The goal of the research plan for this K23 award is to establish the incidence and determinants of bilirubin-induced auditory neuropathy (AN) in high-risk premature infants with hyperbilirubinemia. AN was first reported in 1996. It is functionally defined by an absent or abnormal auditory brainstem response (ABR) and a normal otoacoustic emission (OAE) response. The OAE reflects cochlear function and is the current standard of care in many Neonatal Intensive Care Units (NICU) for hearing screening. Infants with retrocochlear, bilirubin-induced AN are being missed by OAE measures. Bilirubin has specific predilection for the auditory neural pathway, but relatively little is known regarding the prevalence and determinants of AN in high-risk premature infants with hyperbilirubinemia. According to current theory, unbound bilirubin (UB) can cross the intact blood-brain barrier and cause neuronal damage. However, the diagnostic utility of UB levels has not been established nor are these levels routinely measured in NICU infants. We will use OAE, ABR, and laboratory tests for bilirubin-albumin binding variables, including UB, to examine whether the risk of bilirubin-induced AN in premature infants is: 1) increased in infants who, early on, demonstrate abnormal changes in ABR in association with hyperbilirubinemia; 2) more closely associated with UB levels than with estimates of total serum bilirubin or the bilirubin:albumin molar ratio; and 3) increased in the presence of clinical risk factors such as asphyxia, sepsis, hypoxia, acidosis, and hemolysis. Ultimately, these findings will reveal the magnitude of jaundice-related morbidity in premature infants, the usefulness of UB as a predictor of bilirubin-induced AN, and the role of clinical risk factors in bilirubin-induced AN. New knowledge of UB levels that place infants at risk for AN will be important for: 1) developing interventional trials to prevent bilirubin-induced AN and 2) identifying those at-risk infants who need evaluation for AN. n the training component of this award the candidate will acquire and refine basic skills for conducting high-quality patient-oriented research. Namely, he will gain intimate knowledge of epidemiology and biostatistics and experience with advanced clinical and laboratory methods. An outstanding set of mentors and consultants at the University of Maryland and the University of Pennsylvania offer the candidate a rich and vibrant research and training environment in which to advance his career goals and this promising and important new line of research.