Systematic reviews of interventions for the management of corneal diseases were identified from the Cochrane Eyes and Vision US Satellite database of systematic reviews related to eyes and vision.
aReasons for nonapplicability of certain systematic reviews for certain criteria are as follows: For criteria 6, 8, 9, 10, and 13, three systematic reviews did not include any studies. For criterion 7, three systematic reviews did not include any studies, and 13 systematic reviews included studies but did not assess risk of bias in included studies (thus classified as unreliable). For criterion 11, three systematic reviews did not include any studies, and 2 systematic reviews included only 1 study each. For criterion 12, three systematic reviews did not include any studies, 2 systematic reviews included only 1 study each, and 35 systematic reviews included more than 1 study but did not conduct a quantitative synthesis.
bThe 5 criteria used for assessing the reliability of systematic reviews are 1, 3, 6, 12, and 15.
eAppendix. Diseases, Interventions, Outcomes, and Number of Studies and Participants, and Conclusions of all 65 Reliable Systematic Reviews Addressing Corneal Diseases
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Saldanha IJ, Lindsley KB, Lum F, Dickersin K, Li T. Reliability of the Evidence Addressing Treatment of Corneal Diseases: A Summary of Systematic Reviews. JAMA Ophthalmol. 2019;137(7):775–785. doi:10.1001/jamaophthalmol.2019.1063
What is the reliability of the existing systematic reviews addressing interventions for corneal diseases?
This study identified 98 systematic reviews (33 classified as unreliable and 65 as reliable) addressing 15 corneal diseases. The most frequent reasons for unreliability were that searches were not comprehensive, risk of bias was not assessed, and, when a quantitative synthesis was conducted, inappropriate methods were used.
Adherence to well-established best practices regarding systematic review conduct might help make future systematic reviews in eyes and vision more reliable.
Patient care should be informed by clinical practice guidelines, which in turn should be informed by evidence from reliable systematic reviews. The American Academy of Ophthalmology is updating its Preferred Practice Patterns (PPPs) for the management of the following 6 corneal diseases: bacterial keratitis, blepharitis, conjunctivitis, corneal ectasia, corneal edema and opacification, and dry eye syndrome.
To summarize the reliability of the existing systematic reviews addressing interventions for corneal diseases.
The Cochrane Eyes and Vision US Satellite database.
In this study of published systematic reviews from 1997 to 2017 (median, 2014), the Cochrane Eyes and Vision US Satellite database was searched for systematic reviews evaluating interventions for the management of any corneal disease, combining eyes and vision keywords and controlled vocabulary terms with a validated search filter.
Data Extraction and Synthesis
The study classified systematic reviews as reliable when each of the following 5 criteria were met: the systematic review specified eligibility criteria for inclusion of studies, conducted a comprehensive literature search for studies, assessed risk of bias of the individual included studies, used appropriate methods for quantitative syntheses (meta-analysis) (only assessed if meta-analysis was performed), and had conclusions that were supported by the results of the systematic review. They were classified as unreliable if at least 1 criterion was not met.
Main Outcomes and Measures
The proportion of systematic reviews that were reliable and the reasons for unreliability.
This study identified 98 systematic reviews that addressed interventions for 15 corneal diseases. Thirty-three of 98 systematic reviews (34%) were classified as unreliable. The most frequent reasons for unreliability were that the systematic review did not conduct a comprehensive literature search for studies (22 of 33 [67%]), did not assess risk of bias of the individual included studies (13 of 33 [39%]), and did not use appropriate methods for quantitative syntheses (meta-analysis) (12 of 17 systematic reviews that conducted a quantitative synthesis [71%]). Sixty-five of 98 systematic reviews (66%) were classified as reliable. Forty-two of the 65 reliable systematic reviews (65%) addressed corneal diseases relevant to the 2018 American Academy of Ophthalmology PPPs; 33 of these 42 systematic reviews (79%) are cited in the 2018 PPPs.
Conclusions and Relevance
One in 3 systematic reviews addressing interventions for corneal diseases are unreliable and thus were not used to inform PPP recommendations. Careful adherence by systematic reviewers and journal editors to well-established best practices regarding systematic review conduct and reporting might help make future systematic reviews in eyes and vision more reliable.
