Randomization Inference for Cluster-Randomized Test-Negative Designs with Application to Dengue Studies: Unbiased estimation, Partial compliance, and Stepped-wedge design

Abstract: In 2019, the World Health Organization identified dengue as one of the top ten global health threats. For the control of dengue, the Applying Wolbachia to Eliminate Dengue (AWED) study group conducted a cluster-randomized trial in Yogyakarta, Indonesia, and used a novel design, called the cluster-randomized test-negative design (CR-TND). This design can yield valid statistical inference with data collected by a passive surveillance system and thus has the advantage of cost-efficiency compared to traditional cluster-randomized trials. We investigate the statistical assumptions and properties of CR-TND under a randomization inference framework, which is known to be robust and efficient for small-sample problems. We find that, when the differential healthcare-seeking behavior comparing intervention and control varies across clusters (in contrast to the setting of Dufault and Jewell, 2020 where the differential healthcare-seeking behavior is constant across clusters), current analysis methods for CR-TND can be biased and have inflated type I error. We propose the log-contrast estimator that can eliminate such bias and improve precision by adjusting for covariates. Furthermore, we extend our methods to handle partial intervention compliance and a stepped-wedge design, both of which appear frequently in cluster-randomized trials. Finally, we demonstrate our results by simulation studies and re-analysis of the AWED study.