(2026) Causal effects of multiple sclerosis therapies in left-truncated registry data. Multiple sclerosis (Houndmills, Basingstoke, England). pp. 1052-1068. ISSN 1477-0970 (Electronic) 1352-4585 (Print) 1352-4585 (Linking)
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Official URL: https://www.ncbi.nlm.nih.gov/pubmed/42479470
Abstract
BACKGROUND: Left-truncation is an unrecorded interval between multiple sclerosis (MS) onset and initial data in observational studies. This delay may bias estimates of disease-modifying therapy (DMT) effectiveness, especially when determined by patient or disease characteristics. OBJECTIVES: To examine whether causal effect estimates of DMTs over the full disease course can be reliably derived from left-truncated registry data. METHODS: We analysed data from MSBase (144 centres, 41 countries) to assess the impact of left-truncation on causal treatment effect estimates. Cox marginal structural models (MSMs) estimated hazard ratios (HRs) for relapses, disability worsening and improvement, considering left-truncation at random and not-at-random. Fixed-time truncation and multivariable adjustment were applied to remediate bias. RESULTS: The study included 5588 patients tracked from true MS onset. The null model, without left-truncation, estimated the DMT effect on relapse risk (HR = 0.64; 95 confidence interval (CI) = 0.54-0.77). Left-truncation inflated this estimate. Shorter random truncation (1 year) produced greater bias (HR = 0.34), decreasing with longer durations (3-year HR = 0.48). Truncation not-at-random biased relapse estimates (HR = 0.37). Disability outcomes were less sensitive. CONCLUSION: MSMs can reliably estimate DMT effectiveness in left-truncated MS registry data, although accuracy depends on truncation mechanism and duration. Both random and not-at-random truncation impact relapse estimates. Disability outcomes appear less sensitive. Fixed-time truncation and covariate adjustment mitigated bias.
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| Keywords: | Humans *Registries/statistics & numerical data *Multiple Sclerosis/drug therapy/epidemiology/therapy Female Adult Male *Outcome Assessment, Health Care/statistics & numerical data *Immunologic Factors/therapeutic use Middle Aged Disease Progression Time Factors Multiple sclerosis causal inference disease-modifying therapies left-truncation marginal structural modelling conflicts of interest with respect to the research, authorship and/or publication of this article: D.C.H. reports no disclosures relevant to the manuscript I. D. reports no disclosures relevant to the manuscript S.O. reports no disclosures relevant to the manuscript D.H. was supported by the Charles University: Cooperatio Program in Neuroscience, by the project National Institute for Neurological Research (Programme EXCELES, ID Project No. LX22NPO5107) - Funded by the European Union - Next 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 E.K.H. received honoraria/research support from Biogen, Merck Serono, Novartis, Roche and Teva has been member of advisory boards for Actelion, Biogen, Celgene, Merck Serono, Novartis and Sanofi-Genzyme received honoraria/research support from Biogen, Merck Serono, Novartiss, Roche and Teva has been member of advisory boards for Actelion, Biogen, Celgene, Merck Serono, Novartis and Sanofi-Genzyme and has been supported by the Czech Ministry of Education - project Cooperatio LF1, research area Neuroscience and the project National Institute for Neurological Research (Programme EXCELES, ID project No LX22NPO5107) - funded by the European Union-Next Generation EU F.P. received personal compensation for serving on advisory board by Almirall, Alexion, Biogen, Bristol, Janssen, Merck, Novartis and Roche. He further received research grant by Alexion, Almirall, Biogen, Bristol, Merck, Novartis and Roche and by FISM, Reload Association (Onlus), Italian Health Minister and University of Catania S.E. has received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Janssen, Bristol Myers, Bayer, Sanofi-Genzyme, Roche and Teva R.A. received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche and Sanofi-Genzyme A.L. received personal compensation for consulting, serving on a scientific advisory board, speaking or other activities from Alexion, Amgen/Horizon, Biogen, Bristol Myers Squibb/Celgene, Janssen/Johnson & Johnson, Merck Serono, Novartis, Roche and Sanofi/Genzyme, and her institutions received research grants from Novartis, Roche and Sanofi/Genzyme V.T. 