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We previously developed machine-learning tools to estimate 5-year progression risk in people with multiple sclerosis (PwMS). Such models should account for disease-modifying therapy (DMT) and objective outcome definitions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In a retrospective multicenter case\u2013control study, we evaluated adults with relapsing\u2013remitting multiple sclerosis (RRMS) at baseline. Using machine-learning, we developed two complementary tools for individualized 5-year risk estimation: DAAE-M, optimized for transparency, software-neutral use, and mitigation of indication bias, and ELIE, optimized for dynamic landmark-based modeling, complex treatment histories, and mitigation of immortal-time bias. Disease progression was defined using both a clinical outcome (RRMS-to-progressive MS) and an objective outcome (late-stage confirmed progression independent of relapse activity).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Among 34,510 people with RRMS (72.6% female, mean age\u2009=\u200937.1, mean disease duration\u2009=\u20095.8), 9.8% and 21% met clinical and objective progression criteria, respectively, over five years. Both models demonstrated good calibration across risk-groups (Brier scores 0.06\u20130.16). DAAE-M provided patient-level risk estimates with monotonic risk escalation across risk-groups for clinical (3.1%\/11.2%\/22.6%\/33.0%) and objective (8.4%\/14.5%\/23.3%\/38.8%) progression. For DAAE-M, high-efficacy DMT was associated with approximately half the progression risk compared with low-efficacy DMT (risk-ratios: 0.42\u20130.59;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01). ELIE also showed good calibration across risk deciles with increasing incidence for both clinical (0.3%\/1.2%\/1.7%\/2.5%\/3.7%\/5.5%\/7.2%\/10.2%\/14.3%\/21.5%) and objective (0.9%\/1.6%\/2.5%\/4.0%\/5.8%\/7.8%\/10.2%\/15.3%\/20.9%\/32.5%) outcomes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>We developed two well-calibrated machine-learning-based tools for individualized 5-year prediction of clinically- and objectively-defined MS progression, each with distinct strengths in usability, bias handling, and treatment modeling. These findings support future tool use in personalized risk stratification and secondary prevention.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00415-026-13802-4","type":"journal-article","created":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T15:03:02Z","timestamp":1776610982000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Predicting disease progression in multiple sclerosis with clinically accessible information and technology"],"prefix":"10.1007","volume":"273","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0219-3518","authenticated-orcid":false,"given":"Tom A. N.","family":"Fuchs","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menno M.","family":"Schoonheim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva M. 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Grammond has served on advisory boards for Novartis, EMD Serono, Roche, Biogen Idec, Sanofi Genzyme, Pendopharm and has received grant support from Genzyme and Roche, and has received research grants for his institution from Biogen Idec, Sanofi Genzyme, EMD Serono. S. Khoury received compensation for scientific advisory board activity from Merck and Roche, and received compensation for serving on the IDMC for Biogen. M. Sa received consulting fees, speaker honoraria, and\/or travel expenses for scientific meetings from Alexion, Bayer Healthcare, Biogen, Bristol Myers Squibb, Celgene, Janssen, Merck-Serono, Novartis, Roche, Sanofi and Teva. J. Lorscheider received research support from Innosuisse\u2013Swiss Innovation Agency, The University of Basel, Biogen and Novartis; received speaker fees, travel support, and\/or compensation for advisory boards from Bristol Myers Squibb, Novartis, Roche, and Teva. D. Maimone received speaker honoraria for Advisory Board and travel grants from Alexion, Almirall, Bayer, Biogen, Bristol Myers Squibb, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. C. Orja-Guevera received honoraria as consultant on scientific advisory boards or as speaker from Biogen, Celgene-BMS, Janssen, Merck, Novartis, Roche, Sanofi-Genzyme, Sandoz, Teva and Viatris. M. D\u2019hooghe received consultancy and advisory board fees from Roche, Sanofi-Genzyme, Biogen, Merck-Serono, Bayer-Schering, Novartis and Allergan; received congress support from Biogen, Merck-Serono, Teva and Roche. She has also received research support from Novartis, Biogen, Roche, FWO (Research Foundation Flanders) and Fonds D.V. (Ligue Nationale Belge de la Sclerose en Plaques, Fondation Roi Baudouin). M. Fabis-Pedrini received travel compensation from Merck. J. Oh has received research funding from the MS Society of Canada, National MS Society, Brain Canada, Biogen, Roche,\u00a0EMD