An Innovative Unbound Bilirubin Assay to Identify Bilirubin-Induced Neurological Dysfunction (BIND) Risk as Part of a Comprehensive and Novel Point-of-Care Newborn Screening Panel

摘要

ABSTRACT An Innovative Unbound Bilirubin Assay to Identify Bilirubin-Induced Neurological Dysfunction (BIND) Risk as Part of a Comprehensive and Novel Point-of-Care Newborn Screening Panel (Fast Track SBIR) Neonatal hyperbilirubinemia, or elevated bilirubin, occurs in over 80% of newborns and results in jaundice. When treated promptly, hyperbilirubinemia is usually benign but if left untreated elevated bilirubin levels can result in bilirubin toxicity and severe neurological dysfunction. Despite routine newborn screening for elevated total serum bilirubin (TSB) levels as an indicator of hyperbilirubinemia, underlying causes such as glucose-6- phosphate dehydrogenase (G6PD) deficiency and the risk for bilirubin induced neurological dysfunction (BIND) remain an unaddressed public health concern. While many enzyme dysfunction disorders are screened in U.S. state public health laboratories as part of the normal dried-blood spot newborn screening process, G6PD's relatively high-incidence and its association with neonatal jaundice make it uniquely suited to be both screened and severity assessed at the point-of-birth. With existing funding, we are developing FINDER, a small footprint digital microfluidic device for near-patient, medium risk assessment testing in a hospital; the launch panel will assess for hyperbilirubinemia risk by measuring TSB, albumin, direct bilirubin and G6PD deficiency. We expect to submit the FINDER device and launch panel of assays for FDA review within the next year. This Fast-Track project will focus on two key factors that are missing from FINDER for comprehensive G6PD screening and BIND risk assessment: 1) the presence of the challenging, but vitally important, unbound bilirubin (UB) assay; and 2) a digital architecture to support the simplicity requirements of CLIA-waived screening and the necessity to integrate screening results to an eventual large-scale database. The ability to measure unbound bilirubin will allow clinicians to have a more complete understanding of bilirubin binding and thus the risk for bilirubin toxicity; neurotoxicity (including BIND and kernicterus) result from poor bilirubin binding in plasma. Phase I aims will focus on assay development and preliminary digital architecture implementation while Phase II aims will center on a method comparison of the unbound bilirubin assay to a predicate device. The resulting assay panel and platform will be field tested at 4 clinical sites with a high percentage of G6PD deficient patients. This product has the potential to be a paradigm shift in the U.S. for near-patient, universal biochemical screening, normally delegated to state public health laboratories, and can be used in the hospital or physician's office to identify newborns who might need to be admitted to the hospital for prompt treatment. Despite its prevalence and critical role in neonatal hyperbilirubinemia, G6PD enzyme deficiency is rarely screened in the U.S.; hemolysis “crisis” triggers, inadequate treatment with phototherapy, and challenges related to follow-up all put neonates at risk of BIND. The association of G6PD deficiency with BIND risk is indisputable, and a comprehensive screening panel that includes a G6PD assay and a combination of UB, albumin and TSB measurements can assess bilirubin binding capacity in the newborn to determine BIND risk.