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

青少年脑震荡症状持续时间和恢复的多组学预测因子

基本信息

批准号：
10323290
负责人：
Steven Daniel Hicks
金额：
$ 67.68万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10323290
关键词：
21 year old Acute Adolescent Age Algorithms Athletic Berlin Biological Biological Testing Brain Brain Concussion Caring Centers for Disease Control and Prevention (U.S.)Cerebrospinal Fluid Child Childhood Childhood Injury Chronic Clinical Clinical Management Clinical assessments Cohort Studies Collaborations Consensus Emergency Medicine Enrollment Equipment and supply inventories Factor Analysis Family Follow-Up Studies Genetic Transcription Goals Guidelines Hour Injury Learning Measures Mediating Medical Methods MicroRNAs Modeling Molecular Molecular Biology Molecular Profiling Multicenter Studies Neuroglia Neurons Olfactory Nerve Oropharyngeal Outcome Participant Patient Self-Report Patients Pediatric Neurology Performance Peripheral Pharmacological Treatment Phenotype Physicians Pilot Projects Play Post-Concussion Syndrome Prognosis Psychiatric Social Work Psychological Factors Psychology Publishing RNA Reaction Time Recommendation Recovery Reporting Research Research Personnel Risk Saliva Schools Sensitivity and Specificity Serum Severities Standardization Surveys Symptoms TBI treatment Techniques Technology Testing Time Training Untranslated RNA Validation World Health Organization brain repair clinical application cohort concussive symptom exosome experience feature selection innovation mild traumatic brain injury multidisciplinary multiplex assay neurobehavioral patient subsets pediatric patients personalized management prediction algorithm predictive modeling predictive test protein expression psychologic repaired response response to brain injury return to sport saliva sample social social factors success tool transcriptomics

项目摘要

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.

项目概要美国每年有近 300 万起轻度创伤性脑损伤 (mTBI)，其中大多数发生在 21 岁以下的患者的 mTBI 临床评估依赖于症状调查，但不能生物测试可以准确预测症状的持续时间或客观地确定大脑的恢复情况。医生为学校和运动参与提供个性化建议，及时开处方药物治疗，或对有持续性后遗症风险的患者启动早期心理社会服务脑震荡症状 (PPCS) 非编码核糖核酸 (ncRNA)，例如 microRNA，是表观- mTBI 患者中发生改变的转录分子可以在外周生物液中进行测量。例如血清，甚至唾液，我们之前的研究表明，脑脊液中的 ncRNA 会发生变化。反映在唾液中，唾液 ncRNA 水平可以预测 PPCS，这些结果在大量数据中得到验证。独立队列可以产生 PPCS 风险的生物学测量（目标 1），并指导个体化临床这一科学前提构成了我们提出的多中心研究的基础。将招募 750 名患有 mTBI（由世界卫生组织和柏林定义）的青少年（年龄 13-18 岁）我们将测量富含神经和神经胶质外泌体的唾液 ncRNA 水平。急性（<48小时）、亚急性（7天）和慢性（30天）PPCS将由损伤后时间点定义。第 30 天持续存在 ≥ 3 种症状（与受伤前状态相比，由脑震荡后评估结果确定）症状清单；在 250 名参与者（训练集）中，我们将使用 LASSO 技术来完善多变量模型，采用急性和亚急性 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）。将与其余 500 名参与者（测试集）进行外部验证的敏感性和特异性进行比较。我们还将研究经过验证的“5P”临床预测工具。通过因子分析和层次聚类分析表型和 ncRNA 水平在目标 2 中，我们将使用 LASSO。在训练集中 (n=250) 细化第二个多变量模型，该模型使用急性和慢性 ncRNA 水平，结合临床、社会和心理因素来确定脑震荡恢复情况。 PCSI 上“与受伤前没有差异”的自我报告将在外部进行验证。测试集，并与急性和慢性时间点的反应时间表现的准确性进行比较。我们的多学科团队包括儿科、神经病学、分子生物学、心理学和具有公开的合作记录和必要的专业知识的急诊医学该研究的成功将得出 PPCS 风险、脑震荡表型和当与医学、社会和心理评估相结合时，这项技术将允许临床康复。研究人员在生物学定义的患者亚群中研究 mTBI 疗法并个性化脑震荡护理。