Regression modeling of longitudinal data with outcome-dependent observation times: extensions and comparative evaluation

Conventional longitudinal data analysis methods assume that outcomes are independent of the data-collection schedule. However, the independence assumption may be violated, for example, when a specific treatment necessitates a different follow-up schedule than the control arm or when adverse events trigger additional physician visits in between prescheduled follow-ups. Dependence between outcomes and observation times may introduce bias when estimating the marginal association of covariates on outcomes using a standard longitudinal regression model. We formulate a framework of outcome-observation dependence mechanisms to describe conditional independence given observed observation-time process covariates or shared latent variables. We compare four recently developed semi-parametric methods that accommodate one of these mechanisms. To allow greater flexibility, we extend these methods to accommodate a combination of mechanisms. In simulation studies, we show how incorrectly specifying the outcome-observation dependence may yield biased estimates of covariate-outcome associations and how our proposed extensions can accommodate a greater number of dependence mechanisms. We illustrate the implications of different modeling strategies in an application to bladder cancer data. In longitudinal studies with potentially outcome-dependent observation times, we recommend that analysts carefully explore the conditional independence mechanism between the outcome and observation-time processes to ensure valid inference regarding covariate-outcome associations.