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 一种新的无结合胆红素检测方法用于确定胆红素诱导的神经功能障碍(BIND)风险为 全面而新颖的新生儿护理点筛查小组的组成部分 (Fast Track SBIR) 新生儿高胆红素血症或胆红素升高，发生在80%以上的新生儿，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，胆红素水平升高可能会 导致胆红素中毒和严重的神经功能障碍。尽管对新生儿进行常规筛查 血清总胆红素(TSB)水平可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(G6PD)缺乏与胆红素所致神经功能障碍(BIND)的风险 仍然是一个尚未解决的公共卫生问题。虽然在美国对许多酶功能障碍进行了筛查。 国家公共卫生实验室作为正常的干血现场新生儿筛查程序的一部分，G6PD 相对较高的发病率及其与新生儿黄疸的相关性使其特别适合同时进行筛查 以及出生时评估的严重程度。利用现有的资金，我们正在开发Finder，这是一个很小的足迹 用于医院近病人中等风险评估测试的数字微流控设备；发射小组将 通过测量总胆红素、白蛋白、直接胆红素和G6PD缺乏症来评估高胆红素血症的风险。我们预计 在明年内提交发现者设备和测试启动小组供FDA审查。 此Fast-Track项目将重点关注全面G6PD的Finder中缺失的两个关键因素 筛选和绑定风险评估：1)存在具有挑战性但极其重要的未绑定 胆红素(UB)检测；以及2)支持CLIA简单性要求的数字架构--放弃 筛查以及将筛查结果整合到最终大规模数据库的必要性。有能力 测量未结合胆红素将使临床医生对胆红素结合和 因此，胆红素毒性的风险；神经毒性(包括BIND和核黄斑)是由胆红素不足引起的 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上 实施，而第二阶段的目标将集中在未结合胆红素检测与 谓词装置。由此产生的化验小组和平台将在4个临床地点进行现场测试，具有较高的 G6PD缺乏患者所占比例。 该产品有可能成为美国近患者通用生化产品的范例转变 筛查，通常委托给州公共卫生实验室，可以在医院或医生的 该办公室负责识别可能需要入院接受及时治疗的新生儿。尽管它的 G6PD酶缺乏症在新生儿高胆红素血症中的患病率和关键作用 美国；溶血“危机”引发，光疗治疗不足，以及与随访相关的挑战 所有这些都会使新生儿面临绑定的风险。G6PD缺乏与BIND风险的关联是无可争议的，并且 全面的筛查小组，包括G6PD检测和UB、白蛋白和TSB的组合 测量可以评估新生儿的胆红素结合能力，以确定绑定风险。

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.