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 and Lundbeck A.P. reports no disclosures relevant to the manuscript M.G. reports no disclosures relevant to the manuscript M.T. received travel grants from Novartis, Bayer Schering, Merck and Teva has participated in clinical trials by Sanofi-Aventis, Roche and Novartis B.Y. received honoraria, consulting/speaker fees and research grants from Merck Serono, Biogen, Bayer, Novartis and Sanofi S.J.K. received compensation for serving on the IDMC for Biogen P.G. has served in 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 and EMD Serono Y.B. received speaker honoraira/consulting fees from Merck, Biogen, Roche, Brystol, Novartis, Sanofi and Sandoz V.S. reports no disclosures relevant to the manuscript M.F. received economic support for travel and meeting attendance from Roche, Novartis, Merck, Sanofi, Bristol Myers and served as a scientific consultant for Roche and Novartis A.S. received travel and meeting attendance support from Novartis, Biogen, Roche, Merck, Bristol, Sanofi-Genzyme, Almirall and Piam S.N. declares no conflicts of interest or financial disclosures related to the project B.W.-G. is a consultant for EMD Serono, SANA and Immunic Therapeutics. Dr W.-G. also has received grant/research support from Novartis, Biogen and Horizon/Amgen J.P. accepted travel compensation from Novartis, Biogen, Roche and EMD Serono and speaking honoraria from Biogen, Novartis, Roche and EMD Serono M.P.A. received honoraria as a consultant on scientific advisory boards by Biogen, Bayer Schering, Merck, Teva and Sanofi-Aventis and has received research grants by Biogen, Bayer Schering, Merck, Teva and Novartis M.B. 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 O.G. reports no disclosures relevant to the manuscript N.J. is a PI on commercial MS studies sponsored by Novartis, Roche, Biogen and Sanofi. He has received speaker's honoraria from Merck. He has had conference travel and registration reimbursement and consultancy fees from Novartis A.G.K. reports no disclosures relevant to the manuscript M.F.P. received travel compensation from Merck W.C. is a recipient of travel assistance and honoraria for participation in industry-sponsored meetings from and provided advice to Bayer Schering Pharma, Biogen Idec, Novartis, Roche, Genzyme, Sanofi-Aventis, CSL, Teva, Merck and Celgene A.v.W. 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 H.B. received institutional (Monash University) funding from Biogen, Roche, Merck, Alexion and Novartis has carried out contracted research for Novartis, Merck, Roche and Biogen has taken part in speakers' bureaus for Biogen, Novartis, Roche and Merck has received personal compensation from Oxford Health Policy Forum for the Brain Health Steering Committee V.v.P. has received travel grants from Merck Healthcare KGaA (Darmstadt, Germany), Biogen, Sanofi, Bristol Myers Squibb, Almirall, Roche and Eisai. His institution has received research grants and consultancy fees from Roche, Biogen, Sanofi, Merck Healthcare KGaA (Darmstadt, Germany), Bristol Myers Squibb, Janssen, Almirall, Novartis Pharma, Alexion, Neuraxpharm and Eisai A.S. reports no disclosures relevant to the manuscript R.G. has received research grant and/or advisory board honoraria from Biogen, Hikma, Merck, Roche and Sanofi S.M. has received a MENACTRIMS clinical fellowship grant (2020) D.S. 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 E.C. reports no disclosures relevant to the manuscript D.M. received speaker honoraria for advisory board and travel grants from Alexion, Almirall, Bayer, Biogen, Bristol Myers Squibb, Merck, Novartis, Roche, Sanofi-Genzyme and Teva R.A. received conference travel support from Novartis, Teva, Biogen, Bayer and Merck and has participated in clinical trials by Biogen, Novartis, Teva and Actelion G.L. received travel and/or consultancy compensation from Sanofi-Genzyme, Roche, Teva, Merck, Novartis, Celgene and Biogen C.R.T. 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 M.D.G. reports no disclosures relevant to the manuscript E.L. has received speaker fees from AbbVie, Alexion, Novartis, Biogen, EMD Serono, Sanofi-Genzyme and Roche as well as consulting fees from Alexion, Novartis, Biogen, EMD Serono, Lundbeck, Sanofi-Genzyme and Horizon M.S. reports no disclosures relevant to the manuscript R.K. received honoraria for consulting, lectures and advisory boards from Sanofi-Genzyme, Roche, Novartis, Merck Serono, Gen Ilac TR, Sanovel and Teva J.G. received conference travel support from Roche, Merck and Novartis, received speaker honoraria from Biogen and research support from Roche A.A. received speaker honoraria from Novartis and Alexion S.H. 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 J.L.S.-M. 