Identification of significant host factors for HIV dynamics modelled by non‐linear mixed‐effects models

Non-linear mixed-effects models are powerful tools for modelling HIV viral dynamics. In AIDS clinical trials, the viral load measurements for each subject are often sparse. In such cases, linearization procedures are usually used for inferences. Under such linearization procedures, however, standard covariate selection methods based on the approximate likelihood, such as the likelihood ratio test, may not be reliable. In order to identify significant host factors for HIV dynamics, in this paper we consider two alternative approaches for covariate selection: one is based on individual non-linear least square estimates and the other is based on individual empirical Bayes estimates. Our simulation study shows that, if the within-individual data are sparse and the between-individual variation is large, the two alternative covariate selection methods are more reliable than the likelihood ratio test, and the more powerful method based on individual empirical Bayes estimates is especially preferable. We also consider the missing data in covariates. The commonly used missing data methods may lead to misleading results. We recommend a multiple imputation method to handle missing covariates. A real data set from an AIDS clinical trial is analysed based on various covariate selection methods and missing data methods.