THE PEDIATRIC SEPSIS BIOMARKER RISK MODEL

描述(由申请人提供)：本申请涉及广泛的挑战领域(03)生物标记物的发现和验证以及特定的挑战主题确定和验证血液、血管、心脏和呼吸道功能障碍的诊断和治疗反应的临床相关、可量化的生物标记物(03-HL-101和03-AG-112)。感染性休克是成人和儿童的主要公共卫生问题。感染性休克是一种异质综合征，有可能对与这一挑战主题相关的几乎所有器官系统造成负面影响：血液(凝血障碍)、血管(分布性休克)、心脏(心源性休克)和呼吸(急性呼吸窘迫综合征)功能。因此，感染性休克在特定的患者队列中有高度不同的表达。我们提出，该领域的一个关键挑战是通过更有效地对患者进行分层来减少和管理这种异质性，以达到更合理和有效的临床研究和临床管理的目的。基于多生物标志物的分层系统具有巨大的潜力，可以作为临床上可行和有效的策略来应对这一挑战，就像在癌症领域所做的那样。因此，我们建议建立儿科败血症生物标记物风险模型(迄今称为Perevere：儿科败血症生物标记物风险模型)。Perevere将基于15个候选生物标记物，这些标记物是从我们自己的感染性休克儿童大型微阵列数据集中挑选出来的。候选生物标志物的选择过程是系统的，几乎完全没有偏见。重要的是，所有的候选生物标记物都具有生物学上的可能性，并且可以很容易地在血舱中进行测量。我们建议对216名已经存在的感染性休克儿童进行学习/派生队列，基于在感染性休克儿科重症监护病房入院24小时内获得的血液样本。派生后，PERSIVE将在200名感染性休克儿童的前瞻性队列中得到验证。这项应用的预期成果是一个多生物标记物的儿科败血症风险模型(PERSIVE)，它将允许在临床相关的时间点进行结果预测和分层。PERSIVE将对未来针对儿童感染性休克人群的临床试验以及针对感染性休克患者个体的高风险疗法的应用产生重大积极影响。此外，我们将有机会测试和校准成人的持续性，从而对成人感染性休克人群产生潜在的重大影响。该计划的成果将是一个基于多生物标记物的儿科感染性休克风险模型。通过发展更有效地将患者分层进行干预性临床试验和在感染性休克儿童中应用高风险疗法的能力，将对儿童健康产生积极影响。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (03) Biomarker Discovery and Validation and specific Challenge Topic Identify and validate clinically relevant, quantifiable biomarkers of diagnostic and therapeutic responses for blood, vascular, cardiac, and respiratory tract dysfunction (03-HL-101 and 03-AG- 112). Septic shock is a major public health problem in both adults and children. Septic shock is a heterogeneous syndrome with the potential to negatively affect virtually all organ systems relevant to this challenge topic: blood (coagulopathy), vascular (distributive shock), cardiac (cardiogenic shock), and respiratory (acute respiratory distress syndrome) function. As such, septic shock has highly variable expression in a given patient cohort. We propose that a key challenge in the field is to reduce and manage this heterogeneity by more effectively stratifying patients for the purposes of more rational and effective clinical research and clinical management. A multi-biomarker-based stratification system has tremendous potential as a clinically feasible and effective strategy for meeting this challenge, as has been done in the field of cancer. Accordingly, we are proposing to derive the pediatric sepsis biomarker risk model (heretofore called PERSEVERE: PEdiatRic SEpsis biomarkEr Risk modEl). PERSEVERE will be based on 15 candidate biomarkers, which have been selected from our own large microarray data set of children with septic shock. The selection process for the candidate biomarkers is systematic and almost completely unbiased. Importantly, all of the candidate biomarkers have biological plausibility and can be readily measured in the blood compartment. We propose to derive PERSEVERE in a learning / derivation cohort of 216 children with septic shock that already exists, based on blood samples obtained within 24 hours of admission to the pediatric intensive care unit with septic shock. After derivation, PERSEVERE will be validated in a prospectively enrolled cohort of 200 children with septic shock. The expected deliverable from this application is a multi-biomarker pediatric sepsis risk model (PERSEVERE) that will allow for outcome prediction and stratification at a clinically relevant time point. PERSEVERE will have a major positive influence on the future conduct of clinical trials targeted at the pediatric septic shock population and in the application of high risk therapies for individual patients with septic shock. In addition, we will have a potential major influence on the adult septic shock population by having the opportunity to test and calibrate PERSEVERE in adults. The deliverable of this program will be a multi-biomarker-based risk model for pediatric septic shock. Child health will be positively impacted by developing the capability to more effectively stratify patients for interventional clinical trials and for the application of high risk therapies in children with septic shock.