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Background: Disability progression is a key milestone in the disease evolution of people with multiple sclerosis (PwMS). Prediction models of the probability of disability progression have not yet reached the level of trust needed to be adopted in the clinic. A common benchmark to assess model development in multiple sclerosis is also currently lacking., Methods: Data of adult PwMS with a follow-up of at least three years from 146 MS centers, spread over 40 countries and collected by the MSBase consortium was used. With basic inclusion criteria for quality requirements, it represents a total of 15, 240 PwMS. External validation was performed and repeated five times to assess the significance of the results. Transparent Reporting for Individual Prognosis Or Diagnosis (TRIPOD) guidelines were followed. Confirmed disability progression after two years was predicted, with a confirmation window of six months. Only routinely collected variables were used such as the expanded disability status scale, treatment, relapse information, and MS course. To learn the probability of disability progression, state-of-the-art machine learning models were investigated. The discrimination performance of the models is evaluated with the area under the receiver operator curve (ROC-AUC) and under the precision recall curve (AUC-PR), and their calibration via the Brier score and the expected calibration error. All our preprocessing and model code are available at https://gitlab.com/edebrouwer/ms_benchmark, making this task an ideal benchmark for predicting disability progression in MS., Findings: Machine learning models achieved a ROC-AUC of 0⋅71 ± 0⋅01, an AUC-PR of 0⋅26 ± 0⋅02, a Brier score of 0⋅1 ± 0⋅01 and an expected calibration error of 0⋅07 ± 0⋅04. The history of disability progression was identified as being more predictive for future disability progression than the treatment or relapses history., Conclusions: Good discrimination and calibration performance on an external validation set is achieved, using only routinely collected variables. This suggests machine-learning models can reliably inform clinicians about the future occurrence of progression and are mature for a clinical impact study., Competing Interests: The authors declare no competing non-financial interests but the following competing financial interests: - Dana Horakova received speaker honoraria and consulting fees from Biogen, Merck, Teva, Roche, Sanofi Genzyme, and Novartis, as well as support for research activities from Biogen and Czech Minsitry of Education [project Progres Q27/LF1]. - Francesco Patti received speaker honoraria and advisory board fees from Almirall, Bayer, Biogen, Celgene, Merck, Novartis, Roche, Sanofi-Genzyme and TEVA. He received research funding from Biogen, Merck, FISM (Fondazione Italiana Sclerosi Multipla), Reload Onlus Association and University of Catania. - Guillermo Izquierdo received speaking honoraria from Biogen, Novartis, Sanofi, Merck, Roche, Almirall and Teva. - Sara Eichau received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche and Teva. - Marc Girard received consulting fees from Teva Canada Innovation, Biogen, Novartis and Genzyme Sanofi; lecture payments from Teva Canada Innovation, Novartis and EMD. He has also received a research grant from Canadian Institutes of Health Research. - Alessandra Lugaresi has served as a Biogen, Bristol Myers Squibb, Merck Serono, Novartis, Roche, Sanofi/ Genzyme and Teva Advisory Board Member. She received congress and travel/accommodation expense compensations or speaker honoraria from Biogen, Merck, Mylan, Novartis, Roche, Sanofi/Genzyme, Teva and Fondazione Italiana Sclerosi Multipla (FISM). Her institutions received research grants from Novartis and Sanofi Genzyme. - Pierre Grammond has served in advisory boards for Novartis, EMD Serono, Roche, Biogen idec, Sanofi Genzyme, Pendopharm and has received grant support from Genzyme and Roche, has received research grants for his institution from Biogen idec, Sanofi Genzyme, EMD Serono. - Tomas Kalincik served on scientific advisory boards for 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, Sanofi-Genzyme, Teva, BioCSL and Merck and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck. - Raed Alroughani received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche and Sanofi-Genzyme. - Francois Grand’Maison received honoraria or research funding from Biogen, Genzyme, Novartis, Teva Neurosciences, Mitsubishi and ONO Pharmaceuticals. - Murat Terzi received travel grants from Novartis, Bayer-Schering, Merck and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. - Jeannette