A high-dimensional joint model for longitudinal endpoints of different nature

In repeated dose-toxicity studies, many outcomes are repeatedly measured on the same animal to study the toxicity of a compound of interest. This is only one example in which one is confronted with the analysis of many outcomes, possibly of a different type. Probably the most common situation is that of an amalgamation of continuous and categorical outcomes. A possible approach towards the joint analysis of two longitudinal outcomes of a different nature is the use of random-effects models (Models for Discrete Longitudinal Data. Springer Series in Statistics. Springer: New York, 2005). Although a random-effects model can easily be extended to jointly model many outcomes of a different nature, computational problems arise as the number of outcomes increases. To avoid maximization of the full likelihood expression, Fieuws and Verbeke (Biometrics 2006; 62:424-431) proposed a pairwise modeling strategy in which all possible pairs are modeled separately, using a mixed model, yielding several different estimates for the same parameters. These latter estimates are then combined into a single set of estimates. Also inference, based on pseudo-likelihood principles, is indirectly derived from the separate analyses. In this paper, we extend the approach of Fieuws and Verbeke (Biometrics 2006; 62:424-431) in two ways: the method is applied to different types of outcomes and the full pseudo-likelihood expression is maximized at once, leading directly to unique estimates as well as direct application of pseudo-likelihood inference. This is very appealing when interested in hypothesis testing. The method is applied to data from a repeated dose-toxicity study designed for the evaluation of the neurofunctional effects of a psychotrophic drug. The relative merits of both methods are discussed.status: publishe