Cell-ontology guided transcriptome foundation model

Transcriptome foundation models TFMs hold great promises of deciphering the transcriptomic language that dictate diverse cell functions by self-supervised learning on large-scale single-cell gene expression data, and ultimately unraveling the complex mechanisms of human diseases. However, current TFMs treat cells as independent samples and ignore the taxonomic relationships between cell types, which are available in cell ontology graphs. We argue that effectively leveraging this ontology information during the TFM pre-training can improve learning biologically meaningful gene co-expression patterns while preserving TFM as a general purpose foundation model for downstream zero-shot and fine-tuning tasks. To this end, we present \textbf{s}ingle \textbf{c}ell, \textbf{Cell}-\textbf{o}ntology guided TFM scCello. We introduce cell-type coherence loss and ontology alignment loss, which are minimized along with the masked gene expression prediction loss during the pre-training. The novel loss component guide scCello to learn the cell-type-specific representation and the structural relation between cell types from the cell ontology graph, respectively. We pre-trained scCello on 22 million cells from CellxGene database leveraging their cell-type labels mapped to the cell ontology graph from Open Biological and Biomedical Ontology Foundry. Our TFM demonstrates competitive generalization and transferability performance over the existing TFMs on biologically important tasks including identifying novel cell types of unseen cells, prediction of cell-type-specific marker genes, and cancer drug responses.

Joint Analysis of Single-Cell Data across Cohorts with Missing Modalities

Joint analysis of multi-omic single-cell data across cohorts has significantly enhanced the comprehensive analysis of cellular processes. However, most of the existing approaches for this purpose require access to samples with complete modality availability, which is impractical in many real-world scenarios. In this paper, we propose (Single-Cell Cross-Cohort Cross-Category) integration, a novel framework that learns unified cell representations under domain shift without requiring full-modality reference samples. Our generative approach learns rich cross-modal and cross-domain relationships that enable imputation of these missing modalities. Through experiments on real-world multi-omic datasets, we demonstrate that offers a robust solution to single-cell tasks such as cell type clustering, cell type classification, and feature imputation.