Poly-omic predictors of symptom duration and recovery for adolescent concussion

项目总结 在美国，每年有近300万例轻度创伤性脑损伤(MTBI)，其中大多数发生在 年龄在21岁以下的患者。MTBI的临床评估依赖于症状调查，而不能 准确预测症状持续时间或客观识别大脑恢复情况。一项生物测试将允许 医生为参加学校和体育活动提供个性化建议，及时开具处方 对有持续性后抑郁风险的患者进行药物治疗或启动早期心理社会服务 脑震荡症状(PPCS)。非编码核糖核酸(NcRNAs)，如microRNAs，是表观的- MTBI患者的转录分子发生了变化。它们可以在外周生物液中测量到。 比如血清，甚至唾液。我们先前的研究表明，脑脊液中ncRNA的变化 反映在唾液中，唾液ncRNA水平可以预测PPCS。对这些发现的验证在一个大型、 独立队列可以产生PPCS风险的生物学测量(目标1)，并指导个体化临床 管理决策(目标2)。这一科学前提构成了我们提出的多中心研究的基础。我们 将招募750名青少年(13-18岁)患有世界卫生组织和柏林定义的mTBI 共识标准。我们将测量唾液中富含神经元和神经胶质外切体的ncRNA水平 急性(48小时)、亚急性(7天)和慢性(30天)损伤后时间点。PPC将由以下人员定义 ≥3症状在第30天的持续性(与损伤前相比，由震荡后确定 症状清单；PCSI)。在250名参与者(训练集)中，我们将使用套索技术来提炼 多变量模型，使用急性和亚急性ncRNA水平，以及临床、社会和 心理因素，以预测PPCS(同时控制生物协变量)。模型的精确度将是 在其余500名参与者(测试集)中进行外部验证。敏感度和特异度将与 经过验证的“5P”临床预测工具。我们还将检查脑震荡症状之间的关系 表型和ncRNA水平进行因子分析和系统聚类。在目标2中，我们将使用套索 在使用急性和慢性ncRNA水平来精炼第二个多变量模型的训练集(n=250)中， 以及临床、社会和心理因素，以确定脑震荡的恢复。恢复将由以下内容定义 在PCSI上自我报告“与受伤前没有差别”。模型的准确性将在以下方面进行外部验证 测试集，并与急性和慢性时间点的反应时间性能的准确性进行比较。 我们的多学科团队包括儿科、神经学、分子生物学、心理学和 具有已公布的协作记录和所需专业知识的急救医学 求婚成功了。这项研究将对PPCS的风险、脑震荡表型和 临床康复。当与医学、社会和心理评估相结合时，这项技术将允许 研究人员在生物定义的患者亚群中研究mTBI疗法，并使脑震荡护理个性化。

PROJECT SUMMARY There are nearly three million mild traumatic brain injuries (mTBIs) in the U.S. each year, and most occur in patients less than 21 years of age. Clinical assessment of mTBI relies on symptom surveys that cannot accurately predict the duration of symptoms or objectively identify brain recovery. A biologic test would allow physicians to provide individualized recommendations for school and athletics participation, prescribe timely pharmacologic treatments, or initiate early psychosocial services in patients at risk for persistent post- concussion symptoms (PPCS). Non-coding ribonucleic acids (ncRNAs), such as microRNAs, are epi- transcriptional molecules that are altered in patients with mTBI. They can be measured in peripheral biofluids such as serum, or even saliva. Our previous research demonstrates that ncRNA changes in cerebrospinal fluid are reflected in saliva, and that saliva ncRNA levels can predict PPCS. Validation of these findings in a large, independent cohort could yield a biologic measure of PPCS risk (Aim 1), and guide individualized clinical management decisions (Aim 2). This scientific premise forms the basis for our proposed multi-center study. We will enroll 750 adolescents (ages 13-18 years) with mTBI, defined by the World Health Organization and Berlin Consensus Criteria. We will measure levels of saliva ncRNAs enriched in neuronal and glial exosomes at acute (<48 hours), sub-acute (7 days), and chronic (30 days) post-injury time points. PPCS will be defined by persistence of ≥ 3 symptoms on day 30 (compared with pre-injury state, determined by the Post-Concussion Symptom Inventory; PCSI). In 250 participants (training set), we will use a LASSO technique to refine a multivariate model, that employs acute and sub-acute ncRNA levels, along with clinical, social, and psychologic factors, to predict PPCS (while controlling for biologic covariates). Accuracy of the model will be externally validated in the remaining 500 participants (test set). Sensitivity and specificity will be compared to the validated “5P” clinical prediction tool. We will also examine the relationships between concussive symptom phenotypes and ncRNA levels with a factor analysis and hierarchical clustering. In Aim 2, we will use LASSO in a training set (n=250) to refine a second multivariate model, that uses acute and chronic ncRNA levels, along with clinical, social, and psychologic factors to identify concussion recovery. Recovery will be defined by self-report of “no difference from pre-injury” on the PCSI. Accuracy of the model will be externally validated in the test set, and compared to the accuracy of reaction time performance across acute and chronic time points. Our multi-disciplinary team includes experts in pediatrics, neurology, molecular biology, psychology, and emergency medicine with a published track record of collaboration and the expertise necessary for this proposal’s success. The study will yield an objective measure of PPCS risk, concussion phenotype, and clinical recovery. When paired with medical, social, and psychologic assessments, this technology will allow researchers to study mTBI therapies in biologically-defined patient subsets and personalize concussion care.