The mission of the Duke Translational Medicine Institute (DTMI) is to catalyze translation across the continuum from scientific discovery to clinical research to care delivery and global health. We propose to fulfill this mission by achieving four Specific Aims: 1) Implement the next phase of the clinical and translational research at Duke, by enhancing its scope, its operational effectiveness, and the number of researchers it serves; 2) Provide DTMI investigators with biomedical informatics tools and methods needed to enhance the operational effectiveness of this next phase of the DTMI; 3) Train the next generation of clinical and translational research leaders and support continuing education to enhance the skills of the current generation of research leaders; 4) Develop methods and approaches for integrating research results into practice and practice outcomes into research. While we succeeded in building a home for clinical and translational researchers in the first funding cycle of the CTSA grant, recent discussions at the NIH and our own assessments have pointed out the need for further transformation of the system. Major emphasis must be placed on measurable output, project management, enterprise portfolio management, and public-private partnerships. These themes were reflected in the work of the DTMI during our first five years, and we are prepared to accelerate this effort by: implementing innovative approaches to pilot projects, creating a translational technology resource network, and supporting novel methods. A global proof of concept network to study human systems biology is a key element of DTMI. All human research projects in Duke Medicine (over 4,100) will be coordinated within the same electronic management system. Innovative elements of the plan include novel public private partnerships, a highly developed project management system, and an innovative approach to integration of medical, financial, operational, environmental, and social data into a geospatially referenced enterprise data warehouse. This powerful system, combined with tools that enable use of the data in concert with the community, has enabled the planning for a county-wide effort to improve health outcomes while enabling health services research and joint investigation of biological, medical, and social causes of health and disease. Special emphasis will be placed on integration of child health and comparative effectiveness research into DTMI, as well as on health studies that foster both community engagement and analysis of molecular and genomic data in populations. The flexible DTMI approach emphasizes constant evaluation and modifications based on a detailed continuous improvement paradigm.