Dealing with Zero-Events Studies in Meta-analysis: There's a Better Way than Throwing it Away!

When meta-analyzing data from studies examining the incidence of rare events - or those with a small sample size or short follow-up period, it is not uncommon to come across a study with 0 events of the outcome of interest. In fact, approximately one-third of a random sample of 500 Cochrane reviews contained at least one zero-events study.

Zero-events studies are typically categorized as single-arm (there are 0 events reported in just one group) or double-arm (there are 0 events reported in both groups). While some software automatically discard double-arm zero-events studies from a meta-analysis, this is not ideal because these data still add useful information in regards to the overall effect of an intervention. Ideally, meta-analyses could include a pooled event count that may be zero in one arm, both arms, or neither, with various single-arm and double-arm zero-events studies potentially contributing to this final effect. Thus, in a recently published article, Xu and colleagues propose a more detailed framework for approaching zero-events studies in the context of a meta-analysis. 

The authors describe six classifications as follows, with the degree of difficulty when meta-analyzing generally increasing from 1 to 6:

1) MA-SZ: meta-analysis contains zero-events only occurring in single arms, no double-arm-zero-events studies are included, and the total events count in neither arm is zero;

2) MA-MZ: meta-analysis contains zero-events occurring in both single and double arms, and the total events count in neither arm is zero;

3) MA-DZ: meta-analysis contains zero-events only occurring in double arms, and the total events count in neither arm is zero;

4) MA-CSZ: meta-analysis contains zero-events occurring in single arms, and no double-arm-zero-events studies are included, while the total events count in one of the arms is zero;

5) MA-CMZ: meta-analysis contains zero-events occurring in both single arm and double arms, while the total events count in one of the arms is zero;

6) MA-CDZ: meta-analysis only includes double-arm-zero-events studies, while the total events count in both arms are zero

The authors examined data from the Cochrane Database of Systematic Reviews (CDSR), including any review published between January 2003 - May 2018 and meta-analyzing at least two studies. Of the 61,090 reviews identified with binary outcomes, 21,288 (34.85%) contained at least one zero-events study. In a great majority (90.7%) of these, the total event count was greater than zero for both arms and the meta-analysis only included single-arm rather than double-arm zero-events studies. Second most common (6.21%) was the MA-CSZ, in which the total event count includes one arm with zero events, and the zero-events studies included are only single-arm. All others of the four remaining categories each made up less than 1.5% of the whole.

The authors propose that those looking to meta-analyze studies that include zero events first categorize their specific subtype, and then work through one of the suggested methods in the figure below. Finally, a sensitivity analysis should be used following an alternative method to determine the robustness of the results.

Xu C, Furuya-Kanamori L, Zorzela L, Lin L, and Vohra S. (2021). A proposed framework to guide evidence synthesis practice for meta-analysis with zero-events studies. J Clin Epidemiol, in-press.

Manuscript available from the publisher's website here.