs in a health and social care research context. We considered systematic reviews as defined by the authors, provided the methodology followed a recognizable process (ie, searching, screening, data extraction, risk of bias, and synthesis). Preprints and nonpeer-reviewed papers were excluded (<xref ref-type="other" rid="box1">Textbox 1</xref>).</p><boxed-text id="box1"><title> Inclusion and exclusion criteria for the umbrella review applied to the retrieved search results.</title><p>Inclusion criteria:</p><list list-type="bullet"><list-item><p>Published since January 2017</p></list-item><list-item><p>Generative artificial intelligence (GenAI) or large language models (LLMs) used in a health care practice and research context</p></list-item><list-item><p>Outcome for concerns surrounding the use of GenAIs or LLMs</p></list-item><list-item><p>Systematic reviews</p></list-item></list><p>Exclusion criteria:</p><list list-type="bullet"><list-item><p>Published before January 2017</p></list-item><list-item><p>Research context not related to health care practice and research</p></list-item><list-item><p>GenAIs or LLMs concerns not listed as an outcome</p></list-item><list-item><p>Primary studies</p></list-item><list-item><p>Letters</p></list-item><list-item><p>Editorials reviews</p></list-item><list-item><p>Conference abstracts</p></list-item><list-item><p>Commentaries</p></list-item></list></boxed-text></sec><sec id="s2-3"><title>Information Sources</title><p>Searches were completed on February 26, 2025, and updated on February 25, 2026, in seven databases: (1) Ovid MEDLINE (R) and Epub Ahead of Print, In-Process, In-Data-Review and Other Non-Indexed Citations, daily and versions; (2) Ovid Embase; (3) Scopus; (4) Web of Science; (5) JBI Database of Systematic Reviews and Implementation Reports; (6) Cochrane Database of Systematic Reviews; and (7) Epistemonikos.</p><p>Study registry searches, purposeful searching of gray literature sources, and citation chaining were neither performed nor were authors independently contacted for further data.</p></sec><sec id="s2-4"><title>Search Strategy</title><p>A de novo search strategy was developed in MEDLINE (Ovid) using the phenomenon of interest and evaluation measures concepts of the SPIDER framework: (ethic* or concern* or raises questions or equality or equity or racial or discriminat* or EDI or (equity diversity and inclusion) or adversely or perpetuat* or persist* or bolster or pitfall* or controvers* or worry or barrier or impede or obstacle or limitation or hindrance or hurdle) AND ((LLM or large language model or GenAI or generative AI or ChatGPT or OpenAI or gpt or Gemini or DeepSeek or LlaMA or Falcon or Cohere or PaLM or Claude v1 or autoregressive language or encoder-decoder or decoder or transformer or prompt engineer) AND (research or academ*). The strategy was peer reviewed by an information specialist and translated into other databases as appropriate (<xref ref-type="supplementary-material" rid="app1">Multimedia Appendix 1</xref>). A date limit of 2017 onward was applied to all searches, and results were limited to systematic reviews using built-in functions in each database. No language restrictions were applied.</p></sec><sec id="s2-5"><title>Selection Process</title><p>The records from the databases were imported into Rayyan, a free online screening platform, and duplicates were removed [<xref ref-type="bibr" rid="ref32">32</xref>]. The remaining systematic reviews were initially screened by title and abstract in duplicate (FY and PA or MF). Discrepancies were resolved by discussion, and HO provided a final judgment when a consensus could not be reached. Systematic reviews taken forward for full-text screening were independently screened by 2 reviewers (FY and PA or MF). Again, discrepancies were resolved by discussion.</p></sec><sec id="s2-6"><title>Data Collection Process</title><p>The data extraction template was initially trialed on 4 systematic reviews selected at random. Further, 2 reviewers independently extracted data from 50% of the included studies (FY and PA or MF). Discrepancies were resolved via discussion or consultation with HO. The remaining studies were extracted by 1 reviewer (FY) with discussion when required.</p></sec><sec id="s2-7"><title>Data Items</title><p>The following data were extracted: first author, year, title, DOI (Digital Object Identifier), journal, country of the first author, health care or research field, the LLM assessed, number of included studies, included study designs, inclusion criteria, exclusion criteria, key concerns, population raising the concern, notable quotes, statistical methods, and declared limitations.</p></sec><sec id="s2-8"><title>Risk of Bias Assessment</title><p>AMSTAR-2 (A Measurement Tool to Assess Systematic Reviews) was used to assess risk of bias, including reporting bias. The 16 questions outlined in AMSTAR-2 were applied independently by 2 reviewers to each included study, following the guidelines for each question or domain included [<xref ref-type="bibr" rid="ref33">33</xref>,<xref ref-type="bibr" rid="ref34">34</xref>].</p></sec><sec id="s2-9"><title>Synthesis Methods</title><p>The narrative synthesis was conducted by a single reviewer (FY), using a thematic analysis approach with inductive and deductive coding [<xref ref-type="bibr" rid="ref35">35</xref>]. No statistical synthesis or meta-analysis was conducted, and quantitative effect measures were neither appropriate nor available given the qualitative nature of concerns. Concerns from the data extraction tables were analyzed and inductively synthesized into codes. Each systematic review was deductively analyzed to determine whether these codes were present in the text. The codes were organized and synthesized into main themes. The main themes were subsequently organized into overarching themes. An analysis by population was also conducted, which recorded the number of systematic reviews for a particular population that highlighted each of the coded concerns.</p></sec><sec id="s2-10"><title>Certainty Assessment</title><p>The application of GRADE (Grading of Recommendations Assessment, Development, and Evaluation) to systematic reviews of qualitative research gives a measure of how well the findings reflect the phenomenon of interest and provides an indicator of certainty around the evidence. GRADE was applied to assess the depth and breadth of this study, providing an initial rating, downgrading domains (risk of bias, inconsistency, indirectness, imprecision, and publication bias), upgrading domains (large effect or dose response, if confounders would reduce the effect), and an end certainty rating. Assessment was conducted independently by 2 reviewers. Heterogeneity and sensitivity analysis were not assessed within this review.</p></sec></sec><sec id="s3" sec-type="results"><title>Results</title><sec id="s3-1"><title>Systematic Review Selection</title><p>In total, 449 records were identified from databases, as shown in the PRISMA flowchart (<xref ref-type="fig" rid="figure1">Figure 1</xref>).</p><fig position="float" id="figure1"><label>Figure 1.</label><caption><p>PRISMA flow diagram detailing numbers for study retrieval, screening, exclusion, and inclusion. PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses.</p></caption><graphic alt-version="no" mimetype="image" position="float" xlink:type="simple" xlink:href="jmir_v28i1e87804_fig01.png"/></fig><p>Before screening, 63 duplicates were removed. The remaining 386 systematic reviews were initially screened by title and abstract. A total of 317 reviews that did not meet the inclusion criteria were excluded. The remaining 69 systematic reviews underwent an additional full-text screening. Further, 27 reports were excluded, most commonly due to concerns not being addressed, followed by topics being unrelated to health or social care, and not being a systematic review or being inaccessible behind a paywall (<xref ref-type="fig" rid="figure1">Figure 1</xref> and <xref ref-type="supplementary-material" rid="app2">Multimedia Appendix 2</xref>). A final total of 42 remaining systematic reviews were included in this umbrella review.</p></sec><sec id="s3-2"><title>Characteristics of Systematic Reviews</title><p>All studies identified were written in the English language. However, the country of the first author varied across the globe. Most systematic reviews originated from the United States (n=9) [<xref ref-type="bibr" rid="ref10">10</xref>,<xref ref-type="bibr" rid="ref36">36</xref>-<xref ref-type="bibr" rid="ref43">43</xref>], followed by the United Kingdom (n=6) [<xref ref-type="bibr" rid="ref44">44</xref>-<xref ref-type="bibr" rid="ref49">49</xref>], Pakistan (n=4) [<xref ref-type="bibr" rid="ref50">50</xref>-<xref ref-type="bibr" rid="ref53">53</xref>], Australia (n=3) [<xref ref-type="bibr" rid="ref12">12</xref>,<xref ref-type="bibr" rid="ref54">54</xref>,<xref ref-type="bibr" rid="ref55">55</xref>], Canada and Israel (n=2 each) [<xref ref-type="bibr" rid="ref56">56</xref>-<xref ref-type="bibr" rid="ref59">59</xref>], and 16 other countries with 1 systematic review each [<xref ref-type="bibr" rid="ref9">9</xref>,<xref ref-type="bibr" rid="ref11">11</xref>,<xref ref-type="bibr" rid="ref60">60</xref>-<xref ref-type="bibr" rid="ref73">73</xref>]. The most common year of publication was 2024, with 27 reviews, followed by 2023 with 9 reviews and 2025 with 6 reviews. No reviews were found before 2023 (<xref ref-type="table" rid="table1">Table 1</xref>).</p><p>The population raising concerns was as follows. Most commonly, it was researchers only (n=17) and other groups included clinicians (general; n=5), plastic surgeons (n=5), psychiatrists (n=4), and neurosurgeons (n=3). Less common were pediatricians, gastroenterologists, dermatologists, pathologists, cardiologists, ophthalmologists, orthopedics, and ICU nurses (n=1 each; <xref ref-type="table" rid="table1">Table 1</xref>).</p><p>The most common individual LLM was ChatGPT, with 15 systematic reviews focusing on this LLM alone [<xref ref-type="bibr" rid="ref9">9</xref>,<xref ref-type="bibr" rid="ref36">36</xref>,<xref ref-type="bibr" rid="ref39">39</xref>,<xref ref-type="bibr" rid="ref42">42</xref>,<xref ref-type="bibr" rid="ref44">44</xref>,<xref ref-type="bibr" rid="ref48">48</xref>,<xref ref-type="bibr" rid="ref50">50</xref>,<xref ref-type="bibr" rid="ref51">51</xref>,<xref ref-type="bibr" rid="ref59">59</xref>-<xref ref-type="bibr" rid="ref61">61</xref>,<xref ref-type="bibr" rid="ref68">68</xref>,<xref ref-type="bibr" rid="ref70">70</xref>-<xref ref-type="bibr" rid="ref72">72</xref>]. Another 15 systematic reviews considered more than one LLM [<xref ref-type="bibr" rid="ref10">10</xref>,<xref ref-type="bibr" rid="ref12">12</xref>,<xref ref-type="bibr" rid="ref37">37</xref>,<xref ref-type="bibr" rid="ref38">38</xref>,<xref ref-type="bibr" rid="ref40">40</xref>,<xref ref-type="bibr" rid="ref45">45</xref>,<xref ref-type="bibr" rid="ref46">46</xref>,<xref ref-type="bibr" rid="ref49">49</xref>,<xref ref-type="bibr" rid="ref54">54</xref>,<xref ref-type="bibr" rid="ref56">56</xref>-<xref ref-type="bibr" rid="ref58">58</xref>,<xref ref-type="bibr" rid="ref62">62</xref>,<xref ref-type="bibr" rid="ref65">65</xref>,<xref ref-type="bibr" rid="ref67">67</xref>]. A smaller proportion of studies (n=12) examined LLMs within a broader context, such as AI in general [<xref ref-type="bibr" rid="ref11">11</xref>,<xref ref-type="bibr" rid="ref43">43</xref>,<xref ref-type="bibr" rid="ref47">47</xref>,<xref ref-type="bibr" rid="ref53">53</xref>,<xref ref-type="bibr" rid="ref69">69</xref>,<xref ref-type="bibr" rid="ref73">73</xref>], natural language processing [<xref ref-type="bibr" rid="ref41">41</xref>,<xref ref-type="bibr" rid="ref66">66</xref>], conversational agents [<xref ref-type="bibr" rid="ref55">55</xref>,<xref ref-type="bibr" rid="ref63">63</xref>], deep learning [<xref ref-type="bibr" rid="ref52">52</xref>], and GenAI [<xref ref-type="bibr" rid="ref64">64</xref>] (<xref ref-type="table" rid="table1">Table 1</xref>).