2023年11月2日出版的《自然-方法学》杂志发表了美国耶鲁大学David van Dijk、Jeffrey J. Ishizuka、Ellen F. Foxman和南加州大学Rahul M. Dhodapkar研究组合作的最新成果，他们利用CINEMA-OT对单细胞实验扰动效应进行因果识别。

研究人员开发了一种基于因果推断的单细胞扰动分析方法，称为CINEMA-OT（因果独立效应模块归因+最佳传输）。CINEMA-OT将干扰变异源从扰动效应中分离出来，以获得反映事实细胞对的最佳传输匹配。这些细胞对代表了因果扰动反应，并能进行一系列新颖的分析，如个体治疗效果分析、反应聚类、归因分析和协同分析。研究人员在多个模拟和真实数据集的一系列治疗效果评估任务中对CINEMA-OT进行了基准测试，结果表明它优于其他单细胞扰动分析方法。

最后，研究人员对两个新生成的数据集进行了CINEMA-OT分析：分布是(1)鼻病毒和暴露于气道的香烟烟雾有机体和(2)免疫细胞的细胞因子组合刺激。在这些实验中，CINEMA-OT揭示了香烟烟雾暴露导致气道抗病毒反应减弱的潜在机制，以及支配趋化因子分泌和外周免疫细胞招募的机理。

据介绍，最新的单细胞技术可在单细胞分辨率描述实验扰动的特征。虽然已经开发出了分析此类实验的方法，但在单细胞水平推断治疗效果的应用尚未得到探索。

附：英文原文

Title: Causal identification of single-cell experimental perturbation effects with CINEMA-OT

Author: Dong, Mingze, Wang, Bao, Wei, Jessica, de O. Fonseca, Antonio H., Perry, Curtis J., Frey, Alexander, Ouerghi, Feriel, Foxman, Ellen F., Ishizuka, Jeffrey J., Dhodapkar, Rahul M., van Dijk, David

Issue&Volume: 2023-11-02

Abstract: Recent advancements in single-cell technologies allow characterization of experimental perturbations at single-cell resolution. While methods have been developed to analyze such experiments, the application of a strict causal framework has not yet been explored for the inference of treatment effects at the single-cell level. Here we present a causal-inference-based approach to single-cell perturbation analysis, termed CINEMA-OT (causal independent effect module attribution + optimal transport). CINEMA-OT separates confounding sources of variation from perturbation effects to obtain an optimal transport matching that reflects counterfactual cell pairs. These cell pairs represent causal perturbation responses permitting a number of novel analyses, such as individual treatment-effect analysis, response clustering, attribution analysis, and synergy analysis. We benchmark CINEMA-OT on an array of treatment-effect estimation tasks for several simulated and real datasets and show that it outperforms other single-cell perturbation analysis methods. Finally, we perform CINEMA-OT analysis of two newly generated datasets: (1) rhinovirus and cigarette-smoke-exposed airway organoids, and (2) combinatorial cytokine stimulation of immune cells. In these experiments, CINEMA-OT reveals potential mechanisms by which cigarette-smoke exposure dulls the airway antiviral response, as well as the logic that governs chemokine secretion and peripheral immune cell recruitment.

DOI: 10.1038/s41592-023-02040-5

Source: https://www.nature.com/articles/s41592-023-02040-5