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Notable Examples of Network Analysis Applications

In this section, the recent studies that exemplify novel applications of network analysis in disease pathobiology are highlighted. Topological networks of common intermediate phenotypes (endophenotypes) have been constructed by Ghiassian et al,²⁶ including literature-curated molecular determinants of inflammation, thrombosis, and fibrosis, in the context of the human PPI network. These endophenotype modules overlap in their network topology, revealing a significant number of shared mechanisms among them. These overlapping modules are highly enriched with the genes associated with diseases and disease risks and may serve as fruitful targets for therapeutic interventions applicable to multiple disease processes.

A network analysis of molecular mediators of the placebo treatment response enabled construction of the placebome module within the comprehensive human interactome. This module was notably enriched with brain-specific proteins and neurotransmission signaling components, and its network proximity to various disease modules within the human interactome correlated with the magnitude of the placebo effect in specific disease processes.¹⁰⁵

Constructing a subnetwork that integrates fibrosis-specific PPIs and aldosterone-regulated genes expressed by human endothelial cells led to the identification of NEDD9-mediated novel mechanisms of vascular fibrosis in pulmonary arterial hypertension.¹⁰⁶

In a recent study of patients with type 2 diabetes mellitus, the controllability of the network was examined using the control centrality measure to identify the high control centrality pathways in a pancreatic islet–specific gene regulatory network. NFATC4 was identified as one of the important variants that regulate gene expression in multiple high control centrality pathways, and in vitro silencing of its gene product in animal islets led to changes in the expression of multiple downstream genes implicated in type 2 diabetes pathobiology.¹⁰⁷

Cheng et al¹⁶ examined new drug-disease interactions involving over 900 FDA-approved drugs by measuring the network proximity between known drug targets and disease proteins in the human interactome. Selected novel drug-disease associations were validated using large-scale longitudinal patient databases and in vitro mechanistic assays. This study, thus, proposes a novel platform for drug repurposing that is PPI network-based.