The American Academy of Ophthalmology’s (AAO’s) clinical practice guidelines (ie, Preferred Practice Patterns [PPPs]) are “designed to identify characteristics and components of quality eye care.”1(p1) The Institute of Medicine (now called the National Academy of Medicine) explicitly recommended that quality care should be based on guideline recommendations, which in turn should be based on systematic reviews that are of high quality and reliable.2 To inform decision making, a few minimal attributes distinguish reliable systematic reviews from unreliable systematic reviews.3 Reliable systematic reviews (1) use appropriate methods to search for all available evidence, assess the risk of bias in the included evidence, and qualitatively and quantitatively synthesize it in ways that minimize bias; and (2) are reported completely and transparently.2,4
Since 2014, the AAO has partnered with the Cochrane Eyes and Vision US Satellite (CEV@US) to identify reliable systematic reviews that are relevant to updates of the PPPs. Specifically, CEV@US identifies and supplies each PPP panel with relevant reliable systematic reviews that can inform recommendations on the effectiveness of interventions. The 2016 cataract PPP5 and the 2017 refractive error PPP4 are recent examples of the success of this partnership.
Corneal disease is the fourth leading cause of blindness, accounting for approximately 5% of cases of blindness globally.6 To assist the cornea PPP panel in updating their 2018 PPPs, CEV@US identified, assessed, and summarized potentially reliable systematic reviews addressing interventions for the 6 corneal diseases covered in the PPP, including bacterial keratitis, blepharitis, conjunctivitis, corneal ectasia, corneal edema (ie, retention of excess fluid within 1 or multiple corneal layers7) and opacification (ie, presence of additional material [eg, fluid, scar tissue] within 1 or multiple layers of the area that is associated with loss of corneal clarity7), and dry eye syndrome. Our objective in this article is to summarize the reliability of the existing systematic reviews addressing the management of any corneal disease (including the 6 covered in the 2018 PPPs).
To support our collaboration with the AAO, CEV@US has been maintaining, since 2007, a regularly updated database of systematic reviews related to eyes and vision. This database includes both Cochrane and non-Cochrane systematic reviews. To identify the systematic reviews,8 CEV@US searched MEDLINE and Embase from inception to 2007, with periodic updates conducted in 2009, 2012, 2014, 2016, and 2017. To identify systematic reviews, the search combined eyes and vision keywords and controlled vocabulary terms with a validated search filter.9 Full-text reports that claimed to be systematic reviews or meta-analyses or met the definition of a systematic review or a meta-analysis (as defined by the Institute of Medicine2) were included in the database.
For the present project, we searched the CEV@US database of systematic reviews on July 14, 2017, and included systematic reviews that evaluated the effectiveness of interventions for the management of at least 1 corneal disease. When a systematic review had been updated since its initial publication, we included its most recent update. Two individuals (from among 2 authors [I.J.S. and K.B.L.], 2 nonauthor research assistants [Omar Mansour, MHS, and Benjamin Rouse, MHS], and Barbara Hawkins, PhD [a senior faculty member of CEV@US]) independently examined each systematic review to determine whether it addressed corneal disease. For systematic reviews that examined corneal diseases, they classified the specific disease addressed. Dr Hawkins confirmed all classifications.
We adapted a data extraction form used by our team in previous studies.4,5,8,10,11 The form contained 43 items derived from the Critical Appraisal Skills Programme (CASP),12 the Assessment of Multiple Systematic Reviews (AMSTAR),13 and the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA).14 We extracted the following information pertaining to each systematic review: eligibility criteria for including studies in the systematic review (ie, participants, interventions, comparisons, and outcomes of interest); methods used to search for potentially eligible studies; methods used to screen titles, abstracts, and full texts of identified studies for eligibility; whether and how the systematic review investigators assessed risk of bias in the included studies; how data were extracted from the included studies; methods used for quantitative synthesis of the results of the included studies (meta-analysis), when conducted; and whether the conclusions were supported by the results. We also extracted information about any reported financial support for the systematic review and financial relationships for any of the systematic review’s authors. We extracted all information into the Systematic Review Data Repository (SRDR).15,16
Based on the information extracted, we classified each systematic review as either reliable or unreliable. Reliable systematic reviews met each of the following criteria: (1) the systematic review specified eligibility criteria for inclusion of studies in the systematic review, (2) the systematic review conducted a comprehensive literature search for studies, (3) the systematic review assessed risk of bias of the individual included studies, (4) the systematic review used appropriate methods for quantitative syntheses (meta-analysis) (only assessed if meta-analysis was performed), and (5) the systematic review had conclusions that were supported by the results of the systematic review. Table 1 lists the definitions that we used to apply each of these criteria. If at least 1 criterion was not met, we classified the systematic review as unreliable.