</p><p>There was a positively skewed distribution of primary studies included in the systematic reviews. The IQR was between 19 and 83 (median 32; range 5&#x2010;315) studies. Further, 3 systematic reviews were classed as outliers as they examined higher numbers of primary studies, and a further 3 reviews did not share their sample size [<xref ref-type="bibr" rid="ref39">39</xref>,<xref ref-type="bibr" rid="ref58">58</xref>,<xref ref-type="bibr" rid="ref65">65</xref>]. All systematic reviews were qualitative and did not perform a meta-analysis. Only 5.1% (n=2) formally tested for agreement between reviewers using Cohen &#x03BA; (<xref ref-type="supplementary-material" rid="app3">Multimedia Appendix 3</xref> for full data extraction).</p><table-wrap id="t1" position="float"><label>Table 1.</label><caption><p>Characteristics of the 39 included studies in this umbrella review, including AMSTAR-2<sup><xref ref-type="table-fn" rid="table1fn1">a</xref></sup> and GRADE<sup><xref ref-type="table-fn" rid="table1fn2">b</xref></sup> ratings for each included study.</p></caption><table id="table1" frame="hsides" rules="groups"><thead><tr><td align="left" valign="bottom">Reviews</td><td align="left" valign="bottom">Country</td><td align="left" valign="bottom">AI<sup><xref ref-type="table-fn" rid="table1fn3">c</xref></sup> of interest</td><td align="left" valign="bottom">Population raising concerns</td><td align="left" valign="bottom">Included studies (n)</td><td align="left" valign="bottom">AMSTAR-2 rating</td><td align="left" valign="bottom">GRADE rating</td></tr></thead><tbody><tr><td align="left" valign="top">Abi-Rafeh et al [<xref ref-type="bibr" rid="ref44">44</xref>], 2024</td><td align="left" valign="top">United Kingdom</td><td align="left" valign="top">ChatGPT (OpenAI)</td><td align="left" valign="top">Plastic surgeons</td><td align="left" valign="top">175</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Arif et al [<xref ref-type="bibr" rid="ref50">50</xref>], 2024</td><td align="left" valign="top">Pakistan</td><td align="left" valign="top">ChatGPT</td><td align="left" valign="top">Plastic surgeons</td><td align="left" valign="top">32</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Balla et al [<xref ref-type="bibr" rid="ref45">45</xref>], 2023</td><td align="left" valign="top">United Kingdom</td><td align="left" valign="top">AI in general - lists ChatGPT, Bard (Google LLC), and GLASS A.I. 2.0 (Glass Health)</td><td align="left" valign="top">Pediatricians</td><td align="left" valign="top">20</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Banskota et al [<xref ref-type="bibr" rid="ref73">73</xref>], 2025</td><td align="left" valign="top">Nepal</td><td align="left" valign="top">AI (general)</td><td align="left" valign="top">Orthopedics</td><td align="left" valign="top">20</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Be&#x010D;uli&#x0107; et al [<xref ref-type="bibr" rid="ref60">60</xref>], 2024</td><td align="left" valign="top">Bosnia</td><td align="left" valign="top">ChatGPT</td><td align="left" valign="top">Neurosurgeons</td><td align="left" valign="top">13</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Fareed et al [<xref ref-type="bibr" rid="ref53">53</xref>], 2025</td><td align="left" valign="top">Pakistan</td><td align="left" valign="top">LLMs<sup><xref ref-type="table-fn" rid="table1fn4">d</xref></sup></td><td align="left" valign="top">Clinicians</td><td align="left" valign="top">27</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Fatima et al [<xref ref-type="bibr" rid="ref51">51</xref>], 2024</td><td align="left" valign="top">Pakistan</td><td align="left" valign="top">ChatGPT</td><td align="left" valign="top">Clinicians</td><td align="left" valign="top">83</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Low</td></tr><tr><td align="left" valign="top">Garg et al [<xref ref-type="bibr" rid="ref61">61</xref>], 2023</td><td align="left" valign="top">India</td><td align="left" valign="top">ChatGPT</td><td align="left" valign="top">Clinicians</td><td align="left" valign="top">118</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Guo et al [<xref ref-type="bibr" rid="ref46">46</xref>], 2024</td><td align="left" valign="top">UK</td><td align="left" valign="top">LLMs: ChatGPT, BERT<sup><xref ref-type="table-fn" rid="table1fn5">e</xref></sup></td><td align="left" valign="top">Researchers</td><td align="left" valign="top">40</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Low</td></tr><tr><td align="left" valign="top">Haltaufderheide and Ranisch [<xref ref-type="bibr" rid="ref62">62</xref>], 2024</td><td align="left" valign="top">Germany</td><td align="left" valign="top">LLMs, ChatGPT</td><td align="left" valign="top">Researchers</td><td align="left" valign="top">53</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Low</td></tr><tr><td align="left" valign="top">Kiuchi et al [<xref ref-type="bibr" rid="ref63">63</xref>], 2024</td><td align="left" valign="top">Japan</td><td align="left" valign="top">CAs<sup><xref ref-type="table-fn" rid="table1fn6">f</xref></sup></td><td align="left" valign="top">Researchers</td><td align="left" valign="top">315</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Kiwan et al [<xref ref-type="bibr" rid="ref47">47</xref>], 2024</td><td align="left" valign="top">United Kingdom</td><td align="left" valign="top">AI in general</td><td align="left" valign="top">Plastic surgeons</td><td align="left" valign="top">96</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Klang et al [<xref ref-type="bibr" rid="ref36">36</xref>], 2023</td><td align="left" valign="top">United States</td><td align="left" valign="top">ChatGPT 3.5 (OpenAI)</td><td align="left" valign="top">Gastroenterologists</td><td align="left" valign="top">6</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Low</td></tr><tr><td align="left" valign="top">Kolding et al [<xref ref-type="bibr" rid="ref64">64</xref>], 2024</td><td align="left" valign="top">Denmark</td><td align="left" valign="top">GenAI - includes ChatGPT</td><td align="left" valign="top">Psychiatrists</td><td align="left" valign="top">40</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Kucukkaya et al [<xref ref-type="bibr" rid="ref9">9</xref>], 2024</td><td align="left" valign="top">Turkey</td><td align="left" valign="top">ChatGPT</td><td align="left" valign="top">ICU<sup><xref ref-type="table-fn" rid="table1fn7">g</xref></sup> nurses</td><td align="left" valign="top">5</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Kutbi [<xref ref-type="bibr" rid="ref67">67</xref>], 2024</td><td align="left" valign="top">Saudi Arabia</td><td align="left" valign="top">AI (general), LLMs</td><td align="left" valign="top">Researchers</td><td align="left" valign="top">19</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Li and Guenier [<xref ref-type="bibr" rid="ref48">48</xref>], 2024</td><td align="left" valign="top">United Kingdom</td><td align="left" valign="top">ChatGPT 3.5 (4) (OpenAI)</td><td align="left" valign="top">Researchers</td><td align="left" valign="top">14</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Malgaroli et al [<xref ref-type="bibr" rid="ref41">41</xref>], 2023</td><td align="left" valign="top">United States</td><td align="left" valign="top">NLP<sup><xref ref-type="table-fn" rid="table1fn8">h</xref></sup></td><td align="left" valign="top">Psychiatrists</td><td align="left" valign="top">102</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Low</td></tr><tr><td align="left" valign="top">Mohamed et al [<xref ref-type="bibr" rid="ref65">65</xref>], 2024</td><td align="left" valign="top">Oman</td><td align="left" valign="top">LLMs</td><td align="left" valign="top">Researchers</td><td align="left" valign="top">N/R<sup><xref ref-type="table-fn" rid="table1fn9">i</xref></sup></td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Low</td></tr><tr><td align="left" valign="top">Moya-Salazar et al [<xref ref-type="bibr" rid="ref71">71</xref>], 2024</td><td align="left" valign="top">Peru</td><td align="left" valign="top">ChatGPT</td><td align="left" valign="top">Researchers</td><td align="left" valign="top">14</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Nasra et al [<xref ref-type="bibr" rid="ref54">54</xref>], 2025</td><td align="left" valign="top">Australia</td><td align="left" valign="top">AI (general), LLMs</td><td align="left" valign="top">Clinicians</td><td align="left" valign="top">22</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Omar et al [<xref ref-type="bibr" rid="ref56">56</xref>], 2024</td><td align="left" valign="top">Israel</td><td align="left" valign="top">LLMs</td><td align="left" valign="top">Psychiatrists</td><td align="left" valign="top">16</td><td align="left" valign="top">Low</td><td align="left" valign="top">Low</td></tr><tr><td align="left" valign="top">Omar et al [<xref ref-type="bibr" rid="ref57">57</xref>], 2025</td><td align="left" valign="top">Israel</td><td align="left" valign="top">LLMs</td><td align="left" valign="top">Psychiatrists</td><td align="left" valign="top">34</td><td align="left" valign="top">Low</td><td align="left" valign="top">Low</td></tr><tr><td align="left" valign="top">Paganelli et al [<xref ref-type="bibr" rid="ref66">66</xref>], 2024</td><td align="left" valign="top">Italy</td><td align="left" valign="top">NLP</td><td align="left" valign="top">Dermatologists</td><td align="left" valign="top">30</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Pashangpour and Nejat [<xref ref-type="bibr" rid="ref58">58</xref>], 2024</td><td align="left" valign="top">Canada</td><td align="left" valign="top">LLMs</td><td align="left" valign="top">Researchers</td><td align="left" valign="top">N/R</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Patil et al [<xref ref-type="bibr" rid="ref37">37</xref>], 2024</td><td align="left" valign="top">United States</td><td align="left" valign="top">LLMs</td><td align="left" valign="top">Neurosurgeons</td><td align="left" valign="top">51</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Pressman et al [<xref ref-type="bibr" rid="ref10">10</xref>], 2024</td><td align="left" valign="top">United States</td><td align="left" valign="top">LLMs</td><td align="left" valign="top">Plastic surgeons</td><td align="left" valign="top">53</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Pressman et al [<xref ref-type="bibr" rid="ref38">38</xref>], 2024</td><td align="left" valign="top">United States</td><td align="left" valign="top">LLMs</td><td align="left" valign="top">Plastic surgeons</td><td align="left" valign="top">34</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Rehman et al [<xref ref-type="bibr" rid="ref52">52</xref>], 2025</td><td align="left" valign="top">Pakistan</td><td align="left" valign="top">Deep learning (including LLMs)</td><td align="left" valign="top">Researchers</td><td align="left" valign="top">100</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Roman et al [<xref ref-type="bibr" rid="ref68">68</xref>], 2023</td><td align="left" valign="top">United Arab Emirates</td><td align="left" valign="top">ChatGPT</td><td align="left" valign="top">Neurosurgeons</td><td align="left" valign="top">22</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Rudnicka et al [<xref ref-type="bibr" rid="ref69">69</xref>], 2024</td><td align="left" valign="top">Poland</td><td align="left" valign="top">AI (general)</td><td align="left" valign="top">Researchers</td><td align="left" valign="top">253</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Ruksakulpiwat et al [<xref ref-type="bibr" rid="ref70">70</xref>], 2023</td><td align="left" valign="top">Thailand</td><td align="left" valign="top">ChatGPT</td><td align="left" valign="top">Researchers</td><td