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STUDY OBJECTIVE To employ systems biology-based machine learning to identify biologic processes over-represented with genetic variants (gene enrichment) implicated in post-surgical pain. DESIGN Informed systems biology based integrative computational analyses. SETTING Pediatric research and teaching institution. INTERVENTIONS Pubmed search (01/01/2001-10/31/2017) was performed to identify "training" genes associated with postoperative pain in humans. Candidate genes were identified and prioritized using Toppgene suite, based on functional