Design evaluation and optimization for models of hepatitis C viral dynamics

Jeremie Guedj, Caroline Bazzoli, Avidan U. Neumann, France Mentré

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


Mathematical modeling of hepatitis C viral (HCV) kinetics is widely used for understanding viral pathogenesis and predicting treatment outcome. The standard model is based on a system of five non-linear ordinary differential equations (ODE) that describe both viral kinetics and changes in drug concentration after treatment initiation. In such complex models parameter estimation is challenging and requires frequent sampling measurements on each individual. By borrowing information between study subjects, non-linear mixed effect models can deal with sparser sampling from each individual. However, the search for optimal designs in this context has been limited by the numerical difficulty of evaluating the Fisher information matrix (FIM). Using the software PFIM, we show that a linearization of the statistical model avoids most of the computational burden, while providing a good approximation to the FIM. We then compare the precision of the parameters that can be expected using five study designs from the literature. We illustrate the usefulness of rationalizing data sampling by showing that, for a given level of precision, optimal design could reduce the total number of measurements by up 50 per cent. Our approach can be used by a statistician or a clinician aiming at designing an HCV viral kinetics study.

Original languageEnglish
Pages (from-to)1045-1056
Number of pages12
JournalStatistics in Medicine
Issue number10
StatePublished - 10 May 2011


  • Design evaluation
  • Design optimization
  • Hepatitis C
  • Non-linear mixed effect models
  • Ordinary differential equations
  • Viral kinetics


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