Serono (an affiliate of Merck KGaA); and personal compensation for consulting or speaking from Alexion,\u00a0Biogen, Celgene (BMS), EMD Serono (an affiliate of Merck KGaA), Novartis, Roche, and Sanofi-Genzyme. P. Lalive received honoraria for speaking and\/or travel expenses from Biogen, Merck, Novartis, Roche; consulting fees from Biogen, GeNeuro, Merck, Novartis, Roche; research support from Biogen, Merck, Novartis. None were related to this work. Barbara Willekens received honoraria for acting as a member of Scientific Advisory Boards\/Consultancy for Alexion, Almirall, Biogen, Celgene\/BMS, Merck, Janssen, Novartis, Roche, Sandoz, Sanofi-Genzyme and speaker honoraria and travel support from Biogen, Celgene\/BMS, Merck, Novartis, Roche, Sanofi-Genzyme; research and\/or patient support grants from Biogen, Janssen, Merck, Sanofi-Genzyme, Roche. Honoraria and grants were paid to UZA\/UZA Foundation. Further, B.W. Dana Horakova received research funding from FWO-TBM, Belgian Charcot Foundation, Start2Cure Foundation, Queen Elisabeth Medical Foundation for Neurosciences and the National MS Society USA. She was supported by the Charles University: Cooperatio Program in Neuroscience, by the project National Institute for Neurological Research (Programme EXCELES, ID Project No. LX22NPO5107)\u2013Funded by the European Union\u2013Next Generation EU, and by General University Hospital in Prague project MH CZ-DRO-VFN64165. She also received compensation for travel, speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche, and Teva, as well as support for research activities from Biogen Idec. Eva Kubala Havrdova received honoraria\/research support from Biogen, Merck Serono, Novartis, Roche, and Teva; has been a member of advisory boards for Actelion, Biogen, Celgene, Merck Serono, Novartis, and Sanofi Genzyme; and has been supported by the Czech Ministry of Education\u2014project Cooperatio LF1, research area Neuroscience, and the project National Institute for Neurological Research (Programme EXCELES, ID project No LX22NPO5107)\u2014funded by the European Union\u2013Next Generation EU. Sara Eichau has received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Janssen, Bristol Myers, Bayer, Sanofi Genzyme, Roche and Teva. Pierre Duquette served on editorial boards and has been supported to attend meetings by EMD, Biogen, Novartis, Genzyme, and TEVA Neuroscience. He holds grants from the CIHR and the MS Society of Canada and has received funding for investigator-initiated trials from Biogen, Novartis, and Genzyme. Francesco Patti received personal compensation for serving on advisory boards for Almirall, Alexion, Biogen, Bristol, Janssen, Merck, Novartis and Roche. He further received research grants from Alexion, Almirall, Biogen, Bristol, Merck, Novartis and Roche and by FISM, Reload Association (Onlus), Italian Health Minister, and University of Catania. Raed Alroughani received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche and Sanofi-Genzyme. Alessandra Lugaresi has received personal compensation for consulting, serving on a scientific advisory board, speaking or other activities from Alexion, Biogen, Bristol Myers Squibb, Horizon, Janssen, Merck Serono, Novartis, and Sanofi\/Genzyme, and her institutions have received research grants from Novartis and Sanofi\/Genzyme. Prof. Tomassini has received consultation and speaker fees, travel grants and research support from Biogen, Sanofi Genzyme, Merck, Novartis, Roche, Alexion, Viatris, Janssen, Bristol Myers Squibb, Almirall. Murat Terzi received travel grants from Novartis, Bayer-Schering, Merck and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. Maria Pia Amato received honoraria as a consultant on scientific advisory boards from Biogen, Bayer-Schering, Merck, Teva and Sanofi-Aventis; has received research grants from Biogen, Bayer-Schering, Merck, Teva and Novartis. Tomas Kalincik served on scientific advisory boards for MS International Federation and World Health Organization, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Sanofi Genzyme, received conference travel support and\/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Roche, Sanofi-Genzyme, Teva, BioCSL and Merck and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck. Izanne Roos has served on scientific advisory boards, received conference travel support and\/or speaker honoraria from Roche, Novartis, Merck and Biogen. Izanne Roos is supported by MS Australia and the Trish Multiple Sclerosis Research Foundation. Michael Barnett served on scientific advisory boards for Biogen, Novartis and Genzyme and has received conference travel support from Biogen and Novartis. He serves on steering committees for trials conducted by Novartis. His institution has received research support from Biogen, Merck and Novartis. Anneke van der Walt served on advisory boards and receives unrestricted research grants from Novartis, Biogen, Merck