Researchers Overview of the GREAT Study
The Genomic Resource To Enhance Available Therapy Study is an observational cohort study of patients at participating UPMC clinics treating complex disorders. It facilitates a collaborative effort between patients, physicians, and scientists at UPMC and the University of Pittsburgh to build a resource of patient-center translational research, particularly for the implementation of precision medicine. The study is centered within UPMC as a precision medicine initiative intent on improving electronic phenotyping of patients, utilizing limited genetic information and optimizing the use of “omic” and other biomarkers to improve patient care. The GREAT Study allows patients, physicians and scientists to coordinate the collection high-quality information and biological samples in an efficient (automated) way, and to bring new discoveries back to the patient using evidence-based approaches.
The research design is to ascertain a very large and broad cohort of UPMC patients using standardized approaches that are relevant to many conditions (e.g. demographics, disease problem list, quality of life scores). Individual investigators are encouraged to do their own deeper, syndrome-specific studies (e.g. rheumatoid arthritis, asthma). The GREAT Study is a resource and collaboration to provide other departments with valuable data for their own studies to be used as they choose.
The first level of analysis is nested case-control studies (e.g. comparing two groups of patients with the same disorder and different outcomes). This can be done within a disease (e.g. patients with IBD who do or do not respond to biologic therapy), or between diseases (e.g. patients with inflammatory disorders in various organs who do or do not develop chronic pain).
Each medical and surgical specialty focuses on their own specific sets of problems. The GREAT Study is designed to facilitate these independent research efforts by simplifying patient ascertainment, and generating comparison groups with other disciplines (e.g. fibrosis, chronic pain, chronic inflammation). In addition, it will serve to harmonize some standard measures such as pain scales, quality of life measures and biomarker selection for collaboration and comparison studies. The goal is not to direct other research studies, but rather serve co-investigators as a resource to bolster their own studies at Pitt and UPMC, with the ultimate care of application to improve patient care.
The GREAT Study is focused on complex disorders. These include syndromes and common clinical problems in which interaction of multiple factors, that alone are neither necessary or sufficient to cause disease, come together in individuals to cause specific syndromes. It includes disorders where multiple etiologies result in the same syndrome, where the same syndrome has multiple and variable levels of progression, severity and complications, and where treatment effect is unpredictable – either because of pharmacogenetic factors or different disease mechanisms.
The GREAT Study also addresses common and variable systemic complications that make complex disorders worse. These include persistent or altered inflammatory responses, fibrosis, autoimmune disorders, autonomic dysfunction, fibrosis, pain syndromes, obesity, diabetes, microvascular disease, affective and psychiatric disorders, sleep disorders and others.
The rationale is that ALL patients seen by expert physicians serve as either cases or controls for each of the syndromes and complicating factors. Furthermore, uniform data ascertainment, utilizing the electronic health record systems, allows new insights to be gained through study of large nested cohorts. In addition, mechanistic insights into specific disorders that share mechanism with other disorders provide rationale for testing the use of established treatments in the other diseases.
The GREAT Study requires high-level scientific support from multiple disciplines. A primary focus is on gene-environment interactions, as well as epigenetics and higher-level regulation and dysregulation of acquired acute and chronic disorders. The complexity of complex disorders requires systems biology and disease modeling to provide the framework for understanding disease within individual patients or groups of patients, and is linked to quantitative systems pharmacology as a common pathway between patient populations and new therapies.
The GREAT Study also seeks to leverage areas of research strength at the University of Pittsburgh. Areas of focus include genetics, epidemiology, immunology (including autoimmunity and fibrosis), epithelial cell biology, obesity/metabolism, pathology, neurobiology, psychiatry, pain, regenerative medicine, oncology, imaging, computer modeling and simulation.
The rationale is that these systemic disciplines are both relevant to individual syndromes, and that harmonizing sciences across disorders provides statistical leverage and opportunities.