R Estimates and Associated Inferences for Mixed Models with Covariates in a Multi-Center Clinical Trial

Robust rank-based methods are proposed for the analysis of data from multi-center clinical trials using a mixed model (including covariates) in which the treatment effects are assumed to be fixed and the center effects are assumed to be random. These rankbased methods are developed under the usual mixed model structure but without the normality assumption of the random components in the model. For this mixed model, our proposed estimation includes R-estimation of the fixed effects, robust estimation of the variance components, and studentized residuals. Our accompanying inference includes estimates of the standard errors of the fixed effects estimators and tests of general linear hypotheses concerning fixed effects. While the development is for general scores function, the Wilcoxon linear scores are emphasized. A discussion of the relative efficiency results shows that the R-estimates are highly efficient compared to the