# Plausibility Is Not Prediction: Contrastive Evidence for LLM-Based Cellular Perturbation Reasoning

arXiv: https://arxiv.org/abs/2606.01042 · HTML: https://mlsanity.com/paper/2606.01042/

## Key facts

- Cited by 1 papers in the map (data through 14 Oct 2026).
- Placed in Clinical and biomedical applications, one of 17 directions in LLM reasoning.
- Builds on 10 of its 33 references that are in the map.
- First posted on arXiv 31 May 2026.

## Placed in

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

## Builds on (most cited first, 10 of 10)

- [Language Models are Few-Shot Learners](https://mlsanity.com/paper/2005.14165/) (2020)
- [Rethinking the Role of Demonstrations: What Makes In-Context Learning Work?](https://mlsanity.com/paper/2202.12837/) (2022)
- [What Makes Good In-Context Examples for GPT-3?](https://mlsanity.com/paper/2101.06804/) (2021)
- [SGLang: Efficient Execution of Structured Language Model Programs](https://mlsanity.com/paper/2312.07104/) (2023)
- [Fantastically Ordered Prompts and Where to Find Them: Overcoming Few-Shot Prompt Order Sensitivity](https://mlsanity.com/paper/2104.08786/) (2021)
- [Learning To Retrieve Prompts for In-Context Learning](https://mlsanity.com/paper/2112.08633/) (2021)
- [Contextualizing biological perturbation experiments through language](https://mlsanity.com/paper/2502.21290/) (2025)
- [PerturbDiff: Functional Diffusion for Single-Cell Perturbation Modeling](https://mlsanity.com/paper/2602.19685/) (2026)
- [VCWorld: A Biological World Model for Virtual Cell Simulation](https://mlsanity.com/paper/2512.00306/) (2025)
- [CellVerse: Do Large Language Models Really Understand Cell Biology?](https://mlsanity.com/paper/2505.07865/) (2025)

## Built on by (most cited first, 1 of 1)

- [PertMind: Eliciting Emergent Biological Reasoning in LLM via Reinforcement Learning on Cellular Perturbation Data](https://mlsanity.com/paper/2608.16419/) (2026)

## Abstract (arXiv)

Perturbation experiments are central to understanding cellular mechanisms, but remain costly and sparse, motivating prediction of gene expression responses for unobserved conditions. A promising recent direction leverages large language models (LLMs) as "virtual cell" simulators-using stepwise, knowledge-grounded mechanistic reasoning to infer differential expression-pointing toward an interpretable, knowledge-driven paradigm that transcends purely data-driven approaches. However, we find that plausibility is not prediction: despite producing biologically plausible explanations, these methods fail to capture perturbation-specific effects: systematically overestimating differential expression, often underperforming a simple gene-frequency baseline in aggregate evaluations, and collapsing to chance-level performance at the per-gene level. This reveals a reliance on intrinsic gene response tendencies rather than true perturbation reasoning. We trace this failure to how evidence is presented: existing methods evaluate perturbation-gene pairs in isolation, without exposing how related perturbations differ in their effects on the same gene. To address this limitation, we introduce CORE (Contrastive Organization of Relational Evidence), which reframes prediction as a comparison task by organizing evidence into positive and negative outcomes from related perturbations. Using a biomedical knowledge graph for evidence retrieval, CORE improves calibration and substantially boosts perturbation-specific prediction in both LLM-based and non-LLM settings: for example, on drug-perturbation data, CORE-Reasoning improves Qwen3.5-9B aggregate metrics by up to 28.6%, while on generic perturbation data, CORE-Voting raises macro-per-gene AUROC from chance to 0.703 in average across four cell lines. This highlights contrastive evidence organization as essential to reliable LLM-based perturbation reasoning