This proposal is designed to prepare the candidate for an independent academic career in clinical and translational research. The candidate?s long term goal is to discover innovative solutions for children with biliary atresia and other liver diseases. The candidate has PhD training in basic science research, and he cares for patients in a stimulating environment that exposes him to the full spectrum of pediatric liver disorders. Now the candidate seeks formal training in clinical and translational research techniques, to allow him to synthesize clinical observations and patient data and develop novel diagnostic, treatment, and prevention strategies. The immediate goals of this project are threefold: 1) Acquire clinical and translational research skills through formal coursework, research experience, and mentor-guided instruction; 2) Develop ideas for future research, which can serve as the basis for a R03 or R01 grant application to initiate an independent career; and 3) Learn analytical, communication, and decision-making skills from an accomplished mentor, whose successful career path in pediatric hepatology will serve as a template. To accomplish this, the candidate has created a rigorous career developmental plan to occur concurrently while assessing a novel newborn screen for biliary atresia (BA). BA is a serious liver condition with significant morbidity and mortality, and is the leading indication for pediatric liver transplantation in the US. If BA is diagnosed and treated early, infants with disease can delay or even avoid need for liver transplantation; however, infants are often diagnosed later because the disease is difficult to recognize in the first weeks of life. Previously, the candidate observed that infants with BA have elevated direct or conjugated bilirubin levels at birth, and proposed that this simple test could be used to screen newborns for disease. The career development plan will equip the candidate with the necessary knowledge and skills to fully assess newborn direct/conjugated bilirubin screening for BA. The candidate will learn how to conduct multi-center studies and interpret large amounts of population data, by screening 102,000 newborns from 10 different birth hospitals. The candidate will also take formal coursework to learn the theory and practice of cost-effective studies, and then create sophisticated models simulating outcomes with and without screening which also incorporate the screen?s associated costs. Finally, the candidate will learn specialized techniques in the clinical chemistry laboratory and how to evaluate their utility, in the context of testing whether blood spot samples can be used for the BA screening test. At the conclusion of the training period, the candidate should be well trained to address complex problems in pediatric hepatology at a clinical and translational research level. He should have many potential avenues of further investigation, including characterizing the early stages of biliary atresia, generating efficient algorithms for diagnosing biliary atreia, testing blood spot samples on a large scale from state newborn screening laboratories, and potentially implementing a universal newborn screening program for BA at the national level. He will also have benefitted from years of close instruction by a proven leader in the field. These experiences should prepare the candidate to apply for independent funding, and help launch his research career as a successful physician scientist focused on improving the lives of children with liver diseases.

Public Health Relevance

Biliary atresia (BA)?the leading indication for pediatric liver transplantation in the United States?has better outcomes when diagnosed and treated earlier. Unfortunately, BA can be difficult to diagnose initially and is often overlooked until substantial liver injury has already occurred. This proposal addresses the problem of delayed diagnoses, by evaluating the accuracy, effectiveness, and acceptability of a novel newborn screening tool for BA.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23DK109207-02
Application #
9435115
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
Program Officer
Saslowsky, David E
Project Start
2017-02-16
Project End
2022-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Lupo, Philip J; Isenburg, Jennifer L; Salemi, Jason L et al. (2017) Population-based birth defects data in the United States, 2010-2014: A focus on gastrointestinal defects. Birth Defects Res 109:1504-1514
Patel, Kalyani R; Harpavat, Sanjiv; Finegold, Milton et al. (2017) Post-transplant Recurrent Bile Salt Export Pump Disease: A Form of Antibody-mediated Graft Dysfunction and Utilization of C4d. J Pediatr Gastroenterol Nutr 65:364-369
Freeman, A Jay; Ng, Vicky Lee; Harpavat, Sanjiv et al. (2017) Level of ?-glutamyltransferase in 2-Year-old Children With Biliary Atresia Associates With Progression of Portal Hypertension. Clin Gastroenterol Hepatol 15:1133-1135