and Roche. She has received speaker\u2019s honoraria and travel support from Novartis, Roche, and Merck. She receives grant support from the National Health and Medical Research Council of Australia and MS Research Australia. Jeannette Lechner-Scott received travel compensation from Novartis, Biogen, Roche and Merck. Her institution receives the honoraria for talks and advisory board commitment as well as research grants from Biogen, Merck, Roche and Novartis. Vincent van Pesch received travel grants from Merck Healthcare KGaA (Darmstadt, Germany), Biogen, Sanofi, Bristol Meyer Squibb, Almirall and Roche. His institution has received research grants and consultancy fees from Roche, Biogen, Sanofi, Merck Healthcare KGaA (Darmstadt, Germany), Bristol Meyer Squibb, Janssen, Almirall, Novartis Pharma, and Alexion. Andrea Surcinelli received travel and meeting attendance support from Novartis, Biogen, Roche, Merck, Bristol, Sanofi-Genzyme, Almirall. Piam Matteo Foschi received travel and meeting attendance support from Novartis, Biogen, Roche, Sanofi-Genzyme and Merck. Emanuele D\u2019Amico received speaker honoraria for Advisory Board and travel grants from Alexion, Biogen, Bristol Myers Squibb, Merck, Novartis, Roche and Sanofi-Genzyme. Suzanne Hodgkinson has received consulting fees and speaker honoraria from Biogen, Novartis, Roche, Merck, and has received grants for her institution from Biogen, Merck, Novartis, and Roche. Jens Kuhle received speaker fees, research support, travel support, and\/or served on advisory boards for Swiss MS Society, Swiss National Research Foundation (320030_189140\/1), University of Basel, Progressive MS Alliance, Alnylam, Bayer, Biogen, Bristol Myers Squibb, Celgene, Immunic, Merck, Neurogenesis, Novartis, Octave Bioscience, Quanterix, Roche, Sanofi, Stata DX. Rana Karabudak received consulting fees, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, support for attending meetings and travel, and participation on a data safety monitoring board or advisory board from Gen Turkey. Daniele Spitaleri received honoraria as a consultant on scientific advisory boards from Bayer-Schering, Novartis and Sanofi-Aventis and compensation for travel from Novartis, Biogen, Sanofi Aventis, Teva and Merck. Guy Laureys received travel and\/or consultancy compensation from Sanofi-Genzyme, Roche, Teva, Merck, Novartis, Celgene, Biogen. Bruce Taylor received funding for travel and speaker honoraria from Bayer Schering Pharma, CSL Australia, Biogen and Novartis, and has served on advisory boards for Biogen, Novartis, Roche and CSL Australia. Tamara Castillo-Trivi\u00f1o received speaking\/consulting fees and\/or travel funding from Almirall, Biogen, Bristol Myers Squibb, Janssen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. Ayse Altintas received speaker honoraria from Novartis and Alexion. Orla Gray received honoraria as consultant on scientific advisory boards for Genzyme, Biogen, Merck, Roche, and Novartis; has received travel grants from Biogen, Merck, Roche, and Novartis; has participated in \nclinical trials by Biogen and Merck. Her institution has received research grant support from Biogen. Riadh Gouider has received research grant and\/or advisory board honoraria from Biogen, Hikma, Merck, Roche and Sanofi. Jose E Meca-Lallana has received honoraria as a consultant, as a chairman or lecturer in meetings and has participated in clinical trials and other research projects promoted by Alexion, Almirall, Biogen, Bristol-Meyers-Squibb, Horizon, Johnson & Johnson, Merck, Neuraxpharm, Novartis, Roche, Sandoz, Sanofi and UCB. Allan Kermode served on Scientific Advisory Boards for Bayer, BioCSL, Biogen-Idec, Clene Nanomedicine, Eisai, Innate Immunotherapeutics, Lgpharma, Merck, Mitsubishi Tanabe Pharma, NeuroScientific Biopharmaceuticals, Novartis, Roche, Sanofi-Aventis, Sanofi-Genzyme, Teva, and View Health. Koen de Gans served on scientific advisory boards for Roche, Janssen, Sanofi-Genzyme, Novartis and Merck, received conference fee and travel support from Novartis, Biogen, Sanofi-Genzyme, Teva, AbbVie and Merck and received educational event support from Novartis. Jose Luis Sanchez-Menoyo accepted travel compensation from Novartis, Merck and Biogen, speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer and Teva and has participated in clinical trials by Biogen, Merck and Roche. Abdullah Al-Asmi received personal compensation for serving as a Scientific Advisory or speaker\/moderator for Novartis, Biogen, Roche, Sanofi-Genzyme, and Merck. Pamela McCombe received speakers fees and travel grants from Novartis, Biogen, T\u2019\u00e9valua, Sanofi. Mihaela Simu received speaker honoraria, advisory board fees and travel grants from AbbVie, Biogen, Bristol Myers Squibb, Teva, Merck, Roche, Ipsen, Sanofi-Genzyme, Novartis, Boehringer Stada. Norma Deri received funding from Bayer, Merck, Biogen, Genzyme and Novartis. Stella Hughes has received