Predictors of Low-risk Phenotypes after Traumatic Brain Injury Incorporating Proteomic Biomarker Signatures

项目摘要 创伤性脑损伤（TBI）是美国死亡的主要原因，治疗选择有限。 创伤性脑损伤的治疗性临床试验结果令人失望，部分原因是难以统计 TBI中临床上重要的异质性。TBI后早期治疗至关重要， 继发性脑损伤，但无限制地治疗所有脑损伤可能是有害的。TBI刺激A 中枢和外周免疫反应的复杂级联。这些外周免疫 对TBI的反应可以作为风险表型的早期传感器， 血液中的反应。入院时对患者进行风险分层的能力得到提高， 积极的干预-如侵入性神经监测-与选择那些可以 安全观察，减少潜在危害。 冬青E Hinson，医学博士MCR是俄勒冈州健康与科学大学的神经科医生和神经强化医师， 她照顾严重急性脑损伤的病人。该应用程序的目标是开发监督 TBI后可操作的短期和长期结果的学习模型，并询问是否预先指定 免疫调节蛋白增加了模型对单独的临床特征的预测能力。她的中心 假设是免疫调节蛋白质组特征提高了我们对低风险临床 TBI后的表型Hinson博士的初步数据表明，外周细胞因子水平与 TBI后急性可采取行动的临床事件。该项目采用了一种高灵敏度的单分子 免疫阵列（SIMOA）检测免疫调节蛋白， 方法利用全球发现质谱。她将开发和评估一系列模型 结合蛋白质组学特征进行分类：急性进行性颅内出血（Aim 1A），急性 神经功能恶化（Aim 1B）和6个月格拉斯哥结局量表测量的长期结局 (Aim 2）。她将在一个定义明确的临床试验人群（开发集）中开发这些模型，并测试 他们在OHSU的独立前瞻性入组队列中正确分类结局的能力（测试集）。 在多学科专家导师团队的指导下，该项目将产生对低风险表型的新见解。 急性TBI后的识别和结果分类。拟议的以病人为本的研究项目将 通过预测建模和患者表型分析原则的结构化教学计划来增强 （包括蛋白质组学），这将为Hinson博士提供她进行研究所需的关键技能。 在神经创伤领域进行独立、创新的转化临床研究。

PROJECT SUMMARY Traumatic brain injury (TBI) is a leading cause of death in the US, and treatment options are limited. Therapeutic clinical trials in TBI have yielded disappointing results owing in part to the difficulty in accounting for clinically important heterogeneity within TBI. Early delivery of therapy is essential after TBI to reduce secondary brain injury, but unrestricted treatment of all brain injuries could be harmful. TBI stimulates a complex cascade of immunologic responses, both centrally and peripherally. These peripheral immune responses to TBI could serve as an early sensor of risk phenotype given the rapid, readily measurable response in the blood. An improved ability to risk-stratify patients on admission will streamline patient selection for aggressive interventions—such as invasive neuromonitoring—versus selection of those patients who can safely be observed reducing potential harms. Holly E Hinson, MD MCR is a Neurologist and Neurointensivist at Oregon Health and Science University where she cares for patients with severe acute brain injury. The objective of this application is to develop supervised learning models of actionable short- and long-term outcomes post-TBI and to interrogate if pre-specified immunoregulatory proteins add predictive power to the models over clinical features alone. Her central hypothesis is that immunoregulatory proteomic signatures improve our ability to classify a low-risk clinical phenotype after TBI. Dr. Hinson’s preliminary data suggest peripheral cytokine levels are associated with actionable clinical events acutely after TBI. The project employs a highly-sensitive, single molecule immunoarray (SIMOA) to detect immunoregulatory proteins complemented with an unbiased proteomic approach utilizing global discovery mass spectrometry. She will develop and assess a series of models incorporating proteomic signatures to classify: acute progressive intracranial hemorrhage (Aim 1A), acute neurologic deterioration (Aim 1B), and long-term outcomes measured by the 6-month Glasgow Outcome Scale (Aim 2). She will develop these models in a well-defined, clinical trial population (development set), and test their ability to correctly classify outcome in an independent, prospectively enrolled cohort at OHSU (test set). Under a multidisciplinary team of expert mentors, the project will generate new insights into low-risk phenotype recognition and outcome classification after acute TBI. The proposed patient-oriented research project will be enhanced by a structured didactic program in the principles of predictive modeling and patient phenotyping (including proteomics), which will provide Dr. Hinson with the critical skills she will need to conduct independent, innovative translational clinical research in the field of neurotrauma.