Empirical Bayes estimation of random effects of a mixed-effects proportional odds Markov model for ordinal data

Abstract

The objective of this work was to investigate the factors influencing the quality of empirical Bayes estimates (EBEs) of individual random effects of a mixed-effects Markov model for ordered categorical data. It was motivated by an attempt to develop a model-based dose adaptation tool for clinical use in colorectal cancer patients receiving capecitabine, which induces severe hand-and-foot syndrome (HFS) toxicity in more than a half of the patients. This simulation-based study employed a published mixed-effects model for HFS. The quality of EBEs was assessed in terms of accuracy and precision, as well as shrinkage. Three optimization algorithms were compared: simplex, quasi-Newton and adaptive random search. The investigated factors were amount of data per patient, distribution of categories within patients, magnitude of the inter-individual variability, and values of the effect model parameters. The main factors affecting the quality of EBEs were the values of parameters governing the dose–response relationship and the within-subject distribution of categories. For the chosen HFS toxicity model, the accuracy and precision of EBEs were rather low, and therefore the feasibility of their use for individual model-based dose adaptation seemed limited.