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Polygenic diseases have complex pathophysiology and disease heterogeneity, where diverse mechanisms drive disability progression in different patients. Effective treatments of such diseases require patient-specific therapies that target all mechanisms contributing to the patient’s disease expression. Although many putative pathogenic mechanisms have been identified in central nervous system (CNS) autopsy materials from patients with neuroinflammatory diseases such as multiple sclerosis (MS), current clinical practice cannot measure these processes in living human subjects. This limits drug development for CNS diseases and leads to sub-optimal outcomes in clinical practice. Using data-driven approaches with strong emphasis on research reproducibility, the Neuroimmunological Diseases Section (NDS) of the National Institute of Allergy and Infectious Diseases (NIAID) developed and validated (in independent cohorts) new clinical outcomes, molecular diagnostic and prognostic tests for neuroimmunological diseases with significantly higher accuracy than tools currently used in clinical practice. The mechanistic insight from these studies enhanced understanding of pathogenic mechanisms of neuroimmunological diseases and the identified therapeutic targets are currently explored in novel Phase II clinical trials of MS.