Impact of methodological choices in comparative effectiveness studies: application in natalizumab versus fingolimod comparison among patients with multiple sclerosis

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  • M. Lefort
  • S. Sharmin
  • J. B. Andersen
  • S. Vukusic
  • R. Casey
  • M. Debouverie
  • G. Edan
  • J. Ciron
  • A. Ruet
  • J. De Sèze
  • E. Maillart
  • H. Zephir
  • P. Labauge
  • G. Defer
  • C. Lebrun-Frenay
  • T. Moreau
  • E. Berger
  • P. Clavelou
  • J. Pelletier
  • B. Stankoff
  • O. Gout
  • E. Thouvenot
  • O. Heinzlef
  • A. Al-Khedr
  • B. Bourre
  • O. Casez
  • P. Cabre
  • A. Montcuquet
  • A. Wahab
  • J. P. Camdessanché
  • A. Maurousset
  • H. Ben Nasr
  • K. Hankiewicz
  • C. Pottier
  • N. Maubeuge
  • D. Dimitri-Boulos
  • C. Nifle
  • D. A. Laplaud
  • D. Horakova
  • E. K. Havrdova
  • R. Alroughani
  • G. Izquierdo
  • S. Eichau
  • S. Ozakbas
  • F. Patti
  • M. Onofrj
  • A. Lugaresi
  • M. Terzi
  • P. Grammond
  • F. Grand’Maison
  • B. Yamout
  • A. Prat
  • M. Girard
  • P. Duquette
  • C. Boz
  • M. Trojano
  • P. McCombe
  • M. Slee
  • J. Lechner-Scott
  • R. Turkoglu
  • P. Sola
  • D. Ferraro
  • F. Granella
  • V. Shaygannejad
  • J. Prevost
  • D. Maimone
  • O. Skibina
  • K. Buzzard
  • A. Van der Walt
  • R. Karabudak
  • B. Van Wijmeersch
  • T. Csepany
  • D. Spitaleri
  • S. Vucic
  • N. Koch-Henriksen
  • C. C. Hilt Christensen
  • P. V. Rasmussen
  • J. L. Frederiksen
  • S. Bramow
  • H. K. Mathiesen
  • K. I. Schreiber
  • H. Butzkueven
  • M. Magyari
  • T. Kalincik
  • E. Leray

Background: Natalizumab and fingolimod are used as high-efficacy treatments in relapsing–remitting multiple sclerosis. Several observational studies comparing these two drugs have shown variable results, using different methods to control treatment indication bias and manage censoring. The objective of this empirical study was to elucidate the impact of methods of causal inference on the results of comparative effectiveness studies. Methods: Data from three observational multiple sclerosis registries (MSBase, the Danish MS Registry and French OFSEP registry) were combined. Four clinical outcomes were studied. Propensity scores were used to match or weigh the compared groups, allowing for estimating average treatment effect for treated or average treatment effect for the entire population. Analyses were conducted both in intention-to-treat and per-protocol frameworks. The impact of the positivity assumption was also assessed. Results: Overall, 5,148 relapsing–remitting multiple sclerosis patients were included. In this well-powered sample, the 95% confidence intervals of the estimates overlapped widely. Propensity scores weighting and propensity scores matching procedures led to consistent results. Some differences were observed between average treatment effect for the entire population and average treatment effect for treated estimates. Intention-to-treat analyses were more conservative than per-protocol analyses. The most pronounced irregularities in outcomes and propensity scores were introduced by violation of the positivity assumption. Conclusions: This applied study elucidates the influence of methodological decisions on the results of comparative effectiveness studies of treatments for multiple sclerosis. According to our results, there are no material differences between conclusions obtained with propensity scores matching or propensity scores weighting given that a study is sufficiently powered, models are correctly specified and positivity assumption is fulfilled.

TidsskriftBMC Medical Research Methodology
Udgave nummer1
Antal sider14
StatusUdgivet - 2022

Bibliografisk note

Funding Information:
We want to thank all the patients and participants involved in the study. This study was partially co-funded by Michael J. Fox Foundation [RRIA 2014 (Rapid Response Innovation Awards) Program (Grant ID: 10189)], by the Carlos III Health Institute, and the European Union (ERDF/ESF, “A Way to Make Europe”/“Investing in Your Future”) through the projects PI14/00679 and PI16/00005, the Juan Rodes grant “JR15/00008” (I.G.), and by the Department of Health of the Basque Government through the project “2016111009” and “2020333033”. A.J.M. was supported by a predoctoral grant from the Basque Government (PRE_2019_1_0070). M.I. acknowledges financial support from”La Caixa” Foundation (ID 100010434, fellowship LCF/BQ/EU20/11810065). The Edmond and Lily Safra Center for Brain Sciences and the Basque Government (POS_2019_2_0020) to A.E. J.M.C. is funded by Ikerbasque: The Basque Foundation for Science and from the Ministerial de Economia, Industria y Competitividad (Spain) and FEDER (grant DPI2016-79874-R), and from the Department of Economic and Infrastructure Development of the Basque Country (Elkartek Program, KK-2018/00032, KK-2018/00090, and KK-2021/00009/BCB).

Publisher Copyright:
© 2022, The Author(s).

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