align="left" valign="top">6</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Sacoransky et al [<xref ref-type="bibr" rid="ref59">59</xref>], 2024</td><td align="left" valign="top">Canada</td><td align="left" valign="top">ChatGPT</td><td align="left" valign="top">Researchers</td><td align="left" valign="top">8</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Sallam [<xref ref-type="bibr" rid="ref72">72</xref>], 2023</td><td align="left" valign="top">Jordan</td><td align="left" valign="top">ChatGPT</td><td align="left" valign="top">Pathologists</td><td align="left" valign="top">60</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Sanjeewa et al [<xref ref-type="bibr" rid="ref55">55</xref>], 2024</td><td align="left" valign="top">Australia</td><td align="left" valign="top">CAs</td><td align="left" valign="top">Researchers</td><td align="left" valign="top">19</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Low</td></tr><tr><td align="left" valign="top">Sharma et al [<xref ref-type="bibr" rid="ref42">42</xref>], 2024</td><td align="left" valign="top">United States</td><td align="left" valign="top">ChatGPT</td><td align="left" valign="top">Cardiologists</td><td align="left" valign="top">24</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Tangsrivimol et al [<xref ref-type="bibr" rid="ref39">39</xref>], 2025</td><td align="left" valign="top">United States</td><td align="left" valign="top">ChatGPT</td><td align="left" valign="top">Clinicians</td><td align="left" valign="top">N/R</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Villanueva-Miranda et al [<xref ref-type="bibr" rid="ref43">43</xref>], 2025</td><td align="left" valign="top">United States</td><td align="left" valign="top">Deep learning</td><td align="left" valign="top">Researchers</td><td align="left" valign="top">83</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Wang et al [<xref ref-type="bibr" rid="ref40">40</xref>], 2024</td><td align="left" valign="top">United States</td><td align="left" valign="top">LLMs - ChatGPT</td><td align="left" valign="top">Researchers</td><td align="left" valign="top">65</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Wangsa et al [<xref ref-type="bibr" rid="ref12">12</xref>], 2024</td><td align="left" valign="top">Australia</td><td align="left" valign="top">ChatGPT, Bard, Llama (Meta AI), Ernie (Baidu), and Grok (xAI)</td><td align="left" valign="top">Researchers</td><td align="left" valign="top">28</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Wong et al [<xref ref-type="bibr" rid="ref49">49</xref>], 2024</td><td align="left" valign="top">United Kingdom</td><td align="left" valign="top">LLMs</td><td align="left" valign="top">Ophthalmologists</td><td align="left" valign="top">32</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Younis et al [<xref ref-type="bibr" rid="ref11">11</xref>], 2024</td><td align="left" valign="top">Iraq</td><td align="left" valign="top">AI (general)</td><td align="left" valign="top">Researchers</td><td align="left" valign="top">82</td><td align="left" valign="top">Critically low</td><td align="left" valign="top">Very low</td></tr></tbody></table><table-wrap-foot><fn id="table1fn1"><p><sup>a</sup>AMSTAR-2: A Measurement Tool to Assess Systematic Reviews.</p></fn><fn id="table1fn2"><p><sup>b</sup>GRADE: Grading of Recommendations Assessment, Development, and Evaluation.</p></fn><fn id="table1fn3"><p><sup>c</sup>AI: artificial intelligence. </p></fn><fn id="table1fn4"><p><sup>d</sup>LLM: large language model.</p></fn><fn id="table1fn5"><p><sup>e</sup>BERT: Bidirectional Encoder Representations from Transformers.</p></fn><fn id="table1fn6"><p><sup>f</sup>CA: conversational agent.</p></fn><fn id="table1fn7"><p><sup>g</sup>ICU: intensive care unit.</p></fn><fn id="table1fn8"><p><sup>h</sup>NLP: natural language processing.</p></fn><fn id="table1fn9"><p><sup>i</sup>N/R: not reported.</p></fn></table-wrap-foot></table-wrap></sec><sec id="s3-3"><title>Primary Study Overlap</title><p>Due to poor reporting of included primary studies within the systematic reviews, we were unable to calculate the corrected covered area to identify any overlap between primary studies. For example, some reviews listed the number of included studies but only referenced a subset in among supporting references, which meant the primary studies could not be easily identified. However, from manual inspection, it appears that primary studies that have been clearly reported were only included in a single systematic review. In either case, findings should be interpreted with caution as overinflation may be present.</p></sec><sec id="s3-4"><title>Quality Assessments</title><p>Regarding risk of bias in systematic reviews, the overall rating of reviews using AMSTAR-2 was either low (n=2, 4.8% reviews) [<xref ref-type="bibr" rid="ref56">56</xref>,<xref ref-type="bibr" rid="ref57">57</xref>] or critically low (n=40, 95.2% reviews) [<xref ref-type="bibr" rid="ref9">9</xref>-<xref ref-type="bibr" rid="ref11">11</xref>,<xref ref-type="bibr" rid="ref36">36</xref>-<xref ref-type="bibr" rid="ref55">55</xref>,<xref ref-type="bibr" rid="ref58">58</xref>-<xref ref-type="bibr" rid="ref73">73</xref>] (<xref ref-type="table" rid="table1">Table 1</xref>). A total of 40 (95.2%) reviews had a valid research question (Q1) [<xref ref-type="bibr" rid="ref9">9</xref>-<xref ref-type="bibr" rid="ref12">12</xref>,<xref ref-type="bibr" rid="ref36">36</xref>-<xref ref-type="bibr" rid="ref41">41</xref>,<xref ref-type="bibr" rid="ref43">43</xref>-<xref ref-type="bibr" rid="ref65">65</xref>,<xref ref-type="bibr" rid="ref67">67</xref>-<xref ref-type="bibr" rid="ref73">73</xref>], 24 (57.1%) reviews provided descriptions of their included studies (Q3) [<xref ref-type="bibr" rid="ref9">9</xref>,<xref ref-type="bibr" rid="ref11">11</xref>,<xref ref-type="bibr" rid="ref36">36</xref>,<xref ref-type="bibr" rid="ref38">38</xref>,<xref ref-type="bibr" rid="ref40">40</xref>-<xref ref-type="bibr" rid="ref42">42</xref>,<xref ref-type="bibr" rid="ref44">44</xref>,<xref ref-type="bibr" rid="ref46">46</xref>,<xref ref-type="bibr" rid="ref50">50</xref>,<xref ref-type="bibr" rid="ref51">51</xref>,<xref ref-type="bibr" rid="ref54">54</xref>-<xref ref-type="bibr" rid="ref57">57</xref>,<xref ref-type="bibr" rid="ref60">60</xref>-<xref ref-type="bibr" rid="ref62">62</xref>,<xref ref-type="bibr" rid="ref64">64</xref>-<xref ref-type="bibr" rid="ref66">66</xref>,<xref ref-type="bibr" rid="ref68">68</xref>,<xref ref-type="bibr" rid="ref70">70</xref>,<xref ref-type="bibr" rid="ref72">72</xref>], and 27 (64.2%) reviews reported no conflicts of interest (Q16) [<xref ref-type="bibr" rid="ref9">9</xref>-<xref ref-type="bibr" rid="ref12">12</xref>,<xref ref-type="bibr" rid="ref36">36</xref>-<xref ref-type="bibr" rid="ref44">44</xref>,<xref ref-type="bibr" rid="ref46">46</xref>-<xref ref-type="bibr" rid="ref60">60</xref>,<xref ref-type="bibr" rid="ref62">62</xref>,<xref ref-type="bibr" rid="ref63">63</xref>,<xref ref-type="bibr" rid="ref67">67</xref>-<xref ref-type="bibr" rid="ref73">73</xref>].</p><p>However, only 6 (14.2%) reviews had a protocol (Q2) [<xref ref-type="bibr" rid="ref41">41</xref>,<xref ref-type="bibr" rid="ref46">46</xref>,<xref ref-type="bibr" rid="ref56">56</xref>,<xref ref-type="bibr" rid="ref57">57</xref>,<xref ref-type="bibr" rid="ref62">62</xref>,<xref ref-type="bibr" rid="ref68">68</xref>], 3 (7.1%) reviews justified their choice of included studies (Q8) [<xref ref-type="bibr" rid="ref41">41</xref>,<xref ref-type="bibr" rid="ref56">56</xref>,<xref ref-type="bibr" rid="ref65">65</xref>], 10 (23.8%) reviews had a literature search strategy (Q4) [<xref ref-type="bibr" rid="ref41">41</xref>,<xref ref-type="bibr" rid="ref48">48</xref>,<xref ref-type="bibr" rid="ref55">55</xref>-<xref ref-type="bibr" rid="ref57">57</xref>,<xref ref-type="bibr" rid="ref61">61</xref>,<xref ref-type="bibr" rid="ref62">62</xref>,<xref ref-type="bibr" rid="ref64">64</xref>,<xref ref-type="bibr" rid="ref66">66</xref>,<xref ref-type="bibr" rid="ref68">68</xref>], 1 (38%) review was completely double-screened (Q5) [<xref ref-type="bibr" rid="ref10">10</xref>,<xref ref-type="bibr" rid="ref36">36</xref>,<xref ref-type="bibr" rid="ref40">40</xref>,<xref ref-type="bibr" rid="ref41">41</xref>,<xref ref-type="bibr" rid="ref46">46</xref>,<xref ref-type="bibr" rid="ref48">48</xref>,<xref ref-type="bibr" rid="ref49">49</xref>,<xref ref-type="bibr" rid="ref55">55</xref>-<xref ref-type="bibr" rid="ref57">57</xref>,<xref ref-type="bibr" rid="ref61">61</xref>,<xref ref-type="bibr" rid="ref64">64</xref>,<xref ref-type="bibr" rid="ref68">68</xref>,<xref ref-type="bibr" rid="ref70">70</xref>,<xref ref-type="bibr" rid="ref71">71</xref>,<xref ref-type="bibr" rid="ref73">73</xref>], 8 (19%) reviews were completely double data-extracted (Q6) [<xref ref-type="bibr" rid="ref36">36</xref>,<xref ref-type="bibr" rid="ref53">53</xref>,<xref ref-type="bibr" rid="ref54">54</xref>,<xref ref-type="bibr" rid="ref56">56</xref>,<xref ref-type="bibr" rid="ref57">57</xref>,<xref ref-type="bibr" rid="ref61">61</xref>,<xref ref-type="bibr" rid="ref73">73</xref>], 1 (2.3%) review justified their exclusions (Q7) [<xref ref-type="bibr" rid="ref46">46</xref>], 6 (14.2%) reviews had risk of bias assessment (Q9) [<xref ref-type="bibr" rid="ref36">36</xref>,<xref ref-type="bibr" rid="ref46">46</xref>,<xref ref-type="bibr" rid="ref55">55</xref>-<xref ref-type="bibr" rid="ref57">57</xref>,<xref ref-type="bibr" rid="ref62">62</xref>], 6 (14.2%) reviews looked for funding disclosures of constituent studies (Q10) [<xref ref-type="bibr" rid="ref9">9</xref>,<xref ref-type="bibr" rid="ref36">36</xref>,<xref ref-type="bibr" rid="ref43">43</xref>,<xref ref-type="bibr" rid="ref49">49</xref>,<xref ref-type="bibr" rid="ref53">53</xref>,<xref ref-type="bibr" rid="ref73">73</xref>], 6 (14.2%) reviews accounted for risk of bias when interpreting results (Q13) [<xref ref-type="bibr" rid="ref36">36</xref>,<xref ref-type="bibr" rid="ref41">41</xref>,<xref ref-type="bibr" rid="ref55">55</xref>-<xref ref-type="bibr" rid="ref57">57</xref>,<xref ref-type="bibr" rid="ref65">65</xref>], and 5 (11.9%) reviews addressed heterogeneity (Q14) [<xref ref-type="bibr" rid="ref36">36</xref>,<xref ref-type="bibr" rid="ref41">41</xref>,<xref ref-type="bibr" rid="ref55">55</xref>,<xref ref-type="bibr" rid="ref57">57</xref>,<xref ref-type="bibr" rid="ref67">67</xref>]. No reviews completed a meta-analysis (Q11), a risk of bias assessment for a meta-analysis (Q12), or formally assessed for publication bias (Q15; <xref ref-type="table" rid="table2">Table 2</xref>).</p><table-wrap id="t2" position="float"><label>Table 2.</label><caption><p>AMSTAR-2<sup><xref ref-type="table-fn" rid="table2fn1">a</xref></sup> rating for each of the 39 included systematic reviews.