Evaluation of methods to handle nuisance covariates that are non-ignorable

Background: As the frequency of the covariate in the population tends to zero, alpha error inflates. Low frequencies may occur with some genotypes and concomitant medications. Since, (1) the presence of an effect cannot be determined accurately then these “rare” covariates are a nuisance, and (2) if rare covariates influence parameter estimates they are “non-ignorable”. […]

A reduction in between subject variability is not mandatory when adding a new covariate

Background: Population pharmacokinetic-pharmacodynamic (PKPD) analysis involves nonlinear hierarchical modelling where the mean response in a population and the variability in response from different sources are studied. It consists of two model hierarchies: a model for residual error and a model for heterogeneity termed between subject variance (BSV). The overall variability in a parameter within a […]

Design of pharmacokinetic studies for latent covariates

Background: Latent covariates are covariates that are either not available or unobservable at the time of the clinical study. Single nucleotide polymorphisms (SNPs) are of interest in pharmacokinetic studies and are often latent at the time the patient is enrolled. The amount of information provided by latent covariates depends on whether the covariate distribution is […]