Synthesis of evidence from zero-events studies: A comparison of one-stage framework methods

In evidence synthesis, dealing with zero-events studies is an important and complicated task that has generated broad discussion. Numerous methods provide valid solutions to synthesizing data from studies with zero-events, either based on a frequentist or a Bayesian framework. Among frequentist frameworks, the one-stage methods have their unique advantages to deal with zero-events studies, especially for double-arm-zero-events. In this article, we give a concise overview of the one-stage frequentist methods. We conducted simulation studies to compare the statistical properties of these methods to the two-stage frequentist method (continuity correction) for meta-analysis with zero-events studies when double-zero-events studies were included. Our simulation studies demonstrated that the generalized estimating equation with unstructured correlation and beta-binomial method had the best performance among the one-stage methods. The random intercepts generalized linear mixed model showed good performance in the absence of obvious between-study variance. Our results also showed that the continuity correction with inverse-variance heterogeneous (IVhet) analytic model based on the two-stage framework had good performance when the between-study variance was obvious and the group size was balanced for included studies. In summary, the one-stage framework has unique advantages to deal with studies with zero events and is not susceptive to group size ratio. It should be considered in future meta-analyses whenever possible.