TY  - JOUR
AU  - Hamdan, Alzahra
AU  - Traschütz, Andreas
AU  - Beichert, Lukas
AU  - Chen, Xiaomei
AU  - Gagnon, Cynthia
AU  - van de Warrenburg, Bart P.
AU  - Santorelli, Filippo M.
AU  - Başak, Nazlı
AU  - Coarelli, Giulia
AU  - Horvath, Rita
AU  - Klebe, Stephan
AU  - Schüle, Rebecca
AU  - Hooker, Andrew C.
AU  - Synofzik, Matthis
AU  - Karlsson, Mats O.
TI  - Integrated Modeling of Digital‐Motor and Clinician‐Reported Outcomes Using Item Response Theory: Towards Powerful Trials for Rare Neurological Diseases
JO  - CPT: pharmacometrics & systems pharmacology
VL  - 14
IS  - 11
SN  - 2163-8306
CY  - London
PB  - Nature Publ. Group
M1  - DZNE-2025-01285
SP  - 1857 - 1868
PY  - 2025
AB  - Robust and highly sensitive outcomes are crucial for small trials in rare diseases. Combining different outcome types might improve sensitivity to identify disease severity and progression, yet innovative methodologies are scarce. Here we develop an Item Response Theory framework that allows integrated modeling of both continuous and categorical outcomes (ccIRT). With degenerative ataxias, a group of rare neurological coordination diseases, as a showcase, we developed a ccIRT model integrating two ataxia outcome types: a clinician-reported outcome (Scale for the Assessment and Rating of Ataxia; SARA; categorical data) and digital-motor outcomes for gait and limb coordination (continuous data). The ccIRT model leveraged data from 331 assessments from a natural history study for spastic ataxias. The model describes SARA items and digital-motor outcomes data as functions of a common underlying ataxia severity construct, evaluating 9 gait and 17 limb coordination digital-motor measures for their ability to add to SARA in estimating individual ataxia severity levels. Based on our proposed workflow for assessing digital-motor outcomes in ccIRT models, the final model selected three digital gait and three limb coordination measures, reducing average uncertainty in ataxia severity estimates by 49
KW  - Item Response Theory (Other)
KW  - clinical outcome assessments (Other)
KW  - digital‐motor outcomes (Other)
KW  - genetic ataxias (Other)
KW  - rare neurological diseases (Other)
LB  - PUB:(DE-HGF)16
DO  - DOI:10.1002/psp4.70081
UR  - https://pub.dzne.de/record/282315
ER  -