Gokturk Aytug Akarlar

Gokturk Aytug Akarlar

Large language models show promise as autonomous decision-making agents, yet their deployment in high-stakes domains remains fraught with risk. Without architectural safeguards, LLM agents exhibit catastrophic brittleness: identical capabilities produce wildly different outcomes depending solely on prompt framing. We present Chimera, a neuro-symbolic-causal architecture that integrates three complementary components - an LLM strategist, a formally verified symbolic constraint engine, and a causal inference module for counterfactual reasoning. We benchmark Chimera against baseline architectures (LLM-only, LLM with symbolic constraints) across 52-week simulations in a realistic e-commerce environment featuring price elasticity, trust dynamics, and seasonal demand. Under organizational biases toward either volume or margin optimization, LLM-only agents fail catastrophically (total loss of \$99K in volume scenarios) or destroy brand trust (-48.6% in margin scenarios). Adding symbolic constraints prevents disasters but achieves only 43-87% of Chimera's profit. Chimera consistently delivers the highest returns (\$1.52M and \$1.96M respectively, some cases +\$2.2M) while improving brand trust (+1.8% and +10.8%, some cases +20.86%), demonstrating prompt-agnostic robustness. Our TLA+ formal verification proves zero constraint violations across all scenarios. These results establish that architectural design not prompt engineering determines the reliability of autonomous agents in production environments. We provide open-source implementations and interactive demonstrations for reproducibility.

Gokturk Aytug Akarlar

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