{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T11:04:21Z","timestamp":1788519861648,"version":"build-2803163510"},"reference-count":37,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T00:00:00Z","timestamp":1753056000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp;amp; Syst Pharma"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    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\u2010reported outcome (Scale for the Assessment and Rating of Ataxia; SARA; categorical data) and digital\u2010motor 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\u2010motor outcomes data as functions of a common underlying ataxia severity construct, evaluating 9\n                    <jats:italic>gait<\/jats:italic>\n                    and 17\n                    <jats:italic>limb coordination<\/jats:italic>\n                    digital\u2010motor measures for their ability to add to SARA in estimating individual ataxia severity levels. Based on our proposed workflow for assessing digital\u2010motor outcomes in ccIRT models, the final model selected three\n                    <jats:italic>digital gait<\/jats:italic>\n                    and three\n                    <jats:italic>limb coordination<\/jats:italic>\n                    measures, reducing average uncertainty in ataxia severity estimates by 49% (10% SD) compared to the SARA\u2010only IRT model. Trial simulations showed a 49% and 61% reduction in sample sizes needed to detect disease\u2010modifying effects in two genotypes. Overall, our ccIRT framework for combining multiple outcome domains, even of different variable types, facilitates a more precise estimation of disease severity and a higher power, which is particularly relevant for rare diseases with inherently small and short trials.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Trial Registration:<\/jats:bold>\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/jats:ext-link>\n                    : NCT04297891\n                  <\/jats:p>","DOI":"10.1002\/psp4.70081","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T07:29:41Z","timestamp":1753082981000},"page":"1857-1868","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Integrated Modeling of Digital\u2010Motor and Clinician\u2010Reported Outcomes Using Item Response Theory: Towards Powerful Trials for Rare Neurological Diseases"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3102-2707","authenticated-orcid":false,"given":"Alzahra","family":"Hamdan","sequence":"first","affiliation":[{"name":"Pharmacometrics Research Group, Department of Pharmacy Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8165-5898","authenticated-orcid":false,"given":"Andreas","family":"Trasch\u00fctz","sequence":"additional","affiliation":[{"name":"Division Translational Genomics of Neurodegenerative Diseases Hertie\u2010Institute for Clinical Brain Research and Center of Neurology, University of T\u00fcbingen  T\u00fcbingen Germany"},{"name":"German Center for Neurodegenerative Diseases (DZNE)  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9259-9230","authenticated-orcid":false,"given":"Lukas","family":"Beichert","sequence":"additional","affiliation":[{"name":"Division Translational Genomics of Neurodegenerative Diseases Hertie\u2010Institute for Clinical Brain Research and Center of Neurology, University of T\u00fcbingen  T\u00fcbingen Germany"},{"name":"German Center for Neurodegenerative Diseases (DZNE)  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0663-0532","authenticated-orcid":false,"given":"Xiaomei","family":"Chen","sequence":"additional","affiliation":[{"name":"Pharmacometrics Research Group, Department of Pharmacy Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia","family":"Gagnon","sequence":"additional","affiliation":[{"name":"Groupe de recherche interdisciplinaire sur les maladies neuromusculaires (GRIMN), Centre int\u00e9gr\u00e9 universitaire de sant\u00e9 et de services sociaux du Saguenay\u2013Lac\u2010Saint\u2010Jean  Qu\u00e9bec Canada"},{"name":"Centre de recherche du Centre int\u00e9gr\u00e9 universitaire de sant\u00e9 et de services sociaux du Saguenay\u2013Lac\u2010Saint\u2010Jean  Qu\u00e9bec Canada"},{"name":"Facult\u00e9 de m\u00e9decine et des sciences de la sant\u00e9 Universit\u00e9 de Sherbrooke  Qu\u00e9bec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart P.","family":"van de Warrenburg","sequence":"additional","affiliation":[{"name":"Department of Neurology Radboud University Medical Center  Nijmegen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1359-9062","authenticated-orcid":false,"given":"Filippo M.","family":"Santorelli","sequence":"additional","affiliation":[{"name":"IRCCS Stella Maris Foundation  Pisa 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