Maximin design of cluster randomized trials with heterogeneous costs and variances.

Abstract

Cluster randomized trials evaluate the effect of a treatment on persons nested within clusters, with clusters being randomly assigned to treatment. The optimal sample size at the cluster and person level depends on the study cost per cluster and per person, and the outcome variance at the cluster and the person level. The variances are unknown in the design stage and can differ between treatment arms. As a solution, this paper presents a Maximin design that maximizes the minimum relative efficiency (relative to the optimal design) over the variance parameter space, for trials with two treatment arms and a quantitative outcome. This maximin relative efficiency design (MMRED) is compared with a published Maximin design which maximizes the minimum efficiency (MMED). Both designs are also compared with the optimal designs for homogeneous costs and variances (balanced design) and heterogeneous costs and homogeneous variances (cost‐conscious design), for a range of variances based upon three published trials. Whereas the MMED is balanced under high uncertainty about the treatment‐to‐control variance ratio, the MMRED then tends towards a balanced budget allocation between arms, leading to an unbalanced sample size allocation if costs are heterogeneous, similar to the cost‐conscious design. Further, the MMRED corresponds to an optimal design for an intraclass correlation (ICC) in the lower half of the assumed ICC range (optimistic), whereas the MMED is the optimal design for the maximum ICC within the ICC range (pessimistic). Attention is given to the effect of the Welch–Satterthwaite degrees of freedom for treatment effect testing on the design efficiencies.