{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,11]],"date-time":"2026-11-11T23:34:32Z","timestamp":1794440072249,"version":"4.9.1"},"reference-count":46,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,4,6]],"date-time":"2021-04-06T00:00:00Z","timestamp":1617667200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,4,6]],"date-time":"2021-04-06T00:00:00Z","timestamp":1617667200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000890","name":"National Multiple Sclerosis Society","doi-asserted-by":"publisher","award":["PA-1603-08175"],"award-info":[{"award-number":["PA-1603-08175"]}],"id":[{"id":"10.13039\/100000890","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Multiple sclerosis (MS) can be divided into four phenotypes based on clinical evolution. The pathophysiological boundaries of these phenotypes are unclear, limiting treatment stratification. Machine learning can identify groups with similar features using multidimensional data. Here, to classify MS subtypes based on pathological features, we apply unsupervised machine learning to brain MRI scans acquired in previously published studies. We use a training dataset from 6322 MS patients to define MRI-based subtypes and an independent cohort of 3068 patients for validation. Based on the earliest abnormalities, we define MS subtypes as cortex-led, normal-appearing white matter-led, and lesion-led. People with\u00a0the lesion-led subtype have the highest risk of confirmed disability progression (CDP) and the highest relapse rate. People with the\u00a0lesion-led MS subtype show positive treatment response in selected clinical trials. Our findings suggest that MRI-based subtypes predict MS disability progression and response to treatment and may be used to define groups of patients in interventional trials.<\/jats:p>","DOI":"10.1038\/s41467-021-22265-2","type":"journal-article","created":{"date-parts":[[2021,4,6]],"date-time":"2021-04-06T06:02:48Z","timestamp":1617688968000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":234,"title":["Identifying multiple sclerosis subtypes using unsupervised machine learning and MRI data"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6652-3512","authenticated-orcid":false,"given":"Arman","family":"Eshaghi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra L.","family":"Young","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4885-6241","authenticated-orcid":false,"given":"Peter A.","family":"Wijeratne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7872-0142","authenticated-orcid":false,"given":"Ferran","family":"Prados","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas L.","family":"Arnold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sridar","family":"Narayanan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles R. G.","family":"Guttmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3543-3706","authenticated-orcid":false,"given":"Frederik","family":"Barkhof","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2439-350X","authenticated-orcid":false,"given":"Daniel C.","family":"Alexander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4333-8496","authenticated-orcid":false,"given":"Alan J.","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3076-2682","authenticated-orcid":false,"given":"Declan","family":"Chard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Ciccarelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,4,6]]},"reference":[{"key":"22265_CR1","first-page":"2476","volume":"391","author":"The Lancet.","year":"2018","unstructured":"The Lancet. ICD-11: a brave attempt at classifying a new world. Lancet 391, 2476 (2018).","journal-title":"Lancet"},{"key":"22265_CR2","doi-asserted-by":"publisher","first-page":"1622","DOI":"10.1016\/S0140-6736(18)30481-1","volume":"391","author":"AJ Thompson","year":"2018","unstructured":"Thompson, A. J., Baranzini, S. E., Geurts, J., Hemmer, B. & Ciccarelli, O. Multiple sclerosis. Lancet 391, 1622\u20131636 (2018).","journal-title":"Lancet"},{"key":"22265_CR3","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1212\/WNL.0000000000000560","volume":"83","author":"FD Lublin","year":"2014","unstructured":"Lublin, F. D. et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 83, 278\u2013286 (2014).","journal-title":"Neurology"},{"key":"22265_CR4","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1038\/nrn3275","volume":"13","author":"PK Stys","year":"2012","unstructured":"Stys, P. K., Zamponi, G. W., van Minnen, J. & Geurts, J. J. G. Will the real multiple sclerosis please stand up? Nat. Rev. Neurosci. 