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 一种创新的未结合胆红素测定，用于识别胆红素诱导的神经功能障碍（BIND）风险， 一个全面的和新的床旁新生儿筛查小组的一部分 (Fast跟踪SBIR） 新生儿高胆红素血症，或胆红素升高，发生在超过80%的新生儿中，并导致黄疸。 如果及时治疗，高胆红素血症通常是良性的，但如果不及时治疗， 导致胆红素毒性和严重的神经功能障碍。尽管常规新生儿筛查 总血清胆红素（TSB）水平作为高胆红素血症的指标，潜在原因如葡萄糖-6- 磷酸脱氢酶（G6 PD）缺乏和胆红素诱导的神经功能障碍（BIND）的风险 仍然是一个未解决的公共卫生问题。虽然许多酶功能障碍疾病在美国进行筛查， 作为正常干血斑新生儿筛查过程的一部分， 相对高的发病率及其与新生儿黄疸的相关性使其特别适合于筛查 在出生时评估严重程度。利用现有资金，我们正在开发FINDER，这是一个占地面积小的项目， 数字微流控设备，用于医院中的近患者、中等风险评估测试;启动面板将 通过测量TSB、白蛋白、直接胆红素和G6 PD缺乏来评估高胆红素血症风险。我们预计 在明年内提交FINDER设备和启动检测小组供FDA审查。 该快速通道项目将重点关注FINDER中缺少的两个关键因素，用于全面的G6 PD 筛选和BIND风险评估：1）存在具有挑战性但至关重要的未结合的 胆红素（UB）测定;以及2）支持CLIA豁免的简单性要求的数字架构 筛查以及将筛查结果整合到最终的大型数据库中的必要性。的能力 测量未结合胆红素将使临床医生对胆红素结合有更全面的了解， 因此，胆红素毒性的风险;神经毒性（包括BIND和核黄疸）由胆红素不足引起 在血浆中结合。第一阶段的目标将集中在分析开发和初步的数字架构 第二阶段的目标将集中在未结合胆红素测定与 同品种器械。将在4个临床研究中心对所得测定面板和平台进行现场测试， G6 PD缺乏症患者的百分比。 该产品有可能成为美国近患者，通用生化的范式转变 筛查，通常委托给国家公共卫生实验室，并可用于医院或医生的 该办公室负责确定可能需要入院接受及时治疗的新生儿。尽管 在新生儿高胆红素血症中的患病率和关键作用，G6 PD酶缺乏症很少在新生儿高胆红素血症中筛查。 美国;溶血“危象”触发因素、光疗治疗不足以及随访相关挑战 都使新生儿处于BIND的风险中。G6 PD缺乏症与BIND风险的相关性是无可争议的， 包括G6 PD检测和UB、白蛋白和TSB组合的综合筛查组 测量可以评估新生儿的胆红素结合能力，以确定BIND风险。

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.