“Super Gene Set” Causal Relationship Discovery from Functional Genomics Data

In this article, we present a computational framework to identify “causal relationships” among super gene sets. For “causal relationships,” we refer to both stimulatory and inhibitory regulatory relationships, regardless of through direct or indirect mechanisms. For super gene sets, we refer to “pathways, annotated lists, and gene signatures,” or PAGs. To identify causal relationships among PAGs, we extend the previous work on identifying PAG-to-PAG regulatory relationships by further requiring them to be significantly enriched with gene-to-gene co-expression pairs across the two PAGs involved. This is achieved by developing a quantitative metric based on PAG-to-PAG Co-expressions PPC, which we use to infer the likelihood that PAG-to-PAG relationships under examination are causal—either stimulatory or inhibitory. Since true causal relationships are unknown, we approximate the overall performance of inferring causal relationships with the performance of recalling known r-type PAG-to-PAG relationships from causal PAG-to-PAG inference, using a functional genomics benchmark dataset from the GEO database. We report the area-under-curve AUC performance for both precision and recall being 0.81. By applying our framework to a myeloid-derived suppressor cells MDSC dataset, we further demonstrate that this framework is effective in helping build multi-scale biomolecular systems models with new insights on regulatory and causal links for downstream biological interpretations.