Subgroup Analyses in Stepped-Wedge Cluster Randomized Trials: A Systematic Review of Statistical Practice and...

Subgroup analyses can inform whether intervention effects differ systematically across participants, but they are prone to false-positive findings, low power, and selective reporting. Stepped-wedge cluster randomized trials (SW-CRTs) introduce additional inferential complexities (e.g., time effects, clustering, complex interactions) yet subgroup-analysis practice in SW-CRTs has not been systematically evaluated. Our objectives were to describe: (1) the prevalence and extent of subgroup analyses; (2) characteristics of the subgroup variables of interest; (3) adherence to key recommendations such as pre-specification and justification; (4) statistical approaches used; and (5) details of reporting results.

We reviewed primary reports of completed health-related SW-CRTs from a 2016-2023 database to capture statistical and reporting practice. Trials were eligible if they had at least two sequences, three periods, and randomized at least 5 clusters. Two independent reviewers extracted information from each trial and reached consensus through discussion. Results were summarized using median (interquartile ranges) and frequencies (%).

Of 211 eligible reports, 99 (47%) presented results of at least one subgroup analysis; the median number of subgroup analyses (unique outcome by covariate combinations) per trial was 4 (Q1-Q3:2-8; range:1-81). Only 23 (23%) clearly prespecified all presented subgroup analyses. A rationale for all subgroup analyses was provided in 28 (28%), while 53 (54%) provided none. Stratified analyses were common (n=79, 80%); the use of interaction testing was reported in 49 (50%), but only 35 (35%) reported an interaction test result with the treatment indicator. Power calculations for subgroup analyses were rare (n=4, 4%), and multiplicity corrections were uncommon (n=2, 2%). At least one statistically significant stratum-specific treatment effect was observed in 69 (70%) trials.

Subgroup analyses are common in SW-CRTs but are frequently under-specified and inconsistently analyzed and reported, with limited interaction testing, minimal power justification, and rare adjustment for multiple testing. These patterns are broadly consistent with concerns identified in prior subgroup-analysis reviews of randomized trials, suggesting that longstanding vulnerabilities persist in SW-CRTs and may be compounded by design complexity. More explicit, design-aware guidance for planning, analysis, and reporting of subgroup investigations in SW-CRTs may improve the credibility and interpretability of subgroup findings.