Graph Theoretical Analysis of Genome-Scale Data: Examination of Gene Activation Occurring in the Setting of Community-Acquired Pneumonia.

Abstract

We have previously reported evidence that Black individuals appear to have a significantly higher incidence of infection-related hospitalizations compared with White individuals. It is possible that the host immune response is responsible for this vital difference. In support of such a hypothesis, the aim of this study was to determine whether Black and White individuals exhibit differential whole blood gene network activation. We examined whole blood network activation in a subset of patients (n = 22 pairs, propensity score matched (1:1) Black and White patients) with community-acquired pneumonia (CAP) from the Genetic and Inflammatory Markers of Sepsis study. We employed day one whole blood transcriptomic data generated from this cohort and constructed co-expression graphs for each racial group. Pearson correlation coefficients were used to weight edges. Spectral thresholding was applied to ascribe significance. Innovative graph theoretical methods were then invoked to detect densely connected gene networks and provide differential structural analysis. Propensity matching was employed to reduce potential bias due to confounding variables. Although Black and White patients had similar socio- and clinical demographics, we identified novel differences in molecular network activation-dense subgraphs known as paracliques that displayed complete gene connection for both White (three paracliques) and Black patients (one paraclique). Specifically, the genes that comprised the paracliques in the White patients include circadian loop, cell adhesion, mobility, proliferation, tumor suppression, NFκB, and chemokine signaling. However, the genes that comprised the paracliques in the Black patients include DNA and messenger RNA processes, and apoptosis signaling. We investigated the distribution of Black paracliques across White paracliques. Black patients had five paracliques (with almost complete connection) comprised of genes that are critical for host immune response widely distributed across 22 parcliques in the White population. Anchoring the analysis on two critical inflammatory mediators, interleukin (IL)-6 and IL-10 identified further differential network activation among the White and Black patient populations. These results demonstrate that, at the molecular level, Black and White individuals may experience different activation patterns with CAP. Further validation of the gene networks we have identified may help pinpoint genetic factors that increase host susceptibility to community-acquired pneumonia, and may lay the groundwork for personalized management of CAP.