Specification of covariance structure in longitudinal data analysis for randomized clinical trials.

Misspecification of the covariance structure for repeated measurements in longitudinal analysis may lead to biased estimates of the regression parameters and under or overestimation of the corresponding standard errors in the presence of missing data. The so-called sandwich estimator can 'correct' the variance, but it does not reduce the bias in point estimates. Removing all assumptions from the covariance structure (i.e. using an unstructured (UN) covariance) will remove such biases. However, an excessive amount of missing data may cause convergence problems for iterative algorithms, such as the default Newton-Raphson algorithm in the popular SAS PROC MIXED. This article examines, both through theory and simulations, the existence and the magnitude of these biases. We recommend the use of UN covariance as the default strategy for analyzing longitudinal data from randomized clinical trials with moderate to large number of subjects and small to moderate number of time points. We also present an algorithm to assist in the convergence when the UN covariance is used.