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，并通过耶鲁大学医学科学家培训计划获得博士学位，接受过免疫生物学和流行病学研究培训，因为她就读于通过宾夕法尼亚大学 NHLBI K12 奖的支持，获得临床流行病学理学硕士学位。这项 K23 职业发展奖提案将使申请人获得遗传学方面的高级技能。 Balamuth 博士的导师通过利用 RNA 表达谱进行前瞻性研究来开展流行病学和高通量基因表达研究，以提高急诊科对儿科脓毒症的认识，他们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。申请人目前的目标是利用流行病学和生物学工具提高对脓毒症的认识，她 75% 的时间致力于以患者为导向的研究和职业发展。申请人的短期目标是 1. 完成她的 K12 研究，其中包括一项证明严重脓毒症或脓毒性休克患者的预后得到改善的研究，这些患者在急诊室迅速得到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脓毒症电子警报，并表明虽然该警报对于识别脓毒症很敏感，但其误报率很高，并且 2. 开展当前提案中描述的研究申请人的长期职业生涯。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，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，最终目标她将通过基于急诊医学的研究网络败血症干预试验来实现这一目标，通过个性化医学技术进行风险分层，实现这些短期和长期目标将使 Balamuth 博士成为新兴领域的领导者。儿科急诊室的转化研究 环境：该提案通过连接多个学科、学校和机构，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 博士可用的广泛资源。总体而言，CHOP 和宾夕法尼亚大学为研究和培训提供了丰富和多样性的正式教学培训和机会。丰富的研究经验，加上四级儿科急诊科的高临床量，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。过去十年中取得的重大进展表明，通过及时、基于方案的治疗可以改善患者的预后。然而，从急诊科就诊的数千名儿童中找出有严重败血症风险的儿童是一项挑战。每年都有共同的发热性疾病就像大海捞针一样，尽管文献中有许多研究将候选生物标志物作为脓毒症的诊断和治疗目标，但很明显，人类对脓毒症反应的复杂性使得单一标志物成为可能。不太可能成功促进脓毒症识别的策略提供了一个独特的机会，可以在复杂且可能异质的脓毒症病理生理学中获得广泛、高通量的图像，并且使用该技术的一些初步研究已经取得了有希望的结果。预测儿科重症监护病房 (PICU) 患者脓毒症的严重程度以及发烧儿童感染的病因 该研究的广泛长期目标是利用临床预测因素和临床预测来提高急诊科对儿科脓毒症的认识。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 RNA 表达谱之间的关联。以及最初期间疾病的严重程度2. 在急诊科初步发现疑似败血症的儿科患者住院 2 天，以及 2. 确定疑似败血症的儿科 ED 患者的 RNA 表达谱与败血症源病原体之间的关联。