title: Improved utilization of ADAS-cog assessment data through item response theory based pharmacometric modeling.
abstract: OBJECTIVE
  This work investigates improved utilization of ADAS-cog data (the primary outcome in Alzheimer's disease (AD) trials of mild and moderate AD) by combining pharmacometric modeling and item response theory (IRT).
  
  
  METHODS
  A baseline IRT model characterizing the ADAS-cog was built based on data from 2,744 individuals. Pharmacometric methods were used to extend the baseline IRT model to describe longitudinal ADAS-cog scores from an 18-month clinical study with 322 patients. Sensitivity of the ADAS-cog items in different patient populations as well as the power to detect a drug effect in relation to total score based methods were assessed with the IRT based model.
  
  
  RESULTS
  IRT analysis was able to describe both total and item level baseline ADAS-cog data. Longitudinal data were also well described. Differences in the information content of the item level components could be quantitatively characterized and ranked for mild cognitively impairment and mild AD populations. Based on clinical trial simulations with a theoretical drug effect, the IRT method demonstrated a significantly higher power to detect drug effect compared to the traditional method of analysis.
  
  
  CONCLUSIONS
  A combined framework of IRT and pharmacometric modeling permits a more effective and precise analysis than total score based methods and therefore increases the value of ADAS-cog data.
authors.affiliation: Pharmacometrics Research Group Department of Pharmaceutical Biosciences, Uppsala University, P.O. Box 591, SE-751 24, Uppsala, Sweden, sebastian.ueckert@farmbio.uu.se.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Ueckert
authors.forename: Elodie L
authors.initials: EL
authors.lastname: Plan
authors.forename: Kaori
authors.initials: K
authors.lastname: Ito
authors.forename: Mats O
authors.initials: MO
authors.lastname: Karlsson
authors.forename: Brian
authors.initials: B
authors.lastname: Corrigan
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Hooker
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000453:epidemiology* / Q000523:psychology; D000069059:Atorvastatin; D017326:Clinical Trials, Phase III as Topic / Q000592:standards*; D003072:Cognition Disorders / Q000188:drug therapy / Q000453:epidemiology; D016208:Databases, Factual / Q000592:standards*; D006538:Heptanoic Acids / Q000627:therapeutic use; D006801:Humans; D008137:Longitudinal Studies; D008954:Models, Biological; D011758:Pyrroles / Q000627:therapeutic use; D013223:Statistics as Topic / Q000592:standards*
chemical_list: D006538:Heptanoic Acids; D011758:Pyrroles; D000069059:Atorvastatin