Marginal structural Cox models for estimating the association between β-interferon exposure and disease progression in a multiple sclerosis cohort

Am J Epidemiol. 2014 Jul 15;180(2):160-71. doi: 10.1093/aje/kwu125. Epub 2014 Jun 17.


Longitudinal observational data are required to assess the association between exposure to β-interferon medications and disease progression among relapsing-remitting multiple sclerosis (MS) patients in the "real-world" clinical practice setting. Marginal structural Cox models (MSCMs) can provide distinct advantages over traditional approaches by allowing adjustment for time-varying confounders such as MS relapses, as well as baseline characteristics, through the use of inverse probability weighting. We assessed the suitability of MSCMs to analyze data from a large cohort of 1,697 relapsing-remitting MS patients in British Columbia, Canada (1995-2008). In the context of this observational study, which spanned more than a decade and involved patients with a chronic yet fluctuating disease, the recently proposed "normalized stabilized" weights were found to be the most appropriate choice of weights. Using this model, no association between β-interferon exposure and the hazard of disability progression was found (hazard ratio = 1.36, 95% confidence interval: 0.95, 1.94). For sensitivity analyses, truncated normalized unstabilized weights were used in additional MSCMs and to construct inverse probability weight-adjusted survival curves; the findings did not change. Additionally, qualitatively similar conclusions from approximation approaches to the weighted Cox model (i.e., MSCM) extend confidence in the findings.

Keywords: bias (epidemiology); causality; confounding factors (epidemiology); epidemiologic methods; inverse probability weighting; marginal structural Cox model; multiple sclerosis; survival analysis.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • British Columbia
  • Cohort Studies
  • Confounding Factors, Epidemiologic
  • Disease Progression*
  • Humans
  • Immunologic Factors / therapeutic use*
  • Interferon-beta / therapeutic use*
  • Multiple Sclerosis, Relapsing-Remitting / drug therapy*
  • Multiple Sclerosis, Relapsing-Remitting / physiopathology
  • Probability
  • Proportional Hazards Models*
  • Survival Analysis


  • Immunologic Factors
  • Interferon-beta