13, 507\u2013514 (2012).","journal-title":"Nat. Rev. Neurosci."},{"key":"22265_CR5","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1016\/S1474-4422(18)30451-4","volume":"18","author":"M Filippi","year":"2019","unstructured":"Filippi, M. et al. Association between pathological and MRI findings in multiple sclerosis. Lancet Neurol. 18, 198\u2013210 (2019).","journal-title":"Lancet Neurol."},{"key":"22265_CR6","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-05892-0","volume":"9","author":"AL Young","year":"2018","unstructured":"Young, A. L. et al. Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference. Nat. Commun. 9, 4273 (2018).","journal-title":"Nat. Commun."},{"key":"22265_CR7","doi-asserted-by":"publisher","first-page":"1452","DOI":"10.1056\/NEJMra1615014","volume":"379","author":"MA Haendel","year":"2018","unstructured":"Haendel, M. A., Chute, C. G. & Robinson, P. N. Classification, ontology, and precision. Med. N. Engl. J. Med. 379, 1452\u20131462 (2018).","journal-title":"Med. N. Engl. J. Med."},{"key":"22265_CR8","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1038\/nrn3900","volume":"16","author":"M Calabrese","year":"2015","unstructured":"Calabrese, M. et al. Exploring the origins of grey matter damage in multiple sclerosis. Nat. Rev. Neurosci. 16, 147\u2013158 (2015).","journal-title":"Nat. Rev. Neurosci."},{"key":"22265_CR9","doi-asserted-by":"publisher","first-page":"1082","DOI":"10.1016\/S1474-4422(12)70230-2","volume":"11","author":"JJG Geurts","year":"2012","unstructured":"Geurts, J. J. G., Calabrese, M., Fisher, E. & Rudick, R. A. Measurement and clinical effect of grey matter pathology in multiple sclerosis. Lancet Neurol. 11, 1082\u20131092 (2012).","journal-title":"Lancet Neurol."},{"key":"22265_CR10","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1212\/WNL.0000000000002237","volume":"86","author":"B Bodini","year":"2016","unstructured":"Bodini, B. et al. White and gray matter damage in primary progressive MS: the chicken or the egg? Neurology 86, 170\u2013176 (2016).","journal-title":"Neurology"},{"key":"22265_CR11","doi-asserted-by":"publisher","first-page":"2938","DOI":"10.1093\/brain\/aws242","volume":"135","author":"J Kolasinski","year":"2012","unstructured":"Kolasinski, J. et al. A combined post-mortem magnetic resonance imaging and quantitative histological study of multiple sclerosis pathology. Brain 135, 2938\u20132951 (2012).","journal-title":"Brain"},{"key":"22265_CR12","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1093\/brain\/awv353","volume":"139","author":"T J\u00fcrgens","year":"2016","unstructured":"J\u00fcrgens, T. et al. Reconstruction of single cortical projection neurons reveals primary spine loss in multiple sclerosis. Brain 139, 39\u201346 (2016).","journal-title":"Brain"},{"key":"22265_CR13","doi-asserted-by":"crossref","unstructured":"Righart, R. et al. Cortical pathology in multiple sclerosis detected by the T1\/T2-weighted ratio from routine magnetic resonance imaging. Ann. Neurol. 82, 519\u2013529 (2017).","DOI":"10.1002\/ana.25020"},{"key":"22265_CR14","doi-asserted-by":"crossref","unstructured":"Sepulcre, J. et al. Contribution of white matter lesions to gray matter atrophy in multiple sclerosis: evidence from voxel-based analysis of T1 lesions in the visual pathway. Arch. Neurol. 66, 173\u2013179 (2009).","DOI":"10.1001\/archneurol.2008.562"},{"key":"22265_CR15","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1016\/S1474-4422(17)30076-5","volume":"16","author":"JMA Wijnands","year":"2017","unstructured":"Wijnands, J. M. A. et al. Health-care use before a first demyelinating event suggestive of a multiple sclerosis prodrome: a matched cohort study. Lancet Neurol. 16, 445\u2013451 (2017).","journal-title":"Lancet Neurol."},{"key":"22265_CR16","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1093\/brain\/awl007","volume":"129","author":"C Confavreux","year":"2006","unstructured":"Confavreux, C. & Vukusic, S. Natural history of multiple sclerosis: a unifying concept. Brain 129, 606\u2013616 (2006).","journal-title":"Brain"},{"key":"22265_CR17","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1056\/NEJMoa1606468","volume":"376","author":"X Montalban","year":"2017","unstructured":"Montalban, X. et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N. Engl. J. Med. 376, 209\u2013220 (2017).","journal-title":"N. Engl. J. Med."