A critical component of the Federal architecture for the Nationwide Health Information Network is the Electronic Health Record (EHR) employing structured clinical data encoded with Office of the National Coordinator (ONC) standard reference terminologies that support interoperable repurposing of the data for research and public health. These reference terminologies, including SNOMED CT and RXNORM, are large and complex, thereby complicating and historically limiting terminology implementation in support of big data research objectives. This research and development proposal seeks to: a) expand the scope and clinical applicability of these terminologies, b) create metadata tooling in support of ONC reference terminology deployment in clinical data repositories (CDR) and c) assess the utility of that deployment for organizing tissue biobanks and supporting networked research queries. Metadata and software tooling will be developed and made available to the biomedical research community through the National Center for Biomedical Ontologies (NCBO). The harmonization of SNOMED CT and LOINC in the domain of observable entities is an important unification of ONC clinical ontologies. This project will expedite this harmonization to include the domains of anatomic pathology, molecular genetics, and microbiology and create an observables ontology for distribution through the NCBO. Distribution and implementation of an observables ontology will facilitate research that binds patient phenomic data with disease-specific genomic observations in support of research into the genetic basis of disease. The observables ontology will be tested within an i2b2-based CDR in the areas of breast cancer and antimicrobial stewardship. The Patient Centered Outcome Research Initiative (PCORI) seeks to provide timely answers to the research questions of our day by standardizing datasets across research institutions. While employing a common clinical data model, efficient and interoperable query of data employing ONC reference terminologies requires expanded information models, coordination between EHR vendors and shared network protocols. This proposal will deploy the ONC reference terminology metadata including the observables ontology to members of the Greater Plains Consortium (GPC) PCORnet CDRN. Breast cancer and antimicrobial stewardship queries will be deployed between collaborating GPC members for testing of interoperability and demonstration of network functionality.