On the appropriateness of marginal models for repeated measurements in clinical trials

Although models developed directly to describe marginal distributions have become widespread in the analysis of repeated measurements, some of their disadvantages are not well enough known. These include producing profile curves that correspond to no possible individual, possibly showing that a treatment is superior on average when it is poorer for each individual subject, implicitly generating complex and implausible physiological explanations, including underdispersion in subgroups, and sometimes corresponding to no possible probabilistic data generating mechanism. We conclude that such marginal models may sometimes be appropriate for descriptive observational studies, such as sample surveys in epidemiology, but should only be used with great care in causal experimental settings, such as clinical trials.