Aligning LLMs with Biomedical Knowledge using Balanced Fine-Tuning

Despite the success of large language models (LLMs) on general-purpose tasks, their performance in highly specialized domains such as biomedicine remains unsatisfactory. A key limitation is the inability of LLMs to effectively leverage biomedical tools, which clinical experts and biomedical researchers rely on extensively in daily workflows. While recent general-domain tool-calling datasets have substantially improved the capabilities of LLM agents, existing efforts in the biomedical domain largely rely on in-context learning and restrict models to a small set of tools. To address this gap, we introduce BioTool, a comprehensive biomedical tool-calling dataset designed for fine-tuning LLMs. BioTool comprises 34 frequently used tools collected from the NCBI, Ensembl, and UniProt databases, along with 7,040 high-quality, human-verified query-API call pairs spanning variation, genomics, proteomics, evolution, and general biology. Fine-tuning a 4-billion-parameter LLM on BioTool yields substantial improvements in biomedical tool-calling performance, outperforming cutting-edge commercial LLMs such as GPT-5.1. Furthermore, human expert evaluations demonstrate that integrating a BioTool-fine-tuned tool caller significantly improves downstream answer quality compared to the same LLM without tool usage, highlighting the effectiveness of BioTool in enhancing the biomedical capabilities of LLMs. The full dataset and evaluation code are available at https://github.com/gxx27/BioTool

Large Language Models such as GPT-4o and GPT-5 achieve strong zero-shot performance on biomedical claim verification, but cost and opacity limit scalable use. We fine-tune three small LLMs: Phi-3-mini (3.8B), Qwen2.5-3B, and Mistral-7B, via QLoRA on SciFact and HealthVer, providing the first study of QLoRA models against GPT-4o and fine-tuned BioLinkBERT encoders. Mistral-7B QLoRA surpasses both GPT-4o and GPT-5 (up to 12% F1 gain) at a fractional cost using just 1,008 training examples. We conduct extensive in-domain and cross-domain evaluation: models trained on SciFact tested on HealthVer and vice versa, at matched sizes to isolate dataset structure from data quantity. We identify a previously unreported structural artifact in SciFact that inflates in-domain scores, and show through bidirectional out-of-domain evaluation that training on structurally sound data enables robust cross-domain transfer. We plan to release all code and adapter checkpoints.

Biological reasoning models use post-training to connect LLMs to biological foundation model representations and biological text. Their benchmark accuracy is taken as evidence that LLMs reason over these inputs. We test this assumption in six biological reasoning models across DNA, protein, and single-cell tasks. We perturb one biological input while holding the query and other inputs fixed, construct evidence conflicts that pair the foundation model representation of one genome, protein, or cell with the text of another, fit linear probes to the representations the language model receives, and analyze reasoning traces against the biological inputs. Evo2 and ESM3 contribute little to BioReason and BioReason-Pro performance on the evaluated tasks. Shuffling the DNA sequence barely changes BioReason disease prediction accuracy, and in evidence conflicts the two models follow the text in 97.9% and 99.7% of cases. Linear probes trained on the Evo2 and ESM3 representations predict the task targets, so these foundation models encode information relevant to the task, but provide limited overall performance improvement to BioReason and BioReason-Pro. In contrast, foundation model inputs contribute to ChatNT, Prot2Text-V2, and CellWhisperer performance, and differentially expressed genes in the gene sentence contribute to Cell2Sentence-Scale performance. Across SFT and RL checkpoints of BioReason-Pro and 42 BioReason checkpoints, increases in accuracy do not imply greater performance contributions from biological inputs. BioReason traces misstate nucleotide changes, while BioReason-Pro traces describe functions omitted from final predictions under evidence conflicts. We find that current post-training strategies do not ensure that foundation model representations contribute to task performance.