Sub-pathway based approach to systematically track candidate sub-pathway biomarkers for heart failure

Identification of potential novel biomarkers for heart failure was undertaken using a sub-pathway based method. To realize this goal, heart failure-relevant dataset, reference pathways, and lncRNA-miRNA-mRNA interactions were firstly recruited. Secondly, the informative pathways were extracted relying on KEGG pathways and the mRNAs in the PCC-weighted lncRNA-mRNA interactions. Thirdly, lncRNA-regulated sub-pathways were dissected after construction of condition-specific lncRNA competitively regulated pathways (LCRP). To detect crucial heart failure-relevant lncRNAs, degree analysis was conducted for all nodes within the LCRP. Ultimately, the significance of candidate sub-pathways were assessed to further identify the significant sub-pathways. There were 44 lncRNAs, 165 mRNAs and 224 co-expressed interactions. After putting the 165 mRNAs into the reference pathways, 56 informative pathways were obtained which were then embedded into undirected graphs, and 44 lncRNAs were inserted into the pathway graphs to further construct the condition-specific LCRP. According to degree distribution, 4 hub lncRNAs were selected, including ERVK13-1, YLPM1, PDXDC2P, and LINC00482. Based on the LCRP information, a total of 36 sub-pathways mediated by lncRNAs participated in 40 complete pathways. Among these 40 pathways, we mainly concentrated on the top three sub-pathways, including a sub-part of MAPK signaling pathway, an important sub-part in ErbB signaling pathway, and a part of chemokine signaling pathway. In the top 3 significant sub-pathways, gene AKT3 was simultaneously regulated by ERVK13-1, YLPM1, and PDXDC2P. Sub-pathways including MAPK signaling pathway and hub lncRNAs (ERVK13-1, YLPM1, and PDXDC2P) may play an important role in heart failure.