SIEVE: Locus-Anchored Drug Prioritization for Complex Disorders
Strobl, E. V.
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MotivationComplex disorders arise from multiple genetic mechanisms, but most drug-prioritization methods treat each disorder as a single phenotype and therefore miss locus-specific therapeutic opportunities. ResultsWe present SIEVE, a framework that decomposes complex disorders into genetically localized subphenotypes and links GWAS summary statistics, reference expression, and perturbational transcriptional profiles to prioritize compounds that target locus-anchored disease mechanisms. SIEVE also constructs genetically calibrated mechanism vectors, projects away nonspecific expression programs using negative anchors, and aggregates evidence across cell lines, doses, and time points to produce robust drug rankings. Across simulations and analyses of real data, SIEVE improves compound prioritization relative to existing methods and shows that subphenotype-aware, genetics-guided modeling can sharpen therapeutic discovery in heterogeneous disorders. Availability and ImplementationR implementation: github.com/ericstrobl/SIEVE.
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