? Billions of prescriptions are written each year in the hopes of improving health and preventing disease in millions of Americans. Unfortunately, these medications do not work as hoped in everyone, and others suffer from side effects, leading to substantial morbidity and mortality. Although genetic variability in the response to medications has been known for decades to play a critical role in limiting the efficacy and safety of drugs, recent advances in genetics, bioinformatics, pharmacology, epidemiology, and biostatistics have paved the way for tremendous gains in understanding how genetic variability can alter drug response. Despite this promise, the nature of gene-drug interactions is complex, and progress in the field has been hampered by the lack of a true interdisciplinary approach. A complete understanding of the genetic basis for variable responses to medications and appropriate application of this information in human populations will come only through a coordinated and sustained collaboration among the disciplines of genetics, bioinformatics, pharmacology, epidemiology, biostatistics, and bioethics in a new interdisciplinary field that we call Human Pharmacogenomic Epidemiology (HPE). HPE is not simply the merger of multiple disciplines, working in parallel or sequence, but rather a new paradigm of research that must develop novel ways of working synergistically to address the scientific, logistical, and intellectual barriers to interdisciplinary research. ? ? In this application, a group of experienced investigators from each of these disciplines, working within an enriched and supportive academic environment, proposes to develop an interdisciplinary collaboration whose aims are to develop unique and sustainable approaches to solving the significant and complex biomedical problem of variable drug response by developing strategies targeted at all three barriers to interdisciplinary research: ? 1) Scientific: by developing study design and statistical methods aimed at solving problems of the complex, high-dimensional nature of genetic influences on response to medications, ? 2) Logistical: by developing new strategies that improve the coordination and efficiency of HPE research, and ? 3) Intellectual: by designing innovative and sustainable approaches to improve the appreciation among the disciplines of each others' scientific context, opportunities offered, and distinct methods and languages. ? ?
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