Discovery of the Biomarker Signature for Neuropathic Corneal Pain

神经性角膜疼痛生物标志物特征的发现

• 批准号: 10617101
• 负责人: Pedram Hamrah
• 金额: $ 75.07万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10617101
• 关键词: Age; Agreement; Artificial Intelligence; Biological; Biological Markers; Biological Testing; Biopsy; Cell Density; Cellular Morphology; Clinical; Clinical Research; Cohort Studies; Computer software; Cornea; Corneal pain; Data; Data Set; Databases; Detection; Development; Diagnosis; Disease; Drops; Dry Eye Syndromes; Ensure; Expert Systems; Eye; Fiber; Financial Hardship; Funding; Healthcare; Healthcare Systems; Histologic; Image; Image Analysis; Immune; Individual; International; Lasers; Lesion; Manuals; Methods; Molecular; Morphology; Multicenter Studies; Nerve; Nerve Plexus; Neuropathy; Optical Biopsy; Pain; Pain Measurement; Patients; Performance; Phase; Polyneuropathy; Prospective cohort; Quality of life; Reporting; Saline; Sampling; Sensitivity and Specificity; Site; Skin; Societies; Specificity; Surveys; Symptoms; System; Test Result; Testing; Time; Topical application; Training; Validation; Vision; Visualization; artificial neural network; biomarker discovery; biomarker signature; candidate marker; clinical center; clinical research site; deep neural network; density; detection method; diagnostic biomarker; imaging biomarker; imaging study; improved; microscopic imaging; noninvasive diagnosis; novel; novel marker; ocular pain; pain patient; pain symptom; painful neuropathy; programs; prospective; provider adoption; reflectance confocal microscopy; response; sex; software development; somatosensory; statistics; success; suicidal; validation studies

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.

项目摘要 神经性角膜疼痛（NCP）是一种眼部神经性疼痛的类型。它导致患者严重 不适和严重损害的生活质量（QOL）。缺乏标准观察到的迹象 检查导致诊断为干眼症（DED），导致使用效率低下 医疗保健基金。识别用于NCP的诊断生物标志物和检测的开发 方法将允许足够及时的治疗，改善患者的QOL并减少医疗保健 系统的金融伯恩。可以使用激光在体内共聚焦显微镜中进行光学活检 （IVCM），它允许在准途径水平上可视化基底角膜神经。初步的 数据表明，IVCM鉴定了微瘤（由堆积引起的严重神经的末端的灯泡 NCP中存在分子宪法），但不存在DED患者。我们建议验证微尿瘤 作为NCP的新型生物标志物。在AIM 1中，我们将使用超过2,000个DED/NCP主题及以上的数据库 500,000 IIVCM图像确认，微核瘤的存在是NCP的合适生物标志物 比较NCP患者通过微瘤识别与其他IVCM的敏感性和特异性 参数。为此确认的生物标志物评估和 IVCM数据集的观察者内部精度和描述性统计数据将允许确定 高精度微尼瘤检测精度所需的最小图像数量。 AIM 2将提供 微核瘤的生物学验证。眼部疼痛的强度和对QoL的妥协 通过眼部疼痛，通过眼痛评估调查（OPA）来比较这些疼痛 与微尿瘤和没有的那些。此外，响应眼部疼痛/不适的变化 将高质盐盐水滴入眼睛中，将在微尿瘤和 那些没有。在AIM 3中，我们将为自动化开发一个经过验证的人工智能（AI）计划 鉴定微核瘤以允许临床医生快速和广泛地采用。程序的准确性 将通过评估AI计划对IVCM图像的评估的协议来确定 评估2位观察者。将使用从 一个独立的位点，以便可以评估现场的精度。 AI计划还将对其进行评估 NCP识别中的特异性和灵敏度。 AIM 4将建立微瘤的临床实用性 在一项前瞻性，多中心研究中，IVCM视为NCP的生物标志物。生物标志物的精确度， 参考间隔以及站点之间的性能以及敏感性和特异性的协调 NCP诊断方法将使用此前瞻性队列确定。接下来，微冲瘤的发现将是 与OPA和高摩尔功能测试有关生物学验证。最后，AI计划的 提供NCP诊断的能力将使用本研究的IVCM图像进行测试。