Background: Prompted by the frequency of concomitant use of prescription drugs with natural products, and the lack of knowledge regarding the impact of pharmacokinetic-based natural product-drug interactions (PK-NPDIs), the United States National Center for Complementary and Integrative Health has established a center of excellence for PK-NPDI. The Center is creating a public database to help researchers (primarly pharmacologists and medicinal chemists) to share and access data, results, and methods from PK-NPDI studies. In order to represent the semantics of the data and foster interoperability, we are extending the Drug-Drug Interaction and Evidence Ontology (DIDEO) to include definitions for terms used by the data repository. This is feasible due to a number of similarities between pharmacokinetic drug-drug interactions and PK-NPDIs.
Methods: To achieve this, we set up an iterative domain analysis in the following steps. In Step 1 PK-NPDI domain experts produce a list of terms and definitions based on data from PK-NPDI studies, in Step 2 an ontology expert creates ontologically appropriate classes and definitions from the list along with class axioms, in Step 3 there is an iterative editing process during which the domain experts and the ontology experts review, assess, and amend class labels and definitions and in Step 4 the ontology expert implements the new classes in the DIDEO development branch. This workflow often results in different labels and definitions for the new classes in DIDEO than the domain experts initially provided; the latter are preserved in DIDEO as separate annotations.
Results: Step 1 resulted in a list of 344 terms. During Step 2 we found that 9 of these terms already existed in DIDEO, and 6 existed in other OBO Foundry ontologies. These 6 were imported into DIDEO; additional terms from multiple OBO Foundry ontologies were also imported, either to serve as superclasses for new terms in the initial list or to build axioms for these terms. At the time of writing, 7 terms have definitions ready for review (Step 2), 64 are ready for implementation (Step 3) and 112 have been pushed to DIDEO (Step 4). Step 2 also suggested that 26 terms of the original list were redundant and did not need implementation; the domain experts agreed to remove them. Step 4 resulted in many terms being added to DIDEO that help to provide an additional layer of granularity in describing experimental conditions and results, e.g. transfected cultured cells used in metabolism studies and chemical reactions used in measuring enzyme activity. These terms also were integrated into the NaPDI repository.
Conclusion: We found DIDEO to provide a sound foundation for semantic representation of PK-NPDI terms, and we have shown the novelty of the project in that DIDEO is the only ontology in which NPDI terms are formally defined.
Keywords: Biomedical ontologies; Drug-drug interactions; Natural product-drug interactions; OWL; Pharmaceuticals; Pharmacokinetics.