</p></caption><table id="table2" frame="hsides" rules="groups"><thead><tr><td align="left" valign="bottom">Reviews</td><td align="left" valign="bottom">1</td><td align="left" valign="bottom">2</td><td align="left" valign="bottom">3</td><td align="left" valign="bottom">4</td><td align="left" valign="bottom">5</td><td align="left" valign="bottom">6</td><td align="left" valign="bottom">7</td><td align="left" valign="bottom">8</td><td align="left" valign="bottom">9</td><td align="left" valign="bottom">10</td><td align="left" valign="bottom">11</td><td align="left" valign="bottom">12</td><td align="left" valign="bottom">13</td><td align="left" valign="bottom">14</td><td align="left" valign="bottom">15</td><td align="left" valign="bottom">16</td><td align="left" valign="bottom">Overall rating</td></tr></thead><tbody><tr><td align="left" valign="top">Abi-Rafeh et al [<xref ref-type="bibr" rid="ref44">44</xref>], 2024</td><td align="left" valign="top">Y<sup><xref ref-type="table-fn" rid="table2fn2">b</xref></sup></td><td align="left" valign="top">N<sup><xref ref-type="table-fn" rid="table2fn3">c</xref></sup></td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">P<sup><xref ref-type="table-fn" rid="table2fn4">d</xref></sup></td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A<sup><xref ref-type="table-fn" rid="table2fn5">e</xref></sup></td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Arif et al [<xref ref-type="bibr" rid="ref50">50</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Balla et al [<xref ref-type="bibr" rid="ref45">45</xref>], 2023</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Banskota et al [<xref ref-type="bibr" rid="ref73">73</xref>], 2025</td><td align="left" valign="top">Y</td><td align="left" valign="top">P</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">P</td><td align="left" valign="top">Y</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Be&#x010D;uli&#x0107; et al [<xref ref-type="bibr" rid="ref60">60</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Fareed et al [<xref ref-type="bibr" rid="ref53">53</xref>], 2025</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Fatima et al [<xref ref-type="bibr" rid="ref51">51</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Garg et al [<xref ref-type="bibr" rid="ref61">61</xref>], 2023</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Guo et al [<xref ref-type="bibr" rid="ref46">46</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">P</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Haltaufderheide and Ranisch [<xref ref-type="bibr" rid="ref62">62</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">P</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">P</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Kiuchi et al [<xref ref-type="bibr" rid="ref63">63</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Kiwan et al [<xref ref-type="bibr" rid="ref47">47</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Klang et al [<xref ref-type="bibr" rid="ref36">36</xref>], 2023</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Kolding et al [<xref ref-type="bibr" rid="ref64">64</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Kucukkaya et al [<xref ref-type="bibr" rid="ref9">9</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Kutbi [<xref ref-type="bibr" rid="ref67">67</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Li and Guenier [<xref ref-type="bibr" rid="ref48">48</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Malgaroli et al [<xref ref-type="bibr" rid="ref41">41</xref>], 2023</td><td align="left" valign="top">Y</td><td align="left" valign="top">P</td><td align="left" valign="top">Y</td><td align="left" valign="top">P</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Mohamed et al [<xref ref-type="bibr" rid="ref65">65</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Moya-Salazar et al [<xref ref-type="bibr" rid="ref71">71</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Nasra et al [<xref ref-type="bibr" rid="ref54">54</xref>], 2025</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Omar et al [<xref ref-type="bibr" rid="ref56">56</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">P</td><td align="left" valign="top">Y</td><td align="left" valign="top">P</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Low</td></tr><tr><td align="left" valign="top">Omar et al [<xref ref-type="bibr" rid="ref57">57</xref>], 2025</td><td align="left" valign="top">Y</td><td align="left" valign="top">P</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">P</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Low</td></tr><tr><td align="left" valign="top">Paganelli et al [<xref ref-type="bibr" rid="ref66">66</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Pashangpour and Nejat [<xref ref-type="bibr" rid="ref58">58</xref>], 2024</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Patil et al [<xref ref-type="bibr" rid="ref37">37</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Pressman et al [<xref ref-type="bibr" rid="ref10">10</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Pressman et al [<xref ref-type="bibr" rid="ref38">38</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Rehman et al [<xref ref-type="bibr" rid="ref52">52</xref>], 2025</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Roman et al [<xref ref-type="bibr" rid="ref68">68</xref>], 2023</td><td align="left" valign="top">Y</td><td align="left" valign="top">P</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Rudnicka et al [<xref ref-type="bibr" rid="ref69">69</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Ruksakulpiwat et al [<xref ref-type="bibr" rid="ref70">70</xref>], 2023</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Sacoransky et al [<xref ref-type="bibr" rid="ref59">59</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Sallam [<xref ref-type="bibr" rid="ref72">72</xref>], 2023</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Sanjeewa et al [<xref ref-type="bibr" rid="ref55">55</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Sharma et al [<xref ref-type="bibr" rid="ref42">42</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Tangsrivimol et al [<xref ref-type="bibr" rid="ref39">39</xref>], 2025</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Villanueva-Miranda et al [<xref ref-type="bibr" rid="ref43">43</xref>], 2025</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Wang et al [<xref ref-type="bibr" rid="ref40">40</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Wangsa et al [<xref ref-type="bibr" rid="ref12">12</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Wong et al [<xref ref-type="bibr" rid="ref49">49</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr><tr><td align="left" valign="top">Younis et al [<xref ref-type="bibr" rid="ref11">11</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">P</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N/A</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Critically low</td></tr></tbody></table><table-wrap-foot><fn id="table2fn1"><p><sup>a</sup>AMSTAR-2: A Measurement Tool to Assess Systematic Reviews.</p></fn><fn id="table2fn2"><p><sup>b</sup>Y: yes.</p></fn><fn id="table2fn3"><p><sup>c</sup>N: no.</p></fn><fn id="table2fn4"><p><sup>d</sup>P: partial.</p></fn><fn id="table2fn5"><p><sup>e</sup>N/A: not applicable.</p></fn></table-wrap-foot></table-wrap></sec><sec id="s3-5"><title>Certainty of Evidence</title><p>Reviews were overall graded as either low-end certainty (n=9, 21.4%) [<xref ref-type="bibr" rid="ref36">36</xref>,<xref ref-type="bibr" rid="ref41">41</xref>,<xref ref-type="bibr" rid="ref46">46</xref>,<xref ref-type="bibr" rid="ref51">51</xref>,<xref ref-type="bibr" rid="ref55">55</xref>-<xref ref-type="bibr" rid="ref57">57</xref>,<xref ref-type="bibr" rid="ref62">62</xref>,<xref ref-type="bibr" rid="ref65">65</xref>], or very low-end certainty (n=33, 78.6%) [<xref ref-type="bibr" rid="ref9">9</xref>-<xref ref-type="bibr" rid="ref12">12</xref>,<xref ref-type="bibr" rid="ref37">37</xref>-<xref ref-type="bibr" rid="ref40">40</xref>,<xref ref-type="bibr" rid="ref42">42</xref>-<xref ref-type="bibr" rid="ref44">44</xref>,<xref ref-type="bibr" rid="ref47">47</xref>-<xref ref-type="bibr" rid="ref50">50</xref>,<xref ref-type="bibr" rid="ref52">52</xref>-<xref ref-type="bibr" rid="ref54">54</xref>,<xref ref-type="bibr" rid="ref58">58</xref>-<xref ref-type="bibr" rid="ref61">61</xref>,<xref ref-type="bibr" rid="ref63">63</xref>,<xref ref-type="bibr" rid="ref66">66</xref>-<xref ref-type="bibr" rid="ref73">73</xref>]. As there were no randomized controlled trials, all reviews started as low certainty before downgrading or upgrading (initial rating).</p><p>In the downgrading domains, all studies had consistent results (inconsistency) [<xref ref-type="bibr" rid="ref9">9</xref>-<xref ref-type="bibr" rid="ref12">12</xref>,<xref ref-type="bibr" rid="ref36">36</xref>-<xref ref-type="bibr" rid="ref73">73</xref>] and most addressed the core question (indirectness) of this umbrella review (n=36, 85.7%) [<xref ref-type="bibr" rid="ref9">9</xref>-<xref ref-type="bibr" rid="ref12">12</xref>,<xref ref-type="bibr" rid="ref36">36</xref>-<xref ref-type="bibr" rid="ref40">40</xref>,<xref ref-type="bibr" rid="ref42">42</xref>,<xref ref-type="bibr" rid="ref44">44</xref>-<xref ref-type="bibr" rid="ref46">46</xref>,<xref ref-type="bibr" rid="ref48">48</xref>-<xref ref-type="bibr" rid="ref51">51</xref>,<xref ref-type="bibr" rid="ref53">53</xref>-<xref ref-type="bibr" rid="ref62">62</xref>,<xref ref-type="bibr" rid="ref64">64</xref>-<xref ref-type="bibr" rid="ref68">68</xref>,<xref ref-type="bibr" rid="ref70">70</xref>-<xref ref-type="bibr" rid="ref73">73</xref>]. However, only 7 (16.6%) reviews assessed for risk of bias [<xref ref-type="bibr" rid="ref36">36</xref>,<xref ref-type="bibr" rid="ref46">46</xref>,<xref ref-type="bibr" rid="ref52">52</xref>,<xref ref-type="bibr" rid="ref55">55</xref>-<xref ref-type="bibr" rid="ref57">57</xref>,<xref ref-type="bibr" rid="ref73">73</xref>], 14 (33.3%) reviews directly addressed the research question (imprecision) [<xref ref-type="bibr" rid="ref10">10</xref>,<xref ref-type="bibr" rid="ref12">12</xref>,<xref ref-type="bibr" rid="ref36">36</xref>,<xref ref-type="bibr" rid="ref40">40</xref>,<xref ref-type="bibr" rid="ref43">43</xref>,<xref ref-type="bibr" rid="ref46">46</xref>,<xref ref-type="bibr" rid="ref48">48</xref>,<xref ref-type="bibr" rid="ref51">51</xref>,<xref ref-type="bibr" rid="ref53">53</xref>,<xref ref-type="bibr" rid="ref56">56</xref>,<xref ref-type="bibr" rid="ref57">57</xref>,<xref ref-type="bibr" rid="ref62">62</xref>,<xref ref-type="bibr" rid="ref65">65</xref>,<xref ref-type="bibr" rid="ref73">73</xref>], and 4 (9.5%) reviews considered publication bias [<xref ref-type="bibr" rid="ref41">41</xref>,<xref ref-type="bibr" rid="ref51">51</xref>,<xref ref-type="bibr" rid="ref62">62</xref>,<xref ref-type="bibr" rid="ref65">65</xref>].</p><p>In terms of upgrading domains, 8 (19%) reviews were considered as showing large effects [<xref ref-type="bibr" rid="ref10">10</xref>,<xref ref-type="bibr" rid="ref36">36</xref>,<xref ref-type="bibr" rid="ref46">46</xref>,<xref ref-type="bibr" rid="ref51">51</xref>,<xref ref-type="bibr" rid="ref56">56</xref>,<xref ref-type="bibr" rid="ref57">57</xref>,<xref ref-type="bibr" rid="ref62">62</xref>,<xref ref-type="bibr" rid="ref65">65</xref>], but only 1 (2.3%) review mentioned confounders [<xref ref-type="bibr" rid="ref41">41</xref>]. None displayed a dose-response relationship, and as this criterion was not relevant to this review, it was not taken into account for the final scoring (<xref ref-type="table" rid="table3">Table 3</xref>).</p><table-wrap id="t3" position="float"><label>Table 3.</label><caption><p>GRADE<sup><xref ref-type="table-fn" rid="table3fn1">a</xref></sup> assessment for each of the 39 included systematic reviews.