加州大学Nir Yosef小组近日取得一项新成果。经过不懈努力，他们提出了单细胞基因组学中样本水平异质性的深度生成建模。2025年10月13日出版的《自然—方法学》杂志发表了这项成果。

该研究团队提出了多分辨率变分推理（MrVI），这是一种深度生成模型，旨在实现单细胞水平队列研究的潜力。MrVI解决了两个基本的、相互交织的问题：将样品分层分组，评估各组之间的细胞和分子差异，而不需要预先定义细胞状态。利用其单细胞视角，MrVI检测仅在某些细胞亚群中表现出来的COVID-19或炎症性肠病患者队列的临床相关分层，从而实现可能被忽视的新发现。MrVI可以重新识别具有相似生化特性的小分子群，并在大规模摄动研究中评估它们对细胞组成和基因表达的影响。MrVI是一个开放的工具，网址是scvi-tools.org。

据悉，单细胞基因组研究最近在数百个展示复杂设计的样本上进行。这些数据对于发现样本或组织水平的表型如何与细胞和分子组成相关具有巨大的潜力。然而，当前的分析通常是基于这些数据的简化表示，即通过计算单元间的平均信息。

附：英文原文

Title: Deep generative modeling of sample-level heterogeneity in single-cell genomics

Author: Boyeau, Pierre, Hong, Justin, Gayoso, Adam, Kim, Martin, McFaline-Figueroa, Jos L., Jordan, Michael I., Azizi, Elham, Ergen, Can, Yosef, Nir

Issue&Volume: 2025-10-13

Abstract: Single-cell genomic studies were recently conducted on hundred of samples exhibiting complex designs. These data have tremendous potential for discovering how sample- or tissue-level phenotypes relate to cellular and molecular composition. However, current analyses are often based on simplified representations of these data by averaging information across cells. We present multi-resolution variational inference (MrVI), a deep generative model designed to realize the potential of cohort studies at the single-cell level. MrVI tackles two fundamental, intertwined problems: stratifying samples into groups and evaluating the cellular and molecular differences between groups, without requiring predefined cell states. Leveraging its single-cell perspective, MrVI detects clinically relevant stratifications of cohorts of people with COVID-19 or inflammatory bowel disease that are manifested in only certain cellular subsets, enabling new discoveries that would otherwise be overlooked. MrVI can de novo identify groups of small molecules with similar biochemical properties and evaluate their effects on cellular composition and gene expression in large-scale perturbation studies. MrVI is an open-source tool at scvi-tools.org.

DOI: 10.1038/s41592-025-02808-x

Source: https://www.nature.com/articles/s41592-025-02808-x