},{"key":"22265_CR18","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1002\/ana.25019","volume":"82","author":"K Nakamura","year":"2017","unstructured":"Nakamura, K., Chen, J. T., Ontaneda, D., Fox, R. J. & Trapp, B. D. T1-\/T2-weighted ratio differs in demyelinated cortex in multiple sclerosis. Ann. Neurol. 82, 635\u2013639 (2017).","journal-title":"Ann. Neurol."},{"key":"22265_CR19","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1002\/ana.25145","volume":"83","author":"A Eshaghi","year":"2018","unstructured":"Eshaghi, A. et al. Deep gray matter volume loss drives disability worsening in multiple sclerosis. Ann. Neurol. 83, 210\u2013222 (2018).","journal-title":"Ann. Neurol."},{"key":"22265_CR20","doi-asserted-by":"publisher","first-page":"1665","DOI":"10.1093\/brain\/awy088","volume":"141","author":"A Eshaghi","year":"2018","unstructured":"Eshaghi, A. et al. Progression of regional grey matter atrophy in multiple sclerosis. Brain 141, 1665\u20131677 (2018).","journal-title":"Brain"},{"key":"22265_CR21","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1056\/NEJMra1401483","volume":"378","author":"DS Reich","year":"2018","unstructured":"Reich, D. S., Lucchinetti, C. F. & Calabresi, P. A. Multiple sclerosis. N. Engl. J. Med. 378, 169\u2013180 (2018).","journal-title":"N. Engl. J. Med."},{"key":"22265_CR22","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1002\/ana.21867","volume":"66","author":"K Hawker","year":"2009","unstructured":"Hawker, K. et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann. Neurol. 66, 460\u2013471 (2009).","journal-title":"Ann. Neurol."},{"key":"22265_CR23","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1002\/ana.21079","volume":"61","author":"JS Wolinsky","year":"2007","unstructured":"Wolinsky, J. S. et al. Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial. Ann. Neurol. 61, 14\u201324 (2007).","journal-title":"Ann. Neurol."},{"key":"22265_CR24","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1016\/S0140-6736(15)01314-8","volume":"387","author":"F Lublin","year":"2016","unstructured":"Lublin, F. et al. Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet 387, 1075\u20131084 (2016).","journal-title":"Lancet"},{"key":"22265_CR25","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1016\/S1474-4422(18)30069-3","volume":"17","author":"R Kapoor","year":"2018","unstructured":"Kapoor, R. et al. Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND): a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension. Lancet Neurol. 17, 405\u2013415 (2018).","journal-title":"Lancet Neurol."},{"key":"22265_CR26","doi-asserted-by":"publisher","first-page":"2213","DOI":"10.1016\/S0140-6736(13)62242-4","volume":"383","author":"J Chataway","year":"2014","unstructured":"Chataway, J. et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet 383, 2213\u20132221 (2014).","journal-title":"Lancet"},{"key":"22265_CR27","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1016\/S1474-4422(10)70131-9","volume":"9","author":"R Kapoor","year":"2010","unstructured":"Kapoor, R. et al. Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Neurol. 9, 681\u2013688 (2010).","journal-title":"Lancet Neurol."},{"key":"22265_CR28","doi-asserted-by":"publisher","first-page":"e374","DOI":"10.1212\/NXI.0000000000000374","volume":"4","author":"R Spain","year":"2017","unstructured":"Spain, R. et al. Lipoic acid in secondary progressive MS: a randomized controlled pilot trial. Neurol. Neuroimmunol. Neuroinflamm. 4, e374 (2017).","journal-title":"Neurol. Neuroimmunol. Neuroinflamm."},{"key":"22265_CR29","doi-asserted-by":"publisher","first-page":"1551","DOI":"10.1212\/WNL.0b013e318233b240","volume":"77","author":"MS Freedman","year":"2011","unstructured":"Freedman, M. S. et al. A phase III study evaluating the efficacy and safety of MBP8298 in secondary progressive MS. Neurology 77, 1551\u20131560 (2011).","journal-title":"Neurology"},{"key":"22265_CR30","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1016\/S1474-4422(19)30485-5","volume":"19","author":"J Chataway","year":"2020","unstructured":"Chataway, J. et al. Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART): a phase 2b, multiarm, double-blind, randomised placebo-controlled trial. Lancet Neurol. 19, 214\u2013225 (2020).","journal-title":"Lancet Neurol."