PROJECT SUMMARY The global objective of the Personalizing EmerGency/Acute therapeuticS Utilizing Systems biology (PEGASUS-2) Research Program is to improve drug effectiveness and safety in common acute care conditions. Drug therapy for acute conditions in the emergency department is only effective in approximately 50% of cases. There is tremendous opportunity to improve acute therapeutics by implementing precision medicine programs in acute care settings. We will build on the progress of PEGAUS-1 through 1) expand our multi-omic analyses in our target drug classes, 2) expand our statistical analytic methods to include multi-omic, machine learning analyses, and polygenic risk scores, and 3) expand to new sites in order to validate our findings. We will leverage our robust emergency medicine specimen bank (EMSB), the only acute care biorepository that focuses all patients presenting with acute illness, and we will continue to use phenotypic data from our electronic health record linking these data to pharmacogenomic, epigenomic, metabolomic, and proteomic data to discover new mechanisms of drug effectiveness and safety. Ultimately clinical and `omic data are integrated into multi-omic models to improve therapeutic success in acutely ill patients. Through the Maximizing Investigators' Research Award (MIRA) funding, PEGASUS-2 will continue to focus on common acute care conditions such as nausea, pain, and cardiovascular disease. In the future, these models will be tested prospectively. PEGASUS-1 has already identified numerous genetic and metabolic polymorphisms associated with drug effectiveness and expansion of the program will serve to increase our understanding of these mechanisms and improve the treatment of acute conditions.