PROJECT SUMMARY/ABSTRACT Pediatric sepsis is a major global public health problem associated with millions of deaths every year. However, the current criteria to diagnose pediatric sepsis are outdated, lack specificity, do not allow early detection and risk stratification in all settings, and are discordant with clinician-based diagnosis. In 2016, the adult Sepsis-3 task force redefined sepsis as “life-threatening organ dysfunction caused by a dysregulated host response to infection,” emphasizing the pivotal role of organ dysfunction in the pathophysiology of sepsis. Importantly, they used a data-driven approach. The adult Sepsis-3 criteria, however, have been criticized for their limited applicability outside the intensive care unit and in resource-limited settings. The pediatric criteria are still based on the systemic inflammatory response syndrome and unvalidated organ dysfunction criteria. In 2019, the Society of Critical Care Medicine and other major global organizations sponsored the creation of the Pediatric Sepsis Definition Task Force to update the definition and operational criteria for pediatric sepsis. The overall objective of this proposal is to derive and validate novel pediatric sepsis criteria that generalize beyond the ICU and to differently resourced settings. The new criteria will be based on measures of organ dysfunction. However, it remains unknown which organ dysfunction measures are optimal for the new pediatric sepsis criteria. Furthermore, there is currently no pediatric emergency and inpatient database with the granularity and broad representation needed to derive and validate the new sepsis criteria. In this proposal, we will address these critical gaps to advance the science and clinical care of pediatric sepsis. We will extend our prior work and leverage the expertise of our international investigative team to build a large, centralized electronic health record database of pediatric emergency and inpatient care from institutions in both high-income countries and low- and middle-income countries. We will use these rich clinical data to accomplish the following aims: 1) determine the optimal clinical criteria for each pediatric organ dysfunction in differently resourced settings and care environments, 2) develop and validate novel pediatric sepsis criteria, and 3) design, build, and evaluate prototype CDS tools to facilitate use of the new pediatric sepsis criteria. We have assembled an investigative team with a successful track record in the field and will work in partnership with the Pediatric Sepsis Definition Task Force to address this global health priority. We expect the results of this proposal to have a powerful and sustained impact on the science of pediatric sepsis and organ dysfunction and ultimately improve sepsis recognition, accelerate appropriate effective treatment, decrease unnecessary treatment, and improve the outcomes of children with sepsis around the world.