A joint marginalized multilevel model for longitudinal outcomes

Abstract

The shared-parameter model and its so-called hierarchical or random-effects extension are widely used joint modeling approaches for a combination of longitudinal continuous, binary, count, missing, and survival outcomes that naturally occurs in many clinical and other studies. A random effect is introduced and shared or allowed to differ between two or more repeated measures or longitudinal outcomes, thereby acting as a vehicle to capture association between the outcomes in these joint models. It is generally known that parameter estimates in a linear mixed model (LMM) for continuous repeated measures or longitudinal outcomes allow for a marginal interpretation, even though a hierarchical formulation is employed. This is not the case for the generalized linear mixed model (GLMM), that is, for non-Gaussian outcomes. The aforementioned joint models formulated for continuous and binary or two longitudinal binomial outcomes, using the LMM and GLMM, will naturally have marginal interpretation for parameters associated with the continuous outcome but a subject-specific interpretation for the fixed effects parameters relating covariates to binary outcomes. To derive marginally meaningful parameters for the binary models in a joint model, we adopt the marginal multilevel model (MMM) due to Heagerty [13] and Heagerty and Zeger [14] and formulate a joint MMM for two longitudinal responses. This enables to (1) capture association between the two responses and (2) obtain parameter estimates that have a population-averaged interpretation for both outcomes. The model is applied to two sets of data. The results are compared with those obtained from the existing approaches such as generalized estimating equations, GLMM, and the model of Heagerty [13]. Estimates were found to be very close to those from single analysis per outcome but the joint model yields higher precision and allows for quantifying the association between outcomes. Parameters were estimated using maximum likelihood. The model is easy to fit using available tools such as the SAS NLMIXED procedure.