Integration of Microbe and Host Data Diagnosis of Febrile Illness

热病微生物与宿主数据融合诊断

• 批准号: 9241962
• 负责人: DAVID A. RELMAN
• 金额: $ 108.16万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-07 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9241962
• 关键词: Attention; Bacteremia; Base Sequence; Blood; Blood specimen; Clinical; Clinical Data; Clinical Research; Communicable Diseases; Complex Mixtures; Confusion; Critical Illness; DNA; DNA sequencing; Data; Data Analyses; Dengue; Diagnosis; Diagnostic; Disease; Disease Outcome; Early Diagnosis; Endemic Flea-Borne Typhus; Etiology; Fever; Genetic Transcription; Genomics; Goals; Health care facility; Hospital Referrals; Hospitals; Human; Human Genome; Immune response; Individual; Infection; Infectious Agent; Intensive Care; Intervention; Laos; Measurement; Methods; Microbe; Minor; Nature; Nicaragua; Noise; Outcome; Patients; Pattern; Population; Prognostic Marker; RNA; Research; Sampling; Scrub Typhus; Shotguns; Signal Transduction; Site; Skin; Source; Specimen; Staphylococcus aureus; Structure; Syndrome; Systemic infection; Techniques; Technology; Testing; Thailand; Time; Toothbrushing; Typhoid Fever; Undifferentiated; Viral; Whole Blood; base; cohort; computerized tools; design; diagnostic biomarker; genetic signature; genome-wide; human DNA; interest; microbial; novel; outcome forecast; pathogen; peripheral blood; point of care; predict clinical outcome; prognostic signature; tool; viral DNA; viral RNA

Early diagnosis of systemic infection in humans and prediction of clinical outcome both remain elusive, despite the critical need for both. The two basic approaches for diagnosis and prognosis, direct identification of the infectious agent and measurement of host response features, have been limited by reliance on cultivation, pre-test assumptions about specific agents, limited breadth of coverage, and an insufficient signal-to-noise ratio. Recent advances in DNA sequencing technology and computational tools for data analysis provide new opportunities for characterizing complex mixtures of DNA and RNA molecules in a minimally-biased fashion, and for detecting rare sequences of interest in clinical specimens. The goals of this project are to characterize microbial and viral genomic sequences in the peripheral blood of healthy subjects, as well as subjects with fever (and in some cases, known causative infectious agents) at the time of clinical presentation, to characterize human genome-wide RNA patterns in peripheral blood, and then to integrate these complementary forms of data so as to derive putative diagnostic and prognostic signatures for systemic infection. We propose three aims; (1) characterize microbial and viral sequences and host RNAs in peripheral blood of non-febrile, healthy subjects; (2) characterize microbial and viral sequences and host RNAs in human blood during febrile illness; and (3) identify and validate diagnostic and prognostic biomarkers during early stages of febrile illness based on microbial and viral sequences, host RNAs, and clinical features. Our long-term objectives are to validate novel early diagnostic and prognostic signatures for several classes and species of pathogens and their related clinical syndromes, with attention to early predictors of subsequent critical illness requiring intensive care. Sequence-based signatures will serve as the basis for the design of probes on CMOS electrochemical-based active microarrays and other technologies, so that they can be exploited and deployed at the point-of-care in an easy-to-use format.

人类全身性感染的早期诊断和临床结果的预测仍然难以捉摸，尽管这两者都是迫切需要的。诊断和预后的两种基本方法，即直接识别感染因子和测量宿主反应特征，由于依赖于培养，对特定因子的预测试假设，覆盖范围有限以及信噪比不足而受到限制。DNA测序技术和数据分析计算工具的最新进展为以最小偏差的方式表征DNA和RNA分子的复杂混合物以及检测临床标本中感兴趣的罕见序列提供了新的机会。该项目的目标是在临床表现时表征健康受试者以及发烧受试者（在某些情况下，已知的传染性病原体）外周血中的微生物和病毒基因组序列，表征外周血中人类全基因组RNA模式，然后整合这些互补形式的数据，从而得出系统性感染的推定诊断和预后特征。我们提出三个目标；(1)研究非发热健康人外周血中微生物和病毒序列及宿主rna的特征；(2)研究发热性疾病时人体血液中的微生物和病毒序列及宿主rna；(3)根据微生物和病毒序列、宿主rna和临床特征，识别和验证发热性疾病早期的诊断和预后生物标志物。我们的长期目标是验证几种类型和种类的病原体及其相关临床综合征的新的早期诊断和预后特征，并关注随后需要重症监护的危重疾病的早期预测因子。基于序列的签名将作为基于CMOS电化学的有源微阵列和其他技术的探针设计的基础，以便它们可以以易于使用的格式在护理点进行开发和部署。