Metabolomics Evaluation of the Etiology of Pneumonia

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Project Summary Lilliam Ambroggio, PhD, MPH is an infectious diseases epidemiologist whose overarching career goal is to improve outcomes for children with common, serious infections by developing methods to improve diagnostic accuracy and implementing these methods into clinical practice. The research she proposes entitled Metabolomic Evaluation in the Etiology of Pneumonia (MEEP) combines advanced statistical techniques with 1H-Nuclear Magnetic Resonance (NMR) metabolomics methodology to identify metabolites, which will facilitate etiologic diagnosis of community-acquired pneumonia (CAP) in children. Such pathogen identification will result in timely and accurate diagnosis that will permit targeted and effective management of this disease. Candidate: Dr. Ambroggio is an Assistant Professor of Pediatrics with a joint appointment in the Divisions of Hospital Medicine and Biostatistics and Epidemiology at Cincinnati Children's Hospital Medical Center (CCHMC). She completed a Master's in Public Health and a Ph.D. in Epidemiology at Drexel University prior to beginning a post-doctoral fellowship at CCHMC. Her previous work in the clinical management of CAP focusing on antibiotic prescribing and diagnostic tools to detect pneumonia in combination with her previous training in molecular and cellular biology have prepared her to conduct the proposed research. The proposed career development plan will build upon her previous training with four training goals to enhance her trajectory toward becoming an independent investigator: 1) Experiential and didactic learning in study design and execution of quantitative 1H-NMR metabolomics; 2) Acquire and apply advanced statistical analyses; 3) Interpret metabolomics data and its biological context and 4) Develop leadership and professional skills to execute multicenter studies. Dr. Ambroggio proposes training activities that include didactic and experiential learning to enable her to gain the necessary skills for metabolomic research. Mentors/Environment: Dr. Ambroggio and her primary mentor, Samir S. Shah, MD, MSCE, have assembled a strong team of co-mentors and advisors to guide Dr. Ambroggio through the proposed training and research activities. The proposed career development plan utilizes the intellectual and metabolomics resources available through the University of Cincinnati and CCHMC, as well as resources available at the University of Michigan through Dr. Ambroggio's external mentor, Kathleen Stringer, PharmD. In addition Dr. Ambroggio will attend national seminars and workshops when optimal training is not available locally. As an institution CCHMC is committed to supporting junior faculty members through internal grants, administrative support and structured opportunities for faculty networking and education. Dr. Ambroggio will be obtaining biological specimens for this proposal from a fully operational, externally-funded prospective cohort study, CARPE DIEM. Both the ED and inpatient services at CCHMC provide an established research infrastructure and a large ambulatory and hospitalized patient population to conduct the proposed research. In addition all mentors have agreed to participate on Dr. Ambroggio's scholarly oversight committee which has been meeting quarterly since 2013. Research: There is currently no accurate method to identify the etiology of CAP in children. This results in overtreatment with antibiotics or delays in appropriate treatment in children who are at risk for CAP-related morbidity. This proposal is the first step in developing a specific, fast and noninvasive approach for pathogen identification in children diagnosed with CAP. Aim 1 characterizes the sources (e.g. age and sex) of variation that exist in a healthy child's metabolome over three points. Aim 2 compares metabolite profiles from children who had a positive PCR test from either the nasopharynx or the blood for a virus, bacterial infection such as Mycoplasma pneumoniae, or Streptococcus pneumoniae with children who have no known infections. The purpose of this aim is to identify unique metabolite profiles using quantitative 1H-NMR for each pathogen identified. Aim 3 will use urine samples from patients with CAP and compare them with samples from healthy contorls over three time points to determine the impact of antibiotic treatment on metabolite profiles. The completion of these aims will generate a metabolite profile database of common pathogens associated with childhood CAP and drive a systems biology approach to CAP diagnosis and treatment. Summary: The innovation of the proposed research is the integration of robust clinical phenotype data from an ambulatory population with quantitative NMR metabolomics using novel statistical methods to address the clinically challenging problem of pediatric CAP diagnostics. The strong collaborations between the Divisions of Hospital Medicine, Biostatistics and Epidemiology, and Emergency Medicine at CCHMC and with the metabolomics core at the University of Michigan ensure the success of the proposed research. This award will provide Dr. Ambroggio with the training and research needed to be successful in a future, multi-center study to validate the metabolite profiles of pathogens causing CAP in children. Furthermore, this career development award will facilitate Dr. Ambroggio's development into a nationally-recognized independent investigator and leader conducting research that improves diagnostic tools for children with infectious diseases, specifically CAP.