Flexible modeling of disease activity measures improved prognosis of disability progression in relapsing-remitting multiple sclerosis

Objectives: 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). Study Design and Setting: 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 (I) 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. Conclusion: 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. (C) 2015 Elsevier Inc. All rights reserved.