Research Article: Association Between Risk-of-Bias Assessments and Results of Randomized Trials in Cochrane Reviews: The ROBES Meta-Epidemiologic Study

Date Published: May 19, 2018

Publisher: Oxford University Press

Author(s): Jelena Savović, Rebecca M Turner, David Mawdsley, Hayley E Jones, Rebecca Beynon, Julian P T Higgins, Jonathan A C Sterne.


Flaws in the design of randomized trials may bias intervention effect estimates and increase between-trial heterogeneity. Empirical evidence suggests that these problems are greatest for subjectively assessed outcomes. For the Risk of Bias in Evidence Synthesis (ROBES) Study, we extracted risk-of-bias judgements (for sequence generation, allocation concealment, blinding, and incomplete data) from a large collection of meta-analyses published in the Cochrane Library (issue 4; April 2011). We categorized outcome measures as mortality, other objective outcome, or subjective outcome, and we estimated associations of bias judgements with intervention effect estimates using Bayesian hierarchical models. Among 2,443 randomized trials in 228 meta-analyses, intervention effect estimates were, on average, exaggerated in trials with high or unclear (versus low) risk-of-bias judgements for sequence generation (ratio of odds ratios (ROR) = 0.91, 95% credible interval (CrI): 0.86, 0.98), allocation concealment (ROR = 0.92, 95% CrI: 0.86, 0.98), and blinding (ROR = 0.87, 95% CrI: 0.80, 0.93). In contrast to previous work, we did not observe consistently different bias for subjective outcomes compared with mortality. However, we found an increase in between-trial heterogeneity associated with lack of blinding in meta-analyses with subjective outcomes. Inconsistency in criteria for risk-of-bias judgements applied by individual reviewers is a likely limitation of routinely collected bias assessments. Inadequate randomization and lack of blinding may lead to exaggeration of intervention effect estimates in randomized trials.

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Following our selection process, the final ROBES Study data set consisted of 228 meta-analyses containing 2,443 randomized trials (Figure 1). The full list of included reviews and meta-analysis is provided in Web Appendix 3. The median year of publication of included reviews was 2008 (interquartile range (IQR), 2005–2010; range, 1996–2011), and for trials it was 1999 (IQR, 1992–2005, range, 1950–2011). The median sample size was 1,290 (IQR, 676–3,403; range, 110–341,351) for meta-analyses and 114 (IQR, 60–256; range, 8–182,000) for trials. Based on the categorization of clinical areas in the International Classification of Diseases, Tenth Revision, the most frequently assessed conditions were related to pregnancy and childbirth (28 meta-analyses; 12.3%) and mental health (27 meta-analyses; 11.8%), followed by circulatory system conditions (21 meta-analyses; 9.2%) and respiratory system conditions (20 meta-analyses; 8.8%). Subjectively assessed outcomes were reported most frequently, in 127 (55.7%) meta-analyses, followed by all-cause mortality (42 meta-analyses; 18.4%) (Table 1).

Using a collection of 2,443 randomized trials included in 228 meta-analyses, our estimates of the association between average intervention effect estimates and routinely collected risk-of-bias judgements for sequence generation, allocation concealment, blinding, and incomplete outcome data confirm that problems with randomization and a lack of blinding are, on average, associated with a modest (around 10%) exaggeration of treatment effect estimates. Lack of blinding appears to have the largest influence on treatment effect estimates, and this remains after adjustment for other domains. There was little evidence that these biases varied according to the type of outcome measure assessed. Although there were some differences in the ratios of odds ratios for different outcome types in univariable analyses, the 95% credible intervals overlapped, and the differences were attenuated or disappeared in adjusted analyses. We found little evidence that trials assessed as being at high or unclear risk of bias for incomplete outcome data produced systematically different estimates compared with trials at low risk of bias for this domain, for all types of outcome measures. Variability of treatment effects was higher in trials that lacked blinding and had subjective outcomes, suggesting that for such trials the direction and magnitude of bias is unpredictable. Such variability in bias was observed both between trials within a meta-analysis and across meta-analyses. There was little evidence of such variation in bias for other bias domains or for objectively determined outcomes. Multivariable analyses suggested that effects of individual risk-of-bias domain judgements were less than additive, in that estimated effects of 2 bias domain judgements together were less than the combined individual effects.




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