The Scientific Value of Premature Infant Biospecimens Collection

项目总结/摘要 脓毒症的异质性、分层和分期的复杂性导致了脓毒症的不良预后。 目前用于诊断和治疗人类脓毒症的分子模型的可翻译性。国家咨询 普通医学科学理事会建议使用发现方法来表征脓毒症， 生物标本脓毒症是一种危及生命的器官功能障碍，由宿主对脓毒症的反应失调引起。 细菌、病毒或真菌感染是早产儿（≤32周）和低出生体重儿（≤32周）死亡的主要原因。 1500 g）婴儿，并发生在高达25%的此类婴儿中。1 -3收集微生物组和组织的能力 生物标本纵向从多个身体部位在极端控制的情况下之前，期间， 并且贯穿败血症（培养证实）、败血症样（培养阴性危重病）和“正常”生长 早产儿的条件将使我们的团队能够确定最佳的样本收集，储存和处理 使用小体积样本的方案，以提高脓毒症研究的严谨性，并制定新的策略， 通过辨别导致早产儿败血症病理生理学的途径进行败血症检测 新生儿人口。 在R21阶段，我们将纵向收集临床信息和粪便、血液和唾液标本， 出生后第1、3、7、14、21、28、35、42和49天的早产儿（≤32周且≤ 1500 g），此外 在疑似败血症事件期间。样本采集、储存和分析的标准化和文件化 处理和样品验证研究将确保严格性和可重复性，并为实地提供信息。 在R33阶段，我们将从2个临床研究中心收集样本，为机器学习方法提供测试集。 新采集的生物标本和相关临床数据的效用将通过构建 用于从基因/代谢物/临床参数差异预测因果机制的多组学网络 在临床良好的新生儿和培养证实的败血症和培养阴性的全身性 炎症性疾病。我们将建立可检验的因果推论和微生物/宿主的预测模型 基因相互作用和导致败血症的生物学机制可能为未来的研究奠定基础。 机械研究。 我们的新生儿提供者团队，免疫学家，系统生物学家，微生物组专家， 由两个大型四级NICU支持的生物信息学家处于独特的位置，可以收集和分析 极端早产患者危重病之前、期间和之后的生物样本和临床数据。

Project Summary/Abstract The complexities of heterogeneity, stratification, and staging of sepsis have contributed to the poor translatability of current molecular models for diagnosis and treatment of human sepsis. The National Advisory General Medical Sciences Council advised using discovery approaches to characterize sepsis using human biospecimens. Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to a bacterial, viral, or fungal infection, is a major cause of death in premature (≤32 weeks) and low birth weight (≤ 1500g) infants and occurs in up to 25% of such infants.1-3 The ability to collect microbiome and tissue biospecimens longitudinally from multiple body sites under extremely controlled circumstances prior to, during, and throughout sepsis (culture proven), sepsis-like (culture negative critical illness), and "normal" growing premature infant conditions will allow our team to determine optimal sample collection, storage, and processing protocols using small volume samples to enhance sepsis research rigor, and to develop new strategies for sepsis detection by discerning pathways that contribute to the pathophysiology of sepsis in the premature neonatal population. In the R21 phase we will collect clinical information and stool, blood, and saliva specimens longitudinally from preterm infants (≤32 weeks and ≤1500g) on days 1, 3, 7, 14, 21, 28, 35, 42, and 49 of life, and additionally during suspected sepsis events. Standardization and documentation of sample collection, storage, and processing and sample validation studies will ensure rigor and reproducibility and inform the field. In the R33 phase we will collect samples from 2 clinical sites providing a test set for machine learning methods. Utility of the newly collected biospecimens and associated clinical data will be demonstrated by constructing a multi-omic network for predicting causal mechanisms from genes/metabolites/clinical parameters differentially expressed between clinically well neonates and those with culture proven sepsis and culture negative systemic inflammatory illness. We will make establish testable causal inferences and predictive models of microbial/host gene interactions and biologic mechanisms leading to sepsis that could form the foundation for future mechanistic studies. Our team of neonatal providers, immunologists, systems biologists, microbiome specialists, and bioinformaticians supported by two large Level IV NICUs are uniquely positioned to collect and analyze biospecimens and clinical data before, during, and after critical illness in patients with extreme prematurity.