Overlap of the three DSs created by DS-RAI, DS-DC, and DS-GDC algorithms applied to the human PPI network.

<p>Overlap of the three DSs created by DS-RAI, DS-DC, and DS-GDC algorithms applied to the human PPI network.</p

The overlap of BC genes from the four categories in the human PPI network.

<p>The overlap of BC genes from the four categories in the human PPI network.</p

Graphlets, automorphism orbits, and GDVs.

<p>(<b>A</b>) All 9 graphlets with 2, 3 and 4 nodes, denoted by , ,…,; they contain 15 topologically unique node types, called automorphism orbits, denoted by 0, 1, 2, …, 14. In a particular graphlet, nodes belonging to the same orbit are of the same shade (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0023016#pone.0023016-Prulj2" target="_blank">[47]</a> for details). (<b>B</b>) An illustration of the GDV of node ; it is presented in the table for orbits 0 to 14: is touched by 4 edges (orbit 0), end-nodes of 2 graphlets (orbit 1), etc. The figure is taken from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0023016#pone.0023016-Milenkovi3" target="_blank">[53]</a>.</p

An illustration of DSs in a toy network.

<p>The DSs were obtained by (<b>A</b>) DS-RAI and (<b>B</b>) DS-DC algorithms. The example in panel A is taken from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0023016#pone.0023016-Rai1" target="_blank">[57]</a>, and the authors describe the algorithm as follows. In phase 1, nodes 1, 4, 8, 12, and 16 are colored black as members of an independent DS. In phase 2, nodes 2, 9, and 11 are colored dark grey as connectors that connect nodes in the independent DS resulting from phase 1. In phase 3, the connected DS resulting from phase 2 is pruned to reduce it size by removing node 16 from the DS (no other nodes can be removed without violating the requirement of producing a connected DS of the graph). In panel B, all nodes are initially in the DS and then nodes are visited in order of their increasing degrees and removed from the DS if the resulting DS is a valid connected DS of the graph. That is, nodes are removed in the following order: 3, 16, 2, 4, 7, 10, 13, 14, 15, and 9. The resulting DS therefore contains the remaining nodes: 1, 5, 6, 8, 11, and 12. Clearly, the DS produced by DS-DC (black nodes in panel B) is smaller than the DS produced by DS-RAI (black and dark grey nodes in panel A).</p

The top 1% (i.e., 91) GDC-central genes.

<p>If a gene is an aging (“A”), cancer (“C”), HIV (“HIV”), or pathogen-interacting (“PI”) gene, there is an “X” in the corresponding entry.</p

The performance of GDC and its comparison with other centrality measures.

<p>(<b>A</b>) Enrichments in BC genes of the top % of the most GDC-central genes (denoted by “Central”, blue bars) and all remaining genes (denoted by “Non-central”, red bars) in the human PPI network. (<b>B</b>) Enrichment in drug targets of BC genes that are GDC-central (“Central”) and BC genes that are non-GDC-central (“Non-central”). (<b>C</b>) Enrichments in BC genes of the top % of the most central genes in the human PPI network, with respect to the four centrality measures (DC, BWC, SC, and GDC), broken into the four BC gene categories (aging (A), cancer (C), HIV (HIV), and pathogen-interacting (PI) genes). In all panels, the values of where precision and recall cross (as illustrated in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0023016#pone-0023016-g005" target="_blank">Figure 5</a>) are used; equals 3, 10, 12, and 6, for A, C, HIV, and PI genes, respectively, for each of the four centrality measures.</p

An illustration of the differences between DC and GDC.

<p><i>Left:</i> Direct neighborhood of ZAP90, a cancer and HIV gene, in the human PPI network <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0023016#pone.0023016-Radivojac1" target="_blank">[28]</a>. Its degree is 48 and it is ranked as the top gene with respect to DC. <i>Right:</i> Direct neighborhood of PRKACA, an HIV gene, in the network. Its degree is 145 and it is ranked as the top gene with respect to DC. Both proteins have the same GDC and are ranked as top genes with respect to GDC. Hence, GDC rewards the ranking of a low-degree gene if its 4-deep neighborhood is dense (ZAP90) and penalizes the ranking of a high-degree gene if its 4-deep neighborhood is sparse (PRKACA). (For the esthetics of the figure, we only show 1-deep neighborhoods.)</p

The distribution of GDV similarity of protein pairs in the human PPI network.

<p>Horizontal axis represents GDV-similarities of node pairs in the network in bins of . Vertical axis represents percentages of protein pairs that have a particular GDV-similarity.</p

Predicted CVD genes.

<p>The first two columns: predicted CVD genes (Entrez Gene IDs and Official Gene Symbols respectively). The third column: GO terms that the genes are annotated with. We only take into consideration GO terms in which this set of 17 genes is statistically significantly enriched. We only list GO terms that correspond to biological functions that the three drug mechanisms of interest rely on. BP denotes “biological process,” while MF denotes “molecular function” of GO. The fourth column: if we validate that the predicted gene is associated with a CVD, we give the PubMed ID of the corresponding reference; “–”means that we found no literature validation.</p

Summary of the results.

<p>The Core Diseasome of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071537#pone.0071537-Janji1" target="_blank">[22]</a> is overlaid with the results of this study. Green nodes are the Key CVD Genes (from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071537#pone-0071537-t001" target="_blank">Table 1</a>), which are in the Core Diseasome. Blue nodes are predicted CVD genes (from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071537#pone-0071537-t002" target="_blank">Table 2</a>) that we validated in the literature and that are in the Core Diseasome. Red nodes are non-validated CVD gene predictions (from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071537#pone-0071537-t002" target="_blank">Table 2</a>) that are in the Core Diseasome. Triangular nodes are drug targets. Driver genes are bordered in red.</p