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Background Due to clinical and methodological diversity, clinical studies included in meta-analyses often differ in ways that lead to differences in treatment effects across studies. Meta-regression analysis is generally recommended to explore associations between study-level characteristics and treatment effect, however, three key pitfalls of meta-regression may lead to invalid conclusions. Our aims were to determine the frequency of these three pitfalls of meta-regression analyses, examine characteristics associated with the occurrence of these pitfalls, and explore changes between 2002 and 2012. Methods A meta-epidemiological study of studies including aggregate data meta-regression analysis in the years 2002 and 2012. We assessed the prevalence of meta-regression analyses with at least 1 of 3 pitfalls: ecological fallacy, overfitting, and inappropriate methods to regress treatment effects against the risk of the analysed outcome. We used logistic regression to investigate study characteristics associated with pitfalls and examined differences between 2002 and 2012. Results Our search yielded 580 studies with meta-analyses, of which 81 included meta-regression analyses with aggregated data. 57 meta-regression analyses were found to contain at least one pitfall (70%): 53 were susceptible to ecological fallacy (65%), 14 had a risk of overfitting (17%), and 5 inappropriately regressed treatment effects against the risk of the analysed outcome (6%). We found no difference in the prevalence of meta-regression analyses with methodological pitfalls between 2002 and 2012, nor any study-level characteristic that was clearly associated with the occurrence of any of the pitfalls. Conclusion The majority of meta-regression analyses based on aggregate data contain methodological pitfalls that may result in misleading findings.

Background The evaluation of imprecision is a key dimension of the grading of the confidence in the estimate. Grading of Recommendations Assessment, Development and Evaluation (GRADE) gives recommendations on how to downgrade evidence for imprecision, but authors vary in their use. Trial Sequential Analysis (TSA) has been advocated for a more reliable assessment of imprecision. We aimed to evaluate reporting of and adherence to GRADE and to compare the assessment of imprecision of intervention effects assessed by GRADE and TSA in Cochrane systematic reviews. Methods In this cross-sectional study, we included 100 Cochrane reviews irrespective of type of intervention with a key dichotomous outcome meta-analyzed and assessed by GRADE. The methods and results sections of each review were assessed for adequacy of imprecision evaluation. We re-analyzed imprecision following the GRADE Handbook and the TSA Manual. Results Overall, only 13.0% of reviews stated the criteria they applied to assess imprecision. The most common dimensions were the 95% width of the confidence intervals and the optimal information size. Review authors downgraded 48.0% of key outcomes due to imprecision. When imprecision was re-analyzed following the GRADE Handbook, 64% of outcomes were downgraded. Agreement between review authors’ assessment and assessment by the authors of this study was moderate (kappa 0.43, 95% confidence interval [CI] 0.23 to 0.58). TSA downgraded 69.0% outcomes due to imprecision. Agreement between review authors’ GRADE assessment and TSA, irrespective of downgrading levels, was moderate (kappa 0.43, 95% CI 0.21 to 0.57). Agreement between our GRADE assessment following the Handbook and TSA was substantial (kappa 0.66, 95% CI 0.49 to 0.79). Conclusions In a sample of Cochrane reviews, methods for assessing imprecision were rarely reported. GRADE according to Handbook guidelines and TSA led to more severe judgment of imprecision rather than GRADE adopted by reviews’ authors. Cochrane initiatives to improve adherence to GRADE Handbook are warranted. TSA may transparently assist in such development. Electronic supplementary material The online version of this article (10.1186/s13643-018-0770-1) contains supplementary material, which is available to authorized users.