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Stat Med. 2016 May 10;35(10):1565-79. doi: 10.1002/sim.6813. Epub 2015 Nov 23.

An evaluation of constrained randomization for the design and analysis of group-randomized trials.

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Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, 27710, NC, U.S.A.
Duke Clinical Research Institute, Durham, NC 27705, U.S.A.
National Institutes of Health, Office of Disease Prevention, Rockville, MD 20892, U.S.A.
Department of Biostatistics, University of Washington, Seattle, WA 98195, U.S.A.


In group-randomized trials, a frequent practical limitation to adopting rigorous research designs is that only a small number of groups may be available, and therefore, simple randomization cannot be relied upon to balance key group-level prognostic factors across the comparison arms. Constrained randomization is an allocation technique proposed for ensuring balance and can be used together with a permutation test for randomization-based inference. However, several statistical issues have not been thoroughly studied when constrained randomization is considered. Therefore, we used simulations to evaluate key issues including the following: the impact of the choice of the candidate set size and the balance metric used to guide randomization; the choice of adjusted versus unadjusted analysis; and the use of model-based versus randomization-based tests. We conducted a simulation study to compare the type I error and power of the F-test and the permutation test in the presence of group-level potential confounders. Our results indicate that the adjusted F-test and the permutation test perform similarly and slightly better for constrained randomization relative to simple randomization in terms of power, and the candidate set size does not substantially affect their power. Under constrained randomization, however, the unadjusted F-test is conservative, while the unadjusted permutation test carries the desired type I error rate as long as the candidate set size is not too small; the unadjusted permutation test is consistently more powerful than the unadjusted F-test and gains power as candidate set size changes. Finally, we caution against the inappropriate specification of permutation distribution under constrained randomization. An ongoing group-randomized trial is used as an illustrative example for the constrained randomization design.


balance metric; candidate set size; constrained randomization; group-randomized trial; model-based F-test; permutation test

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