Covariate-constrained randomization with cluster selection and substitution.

BACKGROUND: An ongoing cluster-randomized trial for the prevention of arboviral diseases utilizes covariate-constrained randomization to balance two treatment arms across four specified covariates and geographic sector. Each cluster is within a census tract of the city of Mérida, Mexico, and there were 133 eligible tracts from which to select 50. As some selected clusters may have been subsequently found unsuitable in the field, we desired a strategy to substitute new clusters while maintaining covariate balance. METHODS: We developed an algorithm that successfully identified a subset of clusters that maximized the average minimum pairwise distance between clusters in order to reduce contamination and balanced the specified covariates both before and after substitutions were made. SIMULATIONS: Simulations were performed to explore some limitations of this algorithm. The number of selected clusters and eligible clusters were varied along with the method of selecting the final allocation pattern. CONCLUSION: The algorithm is presented here as a series of optional steps that can be added to the standard covariate-constrained randomization process in order to achieve spatial dispersion, cluster subsampling, and cluster substitution. Simulation results indicate that these extensions can be used without loss of statistical validity, given a sufficient number of clusters included in the trial.