Wednesday, July 1, 2020

A Not-So-Non-Event?: New Systematic Review Finds Exclusion of Studies with No Events from a Meta-Analysis Can Affect Direction and Statistical Significance of Findings

Studies with no events in either arm have been considered non-informative within a meta-analytical context, and thus have been left out of these analyses. A new systematic review of 442 such meta-analyses, however, reports that this practice may actually affect the resulting conclusions.

In the July 2020 issue of the Journal of Clinical Epidemiology, Xu and colleagues report their study of meta-analyses of binary outcomes in which at least one included study had no events in either arm. The authors then reanalyzed the data from 442 included papers taken from the Cochrane Database of Systematic Reviews, using modeling to determine the effect of reincorporating the excluded study.

The authors found that in 8 (1.8%) of the 442 meta-analyses, inclusion of the previously excluded studies changed the direction of the pooled odds ratio (“direction flipping”). In 12 (2.72%) of the meta-analyses, the pooled odds ratio (OR) changed by more than the predetermined threshold of 0.2. Additionally, in 41 (9.28%) of these studies, the statistical significance of that findings changed when assuming a p = 0.05 threshold (“significance flipping”). In most of these 41 meta-analyses, excluded (“non-event”) studies made up between 5 and 30% of the total sample size. About half of these alterations led to an expansion of the confidence interval; while in the other half, the incorporation of non-events reduced the confidence interval.

The figure above from Xu et al. shows the proportion of studies reporting no events within the meta-analyses that showed a substantial change in p value when these studies were included. The proportion of the total sample tended to cluster between 5 and 30%. Click to enlarge.

Post hoc simulation studies confirmed the robustness of these findings, and also found that exclusion of studies with no events preferentially affected the pooled ORs of studies that found no effect (OR = 1), whereas a large magnitude of effect was protective against these changes. The opposite was found for the effect of excluding studies with no events on the resulting p values (i.e., large magnitudes of effects were more likely to be affected whereas conclusions of no effect were protected).

In sum, though a common practice in meta-analysis, the exclusion of studies with no events in either arm may affect the direction, magnitude, or statistical significance of the resulting conclusions in a small but non-negligible number of analyses.

Xu, C., Li, L, Lin, L., Chu, H., Thabane, L., Zou, K., & Sun, X. Exclusion of studies with no events in both arms in meta-analysis impacted the conclusions. J Clin Epidemiol, 2020; 123: 91.99.

Manuscript available from the publisher's website here.