Predicting secondary progression in relapsing-remitting multiple sclerosis: a Bayesian analysis

Abstract

With the aid of a Bayesian statistical model of the natural course of relapsing remitting Multiple Sclerosis (MS), we identify short-term clinical predictors of long-term evolution of the disease, with particular focus on predicting onset of secondary progressive course (failure event) on the basis of patient information available at an early stage of disease. The model specifies the full joint probability distribution for a set of variables including early indicator variables (observed during the early stage of disease), intermediate indicator variables (observed throughout the course of disease, prefailure) and the time to failure. Our model treats the intermediate indicators as a surrogate response event, so that in right-censored patients, these indicators provide supplementary information pointing towards the unobserved failure times. Moreover, the full probability modelling approach allows the considerable uncertainty which affects certain early indicators, such as the early relapse rates, to be incorporated in the analysis. With such a model, the ability of early indicators to predict failure can be assessed more accurately and reliably, and explained in terms of the relationship between early and intermediate indicators. Moreover, a model with the aforementioned features allows us to characterize the pattern of disease course in high-risk patients, and to identify short-term manifestations which are strongly related to long-term evolution of disease, as potential surrogate responses in clinical trials. Our analysis is based on longitudinal data from 186 MS patients with a relapsing-remitting initial course. The following important early predictors of the time to progression emerged: age; number of neurological functional systems (FSs) involved; sphincter, or motor, or motor-sensory symptoms; presence of sequelae after onset. During the first 3 years of follow up, to reach EDSS> or =4 outside relapse, to have sphincter or motor relapses and to reach moderate pyramidal involvement were also found to be unfavourable prognostic factors.