</p></caption><table id="table3" frame="hsides" rules="groups"><thead><tr><td align="left" valign="bottom" colspan="4"/><td align="left" valign="bottom" colspan="5">Downgrading domains</td><td align="left" valign="bottom" colspan="3">Upgrading domains</td><td align="left" valign="bottom"/></tr><tr><td align="left" valign="top">Reviews</td><td align="left" valign="top">Depth of concerns</td><td align="left" valign="top">Breadth of concerns</td><td align="left" valign="top">Initial rating</td><td align="left" valign="top">RoB<sup><xref ref-type="table-fn" rid="table3fn2">b</xref></sup></td><td align="left" valign="top">Inconsistency</td><td align="left" valign="top">Indirectness</td><td align="left" valign="top">Imprecision</td><td align="left" valign="top">Publication bias</td><td align="left" valign="top">Large effect</td><td align="left" valign="top">Dose response</td><td align="left" valign="top">Confounders would reduce the effect</td><td align="left" valign="top">End certainty rating</td></tr></thead><tbody><tr><td align="left" valign="top">Abi-Rafeh et al [<xref ref-type="bibr" rid="ref44">44</xref>], 2024</td><td align="left" valign="top">Y<sup><xref ref-type="table-fn" rid="table3fn3">c</xref></sup></td><td align="left" valign="top">Y</td><td align="left" valign="top">Low</td><td align="left" valign="top">N<sup><xref ref-type="table-fn" rid="table3fn4">d</xref></sup></td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Arif et al [<xref ref-type="bibr" rid="ref50">50</xref>], 2024</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Balla et al [<xref ref-type="bibr" rid="ref45">45</xref>], 2023</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Banskota et al [<xref ref-type="bibr" rid="ref73">73</xref>], 2025</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Low</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Be&#x010D;uli&#x0107; et al [<xref ref-type="bibr" rid="ref60">60</xref>], 2024</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Fareed et al [<xref ref-type="bibr" rid="ref53">53</xref>], 2025</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Fatima et al [<xref ref-type="bibr" rid="ref51">51</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Low</td></tr><tr><td align="left" valign="top">Garg et al [<xref ref-type="bibr" rid="ref61">61</xref>], 2023</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Guo et al [<xref ref-type="bibr" rid="ref46">46</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Low</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Low</td></tr><tr><td align="left" valign="top">Haltaufderheide and Ranisch [<xref ref-type="bibr" rid="ref62">62</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Low</td></tr><tr><td align="left" valign="top">Kiuchi et al [<xref ref-type="bibr" rid="ref63">63</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Kiwan et al [<xref ref-type="bibr" rid="ref47">47</xref>], 2024</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Klang et al [<xref ref-type="bibr" rid="ref36">36</xref>], 2023</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">Low</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Low</td></tr><tr><td align="left" valign="top">Kolding et al [<xref ref-type="bibr" rid="ref64">64</xref>], 2024</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Kucukkaya et al [<xref ref-type="bibr" rid="ref9">9</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Kutbi [<xref ref-type="bibr" rid="ref67">67</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Li and Guenier [<xref ref-type="bibr" rid="ref48">48</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Malgaroli et al [<xref ref-type="bibr" rid="ref41">41</xref>], 2023</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Low</td></tr><tr><td align="left" valign="top">Mohamed et al [<xref ref-type="bibr" rid="ref65">65</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Low</td></tr><tr><td align="left" valign="top">Moya-Salazar et al [<xref ref-type="bibr" rid="ref71">71</xref>], 2024</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Nasra et al [<xref ref-type="bibr" rid="ref54">54</xref>], 2025</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Omar et al [<xref ref-type="bibr" rid="ref56">56</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">Low</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Low</td></tr><tr><td align="left" valign="top">Omar et al [<xref ref-type="bibr" rid="ref57">57</xref>], 2025</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Low</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Low</td></tr><tr><td align="left" valign="top">Paganelli et al [<xref ref-type="bibr" rid="ref66">66</xref>], 2024</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Pashangpour and Nejat [<xref ref-type="bibr" rid="ref58">58</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Patil et al [<xref ref-type="bibr" rid="ref37">37</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Pressman et al [<xref ref-type="bibr" rid="ref10">10</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Pressman et al [<xref ref-type="bibr" rid="ref38">38</xref>], 2024</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Rehman et al [<xref ref-type="bibr" rid="ref52">52</xref>], 2025</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Low</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Roman et al [<xref ref-type="bibr" rid="ref68">68</xref>], 2023</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Rudnicka et al [<xref ref-type="bibr" rid="ref69">69</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Ruksakulpiwat et al [<xref ref-type="bibr" rid="ref70">70</xref>], 2023</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Sacoransky et al [<xref ref-type="bibr" rid="ref59">59</xref>], 2024</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Sallam [<xref ref-type="bibr" rid="ref72">72</xref>], 2023</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Sanjeewa et al [<xref ref-type="bibr" rid="ref55">55</xref>], 2024</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Low</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Low</td></tr><tr><td align="left" valign="top">Sharma et al [<xref ref-type="bibr" rid="ref42">42</xref>], 2024</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Tangsrivimol et al [<xref ref-type="bibr" rid="ref39">39</xref>], 2025</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Villanueva-Miranda et al [<xref ref-type="bibr" rid="ref43">43</xref>], 2025</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Wang et al [<xref ref-type="bibr" rid="ref40">40</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Wangsa et al [<xref ref-type="bibr" rid="ref12">12</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Wong et al [<xref ref-type="bibr" rid="ref49">49</xref>], 2024</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr><tr><td align="left" valign="top">Younis et al [<xref ref-type="bibr" rid="ref11">11</xref>], 2024</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">Low</td><td align="left" valign="top">N</td><td align="left" valign="top">Y</td><td align="left" valign="top">Y</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">N</td><td align="left" valign="top">Very low</td></tr></tbody></table><table-wrap-foot><fn id="table3fn1"><p><sup>a</sup>GRADE: Grading of Recommendations Assessment, Development, and Evaluation.</p></fn><fn id="table3fn2"><p><sup>b</sup>RoB: Risk of Bias.</p></fn><fn id="table3fn3"><p><sup>c</sup>Y: Yes.</p></fn><fn id="table3fn4"><p><sup>d</sup>N: No.</p></fn></table-wrap-foot></table-wrap></sec><sec id="s3-6"><title>Interrater Reliability</title><p>&#x03BA; statistics were calculated between the reviewers (FY and one of PA, MF, or HO). Significant agreement was seen for both AMSTAR-2 (0.92, indicating near-perfect agreement) and GRADE (0.75, indicating substantial agreement). The &#x03BA; statistic was considered significant where it was 0.6 (substantial agreement) or higher (<xref ref-type="table" rid="table4">Table 4</xref>) [<xref ref-type="bibr" rid="ref74">74</xref>].</p><table-wrap id="t4" position="float"><label>Table 4.</label><caption><p>Interrater reliability, Cohen &#x03BA;, detailing the agreement rates between reviewers when assessing risk of bias (AMSTAR-2<sup><xref ref-type="table-fn" rid="table4fn1">a</xref></sup>) and certainty of the evidence (GRADE<sup><xref ref-type="table-fn" rid="table4fn2">b</xref></sup>).</p></caption><table id="table4" frame="hsides" rules="groups"><thead><tr><td align="left" valign="bottom">Reviewer combination</td><td align="left" valign="bottom">AMSTAR-2</td><td align="left" valign="bottom">GRADE</td></tr></thead><tbody><tr><td align="left" valign="top">FY and PA</td><td align="left" valign="top">0.88<sup><xref ref-type="table-fn" rid="table4fn3">c</xref></sup></td><td align="left" valign="top">0.75<sup><xref ref-type="table-fn" rid="table4fn4">d</xref></sup></td></tr><tr><td align="left" valign="top">FY and MF</td><td align="left" valign="top">0.88<sup><xref ref-type="table-fn" rid="table4fn3">c</xref></sup></td><td align="left" valign="top">0.5</td></tr><tr><td align="left" valign="top">FY and HO</td><td align="left" valign="top">1.00<sup><xref ref-type="table-fn" rid="table4fn3">c</xref></sup></td><td align="left" valign="top">1.00<sup><xref ref-type="table-fn" rid="table4fn3">c</xref></sup></td></tr><tr><td align="left" valign="top">Average</td><td align="left" valign="top">0.92<sup><xref ref-type="table-fn" rid="table4fn3">c</xref></sup> (SD 0.05)</td><td align="left" valign="top">0.75<sup><xref ref-type="table-fn" rid="table4fn4">d</xref></sup> (SD 0.2)</td></tr></tbody></table><table-wrap-foot><fn id="table4fn1"><p><sup>a</sup>AMSTAR-2: A Measurement Tool to Assess Systematic Reviews.</p></fn><fn id="table4fn2"><p><sup>b</sup>GRADE: Grading of Recommendations Assessment, Development, and Evaluation.</p></fn><fn id="table4fn3"><p><sup>c</sup>Shows statistical significance of near-perfect agreement between reviewers.</p></fn><fn id="table4fn4"><p><sup>d</sup>Shows statistical significance of substantial agreement.</p></fn></table-wrap-foot></table-wrap></sec><sec id="s3-7"><title>Synthesis of Results</title><p>Qualitative coding is a means of deriving descriptive tags to categorize data, which can then be used to generate themes. A total of 29 codes were generated from the synthesis (<xref ref-type="supplementary-material" rid="app3">Multimedia Appendix 3</xref>), and seven themes emerged: (1) data quality and reliability; (2) transparency and reproducibility; (3) performance and capability; (4) technical and operational; (5) human interaction and social impact; (6) ethical, legal, and safety; and (7) costs. These could be grouped under 3 core themes: technical capability; ethical, legal, and societal; and costs. For most population groups, mentions of technical capability concerns were the greatest, followed by ethical, legal, and societal concerns, and then cost concerns (<xref ref-type="table" rid="table5">Table 5</xref>).</p><table-wrap id="t5" position="float"><label>Table 5.</label><caption><p>Count of systematic reviews raising concerns by population groups under the themes derived from qualitative thematic analysis.</p></caption><table id="table5" frame="hsides" rules="groups"><thead><tr><td align="left" valign="bottom"/><td align="left" valign="bottom">Cardio<sup><xref ref-type="table-fn" rid="table5fn1">a</xref></sup> (1)</td><td align="left" valign="bottom">Derma<sup><xref ref-type="table-fn" rid="table5fn2">b</xref></sup> (1)</td><td align="left" valign="bottom">Gastro<sup><xref ref-type="table-fn" rid="table5fn3">c</xref></sup> (1)</td><td align="left" valign="bottom">GC<sup><xref ref-type="table-fn" rid="table5fn4">d</xref></sup> (5)</td><td align="left" valign="bottom">ICU<sup><xref ref-type="table-fn" rid="table5fn5">e</xref></sup> nurses (1)</td><td align="left" valign="bottom">Neuro<sup><xref ref-type="table-fn" rid="table5fn6">f</xref></sup> (3)</td><td align="left" valign="bottom">Ophtha<sup><xref ref-type="table-fn" rid="table5fn7">g</xref></sup> (1)</td><td align="left" valign="bottom">Ortho<sup><xref ref-type="table-fn" rid="table5fn8">h</xref></sup> (1)</td><td align="left" valign="bottom">Pedia<sup><xref ref-type="table-fn" rid="table5fn9">i</xref></sup> (1)</td><td align="left" valign="bottom">Patho<sup><xref ref-type="table-fn" rid="table5fn10">j</xref></sup> (1)</td><td align="left" valign="bottom">Psurg<sup><xref ref-type="table-fn" rid="table5fn11">k</xref></sup> (5)</td><td align="left" valign="bottom">Psychia<sup><xref ref-type="table-fn" rid="table5fn12">l</xref></sup> (4)</td><td align="left" valign="bottom">Resea<sup><xref ref-type="table-fn" rid="table5fn13">m</xref></sup> (17)</td></tr></thead><tbody><tr><td align="left" valign="top" colspan="14">Technical capabilities</td></tr><tr><td align="left" valign="top"><named-content content-type="indent">&#x00A0;&#x00A0;&#x00A0;&#x00A0;</named-content>Data quality and reliability</td><td align="left" valign="top">1</td><td