},{"key":"22265_CR31","doi-asserted-by":"publisher","first-page":"1098","DOI":"10.1056\/NEJMoa1114287","volume":"367","author":"R Gold","year":"2012","unstructured":"Gold, R. et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N. Engl. J. Med. 367, 1098\u20131107 (2012).","journal-title":"N. Engl. J. Med."},{"key":"22265_CR32","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1056\/NEJMoa1601277","volume":"376","author":"SL Hauser","year":"2017","unstructured":"Hauser, S. L. et al. Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N. Engl. J. Med. 376, 221\u2013234 (2017).","journal-title":"N. Engl. J. Med."},{"key":"22265_CR33","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1007\/s00415-014-7264-4","volume":"261","author":"TL Vollmer","year":"2014","unstructured":"Vollmer, T. L. et al. A randomized placebo-controlled phase III trial of oral laquinimod for multiple sclerosis. J. Neurol. 261, 773\u2013783 (2014).","journal-title":"J. Neurol."},{"key":"22265_CR34","doi-asserted-by":"publisher","first-page":"1523","DOI":"10.1038\/nn.4393","volume":"19","author":"KL Miller","year":"2016","unstructured":"Miller, K. L. et al. Multimodal population brain imaging in the UK Biobank prospective epidemiological study. Nat. Neurosci. 19, 1523\u20131536 (2016).","journal-title":"Nat. Neurosci."},{"key":"22265_CR35","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.neuroimage.2013.05.041","volume":"80","author":"DC Van Essen","year":"2013","unstructured":"Van Essen, D. C. et al. The WU-Minn Human Connectome Project: an overview. Neuroimage 80, 62\u201379 (2013).","journal-title":"Neuroimage"},{"key":"22265_CR36","unstructured":"De Stefano, N. et al. Establishing pathological cut-offs of brain atrophy rates in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 87, 93\u201399 (2016)."},{"key":"22265_CR37","doi-asserted-by":"publisher","first-page":"1225","DOI":"10.1002\/hbm.21279","volume":"33","author":"K Bendfeldt","year":"2012","unstructured":"Bendfeldt, K. et al. Longitudinal gray matter changes in multiple sclerosis-differential scanner and overall disease-related effects. Hum. Brain Mapp. 33, 1225\u20131245 (2012).","journal-title":"Hum. Brain Mapp."},{"key":"22265_CR38","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1001\/jamaneurol.2014.3537","volume":"72","author":"DL Rotstein","year":"2015","unstructured":"Rotstein, D. L., Healy, B. C., Malik, M. T., Chitnis, T. & Weiner, H. L. Evaluation of no evidence of disease activity in a 7-year longitudinal multiple sclerosis cohort. JAMA Neurol. 72, 152\u2013158 (2015).","journal-title":"JAMA Neurol."},{"key":"22265_CR39","doi-asserted-by":"publisher","first-page":"1444","DOI":"10.1212\/WNL.33.11.1444","volume":"33","author":"JF Kurtzke","year":"1983","unstructured":"Kurtzke, J. F. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33, 1444\u20131452 (1983).","journal-title":"Neurology"},{"key":"22265_CR40","doi-asserted-by":"crossref","unstructured":"Ganzetti, M., Wenderoth, N. & Mantini, D. Whole brain myelin mapping using T1- and T2-weighted MR imaging data. Front. Hum. Neurosci. 8, 671 (2014).","DOI":"10.3389\/fnhum.2014.00671"},{"key":"22265_CR41","doi-asserted-by":"publisher","unstructured":"Merlise Clyde, V. & Raj, A. Merliseclyde\/Bas: Bas Version 1.5.3. (Zenodo, 2018). https:\/\/doi.org\/10.5281\/zenodo.1475297.","DOI":"10.5281\/zenodo.1475297"},{"key":"22265_CR42","unstructured":"A Phase 2 Clinical Study in Subjects With Primary Progressive Multiple Sclerosis to Assess the Efficacy, Safety and Tolerability of Two Oral Doses of Laquinimod Either of 0.6 mg\/Day or 1.5mg\/Day (Experimental Drug) as Compared to Placebo - Full Text View - ClinicalTrials.gov. https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02284568."},{"key":"22265_CR43","first-page":"401","volume":"7","author":"A Bhattacharyya","year":"1946","unstructured":"Bhattacharyya, A. On a Measure of Divergence between Two Multinomial Populations. Sankhy\u0101: Indian J. Stat. (1933\u20131960) 7, 401\u2013406 (1946).","journal-title":"Sankhy\u0101: Indian J. Stat. (1933\u20131960)"},{"key":"22265_CR44","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1002\/ana.25313","volume":"84","author":"JS Wolinsky","year":"2018","unstructured":"Wolinsky, J. S. et al. Evaluation of no evidence of progression or active disease (NEPAD) in patients with primary progressive multiple sclerosis in the ORATORIO trial. Ann. Neurol. 84, 527\u2013536 (2018).","journal-title":"Ann. Neurol."},{"key":"22265_CR45","unstructured":"R. Core Team. R: A Language and Environment for Statistical Computing. (R Foundation for Statistical Computing, 2014)."