建模细胞扰动的动态潜变量机制,提升对未知干预的预测能力。
Learning Latent Dynamical Causal Processes for Single-Cell Perturbation Prediction

- 构建潜空间中的动态因果生成模型,捕捉扰动驱动的细胞程序演化。
- 在真实CRISPR数据上实现比现有方法更高的未见扰动泛化性能。
- 适合研究细胞响应机制与可解释性建模的研究者使用。
单细胞扰动预测旨在推断细胞对未知干预的响应并实现分布外(OOD)泛化,为理解扰动如何随时间重塑细胞程序提供计算路径。现有机器学习方法多仅捕捉响应的一侧,而潜因果方法虽支持泛化与解释,但常将扰动效应视为静态结果;时序模型能描述基因表达变化,却通常不显式恢复驱动变化的潜因果机制。实践中,扰动效应兼具潜变量与动态性:干预通过未观测的细胞程序起作用,其状态随时间演化并产生可观测表达谱。基于此,我们提出一种单细胞扰动数据的潜动态因果生成模型,联合建模潜细胞程序、扰动条件下的机制及时间演化。我们进一步提供可辨识性分析,表明在合适条件下,潜因果变量可恢复至标准等价类。基于此,我们开发CITE-VAE框架,从单细胞测序数据中恢复潜细胞程序及其扰动驱动的动力学。在Causal-3DIdent上的实验验证了理论结果与方法有效性;在真实CRISPR单细胞扰动数据上的额外实验表明,相比前沿基线,本方法在未见扰动上表现更优,凸显其实际鲁棒性。
原文摘要 · Abstract (English)
Single-cell perturbation prediction aims to infer how cells respond to unseen interventions and to achieve out-of-distribution (OOD) generalization, providing a computational route to understanding how perturbations reshape cellular programs over time. Existing machine learning methods have made important progress, but typically capture only one side of the response. Latent causal approaches seek mechanisms that support generalization and interpretation, yet often treat perturbation effects as static outcomes. Temporal models describe how gene expression changes across time, but usually do not explicitly recover the latent causal generative mechanisms driving these changes. In practice, perturbation effects are both latent and dynamical: interventions act through unobserved cellular programs, whose states evolve over time and give rise to observed expression profiles. Motivated by this view, we propose a latent dynamical causal generative model for single-cell perturbation data that jointly captures latent cellular programs, perturbation-conditioned mechanisms, and temporal evolution. We further provide an identifiability analysis showing that, under suitable conditions, the latent causal variables are recoverable up to standard equivalence classes. Guided by this analysis, we develop CITE-VAE, a learning framework for recovering latent cellular programs and their perturbation-driven dynamics from single-cell sequencing data. Experiments on Causal-3DIdent validate the theoretical results and the effectiveness of the proposed method in controlled settings. Additional experiments on real-world CRISPR-based single-cell perturbation data show improved generalization to unseen perturbations compared with state-of-the-art baselines, highlighting the practical robustness of our approach.
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