Panayiotis V. Benos

Haiyi Mao, Minxue Jia, Jason Xiaotian Dou et al.

Metacells are disjoint and homogeneous groups of single-cell profiles, representing discrete and highly granular cell states. Existing metacell algorithms tend to use only one modality to infer metacells, even though single-cell multi-omics datasets profile multiple molecular modalities within the same cell. Here, we present \textbf{C}ross-M\textbf{O}dal \textbf{E}mbedding for \textbf{M}etaCell Identification (COEM), which utilizes an embedded space leveraging the information of both scATAC-seq and scRNA-seq to perform aggregation, balancing the trade-off between fine resolution and sufficient sequencing coverage. COEM outperforms the state-of-the-art method SEACells by efficiently identifying accurate and well-separated metacells across datasets with continuous and discrete cell types. Furthermore, COEM significantly improves peak-to-gene association analyses, and facilitates complex gene regulatory inference tasks.

Haiyi Mao, Romain Lopez, Kai Liu et al.

The study of cells and their responses to genetic or chemical perturbations promises to accelerate the discovery of therapeutic targets. However, designing adequate and insightful models for such data is difficult because the response of a cell to perturbations essentially depends on its biological context (e.g., genetic background or cell type). For example, while discovering therapeutic targets, one may want to enrich for drugs that specifically target a certain cell type. This challenge emphasizes the need for methods that explicitly take into account potential interactions between drugs and contexts. Towards this goal, we propose a novel Factorized Causal Representation (FCR) learning method that reveals causal structure in single-cell perturbation data from several cell lines. Based on the framework of identifiable deep generative models, FCR learns multiple cellular representations that are disentangled, comprised of covariate-specific ($\mathbf{z}_x$), treatment-specific ($\mathbf{z}_{t}$), and interaction-specific ($\mathbf{z}_{tx}$) blocks. Based on recent advances in non-linear ICA theory, we prove the component-wise identifiability of $\mathbf{z}_{tx}$ and block-wise identifiability of $\mathbf{z}_t$ and $\mathbf{z}_x$. Then, we present our implementation of FCR, and empirically demonstrate that it outperforms state-of-the-art baselines in various tasks across four single-cell datasets.

Myles Joshua Toledo Tan, Maria Kapetanaki, Panayiotis V. Benos

Differentiating between the two main subtypes of Inflammatory Bowel Disease (IBD): Crohns disease (CD) and ulcerative colitis (UC) is a persistent clinical challenge due to overlapping presentations. This study introduces a novel computational framework that employs spatial transcriptomics (ST) to create an explainable machine learning model for IBD classification. We analyzed ST data from the colonic mucosa of healthy controls (HC), UC, and CD patients. Using Non-negative Matrix Factorization (NMF), we first identified four recurring cellular niches, representing distinct functional microenvironments within the tissue. From these niches, we systematically engineered 44 features capturing three key aspects of tissue pathology: niche composition, neighborhood enrichment, and niche-gene signals. A multilayer perceptron (MLP) classifier trained on these features achieved an accuracy of 0.774 +/- 0.161 for the more challenging three-class problem (HC, UC, and CD) and 0.916 +/- 0.118 in the two-class problem of distinguishing IBD from healthy tissue. Crucially, model explainability analysis revealed that disruptions in the spatial organization of niches were the strongest predictors of general inflammation, while the classification between UC and CD relied on specific niche-gene expression signatures. This work provides a robust, proof-of-concept pipeline that transforms descriptive spatial data into an accurate and explainable predictive tool, offering not only a potential new diagnostic paradigm but also deeper insights into the distinct biological mechanisms that drive IBD subtypes.

Vineet K Raghu, Xiaoyu Ge, Arun Balajee et al.

High throughput genome sequencing technologies such as RNA-Seq and Microarray have the potential to transform clinical decision making and biomedical research by enabling high-throughput measurements of the genome at a granular level. However, to truly understand causes of disease and the effects of medical interventions, this data must be integrated with phenotypic, environmental, and behavioral data from individuals. Further, effective knowledge discovery methods that can infer relationships between these data types are required. In this work, we propose a pipeline for knowledge discovery from integrated genomic and clinical data. The pipeline begins with a novel variable selection method, and uses a probabilistic graphical model to understand the relationships between features in the data. We demonstrate how this pipeline can improve breast cancer outcome prediction models, and can provide a biologically interpretable view of sequencing data.

Andrew J Sedgewick, Joseph D. Ramsey, Peter Spirtes et al.

Graphical causal models are an important tool for knowledge discovery because they can represent both the causal relations between variables and the multivariate probability distributions over the data. Once learned, causal graphs can be used for classification, feature selection and hypothesis generation, while revealing the underlying causal network structure and thus allowing for arbitrary likelihood queries over the data. However, current algorithms for learning sparse directed graphs are generally designed to handle only one type of data (continuous-only or discrete-only), which limits their applicability to a large class of multi-modal biological datasets that include mixed type variables. To address this issue, we developed new methods that modify and combine existing methods for finding undirected graphs with methods for finding directed graphs. These hybrid methods are not only faster, but also perform better than the directed graph estimation methods alone for a variety of parameter settings and data set sizes. Here, we describe a new conditional independence test for learning directed graphs over mixed data types and we compare performances of different graph learning strategies on synthetic data.