AssayBench: An Assay-Level Virtual Cell Benchmark for LLMs and Agents

TL;DR

AssayBench is a new benchmark dataset for evaluating large language models and agents on phenotypic cell screening tasks, enabling progress in virtual cell modeling and drug discovery.

Contribution

This work introduces AssayBench, a comprehensive benchmark for phenotypic screen prediction using diverse CRISPR data, and evaluates LLMs' performance on this task.

Findings

Zero-shot LLMs outperform biology-specific models.

Fine-tuning and prompt optimization improve LLM performance.

Existing methods are far from performance ceilings.

Abstract

Recent advances in machine learning and large-scale biological data collections have revived the prospect of building a virtual cell, a computational model of cellular behavior that could accelerate biological discovery. One of the most compelling promises of this vision is the ability to perform in silico phenotypic screens, in which a model predicts the effects of cellular perturbations in unseen biological contexts. This task combines heterogeneous textual inputs with diverse phenotypic outputs, making it particularly well-suited to LLMs and agentic systems. Yet, no standard benchmark currently exists for this task, as existing efforts focus on narrower molecular readouts that are only indirectly aligned with the phenotypic endpoints driving many real-world drug discovery workflows. In this work, we present AssayBench, a benchmark for phenotypic screen prediction, built from 1,920 publicly available CRISPR screens spanning five broad classes of cellular phenotypes. We formulate the screen prediction task as a gene rank prediction for each screen and introduce the adjusted nDCG, a continuous metric for comparing performance across heterogeneous assays. Our extensive evaluation shows that existing methods remain far from empirically estimated performance ceilings and zero-shot generalist LLMs outperform biology-specific LLMs and trainable baselines. Optimization techniques such as fine-tuning, ensembling, and prompt optimization can further improve LLM performance on this task. Overall, AssayBench offers a practical testbed for measuring progress toward in silico phenotypic screening and, more broadly, virtual cell models.