Development of Flow Based Biomarkers for Retinopathy of Prematurity - Supplemental Aim

摘要 此申请是对我们资助的拨款ID 1R43EY030798-01的行政补充申请。 早产儿视网膜病变(ROP)是一种潜在的致盲疾病，发生在生命的最初几周。这个 疾病目前是世界上导致儿童失明的三大原因之一，也是头号原因 中等经济发展水平国家的失明原因。每九个孩子中就有一个出生在 在美国，每年有50万名婴儿早产；在世界范围内，这一数字估计为15 百万美元。目前的美国儿科学会指南要求进行眼科筛查检查 对这些婴儿中的2-5%评估发生ROP的风险。眼科医生诊断和制作 根据视网膜血管的外观决定ROP的初始治疗。这个 目前诊断ROP的标准是对血管扩张和弯曲的主观评估 基于一张静态眼底照片。市面上唯一一种用于对婴儿视网膜进行成像的仪器 辅助ROP诊断既笨重又昂贵，不适合广泛使用。因此，在这里 迫切需要一种标准化的、更准确的方法来筛查婴儿的ROP， 实惠，便携的仪器。可以用半自动的方法来量化血管 ROP中可见的形态变化；然而，这些技术缺乏客观和 自动量化和检测条件。 第一阶段的工作是设计和开发XyCAMneo™--一种手持非侵入式成像仪 能够以高空间分辨率测量视网膜血流，用于ROP的诊断和治疗 并测试XyCAM neo派生的基于流的指标可用于监控的关键假设 ROP和Plus病的状况。XyCAM近地天体将使用激光散斑对比成像(LSCI)来捕获 婴儿视网膜广泛视野的血流信息，无需外源染料。 这一附加信息是对使用眼底照相获得的信息的补充，并且添加了 将新的基于流动的生物标记物与传统的生物标记物相比较，例如血管扭曲、直径、长度 而密度有望提高诊断水平。具体来说，我们建议调整我们的视网膜成像 已在成人受试者中验证用于新生儿早产儿的技术 重症监护病房(NICU)环境；并通过早期可行性临床研究证明 重度ROP早产儿与低度ROP早产儿血流速度不同。在此过程中， 我们还希望展示XyCAM neo衍生的基于Flow的生物标记物的能力和潜力 区分严重和轻微的疾病状态。本申请要求行政部门 附录寻求资金，以重新设计光学组件和计算机硬件 建议的XyCAM neo系统以满足修改后的用例要求并提高 成功。 如果成功，我们预计将进行第二阶段项目，以进行严格的临床研究，以统计 在大量受试者中评估XyCAM neo基于指标识别ROP的能力 在可行性研究中确定(即表征诊断灵敏度和特异度)并比较 结果与使用现行实践标准所获得的结果相一致。我们将调查流动的适用性- 用于表征对各种ROP治疗方案的短期和长期反应的基于评估， 从而允许更大程度地优化治疗。这项工作的结果将促进一种 用于及时诊断影响儿童方方面面的疾病的范式转换医疗设备 发展和塑造他们成为成年人的过程。

ABSTRACT This application is a request for an administrative supplement to our funded grant ID 1R43EY030798-01. Retinopathy of Prematurity (ROP) is a potentially blinding disease that occurs in the earliest weeks of life. The disease is currently one of the top three causes of childhood blindness in the world and is the number one cause of blindness in countries of a medium level of economic development. One in nine children born in the US, or half a million babies per year, are born prematurely; worldwide, the number is estimated at 15 million. Current American Academy of Pediatrics guidelines mandate an ophthalmology screening exam for 2-5% of these infants to assess the risk of developing ROP. Ophthalmologists diagnose and make decisions about the initial treatment of ROP based on the appearance of the retinal blood vessels. The current standard of care for diagnosis of ROP is a subjective evaluation of vessel dilatation and tortuosity based on a static fundus photograph. The only instruments marketed for imaging the infant retina that may assist in ROP diagnostics are bulky and expensive making them unsuitable for widespread use. Hence, there is a critical need for a standardized, more accurate method of screening infants for ROP using a convenient, affordable, and portable instrument. Semi-automated methods are available to quantify the vascular morphologic changes seen in ROP; however, these technologies lack the ability to objectively and automatically quantify and detect the condition. This Phase I effort proposes to design and develop the XyCAM NEO™—a handheld, noninvasive imager capable of measuring retinal blood flow with high spatial resolution, for diagnosis and management of ROP and test the crucial hypothesis that XyCAM NEO derived flow-based metrics can be utilized for monitoring of status of ROP and Plus Disease. The XyCAM NEO will use laser speckle contrast imaging (LSCI) to capture blood flow information over a wide field of view of the infant retina without the need for exogenous dyes. This additional information is complementary to that available using fundus photography, and the addition of novel flow-based biomarkers to conventional biomarkers such as vessel tortuosities, diameters, lengths, and densities is expected to improve diagnostics. Specifically, we propose to adapt our retinal imaging technology that has been validated in adult human subjects for use in premature infants in the neonatal intensive care unit (NICU) environment; and demonstrate through an early feasibility clinical study that blood flow in premature infants with severe ROP is different than in those with low-grade ROP. In doing so, we also expect to demonstrate the ability and potential of the XyCAM NEO derived flow-based biomarkers to discriminate between a severe and mild disease state. The present request for an administrative supplement seeks funds for re-engineering the optical assembly and the computational hardware of the proposed XyCAM NEO system to meet modified use case requirements and improve the likelihood of success. If successful, we anticipate undertaking a Phase II project to conduct a rigorous clinical study to statistically evaluate, in a large number of subjects, the ability of the XyCAM NEO to identify ROP based on the metrics identified in the feasibility study (i.e., characterize the diagnostic sensitivity and specificity) and compare the results with those obtained using current practice standards. We will investigate the suitability of flow- based assessment for characterizing the short- and long-term response to various ROP treatment options, thereby permitting greater optimization of therapy. The results of this work will facilitate marketing of a paradigm shifting medical device for timely diagnosis of a condition that impacts all aspects of a child's development and shapes the adult they become.