Elucidating the semantics-topology trade-off for knowledge inference-based pharmacological discovery

Abstract

Leveraging AI for synthesizing the deluge of biomedical knowledge has great potential for pharmacological discovery with applications including developing new therapeutics for untreated diseases and repurposing drugs as emergent pandemic treatments. Creating knowledge graph representations of interacting drugs, diseases, genes, and proteins enables discovery via embedding-based ML approaches and link prediction. Previously, it has been shown that these predictive methods are susceptible to biases from network structure, namely that they are driven not by discovering nuanced biological understanding of mechanisms, but based on high-degree hub nodes. In this work, we study the confounding effect of network topology on biological relation semantics by creating an experimental pipeline of knowledge graph semantic and topological perturbations. We show that the drop in drug repurposing performance from ablating meaningful semantics increases by 21% and 38% when mitigating topological bias in two networks. We demonstrate that new methods for representing knowledge and inferring new knowledge must be developed for making use of biomedical semantics for pharmacological innovation, and we suggest fruitful avenues for their development.