A Data-Driven Analysis of Pediatric Organ Dysfunction Patterns To Discover Sepsis Phenotypes

对儿科器官功能障碍模式进行数据驱动分析以发现脓毒症表型

基本信息

批准号：
9895827
负责人：
Lazaro Nelson Sanchez-Pinto
金额：
$ 20.93万
依托单位：
LURIE CHILDREN'S HOSPITAL OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-09 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9895827
关键词：
Acute Adjuvant Adjuvant Therapy Adrenal Cortex Hormones Adult Advisory Committees Affect Age Albumins Biological Markers Cardiovascular system Cessation of life Characteristics Child Childhood Clinical Clinical Data Computerized Medical Record Consensus Creatinine Critical Illness Critically ill children Data Data Analyses Dependence Electronic Health Record Follow-Up Studies Foundations Functional disorder Genetic Heart Hematology Hepatic Hospital Mortality Hour Immune response Individual Infection Infusion procedures International Kidney Life Light Logistics Lung Methods Modeling Molecular Multiple Organ Failure Neurologic Organ Organ failure Outcome Pathway interactions Patients Pattern Pediatric Intensive Care Units Performance Pharmaceutical Preparations Phase Phenotype Reproducibility Research Personnel Sepsis Septic Shock Syndrome Techniques Testing Therapeutic Validation Weight base body system cohort design effective therapy improved individualized medicine loss of function mortality novel patient subsets pressure prognostic respiratory response secondary analysis theories

项目摘要

PROJECT SUMMARY Sepsis is a common cause of pediatric multiple organ dysfunction syndrome (MODS), which, in turn, is a final common pathway for death in most critically ill children. Unfortunately, approaching sepsis as a uniform clinical syndrome has contributed to dozens of failed drug trials and hundreds of single biomarkers demonstrating poor performance. In light of this, some sepsis researchers have focused their efforts in discovering sepsis subtypes that represent the specific pathobiological pattern underlying the syndrome in different subgroups of patients. These subtypes, in theory, are associated with therapy response and outcomes and could be used to guide individualized therapy. While optimal methods to uncover sepsis subtypes are still unclear, there are strong advantages to using a phenotype-based approach, where the clinical characteristics of patients are used as surrogates of the underlying pathobiology. We hypothesize that the clinical characteristics of children with sepsis can be adequately quantified using calibrated pediatric organ dysfunction scores and that the early patterns of organ dysfunction can be used to identify novel phenotypes of sepsis with prognostic and therapeutic relevance. Existing pediatric organ dysfunction scores are weighted in a multivariable model to predict mortality and are not designed to represent the progressive loss of function of each individual organ system. In light of this, we recently adapted and validated a pediatric version of the Sequential Organ Failure Assessment score (pSOFA) which allocates similar weight to each failing organ system. However, the validation of pSOFA was performed in a single center and no attempts were made to calibrate the organ-specific subscores to optimize the grading of each organ dysfunction (i.e. respiratory, cardiovascular, hepatic, renal, neurologic, and hematologic). In this study, we aim to: 1) re-calibrate and validate the pSOFA subscores using a multi-center observational cohort of critically ill children with confirmed or suspected infection; and (2) analyze the early patterns of organ dysfunction in critically ill children with sepsis using the pSOFA subscores in order to identify novel phenotypes of sepsis with prognostic and therapeutic relevance. We will use Subgraph Augmented Non-Negative Matrix Factorization to model and visualize the patterns of organ dysfunction during the acute phase of sepsis. These patterns will form the basis for the characterization of novel sepsis phenotypes. We will then evaluate whether the novel sepsis phenotypes are associated with outcomes in a validation cohort and independently associated with response to two common adjuvant treatments: corticosteroids and albumin infusions. The results from this study will be used as the foundation for follow-up studies to characterize the underlying molecular and cellular perturbations associated with the identified phenotypes.

项目摘要败血症是小儿多器官功能障碍综合征（mods）的常见原因，而这又是大多数重症儿童死亡的最终常见途径。不幸的是，接近败血症统一的临床综合征已导致数十个失败的药物试验和数百个单个生物标志物表现出差的性能。鉴于此，一些败血症研究人员将精力集中在发现代表综合征基础的特定病理生物学模式的败血症亚型不同的患者亚组。从理论上讲，这些亚型与治疗反应和结果有关可以用来指导个性化治疗。虽然发现败血症亚型的最佳方法仍然是尚不清楚，使用基于表型的方法具有很强的优势，在此，患者被用作基础病理生物学的替代物。我们假设临床特征使用校准的小儿器官功能障碍评分和器官功能障碍的早期模式可用于识别具有预后的败血症的新表型和治疗意义。现有的儿科器官功能障碍分数以多变量模型加权到预测死亡率，并非旨在代表每个器官的功能逐渐丧失系统。鉴于此，我们最近改编并验证了连续器官衰竭的儿科版本评估评分（PSOFA），将相似的重量分配给每个故障器官系统。但是，验证在单个中心进行psofa，没有尝试校准特定器官测试以优化每个器官功能障碍的分级（即呼吸，心血管，肝，肾脏，神经系统和血液学）。在这项研究中，我们的目的是：1）使用多中心的观察群体批评儿童确认或怀疑感染；（2）使用psofa subscores分析重病患病儿童的器官功能障碍的早期模式为了鉴定具有预后和治疗相关性的败血症的新表型。我们将使用子图增强非负矩阵分解，以建模和可视化器官功能障碍的模式败血症的急性相。这些模式将构成新型败血症表型表征的基础。然后，我们将评估新型败血症表型是否与验证队列中的结果相关并且与对两种常见辅助治疗的反应独立相关：皮质类固醇和白蛋白输注。这项研究的结果将用作后续研究的基础，以表征与已鉴定的表型相关的基本分子和细胞扰动。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Excessive Oxygen Supplementation in the First Day of Mechanical Ventilation Is Associated With Multiple Organ Dysfunction and Death in Critically Ill Children.

DOI：
10.1097/pcc.0000000000002861
发表时间：
2022-02-01
期刊：
Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies
影响因子：
0
作者：
Balcarcel DR;Coates BM;Chong G;Sanchez-Pinto LN
通讯作者：
Sanchez-Pinto LN

Three Data-Driven Phenotypes of Multiple Organ Dysfunction Syndrome Preserved from Early Childhood to Middle Adulthood.

从幼儿期到成年中期保留的三种数据驱动的多器官功能障碍综合征表型。

DOI：
发表时间：
2020
期刊：
AMIA ... Annual Symposium proceedings. AMIA Symposium
影响因子：
0
作者：
Ye,Jiancheng;Sanchez-Pinto,LNelson
通讯作者：
Sanchez-Pinto,LNelson

External validation and biomarker assessment of a high-risk, data-driven pediatric sepsis phenotype characterized by persistent hypoxemia, encephalopathy, and shock.

对以持续低氧血症、脑病和休克为特征的高风险、数据驱动的儿童脓毒症表型进行外部验证和生物标志物评估。

DOI：
10.21203/rs.3.rs-3216613/v1
发表时间：
2023
期刊：
Research square
影响因子：
0
作者：
Atreya,MihirR;Bennett,TellenD;Geva,Alon;Faustino,EVincentS;Rogerson,ColinM;Lutfi,Riad;Cvijanovich,NatalieZ;Bigham,MichaelT;Nowak,Jeffrey;Schwarz,AdamJ;Baines,Torrey;Haileselassie,Bereketeab;Thomas,NealJ;Luo,Yuan;Sanche
通讯作者：
Sanche