Candidate: Dr. Balamuth has clinical training in pediatric emergency medicine, and research training both in immunobiology, having received a PhD through the Medical Scientist Training Program at Yale University, and epidemiology, as she is enrolled in the Masters of Science in Clinical Epidemiology program through the support of an NHLBI K12 award at the University of Pennsylvania. This proposal for a K23 Career Development Award will position the applicant to gain advanced skills in genetic epidemiology and high throughput gene expression studies through the conduct of a prospective study utilizing RNA expression profiling to improve pediatric sepsis recognition in the emergency department. Dr. Balamuth's mentors have expertise in epidemiology and immunology, and will ensure that both the career development and research plan are carried out successfully. The applicant's current objectives are to improve sepsis recognition in ED patients using both epidemiologic and biologic tools. With 75% of her time dedicated to patient oriented research and her career development, the applicant's short term goals are 1. To complete her K12 studies. These include a study which demonstrates improved outcomes for patients with severe sepsis or septic shock who were recognized rapidly in the ED and treated according to a clinical practice guideline and a study which evaluates a vital sign based electronic alert for sepsis in the emergency department and demonstrates that although the alert is sensitive for identifying sepsis, that it has a high false positive rate and 2. To carry out the studies described in the current proposal. The applicant's long term career goal is to become an independent academic physician-scientist with an established NIH-funded program to accurately identify pediatric patients with sepsis in the ED setting, and to risk stratify patients so that they receive appropriate and personalized interventions based on their underlying biology, with the ultimate goal of decreasing morbidity and mortality. She will achieve this through emergency medicine based research network sepsis intervention trials using risk stratification through personalized medicine techniques. Achieving these short and long term goals will develop Dr. Balamuth as a leader in the nascent field of translational research in the pediatric ED. Environment: The proposal takes advantage of the extensive resources available to Dr. Balamuth at The Children's Hospital of Philadelphia (CHOP) and the University of Pennsylvania Perelman School of Medicine (Penn) by bridging multiple disciplines, schools, and research centers to create a unique program aimed towards developing skills in advanced genetic epidemiology, and high throughput methods. Overall, CHOP and Penn provide a rich environment for research and training. The wealth and diversity of both formal didactic training and opportunities for mentored research experiences, combined with the high clinical volume of a quaternary pediatric emergency department is unique, and create an ideal environment for Dr. Balamuth's ongoing career development. Research: Severe sepsis is an important cause of morbidity and mortality in children. There have been significant advances over the past decade, which have demonstrated improved patient outcomes with timely, protocol-based therapies. However, identifying which children require these intensive therapies is challenging. Finding the children at risk for severe sepsis from among the thousands who present to emergency departments each year with common febrile illness is akin to finding a needle in a haystack. Although there have been many studies in the literature investigating candidate biomarkers as both diagnostic and therapeutic targets in sepsis, it has become clear that the complex nature of the human response to sepsis makes single marker strategies unlikely to succeed in facilitating sepsis recognition. RNA expression profiling provides a unique opportunity to gain a broad, high throughput picture in the complex and likely heterogeneous pathophysiology of sepsis, and several preliminary studies have yielded promising results using this technique in predicting both sepsis severity in pediatric intensive care unit (PICU) patients as well as etiology of infections in children with fever. The broad long-term objective of this line of research is to improve pediatric sepsis recognition in the emergency department using both clinical predictors and biomarker strategies. As a first step towards achieving this goal, the current proposal focuses on using RNA expression profiling to predict both illness severity and source pathogen in pediatric sepsis.
The aims of this proposal are: 1. To determine association between the RNA expression profile and severity of illness during the initial 2 days of hospitalization in pediatri patients with suspected sepsis initially identified in the ED., and 2. To determine association between the RNA expression profile and sepsis source pathogen in pediatric ED patients with suspected sepsis.
Sepsis is an important cause of morbidity and mortality in children. However, children with sepsis can have similar signs and symptoms to children with benign febrile illnesses, and can be difficult to identify. By using the technique of RNA expression profiling, we propose to evaluate expression of many genes simultaneously in children with suspected sepsis, identify patterns predictive of severe illness, and ultimately improve outcomes for children.
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