title: Flexible modeling of disease activity measures improved prognosis of disability progression in relapsing-remitting multiple sclerosis.
abstract: OBJECTIVE
  To illustrate the advantages of updating time-varying measures of disease activity and flexible modeling in prognostic clinical studies using the example of the association between the frequency of past relapses and occurrence of ambulation-related disability in multiple sclerosis (MS).
  
  
  METHODS
  Longitudinal population-based study of 288 patients from Burgundy, France, diagnosed with relapsing-remitting MS in 1990-2003. The end point was a nonreversible moderate MS disability (European Database for Multiple Sclerosis score ≥ 3.0 derived from Extended Disability Status Scale). Alternative time-varying measures of attacks frequency included (1) conventional number of early MS attacks in the first 2 years after diagnosis; and two new measures, continuously updated during the follow-up; (2) cumulative number of past attacks; and (3) number of recent attacks, during the past 2 years. Multivariate analyses used Cox proportional hazards model and its flexible generalization, which accounted for time-dependent changes in the hazard ratios (HRs) for different attack frequency measures.
  
  
  RESULTS
  HRs for all measures decreased significantly with increasing follow-up time. The proposed updated number of recent attacks improved model's fit to data, relative to alternative measures of attack frequency, and was associated with a statistically significantly increased hazard of developing ambulation-related MS disability in the next 2 years during the entire follow-up period.
  
  
  CONCLUSIONS
  Updated measures of recent disease activity, such as frequency of recent attacks and modeling of their time-dependent effects, may substantially improve prognosis of clinical outcomes, such as development of MS disability.
authors.affiliation: Department of Biostatistics and Epidemiology, Institut Gustave Roussy, Villejuif, Paris, France.
authors.forename: Gwénaël
authors.initials: G
authors.lastname: Le Teuff
authors.affiliation: Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada; Division of Clinical Epidemiology, McGill University Health Centre, Royal Victoria Hospital, 687 Pine Avenue West, V Building, Montreal, Quebec, Canada H3A 1A1.
authors.forename: Michal
authors.initials: M
authors.lastname: Abrahamowicz
authors.affiliation: Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada; Division of Clinical Epidemiology, McGill University Health Centre, Royal Victoria Hospital, 687 Pine Avenue West, V Building, Montreal, Quebec, Canada H3A 1A1.
authors.forename: Willy
authors.initials: W
authors.lastname: Wynant
authors.affiliation: INSERM, CIC 1432, 21000 Dijon, France; Clinical Investigation Center, Dijon University Hospital, Clinical Epidemiology/Clinical Trials Unit, Dijon, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Binquet
authors.affiliation: Department of Neurology, Centre Hospitalier Universitaire de Dijon, BP 77908, 21079 Dijon Cedex, France.
authors.forename: Thibault
authors.initials: T
authors.lastname: Moreau
authors.affiliation: INSERM, CIC 1432, 21000 Dijon, France; Clinical Investigation Center, Dijon University Hospital, Clinical Epidemiology/Clinical Trials Unit, Dijon, France; Department of Neurology, Centre Hospitalier Universitaire de Dijon, BP 77908, 21079 Dijon Cedex, France; Department of Biostatistics and Medical Informatics, Centre Hospitalier Universitaire de Dijon, BP 77908, 21079 Dijon Cedex, France. Electronic address: catherine.quantin@chu-dijon.fr.
authors.forename: Catherine
authors.initials: C
authors.lastname: Quantin
mesh_terms: D000328:Adult; D016208:Databases, Factual; D004185:Disability Evaluation; D018450:Disease Progression; D005260:Female; D005602:France / Q000453:epidemiology; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D015233:Models, Statistical; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000175:diagnosis*; D011379:Prognosis; D012008:Recurrence; D012720:Severity of Illness Index; D055815:Young Adult
keywords: Attack frequency; Disability; Multiple sclerosis; Prognostic studies; Time-dependent effects; Time-varying covariates