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 T.C.T. received speaking/consulting fees and/or travel funding from Almirall, Biogen, Bristol Myers Squibb, Janssen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva M.H. received consultation and/or speaker fees from Biogen, Merck, Novartis, Roche, Astra Zeneca and Amgen A.A.A. received personal compensation for serving as a Scientific Advisory or speaker/moderator for Novartis, Biogen, Roche, Sanofi-Genzyme and Merck T.A.H. reports no disclosures relevant to the manuscript T.C. received speaker honoraria/ conference travel support from Biogen, Merck, Novartis, Roche, Sanofi-Aventis and Teva S.C.R. in the past 3 years 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 Neurologica Colombiana and a member of the editorial board of Frontiers of Neurology B.T. 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 Y.C.F. received travel compensation and honoraria from Biogen and Roche and research grant support from the National Health and Medical Research Council, Multiple Sclerosis Research Australia and Australian and New Zealand Association of Neurologists B.W. received honoraria for acting as a member of Scientific Advisory Boards/Consultancy for Alexion, Almirall, Biogen, Celgene/BMS, Merck, Galapagos, Janssen, Novartis, Roche, Sandoz, Sanofi-Genzyme and speaker honoraria and travel support from EAN, ECTRIMS, Biogen, Celgene/BMS, Merck, Novartis, Roche, Sanofi-Genzyme and UCB research and/or patient support grants from Amgen, Biogen, Janssen, Merck, Sanofi-Genzyme and Roche. Honoraria and grants were paid to UZA/UZA Foundation. Furthermore, B.W. received research funding from UZA Foundation, FWO-TBM, Belgian Charcot Foundation, Start2Cure Foundation, Queen Elisabeth Medical Foundation for Neurosciences and the National MS Society US N.S. reports no disclosures relevant to the manuscript F.M. participated in clinical trials sponsored by EMD Serono and Novartis C.M. received honoraria as consultant on scientific advisory boards for Genzyme, BMS, Janssen, Biogen, Merck, Roche and Novartis has received travel grants from Roche & Novartis S.M.B. have served on scientific advisory boards and have received conference travel support and/or speaker honoraria from several pharmaceutical companies including Roche, Novartis, Merck, Cinnagen, Nanoalvand and Biogen J.M. reports no disclosures relevant to the manuscript T.A.H. 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 S.R. 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 K.G.P. received honoraria for speaking and/or travel expense from Biogen, Merck, Novartis, Roche, Sandoz and Janssen O.G. 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 and has participated in clinical trials by Biogen and Merck. Her institution has received research grant support from Biogen D.D. received compensation for travel, speaker honoraria and consultant fees from Biogen, Novartis, Merck KGaA, Bayer, Sanofi/Genzyme, Roche and Teva, as well as support for research activities from Biogen, Novartis, Merck, Sanofi, Roche & Teva C.S. received travel assistance from Biogen and Novartis P.M. received honoraria and consulting fees from Novartis, Bayer Schering and Sanofi and travel grants from Novartis, Biogen and Bayer Schering C.R. received speaker honoraria from Bayer Schering, Novartis and Biogen and congress and travel expense compensations from Biogen, Teva, Merck and Bayer Schering E.S. reports no disclosures relevant to the manuscript S.S. reports no disclosures relevant to the manuscript I.R. served on scientific advisory boards and received conference travel support and/or speaker honoraria from Roche, Novartis, Merck and Biogen. I.R. is supported by MS Australia and the Trish Multiple Sclerosis Research Foundation T.K. served on scientific advisory boards or as a consultant for the MS International Federation and World Health Organization, Therapeutic Goods Administration, BMS, Roche, Janssen, Genzyme, Novartis, Merck and Biogen received conference travel support and/or speaker honoraria from WebMD Global, Merck, Sandoz, Novartis, Biogen, Roche, Eisai, Genzyme, Teva and BioCSL and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck. |
| Page Range: | pp. 1052-1068 |
| Journal or Publication Title: | Multiple sclerosis (Houndmills, Basingstoke, England) |
| Journal Index: | Pubmed |
| Volume: | 32 |
| Number: | 10 |
| Identification Number: | https://doi.org/10.1177/13524585261459943 |
| ISSN: | 1477-0970 (Electronic) 1352-4585 (Print) 1352-4585 (Linking) |
| Depositing User: | خانم ناهید ضیائی |
| URI: | http://eprints.mui.ac.ir/id/eprint/34505 |
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