Predicting upper limb disability progression in primary progressive multiple sclerosis using machine learning and statistical methods

Abstract

Multiple sclerosis (MS) is a heterogeneous immune-mediated disorder of the central nervous system, and primary progressive MS (PPMS) is characterized by insidious injury independent of clinical relapses from disease onset. Predicting disease progression remains an unmet need across the MS disease spectrum. We evaluated statistical and machine learning (ML) models for predicting progression in 596 patients with PPMS from ORATORIO, a randomized, placebo (PBO)-controlled, phase 3 clinical study of ocrelizumab (OCR). Using baseline clinical, magnetic resonance imaging, and biomarker (neurofilament light chain [NfL]) data, we trained 6 ML models to predict a progression event (logistic regression, support vector machines, random forest, neural network, gradient boosting, and extreme gradient boosting) and the time to progression (Cox proportional hazards [PH]) on upper limb function, as measured by 20% confirmed worsening on the 9-hole peg test (9HPT). Predictive performance was similar across the six ML models (area under the curve = 0.63 to 0.67) and was modest using the Cox PH model (C-index = 0.76, an improvement over previous studies). In the Cox PH model, treatment arm, baseline 9HPT, neurologic functional system scores, and serum NfL levels were identified as factors associated with progression; model performance was similar across the OCR, PBO, and combined OCR + PBO treatment arms. Accounting for potential interactions with treatment arm resulted in similar predictive performance. To our knowledge, this is the first study to systematically evaluate ML models and statistical methods for predicting progression in PPMS using a well-characterized clinical trial cohort.