Two individuals (from among 2 authors [I.J.S. and K.B.L.] and 4 nonauthor research assistants [Jessica Gayleard, MS, Sueko Ng, MHS, Yuanxi Xia, MSc, and Jiajun Wen, MD]) independently extracted from each systematic review all information, including the criteria used to assess reliability. We adjudicated disagreements between extractors through discussion and, whenever agreement was not reached, through discussion with a third extractor.
Two points about our assessment of reliability are worthy of clarification. First, for each systematic review, we extracted information from the report of the completed systematic review; we did not examine the systematic review protocols for additional information. Second, we determined reliability based on the methods that the systematic review authors reported and not on the quality or quantity of the studies included in the systematic reviews. For example, a reliable systematic review may find no evidence at all or may find only low-quality evidence from nonrandomized studies. As such, the reliability of systematic reviews defined by our 5 criteria should not be confused with an assessment of quality of the body of evidence identified in the reviews.
As of July 14, 2017, we identified 98 systematic reviews related to interventions for the management of 15 corneal diseases in the CEV@US database (Figure 1). These systematic reviews were published between 1997 and 2017 (median, 2014) (Table 2).
We classified 33 of 98 systematic reviews (34%) as unreliable (Figure 2).17,19,21,24-53 Among the unreliable systematic reviews, the reasons for unreliability (each systematic review could have more than 1 reason) were that the systematic review did not conduct a comprehensive literature search for studies (22 of 33 [67%]), the systematic review did not assess risk of bias in the individual included studies (13 of 33 [39%]), the systematic review did not use appropriate methods for quantitative syntheses (meta-analysis) (12 of 17 systematic reviews that conducted a quantitative synthesis [71%]), and the systematic review did not specify eligibility criteria for inclusion of studies in the systematic review (3 of 33 [9%]). Table 1 lists illustrative examples of each reason for unreliability. The percentage of systematic reviews that were unreliable was 25% (5 of 20 systematic reviews) before 2012 and 36% (28 of 78 systematic reviews) in 2012 onward.
Table 2 lists the characteristics of the 98 included systematic reviews. The 65 of 98 systematic reviews (66%) classified as reliable54-118 (Figure 1) were published between 1997 and 2017 (median, 2014). The most frequent diseases addressed in these systematic reviews were conjunctivitis (21 of 65 systematic reviews [32%]) and dry eye syndrome (10 of 65 systematic reviews [15%]); both of these diseases were of interest to the AAO Cornea/External Disease PPP Panel. The other 4 diseases of interest to the panel (bacterial keratitis, blepharitis, corneal ectasia, and corneal edema and opacification) were addressed in 3 of 65 reliable systematic reviews (5%) for bacterial keratitis, 4 of 65 (6%) for blepharitis, 5 of 65 (8%) for corneal ectasia, and 3 of 65 (5%) for corneal edema and opacification.
Most of the 65 reliable systematic reviews evaluated medications (44 [68%]) or surgery (18 [28%]) (Table 2). The most frequent outcome domains assessed in the reliable systematic reviews were adverse events (n = 43), symptom improvement (n = 31), visual acuity (n = 19), quality of life (n = 19), costs (n = 14), symptom resolution (n = 10), and tear production (n = 10). Most of the reliable systematic reviews (64 of 65 [98%]) included experimental studies (ie, randomized clinical trials or non–randomized clinical trials). Nine reliable systematic reviews (14%) also included observational studies. Almost two-thirds (41 of 65 [63%]) of the reliable systematic reviews conducted quantitative syntheses.
