{"ID":2852238,"CreatedAt":"2026-06-01T04:54:23.091178241Z","UpdatedAt":"2026-06-01T04:54:23.091178241Z","DeletedAt":null,"paper_url":"https://arxiv.org/abs/2510.18571","arxiv_id":"2510.18571","title":"A Multi-Evidence Framework Rescues Low-Power Prognostic Signals and Rejects Statistical Artifacts in Cancer Genomics","abstract":"Motivation: Standard genome-wide association studies in cancer genomics rely on statistical significance with multiple testing correction, but systematically fail in underpowered cohorts. In TCGA breast cancer (n=967, 133 deaths), low event rates (13.8%) create severe power limitations, producing false negatives for known drivers and false positives for large passenger genes. Results: We developed a five-criteria computational framework integrating causal inference (inverse probability weighting, doubly robust estimation) with orthogonal biological validation (expression, mutation patterns, literature evidence). Applied to TCGA-BRCA mortality analysis, standard Cox+FDR detected zero genes at FDR\u003c0.05, confirming complete failure in underpowered settings. Our framework correctly identified RYR2 -- a cardiac gene with no cancer function -- as a false positive despite nominal significance (p=0.024), while identifying KMT2C as a complex candidate requiring validation despite marginal significance (p=0.047, q=0.954). Power analysis revealed median power of 15.1% across genes, with KMT2C achieving only 29.8% power (HR=1.55), explaining borderline statistical significance despite strong biological evidence. The framework distinguished true signals from artifacts through mutation pattern analysis: RYR2 showed 29.8% silent mutations (passenger signature) with no hotspots, while KMT2C showed 6.7% silent mutations with 31.4% truncating variants (driver signature). This multi-evidence approach provides a template for analyzing underpowered cohorts, prioritizing biological interpretability over purely statistical significance. Availability: All code and analysis pipelines available at github.com/akarlaraytu/causal-inference-for-cancer-genomics","short_abstract":"Motivation: Standard genome-wide association studies in cancer genomics rely on statistical significance with multiple testing correction, but systematically fail in underpowered cohorts. In TCGA breast cancer (n=967, 133 deaths), low event rates (13.8%) create severe power limitations, producing false negatives for kn...","url_abs":"https://arxiv.org/abs/2510.18571","url_pdf":"https://arxiv.org/pdf/2510.18571v1","authors":"[\"Gokturk Aytug Akarlar\"]","published":"2025-10-21T12:27:18Z","proceeding":"q-bio.GN","tasks":"[\"q-bio.GN\",\"cs.LG\"]","methods":"[]","has_code":false}