Systematic Identification of Context-dependent Conflicting Information in Biological Pathways

Interactions between biological entities such as genes, proteins and metabolites, so called pathways, are key features to understand molecular mechanisms of life. As pathway information is being accumulated rapidly through various knowledge resources, there are growing interests in maintaining integrity of the heterogeneous databases. Here, we defined conflict as a status where two contradictory evidences (i.e. 'A increases B' and 'A decreases B') coexist in a same pathway. This conflict damages unity so that inference of simulation on the integrated pathway network might be unreliable. We defined rule and rule group. A rule consists of interaction of two entities, meta-relation (increase or decrease), and contexts terms about tissue specificity or environmental conditions. The rules, which have the same interaction, are grouped into a rule group. If the rules don't have unanimous meta-relation, the rule group and the rules are judged as being conflicting. This analysis revealed that almost 20% of known interactions suffer from conflicting information and conflicting information occurred much more frequently in the literatures than the public database. With consideration for dual functions depending on context, we thought it might resolve conflict to consider context. We grouped rules, which have the same context terms as well as interaction. It's revealed that up to 86% of the conflicts could be resolved by considering context. Subsequent analysis also showed that those contradictory records generally compete each other closely, but some information might be suspicious when their evidence levels are seriously imbalanced. By identifying and resolving the conflicts, we expect that pathway databases can be cleaned and used for better secondary analyses such as gene/protein annotation, network dynamics and qualitative/quantitative simulation.