SAGE: Agentic Framework for Interpretable and Clinically Translatable Computational Pathology Biomarker Discovery

Sahar Almahfouz Nasser; Juan Francisco Pesantez Borja; Jincheng Liu; Sandeep Manandhar; Shikhar Shiromani; Mohammad Tanvir Hasan; Zenghan Wang; Suman Ghosh; Jinchu Li; Xuejian Xu; Aniket Ramkrishnan Iyer; Naoto Tokuyama; Twisha Shah; Tilak Pathak; Soundharya Kumaresan; Yohei Abe; Himanshu Maurya; Anant Madabhushi

arXiv · 2602.00953

SAGE: Agentic Framework for Interpretable and Clinically Translatable Computational Pathology Biomarker Discovery

Sahar Almahfouz Nasser·Juan Francisco Pesantez Borja·Jincheng Liu·Sandeep Manandhar·Shikhar Shiromani·Mohammad Tanvir Hasan·Zenghan Wang·Suman Ghosh·Jinchu Li·Xuejian Xu·Aniket Ramkrishnan Iyer·Naoto Tokuyama·Twisha Shah·Tilak Pathak·Soundharya Kumaresan·Yohei Abe·Himanshu Maurya·Anant Madabhushi

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Abstract

Engineered image-based biomarkers offer a clinically interpretable alternative to black-box AI in computational pathology, yet their discovery remains largely intuition-driven, guided by fragmented literature rather than rigorous biological validation. We introduce SAGE (Structured Agentic system for hypothesis Generation and Evaluation), a multi-agent framework that grounds biomarker discovery in biological evidence through three mechanisms: (i) knowledge-graph-anchored hypothesis generation via multi-path ontological reasoning, (ii) a debate-based multi-agent novelty assessment that stress-tests candidate biomarkers against existing literature, and (iii) an end-to-end automated validation pipeline that translates hypotheses directly into executable analyses on multimodal pathology datasets. Together, these components shift biomarker discovery from an intuition-driven, literature-browsing exercise into a structured, traceable reasoning process that clinicians and researchers can inspect, trust, and build upon.

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Sahar Almahfouz Nasser, Juan Francisco Pesantez Borja, Jincheng Liu, Sandeep Manandhar, Shikhar Shiromani, Mohammad Tanvir Hasan, Zenghan Wang, Suman Ghosh, Jinchu Li, Xuejian Xu, Aniket Ramkrishnan Iyer, Naoto Tokuyama, Twisha Shah, Tilak Pathak, Soundharya Kumaresan, Yohei Abe, Himanshu Maurya, Anant Madabhushi. 2026-05-10. SAGE: Agentic Framework for Interpretable and Clinically Translatable Computational Pathology Biomarker Discovery. https://arxiv.org/abs/2602.00953

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