Rapid saliva test for diagnosis of mTBI and prognosis of Persistent Post-conccussion Symptoms (PPCS) in children and adults

快速唾液检测用于诊断儿童和成人 mTBI 以及持续性脑震荡后症状 (PPCS) 的预后

• 批准号: 10326264
• 负责人: Robert J Elbin
• 金额: $ 86.6万
• 依托单位: GAIA MEDICAL INSTITUTE, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10326264
• 关键词: Accounting; Adolescent; Adoption; Adult; Age; Arkansas; Biological; Biological Assay; Biological Markers; Brain; Brain Concussion; Buffers; Caring; Cause of Death; Child; Clinical; Clinical Data; Data; Devices; Diagnosis; Diagnostic; Diagnostic Procedure; Dose; Emergency Department patient; Enrollment; Geography; Goals; HIF1A gene; Immunoassay; Injury; Laboratories; Lateral; Legal patent; Letters; Logistic Regressions; Measures; Modeling; Morbidity - disease rate; Normal Range; Orthopedics; Outcome; POR gene; Pathway interactions; Patients; Performance; Phase; Post-Concussion Syndrome; Prognosis; Prospective cohort study; Public Health; ROC Curve; Race; Research; Risk; Saliva; Sample Size; Sampling; Schools; Sensitivity and Specificity; Small Business Innovation Research Grant; Specificity; Specimen; Sports; Standardization; Statistical Data Interpretation; Statistical Models; Symptoms; Testing; Time; Training; Translating; Trauma; United States National Institutes of Health; Validation; Visual; Work; base; biomarker validation; candidate marker; cohort; college; design; digital; disability; high risk; high school; innovation; junior high school; lateral flow assay; mild traumatic brain injury; mind control; mortality; phase 2 study; point of care; predictive marker; prevent; prognostic; prognostic performance; prototype; saliva sample; salivary assay; sex; tool

Project Summary Rapid saliva test for diagnosis of mTBI and prognosis of Persistent Post-concussion Symptoms (PPCS) in children and adults Mild traumatic brain injury (mTBI) is a leading cause of mortality and morbidity. Children are at a higher risk due to high vulnerability of the immature brain to trauma. mTBI is a significant public health concern because approximately 30% patients develop Persistent Post-concussion Symptoms (PPCS) preventing return to work, school and sports. Current diagnostic methods for mTBI and PPCS are inaccurate due to lack of standard diagnostic criteria. There is unmet need for objective biomarker test. The ultimate goal of this SBIR project is to develop a commercial saliva test for diagnosis of mTBI and prognosis of PPCS. Phase I showed feasibility of the key innovation: saliva biomarkers for diagnosis of mTBI and prognosis of PPCS in children and adults. The proposed Phase II study aims to clinically validate the final biomarker for the commercial test and develop a prototype device showing feasibility of the commercial product. SA1 will collect N=465 serial saliva samples from N=225 adolescent athletes age 11-21 during a multisite prospective cohort study of mTBI, orthopedic injury controls (OI) and healthy controls (HC). mTBI will be diagnosed at ≤72h and PPCS at 30d postinjury. Saliva samples will be collected at ≤72h, 7d and 14d postinjury from mTBI and at enrollment form OI and HC. The proposed sample size will provide >80% statistical power to obtain statistically significant biomarker data. SA2 will measure 5 candidate biomarkers in N=1063 saliva samples (N=465 samples from SA1 plus N=598 existing samples from ED patients and adult athletes). Statistical modeling of a Training set of subjects (N=475) will down select the final marker and endpoint for the commercial test based on best diagnostic and prognostic performance. The selected marker and endpoint will be validated using a Validation set (N=240) based on ≥90% accuracy, sensitivity and specificity of mTBI diagnosis and PPCS prognosis in children and adults. OI will show mTBI specificity. HC will define normal range of marker concentrations and biological variability. SA3 will develop a prototype lateral flow immunoassay (LFA) for a selected biomarker. Expected Outcomes: Results will rigorously clinically validate the saliva biomarker of mTBI and PPCS for the commercial product. Large and representative sample size (N=715 subjects across mTBI mechanisms of injury, outcome, age, sex and geography) will provide statistically significant, generalizable clinical data. N=1063 serial saliva samples and analytically validated assays will provide accurate and reliable biomarker data. The prototype device will show technical feasibility of the commercial test. Overall, this project has high potential for a wide-ranging impact on TBI care by providing an objective, clinically feasible biological biomarker of mTBI and PPCS, and translating this innovation into a practical tool for clinical use in point-of- care. The proposed product has a strong commercial potential based on a proven and low risk LFA device, achievable FDA path, key opinion leaders committed to clinical adoption, competitive patent portfolio and limited competition.

