# PertReason: A Knowledge-Grounded Benchmark and Framework for Cell-State-Conditioned Mechanistic Reasoning of Perturbation Effects

arXiv: https://arxiv.org/abs/2607.18777 · HTML: https://mlsanity.com/paper/2607.18777/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Placed in Clinical and biomedical applications, one of 17 directions in LLM reasoning.
- Builds on 13 of its 58 references that are in the map.
- First posted on arXiv 21 Jul 2026.

## Placed in

- LLM reasoning / [Clinical and biomedical applications](https://mlsanity.com/lr/clinical-and-biomedical-applications/)

## Builds on (most cited first, 13 of 13)

- [DeepSeekMath: Pushing the Limits of Mathematical Reasoning in Open Language Models](https://mlsanity.com/paper/2402.03300/) (2024)
- [Retrieval-Augmented Generation for Knowledge-Intensive NLP Tasks](https://mlsanity.com/paper/2005.11401/) (2020)
- [Qwen3 Technical Report](https://mlsanity.com/paper/2505.09388/) (2025)
- [DeepSeek-R1: Incentivizing Reasoning Capability in LLMs via Reinforcement Learning](https://mlsanity.com/paper/2501.12948/) (2025)
- [Large Language Models Encode Clinical Knowledge](https://mlsanity.com/paper/2212.13138/) (2022)
- [Capabilities of GPT-4 on Medical Challenge Problems](https://mlsanity.com/paper/2303.13375/) (2023)
- [BioMistral: A Collection of Open-Source Pretrained Large Language Models for Medical Domains](https://mlsanity.com/paper/2402.10373/) (2024)
- [Orca 2: Teaching Small Language Models How to Reason](https://mlsanity.com/paper/2311.11045/) (2023)
- [Nature Language Model: Deciphering the Language of Nature for Scientific Discovery](https://mlsanity.com/paper/2502.07527/) (2025)
- [BioMaze: Benchmarking and Enhancing Large Language Models for Biological Pathway Reasoning](https://mlsanity.com/paper/2502.16660/) (2025)
- [TxPert: Leveraging Biochemical Relationships for Out-of-Distribution Transcriptomic Perturbation Prediction](https://mlsanity.com/paper/2505.14919/) (2025)
- [SynthPert: Enhancing LLM Biological Reasoning via Synthetic Reasoning Traces for Cellular Perturbation Prediction](https://mlsanity.com/paper/2509.25346/) (2025)
- [Progressive Multi-Agent Reasoning for Biological Perturbation Prediction](https://mlsanity.com/paper/2602.07408/) (2026)

## Abstract (arXiv)

Evaluating machine learning in scientific domains requires separating correct predictions from correct reasons under realistic distribution shifts. We introduce PertReason, a knowledge-grounded benchmark and framework suite for cell-state--conditioned reasoning about perturbation effects. At its core, PertReasonQA is a benchmark that tests whether models can generate mechanistically faithful explanations while remaining robust to complex shifts, such as new cells and unseen perturbations. PertReasonQA combines single-cell genetic and chemical perturbation data across multiple cellular contexts with knowledge graphs, and dynamically conditions pathways on cell-specific basal states to avoid generic memorization. Evaluations on state-of-the-art models reveal systematic gaps between predictive accuracy and mechanistic reasoning. Specifically, these models exhibit failure modes largely invisible to standard benchmarks, such as deriving correct answers through flawed logic, ignoring cellular context, and generating directionally inconsistent mechanisms. As a reference probe of the benchmark, we present PertReasonLM, a large language model trained to align outcome predictions with context-specific mechanistic reasoning. Our model targets the identified failure modes by grounding rationales in context-specific pathways and tightening agreement between outcomes and mechanisms. Together, we provide a diagnostic framework for exposing and mitigating failures in faithful reasoning in data-rich scientific systems.