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Statistical Methods for Quantifying Between-study Heterogeneity in Meta-analysis with Focus on Rare Binary Events.

ABSTRACT: Meta-analysis, the statistical procedure for combining results from multiple independent studies, has been widely used in medical research to evaluate intervention efficacy and drug safety. In many practical situations, treatment effects vary notably among the collected studies, and the variation, often modeled by the between-study variance parameter ? ², can greatly affect the inference of the overall effect size. In the past, comparative studies have been conducted for both point and interval estimation of ? ². However, most are incomplete, only including a limited subset of existing methods, and some are outdated. Further, none of the studies covers descriptive measures for assessing the level of heterogeneity, nor are they focused on rare binary events that require special attention. We summarize by far the most comprehensive set including 11 descriptive measures, 23 estimators, and 16 confidence intervals. In addition to providing synthesized information, we further categorize these methods according to their key features. We then evaluate their performance based on simulation studies that examine various realistic scenarios for rare binary events, with an illustration using a data example of a gestational diabetes meta-analysis. We conclude that there is no uniformly "best" method. However, methods with consistently better performance do exist in the context of rare binary events, and we provide practical guidelines based on numerical evidences.

SUBMITTER: Zhang C

PROVIDER: S-EPMC7901832 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Statistical Methods for Quantifying Between-study Heterogeneity in Meta-analysis with Focus on Rare Binary Events.

Zhang Chiyu C Chen Min M Wang Xinlei X

Statistics and its interface 20200101 4

Meta-analysis, the statistical procedure for combining results from multiple independent studies, has been widely used in medical research to evaluate intervention efficacy and drug safety. In many practical situations, treatment effects vary notably among the collected studies, and the variation, often modeled by the between-study variance parameter <i>τ</i> <sup>2</sup>, can greatly affect the inference of the overall effect size. In the past, comparative studies have been conducted for both p ...[more]

PMID: 33628357

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Project description:Background/aimsRegulatory approval of a drug or device involves an assessment of not only the benefits but also the risks of adverse events associated with the therapeutic agent. Although randomized controlled trials (RCTs) are the gold standard for evaluating effectiveness, the number of treated patients in a single RCT may not be enough to detect a rare but serious side effect of the treatment. Meta-analysis plays an important role in the evaluation of the safety of medical products and has advantage over analyzing a single RCT when estimating the rate of adverse events.MethodsIn this article, we compare 15 widely used meta-analysis models under both Bayesian and frequentist frameworks when outcomes are extremely infrequent or rare. We present extensive simulation study results and then apply these methods to a real meta-analysis that considers RCTs investigating the effect of rosiglitazone on the risks of myocardial infarction and of death from cardiovascular causes.ResultsOur simulation studies suggest that the beta hyperprior method modeling treatment group-specific parameters and accounting for heterogeneity performs the best. Most models ignoring between-study heterogeneity give poor coverage probability when such heterogeneity exists. In the data analysis, different methods provide a wide range of log odds ratio estimates between rosiglitazone and control treatments with a mixed conclusion on their statistical significance based on 95% confidence (or credible) intervals.ConclusionIn the rare event setting, treatment effect estimates obtained from traditional meta-analytic methods may be biased and provide poor coverage probability. This trend worsens when the data have large between-study heterogeneity. In general, we recommend methods that first estimate the summaries of treatment-specific risks across studies and then relative treatment effects based on the summaries when appropriate. Furthermore, we recommend fitting various methods, comparing the results and model performance, and investigating any significant discrepancies among them.

Project description: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.

Dataset Information

Statistical Methods for Quantifying Between-study Heterogeneity in Meta-analysis with Focus on Rare Binary Events.

Publications

Statistical Methods for Quantifying Between-study Heterogeneity in Meta-analysis with Focus on Rare Binary Events.

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