项目概要 快速唾液检测用于诊断 mTBI 和持续性脑震荡后症状的预后 (PPCS) 儿童和成人 轻度创伤性脑损伤（mTBI）是死亡和发病的主要原因。儿童面临更高的风险 由于不成熟的大脑很容易受到创伤。 mTBI 是一个重大的公共卫生问题，因为 大约 30% 的患者出现持续性脑震荡后症状 (PPCS)，无法重返工作岗位， 学校和体育。由于缺乏标准，目前的 mTBI 和 PPCS 诊断方法不准确 诊断标准。客观生物标志物测试的需求尚未得到满足。该 SBIR 项目的最终目标是 开发一种商业唾液测试，用于诊断 mTBI 和 PPCS 预后。第一阶段显示了可行性 关键创新：用于儿童和成人 mTBI 诊断和 PPCS 预后的唾液生物标志物。这 拟议的 II 期研究旨在临床验证商业测试的最终生物标志物，并开发一种 原型设备显示商业产品的可行性。 SA1将采集N=465个系列唾液样本 来自 N = 225 名 11-21 岁青少年运动员的 mTBI、骨科多中心前瞻性队列研究 损伤对照（OI）和健康对照（HC）。 mTBI 将在伤后 ≤72 小时诊断，PPCS 在伤后 30 天诊断。 唾液样本将在 mTBI 受伤后 ≤72 小时、7 天和 14 天以及登记表 OI 和 HC 时采集。 建议的样本量将提供 >80% 的统计功效，以获得具有统计学意义的生物标志物数据。 SA2 将测量 N=1063 个唾液样本中的 5 个候选生物标志物（N=465 个来自 SA1 的样本加上 N=598 个唾液样本） 来自 ED 患者和成年运动员的现有样本）。受试者训练集的统计建模 (N=475) 将根据最佳诊断和结果选择商业测试的最终标记和终点 预后表现。将使用验证集验证所选标记和端点 (N=240) 基于儿童 mTBI 诊断和 PPCS 预后≥90% 的准确性、敏感性和特异性 成年人。 OI 将显示 mTBI 特异性。 HC 将定义标记物浓度和生物学的正常范围 可变性。 SA3 将为选定的生物标志物开发原型侧流免疫测定 (LFA)。预期的 结果：结果将严格临床验证 mTBI 和 PPCS 的唾液生物标志物 商业产品。样本量大且具有代表性（N = 715 名受试者，涉及 mTBI 机制） 伤害、结果、年龄、性别和地理位置）将提供具有统计学意义的、可概括的临床数据。 N=1063 连续唾液样本和经过分析验证的检测将提供准确可靠的生物标志物 数据。该原型设备将展示商业测试的技术可行性。总体而言，该项目具有较高的 通过提供客观的、临床上可行的生物学方法，对 TBI 护理产生广泛影响的潜力 mTBI 和 PPCS 的生物标志物，并将这一创新转化为临床使用的实用工具 关心。基于经过验证的低风险 LFA 设备，拟议产品具有强大的商业潜力， 可实现的 FDA 路径、致力于临床采用的关键意见领袖、有竞争力的专利组合和 有限的竞争。