Risk of Bias Assessments in Ophthalmology Systematic Reviews and Meta-Analyses

Introduction

In order for systematic reviews to make accurate inferences concerning clinical therapy, the primary studies that constitute the review must provide valid results. The Cochrane Handbook for Systematic Reviews states that assessment of validity is an “essential component” of a review that “should influence the analysis, interpretation, and conclusions of the review”(p. 188) (Higgins 2008). The internal validity of a review’s primary studies must be considered to ensure that bias has not compromised the results, leading to inaccurate estimates of summary effect sizes.

In ophthalmology, there is a need for closer examination of the validity of primary studies comprising a review. As an illustrative example, Chakrabarti et al. (2012) discussed emerging ophthalmic treatments for proliferative (PDR) and nonproliferative diabetic retinopathy (NDR) noting that anti-vascular endothelial growth factor (VEGF) agents consistently received recognition as a possible alternative treatment for diabetic retinopathy. Treatment guidelines from the Scottish Intercollegiate Guidelines Network and the American Academy of Ophthalmology consider anti-VEGF treatment as merely useful as an adjunct to laser for treatment of PDR; however, the Malaysian guidelines indicate that these same agents were to be considered in combination with intraocular steroids and vitrectomy. Most extensively, the National Health and Medical Research Council guidelines recommend the addition of anti-VEGF to laser therapy prior to vitrectomy (Chakrabarti 2012). The evidence base informing these guidelines is comprised of trials of questionable quality. Martinez-Zapata et al. (2014) conducted a systematic review of this anti-VEGF treatment for diabetic retinopathy, which included 18 randomized controlled trials (RCTs). Of these trials, seven were at high risk of bias while the rest were unclear in one or more domains. The authors concluded, “there is very low or low quality evidence from RCTs for the efficacy and safety of anti-VEGF agents when used to treat PDR over and above current standard treatments" (Martinez-Zapata 2014). Thus, low quality evidence provides less confidence regarding the efficacy of treatment, makes suspect guidelines advocating use, and impairs the clinicians ablility to make sound judgements regarding treatment.

Over the years, researchers have conceived many methods in attempt to evaluate the validity or methodological quality of primary studies. Initially, checklists and scales were developed to evaluate whether particular aspects of experimental design, such as randomization, blinding, or allocation concealment were incorporated into the study. These approaches have been criticized for falsely elevating quality scores. Many of these scales and checklists include items that have no bearing on the validity of study findings, such as whether investigators used informed consent or whether ethical approval was obtained (Moher 1995). Furthermore, with the proliferation of quality appraisal scales, it was found that the choice of scale could alter the results of systematic reviews due to weighting differences of scale components (Jüni 1999). Two such scales, the Jadad scale - also called the Oxford Scoring System (Jadad 1996) and the Downs and Black checklist (Downs 1998) were among the popular alternatives. Quality of Reporting of Meta-analyses (QUORUM) (Moher 1999), the dominant reporting guidelines at that time, called for the evaluation of methodological quality of the primary studies in systematic reviews. This recommendation was short lived as the Cochrane Collaboration began to advocate for a new approach to assess the validity of primary studies. This new method assessed the risk of bias of 6 particular design features of primary studies, with each domain receiving a rating of either low, unclear, or high risk of bias (Higgins 2008). Following suit, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) - updated reporting guidelines, now calls for the evaluation of bias in all systematic reviews (Moher 2009).

A previous review examining primary studies from multiple fields of medicine revealed that the failure to incorporate an assessment of methodological quality can result in the implementation of interventions founded on misleading evidence (Kjaergard 2001). Yet, questions remain regarding the assessment of quality and risk of bias in clinical specialties. Therefore, we examined ophthalmology systematic reviews to determine the degree to which methodological quality and risk of bias assessments were conducted. We also evaluated the particular method used in the evaluation, the quality components comprising these assessments, and how systematic reviewers integrated primary studies with low quality or high risk of bias into their results.