Quantifying differential gene connectivity between disease states for objective identification of disease-relevant genes.

Background: Network modeling of whole transcriptome expression data enables characterization of complex epistatic (gene-gene) interactions that underlie cellular functions. Though numerous methods have been proposed and successfully implemented to develop these networks, there are no formal methods for comparing differences in network connectivity patterns as a function of phenotypic trait.

Results: Here we describe a novel approach for quantifying the differences in gene-gene connectivity patterns across disease states based on Graphical Gaussian Models (GGMs). We compare the posterior probabilities of connectivity for each gene pair across two disease states, expressed as a posterior odds-ratio (postOR) for each pair, which can be used to identify network components most relevant to disease status. The method can also be generalized to model differential gene connectivity patterns within previously defined gene sets, gene networks and pathways. We demonstrate that the GGM method reliably detects differences in network connectivity patterns in datasets of varying sample size. Applying this method to two independent breast cancer expression data sets, we identified numerous reproducible differences in network connectivity across histological grades of breast cancer, including several published gene sets and pathways. Most notably, our model identified two gene hubs (MMP12 and CXCL13) that each exhibited differential connectivity to more than 30 transcripts in both datasets. Both genes have been previously implicated in breast cancer pathobiology, but themselves are not differentially expressed by histologic grade in either dataset, and would thus have not been identified using traditional differential gene expression testing approaches. In addition, 16 curated gene sets demonstrated significant differential connectivity in both data sets, including the matrix metalloproteinases, PPAR alpha sequence targets, and the PUFA synthesis pathway.

Conclusions: Our results suggest that GGM can be used to formally evaluate differences in global interactome connectivity across disease states, and can serve as a powerful tool for exploring the molecular events that contribute to disease at a systems level.