align="left" valign="top">1</td><td align="left" valign="top">1</td><td align="left" valign="top">5</td><td align="left" valign="top">0</td><td align="left" valign="top">3</td><td align="left" valign="top">1</td><td align="left" valign="top">1</td><td align="left" valign="top">1</td><td align="left" valign="top">1</td><td align="left" valign="top">5</td><td align="left" valign="top">4</td><td align="left" valign="top">15</td></tr><tr><td align="left" valign="top"><named-content content-type="indent">&#x00A0;&#x00A0;&#x00A0;&#x00A0;</named-content>Transparency and reproducibility</td><td align="left" valign="top">1</td><td align="left" valign="top">0</td><td align="left" valign="top">0</td><td align="left" valign="top">3</td><td align="left" valign="top">0</td><td align="left" valign="top">3</td><td align="left" valign="top">0</td><td align="left" valign="top">1</td><td align="left" valign="top">1</td><td align="left" valign="top">1</td><td align="left" valign="top">3</td><td align="left" valign="top">2</td><td align="left" valign="top">8</td></tr><tr><td align="left" valign="top"><named-content content-type="indent">&#x00A0;&#x00A0;&#x00A0;&#x00A0;</named-content>Performance and capability</td><td align="left" valign="top">1</td><td align="left" valign="top">1</td><td align="left" valign="top">1</td><td align="left" valign="top">5</td><td align="left" valign="top">0</td><td align="left" valign="top">2</td><td align="left" valign="top">1</td><td align="left" valign="top">1</td><td align="left" valign="top">1</td><td align="left" valign="top">1</td><td align="left" valign="top">4</td><td align="left" valign="top">4</td><td align="left" valign="top">12</td></tr><tr><td align="left" valign="top"><named-content content-type="indent">&#x00A0;&#x00A0;&#x00A0;&#x00A0;</named-content>Technical and operations</td><td align="left" valign="top">0</td><td align="left" valign="top">0</td><td align="left" valign="top">0</td><td align="left" valign="top">1</td><td align="left" valign="top">0</td><td align="left" valign="top">1</td><td align="left" valign="top">0</td><td align="left" valign="top">1</td><td align="left" valign="top">0</td><td align="left" valign="top">0</td><td align="left" valign="top">0</td><td align="left" valign="top">1</td><td align="left" valign="top">6</td></tr><tr><td align="left" valign="top" colspan="14">Ethical, legal, and societal</td></tr><tr><td align="left" valign="top"><named-content content-type="indent">&#x00A0;&#x00A0;&#x00A0;&#x00A0;</named-content>Human interaction and social impact</td><td align="left" valign="top">0</td><td align="left" valign="top">1</td><td align="left" valign="top">0</td><td align="left" valign="top">5</td><td align="left" valign="top">1</td><td align="left" valign="top">1</td><td align="left" valign="top">0</td><td align="left" valign="top">0</td><td align="left" valign="top">0</td><td align="left" valign="top">1</td><td align="left" valign="top">5</td><td align="left" valign="top">2</td><td align="left" valign="top">12</td></tr><tr><td align="left" valign="top"><named-content content-type="indent">&#x00A0;&#x00A0;&#x00A0;&#x00A0;</named-content>Legal, ethical, and safety</td><td align="left" valign="top">1</td><td align="left" valign="top">1</td><td align="left" valign="top">1</td><td align="left" valign="top">5</td><td align="left" valign="top">1</td><td align="left" valign="top">3</td><td align="left" valign="top">1</td><td align="left" valign="top">1</td><td align="left" valign="top">1</td><td align="left" valign="top">1</td><td align="left" valign="top">5</td><td align="left" valign="top">4</td><td align="left" valign="top">16</td></tr><tr><td align="left" valign="top" colspan="14">Costs</td></tr><tr><td align="left" valign="top"><named-content content-type="indent">&#x00A0;&#x00A0;&#x00A0;&#x00A0;</named-content>All costs</td><td align="left" valign="top">0</td><td align="left" valign="top">0</td><td align="left" valign="top">0</td><td align="left" valign="top">1</td><td align="left" valign="top">0</td><td align="left" valign="top">1</td><td align="left" valign="top">0</td><td align="left" valign="top">1</td><td align="left" valign="top">0</td><td align="left" valign="top">0</td><td align="left" valign="top">0</td><td align="left" valign="top">0</td><td align="left" valign="top">4</td></tr></tbody></table><table-wrap-foot><fn id="table5fn1"><p><sup>a</sup>Cardio: cardiologists.</p></fn><fn id="table5fn2"><p><sup>b</sup>Derma: dermatologists.</p></fn><fn id="table5fn3"><p><sup>c</sup>Gastro: gastroenterologists.</p></fn><fn id="table5fn4"><p><sup>d</sup>GC: general clinicians.</p></fn><fn id="table5fn5"><p><sup>e</sup>ICU: intensive care unit.</p></fn><fn id="table5fn6"><p><sup>f</sup>Neuro: neurosurgeons.</p></fn><fn id="table5fn7"><p><sup>g</sup>Ophtha: ophthalmologists.</p></fn><fn id="table5fn8"><p><sup>h</sup>Ortho: orthopedics.</p></fn><fn id="table5fn9"><p><sup>i</sup>Pedia: pediatricians.</p></fn><fn id="table5fn10"><p><sup>j</sup>Patho: pathologists.</p></fn><fn id="table5fn11"><p><sup>k</sup>Psurg: plastic surgeons.</p></fn><fn id="table5fn12"><p><sup>l</sup>Psychia: psychiatrists.</p></fn><fn id="table5fn13"><p><sup>m</sup>Resea: researchers.</p></fn></table-wrap-foot></table-wrap></sec><sec id="s3-8"><title>Data Quality and Reliability</title><p>The 42 studies reflected that bias in training algorithms and datasets mirrors what is already known on the subject, with estimates that around a quarter of studies on LLMs show bias [<xref ref-type="bibr" rid="ref40">40</xref>]. For sensitive topics, this may be reduced to around 15% [<xref ref-type="bibr" rid="ref65">65</xref>]. Key demographic barriers were mentioned, including sex, race, culture, language, and religion [<xref ref-type="bibr" rid="ref43">43</xref>,<xref ref-type="bibr" rid="ref55">55</xref>,<xref ref-type="bibr" rid="ref61">61</xref>]. Political biases were also highlighted in closed-source algorithms [<xref ref-type="bibr" rid="ref12">12</xref>]. Specifically, racial biases affecting individuals of black ethnicity were mentioned [<xref ref-type="bibr" rid="ref62">62</xref>]. Sexual discrimination, bias toward female doctors was highlighted, with AI recommending fewer female doctors than male doctors. In pediatric medicine, a key issue was a limited, fragmented, or total lack of standardized training sets for LLMs in genetic disorders [<xref ref-type="bibr" rid="ref45">45</xref>]. Most genetic disorders are rare and disproportionately affect children, which may contribute to the incomplete training sets [<xref ref-type="bibr" rid="ref75">75</xref>].</p><p>Furthermore, outdated and limited datasets were commonly mentioned, with the date cutoffs highlighted for various ChatGPT models. For example, ChatGPT 3.5 was pretrained until September 2021 only and did not incorporate information from the internet [<xref ref-type="bibr" rid="ref11">11</xref>,<xref ref-type="bibr" rid="ref76">76</xref>]. ChatGPT 4 was pretrained up until April 2023 only [<xref ref-type="bibr" rid="ref46">46</xref>,<xref ref-type="bibr" rid="ref59">59</xref>,<xref ref-type="bibr" rid="ref73">73</xref>]. Obvious problems with this include a lack of recent knowledge, obsolete knowledge, or misalignment with current clinical guidelines [<xref ref-type="bibr" rid="ref50">50</xref>,<xref ref-type="bibr" rid="ref53">53</xref>]. Another study also acknowledged that hospital-specific protocols should be adhered to, which LLMs may not include in their outputs [<xref ref-type="bibr" rid="ref9">9</xref>]. From clinical practice, trust guidelines may differ from general ones, particularly in the case of antimicrobials, as location affects the presence of different microbes [<xref ref-type="bibr" rid="ref77">77</xref>].</p><p>Fabricated or fake references were highlighted in 4 of the reviews [<xref ref-type="bibr" rid="ref40">40</xref>,<xref ref-type="bibr" rid="ref50">50</xref>,<xref ref-type="bibr" rid="ref51">51</xref>,<xref ref-type="bibr" rid="ref54">54</xref>]. Constituent studies that examined image references were anatomically incorrect or fabricated in 81% of cases [<xref ref-type="bibr" rid="ref9">9</xref>]. Model overfitting, where a model is trained too specifically so that it cannot generalize on unseen data, was explored in reviews that examine image-based medical applications. Radiologically, x-ray images may be prone to overfitting [<xref ref-type="bibr" rid="ref52">52</xref>]. Dermatology, which relies heavily on pattern recognition, may also be prone to this phenomenon [<xref ref-type="bibr" rid="ref66">66</xref>]. Disease management options often featured fabricated references in all versions of ChatGPT [<xref ref-type="bibr" rid="ref59">59</xref>]. Furthermore, the potential for such references to mislead junior colleagues, including resident doctors, was mentioned [<xref ref-type="bibr" rid="ref59">59</xref>]. Similarly, several studies mentioned that hallucinations were a cause of concern [<xref ref-type="bibr" rid="ref39">39</xref>,<xref ref-type="bibr" rid="ref43">43</xref>,<xref ref-type="bibr" rid="ref51">51</xref>,<xref ref-type="bibr" rid="ref53">53</xref>,<xref ref-type="bibr" rid="ref58">58</xref>,<xref ref-type="bibr" rid="ref64">64</xref>]. Some studies emphasized that it was easy to be convinced by hallucinations [<xref ref-type="bibr" rid="ref51">51</xref>,<xref ref-type="bibr" rid="ref64">64</xref>]. Other aspects addressed included that hallucinations were often confidently given by LLMs, especially when parameter settings that encourage more varied, random outputs are used [<xref ref-type="bibr" rid="ref46">46</xref>]. Other factors that influenced hallucination generation were the quality of prompts, with prompts phrased as stories often causing hallucinations [<xref ref-type="bibr" rid="ref58">58</xref>]. It was estimated in 1 review that 40% of discharge summaries written by AI have hallucinations [<xref ref-type="bibr" rid="ref39">39</xref>].</p></sec><sec id="s3-9"><title>Transparency and Reproducibility</title><p>Several studies highlight the difficulties with the transparency of LLMs, with some referring to the technology as a &#x201C;black box&#x201D; [<xref ref-type="bibr" rid="ref37">37</xref>,<xref ref-type="bibr" rid="ref43">43</xref>,<xref ref-type="bibr" rid="ref51">51</xref>,<xref ref-type="bibr" rid="ref56">56</xref>,<xref ref-type="bibr" rid="ref69">69</xref>,<xref ref-type="bibr" rid="ref73">73</xref>]. Ethical discussions are highlighted as a way to build transparency of models [<xref ref-type="bibr" rid="ref10">10</xref>]. Profit-driven lack of transparency was only mentioned in 1 review, but another highlighted how the proprietary nature of LLMs can complicate openness and trust [<xref ref-type="bibr" rid="ref53">53</xref>,<xref ref-type="bibr" rid="ref62">62</xref>]. Another review emphasized that a lack of transparency can be ascribed to multiple stages, including the design and training of LLMs [<xref ref-type="bibr" rid="ref65">65</xref>]. The same review also emphasized that care should be taken so that interventions aimed at increasing transparency do not inadvertently expose patient data. Leaked personal data can potentially also amplify bias through normalizing biased correlations as real patterns [<xref ref-type="bibr" rid="ref65">65</xref>].</p><p>The issue of repeatability with the same or similar prompts was also isolated as a concern. Most constituent primary research papers were identified as prompt experiments [<xref ref-type="bibr" rid="ref64">64</xref>]. However, Patil et al [<xref ref-type="bibr" rid="ref37">37</xref>] reported that about a quarter of the research papers were found not to disclose their prompts. Another review underlined that when they were disclosed, prompts tended to be single, standalone 1-shot prompts [<xref ref-type="bibr" rid="ref59">59</xref>]. The concept of biased prompts was raised, and prompt injection, where prompts are engineered to extract information or cause disruption for nefarious purposes, was also highlighted as a concern [<xref ref-type="bibr" rid="ref36">36</xref>,<xref ref-type="bibr" rid="ref43">43</xref>].