unrestricted educational grants or speaking honoraria from Biogen, Merck Serono, Novartis, Roche and Sanofi Genzyme. Tunde Csepany received speaker honoraria\/conference travel support from Biogen, Merck, Novartis, Roche, Sanofi-Aventis and Teva. Sudarshini Ramanathan has received research funding from the National Health and Medical Research Council (NHMRC, Australia), the Petre Foundation, the Brain Foundation, the Royal Australasian College of Physicians, and the University of Sydney. She is supported by an NHMRC Investigator Grant (GNT2008339). She serves as a consultant on the International Steering Committee for a clinical trial led by UCB (NCT05063162). She is on the advisory board for educational activities led by Limbic Neurology. She has been an invited speaker for educational\/research sessions coordinated by Biogen, Alexion, Novartis, Excemed and Limbic Neurology. She is on the medical advisory board (non-remunerated positions) of The MOG Project and the Sumaira Foundation. Todd A. Hardy received speaker honoraria\/conference travel support or served on advisory boards for Bayer Schering, Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, Bristol Myers Squibb and Teva. Sim\u00f3n C\u00e1rdenas-Robledo has, in the past three years, he has received travel expenses for scientific meetings from Biopas, Roche, Merck, and Genzyme; compensation for consulting services or participation on advisory boards from Merck, Biogen-Idec, Sanofi and Novartis; lecture fees from Biopas, Novartis, Merck, Sanofi, Janssen and Biogen-Idec; and research support from Biogen-Idec and Novartis. He is a subject editor on Multiple Sclerosis for Acta Neurol\u00f3gica Colombiana and a member of the editorial board of Frontiers of Neurology. Mario Habek participated as a clinical investigator and\/or received consultation and\/or speaker fees from Biogen, Sanofi Genzyme, Merck, Bayer, Novartis, Pliva\/Teva, Roche, Alvogen, Actelion, Alexion Pharmaceuticals, TG Pharmaceuticals. Bhim Singhal received consultancy honoraria and compensation for travel from Biogen and Merck. Nikolaos Grigoriadis received honoraria and travel support, consultancy and lecture fees, research grants from Biogen Idec, Novartis, Teva, Merck Serono, Genesis Pharma, Sanofi-Genzyme, Roche. Magdolna Simo received speaker honoraria from Novartis, Biogen, Bayer Schering, Sanofi, Merck, Roche; congress\/travel compensation from Teva, Biogen, Merck, Bayer Schering, Novartis, Roche. Yolanda Blanco received speaker honoraria\/consulting fees from Merck, Biogen, Roche, Bristol, Novartis, Sanofi and Sandoz. Cristina Ramo-Tello has received consulting fees, speaker honoraria, support for attending meetings and\/or travel, participation on advisory board and research grants for her institution from Biogen, Novartis, Sanofi, Bristol, Roche, Almirall, Janssen, Sandoz and Merck. Pamela McCombe received speakers fees and travel grants from Novartis, Biogen, T\u2019\u00e9valua, Sanofi. Eduardo Aguera-Morales has received honoraria as a speaker from Biogen, Merck, Novartis and Sanofi-Genzyme and for serving on scientific advisory boards from Novartis. Justin Garber received conference travel support from Roche, Merck and Novartis, received speaker honoraria from Biogen and research support from Roche. Claudio Solaro served on scientific advisory boards for Merck, Genzyme, Almirall, and Biogen; received honoraria and travel grants from Sanofi Aventis, Novartis, Biogen, Merck, Genzyme and Teva. Chris McGuigan received honoraria as consultant on scientific advisory boards for Genzyme, BMS, Janssen, Biogen, Merck, Roche, and Novartis; has received travel grants from Roche & Novartis. Neil Shuey received travel compensation from Bayer Schering, Novartis, and Biogen Idec. Nevin John is a PI on commercial MS studies sponsored by Novartis, Roche, Biogen and Sanofi. He has received speaker\u2019s honoraria and consulting fees from Merck. He has received conference travel, registration reimbursement and consulting fees from Novartis. William M Carroll is recipient of travel assistance and honoraria for participation in industry sponsored meetings from, and has provided advice to, Bayer Schering Pharma, Biogen-Idec, Novartis, Roche, Genzyme, Sanofi-Aventis, CSL, Teva, Merck and Cellgene. Thor Petersen received funding from Biogen, Merck, Novartis, Sanofi-Aventis, Roche, and Genzyme. Mehmet Yetkin received travel grants from Novartis, Bayer-Schering, Merck, and Teva; has participated in clinical trials by Sanofi Aventis, Roche, and Novartis. Gregor Jakob received honoraria as a speaker and member of scientific advisory boards from Sanofi, Bayer, Biogen, Merck, Janssen, Novartis, Roche and Aspen. Todd Hardy received speaker honoraria\/conference travel support or served on advisory boards for Bayer Schering, Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, Bristol Myers Squibb and Teva.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"281"}}