Investigating heterogeneity in meta-analysis of studies with rare events

In many meta-analyses, the variable of interest is frequently a count outcome reported in an intervention and a control group. Single- or double-zero studies are often observed in this type of data. Given this setting, the well-known Cochran’s Q statistic for testing homogeneity becomes undefined. In this paper, we propose two statistics for testing homogeneity of the risk ratio, particularly for application in the case of rare events in meta-analysis. The first one is a chi-square type statistic. It is constructed based on information of the conditional probability of the number of events in the treatment group given the total number of events. The second one is a likelihood ratio statistic, derived from the logistic regression models allowing fixed and random effects for the risk ratio. Both proposed statistics are well defined even in the situation of single-zero studies. In a simulation study, the proposed tests show a performance better than the traditional test in terms of type I error and power of the test under common and rare event situations. However, as the performance of the two newly proposed tests is still unsatisfactory in the very rare events setting, we suggest a bootstrap approach that does not rely on asymptotic distributional theory and it is shown that the bootstrap approach performs well in terms of type I error. Furthermore, a number of empirical meta-analyses are used to illustrate the methods.