A Multi-Evidence Framework Rescues Low-Power Prognostic Signals and Rejects Statistical Artifacts in Cancer Genomics
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arXiv
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| Format: | Preprint |
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2025
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| author | Akarlar, Gokturk Aytug |
| author_facet | Akarlar, Gokturk Aytug |
| contents | 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<0.05, 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 |
| format | Preprint |
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arxiv_https___arxiv_org_abs_2510_18571 |
| institution | arXiv |
| publishDate | 2025 |
| record_format | arxiv |
| spellingShingle | A Multi-Evidence Framework Rescues Low-Power Prognostic Signals and Rejects Statistical Artifacts in Cancer Genomics Akarlar, Gokturk Aytug Genomics Machine Learning 92B15, 62P10, 62F10, 62H17 J.3; I.2.6; G.3 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<0.05, 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 |
| title | A Multi-Evidence Framework Rescues Low-Power Prognostic Signals and Rejects Statistical Artifacts in Cancer Genomics |
| topic | Genomics Machine Learning 92B15, 62P10, 62F10, 62H17 J.3; I.2.6; G.3 |
| url | https://arxiv.org/abs/2510.18571 |