{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T14:32:07Z","timestamp":1787668327946,"version":"build-2736575974"},"reference-count":47,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T00:00:00Z","timestamp":1766707200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Federal Ministry of Research, Technology and Space, Germany","award":["BMBF 01ZZ1804C"],"award-info":[{"award-number":["BMBF 01ZZ1804C"]}]},{"name":"Federal Ministry of Research, Technology and Space, Germany","award":["BMBF 01ZZ1804C"],"award-info":[{"award-number":["BMBF 01ZZ1804C"]}]},{"name":"Federal Ministry of Research, Technology and Space, Germany","award":["BMBF 01ZZ1804B"],"award-info":[{"award-number":["BMBF 01ZZ1804B"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Individual-level surrogacy (ILS) assesses how\u00a0well a surrogate endpoint predicts treatment effect at the individual level. The paper discusses mutual information (MI) and the likelihood reduction factor (LRF) as ways to quantify ILS. It also reassesses ILS statements for people with relapsing-remitting multiple sclerosis (RRMS) by using T2 MRI lesions (T2L) as surrogates for disability and disease activity. ILS is often reported using inadequate concepts, e.g. subgroup analysis, correlation, odds ratios, sensitivity\/specificity, or metrics based on\u00a0Prentice\u2019s\u00a0criteria.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>LRF assesses ILS quality by determining prediction quality through shared information (MI) between surrogate(s) and clinical endpoint(s). A simulation study validates LRF as a measure of ILS quality. Individual-level data from ten randomized controlled trials (n\u2009=\u20095673) provided longitudinal information on T2L, T2 MRI lesion volumes (T2V), future disability progression (EDSS), and relapses. LRFs for different scenarios were calculated. Results were compared to those obtained by methods commonly applied in RRMS literature.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Simulations confirmed the robustness of LRF as a reliable ILS quality measure. Two of ten trials showed weak ILS between T2V and EDSS (LRF\u2009=\u20090.21, CI95%: 0.16\u20130.26; LRF\u2009=\u20090.28, CI95%: 0.23\u20130.34). Other LRFs were below 0.2. A method commonly used in the MS literature also showed no strong ILS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>LRF is an important measure to quantify ILS and prediction quality. But it is rarely applied in RRMS research. LRF did not reveal robust surrogacy patterns when applied to data of ten clinical trials. Existing surrogacy claims should be reassessed since ILS assessments in the MS literature may have major limitations.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0337893","type":"journal-article","created":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T18:36:52Z","timestamp":1766774212000},"page":"e0337893","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Individual-level surrogacy of MRI lesions for disease severity in RRMS: Methods to quantify predictive power and their application to longitudinal data from recent trials"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5453-3406","authenticated-orcid":true,"given":"Stefan","family":"Buchka","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim","family":"Havla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beg\u00fcm Irmak","family":"\u00d6n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphael","family":"Rehms","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9955-8906","authenticated-orcid":true,"given":"Ulrich","family":"Mansmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,12,26]]},"reference":[{"issue":"10","key":"pone.0337893.ref001","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1038\/nrneurol.2015.157","article-title":"Evidence-based guidelines: MAGNIMS consensus guidelines on the use of MRI in multiple sclerosis--establishing disease prognosis and monitoring patients","volume":"11","author":"MP Wattjes","year":"2015","journal-title":"Nat Rev Neurol"},{"issue":"8","key":"pone.0337893.ref002","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/S1474-4422(21)00095-8","article-title":"2021 MAGNIMS-CMSC-NAIMS consensus recommendations on the use of MRI in patients with multiple sclerosis","volume":"20","author":"MP Wattjes","year":"2021","journal-title":"Lancet Neurol"},{"key":"pone.0337893.ref003","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1017\/S0317167100014244","article-title":"Treatment