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）生物标志物发现和验证以及特定的挑战主题，确定并验证血液、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、可量化的生物标志物（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。脓毒性休克是一种异质性综合征，有可能对与该挑战主题相关的几乎所有器官系统产生负面影响：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，脓毒性休克在给定的患者队列中具有高度可变的表达。我们建议，在该领域的一个关键挑战是减少和管理这种异质性，更有效地分层患者的目的是更合理和有效的临床研究和临床管理。基于多生物标志物的分层系统作为应对这一挑战的临床可行和有效的策略具有巨大的潜力，正如在癌症领域所做的那样。因此，我们提出导出儿科脓毒症生物标志物风险模型（迄今称为PERSEVERE：PEdiatRic SEpsis biokEr Risk modEl）。PERSEVERE将基于15个候选生物标志物，这些生物标志物是从我们自己的感染性休克儿童大型微阵列数据集中选择的。候选生物标志物的选择过程是系统的，几乎完全无偏的。重要的是，所有候选生物标志物都具有生物相容性，并且可以在血液隔室中容易地测量。我们建议在216例感染性休克儿童的学习/推导队列中推导出PERSEVERE，该队列基于感染性休克患儿入院后24小时内获得的血液样本。推导后，将在前瞻性入组的200例感染性休克儿童队列中对PERSEVERE进行验证。该应用程序的预期可交付成果是一个多生物标志物儿科脓毒症风险模型（PERSEVERE），该模型将允许在临床相关时间点进行结局预测和分层。PERSEVERE将对未来针对儿科感染性休克人群的临床试验的开展以及感染性休克个体患者高风险治疗的应用产生重大积极影响。此外，我们将有机会在成人中测试和校准PERSEVERE，从而对成人感染性休克人群产生潜在的重大影响。该项目的交付成果将是一个基于多生物标志物的儿科感染性休克风险模型。通过开发更有效地对患者进行分层以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.