</p></sec><sec id="s3-10"><title>Performance and Capability</title><p>The reviews in this study broadly agreed that the performance of LLMs was comparable to or exceeded that of humans. Latest estimates of correct responses on neurology licensing examination questions revealed ChatGPT 4 had 85% accuracy compared to human performance at 73.8% [<xref ref-type="bibr" rid="ref46">46</xref>]. Fracture detection rates with deep learning were also close to this figure at 83% [<xref ref-type="bibr" rid="ref67">67</xref>]. Approximately 76.5% (32/42) of studies used human performance as a benchmark, and 50% (21/42) compared LLMs to human performance alone. It is essential to measure success on diverse tasks, and some reviews agreed that LLMs often struggle with complexity [<xref ref-type="bibr" rid="ref11">11</xref>,<xref ref-type="bibr" rid="ref39">39</xref>,<xref ref-type="bibr" rid="ref45">45</xref>,<xref ref-type="bibr" rid="ref69">69</xref>,<xref ref-type="bibr" rid="ref72">72</xref>]. Lack of originality was also a commonly cited concern [<xref ref-type="bibr" rid="ref11">11</xref>,<xref ref-type="bibr" rid="ref36">36</xref>,<xref ref-type="bibr" rid="ref44">44</xref>,<xref ref-type="bibr" rid="ref51">51</xref>,<xref ref-type="bibr" rid="ref61">61</xref>,<xref ref-type="bibr" rid="ref70">70</xref>,<xref ref-type="bibr" rid="ref72">72</xref>]. Most systematic reviews emphasized that LLMs needed human oversight, and several mentioned it should only be viewed as a &#x201C;supplementary tool&#x201D; [<xref ref-type="bibr" rid="ref9">9</xref>,<xref ref-type="bibr" rid="ref39">39</xref>,<xref ref-type="bibr" rid="ref45">45</xref>,<xref ref-type="bibr" rid="ref50">50</xref>,<xref ref-type="bibr" rid="ref56">56</xref>,<xref ref-type="bibr" rid="ref57">57</xref>,<xref ref-type="bibr" rid="ref60">60</xref>].</p></sec><sec id="s3-11"><title>Technical and Operational Challenges</title><p>Few studies explored technical and operational challenges. Further, 1 review cited a primary study that examined system crashes [<xref ref-type="bibr" rid="ref48">48</xref>]. Another review highlighted slow response times and how this was a problem in robotics [<xref ref-type="bibr" rid="ref58">58</xref>]. Similarly, a second review noted slower clinical workflows due to the verification process [<xref ref-type="bibr" rid="ref53">53</xref>]. Aside from the speed of development outstripping research, it was noted that a lack of research was problematic [<xref ref-type="bibr" rid="ref64">64</xref>]. Another review quoted that only 26% of studies used randomized controlled trial&#x2013;type designs in assessing LLMs by users, suggesting that conclusions from research may not be completely reliable [<xref ref-type="bibr" rid="ref55">55</xref>]. Additionally, 1 review called for rigorous validation in real-world settings, which was supported by another review raising gaps in validation as a concern [<xref ref-type="bibr" rid="ref43">43</xref>,<xref ref-type="bibr" rid="ref73">73</xref>].</p></sec><sec id="s3-12"><title>Human Interaction and Social Impact</title><p>There was a mix of views regarding empathy and LLMs. Some reviews stressed that LLMs&#x2019; empathy was good, although it was usually assessed through technical expert reports rather than by both users and experts. Only a minority of studies (n=10) used an explicit definition of the term &#x201C;empathy&#x201D; [<xref ref-type="bibr" rid="ref46">46</xref>,<xref ref-type="bibr" rid="ref54">54</xref>,<xref ref-type="bibr" rid="ref55">55</xref>]. Others stated there was a general lack of empathy [<xref ref-type="bibr" rid="ref11">11</xref>,<xref ref-type="bibr" rid="ref39">39</xref>,<xref ref-type="bibr" rid="ref50">50</xref>,<xref ref-type="bibr" rid="ref64">64</xref>]. Only 1 study gave a mix of such opinions [<xref ref-type="bibr" rid="ref47">47</xref>].</p><p>Furthermore, some reviews expressed that LLMs could cause potential damage to the doctor-patient relationship [<xref ref-type="bibr" rid="ref38">38</xref>,<xref ref-type="bibr" rid="ref44">44</xref>,<xref ref-type="bibr" rid="ref46">46</xref>,<xref ref-type="bibr" rid="ref62">62</xref>]. There was a large overlap between this finding and reviews that addressed deskilling of the workforce or impacts on the job market [<xref ref-type="bibr" rid="ref11">11</xref>,<xref ref-type="bibr" rid="ref44">44</xref>,<xref ref-type="bibr" rid="ref46">46</xref>,<xref ref-type="bibr" rid="ref62">62</xref>,<xref ref-type="bibr" rid="ref65">65</xref>]. Additionally, a lack of a sustainable relationship between new technologies and the user was emphasized in robotics due to problems with &#x201C;semantics, consistency, and interactiveness&#x201D; [<xref ref-type="bibr" rid="ref63">63</xref>]. Researchers raised concerns around challenges with linguistic complexity, such as understanding irony and sarcasm [<xref ref-type="bibr" rid="ref43">43</xref>].</p><p>User acceptance was identified as an important factor in 2 reviews [<xref ref-type="bibr" rid="ref46">46</xref>,<xref ref-type="bibr" rid="ref67">67</xref>]. The importance of acceptance by various groups, including physicians, caregivers, and providers, was highlighted [<xref ref-type="bibr" rid="ref63">63</xref>]. Potential mistrust of LLMs and humanization issues were highlighted in the mental health field [<xref ref-type="bibr" rid="ref43">43</xref>,<xref ref-type="bibr" rid="ref55">55</xref>]. Yet, public acceptance was viewed as very positive in 1 systematic review [<xref ref-type="bibr" rid="ref40">40</xref>]. There was an acknowledgment that this area needs more research [<xref ref-type="bibr" rid="ref48">48</xref>].</p><p>Further, 5 reviews emphasized that existing inequalities could become more entrenched with LLMs [<xref ref-type="bibr" rid="ref40">40</xref>,<xref ref-type="bibr" rid="ref47">47</xref>,<xref ref-type="bibr" rid="ref62">62</xref>,<xref ref-type="bibr" rid="ref65">65</xref>,<xref ref-type="bibr" rid="ref70">70</xref>]. This is separate from concerns over bias, which could also contribute to the deepening of inequalities. Both of these events could perpetuate the other, whereby biased outputs could deepen inequalities, which in turn could lead to the introduction of further biases.</p></sec><sec id="s3-13"><title>Legal, Ethical, and Safety Concerns</title><p>Almost all reviews mentioned ethical concerns as a potential problem with LLM use, with varying degrees of explanation on this topic. Accountability was addressed from a 2-fold perspective, with 4 reviews focusing on medicolegal accountability [<xref ref-type="bibr" rid="ref11">11</xref>,<xref ref-type="bibr" rid="ref44">44</xref>,<xref ref-type="bibr" rid="ref59">59</xref>,<xref ref-type="bibr" rid="ref72">72</xref>]. Others were focused on legitimacy and accountability in research [<xref ref-type="bibr" rid="ref50">50</xref>,<xref ref-type="bibr" rid="ref51">51</xref>]. Suggested solutions included clear guidelines on accountability [<xref ref-type="bibr" rid="ref12">12</xref>,<xref ref-type="bibr" rid="ref48">48</xref>,<xref ref-type="bibr" rid="ref55">55</xref>]. Another potential solution was policy and regulations [<xref ref-type="bibr" rid="ref40">40</xref>,<xref ref-type="bibr" rid="ref65">65</xref>]. Related to this was the issue of academic integrity, alternatively phrased as &#x201C;pedagogical risk&#x201D; [<xref ref-type="bibr" rid="ref9">9</xref>,<xref ref-type="bibr" rid="ref11">11</xref>,<xref ref-type="bibr" rid="ref12">12</xref>,<xref ref-type="bibr" rid="ref44">44</xref>,<xref ref-type="bibr" rid="ref62">62</xref>,<xref ref-type="bibr" rid="ref65">65</xref>,<xref ref-type="bibr" rid="ref68">68</xref>].</p><p>Most reviews raised privacy and security concerns regarding LLMs. The privacy problems highlighted by studies can be seen as a triad involving information leaks from embedded training examples, inferential disclosure, and insufficiently deidentified data [<xref ref-type="bibr" rid="ref40">40</xref>]. There may be a trade-off between data utility and privacy [<xref ref-type="bibr" rid="ref40">40</xref>,<xref ref-type="bibr" rid="ref65">65</xref>]. The need to comply with existing laws, including GDPR, was emphasized by 3 systematic reviews [<xref ref-type="bibr" rid="ref9">9</xref>,<xref ref-type="bibr" rid="ref12">12</xref>,<xref ref-type="bibr" rid="ref59">59</xref>]. Other studies acknowledged that further efforts were necessary, such as limiting personal data collection or conducting audits [<xref ref-type="bibr" rid="ref39">39</xref>,<xref ref-type="bibr" rid="ref40">40</xref>,<xref ref-type="bibr" rid="ref55">55</xref>,<xref ref-type="bibr" rid="ref73">73</xref>].</p><p>Only 9 reviews discussed obtaining consent to collect personal data [<xref ref-type="bibr" rid="ref10">10</xref>,<xref ref-type="bibr" rid="ref12">12</xref>,<xref ref-type="bibr" rid="ref37">37</xref>,<xref ref-type="bibr" rid="ref39">39</xref>,<xref ref-type="bibr" rid="ref43">43</xref>,<xref ref-type="bibr" rid="ref44">44</xref>,<xref ref-type="bibr" rid="ref53">53</xref>,<xref ref-type="bibr" rid="ref62">62</xref>,<xref ref-type="bibr" rid="ref73">73</xref>]. This reflects the limited literature available on ensuring informed consent when using LLMs and highlights the fact that new technology is outpacing safety. Just 1 review sought to explain consent itself, which entails providing a full disclosure of the risks and benefits in such a way that the participant comprehends and agrees [<xref ref-type="bibr" rid="ref10">10</xref>]. Further, 2 reviews suggested that protocols are needed to obtain consent [<xref ref-type="bibr" rid="ref12">12</xref>,<xref ref-type="bibr" rid="ref39">39</xref>]. Consent is crucial in anticipation of seen and unforeseen ethical issues with LLMs, and yet other systematic reviews chose to discuss LLMs as a way to streamline consent forms [<xref ref-type="bibr" rid="ref37">37</xref>,<xref ref-type="bibr" rid="ref44">44</xref>,<xref ref-type="bibr" rid="ref62">62</xref>].</p><p>Safety may become a population-wide problem as well as an individual one. Mass-scale problems may become apparent with the potential of infodemics perpetuated by LLMs, according to some reviews [<xref ref-type="bibr" rid="ref51">51</xref>,<xref ref-type="bibr" rid="ref53">53</xref>,<xref ref-type="bibr" rid="ref62">62</xref>,<xref ref-type="bibr" rid="ref65">65</xref>,<xref ref-type="bibr" rid="ref72">72</xref>]. The saturation of scientific literature with low-quality automated reviews, which may fuel infodemics, was also discussed [<xref ref-type="bibr" rid="ref62">62</xref>]. In a pandemic context such as COVID-19, there could be even greater consequences [<xref ref-type="bibr" rid="ref65">65</xref>].</p><p>Finally, the risk of self-propagating and uncontrolled evolution was described as &#x201C;unknown&#x201D; by 1 review in passing [<xref ref-type="bibr" rid="ref44">44</xref>]. Self-propagating and uncontrolled evolution relates to the LLM&#x2019;s ability to grow and change on its own. Considering that this could be very detrimental and have long-term impacts, this is important. While this possibility has been informally mentioned in technology circles for some time, there are only a small number of new reports in the literature examining this possibility, so this finding is expected.</p></sec><sec id="s3-14"><title>Environmental, Processing, and Economic Costs</title><p>None of the reviews examined more than one cost aspect, and most lacked depth of answers in relation to this topic. Costs were broadly environmental related to computational processing [<xref ref-type="bibr" rid="ref43">43</xref>,<xref ref-type="bibr" rid="ref58">58</xref>,<xref ref-type="bibr" rid="ref65">65</xref>]. Given the scale of climate change and its importance to health, this is an area of great interest and should be explored further [<xref ref-type="bibr" rid="ref78">78</xref>,<xref ref-type="bibr" rid="ref79">79</xref>]. Other costs mentioned were financial costs incurred by users [<xref ref-type="bibr" rid="ref40">40</xref>,<xref ref-type="bibr" rid="ref60">60</xref>].