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.

项目摘要美国每年有将近三百万个轻度创伤性脑损伤（MTBI），大多数发生在患者不到21岁。 MTBI的临床评估依赖于无法的症状调查生物学测试将允许准确预测症状的持续时间或客观地识别大脑恢复。医生为学校和体育参与提供个性化建议，规定及时药理治疗或在有持续的持续性后患者的早期社会心理服务脑震荡症状（PPC）。非编码核糖核酸（NCRNA），例如microRNA，是表演 MTBI患者改变的转录分子。它们可以在外围生物流体中测量例如血清，甚至是唾液。我们先前的研究表明，脑脊液的NCRNA变化反映在唾液中，唾液ncRNA水平可以预测PPC。验证这些发现中的独立队列可以产生PPC风险的生物学测量（AIM 1），并指导个性化的临床管理决策（目标2）。这种科学的前提构成了我们提出的多中心研究的基础。我们将与MTBI一起注册750名青少年（13-18岁），由世界卫生组织和柏林定义共识标准。我们将测量富含神经元和神经胶质外泌体的唾液NCRNA水平急性（<48小时），亚急性（7天）和伤害后时间点慢性（30天）。 PPC将由第30天的持续性≥3个症状（与受伤前状态相比，脑震荡后确定症状清单； PCSI）。在250名参与者（培训集）中，我们将使用套索技术来完善使用急性和亚急性NCRNA水平的多元模型以及临床，社会和心理因素，以预测PPC（在控制生物协变量的同时）。模型的精度将是在其余500名参与者（测试集）中进行外部验证。将灵敏度和特异性与经过验证的“ 5p”临床预测工具。我们还将检查脑震荡症状之间的关系具有因子分析和分层聚类的表型和NCRNA水平。在AIM 2中，我们将使用套索在训练集（n = 250）中，以完善第二个多变量模型，该模型使用急性和慢性NCRNA水平，以及临床，社会和心理因素，以确定咨询恢复。恢复将由 PCSI上“与受伤没有差异”的自我报告。该模型的准确性将在外部验证该测试集，并将其与急性和慢性时间点的反应时间性能的准确性进行了比较。我们的多学科团队包括儿科，神经病学，分子生物学，心理学和急诊医学，其合作记录及其所必需的专业知识提案的成功。该研究将产生PPCS风险，咨询表型和临床恢复。当与医学，社会和心理评估配对时，该技术将允许研究人员研究生物定义的患者子集中MTBI疗法并个性化咨询护理。