Biochemical pathways are commonly used as a reference to conduct functional analysis on biomedical omics data sets, where experimental results are mapped to knowledgebases comprising known molecular interactions collected from the literature. Due to their central role, the content of the functional knowledgebases directly influences the outcome of pathway analyses. In this study, we investigate the structure of the current pathway knowledge, as exemplified by Reactome, discuss the consequences for biological interpretation, and outline possible improvements in the use of pathway knowledgebases. By providing a view of the underlying protein interaction network, we aim to help pathway analysis users manage their expectations and better identify possible artifacts in the results.
Keywords: pathway analysis; protein networks; protein−protein interactions.