An individualized causal framework for learning intercellular communication networks that define microenvironments of individual tumors.

Cells within a tumor microenvironment (TME) dynamically communicate and influence each other's cellular states through an intercellular communication network (ICN). In cancers, intercellular communications underlie immune evasion mechanisms of individual tumors. We developed an individualized causal analysis framework for discovering tumor specific ICNs. Using head and neck squamous cell carcinoma (HNSCC) tumors as a testbed, we first mined single-cell RNA-sequencing data to discover gene expression modules (GEMs) that reflect the states of transcriptomic processes within tumor and stromal single cells. By deconvoluting bulk transcriptomes of HNSCC tumors profiled by The Cancer Genome Atlas (TCGA), we estimated the activation states of these transcriptomic processes in individual tumors. Finally, we applied individualized causal network learning to discover an ICN within each tumor. Our results show that cellular states of cells in TMEs are coordinated through ICNs that enable multi-way communications among epithelial, fibroblast, endothelial, and immune cells. Further analyses of individual ICNs revealed structural patterns that were shared across subsets of tumors, leading to the discovery of 4 different subtypes of networks that underlie disparate TMEs of HNSCC. Patients with distinct TMEs exhibited significantly different clinical outcomes. Our results show that the capability of estimating individual ICNs reveals heterogeneity of ICNs and sheds light on the importance of intercellular communication in impacting disease development and progression.

Instance-Specific Bayesian Network Structure Learning.

Bayesian network (BN) structure learning algorithms are almost always designed to recover the structure that models the relationships that are shared by the instances in a population. While accurately learning such population-wide Bayesian networks is useful, learning Bayesian networks that are specific to each instance is often important as well. For example, to understand and treat a patient (instance), it is critical to understand the specific causal mechanisms that are operating in that particular patient. We introduce an instance-specific BN structure learning method that searches the space of Bayesian networks to build a model that is specific to an instance by guiding the search based on attributes of the given instance (e.g., patient symptoms, signs, lab results, and genotype). The structure discovery performance of the proposed method is compared to an existing state-of-the-art BN structure learning method, namely an implementation of the Greedy Equivalence Search algorithm called FGES, using both simulated and real data. The results show that the proposed method improves the precision of the model structure that is output, when compared to GES, especially for those variables that exhibit context-specific independence.

Discovery of Causal Models that Contain Latent Variables through Bayesian Scoring of Independence Constraints.

Discovering causal structure from observational data in the presence of latent variables remains an active research area. Constraint-based causal discovery algorithms are relatively efficient at discovering such causal models from data using independence tests. Typically, however, they derive and output only one such model. In contrast, Bayesian methods can generate and probabilistically score multiple models, outputting the most probable one; however, they are often computationally infeasible to apply when modeling latent variables. We introduce a hybrid method that derives a Bayesian probability that the set of independence tests associated with a given causal model are jointly correct. Using this constraint-based scoring method, we are able to score multiple causal models, which possibly contain latent variables, and output the most probable one. The structure-discovery performance of the proposed method is compared to an existing constraint-based method (RFCI) using data generated from several previously published Bayesian networks. The structural Hamming distances of the output models improved when using the proposed method compared to RFCI, especially for small sample sizes.