Forty percent (26 of 65) of the reliable systematic reviews were Cochrane reviews (Table 2). Thirty-two reliable systematic reviews (49%) had 2 to 4 authors, and 22 (34%) had 5 to 7 authors. Almost one-half of the reliable systematic reviews (48% [31 of 65]) were funded by government sources; 37% (24 of 65) did not report a funding source. Almost two-thirds (63% [41 of 65]) of the reliable systematic reviews explicitly stated that none of the authors had any financial relationships relevant to the systematic review’s content. The eAppendix in the Supplement provides the objectives, diseases addressed, interventions and comparisons, outcomes, number of included studies, number of participants in included studies, and conclusions for all 65 reliable systematic reviews.
The 65 reliable systematic reviews included a median of 9 (interquartile range [IQR], 5-23) studies each; 3 systematic reviews were “empty” (ie, they did not include any studies) (Table 3). The 65 reliable systematic reviews analyzed data from a median of 556 (IQR, 227-1795) study participants each. The 3 empty systematic reviews did not include any study participants, and 13 of 65 systematic reviews (20%) did not report how many participants were included.
There were some notable differences between systematic reviews that were reliable and those that were not (Table 2). For example, while dry eye syndrome was the most frequent disease addressed in the unreliable systematic reviews (12 of 33 [36%]), conjunctivitis was the most frequent disease addressed in the reliable systematic reviews (21 of 65 [32%]). While surgery was the most frequent type of management addressed in the unreliable systematic reviews (15 of 33 [45%]), medication was the most frequent type of management addressed in the reliable systematic reviews (44 of 65 [68%]). Systematic reviews that were unreliable included higher median numbers of studies (15 vs 9) and study participants (827 vs 556) than reliable systematic reviews (Table 3), but somewhat less frequently included quantitative syntheses (52% [17 of 33] vs 63% [41 of 65]) (Table 2).
No unreliable systematic reviews were Cochrane reviews, but 40% (26 of 65) of the reliable systematic reviews were Cochrane reviews (Table 2). Larger proportions of reliable systematic reviews than unreliable systematic reviews were funded by government sources (48% [31 of 65] vs 18% [6 of 33]) or reported explicitly that the authors had no relevant financial relationships (63% [41 of 65] vs 45% [15 of 33]).
Forty-two of the 65 reliable systematic reviews (65%) addressed corneal diseases being covered in the 2018 AAO Cornea/External Disease PPPs update. The AAO sent references for the 42 systematic reviews to the respective PPP panels, and 33 of 42 relevant reliable systematic reviews (79%) are cited in the 2018 PPPs. The reasons for noncitation of the other 9 systematic reviews were that the systematic reviews addressed interventions not being discussed in the PPP (4 systematic reviews68,106,108,115), addressed the setting of primary care (1 systematic review81), found an insufficient number of included studies (1 systematic review103), reported methodologic flaws in included studies (1 systematic review97), reported a lack of relevant outcomes in included studies (1 systematic review107), or reported inconsistent outcomes across included studies (1 systematic review104).
Over the last decade, there has been a 3-fold surge in the number of systematic reviews on health topics.119 Within ophthalmology, when CEV@US started compiling its database of eyes and vision systematic reviews in 2007, there were 547 systematic reviews.10 In 2017, this number increased almost 7-fold, to 3777 (as reported herein). The present investigation reveals a cause for concern. It contributes to the evidence that only a fraction of systematic reviews in ophthalmology are deemed to be reliable (subspecialty-specific estimates range from 28% to 70%4,5,8). The late renowned statistician Professor Douglas Altman famously wrote that “We need less research, better research, and research done for the right reasons.”120(p284) As with other fields, it indeed is time for those involved in the ecosystem of evidence-based health care in ophthalmology to address the problem of an ever-growing number of poorly conceived and unreliable systematic reviews.
