Blood transcriptomics as CT adjuvant to exclude hemorrhage in acute stroke

血液转录组学作为 CT 佐剂排除急性中风出血

• 批准号: 10396630
• 负责人: ROBERT MELLER
• 金额: $ 56.08万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10396630
• 关键词: Accreditation; Adjuvant; Admission activity; Affect; African American; African American population; Alteplase; Biological; Biological Assay; Biological Markers; Blood; Blood Tests; Blood specimen; Brain hemorrhage; Cardiovascular Diseases; Caucasians; Cause of Death; Cerebral hemisphere hemorrhage; Clinical; Collaborations; Data; Data Analyses; Data Set; Diagnosis; Diagnostic; Diagnostic tests; Disease; Emergency Department Physician; Female; Genetic Transcription; Genomics; Goals; Hemorrhage; Hospitals; Hour; Image Analysis; Ischemic Stroke; Joints; Libraries; Measurement; Measures; Methods; Minority Groups; Modeling; Morbidity - disease rate; Morehouse School of Medicine; Needles; Patient Recruitments; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Population; Preparation; RNA; Race; Reading; Recovery; Research; Research Personnel; Risk; Severities; Side; Speed; Stratification; Stroke; Symptoms; Techniques; Technology; Testing; Therapeutic; Thrombolytic Therapy; Time; Universities; Venous; Whole Blood; Woman; X-Ray Computed Tomography; acute stroke; base; diagnostic panel; diagnostic signature; disability; effective therapy; experimental study; gene environment interaction; high risk; imaging facilities; improved; improved outcome; male; mortality; nanopore; next generation; next generation sequencing; novel; outcome prediction; peripheral blood; point of care; point-of-care diagnostics; predictive modeling; programs; radiologist; rapid test; response; secondary analysis; sex; stroke incidence; stroke patient; time use; transcriptome; transcriptome sequencing; transcriptomics; treatment response

What? We will test the accuracy of an RNA-seq based biomarker assay to predict the diagnosis of stroke in a minority population (African American). We will investigate the impact of sex and race on test accuracy, and investigate novel sequencing approaches to speed up the time to obtain actionable results (Nanopores). Why? When using the thrombolytic tPA, time is of the essence, as the drug must be administered within 3-4.5 hrs of stroke onset. The sooner with in this time window that tPA can be administered, the greater the benefit. In addition, intracerebral hemorrhage must have been excluded by CT scanning; currently the sole method to make this therapeutically critical determination. Delays in radiologist interpretation of CT results, or lack of available imaging facilities is the most common reason for thrombolytic treatment not being initiated. . Thus corroborative use of a highly sensitive blood test would permit ER physicians to be confident of their CT interpretation in settings without onsite CT reading by a radiologist. Timely administration of tPA would thereby be permitted reducing stroke burden. Accordingly, a rapid biomarker test to exclude hemorrhage in acute stroke would reduce door to needle times, lower mortality, and improve outcome in stroke. Stroke burden is higher in African Americans and females, yet these populations have lower representation in genomic research. We test the impact of sex and race by assessing test accuracy derived from a single sex or race, and then tested in the opposite sex, or Caucasians. These experiments will determine whether mixed sex or race derived tests are more accurate than those derived from a single population. Finally, we investigate approaches to speed up testing using novel Nanopore sequencing technology. How? Our studies of blood biomarkers, developed at Grady Memorial Hospital Marcus Stroke Center, offers a diagnostic blood test that discriminates between ischemic and hemorrhagic stroke. We do not rely on single biomarkers but rather use analysis of the entire transcriptome (all RNA) in venous blood, by the use of next generation RNA sequencing. These data provide highly accurate stroke diagnosis, determine stroke subtype, offer powerful prediction of outcome, and show differences and treatment response by sex. We hypothesize transcriptome differences in peripheral blood can predict CT diagnosis of hemorrhagic vs. ischemic stroke. We propose to recruit patients from the Grady memorial hospital, and obtain blood samples for RNA sequencing. From this dataset we will test three specific aims: AIM ONE: Determine the accuracy of blood RNA profiles to predict CT documented hemorrhagic stroke. AIM TWO: Determine the effect of sex and race on transcriptomic profile accuracy. AIM THREE: Show the accuracy of rapid RNA measurement techniques to identify ischemic brain hemorrhage profiles. IMPACT: A rapid point of care blood test to diagnosis stroke and stroke subtype will increase the percentage of the acute stroke population eligible for tPA therapy, significantly reducing stroke morbidity and mortality.

什么？我们将测试基于 RNA-seq 的生物标志物测定的准确性，以预测中风诊断 少数民族人口（非裔美国人）。我们将调查性别和种族对测试准确性的影响，以及 研究新的测序方法以加快获得可操作结果的时间（纳米孔）。 为什么？使用溶栓 tPA 时，时间至关重要，因为药物必须在 3-4.5 天内给药 中风发作的小时数。在此时间窗口内越早施用 tPA，益处就越大。 此外，CT扫描必须排除脑出血；目前唯一的方法是 做出这一治疗上关键的决定。放射科医生对 CT 结果的解释存在延迟，或缺乏 可用的成像设施是未开始溶栓治疗的最常见原因。 。因此 高度敏感的血液测试的确证使用将使急诊医生对他们的 CT 充满信心 在没有放射科医生现场 CT 读数的情况下进行解读。因此，及时施用 tPA 将 被允许减少中风负担。因此，需要进行快速生物标志物测试来排除急性出血 中风将减少就诊时间、降低死亡率并改善中风治疗结果。 非裔美国人和女性的中风负担较高，但这些人群的代表性较低 基因组研究。我们通过评估单一性别或种族的测试准确性来测试性别和种族的影响 种族，然后在异性或白种人中进行测试。这些实验将确定是否混合性别 或种族衍生的测试比源自单一人群的测试更准确。最后，我们调查 使用新型纳米孔测序技术加速测试的方法。 如何？我们在格雷迪纪念医院马库斯中风中心开发的血液生物标志物研究提供了 区分缺血性和出血性中风的诊断性血液检查。我们不依赖单一 生物标志物，而是使用静脉血中整个转录组（所有 RNA）的分析，通过使用下一个 一代RNA测序。这些数据提供高度准确的中风诊断，确定中风亚型， 提供强有力的结果预测，并显示性别差异和治疗反应。我们假设 外周血转录组差异可以预测出血性中风与缺血性中风的 CT 诊断。我们 提议从格雷迪纪念医院招募患者，并获取血液样本进行RNA测序。 从这个数据集中，我们将测试三个具体目标： 目标一：确定血液 RNA 谱的准确性 预测 CT 记录的出血性中风。目标二：确定性别和种族对转录组的影响 轮廓精度。目标三：展示快速 RNA 测量技术识别缺血的准确性 脑出血概况。 影响：用于诊断中风和中风亚型的快速护理点血液检测将增加中风的百分比 适合接受 tPA 治疗的急性卒中人群，显着降低卒中发病率和死亡率。