title: Application of Item Response Theory to Modeling of Expanded Disability Status Scale in Multiple Sclerosis.
abstract: In this study, we report the development of the first item response theory (IRT) model within a pharmacometrics framework to characterize the disease progression in multiple sclerosis (MS), as measured by Expanded Disability Status Score (EDSS). Data were collected quarterly from a 96-week phase III clinical study by a blinder rater, involving 104,206 item-level observations from 1319 patients with relapsing-remitting MS (RRMS), treated with placebo or cladribine. Observed scores for each EDSS item were modeled describing the probability of a given score as a function of patients' (unobserved) disability using a logistic model. Longitudinal data from placebo arms were used to describe the disease progression over time, and the model was then extended to cladribine arms to characterize the drug effect. Sensitivity with respect to patient disability was calculated as Fisher information for each EDSS item, which were ranked according to the amount of information they contained. The IRT model was able to describe baseline and longitudinal EDSS data on item and total level. The final model suggested that cladribine treatment significantly slows disease-progression rate, with a 20% decrease in disease-progression rate compared to placebo, irrespective of exposure, and effects an additional exposure-dependent reduction in disability progression. Four out of eight items contained 80% of information for the given range of disabilities. This study has illustrated that IRT modeling is specifically suitable for accurate quantification of disease status and description and prediction of disease progression in phase 3 studies on RRMS, by integrating EDSS item-level data in a meaningful manner.
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 751 24, Uppsala, Sweden. ana.kalezic@farmbio.uu.se.
authors.forename: A M
authors.initials: AM
authors.lastname: Novakovic
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 751 24, Uppsala, Sweden.|Division of Pharmacology, Leiden Academic Centre of Drug Research, Leiden University, Leiden, Netherlands.
authors.forename: E H J
authors.initials: EH
authors.lastname: Krekels
authors.affiliation: Merck Institute for Pharmacometrics, Merck Serono, Lausanne, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Munafo
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 751 24, Uppsala, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Ueckert
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 751 24, Uppsala, Sweden.
authors.forename: M O
authors.initials: MO
authors.lastname: Karlsson
mesh_terms: D017338:Cladribine / Q000627:therapeutic use; D017326:Clinical Trials, Phase III as Topic; D004185:Disability Evaluation; D018450:Disease Progression; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016015:Logistic Models; D008962:Models, Theoretical; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000175:diagnosis* / Q000188:drug therapy; D012720:Severity of Illness Index
chemical_list: D007166:Immunosuppressive Agents; D017338:Cladribine
keywords: cladribine tablets; disease progression model; expanded disability status scale; item response theory; multiple sclerosis