One-third (33 of 98) of the published systematic reviews addressing corneal diseases we assessed were classified as unreliable, constituting a waste of research resources and potentially misinformed health care decisions. A particularly concerning aspect is that the percentage of unreliable systematic reviews has not diminished, but rather has increased somewhat (from 25% [5 of 20] to 36% [28 of 78]) since 2012, the year after the landmark Institute of Medicine2 standards for systematic reviews were published. A large proportion of the unreliable systematic reviews (85% [28 of 33]) were published since 2012. The most frequent reasons why systematic reviews addressing the management of corneal diseases were judged to be unreliable were that the systematic review did not conduct a comprehensive literature search for other studies, did not assess risk of bias in the individual included studies, and did not use appropriate methods for quantitative syntheses (meta-analysis). Two-thirds (22 of 33) of the unreliable systematic reviews did not describe a comprehensive literature search. A comprehensive and reproducible literature search is a key tenet of what makes a systematic review systematic. The search should target (1) published studies using both free text and Medical Subject Headings (MeSH) in more than 1 electronic database (eg, MEDLINE and Embase) and (2) unpublished studies and ongoing studies (eg, ClinicalTrials.gov).18 Failure to search multiple databases or to describe the search terms, Boolean operators, restrictions/filters, and search dates compromises the reproducibility of the search. Systematic reviewers should follow the Institute of Medicine standards and engage an experienced information specialist when designing and documenting their searches.
More than one-third (39% [13 of 33]) of the unreliable systematic reviews did not provide a risk of bias assessment. Assessing risk of bias is crucial because it informs the extent to which the results of included studies are valid.18 When systematic reviewers do not provide risk of bias assessments, decision makers are unsure about the dependability of the systematic review’s findings. It should be noted that the field has moved away from assigning quality scores for studies to domain-based assessments of risk of bias. Systematic reviewers should be trained in state-of-the-art methods of assessing risk of bias, such as the revised Cochrane risk-of-bias tool for randomized trials (RoB 2.0).121
Approximately 70% (12 of 17) of the unreliable systematic reviews that conducted a quantitative synthesis did so using inappropriate methods. When a quantitative synthesis is conducted using inappropriate methods, such as in the context of substantial statistical heterogeneity of results, a synthesis of available data could be inaccurate and thus misleading to decision makers.
Another problem in the systematic reviews we examined was that many (almost one-half [15 of 33] of the unreliable systematic reviews and about one-third [24 of 65] of the reliable systematic reviews) did not report funding sources. To promote transparency, sources of support need to be reported in systematic reviews.13,14 Within ophthalmology, there has been increasing recognition of the influence of author conflicts of interest, either in the form of financial relationships or intellectual beliefs.122,123 Conflicts of interest, financial or intellectual, can alter the interpretation of identified studies, potentially leading to bias.124 Another factor that was inadequately reported was the number of participants in the studies included in the systematic reviews; approximately 1 in 5 (20 of 98) systematic reviews did not report this information.
Our finding that a sizable proportion of systematic reviews addressing corneal diseases (33% [33 of 98]) are unreliable is in keeping with other investigations that have found similar problems with systematic reviews of eye diseases. Based on systematic reviews identified through the same database that we used, Mayo-Wilson et al4 and Lindsley et al8 found as many as 70% and 30% of systematic reviews addressing refractive error and age-related macular degeneration, respectively, to be unreliable. Similarly, Downie and colleagues124 assessed the methodologic rigor of 71 systematic reviews addressing age-related macular degeneration and found adequate adherence to a mean of only 5.8 of 11 AMSTAR items. Suboptimal conduct and reporting of systematic reviews might indicate that previous incorrect approaches to meta-analysis are simply being propagated in the field.125
For guideline developers, trusting the information reported in unreliable systematic reviews can be dangerous because it can lead to recommendations and, consequently, health care decisions that are misinformed. However, disentangling reliable from unreliable systematic reviews requires skills and resources. The partnership between the AAO and CEV@US is an ophthalmology success story that has required leadership and commitment from both entities. Such a partnership has been a win-win collaboration: CEV@US has magnified the influence of its work, and the AAO has ensured that its guidelines (ie, PPPs) are informed by reliable systematic review evidence. This model should be emulated in other fields.
