Plasma Protein Biomarker-Based Diagnostics Of Outcome I*

描述(由申请人提供)：一项涉及6个组织的研究人员的多学科合作努力被提出，以开发针对严重败血症(SS)和社区获得性肺炎(CAP)的新型体外诊断测试(IVD)。具体目标1：早期、准确地识别将发展为器官功能障碍(SS)的脓毒症患者是有效治疗和积极结果的关键。我们建议开发一种快速的护理点(POC) IVD用于SS的早期诊断。我们的初步研究已经确定了SS的候选生物标记物，我们建议在3家三级护理医院和急诊科使用蛋白质组技术(质谱仪和多重免疫分析)进行的脓毒症前瞻性临床研究中验证这些标志物。将进行双变量分析，以确定和验证不同组之间的生物标志物差异。将对经过验证的生物标记物进行多变量分析，以得出用于SS早期诊断的生物标记物小组。生物标记物小组将与代谢终点和APACHE II评分等预后指标进行比较。生物标志物小组将被开发成一种在Biosite分诊平台上对单一血液样本进行寡蛋白IVD免疫分析的方法，结果的时间不到30分钟。具体目的2：CAP的并发症是发病率和死亡率的主要决定因素。早，准确 确定哪些CAP患者的病程复杂或预后不佳(严重的CAP)对于有效的治疗和积极的结果至关重要。我们建议在Aim 1临床研究中通过对CAP患者的单独分析来确定用于早期诊断重症CAP的生物标志物。将进行双变量和多变量分析，以确定生物标记物的差异，并得出用于严重CAP早期诊断的生物标记物小组。这一小组将与预后指数进行比较，如Port Score。具体目标3：目前，脓毒症和CAP的初始抗菌治疗是经验性的。我们建议为脓毒症和CAP常见病原体的早期鉴别提供宿主生物标志物，以便能够进行更有针对性的初始治疗，从而降低无效治疗相关的成本和减少抗生素耐药的可能性。将对AIM 1研究中确诊为脓毒症和CAP病原体(如肺炎球菌)的患者进行双变量和多变量分析，以确定 生物标志物和生物标志物组合用于脓毒症和CAP中特定类别药物的早期区分。

DESCRIPTION (provided by applicant): A multidisciplinary, collaborative effort involving investigators at 6 organizations is proposed to develop novel, in vitro diagnostic tests (IVD) for severe sepsis (SS) and community acquired pneumonia (CAP). Specific Aim 1: Early, accurate identification of sepsis patients who will develop organ dysfunction (SS) is critical for effective management and positive outcome. We propose to develop a rapid, point-of-care (POC) IVD for early diagnosis of SS. Our preliminary studies have identified candidate biomarkers of SS that we propose to validate in a prospective clinical study of sepsis at 3 tertiary care hospitals and emergency departments employing proteomic technologies (mass spectrometry and multiplexed immunoassays). Bivariable analyses will be performed to identify and validate biomarker differences between groups. Multivariable analyses will be performed on validated biomarkers to derive a biomarker panel for early diagnosis of SS. The biomarker panel will be compared with prognostic indices, such as metabolic endpoints and APACHE II score. The biomarker panel will be developed into an oligoplex IVD immunoassay performed on a single blood sample on the Biosite Triage platform, with a time-to-result of less than 30 minutes. Specific Aim 2: Complications of CAP are major determinants of morbidity and mortality. Early, accurate identification of patients with CAP who will have a complicated course or poor outcome (severe CAP) is critical for effective management and positive outcome. We propose to identify biomarkers for early diagnosis of severe CAP by separate analysis of CAP patients in the Aim 1 clinical study. Bi- and multivariable analyses will be performed to identify biomarker differences and derive a biomarker panel for early diagnosis of severe CAP. This panel will be compared with prognostic indices, such as PORT score. Specific Aim 3: Currently, initial antimicrobial treatment of sepsis and CAP is empiric. We propose to identify host biomarkers for early differentiation of common etiologic agents in sepsis and CAP, in order to allow more targeted initial therapy, thereby decreasing cost associated with ineffective therapy and lessening likelihood of antibiotic resistance. Bi- and multi-variable analyses will be performed on groups of patients from the Aim 1 study with confirmed sepsis and CAP pathogens (such as pneumococcus) in order to identify biomarkers and a biomarker panel for early differentiation of specific class agent in sepsis and CAP.