Intent-to-treat analysis of cluster randomized trials when clusters report unidentifiable outcome proportions

Abstract

Background

Cluster randomized trials are designed to evaluate interventions at the cluster or group level. When clusters are randomized but some clusters report no or non-analyzable data, intent-to-treat analysis, the gold standard for the analysis of randomized controlled trials, can be compromised. This article presents a very flexible statistical methodology for cluster randomized trials whose outcome is a cluster-level proportion (e.g. proportion from a cluster reporting an event) in the setting where clusters report non-analyzable data (which in general could be due to nonadherence, dropout, missingness, etc.). The approach is motivated by a previously published stratified randomized controlled trial called, “The Randomized Recruitment Intervention Trial (RECRUIT),” designed to examine the effectiveness of a trust-based continuous quality improvement intervention on increasing minority recruitment into clinical trials (ClinicalTrials.gov Identifier: NCT01911208).

Methods

The novel approach exploits the use of generalized estimating equations for cluster-level reports, such that all clusters randomized at baseline are able to be analyzed, and intervention effects are presented as risk ratios. Simulation studies under different outcome missingness scenarios and a variety of intra-cluster correlations are conducted. A comparative analysis of the method with imputation and per protocol approaches for RECRUIT is presented.

Results

Simulation results show the novel approach produces unbiased and efficient estimates of the intervention effect that maintain the nominal type I error rate. Application to RECRUIT shows similar effect sizes when compared to the imputation and per protocol approach.

Conclusion

The article demonstrates that an innovative bivariate generalized estimating equations framework allows one to implement an intent-to-treat analysis to obtain risk ratios or odds ratios, for a variety of cluster randomized designs.

Keywords

Cluster randomized trials randomized controlled trials missing data clinical trials intent to treat

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