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Why Sample What You Can Enumerate? Exact Policy Optimization for Genomic Tool Selection

arXiv:2609.10221v1 Announce Type: new Abstract: Reinforcement learning over a frozen reasoner has become a common recipe for teaching a policy which external tools to invoke. We show that this recipe becomes structurally mismatched in specialist scientific settings where the complete tool-subset space is enumerable. There, a small set of recurring computational capabilities covers the domain, so the space of tool subsets is combinatorial yet small enough to enumerate, and GRPO still estimates an action expectation from a handful of sampled rollouts. Worse, the approximation degrades as training succeeds: as the policy concentrates on preferred subsets it resamples them, sampled rewards collide, and the group-normalized advantage vanishes. On genomic reasoning the fraction of questions yielding no reward signal rises from 0.2% under a uniform reference policy to 20.8% after GRPO training. As a remedy, we introduce FGPO (Full-Group Policy Optimization), which (1) scores every tool subset and optimizes the exact action expectation, so each update sees the complete action space, and (2) precomputes the reward of each question--subset pair into an exhaustive table, removing frozen-reasoner calls from the training loop entirely. Across five frozen reasoners and three genomic benchmarks, FGPO outperforms GRPO in all 15 settings by 6.75 points on average and up to 14.20, while a standard on-demand GRPO schedule would require 2.4 times as many frozen-reasoner reward evaluations and, on GenomeQA, FGPO cuts invoked tools per question from 2.36 to 1.40.

Pulmonary-Intestinal Axis: Shared Genetic Basis and Mediating Factors Identified Through Multi-Omics Analysis

14 April 2026 at 18:00

Int J Chron Obstruct Pulmon Dis. 2026 Apr 7;21:561645. doi: 10.2147/COPD.S561645. eCollection 2026.

ABSTRACT

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a systemic condition with comorbidities beyond the lung (eg, cardiovascular and metabolic disorders), and gastrointestinal (GI) disorders are also common. The shared genetic basis of COPD-GI comorbidity and its mediating factors remain unclear. We hypothesized that COPD and GI diseases share pleiotropic genetic architecture implicating lipid-metabolic pathways, with smoking mediating part of the association.

METHODS: We analyzed publicly available European-ancestry GWAS summary statistics for COPD (Global Biobank Meta-analysis Initiative), 15 GI diseases (FinnGen), and smoking phenotypes (UK Biobank). Genetic correlation was estimated using linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL). Multi-trait analysis of GWAS (MTAG) boosted COPD discovery by leveraging genetically correlated GI traits. We integrated locus-to-gene mapping with multi-tissue expression quantitative trait loci (eQTL) and plasma protein quantitative trait loci (pQTL) evidence to prioritize shared loci, genes, and proteins. Bidirectional two-sample Mendelian randomization (MR) tested causal directions, and two-step mediation MR evaluated smoking.

RESULTS: COPD showed significant genetic correlation with nine GI diseases. We identified six comorbidity-associated loci (three with CADD > 12.37) and 13 unique candidate pleiotropic genes; APOE was supported by proteomic evidence. Enrichment analyses highlighted lipid-metabolism pathways. MR suggested COPD increases risk of gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), acute appendicitis, and gastric ulcer, while diverticular disease showed reverse causality toward COPD. Smoking partially mediated the COPD effect on GERD, acute appendicitis, and gastric ulcer.

CONCLUSION: COPD and multiple GI disorders share a distributed pleiotropic genetic basis within the broader systemic comorbidity spectrum of COPD. Multi-omics evidence supports a genomic pulmonary-intestinal axis in which lipid metabolism and smoking-related mechanisms contribute to COPD and GI comorbidity, providing targets for risk stratification and potential intervention.

PMID:41978582 | PMC:PMC13070119 | DOI:10.2147/COPD.S561645

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