},{"key":"22265_CR46","unstructured":"Pinheiro, J., Bates, D., DebRoy, S., Sarkar, D. & R Core Team. nlme: Linear and Nonlinear Mixed Effects Models. https:\/\/cran.r-project.org\/web\/packages\/nlme\/citation.html (2017)."}],"updated-by":[{"DOI":"10.1038\/s41467-021-23538-6","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2021,5,20]],"date-time":"2021-05-20T00:00:00Z","timestamp":1621468800000}}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-22265-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-22265-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-22265-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T06:30:24Z","timestamp":1669962624000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-22265-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,6]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["22265"],"URL":"https:\/\/doi.org\/10.1038\/s41467-021-22265-2","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/19011080","asserted-by":"object"}]},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,6]]},"assertion":[{"value":"29 October 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 March 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 April 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 May 2021","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1038\/s41467-021-23538-6","URL":"https:\/\/doi.org\/10.1038\/s41467-021-23538-6","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A.E. has received speaker\u2019s honoraria from Biogen and At The Limits educational programme. He has received travel support from the National Multiple Sclerosis Society and honorarium from the Journal of Neurology, Neurosurgy and Psychiatry for Editorial Commentaries. In the last 3 years D.C. has received honoraria from Excemed (2017) for faculty-led education work; had meeting expenses funded by the IMSCOGS (2019), EAN (2018), ECTRIMS (2018) and Soci\u00e9t\u00e9 des Neurosciences (2017). He is a consultant for Biogen and Hoffmann-La Roche. He has received research funding from the International Progressive MS Alliance, the MS Society, and the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre. He is a member of the MS Society\u2019s Biomedical Grant Review Panel and a trustee of the MS Trust. O.C. has received research grants from the MS Society of Great Britain & Northern Ireland, National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, EUH2020, Spinal Cord Research Foundation, and Rosetrees Trust. She serves as a consultant for Novartis, Teva, and Roche and has received an honorarium from the American Academy of Neurology as Associate Editor of Neurology and serves on the Editorial Board of Multiple Sclerosis Journal. CRGG has received research grants form Sanofi and the National Multiple Sclerosis Society. F.B. has received compensation for consulting services and\/or speaking activities from Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, Genzyme, Synthon BV, Roche, Teva, Jansen research and IXICO and is supported by the NIHR Biomedical Research Centre at UCLH. A.J.T. has received honoraria\/support for travel for consultancy from Eisai, Hoffman La Roche, Almirall, and Excemed, and support for travel for consultancy as chair of the International Progressive MS Alliance Scientific Steering Committee, and from the National MS Society (USA) as a member of the Research Programs Advisory Committee. He receives an honorarium from SAGE Publishers as Editor-in-Chief of Multiple Sclerosis. Journal and a free subscription from Elsevier as a board member for the Lancet Neurology. D.L.A. has received research grant funding and\/ or personal compensation for consulting from Acorda, Adelphi, Alkermes, Biogen, Celgene, Frequency Therapeutics, Genentech, Genzyme, Hoffman-La Roche, Immuene Tolerance Network, Immunotec, MedDay, EMD Serono, Novartis, Pfizer, Receptos, Roche, Sanofi-Aventis, Canadian Institutes of Health Research, MS Society of Canada, and International Progressive MS Alliance; and holds an equity interest in NeuroRx Research. F.B., D.C.A. and A.E. hold equity stake in Queen Square Analytics. S.N. has received research funding from the Canadian Institutes of Health Research, the International Progressive MS Alliance, the Myelin Repair Foundation and Immunotec. He has received honoraria\/travel support from Genentech and MedDay, and personal compensation from NeuroRx Research.\u00a0The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"2078"}}