optimization in MS: Canadian MS Working Group updated recommendations","volume":"40","author":"MS Freedman","year":"2013","journal-title":"Canadian Journal of Neurological Sciences"},{"issue":"4","key":"pone.0337893.ref004","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1017\/cjn.2020.66","article-title":"Treatment optimization in multiple sclerosis: canadian ms working group recommendations","volume":"47","author":"MS Freedman","year":"2020","journal-title":"Can J Neurol Sci"},{"key":"pone.0337893.ref005","doi-asserted-by":"crossref","first-page":"17562864241229325","DOI":"10.1177\/17562864241229325","article-title":"Prognostic relevance of MRI in early relapsing multiple sclerosis: ready to guide treatment decision making?","volume":"17","author":"O Hoffmann","year":"2024","journal-title":"Ther Adv Neurol Disord"},{"key":"pone.0337893.ref006","doi-asserted-by":"crossref","DOI":"10.1201\/9781315372662","volume-title":"Applied surrogate endpoint evaluation methods with SAS and R","author":"A Alonso","year":"2016"},{"issue":"9","key":"pone.0337893.ref007","article-title":"Prognostic models for predicting clinical disease progression, worsening and activity in people with multiple sclerosis","volume":"9","author":"K Reeve","year":"2023","journal-title":"Cochrane Database Syst Rev"},{"key":"pone.0337893.ref008","doi-asserted-by":"crossref","first-page":"101928","DOI":"10.1016\/j.msard.2020.101928","article-title":"Predictive medicine in multiple sclerosis: A systematic review","volume":"40","author":"J Havas","year":"2020","journal-title":"Mult Scler Relat Disord"},{"issue":"2","key":"pone.0337893.ref009","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1212\/WNL.0000000000002830","article-title":"Assessing response to interferon-\u03b2 in a multicenter dataset of patients with MS","volume":"87","author":"MP Sormani","year":"2016","journal-title":"Neurology"},{"issue":"5","key":"pone.0337893.ref010","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1177\/1352458513502399","article-title":"Interferon beta failure predicted by EMA criteria or isolated MRI activity in multiple sclerosis","volume":"20","author":"L Prosperini","year":"2014","journal-title":"Mult Scler"},{"issue":"5","key":"pone.0337893.ref011","doi-asserted-by":"crossref","DOI":"10.1212\/NXI.0000000000000379","article-title":"Predicting long-term disability outcomes in patients with MS treated with teriflunomide in TEMSO","volume":"4","author":"MP Sormani","year":"2017","journal-title":"Neurol Neuroimmunol Neuroinflamm"},{"key":"pone.0337893.ref012","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.msard.2016.05.012","article-title":"A lesion topography-based approach to predict the outcomes of patients with multiple sclerosis treated with Interferon Beta","volume":"8","author":"S Galassi","year":"2016","journal-title":"Mult Scler Relat Disord"},{"issue":"4","key":"pone.0337893.ref013","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1177\/1352458507085555","article-title":"Relationship between MRI lesion activity and response to IFN-beta in relapsing-remitting multiple sclerosis patients","volume":"14","author":"J R\u00edo","year":"2008","journal-title":"Mult Scler"},{"issue":"5","key":"pone.0337893.ref014","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1177\/1352458512460605","article-title":"Scoring treatment response in patients with relapsing multiple sclerosis","volume":"19","author":"MP Sormani","year":"2013","journal-title":"Mult Scler"},{"issue":"3","key":"pone.0337893.ref015","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1177\/1352458517698052","article-title":"Disability progression markers over 6-12\u2009years in interferon-\u03b2-treated multiple sclerosis patients","volume":"24","author":"J R\u00edo","year":"2018","journal-title":"Mult Scler"},{"key":"pone.0337893.ref016","doi-asserted-by":"crossref","DOI":"10.1212\/WNL.84.14_supplement.P7.239","article-title":"Disease activity in the first year predicts longer-term clinical outcomes in the pooled population of the phase III FREEDOMS and FREEDOMS II studies (P7.239)","volume":"84","author":"A Boster","year":"2015","journal-title":"Neurology"},{"issue":"6","key":"pone.0337893.ref017","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1177\/1352458507088104","article-title":"Magnetic resonance imaging as a surrogate outcome for multiple sclerosis relapses","volume":"14","author":"J Petkau","year":"2008","journal-title":"Mult