RNA Expression Profiling in Pediatric Patients with Suspected Sepsis

疑似败血症儿科患者的 RNA 表达谱

• 批准号: 8967019
• 负责人: Frances B Balamuth
• 金额: $ 12.63万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8967019
• 关键词: Accident and Emergency department; Acute; Adherence; Antigen Presentation; Applied Research; Basic Science; Benign; Biological Markers; Biology; Caring; Child; Childhood; Clinical; Clinical Oncology Supplement (K12); Clinical Practice Guideline; Complex; Convulsive therapy; Data; Decision Making; Development; Diagnostic; Discipline; Doctor of Philosophy; Electronics; Emergency Care; Emergency Department patient; Emergency Medicine; Emergency department visit; Enrollment; Ensure; Environment; Epidemiology; Etiology; Evaluation; Fever; Fingerprint; Functional disorder; Funding; Future; Gene Expression; Genes; Genetic Transcription; Goals; Health Expenditures; Hospitalization; Hospitals; Human Characteristics; Immunobiology; Immunology; Infant; Infection; Integrin Signaling Pathway; Integrins; Interferons; Intervention Trial; K-Series Research Career Programs; Lead; Liquid substance; Literature; Master of Science; Measures; Medical; Mentors; Methods; Microarray Analysis; Molecular Profiling; Morbidity - disease rate; Multicenter Studies; National Heart, Lung, and Blood Institute; Natural Immunity; Organ failure; Organism; Outcome; Pathway interactions; Patients; Pattern; Pediatric Hospitals; Pediatric Intensive Care Units; Pennsylvania; Philadelphia; Physicians; Population; Positioning Attribute; Principal Investigator; Prospective Studies; Protocols documentation; Regimen; Research; Research Training; Resources; Risk; Role; SECTM1 gene; Schools; Scientist; Sepsis; Septic Shock; Severities; Severity of illness; Shock; Signal Pathway; Signal Transduction; Signs and Symptoms; Source; Stratification; Techniques; Technology; Test Result; Testing; Time; Training; Training Programs; Translational Research; United States; United States National Institutes of Health; Universities; Vasoconstrictor Agents; Viral; Zinc; adaptive immunity; base; career; career development; clinical epidemiology; clinical predictors; experience; genetic epidemiology; improved; interest; medical schools; mortality; pathogen; patient oriented research; pediatric patients; personalized intervention; personalized medicine; programs; public health relevance; research and development; research study; response; skills; therapeutic target; tool; translational study

 DESCRIPTION (provided by applicant): Candidate: Dr. Balamuth has clinical training in pediatric emergency medicine, and research training both in immunobiology, having received a PhD through the Medical Scientist Training Program at Yale University, and epidemiology, as she is enrolled in the Masters of Science in Clinical Epidemiology program through the support of an NHLBI K12 award at the University of Pennsylvania. This proposal for a K23 Career Development Award will position the applicant to gain advanced skills in genetic epidemiology and high throughput gene expression studies through the conduct of a prospective study utilizing RNA expression profiling to improve pediatric sepsis recognition in the emergency department. Dr. Balamuth's mentors have expertise in epidemiology and immunology, and will ensure that both the career development and research plan are carried out successfully. The applicant's current objectives are to improve sepsis recognition in ED patients using both epidemiologic and biologic tools. With 75% of her time dedicated to patient oriented research and her career development, the applicant's short term goals are 1. To complete her K12 studies. These include a study which demonstrates improved outcomes for patients with severe sepsis or septic shock who were recognized rapidly in the ED and treated according to a clinical practice guideline and a study which evaluates a vital sign based electronic alert for sepsis in the emergency department and demonstrates that although the alert is sensitive for identifying sepsis, that it has a high false positive rate and 2. To carry out the studies described in the current proposal. The applicant's long term career goal is to become an independent academic physician-scientist with an established NIH-funded program to accurately identify pediatric patients with sepsis in the ED setting, and to risk stratify patients so that they receive appropriate and personalized interventions based on their underlying biology, with the ultimate goal of decreasing morbidity and mortality. She will achieve this through emergency medicine based research network sepsis intervention trials using risk stratification through personalized medicine techniques. Achieving these short and long term goals will develop Dr. Balamuth as a leader in the nascent field of translational research in the pediatric ED. Environment: The proposal takes advantage of the extensive resources available to Dr. Balamuth at The Children's Hospital of Philadelphia (CHOP) and the University of Pennsylvania Perelman School of Medicine (Penn) by bridging multiple disciplines, schools, and research centers to create a unique program aimed towards developing skills in advanced genetic epidemiology, and high throughput methods. Overall, CHOP and Penn provide a rich environment for research and training. The wealth and diversity of both formal didactic training and opportunities for mentored research experiences, combined with the high clinical volume of a quaternary pediatric emergency department is unique, and create an ideal environment for Dr. Balamuth's ongoing career development. Research: Severe sepsis is an important cause of morbidity and mortality in children. There have been significant advances over the past decade, which have demonstrated improved patient outcomes with timely, protocol-based therapies. However, identifying which children require these intensive therapies is challenging. Finding the children at risk for severe sepsis from among the thousands who present to emergency departments each year with common febrile illness is akin to finding a needle in a haystack. Although there have been many studies in the literature investigating candidate biomarkers as both diagnostic and therapeutic targets in sepsis, it has become clear that the complex nature of the human response to sepsis makes single marker strategies unlikely to succeed in facilitating sepsis recognition. RNA expression profiling provides a unique opportunity to gain a broad, high throughput picture in the complex and likely heterogeneous pathophysiology of sepsis, and several preliminary studies have yielded promising results using this technique in predicting both sepsis severity in pediatric intensive care unit (PICU) patients as well as etiology of infections in children with fever. The broad long-term objective of this line of research is to improve pediatric sepsis recognition in the emergency department using both clinical predictors and biomarker strategies. As a first step towards achieving this goal, the current proposal focuses on using RNA expression profiling to predict both illness severity and source pathogen in pediatric sepsis. The aims of this proposal are: 1. To determine association between the RNA expression profile and severity of illness during the initial 2 days of hospitalization in pediatri patients with suspected sepsis initially identified in the ED., and 2. To determine association between the RNA expression profile and sepsis source pathogen in pediatric ED patients with suspected sepsis.

 描述（由申请人提供）：候选人：Balamuth博士在儿科急诊医学方面接受过临床培训，并在免疫生物学方面接受过研究培训，通过耶鲁大学的医学科学家培训计划获得了博士学位，并通过宾夕法尼亚大学NHLBI K12奖的支持参加了临床流行病学硕士课程。K23职业发展奖的这一提议将使申请人能够通过利用RNA表达谱进行前瞻性研究来提高急诊科对儿科败血症的认识，从而获得遗传流行病学和高通量基因表达研究方面的先进技能。Balamuth博士的导师拥有流行病学和免疫学方面的专业知识，并将确保职业发展和研究计划的成功实施。 申请人目前的目标是使用流行病学和生物学工具提高艾德患者的脓毒症识别。她的75%的时间致力于以病人为导向的研究和她的职业发展，申请人的短期目标是1。完成她的K12研究。其中包括一项研究，该研究证明了在艾德中迅速识别并根据临床实践指南治疗的严重脓毒症或脓毒性休克患者的结局改善，以及一项研究，该研究评价了急诊科中基于生命体征的脓毒症电子警报，并证明尽管警报对识别脓毒症敏感，但其具有较高的假阳性率，2.开展本提案所述的研究。 申请人的长期职业目标是成为一名独立的学术医生-科学家，拥有一个由NIH资助的项目，以准确识别艾德环境中的脓毒症儿科患者，并对患者进行风险分层，以便他们根据其基础生物学接受适当和个性化的干预，最终目标是降低发病率和死亡率。她将通过基于急诊医学的研究网络脓毒症干预试验，通过个性化医疗技术使用风险分层来实现这一目标。实现这些短期和长期目标将使Balamuth博士成为儿科ED转化研究新兴领域的领导者。环境：该提案利用了费城儿童医院（CHOP）和宾夕法尼亚大学佩雷尔曼医学院（Penn）的Balamuth博士可利用的广泛资源，将多个学科、学校、和研究中心创建一个独特的计划，旨在发展先进的遗传流行病学和高通量方法的技能。总的来说，CHOP和宾夕法尼亚大学为研究和培训提供了丰富的环境。正式的教学培训和指导研究经验的机会的丰富性和多样性，以及四级儿科急诊科的高临床量是独一无二的，并为Balamuth博士的持续职业发展创造了理想的环境。研究：严重脓毒症是儿童发病和死亡的重要原因。在过去的十年中，已经取得了重大进展，这些进展已经证明了及时的基于方案的治疗可以改善患者的结局。然而，确定哪些儿童需要这些强化治疗是具有挑战性的。从每年因常见发热性疾病而到急诊室就诊的数千名儿童中找到有严重败血症风险的儿童类似于大海捞针。尽管文献中有许多研究调查了作为脓毒症诊断和治疗靶点的候选生物标志物，但很明显，人类对脓毒症反应的复杂性质使得单一标志物策略不太可能成功促进脓毒症识别。RNA表达谱分析提供了一个独特的机会，以获得广泛的，高通量的图片在复杂的和可能的异质性的脓毒症的病理生理学，和一些初步的研究已经取得了可喜的结果，使用这种技术在预测脓毒症的严重程度在儿科重症监护病房（PICU）的患者以及感染的病因在发烧的儿童。这一系列研究的广泛长期目标是使用临床预测因子和生物标志物策略来提高急诊科对儿科败血症的识别。作为实现这一目标的第一步，目前的建议侧重于使用RNA表达谱来预测儿科脓毒症的疾病严重程度和病原体来源。本提案的目的是：1.为了确定在急诊室最初确定的疑似败血症的儿科患者住院最初2天期间RNA表达谱与疾病严重程度之间的关系，和2.目的：探讨小儿艾德疑似脓毒症患者RNA表达谱与脓毒症病原体之间的关系。