用简单Transformer预测基因扰动后细胞表达变化,效果超群且可扩展。
OCOO-T : A Simple and Scalable Virtual Cell Model for Transcriptional Perturbation Response Prediction

- 直接用Transformer处理连续基因表达数据,通过去噪过程预测扰动响应。
- 在多个数据集上表现超越现有方法,能处理长达数千基因的表达谱。
- 架构简洁易用,适合药物研发和基因调控网络研究者快速实验。
预测单细胞在基因、化学或细胞因子扰动下的转录响应是计算生物学与AI虚拟细胞建模的核心挑战,对药物发现和基因调控网络解析具有重要意义。现有方法常依赖辅助细胞状态编码器、分层变分自编码器、专用Transformer编解码模块或基因互作先验,将高维表达谱压缩为潜在表示,虽有效但增加模型复杂度,限制可扩展性和泛化能力。本文提出OCOO-T,一种基于流匹配的极简虚拟细胞模型,直接在连续基因表达谱上运行纯Transformer堆叠,并将扰动响应预测建模为连续时间去噪过程。通过自适应层归一化和上下文嵌入,整合扰动类型、剂量及细胞系/细胞类型特异性信息。在Tahoe100M、Replogle和PBMC基准上的全面评估显示,OCOO-T在多种扰动和细胞类型下均达到当前最优性能,通过上下文分块与重组技术有效扩展至长转录表达谱。该模型利用Transformer-based去噪实现单细胞组学的高效模拟,提供了一个有效且可扩展的体外细胞仿真框架。
原文摘要 · Abstract (English)
Predicting single-cell transcriptional responses to genetic, chemical and cytokine perturbations is a fundamental challenge in computational biology and AI Virtual Cell (AIVC) modeling, with direct implications for drug discovery and the elucidation of gene regulatory networks. Existing approaches often rely on auxiliary cell-state encoders, hierarchical variational autoencoders, dedicated Transformer encoder-decoder modules, or gene-interaction priors to compress high-dimensional expression profiles into latent representations. While effective, these designs increase architectural complexity and may limit scalability and generalizability. This paper introduces OCOO-T, a minimalist flow-matching-based AIVC model for transcriptional perturbation response prediction. OCOO-T utilizes a vanilla Transformer stack that operates directly on continuous gene expression profiles and formulates perturbation response prediction as a continuous-time denoising process. Perturbation embeddings, dosage information, and cell-line/cell-type specificity are integrated through adaptive layer normalization and in-context tokens. Comprehensive evaluations on Tahoe100M, Replogle, and PBMC benchmarks demonstrate that OCOO-T achieves state-of-the-art performance across diverse perturbations and cell types while effectively scaling to long transcriptional profiles through patching and depatching of cellular contexts. By leveraging the simplicity of Transformer-based denoising for single-cell omics, OCOO-T provides an effective and scalable framework for in-silico cellular simulation.
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