Integrated directed pathways

We constructed a directed backbone network having ‘effect type’ and ‘effect direction’ by integrating Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway [14]. Although KEGG pathway does not cover entire molecular entries and pathways in human, it provides manually curated pathways with highly reliable relations having ‘effect type’ and ‘effect direction’ information. We downloaded KEGG Markup Language (KGML) files of 286 human pathways using KEGGgraph package [15]. We only used gene entries and relations with obvious ‘effect direction’ like activation, inhibition, expression, and repression. Then, the 166 human pathways including signal transduction and transcription pathways were merged into a Directed KEGG pathways (DKEGG) consisting of 3,307 nodes and 28,808 directed edges. Each node in DKEGG is a gene and each edge represents a relation with ‘effect type’ and ‘effect direction’ from gene A to gene B, for example, gene A activates (inhibits) gene B. In DKEGG, if the effect type from gene A to gene B was ‘activation-like effect types’ like activation or expression, we assigned the edge weight from node A to B as ‘+1’ and if the effect type from node A to B was inhibition or repression, the edge weight from node A to B was set to ‘-1’.