Lechner-Scott 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, TEVA and Novartis. - Samia J. Khoury received compensation for participation in the Novartis Maestro program. - Vincent van Pesch has received travel grants from Merck, Biogen, Sanofi, Bristol Myers Squibb, Almirall and Roche; his institution receives honoraria for consultancy and lectures and research grants from Roche, Biogen, Sanofi, Merck, Bristol Myers Squibb, Janssen, Almirall and Novartis Pharma. - Radek Ampapa received conference travel support from Novartis, Teva, Biogen, Bayer and Merck and has participated in a clinical trials by Biogen, Novartis, Teva and Actelion. - Daniele Spitaleri received honoraria as a consultant on scientific advisory boards by Bayer-Schering, Novartis and Sanofi-Aventis and compensation for travel from Novartis, Biogen, Sanofi Aventis, Teva and Merck. - 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. - Davide Maimone served on scientific advisory boards for Bayer, Biogen, Merck, Sanofi-Genzyme, Novartis, Roche, and Almirall; received honoraria and travel grants from Sanofi Genzyme, Novartis, Biogen, Merck, and Roche. - Gerardo Iuliano (retired - no PI successor but has approved ongoing use of data) had travel/accommodations/meeting expenses funded by Bayer Schering, Biogen, Merck, Novartis, Sanofi Aventis, and Teva. - Bart Van Wijmeersch received research and travel grants, honoraria for MS-Expert advisor and Speaker fees from Bayer-Schering, Biogen, Sanofi Genzyme, Merck, Novartis, Roche and Teva. - Tamara Castillo Triviño received speaking/consulting fees and/or travel funding from Bayer, Biogen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. - 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 - Guy Laureys received travel and/or consultancy compensation from Sanofi-Genzyme, Roche, Teva, Merck, Novartis, Celgene, Biogen. - Anneke van der Walt served on advisory boards and receives unrestricted research grants from Novartis, Biogen, Merck and Roche She has received speaker’s 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. - Jiwon Oh has received research funding from the MS Society of Canada, National MS Society, Brain Canada, Biogen, Roche, EMD Serono (an affiliate of Merck KGaA); and personal compensation for consulting or speaking from Alexion, Biogen, Celgene (BMS), EMD Serono (an affiliate of Merck KGaA), Novartis, Roche, and Sanofi-Genzyme. - Ayse Altintas received speaker honoraria from Merck, Alexion,; received travel and registration grants from Merck, Biogen - Gen Pharma, Roche, Sanofi-Genzyme. - Yara Fragoso received honoraria as a consultant on scientific advisory boards by Novartis, Teva, Roche and Sanofi-Aventis and compensation for travel from Novartis, Biogen, Sanofi Aventis, Teva, Roche and Merck. - Tunde Csepany received speaker honoraria/ conference travel support from Bayer Schering, Biogen, Merck, Novartis, Roche, Sanofi-Aventis and Teva. - Suzanne Hodgkinson received honoraria and consulting fees from Novartis, Bayer Schering and Sanofi, and travel grants from Novartis, Biogen Idec and Bayer Schering. - Norma Deri received funding from Bayer, Merck, Biogen, Genzyme and Novartis. - 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. - Fraser Moore participated in clinical trials sponsored by EMD Serono and Novartis. - 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 clinical trials by Biogen and Merck. - Csilla Rozsa received speaker honoraria from Bayer Schering, Novartis and Biogen, congress and travel expense compensations from Biogen, Teva, Merck and Bayer Schering. - Allan Kermode received speaker honoraria and scientific advisory board fees from Bayer, BioCSL, Biogen, Genzyme, Innate Immunotherapeutics, Merck, Novartis, Sanofi, Sanofi-Aventis, and Teva. - Magdolna Simo received speaker honoraria from Novartis, Biogen, Bayer Schering; congress/travel compensation from Teva, Biogen, Merck, Bayer Schering. - Todd Hardy has received speaking fees or received honoraria for serving on advisory boards for Biogen, Merck, Teva, Novartis, Roche, Bristol-Myers Squibb and Sanofi-Genzyme, is Co-Editor of Advances in Clinical Neurosciences and Rehabilitation, and serves on the editorial board of Journal of Neuroimmunology and Frontiers in Neurology. - Nikolaos Grigoriadis received honoraria, consultancy/lecture fees, travel support and research grants from Biogen Idec, Biologix, Novartis, TEVA, Bayer, Merck Serono, Genesis Pharma, Sanofi – Genzyme, ROCHE, Cellgene, ELPEN and research grants from Hellenic Ministry of Development., (Copyright: © 2024 De Brouwer et al. 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