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Biometrics. 2016 Dec;72(4):1066-1077. doi: 10.1111/biom.12519. Epub 2016 Apr 8.

Accounting for interactions and complex inter-subject dependency in estimating treatment effect in cluster-randomized trials with missing outcomes.

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Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, U.S.A.
Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, Massachusetts, U.S.A.
Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, U.S.A.


Semi-parametric methods are often used for the estimation of intervention effects on correlated outcomes in cluster-randomized trials (CRTs). When outcomes are missing at random (MAR), Inverse Probability Weighted (IPW) methods incorporating baseline covariates can be used to deal with informative missingness. Also, augmented generalized estimating equations (AUG) correct for imbalance in baseline covariates but need to be extended for MAR outcomes. However, in the presence of interactions between treatment and baseline covariates, neither method alone produces consistent estimates for the marginal treatment effect if the model for interaction is not correctly specified. We propose an AUG-IPW estimator that weights by the inverse of the probability of being a complete case and allows different outcome models in each intervention arm. This estimator is doubly robust (DR); it gives correct estimates whether the missing data process or the outcome model is correctly specified. We consider the problem of covariate interference which arises when the outcome of an individual may depend on covariates of other individuals. When interfering covariates are not modeled, the DR property prevents bias as long as covariate interference is not present simultaneously for the outcome and the missingness. An R package is developed implementing the proposed method. An extensive simulation study and an application to a CRT of HIV risk reduction-intervention in South Africa illustrate the method.


Augmentation; Cluster-randomized trials; Generalized estimating equation (GEE); Interactions; Interference; Inverse probability weighting (IPW); Missing at random (MAR); Outcome Model; Propensity Score; R package; Semi-parametric methods

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