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Multivariate and multimodal investigations integrating demographic, clinical, multi-omics, and neuroimaging data provide opportunities for nuanced analyses, aimed to define disease progression markers. We used data from a 12-year longitudinal multicenter cohort of 88 people with multiple sclerosis, to test the predictive value of multi-omics, T<jats:sub>1<\/jats:sub>-weighted MRI (lesion count and volume, lesion-filled brain-predicted age), clinical examinations, self-reports on quality of life, demographics, and general health-related variables for future functional and cognitive disability. Systematic increases in Expanded Disability Status Scale (EDSS) scores were used to stratify a progressive disability group (PDG) from relatively stabile disability. A processing speed decline group (PSDG) was defined by a \u2265 20% decrease of Paced Auditory Serial Addition Test score from previous timepoints. We used a multiverse approach to identify which baseline variables were most predictive for PDG and PSDG memberships, considering multiple analysis paths. Future disability (median area under the curve: mAUC = 0.83 \u00b1 0.04, median Brier score: mBS = 0.16 \u00b1 0.02) and the loss of processing speed (mAUC = 0.89 \u00b1 0.05, mBS = 0.10 \u00b1 0.03) could be successfully classified across models. Varibles significantly (median p-values &lt; 0.05) predicting stable disability included receiving disease modifying treatment at 12-year follow-up (median Odds Ratio: mOR<jats:sub>PDG<\/jats:sub> = 7.44 \u00b1 4.07, p<jats:sub>median<\/jats:sub> = 0.013, proportion of the OR\u2019s directionality: PORSD = 100%), lower baseline EDSS for each 1-unit (mOR<jats:sub>PDG<\/jats:sub> = 0.25 \u00b1 0.11, p<jats:sub>median<\/jats:sub> = 0.013, PORSD = 100%), and counter-intuitively every year increase in baseline age (mOR<jats:sub>PDG<\/jats:sub> = 1.12 \u00b1 0.04, p<jats:sub>median<\/jats:sub> = 0.020, PORSD = 100%), and lower vitamin A per 1 umol\/L (mOR<jats:sub>PDG<\/jats:sub> = 0.10 \u00b1 0.05, p<jats:sub>median<\/jats:sub> = 0.016, PORSD = 99.7%) and D levels per 1\u00a0nmol\/L (mOR<jats:sub>PDG<\/jats:sub> = 0.95 \u00b1 0.02, p<jats:sub>median<\/jats:sub> = 0.025, PORSD = 100%). Variables significantly predicting stable processing speed were receiving disease modifying treatment at 12-year follow-up (mOR<jats:sub>PSDG<\/jats:sub> = 0.10 \u00b1 0.08, p<jats:sub>median<\/jats:sub> = 0.013, PORSD = 100%) and baseline PASAT score (mOR<jats:sub>PSDG<\/jats:sub> = 0.86 \u00b1 0.03, p<jats:sub>median<\/jats:sub> = 0.005, PORSD = 99.73%). These findings were supported by an additional simulation study. Concordant with the literature, disease modifying treatments influence disability progression, as well as a higher EDSS and PASAT scores at measurement start. Experimental and counterintuitive findings on vitamin A and D levels require further validation. The large variability across models suggests a strong influence of analytic flexibility, such as the selection of covariates.<\/jats:p>","DOI":"10.1038\/s41598-025-17894-2","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T09:25:14Z","timestamp":1760606714000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Multimodal predictors of disability progression and processing speed decline in relapsing\u2013remitting multiple sclerosis"],"prefix":"10.1038","volume":"15","author":[{"given":"Max","family":"Korbmacher","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid Anne","family":"Lie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin","family":"Wesnes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Westman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Espeseth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karsten","family":"Specht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ole Andreas","family":"Andreassen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars Tjelta","family":"Westlye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stig","family":"Wergeland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kjell-Morten","family":"Myhr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d8ivind","family":"Torkildsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Einar August","family":"H\u00f8gest\u00f8l","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,16]]},"reference":[{"key":"17894_CR1","doi-asserted-by":"publisher","first-page":"1816","DOI":"10.1177\/1352458520970841","volume":"26","author":"C Walton","year":"2020","unstructured":"Walton, C. et al. 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LTW is a minor shareholder of baba.vision. KMM has served on scientific advisory board for Alexion, received speaker honoraria from Biogen, Novartis, Roche and Sanofi, and has participated in clinical trials organized by Biogen, Merck, Novartis, Otivio, Roche and Sanofi. EAH received honoraria for advisory board activity from Sanofi-Genzyme, and his department has received honoraria for lecturing from Biogen and Merck. \u00d8T received speaker honoraria from and served on scientific advisory boards of Biogen, Sanofi-Aventis, Merck, and Novartis, and has participated in clinical trials organized by Merck, Novartis, Roche and Sanofi. The remaining authors declare no other competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The study was approved by the Norwegian Regional Committees for Medical and Health Research Ethics (REK, 814351). The OFAMS-study and the 10-year follow-up were previously approved by REK (2016\/1906) and registered as clinical trial (clinicaltrials.gov identifier: NCT00360906). Ethical approval for the different brain age training datasets was obtained (REK 567301, PVO 17\/21624), as well as for the longitudinal validation set (Bergen Breakfast Scanning Club, REK 238310), and the cross-sectional MS data (REK 2011\/1846, REK 2016\/102). All participants gave their written informed consent. All methods were performed in accordance with the relevant guidelines and regulations (Declaration of Helsiniki).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}],"article-number":"36156"}}