Unveiling hidden connections in omics data via pyPARAGON: an integrative hybrid approach for disease network construction.

Network inference or reconstruction algorithms play an integral role in successfully analyzing and identifying causal relationships between omics hits for detecting dysregulated and altered signaling components in various contexts, encompassing disease states and drug perturbations. However, accurate representation of signaling networks and identification of context-specific interactions within sparse omics datasets in complex interactomes pose significant challenges in integrative approaches. To address these challenges, we present pyPARAGON (PAgeRAnk-flux on Graphlet-guided network for multi-Omic data integratioN), a novel tool that combines network propagation with graphlets. pyPARAGON enhances accuracy and minimizes the inclusion of nonspecific interactions in signaling networks by utilizing network rather than relying on pairwise connections among proteins. Through comprehensive evaluations on benchmark signaling pathways, we demonstrate that pyPARAGON outperforms state-of-the-art approaches in node propagation and edge inference. Furthermore, pyPARAGON exhibits promising performance in discovering cancer driver networks. Notably, we demonstrate its utility in network-based stratification of patient tumors by integrating phosphoproteomic data from 105 breast cancer tumors with the interactome and demonstrating tumor-specific signaling pathways. Overall, pyPARAGON is a novel tool for analyzing and integrating multi-omic data in the context of signaling networks. pyPARAGON is available at https://github.com/netlab-ku/pyPARAGON.

Computational approaches leveraging integrated connections of multi-omic data toward clinical applications.

In line with the advances in high-throughput technologies, multiple omic datasets have accumulated to study biological systems and diseases coherently. No single omics data type is capable of fully representing cellular activity. The complexity of the biological processes arises from the interactions between omic entities such as genes, proteins, and metabolites. Therefore, multi-omic data integration is crucial but challenging. The impact of the molecular alterations in multi-omic data is not local in the neighborhood of the altered gene or protein; rather, the impact diffuses in the network and changes the functionality of multiple signaling pathways and regulation of the gene expression. Additionally, multi-omic data is high-dimensional and has background noise. Several integrative approaches have been developed to accurately interpret the multi-omic datasets, including machine learning, network-based methods, and their combination. In this review, we overview the most recent integrative approaches and tools with a focus on network-based methods. We then discuss these approaches according to their specific applications, from disease-network and biomarker identification to patient stratification, drug discovery, and repurposing.