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 博士接受过儿科急诊医学临床培训，并接受过免疫生物学研究培训（通过耶鲁大学医学科学家培训项目获得博士学位）和流行病学研究培训，因为她在宾夕法尼亚大学 NHLBI K12 奖的支持下入读临床流行病学理学硕士项目。这项 K23 职业发展奖提案将使申请人能够通过利用 RNA 表达谱进行前瞻性研究来获得遗传流行病学和高通量基因表达研究方面的高级技能，以提高急诊科对儿科脓毒症的识别。 Balamuth博士的导师拥有流行病学和免疫学方面的专业知识，将确保职业发展和研究计划的成功实施。 申请人当前的目标是利用流行病学和生物学工具提高对急诊科患者脓毒症的识别。申请人 75% 的时间致力于以患者为导向的研究和职业发展，其短期目标是 1. 完成 K12 学习。其中包括一项研究，证明严重败血症或败血性休克患者的预后得到改善，这些患者在急诊科迅速被识别并根据临床实践指南进行治疗，以及一项评估急诊科基于生命体征的败血症电子警报的研究，并表明虽然该警报对于识别败血症很敏感，但其假阳性率很高，并且 2. 开展当前提案中描述的研究。 申请人的长期职业目标是成为一名独立的学术医师科学家，拥有 NIH 资助的既定项目，以准确识别急诊科脓毒症儿科患者，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措施，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来实现这一目标，该试验利用个性化医疗技术进行风险分层。实现这些短期和长期目标将使 Balamuth 博士成为儿科急诊转化研究新兴领域的领导者。环境：该提案利用费城儿童医院 (CHOP) 和宾夕法尼亚大学佩雷​​尔曼医学院 (Penn) 的 Balamuth 博士可用的广泛资源，通过连接多个学科、学校和研究中心来创建一个独特的项目，旨在培养高级遗传流行病学和高通量方法方面的技能。总体而言，CHOP 和宾夕法尼亚大学为研究和培训提供了丰富的环境。正式教学培训和指导研究经验机会的丰富性和多样性，加上四级儿科急诊科的高临床量是独一无二的，为 Balamuth 医生持续的职业发展创造了理想的环境。研究：严重败血症是儿童发病和死亡的重要原因。过去十年取得了重大进展，证明及时的、基于方案的治疗可以改善患者的治疗结果。然而，确定哪些儿童需要这些强化治疗具有挑战性。从每年因常见发热性疾病到急诊室就诊的数千名儿童中找出有严重败血症风险的儿童就像大海捞针一样。尽管文献中有许多研究调查候选生物标志物作为脓毒症的诊断和治疗靶点，但很明显，人类对脓毒症反应的复杂性使得单一标志物策略不太可能成功促进脓毒症识别。 RNA 表达谱为获得脓毒症复杂且可能异质的病理生理学的广泛、高通量图像提供了独特的机会，并且利用该技术预测儿科重症监护病房 (PICU) 患者脓毒症严重程度以及发烧儿童感染的病因学的一些初步研究已经取得了有希望的结果。该研究的广泛长期目标是利用临床预测因子和生物标志物策略来提高急诊科对儿科脓毒症的识别。作为实现这一目标的第一步，当前提案的重点是使用 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。该提案的目的是： 1. 确定急诊室最初发现的疑似脓毒症儿科患者住院最初 2 天期间 RNA 表达谱与疾病严重程度之间的关联，以及 2. 确定疑似脓毒症儿科 ED 患者的 RNA 表达谱与脓毒症源病原体之间的关联。