Developing a clinical–environmental–genotypic prognostic index for relapsing-onset multiple sclerosis and clinically isolated syndrome
Authors: Fuh-Ngwa Valery , Zhou Yuan , Charlesworth Jac C , Ponsonby Anne-Louise , Simpson-Yap Steve , Lechner-Scott Jeannette , Taylor Bruce V ,   AusLong/Ausimmune Investigators Group, Dear Keith , Dwyer Terry , van der Mei Ingrid , Kilpatrick Trevor , Williams David , Lechner-Scott Jeanette , Shaw Cameron , Chapman Caron , Coulthard Alan , Pender Michael P , Valery Patricia 
Published: November 2021

Our inability to reliably predict disease outcomes in multiple sclerosis remains an issue for clinicians and clinical trialists. This study aims to create, from available clinical, genetic and environmental factors; a clinical–environmental–genotypic prognostic index to predict the probability of new relapses and disability worsening. The analyses cohort included prospectively assessed multiple sclerosis cases (N = 253) with 2858 repeated observations measured over 10 years. N = 219 had been diagnosed as relapsing-onset, while N = 34 remained as clinically isolated syndrome by the 10th-year review. Genotype data were available for 199 genetic variants associated with multiple sclerosis risk. Penalized Cox regression models were used to select potential genetic variants and predict risk for relapses and/or worsening of disability. Multivariable Cox regression models with backward elimination were then used to construct clinical–environmental, genetic and clinical–environmental–genotypic prognostic index, respectively. Robust time-course predictions were obtained by Landmarking. To validate our models, Weibull calibration models were used, and the Chi-square statistics, Harrell’s C-index and pseudo-R2 were used to compare models. The predictive performance at diagnosis was evaluated using the Kullback–Leibler and Brier (dynamic) prediction error (reduction) curves. The combined index (clinical–environmental–genotypic) predicted a quadratic time-dynamic disease course in terms of worsening (HR = 2.74, CI: 2.00–3.76; pseudo-R2=0.64; C-index = 0.76), relapses (HR = 2.16, CI: 1.74–2.68; pseudo-R2 = 0.91; C-index = 0.85), or both (HR = 3.32, CI: 1.88–5.86; pseudo-R2 = 0.72; C-index = 0.77). The Kullback–Leibler and Brier curves suggested that for short-term prognosis (≤5 years from diagnosis), the clinical–environmental components of disease were more relevant, whereas the genetic components reduced the prediction errors only in the long-term (≥5 years from diagnosis). The combined components performed slightly better than the individual ones, although their prognostic sensitivities were largely modulated by the clinical–environmental components. We have created a clinical–environmental–genotypic prognostic index using relevant clinical, environmental, and genetic predictors, and obtained robust dynamic predictions for the probability of developing new relapses and worsening of symptoms in multiple sclerosis. Our prognostic index provides reliable information that is relevant for long-term prognostication and may be used as a selection criterion and risk stratification tool for clinical trials. Further work to investigate component interactions is required and to validate the index in independent data sets.