Network-based analysis reveals distinct association patterns in a semantic MEDLINE-based drug-disease-gene network

A huge amount of associations among different biological entities (e.g., disease, drug, and gene) are scattered in millions of biomedical articles. Systematic analysis of such heterogeneous data can infer novel associations among different biological entities in the context of personalized medicine and translational research. Recently, network-based computational approaches have gained popularity in investigating such heterogeneous data, proposing novel therapeutic targets and deciphering disease mechanisms. However, little effort has been devoted to investigating associations among drugs, diseases, and genes in an integrative manner.

We propose a novel network-based computational framework to identify statistically over-expressed subnetwork patterns, called network motifs, in an integrated disease-drug-gene network extracted from Semantic MEDLINE. The framework consists of two steps. The first step is to construct an association network by extracting pair-wise associations between diseases, drugs and genes in Semantic MEDLINE using a domain pattern driven strategy. A Resource Description Framework (RDF)-linked data approach is used to re-organize the data to increase the flexibility of data integration, the interoperability within domain ontologies, and the efficiency of data storage. Unique associations among drugs, diseases, and genes are extracted for downstream network-based analysis. The second step is to apply a network-based approach to mine the local network structure of this heterogeneous network. Significant network motifs are then identified as the backbone of the network. A simplified network based on those significant motifs is then constructed to facilitate discovery. We implemented our computational framework and identified five network motifs, each of which corresponds to specific biological meanings. Three case studies demonstrate that novel associations are derived from the network topology analysis of reconstructed networks of significant network motifs, further validated by expert knowledge and functional enrichment analyses.

We have developed a novel network-based computational approach to investigate the heterogeneous drug-gene-disease network extracted from Semantic MEDLINE. We demonstrate the power of this approach by prioritizing candidate disease genes, inferring potential disease relationships, and proposing novel drug targets, within the context of the entire knowledge. The results indicate that such approach will facilitate the formulization of novel research hypotheses, which is critical for translational medicine research and personalized medicine.