Cluster-Randomized Test-Negative Design Trials: A Novel and Efficient Method to Assess the Efficacy of Community-Level Dengue Interventions

Abstract

Abstract Cluster-randomized controlled trials are the gold standard for assessing efficacy of community-level interventions, such as vector-control strategies against dengue. We describe a novel cluster-randomized trial methodology with a test-negative design (CR-TND), which offers advantages over traditional approaches. This method uses outcome-based sampling of patients presenting with a syndrome consistent with the disease of interest, who are subsequently classified as test-positive cases or test-negative controls on the basis of diagnostic testing. We used simulations of a cluster trial to demonstrate validity of efficacy estimates under the test-negative approach. We demonstrated that, provided study arms are balanced for both test-negative and test-positive illness at baseline and that other test-negative design assumptions are met, the efficacy estimates closely match true efficacy. Analytical considerations for an odds ratio–based effect estimate arising from clustered data and potential approaches to analysis are also discussed briefly. We concluded that application of the test-negative design to certain cluster-randomized trials could increase their efficiency and ease of implementation.