arXiv:2605.00930q-bio.GNcs.AI2026-05

用马尔可夫链采样模拟基因扰动,实现更真实的单细胞多组学预测。

CellxPert: Inference-Time MCMC Steering of a Multi-Omics Single-Cell Foundation Model for In-Silico Perturbation

  • 通过马尔可夫链采样动态调整基因表达,避免突变导致的异常结果。
  • 在多个数据集上实现154种细胞类型的精准注释和基因扰动响应预测。
  • 适合生物医学研究者进行虚拟基因实验和多组学数据整合分析。

本文提出CellxPert,一个可扩展的多模态基础模型,将单细胞转录组(scRNA-seq)、染色质可及性(ATAC-seq)和表面蛋白组(CITE-seq)统一于共同表示空间,并直接整合MERFISH与成像质谱流式数据作为二维或三维空间视觉层。该模型开箱即用支持四项核心任务:(i) 在包含154种高度重叠细胞类型的大规模注释体系中实现细胞类型注释,是目前最精细的标签空间测试;(ii) 使用低秩适应(LoRA)高效微调;(iii) 预测全基因组转录组对虚拟扰动(ISP)的响应;(iv) 跨不同检测平台无缝整合多组学数据。不同于现有模型通过删除或重排基因表达词元来近似扰动,CellxPert采用基于模型掩码条件分布的提议核的梅特罗波利斯-哈斯廷斯采样器,生成生物可解释的转录状态轨迹,有效缓解因突变引入的分布外偏差。在PBMC68K、Replogle Perturb-seq、Systema和BMMC基准测试中,其在细胞类型注释、扰动响应预测和多组学整合方面均超越经典与先进基线方法。

原文摘要 · Abstract (English)

In this work, we introduce CellxPert, a scalable multimodal foundation model that unifies single-cell and spatial multi-omics within a common representation space. CellxPert jointly encodes transcriptomic (scRNA-seq), chromatin-accessibility (ATAC-seq), and surface-proteomic (CITE-seq) measurements, while directly incorporating MERFISH and imaging mass-cytometry data as 2D or 3D spatial-visual layers. CellxPert facilitates four key downstream tasks out of the box: (i) cell-type annotation across a broad ontology of 154 largely overlapping identities -- the largest label space addressed to date and a stringent test of fine-grained discrimination, (ii) efficient fine-tuning using Low Rank Adaptation (LoRA), (iii) genome-wide transcriptomic response prediction to in-silico perturbations (ISP), and (iv) seamless multi-omic integration across various assays and platforms. Unlike current single-cell foundation models, which approximate gene perturbations by deleting or reordering tokenized gene expression ranks, CellxPert employs a Metropolis-Hastings sampler whose proposal kernel uses the model's masked conditional distributions to transition to new transcriptomic states conditioned on the perturbed genes. This Markov-chain procedure mitigates out-of-distribution artifacts introduced by abrupt token manipulation and produces trajectories that are biologically interpretable. Evaluations on PBMC68K, Replogle Perturb-seq, Systema, and BMMC benchmarks show that CellxPert surpasses classical and state-of-the-art baselines in cell-type annotation, perturbation response prediction, and multi-omic integration.

单细胞多组学虚拟扰动生成模型

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