title: Systematic evaluation of the descriptive and predictive performance of paediatric morphine population models.
abstract: OBJECTIVE
  A framework for the evaluation of paediatric population models is proposed and applied to two different paediatric population pharmacokinetic models for morphine. One covariate model was based on a systematic covariate analysis, the other on fixed allometric scaling principles.
  
  
  METHODS
  The six evaluation criteria in the framework were 1) number of parameters and condition number, 2) numerical diagnostics, 3) prediction-based diagnostics, 4) η-shrinkage, 5) simulation-based diagnostics, 6) diagnostics of individual and population parameter estimates versus covariates, including measurements of bias and precision of the population values compared to the observed individual values. The framework entails both an internal and external model evaluation procedure.
  
  
  RESULTS
  The application of the framework to the two models resulted in the detection of overparameterization and misleading diagnostics based on individual predictions caused by high shrinkage. The diagnostic of individual and population parameter estimates versus covariates proved to be highly informative in assessing obtained covariate relationships. Based on the framework, the systematic covariate model proved to be superior over the fixed allometric model in terms of predictive performance.
  
  
  CONCLUSIONS
  The proposed framework is suitable for the evaluation of paediatric (covariate) models and should be applied to corroborate the descriptive and predictive properties of these models.
authors.affiliation: Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands.
authors.forename: Elke H J
authors.initials: EH
authors.lastname: Krekels
authors.forename: Johan G C
authors.initials: JG
authors.lastname: van Hasselt
authors.forename: Dick
authors.initials: D
authors.lastname: Tibboel
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
authors.forename: Catherijne A J
authors.initials: CA
authors.lastname: Knibbe
mesh_terms: D002675:Child, Preschool; D003198:Computer Simulation; D005544:Forecasting; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D009022:Morphine Derivatives / Q000493:pharmacokinetics*
chemical_list: D009022:Morphine Derivatives; C035349:morphine-6-glucuronide; C018108:morphine-3-glucuronide