</p></sec></sec><sec id="s4" sec-type="discussion"><title>Discussion</title><sec id="s4-1"><title>Principal Findings</title><p>This umbrella review aimed to narratively synthesize the concerns that health care professionals and researchers face when using AI. A wide variety of concerns are raised, which overlap and interlink, consistently affecting multiple populations. The findings indicate 3 core areas of shared concern within the health care field: technical capability of AI; ethical, legal, and societal implications for use; and associated costs.</p><p>Much of the concern surrounding technical capability lies with data quality and reproducibility. For research to be as robust as possible, we must use AI for tasks that are appropriate, judicious, and sense-checked, as well as monitoring the functions and effects of LLMs [<xref ref-type="bibr" rid="ref38">38</xref>,<xref ref-type="bibr" rid="ref39">39</xref>]. A good starting point is to acknowledge where, how, and when AI was used. Research integrity policies, reporting guidelines, and audits will be crucial in meeting quality standards and enabling reproducibility [<xref ref-type="bibr" rid="ref9">9</xref>,<xref ref-type="bibr" rid="ref37">37</xref>,<xref ref-type="bibr" rid="ref40">40</xref>,<xref ref-type="bibr" rid="ref65">65</xref>,<xref ref-type="bibr" rid="ref73">73</xref>]. Most of the reviews included here advocated for guidelines, although none explored direct examples or attempted to construct a guideline. This is expected, given that international and national guidelines are only gradually emerging. However, it could be argued that research should be a proactive driver for exploring these issues rather than a reactive one.</p><p>Ethical, legal, and societal implications were varied and broad-ranging. Concerns over hallucinations, bias, inequalities, and consent provide interesting and often deeply interrelated perspectives that triangulate with the technical capabilities of AI. For instance, bias that perpetuates &#x201C;hallucinations&#x201D; was commonly cited [<xref ref-type="bibr" rid="ref61">61</xref>,<xref ref-type="bibr" rid="ref62">62</xref>,<xref ref-type="bibr" rid="ref72">72</xref>]. Efforts for transparency may inadvertently perpetuate bias, as implicit biases in models can exist even when they show no explicit biases [<xref ref-type="bibr" rid="ref80">80</xref>]. This gives a false sense of security surrounding systems that are lacking in objectivity. The reuse of biased datasets from such models will worsen this problem, and further research is needed to explore these perpetuating cycles. Ultimately, transparency must be judged by humans who may reinforce biases inadvertently or fail to acknowledge problems because features are unreported or untested. Therefore, while we should strive for more transparency, particularly through legislation, guidance, and reporting, we should avoid labeling any LLM as completely &#x201C;transparent.&#x201D;</p><p>Some biases were thought to be pervasive, for instance, &#x201C;social biases entrenched in data.&#x201D; Specifically, female ophthalmologists were recommended less than one-third as often as their male counterparts [<xref ref-type="bibr" rid="ref47">47</xref>]. Biases were present in topical issues; for example, &#x201C;unfavorable attitudes&#x201D; were described when ChatGPT was prompted to discuss topics such as climate change and Black Lives Matter [<xref ref-type="bibr" rid="ref65">65</xref>]. Research is uncovering both implicit and overt biases toward already disadvantaged populations, which is why careful consideration of LLMs and their applications is necessary to prevent exacerbating existing health inequalities. Education surrounding considerations of equality, diversity, and inclusion when using LLMs may be helpful on an individual level. However, discriminatory biases may only be overcome by careful curation of training data underpinning the LLMs.</p><p>Some terms regarding LLMs could be revised for clarity and to destigmatize. Findings indicate the term &#x201C;hallucination&#x201D; for AI issues is considered unhelpful and stigmatizing for those with a psychiatric disorder, reflecting proposals in the literature for the term &#x201C;AI misinformation&#x201D; [<xref ref-type="bibr" rid="ref64">64</xref>,<xref ref-type="bibr" rid="ref81">81</xref>]. The term &#x201C;hallucination&#x201D; was originally used in computing science to refer to retained outputs even when artificial neural networks were pruned by removing some connections [<xref ref-type="bibr" rid="ref82">82</xref>]. The term has evolved, first to positively describe tasks related to computer vision and improved facial recognition, and then to mean the generation of incorrect outputs in translation or object detection. Currently, it is used to mean incorrect LLM outputs produced with confidence [<xref ref-type="bibr" rid="ref83">83</xref>]. As an overall term to describe confidently produced errors, AI &#x201C;hallucination&#x201D; may, on the surface, be useful. However, LLMs are not produced the same way as biological hallucination, which occurs in the absence of external stimuli [<xref ref-type="bibr" rid="ref84">84</xref>]. By contrast, LLMs have external stimuli in the form of training data and prompts but still produce nonsensical outputs. This can be stigmatizing for those with a psychiatric disorder and is technically imprecise. AI generalization, fact fabrication, or stochastic parroting could be used as more distinct terms depending on the types of error seen [<xref ref-type="bibr" rid="ref83">83</xref>].</p><p>Interestingly, while cost was a core theme, there was no definitive cost element that was unifying across reviews. Further explorations of cost concerns could inform cost-benefit analyses and full economic evaluations of AI use cases. We have seen such evaluations for AI-assisted health care technologies, but not regarding AI use in general health care practice and research [<xref ref-type="bibr" rid="ref85">85</xref>].</p></sec><sec id="s4-2"><title>Limitations of This Review</title><p>The constituent systematic reviews comprised primary research papers that were heterogeneous. For example, different papers used different methods of evaluation in 1 review, ranging from surveys to response ratings and interview feedback [<xref ref-type="bibr" rid="ref55">55</xref>]. Moreover, the authors used different methods to classify the accuracy of LLMs and did not adhere to standard formal procedures for assessment [<xref ref-type="bibr" rid="ref40">40</xref>]. The quality of the included reviews was generally poor, and the extent of publication bias was unknown. Many of the poorly reported reviews included studies, meaning we were unable to determine the overlap between primary studies using the corrected covered area. Caution should be taken that different populations&#x2019; views of LLM limitations are not a complete representation of views of the broader population, and that findings may be overinflated due to the unknown overlap of primary studies.</p><p>Furthermore, thematic analyses have an element of subjectivity. Potential sources of bias include researcher bias and confirmation bias, whereby preexisting beliefs and experiences may have influenced the coding. We have attempted to limit this through group discussion of codes; however, future studies could incorporate a blinded dual coding process.</p><p>This review is also limited by the search dates of the included systematic reviews. As the field of LLMs rapidly evolves, primary studies published after the search dates may provide valuable insights into current thinking.</p></sec><sec id="s4-3"><title>Conclusions</title><p>To our knowledge, this is the first umbrella review to address the concerns of LLMs in health care research and practice. Thematic analyses provided insight into the complexity of different perspectives, and by using a whole population approach, it demonstrates common narratives. However, the poor quality of the included studies is a substantial limitation, and results should be interpreted with caution. Data quality is at the heart of these concerns, and combative action must ensure health care professionals and researchers have the resources required to overcome these apprehensions if AI is to be used routinely. Ethical, legal, and societal implications of AI use were also commonly raised. As technology accelerates and demands on health care increase, we must adapt and embrace change with equity, diversity, inclusion, and safety at the core.</p></sec></sec></body><back><ack><p>We give thanks to Dr Chris Marshall and Dr Malcolm Moffat for providing support and guidance. The authors declare that no artificial intelligence tools were used in the writing of this paper, nor for any element of the work, including the processing of data or creation of images or tables.</p></ack><notes><sec><title>Funding</title><p>The authors are funded by the NIHR (National Institute for Health and Care Research; HSRIC-2016-10009/Innovation Observatory). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.</p></sec><sec><title>Data Availability</title><p>All data analyzed during this study are available as supplemental materials.</p></sec></notes><fn-group><fn fn-type="con"><p>HO and DC conceptualized this study's design. FY, PA, and MF conducted this review, with support from HO and DC. The first draft of this paper was written by FY and refined by HO. All authors commented on previous versions of this paper. All authors read and approved this final paper.</p></fn><fn fn-type="conflict"><p>DC is Director of the NIHR (National Institute for Health and Care Research) Innovation Observatory. All other authors declare no conflicts of interest.</p></fn></fn-group><glossary><title>Abbreviations</title><def-list><def-item><term id="abb1">AI</term><def><p>artificial intelligence</p></def></def-item><def-item><term id="abb2">AMSTAR-2</term><def><p>A Measurement Tool to Assess Systematic Reviews</p></def></def-item><def-item><term id="abb3">DOI</term><def><p>Digital Object Identifier</p></def></def-item><def-item><term id="abb4">GDPR</term><def><p>General Data Protection Regulation</p></def></def-item><def-item><term id="abb5">GenAI</term><def><p>generative artificial intelligence</p></def></def-item><def-item><term id="abb6">GRADE</term><def><p>Grading of Recommendations Assessment, Development, and Evaluation</p></def></def-item><def-item><term id="abb7">LLM </term><def><p>large language model</p></def></def-item><def-item><term id="abb8">NICE </term><def><p>National Institute of Health and Care Excellence</p></def></def-item><def-item><term id="abb9">PRIOR</term><def><p>Preferred Reporting Items for Systematic Reviews and Meta-Analyses</p></def></def-item><def-item><term id="abb10">PRISMA</term><def><p>Preferred Reporting Items for Systematic Reviews and Meta-Analyses</p></def></def-item><def-item><term id="abb11">PRISMA-S</term><def><p>Preferred Reporting Items for Systematic Reviews and Meta-Analyses - Search</p></def></def-item><def-item><term id="abb12">SPIDER </term><def><p>Sample, Phenomenon of Interest, Design, Evaluation, Research Type</p></def></def-item></def-list></glossary><ref-list><title>References</title><ref id="ref1"><label>1</label><nlm-citation citation-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Batko</surname><given-names>K</given-names> </name><name name-style="western"><surname>&#x015A;l&#x0119;zak</surname><given-names>A</given-names> </name></person-group><article-title>The use of big data analytics in healthcare</article-title><source>J Big 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