Advancing Clinical Genomic Analysis with a Skill-Centred Agent

Background. Large language models and AI agents are increasingly used to support biomedical research, but native model outputs may omit key analytical steps, misuse methods, or overstate conclusions. We evaluated whether autonomous access to a medical research skill package was associated with higher-quality AI-generated transcriptomic research-analysis outputs compared with native AI without skills. Methods. We conducted an exploratory multi-model human evaluation using a non-small cell lung cancer immunotherapy biomarker task. Six model backbones were tested. The evaluation included 21 anonymized outputs: 9 native-AI outputs and 12 skill-augmented outputs generated through an AI agent implementation represented by OpenClaw. Four non-expert biomedical reviewers and two blinded experts evaluated each output, with two ratings from each reviewer type. The primary outcome was expert-rated overall quality. Results. Skill-augmented outputs showed directionally higher expert overall quality than native-AI outputs (mean 5.50 vs 5.11; difference=0.39; bootstrap 95% CI, -0.04 to 0.90; Welch p=0.156). Non-expert reviewer quality showed the same direction (mean 4.72 vs 4.47; difference=0.26; bootstrap 95% CI, -0.25 to 0.80; Welch p=0.373). Expert agreement was limited (single-rating ICC=-0.15), and model-specific effects were descriptive and heterogeneous. Conclusions. Autonomous skill access showed a directional quality signal in this exploratory sample, but the signal was smaller than expert-rating noise and should not be interpreted as confirmatory evidence. The findings primarily motivate larger evaluations of skill-augmented AI agents with stronger reliability controls, platform replication, and biological-validity assessment.

Disease severity classification for genetic conditions is subjective and labor-intensive, creating bottlenecks in genomic screening, where commercial panels vary widely in size and overlap. We developed an autonomous AI agent integrating Reasoning and Acting (ReAct) with Retrieval-Augmented Generation (RAG) to classify 10,211 Human Phenotype Ontology terms. It uses American College of Medical Genetics (ACMG)-endorsed severity guidelines and American College of Obstetricians and Gynecologists (ACOG) quality-of-life criteria to retrieve PubMed literature, generate interpretable reasoning chains, and independently verify claims. At the phenotype level, using expert-curated cohorts, the agent achieved 93.55% accuracy (MCC 0.9237) with 82.6% to 91.4% of claims supported by direct evidence or valid inferences. Gene-level severity was aggregated across 8,738 pairs, identifying 3,283 autosomal recessive pairs with severe or profound presentations. External validation showed 95.2% concordance with Mackenzie's Mission gene list. This system enables standardized panel design by providing reliable, automated classification supported by direct evidence.

Clinical reasoning agents based on large language models (LLMs) aim to automate tasks such as intensive care unit (ICU) monitoring and patient state tracking from electronic health records (EHRs). Existing systems typically rely on manually curated clinical tools or skills for concepts such as sepsis detection and organ failure assessment. However, maintaining these tool libraries requires substantial expert effort, while zero-shot querying or code generation often produces inefficient and unreliable reasoning chains, especially under institution-specific clinical policies. We introduce CodeClinic, a benchmark built on MIMIC-IV for evaluating whether LLM agents can synthesize and compose reusable clinical skills instead of relying on fixed toolboxes. The benchmark contains two complementary tasks: longitudinal ICU surveillance and compositional information seeking. The longitudinal setting simulates monitoring patient trajectories with structured decisions every four hours across 25 findings and eight clinical families, while the compositional setting spans 63k instances across 259 tasks in nine domains and is stratified by compositional dependency depth to evaluate increasingly complex multi-step reasoning. We further propose an offline autoformalization pipeline that converts natural-language clinical guidelines into reusable and verified Python skill libraries through iterative LLM refinement. Compared with zero-shot code generation, the resulting libraries improve consistency while reducing per-query token usage by up to 40%.