DESCRIPTION (provided by applicant): Diarrhea causes nearly two million deaths annually in children under five, or one fifth of all child deaths worldwide. As the severity of the disease depends on the degree of fluid loss, accurately assessing dehydration status remains a crucial step in preventing morbidity and mortality. While children with severe dehydration require immediate treatment with intravenous fluids to prevent hemodynamic compromise and death, children with mild to moderate dehydration have a significant reduction in hospital length of stay and fewer adverse events when treated with relatively inexpensive oral rehydration solution (ORS) as compared to treatment with costly intravenous fluids. While the World Health Organization (WHO) recommends using a four-point clinical scale for determining the severity of dehydration in children, this scale has never been validated against a physiologic gold standard (such as the accepted standard of percent weight change with rehydration). While several prior authors have developed alternative clinical prediction rules for severe dehydration in children, these scales have not been externally validated against a physiologic gold standard in a developing country, where the vast majority of pediatric deaths from diarrhea occur, and where clinician expertise and varying disease patterns may affect the accuracy of any clinical scale derived in a developed country. There is an urgent need for research into new clinical tools that can accurately and reliably assess dehydration in a resource-limited setting. As part of this K01 award, we will conduct a series of three studies that will derive, validate, and assess the reliability of a new clinical prediction rule for severe dehydration in children with diarrhea in te developing world. In addition, we will validate and assess the reliability of ultrasound of the inferior vena cava (IVC) for predicting severe dehydration in children with diarrhea in the developing world. Finally, we will compare the accuracy of each of these new diagnostic tools to that of the WHO scale, using percent weight change with rehydration as the gold standard for all of our measures of dehydration, in order to determine whether either of these new methods may improve upon the current standard of care. My prior training and research experience have provided me with a solid foundation for this career development award. I have completed a Doctorate of Medicine at the University of California, San Francisco and a Masters of Public Health in International Health at the University of California, Berkeley. I also have experience designing and managing two small research studies conducted in resource-limited settings, including one study providing preliminary data for this International Research Scientist Development Award (IRSDA) application. However, I would benefit from additional targeted training in specific areas, including advanced regression analysis and recursive partitioning, clinical trial design and management, cost- effectiveness analysis, the pathophysiology of diarrhea and malnutrition, and the ethics of conducting research in resource-limited settings, which will be completed during the five years of this K01 award through formal coursework, seminars, directed reading, and individualized tutorials. I will also benefit from the additional experience of managing large, prospective studies under the mentorship of three scientists with extensive experience in conducting public health and global health research, including Dr. Jennifer Friedman of Brown Medical School, Dr. Nur Haque Alam of the International Center for Diarrheal Disease and Research, Bangladesh (ICDDRB), and Dr. Earl F. Cook of the Harvard School of Public Health. After this K01 award, I plan to apply for an R01 grant to fund a randomized controlled trial comparing these new methods for diagnosing and managing dehydration in children with diarrhea to the current standard of care, analyzing both health-related outcomes, such as adverse events, and total costs. Improved methods for assessing severe dehydration have the potential to help clinicians in the developing world identify the children with diarrhea at greatest need for emergent intervention, while also preventing the adverse events and wasted resources associated with the inappropriate use of intravenous fluids. These new methods have the potential to improve the delivery of care in both developed and developing country hospitals and clinics, as well as in refugee camp settings where outbreaks of diarrheal disease are common. In addition to funding research into the development of these new methods, the IRSDA will also provide me with the support necessary to launch my career as an independently funded physician-scientist in translational global health research. Utilizing the knowledge and skills gained as part of the IRSDA, I am committed to a career aimed at improving the evidence base for the diagnosis and management of dehydration in resource-limited settings, thereby improving both the effectiveness and cost- effectiveness of care and potentially saving thousands of lives each year.

PUBLIC HEALTH RELEVANCE: Nearly two million children in developing countries die each year from severe dehydration due to diarrhea. This research aims to develop new and improved clinical and ultrasound-based methods for diagnosing severe dehydration in children with diarrhea. These new methods will help doctors and nurses in the developing world identify those children at greatest need for emergent intervention, prevent adverse events, and improve health outcomes, all while conserving scarce healthcare resources.