Multimodal predictors of functional and cognitive decline in relapsing-remitting multiple sclerosis

The underlying mechanisms for neurodegeneration in multiple sclerosis are complex and incompletely understood. Multivariate and multimodal investigations integrating demographic, clinical, multi-omics, and neuroimaging data provide opportunities for nuanced analyses, aimed to define disease progression markers. We used data from a 12-year longitudinal multicenter cohort of 88 people with multiple sclerosis, to test the predictive value of multi-omics, T1-weighted MRI (lesion count and volume, lesion-filled brain-predicted age), clinical examinations, self-reports on quality of life, demographics, and general health-related variables for future functional and cognitive disability. Systematic increases in Expanded Disability Status Scale (EDSS) scores were used to stratify a progressive disability group (PDG) from relatively stabile disability. A processing speed decline group (PSDG) was defined by a [&ge;]20% decrease from the maximum (cognitive) Paced Auditory Serial Addition Test score. We used a multiverse approach to identify which baseline variables were most predictive for PDG and PSDG memberships, considering multiple analysis paths. Future disability (median area under the curve: mAUC=0.83{+/-}0.04, median Brier score: mBS=0.16{+/-}0.02) and the loss of processing speed (mAUC=0.89{+/-}0.05, mBS=0.10{+/-}0.03) could be successfully classified across models. Varibles significantly (median p-values<0.05) predicting stable disability included receiving disease modifying treatment at 12-year follow-up (median Odds Ratio: mORPDG=7.44{+/-}4.07, pmedian=0.013, proportion of the ORs directionality: PORSD=100%), lower baseline EDSS for each 1-unit (mORPDG=0.25{+/-}0.11, pmedian=0.013, PORSD=100%), and counter-intuitively every year increase in baseline age (mORPDG=1.12{+/-}0.04, pmedian=0.020, PORSD=100%), and lower vitamin A per 1 umol/L (mORPDG=0.10{+/-}0.05, pmedian=0.016, PORSD=99.7%) and D levels per 1 nmol/L (mORPDG=0.95{+/-}0.02, pmedian=0.025, PORSD=100%). Variables significantly predicting stable processing speed were receiving disease modifying treatment at 12-year follow-up (mORPSDG=0.10{+/-}0.08, pmedian=0.013, PORSD=100%) and baseline PASAT score (mORPSDG=0.86{+/-}0.03, pmedian=0.005, PORSD=99.73%). These findings were supported by an additional simulation study. Concordant with the literature, disease modifying treatments influence disability progression, as well as a higher EDSS and PASAT scores at measurement start. Experimental and counterintuitive findings on vitamin A and D levels require further validation. The large variability across models suggests a strong influence of analytic flexibility, such as the selection of covariates.