Discovery of the Biomarker Signature for Neuropathic Corneal Pain

项目摘要 神经性角膜疼痛（NCP）是一种眼部类型的神经性疼痛。它会导致病人有严重的 不适和严重受损的生活质量（QoL）。缺乏标准观察到的迹象 检查已导致误诊为干眼病（DED），从而导致 医疗基金。NCP诊断生物标志物的鉴定和检测方法的开发 方法将允许充分和及时的治疗，改善患者的生活质量，并减少医疗保健 系统的财政负担。可以使用激光体内共聚焦显微镜进行光学活检 （IVCM），其允许在准组织学水平上可视化基底下角膜神经。初步 数据显示，IVCM鉴定出了微神经瘤（由积聚引起的切断神经末端的球状物 分子成分）存在于NCP患者中，而不是DED患者中。我们建议验证微神经瘤 作为NCP的一种新的生物标志物。在目标1中，我们将使用超过2，000名DED/NCP受试者的数据库， 500，000个IVCM图像，以确认微神经瘤的存在是NCP的适当生物标志物， 比较通过微神经瘤与其他IVCM识别NCP患者的敏感性和特异性 参数三名观察员将各自对该确认的生物标志物的图像进行两次分级，以评估间和 观察者内精密度和IVCM数据集的描述性统计将允许确定 高精度微神经瘤检测所需的最小数量的图像。目标2将提供 微神经瘤的生物学验证。眼痛的强度和对生活质量的损害都导致了 根据眼部疼痛评估调查（OPAS）评估的眼部疼痛， 有微小神经瘤的和没有的此外，眼痛/不适的变化响应于 将比较微神经瘤患者和 那些没有。在目标3中，我们将开发一个经过验证的人工智能（AI）程序， 识别微小神经瘤，以允许临床医生快速和广泛采用。程序的准确性 将通过评价AI程序对IVCM图像的评估与 2名观察员的评估。将使用从以下来源获得的图像进行类似的准确度评估： 一个独立的站点，以便可以评估站点间的精度。人工智能计划也将被评估其 NCP鉴定的特异性和灵敏度。目的4建立显微神经瘤的临床应用 在一项前瞻性、多中心研究中，通过IVCM观察到的作为NCP生物标志物。生物标记的精确度， 参考区间、研究中心之间的性能协调以及灵敏度和特异性 NCP的诊断将使用该前瞻性队列来确定。接下来，微神经瘤的发现将是 与OPAS和高渗功能试验相关，用于生物学验证。最后，AI程序 将使用本研究的IVCM图像测试提供NCP诊断的能力。

PROJECT ABSTRACT Neuropathic corneal pain (NCP) is an ocular type of neuropathic pain. It causes patients to have severe discomfort and a severely compromised quality of life (QoL). The lack of signs observed by standard examination has resulted in misdiagnosis as dry eye disease (DED) resulting in an inefficient use of healthcare funds. The identification of a diagnostic biomarker for NCP and development of a detection method would allow adequate and timely treatment, improve patients’ QoL, and decrease the health care system’s financial burden. An optical biopsy can be performed using laser in vivo confocal microscopy (IVCM), which allows for visualization of subbasal corneal nerves at a quasi-histological level. Preliminary data has shown that IVCM identified microneuromas (a bulb at the end of a severed nerve caused by build-up of molecular constituents) are present in NCP, but not DED, patients. We propose to validate microneuromas as a novel biomarker for NCP. In Aim 1 we will use our database of over 2,000 DED/NCP subjects and over 500,000 IVCM images to confirm that the presence of microneuromas is an appropriate biomarker for NCP by comparing the sensitivity and specificity of identification of NCP patients via microneuromas to other IVCM parameters. Three observers will each grade images twice for this confirmed biomarker to assess inter- and intra-observer precision, and descriptive statistics of the IVCM datasets will allow for determination of the minimum number of images necessary for high precision of microneuroma detection. Aim 2 will provide biological validation of microneuromas. Both the intensity of ocular pain and the compromise to QoL caused by ocular pain as assessed by the Ocular Pain Assessment Survey (OPAS) will be compared between those with microneuromas and those without. Further, the change in ocular pain/discomfort in response to instillation of hyperosmolar saline into the eyes will be compared between those with microneuromas and those without. In Aim 3 we will develop a validated artificial intelligence (AI) program for automated identification of microneuromas to allow rapid and wide-scale adoption by clinicians. Accuracy of the program will be determined by evaluating the agreement of the AI program’s assessment of IVCM images with the assessment of 2 observers. A similar assessment of accuracy will be assessed using images obtained from an independent site so that inter-site precision can be evaluated. The AI program will also be assessed for its specificity and sensitivity in NCP identification. Aim 4 will establish the clinical utility of microneuromas observed by IVCM as a biomarker for NCP in a prospective, multi-center study. The biomarker’s precision, reference intervals, and harmonization of performance between sites as well as the sensitivity and specificity of NCP diagnosis will be determined using this prospective cohort. Next, the microneuroma findings will be correlated with the OPAS and hyperosmolar functional tests for biological validation. Finally, the AI program’s ability to provide a diagnosis of NCP will be tested using the IVCM images from this study.