用统一模型预测不同细胞类型的基因扰动效应,省去重复建模。
CFM-GP: Unified Conditional Flow Matching to Learn Gene Perturbation Across Cell Types
- 基于连续流匹配,建模基因表达从正常到扰动的动态变化。
- 在5个数据集上均超越现有方法,R²和斯皮尔曼相关性更优。
- 适合需要跨细胞类型预测的生物医学研究者使用。
理解基因扰动在不同细胞背景下的效应是功能基因组学的核心挑战,对药物发现和精准医疗具有重要意义。单细胞技术可高分辨率测量转录响应,但每种细胞类型重复实验成本高、耗时长。现有计算方法通常需为每种细胞类型单独建模,难以扩展和泛化。我们提出CFM-GP,一种细胞类型无关的基因扰动预测方法。该方法通过条件流匹配学习未扰动与扰动基因表达分布间的连续时间变换,仅用一个模型即可跨所有细胞类型进行预测。相比以往离散建模方法,CFM-GP采用流匹配目标,实现可扩展的扰动动态建模。我们在五个数据集上评估:SARS-CoV-2感染、IFN-beta刺激的PBMCs、胶质母细胞瘤经Panobinostat治疗、狼疮在IFN-beta刺激下、以及Statefate祖细胞命运映射。CFM-GP在R²和斯皮尔曼相关性上持续优于最先进基线,通路富集分析也验证了关键生物通路的有效恢复。结果表明,CFM-GP是一种稳健且具备生物学真实性的跨细胞类型基因扰动预测可扩展解决方案。
原文摘要 · Abstract (English)
Understanding gene perturbation effects across diverse cellular contexts is a central challenge in functional genomics, with important implications for therapeutic discovery and precision medicine. Single-cell technologies enable high-resolution measurement of transcriptional responses, but collecting such data is costly and time-consuming, especially when repeated for each cell type. Existing computational methods often require separate models per cell type, limiting scalability and generalization. We present CFM-GP, a method for cell type-agnostic gene perturbation prediction. CFM-GP learns a continuous, time-dependent transformation between unperturbed and perturbed gene expression distributions, conditioned on cell type, allowing a single model to predict across all cell types. Unlike prior approaches that use discrete modeling, CFM-GP employs a flow matching objective to capture perturbation dynamics in a scalable manner. We evaluate on five datasets: SARS-CoV-2 infection, IFN-beta stimulated PBMCs, glioblastoma treated with Panobinostat, lupus under IFN-beta stimulation, and Statefate progenitor fate mapping. CFM-GP consistently outperforms state-of-the-art baselines in R-squared and Spearman correlation, and pathway enrichment analysis confirms recovery of key biological pathways. These results demonstrate the robustness and biological fidelity of CFM-GP as a scalable solution for cross-cell type gene perturbation prediction.
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