Conducting a systematic review is expensive and time-consuming. According to a recent examination of the international Prospective Register of Systematic Reviews (PROSPERO), systematic reviews take a median of 66 (range, 6-186) weeks from registration to publication.126 When systematic reviews are unreliable, it amounts to a monumental waste of crucial research resources.127 Moreover, to help guard against inappropriate decisions regarding clinical management, clinicians, patients, guideline developers, and other decision makers should be made aware that not all systematic reviews are reliable. Articles like the present one may help spread such awareness, thus positively altering the influence of this and similar research. In addition, systematic reviewers should stay abreast of widely available standards for the conduct of systematic reviews.2,18
We agree with the recommendations by Mayo-Wilson and colleagues4 that journal editors should have a greater role by enforcing the following 4 author requirements/policies for systematic review submissions: (1) publication/provision of systematic review protocols, (2) correct completion of a PRISMA checklist, (3) clear justification for the systematic review (to avoid redundancy of systematic reviews), and (4) review of submissions by an expert in systematic reviews. Regarding this last recommended policy, the Cochrane Eyes and Vision Group now has 11 systematic review experts who serve as associate editors and handle systematic review submissions received by 11 major eyes and vision journals in the world (https://eyes.cochrane.org/associate-editors-eyes-and-vision-journals). By promoting best practices in systematic review development and reporting in articles in these journals, we are optimistic that the proportion of reliable systematic reviews in eyes and vision will improve over time.
Our study has some limitations. One limitation is that we searched for systematic reviews using MEDLINE and Embase only. Although our search in these databases has been updated biennially, it is possible that we missed some systematic reviews indexed in only other databases, such as some not published in English. A second limitation is that our assessment of reliability involved judgment and reflected our affiliation with Cochrane Eyes and Vision.
Two-thirds (65 of 98) of the identified systematic reviews of treatments for corneal diseases are reliable. These reliable systematic reviews may be useful to clinicians, patients, guideline developers (eg, AAO PPP panel members), and other decision makers. Careful adherence by systematic reviewers to best practices (eg, the Institute of Medicine2 standards for systematic reviews) and by journal editors to recommendations regarding reporting14 and editorial review4 can help improve the reliability of future systematic reviews in eyes and vision.
Accepted for Publication: February 25, 2019.
Corresponding Author: Ian J. Saldanha, MBBS, MPH, PhD, Center for Evidence Synthesis in Health, Department of Health Services, Policy, and Practice, Brown University School of Public Health, 121 S Main St, PO Box G-S121-8, Providence, RI 02903 (firstname.lastname@example.org).
Published Online: May 9, 2019. doi:10.1001/jamaophthalmol.2019.1063
Author Contributions: Dr Saldanha had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Saldanha, Lindsley, Li.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Saldanha.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Saldanha, Lindsley.
Obtained funding: Dickersin.
Administrative, technical, or material support: All authors.
Supervision: Saldanha, Lindsley, Dickersin, Li.
Conflict of Interest Disclosures: Drs Saldanha, Dickersin, and Li and Ms Lindsley reported being affiliated with Cochrane Eyes and Vision during conduct of the work related to this article. Some of the systematic reviews examined in this article were produced by Cochrane Eyes and Vision. Drs Saldanha, Dickersin, and Li and Ms Lindsley reported receiving grants from the National Eye Institute. Dr Lum reported being employed by the American Academy of Ophthalmology (AAO). This article describes systematic reviews that are underpinning the AAO Cornea/External Disease Preferred Practice Patterns being produced by the American Academy of Ophthalmology.
Funding/Support: This work was funded by grant UG1 EY020522 from the National Institutes of Health (Dr Dickersin through 2018 and Dr Li from 2019 onward).
Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Disclaimer: Dr Dickersin is the Reviews Editor of JAMA Ophthalmology but was not involved in any of the decisions regarding review of the manuscript or its acceptance.
Additional Contributions: We thank Steven P. Dunn, MD, and Francis S. Mah, MD, the cochairs of the American Academy of Ophthalmology (AAO) Cornea/External Disease Preferred Practice Patterns (PPP) Panel of the AAO PPP Committee. We thank Omar Mansour, MHS, Benjamin Rouse, MHS, and Barbara Hawkins, PhD (all received compensation) for their assistance with identifying systematic reviews addressing the management of corneal diseases in the Cochrane Eyes and Vision US Satellite database. We thank Jessica Gayleard, MS, Sueko Ng, MHS, Yuanxi Xia, MSc, and Jiajun Wen, MD (all received compensation) for their assistance with data extraction and assessment of the reliability of the systematic reviews.
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