title: Establishing long-term efficacy in chronic disease: use of recursive partitioning and propensity score adjustment to estimate outcome in MS.
abstract: BACKGROUND
  Establishing the long-term benefit of therapy in chronic diseases has been challenging. Long-term studies require non-randomized designs and, thus, are often confounded by biases. For example, although disease-modifying therapy in MS has a convincing benefit on several short-term outcome-measures in randomized trials, its impact on long-term function remains uncertain.
  
  
  OBJECTIVE
  Data from the 16-year Long-Term Follow-up study of interferon-beta-1b is used to assess the relationship between drug-exposure and long-term disability in MS patients.
  
  
  METHODS
  To mitigate the bias of outcome-dependent exposure variation in non-randomized long-term studies, drug-exposure was measured as the medication-possession-ratio, adjusted up or down according to multiple different weighting-schemes based on MS severity and MS duration at treatment initiation. A recursive-partitioning algorithm assessed whether exposure (using any weighing scheme) affected long-term outcome. The optimal cut-point that was used to define "high" or "low" exposure-groups was chosen by the algorithm. Subsequent to verification of an exposure-impact that included all predictor variables, the two groups were compared using a weighted propensity-stratified analysis in order to mitigate any treatment-selection bias that may have been present. Finally, multiple sensitivity-analyses were undertaken using different definitions of long-term outcome and different assumptions about the data.
  
  
  METHODS
  Long-Term Disability.
  
  
  RESULTS
  In these analyses, the same weighting-scheme was consistently selected by the recursive-partitioning algorithm. This scheme reduced (down-weighted) the effectiveness of drug exposure as either disease duration or disability at treatment-onset increased. Applying this scheme and using propensity-stratification to further mitigate bias, high-exposure had a consistently better clinical outcome compared to low-exposure (Cox proportional hazard ratio = 0.30-0.42; p<0.0001).
  
  
  CONCLUSIONS
  Early initiation and sustained use of interferon-beta-1b has a beneficial impact on long-term outcome in MS. Our analysis strategy provides a methodological framework for bias-mitigation in the analysis of non-randomized clinical data.
  
  
  BACKGROUND
  Clinicaltrials.govNCT00206635.
authors.affiliation: Department of Neurology, University of California San Francisco, San Francisco, California, United States of America. douglas.goodin@ucsf.edu
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Goodin
authors.forename: Jason
authors.initials: J
authors.lastname: Jones
authors.forename: David
authors.initials: D
authors.lastname: Li
authors.forename: Anthony
authors.initials: A
authors.lastname: Traboulsee
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Reder
authors.forename: Karola
authors.initials: K
authors.lastname: Beckmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Konieczny
authors.forename: Volker
authors.initials: V
authors.lastname: Knappertz
mesh_terms: D000328:Adult; D000465:Algorithms; D002908:Chronic Disease; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000068576:Interferon beta-1b; D016899:Interferon-beta / Q000627:therapeutic use; D008297:Male; D009103:Multiple Sclerosis / Q000188:drug therapy*; D017063:Outcome Assessment, Health Care / Q000379:methods*; D057216:Propensity Score; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D013997:Time Factors
chemical_list: D000068576:Interferon beta-1b; D016899:Interferon-beta