Serial correlation in optimal design for nonlinear mixed effects models.

In population modeling two sources of variability are commonly included; inter individual variability and residual variability. Rich sampling optimal design (more samples than model parameters) using these models will often result in a sampling schedule where some measurements are taken at exactly the same time point, thereby maximizing the signal-to-noise ratio. This behavior is a result of not appropriately taking into account error generation mechanisms and is often clinically unappealing and may be avoided by including intrinsic variability, i.e. serially correlated residual errors. In this paper we extend previous work that investigated optimal designs of population models including serial correlation using stochastic differential equations to optimal design with the more robust, and analytic, AR(1) autocorrelation model. Further, we investigate the importance of correlation strength, design criteria and robust designs. Finally, we explore the optimal design properties when estimating parameters with and without serial correlation. In the investigated examples the designs and estimation performance differs significantly when handling serial correlation.