Scler"},{"issue":"4","key":"pone.0337893.ref018","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1002\/ana.20224","article-title":"Defining interferon beta response status in multiple sclerosis patients","volume":"56","author":"RA Rudick","year":"2004","journal-title":"Ann Neurol"},{"issue":"2","key":"pone.0337893.ref019","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1002\/sim.4780110204","article-title":"Statistical validation of intermediate endpoints for chronic diseases","volume":"11","author":"LS Freedman","year":"1992","journal-title":"Stat Med"},{"issue":"5","key":"pone.0337893.ref020","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1177\/1352458510391837","article-title":"Magnetic resonance active lesions as individual-level surrogate for relapses in multiple sclerosis","volume":"17","author":"MP Sormani","year":"2011","journal-title":"Mult Scler"},{"issue":"18","key":"pone.0337893.ref021","doi-asserted-by":"crossref","first-page":"1684","DOI":"10.1212\/WNL.0b013e31823648b9","article-title":"Combined MRI lesions and relapses as a surrogate for disability in multiple sclerosis","volume":"77","author":"MP Sormani","year":"2011","journal-title":"Neurology"},{"key":"pone.0337893.ref022","doi-asserted-by":"crossref","first-page":"17562864231161892","DOI":"10.1177\/17562864231161892","article-title":"Retrospective cohort study to devise a treatment decision score predicting adverse 24-month radiological activity in early multiple sclerosis","volume":"16","author":"A Hapfelmeier","year":"2023","journal-title":"Ther Adv Neurol Disord"},{"key":"pone.0337893.ref023","unstructured":"Clinical Data Study Request. [Cited 2024 February 7]. www.ClinicalStudyDataRequest.com"},{"issue":"14","key":"pone.0337893.ref024","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1212\/WNL.0b013e31824e8ee7","article-title":"Alemtuzumab more effective than interferon \u03b2-1a at 5-year follow-up of CAMMS223 clinical trial","volume":"78","author":"AJ Coles","year":"2012","journal-title":"Neurology"},{"issue":"9856","key":"pone.0337893.ref025","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1016\/S0140-6736(12)61769-3","article-title":"Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial","volume":"380","author":"JA Cohen","year":"2012","journal-title":"Lancet"},{"issue":"11","key":"pone.0337893.ref026","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1212\/WNL.0000000000004354","article-title":"Alemtuzumab CARE-MS II 5-year follow-up: Efficacy and safety findings","volume":"89","author":"AJ Coles","year":"2017","journal-title":"Neurology"},{"issue":"9","key":"pone.0337893.ref027","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1177\/1352458511435984","article-title":"A randomized, controlled trial of fingolimod (FTY720) in Japanese patients with multiple sclerosis","volume":"18","author":"T Saida","year":"2012","journal-title":"Mult Scler"},{"issue":"5","key":"pone.0337893.ref028","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1056\/NEJMoa0909494","article-title":"A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis","volume":"362","author":"L Kappos","year":"2010","journal-title":"N Engl J Med"},{"issue":"5","key":"pone.0337893.ref029","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1056\/NEJMoa0907839","article-title":"Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis","volume":"362","author":"JA Cohen","year":"2010","journal-title":"N Engl J Med"},{"issue":"6","key":"pone.0337893.ref030","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/S1474-4422(14)70049-3","article-title":"Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial","volume":"13","author":"PA Calabresi","year":"2014","journal-title":"Lancet Neurol"},{"issue":"3","key":"pone.0337893.ref031","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1056\/NEJMoa1601277","article-title":"Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis","volume":"376","author":"SL Hauser","year":"2017","journal-title":"N Engl J Med"},{"issue":"9805","key":"pone.0337893.ref032","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1016\/S0140-6736(11)61649-8","article-title":"Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial","volume":"378","author":"L Kappos","year":"2011","journal-title":"Lancet"},{"key":"pone.0337893.ref033","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1093\/biomet\/35.3-4.246","article-title":"The transformation of poisson, binomial and negative-binomial data","volume":"35","author":"FJ Anscombe","year":"1948","journal-title":"Biometrika"},{"key":"pone.0337893.ref034","article-title":"Variance stabilization applied to microarray data calibration and to the quantification of differential expression","author":"W Huber","year":"2002","journal-title":"Bioinformatics"},{"issue":"4","key":"pone.0337893.ref035","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1002\/sim.4780080407","article-title":"Surrogate endpoints in clinical trials: definition and operational criteria","volume":"8","author":"RL Prentice","year":"1989","journal-title":"Stat Med"},{"issue":"2","key":"pone.0337893.ref036","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1002\/sim.2315","article-title":"A unifying approach for surrogate marker validation based on Prentice\u2019s criteria","volume":"25","author":"A Alonso","year":"2006","journal-title":"Stat Med"},{"issue":"1","key":"pone.0337893.ref037","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1093\/biomet\/70.1.163","article-title":"Information gain and a general measure of correlation","volume":"70","author":"JT KENT","year":"1983","journal-title":"Biometrika"},{"key":"pone.0337893.ref038","doi-asserted-by":"crossref","DOI":"10.1007\/b138566","volume-title":"The evaluation of surrogate endpoints","author":"T Burzykowski","year":"2005"},{"key":"pone.0337893.ref039","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1002\/asmb.2072","article-title":"Simulation of correlated poisson variables","volume":"31","author":"A Barbiero","year":"2015","journal-title":"Applied Stochastic Models in Business and Industry"},{"issue":"1","key":"pone.0337893.ref040","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1111\/1467-985X.00122","article-title":"Building multivariable prognostic and diagnostic models: transformation of the predictors by using fractional polynomials","volume":"162","author":"W Sauerbrei","year":"1999","journal-title":"Journal of the Royal Statistical Society Series A: Statistics in Society"},{"key":"pone.0337893.ref041","unstructured":"OpenAI. ChatGPT. 2025. https:\/\/www.openai.com"},{"issue":"5","key":"pone.0337893.ref042","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1097\/PAP.0000000000000072","article-title":"New guideline for the reporting of studies developing, validating, or updating a multivariable clinical prediction model: The TRIPOD statement","volume":"22","author":"Transparent Reporting of a Multivariate Prediction Model for Individual Prognosis or Development Initiative","year":"2015","journal-title":"Adv Anat Pathol"},{"key":"pone.0337893.ref043","volume-title":"Validity of surrogate endpoints in oncology","author":"IQWiG","year":"2011"},{"issue":"4","key":"pone.0337893.ref044","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1212\/CPJ.0000000000000254","article-title":"Consensus opinion of US neurologists on practice patterns in RIS, CIS, and RRMS: Evolution of treatment practices","volume":"6","author":"C Tornatore","year":"2016","journal-title":"Neurol Clin Pract"},{"issue":"1","key":"pone.0337893.ref045","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1186\/s12874-024-02264-9","article-title":"Framework for personalized prediction of treatment response in relapsing-remitting multiple sclerosis: a replication study in independent data","volume":"24","author":"AM Sakr","year":"2024","journal-title":"BMC Med Res Methodol"},{"key":"pone.0337893.ref046","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s41512-019-0064-7","article-title":"A simple, step-by-step guide to interpreting decision curve analysis","volume":"3","author":"AJ Vickers","year":"2019","journal-title":"Diagn Progn Res"},{"issue":"9","key":"pone.0337893.ref047","doi-asserted-by":"crossref","DOI":"10.1136\/bmjopen-2020-041537","article-title":"TRIPOD statement: a preliminary pre-post analysis of reporting and methods of prediction models","volume":"10","author":"AH Zamanipoor Najafabadi","year":"2020","journal-title":"BMJ Open"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0337893","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T18:37:02Z","timestamp":1766774222000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0337893"}},"subtitle":[],"editor":[{"given":"Simone","family":"Agostini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,12,26]]},"references-count":47,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12,26]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0337893","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,26]]}}}