Understanding genotype-phenotype relationships or development/validation of biomarkers requires large multicenter cohorts integrated by universal quantification of crucial phenotypical traits, such as central nervous system (CNS) tissue destruction. We hypothesized that mathematical modeling-guided combination of biologically meaningful, semi-quantitative MRI elements characterized by high signal-to-noise ratio will provide such reliable, universal tool for measuring CNS tissue destruction. We retrospectively graded 15 elements in MRI scans performed in 419 untreated subjects with or without neurological diseases, while being blinded to their prospectively acquired clinical scores. We then used 305 subjects for disability-guided mathematical modeling to select and combine MRI elements that had non-redundant contributions to clinical disability, resulting in Combinatorial MRI Scale (COMRIS). We validated our model on the remaining 114 independent subjects. COMRIS requires 5-10 minutes per scan on average to compute and demonstrates highly significant (p<0.0001) and validation-consistent Spearman correlation coefficients (0.75, 0.76, and 0.65) for the expanded disability status scale (EDSS), Scripps neurological rating scale (SNRS), and symbol digit modality test (SDMT) measures of neurological disability, respectively. Because COMRIS is not greatly influenced by MRI scanners or protocols and can be computed even in the presence of some motion artifacts, it does not require censoring out patients and it provides comparable results across different cohorts. As such, it represents a broadly available clinical and research tool that can facilitate multicenter research studies and comparative analyses across patient cohorts and research projects via Multiple Sclerosis and Related Disorders.
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