{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T10:26:13Z","timestamp":1788517573654,"version":"build-2803163510"},"reference-count":36,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["101057385"],"award-info":[{"award-number":["101057385"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["777394"],"award-info":[{"award-number":["777394"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2026,8]]},"abstract":"Abstract<\/jats:title>\n \n Objective<\/jats:title>\n Epilepsy affects ~1% of the global population and often requires lifelong antiseizure medication (ASM) therapy. Valproic acid (VPA) is a commonly prescribed first\u2010line ASM, yet only approximately half of patients achieve sustained seizure freedom. Treatment selection remains largely empirical. We aimed to develop and independently validate a multimodal predictive model to estimate response to VPA and support more individualized treatment strategies.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n This cross\u2010sectional treatment response modeling study used data from a subset of the international Epi25 cohort (Belgium, Finland, Germany). Individuals with epilepsy were included if they had received VPA monotherapy and had available genetic or clinical data. Discovery data (1965\u20132021, 58% female) were split into a training set (\n n<\/jats:italic>\n \u2009=\u2009196) and test set (\n n<\/jats:italic>\n \u2009=\u2009133). Independent validation was performed in a Canadian cohort (2021\u20132022,\n n<\/jats:italic>\n \u2009=\u2009156, 40% female). The primary outcome was binary VPA response. Responders achieved \u226512\u2009months of seizure freedom attributed to VPA; nonresponders had >50% seizure recurrence or discontinued VPA due to inefficacy, adverse effects, or unclear reasons. The predictive algorithm integrated features derived from common and rare variants in VPA pharmacokinetic and pharmacodynamic genes, in\u00a0vitro neuronal VPA response measures, and clinical features. Model performance was assessed using accuracy, predictive values (negative predictive value [NPV]\/positive predictive value [PPV]), and area under the curve (AUC).\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n In the independent validation cohort, the multimodal classifier achieved a balanced accuracy of 63% (95% confidence interval [CI] =\u200952%\u201373%), NPV of 70% (95% CI\u2009=\u200951%\u201385%), PPV of 60% (95% CI\u2009=\u200946%\u201372%), and AUC of .73 (95% CI = .63\u2013.83). Models restricted to single or dual data modalities showed consistently lower predictive performance.<\/jats:p>\n <\/jats:sec>\n \n Significance<\/jats:title>\n This proof\u2010of\u2010concept study demonstrates that integrating genetic, cellular, and clinical data enables prediction of VPA treatment response with clinically meaningful accuracy. Although not yet ready for clinical application, this approach supports the feasibility of biomarker\u2010informed ASM selection and may ultimately reduce time to effective seizure control.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/epi.70300","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T10:26:04Z","timestamp":1779272764000},"page":"4037-4050","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A translational multimodal machine\u2010learning prototype predicting valproate response in epilepsy treatment"],"prefix":"10.1002","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3429-8306","authenticated-orcid":false,"given":"Simeon","family":"Platte","sequence":"first","affiliation":[{"name":"Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy Goethe University Frankfurt, University Hospital Frankfurt 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McGill University Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1859-4295","authenticated-orcid":false,"given":"Denise","family":"Haslinger","sequence":"additional","affiliation":[{"name":"Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy Goethe University Frankfurt, University Hospital Frankfurt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7052-1651","authenticated-orcid":false,"given":"Colin B.","family":"Josephson","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, Cumming School of Medicine University of Calgary Calgary Alberta Canada"},{"name":"Hotchkiss Brain Institute University of Calgary Calgary Alberta Canada"},{"name":"O'Brien Institute for Public Health, Cumming School of Medicine University of Calgary Calgary Alberta Canada"},{"name":"Centre for Health Informatics, Cumming School of Medicine University of Calgary Calgary Alberta Canada"},{"name":"Institute of Health Informatics University College London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3123-5879","authenticated-orcid":false,"given":"Guillermo","family":"Delgado\u2010Garc\u00eda","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, Cumming School of Medicine University of Calgary Calgary Alberta Canada"},{"name":"Hotchkiss Brain Institute University of Calgary Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Navprabhjot","family":"Kaur","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, Cumming School of Medicine University of Calgary Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela\u2010Pauline","family":"Lux","sequence":"additional","affiliation":[{"name":"Social Work in Epilepsy 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