Process-Reward Tactic Evolution for Long-Horizon Bioinformatics Workflows

Large language model agents have shown promise in bioinformatics, but most existing systems focus primarily on producing final answers, treating planning, tool use, and code execution as transient interactions. This design is poorly suited to long-horizon bioinformatics tasks, where conclusions must remain connected to the data, computations, and intermediate evidence that support them. We introduce \textbf{Bioinfoysis}, a multi-agent harness that represents each request as a persistent, artifact-grounded analysis run. Bioinfoysis combines global planning with step-wise, evidence-driven replanning: the planner maintains an executable checklist and revises pending steps using structured handoffs returned after each worker execution. These handoffs bind intermediate results to their responsible agent, checklist step, and plan generation, preventing stale evidence from being silently reused after replanning. A controlled runtime validates generated scripts, tables, and figures before they are used in downstream analysis or reporting, while role-specific context, persistent memory, and governed bioinformatics skills support reliable execution over long analysis trajectories. We evaluate Bioinfoysis on BixBench and two question-answering tracks of LAB-Bench 2. On BixBench, Bioinfoysis achieves state-of-the-art accuracy of 82.4%. Across four underlying language models, Bioinfoysis increases average accuracy from 27.81% to 64.13% on SeqQA2 and from 3.13% to 31.25% on DbQA2. These results demonstrate that reliable bioinformatics automation depends not only on model capability, but also on the harness that governs planning, execution, memory, and evidence flow. We hope that the emergence of Bioinfoysis will play a driving and leading role in the development of the bioinformatics community. Our demo website can be seen in https://report.bioinfoysis.com/.

Large language model agents increasingly plan, execute, and interpret biological analyses, yet fluent responses, successful tool calls, and benchmark performance alone do not establish scientific credibility. Existing reviews primarily organize biological agents by application, architecture, and agentic capability, but do not jointly operationalize the accountability of agent-generated workflows. We address this gap by treating the inspectable workflow trajectory, rather than architecture or final output alone, as the primary unit of analysis. We introduce the Function--Evidence--Validation (FEV) framework, which separates demonstrated workflow operations, traceable support for actions and claims, and use-case-specific validation. Using FEV, we map 109 agentic or agent-adjacent systems and 28 benchmark or evaluation resources, representing 128 unique publications across genomics, single-cell and spatial omics, protein science, drug discovery, computational pathology, and general bioinformatics automation. Across domains, planning and tool-mediated execution have advanced more rapidly than replayability, provenance, robust scientific assessment, external validation, and prospective empirical testing. We therefore argue that agentic bioinformatics should be assessed through workflow correctness rather than final-answer correctness alone. FEV provides a practical basis for comparing systems and designing transparent, auditable, and scientifically accountable bioinformatics workflows.

Artificial intelligence (AI) promises to accelerate biological research by automating computational analyses. Yet the ability of AI agents to execute on computational biology at the scale of complete research studies has not been systematically evaluated. Here we introduce BixBench3, a benchmark that measures the capacity of AI agents to process raw biological data through to scientific results. We designed BixBench3 tasks to mirror the delegation of work from a scientist to an agent: the scientist chooses the research question and high-level methods, then delegates implementation of all analyses to the agent. In each task, an agent receives a research objective, methodological guidance, and raw data derived from a published scientific study, and must execute a sequence of analyses to achieve the research objective. The data artifacts resulting from these analyses, such as peak call matrices or differential expression tables, are programmatically graded against the corresponding artifacts generated and reported in the original study. Across 20 BixBench3 tasks encompassing the generation of 138 unique artifacts, we find that 13 frontier models achieve scores ranging from 0.00 for Gemini 3.1 Flash Lite to 0.48 for GPT 5.6 Sol. Agents perform worse on tasks with larger raw datasets (0.36 on tasks with <100 GB versus 0.10 on tasks with >100 GB) and on analyses requiring more sequential steps (0.36 at 1-2 steps vs 0.24 at 3+). On average, agents use 6.8 hours, 102 million tokens, and $43 to complete each task, with the longest attempts consuming 24 hours, 1.07 billion tokens, and $525. Notably, the highest-scoring agents used fewer tokens and were cheaper than less performant options. These results reveal that LLMs vary substantially in their ability to (1) execute multiple sequential analysis steps coherently, (2) manage large quantities of raw data, and (3) work across scientific domains.