Improving diagnosis of post-traumatic sepsis using plasma microbial DNA sequencing

利用血浆微生物 DNA 测序改善创伤后脓毒症的诊断

• 批准号: 10572825
• 负责人: Mehreen T Kisat
• 金额: $ 19.04万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10572825
• 关键词: Address; Antibiotics; Antimicrobial Resistance; Bacterial DNA; Bioinformatics; Biological Assay; Biological Markers; Blood; Blood specimen; Cessation of life; Clinical; Clinical Management; Clinical Trials; Communicable Diseases; Communities; Computing Methodologies; DNA; DNA sequencing; Data; Data Analyses; Dedications; Deterioration; Development; Development Plans; Diagnosis; Diagnostic; Diagnostic tests; Discipline; Early Diagnosis; Early identification; Emergency Situation; Etiology; Genomics; Hospitalization; Hospitals; Hour; Individual; Infection; Inflammation; Inflammatory Response; Injury; Intensive Care Units; Judgment; Laboratories; Life; Literature; Measures; Medical; Mentorship; Microbiology; Monitor; Multiple Organ Failure; Operative Surgical Procedures; Organism; Outcome; Pathogen detection; Patient Admission; Patients; Physicians; Physiological; Plasma; Research; Sampling; Scientist; Sepsis; Septic Shock; Source; Surgeon; Testing; Time; Training; Translational Research; Trauma; Trauma patient; Traumatic injury; Universities; Wisconsin; Withholding Treatment; Work; Writing; antimicrobial; career development; cell free DNA; clinically relevant; diagnostic accuracy; early detection biomarkers; experience; genome sequencing; genomic data; healthy volunteer; improved; improved outcome; individualized medicine; metagenomic sequencing; microbial; microbial genomics; mortality; pathogen; professor; prospective; radiological imaging; rapid diagnosis; response; response to injury; standard of care; systemic inflammatory response; tissue injury; trauma surgery; treatment response; whole genome

PROJECT SUMMARY/ABTRACT This proposal presents a five-year research career development plan focused on improving diagnosis of post-traumatic sepsis using microbial DNA sequencing in plasma. I am an Assistant Professor of Surgery at the University of Wisconsin-Madison, with previous clinical and research experience in trauma surgery, patient- centric predictors of sepsis, and lab-based genomic analyses of plasma in patients with sepsis. I have assembled an outstanding mentorship team with expertise in infectious disease, cell-free DNA, genomic data analysis, and bioinformatics. The proposed training will enhance my development across the disciplines of translational research, laboratory and computational methods in genomics, and scientific writing. This will enable me to transition to research independence as a surgeon-scientist dedicated to improving outcomes for trauma patients with sepsis by developing better diagnostic tests based on microbial genomics. Sepsis is a life-threatening condition, estimated to cause one-fifth of all deaths worldwide. Approximately 25% of trauma patients develop sepsis during their hospital course and more than 20% of such patients die during the same hospitalization. Sepsis, if not recognized and treated early, may evolve into septic shock and multiple organ failure. Thus, the treatment of sepsis emphasizes timely initiation of antibiotics and source control in surgery/trauma patients. However, the diagnosis of sepsis in patients with traumatic injury is complicated because systemic inflammatory response to injury mimics sepsis. In the current paradigm, confirmation of sepsis is based on clinical signs, laboratory and radiographic findings, and medical scores which are usually obtained after sepsis onset. There are approximately 200 biomarkers of sepsis described in literature but nearly all such biomarkers rely on measuring inflammatory response, which is confounded in patients with trauma. Recent studies, including my preliminary work, have shown that metagenomic sequencing of plasma DNA can rapidly identify pathogens in patients with clinical suspicion of sepsis but these assays have not been investigated in trauma patients. To address this gap, I propose to develop and evaluate a metagenomic sequencing-based assay for analysis of microbial DNA shed into the blood. My central hypothesis is that quantitative analysis of microbial DNA levels in trauma patients can predict sepsis, rapidly identify the causative organism of sepsis, and help decrease the duration of antimicrobial treatment. Using prospectively collected plasma samples from trauma patients, I propose the following aims: 1) To determine if an increase in circulating microbial DNA levels is predictive of sepsis in trauma patients, 2) To assess concordance between causative organism identified using standard-of-care microbiology and detection of pathogen-specific DNA in plasma, and 3) To evaluate circulating microbial DNA levels in plasma as a biomarker for monitoring antimicrobial response.

项目概要/摘要 该提案提出了一个五年研究职业发展计划，重点是改善诊断 使用血浆中微生物 DNA 测序来治疗创伤后脓毒症。我是外科助理教授 威斯康星大学麦迪逊分校，具有创伤外科、患者的临床和研究经验 脓毒症的中心预测因子，以及脓毒症患者血浆的实验室基因组分析。我有 组建了一支优秀的导师团队，拥有传染病、游离DNA、基因组数据方面的专业知识 分析和生物信息学。拟议的培训将促进我跨学科的发展 基因组学的转化研究、实验室和计算方法以及科学写作。这将 使我能够作为一名致力于改善结果的外科医生科学家过渡到研究独立性 通过基于微生物基因组学开发更好的诊断测试来治疗患有脓毒症的创伤患者。 脓毒症是一种危及生命的疾病，估计导致全世界死亡人数的五分之一。大约 25% 的创伤患者在住院期间出现败血症，其中 20% 以上的患者死亡 同一住院期间。败血症如果不及早识别和治疗，可能会演变成败血性休克， 多器官衰竭。因此，脓毒症的治疗强调及时启动抗生素和源头治疗。 手术/创伤患者的控制。然而，创伤性损伤患者脓毒症的诊断是 很复杂，因为对损伤的全身炎症反应类似于脓毒症。在当前范式中， 脓毒症的确认基于临床体征、实验室和放射学检查结果以及医疗评分 通常在脓毒症发作后获得。大约有 200 种脓毒症生物标志物 文献中，但几乎所有此类生物标志物都依赖于测量炎症反应，这在 有外伤的患者。最近的研究，包括我的初步工作，表明宏基因组 血浆 DNA 测序可以快速识别临床怀疑脓毒症患者的病原体，但这些 尚未在创伤患者中进行测定。为了弥补这一差距，我建议开发和评估 一种基于宏基因组测序的分析方法，用于分析流入血液中的微生物 DNA。我的中央 假设对创伤患者的微生物 DNA 水平进行定量分析可以快速预测脓毒症 识别脓毒症的致病微生物，并有助于缩短抗菌治疗的持续时间。使用 前瞻性地从创伤患者身上收集血浆样本，我提出以下目标：1）确定是否 循环微生物 DNA 水平的增加可预测创伤患者的脓毒症，2) 评估 使用标准护理微生物学鉴定的致病微生物与检测之间的一致性 血浆中病原体特异性 DNA，以及 3) 评估血浆中循环微生物 DNA 水平作为 用于监测抗菌反应的生物标志物。