Refinement of a rapid saliva miRNA diagnostic test for concussion

摘要/摘要-跨骏生物科学公司正在开发一种新的诊断方法，以帮助临床检测轻度 学龄儿童和青壮年(13-22岁)的创伤性脑损伤。根据唾液 MicroRNA(MiRNA)生物标志物，跨骏的诊断将提供准确、客观和非侵入性的 颅脑损伤的诊断方法。这种方法是非常必要的，因为儿科MTBI的数量正在上升， 而年轻患者发育中的大脑更容易受到机械力的后遗症的影响，导致 对身体、认知和心理功能产生广泛的负面影响。诊断和 青少年mTBI的评估具有挑战性，并依赖于主观测量，导致许多MTBI 得不到诊断或被漏报。这导致了伤害后治疗和病人管理的次优结果。一个 因此，准确诊断青少年mTBI的生物检测方法将为临床提供宝贵的指导 护理，潜在地指导成像、重返游戏、重返学校和治疗干预的决策。 虽然已经提出了一些用于客观检测mTBI的潜在生物标志物，包括血液 生物标记物胶质纤维酸性蛋白(GFAP)和泛素C末端水解酶(UCH-L1)的最新研究 质疑基于血液的生物标记物区分mTBI患者和急性脑损伤患者的能力 骨科创伤，尤其是在儿科人群中。此外，这些检测需要静脉穿刺术的专业知识。 这并不总是可用的，特别是在与运动相关的脑震荡的情况下，这占到了近三分之一 在这一患者群体中的MTBI的比例。为了解决这些缺点，跨骏生物科学公司正在创作一部小说， 基于一组在患者中差异表达的唾液miRNA生物标志物的客观诊断工具 使用mTBI。对200多名mTBI患者的初步研究发现，一组唾液miRNAs能够 诊断脊髓损伤并预测症状持续时间。在提议的快速通道项目中，跨骏将推进 通过建立一种快速、准确的方法来定量这些miRNA和 改进/验证诊断算法以区分患有mTBI的青少年和年轻人与患有 模拟mTBI的症状(例如慢性头痛、焦虑/抑郁、多动症、运动性疲劳、 和骨科损伤)。在第一阶段，跨骏将使用快速量化来完善mTBI的诊断算法 唾液miRNAs技术。机器学习将被用于开发一种诊断算法，该算法采用 从快速多重分析结合参与者的医学和人口学特征到 预测mTBI状态。在第二阶段，跨骏将验证区分mTBI和 对2500名青少年和青少年进行的前瞻性病例对照研究 青壮年(13-22岁)完善基于唾液的mTBI辅助诊断。最终，跨骏的 建议的唾液miRNA检测将产生一种有助于诊断的微创、客观的生物检测方法。 包括有令人困惑的心理状况的患者。

Summary/Abstract - Quadrant Biosciences is developing a new diagnostic to aid in the clinical detection of mild traumatic brain injury (mTBI) in school-aged children and young adults (13–22 years). Based on salivary microRNA (miRNA) biomarkers, Quadrant’s diagnostic will provide an accurate, objective, and non-invasive method for mTBI diagnosis. Such a method is critically needed, as the number of pediatric mTBIs is on the rise, and the developing brains of young patients are more vulnerable to the after-effects of mechanical forces, leading to a wide range of negative effects on physical, cognitive, and psychological function. The diagnosis and assessment of mTBI in adolescents are challenging and rely on subjective measures, leading many mTBIs to go undiagnosed or underreported. This results in suboptimal post-injury treatment and patient management. A biologic assay to accurately diagnose adolescent mTBI would therefore provide an invaluable guide for clinical care, potentially guiding decisions for imaging, return to play, return to school, and therapeutic interventions. While a number of potential biomarkers for objectively detecting mTBI have been proposed, including the blood biomarkers glial fibrillary acidic protein (GFAP) and ubiquitin c-terminal hydrolase (UCH-L1), recent research questions the ability of blood-based biomarkers to differentiate patients with mTBI from those with acute orthopedic trauma, particularly in pediatric populations. Moreover, these assays require venipuncture expertise that is not always available, particularly in the case of sports-related concussions, which account for nearly 1/3 of mTBIs in this patient population. To address these shortcomings, Quadrant Biosciences is creating a novel, objective diagnostic tool based on a panel of saliva miRNA biomarkers that are differentially expressed in patients with mTBI. Pilot studies in over 200 individuals with mTBI have identified a panel of saliva miRNAs capable of diagnosing mTBI and predicting symptom duration. In the proposed Fast Track project, Quadrant will advance development of this test by establishing a rapid, accurate method for quantifying these miRNAs and refining/validating a diagnostic algorithm to differentiate adolescents and young adults with mTBI from peers with symptomology that mimics mTBI (e.g. chronic headaches, anxiety/depression, ADHD, exercise-related fatigue, and orthopedic injury). In Phase I, Quadrant will refine a diagnostic algorithm for mTBI using a rapid quantification technique for saliva miRNAs. Machine learning will be used to develop a diagnostic algorithm that employs miRNA levels from the rapid multiplex assay alongside participant medical and demographic characteristics to predict mTBI status. In Phase II, Quadrant will validate the diagnostic algorithm for differentiating mTBI from medical conditions with overlapping symptomology in a prospective, case-control study of 2500 adolescents and young adults (age 13–22 years) to refine the saliva-based diagnostic aid for mTBI. Ultimately, Quadrant’s proposed salivary miRNA-based test will yield a minimally invasive, objective, biologic test that can aid diagnosis of mTBI, including among patients with confounding psychologic conditions.