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

摘要 本申请是对我们资助的补助金ID 1 R43 EY 030798 -01的行政补充申请。 早产儿视网膜病变（ROP）是一种发生在生命最初几周的潜在致盲性疾病。的 疾病是目前世界上儿童失明的三大原因之一， 在中等经济发展水平的国家，这是失明的原因。每九个出生在 在美国，每年有50万婴儿早产;在世界范围内，这个数字估计为15 万目前美国儿科学会的指南要求进行眼科筛查检查 2-5%的婴儿，以评估发生ROP的风险。眼科医生诊断并使 根据视网膜血管的外观决定ROP的初始治疗。的 目前用于诊断ROP的护理标准是对血管扩张和迂曲的主观评价 基于静态眼底照片。市场上唯一的用于婴儿视网膜成像的仪器， 辅助ROP诊断是庞大和昂贵的，使得它们不适合广泛使用。因此， 迫切需要一种标准化的、更准确的方法， 价格实惠的便携式仪器。半自动化方法可用于量化血管 ROP中观察到的形态学变化;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XyCAM NEO™-一种手持式非侵入式成像仪 能够以高空间分辨率测量视网膜血流，用于ROP的诊断和管理 并测试了XyCAM NEO衍生的基于流量的指标可用于监测的关键假设 ROP和Plus疾病的状态。XyCAM NEO将使用激光散斑对比成像（LSCI）来捕获 在婴儿视网膜的宽视野上的血流信息，而不需要外源染料。 该附加信息是对使用眼底照相术可获得的信息的补充，并且该附加信息 新的基于流动的生物标志物与传统的生物标志物如血管弯曲度、直径、长度 并且密度有望改善诊断。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中早产儿的技术 重症监护室（NICU）环境;并通过早期可行性临床研究证明， 患有重度视网膜病变的早产儿的血流与患有轻度视网膜病变的早产儿的血流不同。在这样做时， 我们还希望证明XyCAM NEO衍生的基于流动的生物标志物的能力和潜力 来区分严重和轻微的疾病状态。目前的行政请求 补充寻求资金，重新设计的光学组件和计算硬件的 提出的XyCAM NEO系统可满足修改后的用例要求并提高发生以下情况的可能性 成功 如果成功，我们预计将进行第二阶段项目，进行严格的临床研究， 在大量受试者中评估XyCAM NEO根据指标识别ROP的能力 在可行性研究中确定的（即，描述诊断灵敏度和特异性），并比较 结果与使用现行实践标准获得的结果一致。我们会调查流动的适宜性- 用于表征对各种ROP治疗选择的短期和长期反应的基于评估， 从而允许更好地优化治疗。这项工作的结果将有助于销售一种 用于及时诊断影响儿童健康的各个方面的状况的范式转变医疗装置 发展和塑造他们成为成年人。

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.