Applications of simple and accessible methods for meta-analysis involving rare events: A simulation study.

Meta-analysis of clinical trials targeting rare events face particular challenges when the data lack adequate number of events and are susceptible to high levels of heterogeneity. The standard meta-analysis methods (DerSimonian Laird (DL) and Mantel-Haenszel (MH)) often lead to serious distortions because of such data sparsity. Applications of the methods suited to specific incidence and heterogeneity characteristics are lacking, thus we compared nine available methods in a simulation study. We generated 360 meta-analysis scenarios where each considered different incidences, sample sizes, between-study variance (heterogeneity) and treatment allocation. We include globally recommended methods such as inverse-variance fixed/random-effect (IV-FE/RE), classical-MH, MH-FE, MH-DL, Peto, Peto-DL and the two extensions for MH bootstrapped-DL (bDL) and Peto-bDL. Performance was assessed on mean bias, mean error, coverage and power. In the absence of heterogeneity, the coverage and power when combined revealed small differences in meta-analysis involving rare and very rare events. The Peto-bDL method performed best, but only in smaller sample sizes involving rare events. For medium-to-larger sample sizes, MH-bDL was preferred. For meta-analysis involving very rare events, Peto-bDL was the best performing method which was sustained across all sample sizes. However, in meta-analysis with 20% or more heterogeneity, the coverage and power were insufficient. Performance based on mean bias and mean error was almost identical across methods. To conclude, in meta-analysis of rare binary outcomes, our results suggest that Peto-bDL is better in both rare and very rare event settings in meta-analysis with limited sample sizes. However, when heterogeneity is large, the coverage and power to detect rare events are insufficient. Whilst this study shows that some of the less studied methods appear to have good properties under sparse data scenarios, further work is needed to assess them against the more complex distributional-based methods to understand their overall performances.