提出可分解的因果表示学习方法,揭示细胞对药物响应的隐藏机制。
Learning Identifiable Factorized Causal Representations of Cellular Responses
- 将细胞响应分解为背景、药物、交互三类独立表示,实现因果解耦。
- 在4个单细胞数据集上,优于现有最优基线模型,显著提升预测性能。
- 适合生物医学研究者用于发现靶向特定细胞类型的精准药物。
研究细胞及其对基因或化学扰动的响应,有望加速治疗靶点发现。然而,由于细胞响应高度依赖其生物学背景(如遗传背景或细胞类型),设计有效且有洞察力的模型极具挑战。例如,在寻找治疗靶点时,可能希望筛选仅针对特定细胞类型的药物。这凸显了需显式建模药物与背景间相互作用的方法。为此,本文提出一种新型可分解因果表示(FCR)学习方法,从多个细胞系的单细胞扰动数据中揭示因果结构。基于可识别深度生成模型框架,FCR学习到多组解耦的细胞表示,包含协变量特异(z_x)、处理特异(z_t)和交互特异(z_tx)块。基于非线性ICA理论最新进展,证明了z_tx的逐分量可识别性及z_t、z_x的分块可识别性。我们实现了FCR,并在四个单细胞数据集上实证表明,其在各类任务中均优于现有最先进基线模型。
原文摘要 · Abstract (English)
The study of cells and their responses to genetic or chemical perturbations promises to accelerate the discovery of therapeutic targets. However, designing adequate and insightful models for such data is difficult because the response of a cell to perturbations essentially depends on its biological context (e.g., genetic background or cell type). For example, while discovering therapeutic targets, one may want to enrich for drugs that specifically target a certain cell type. This challenge emphasizes the need for methods that explicitly take into account potential interactions between drugs and contexts. Towards this goal, we propose a novel Factorized Causal Representation (FCR) learning method that reveals causal structure in single-cell perturbation data from several cell lines. Based on the framework of identifiable deep generative models, FCR learns multiple cellular representations that are disentangled, comprised of covariate-specific ($\mathbf{z}_x$), treatment-specific ($\mathbf{z}_{t}$), and interaction-specific ($\mathbf{z}_{tx}$) blocks. Based on recent advances in non-linear ICA theory, we prove the component-wise identifiability of $\mathbf{z}_{tx}$ and block-wise identifiability of $\mathbf{z}_t$ and $\mathbf{z}_x$. Then, we present our implementation of FCR, and empirically demonstrate that it outperforms state-of-the-art baselines in various tasks across four single-cell datasets.
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