Multiple organ dysfunction syndrome (MODS) is a critical driver of sepsis morbidity and mortality in children. Early identification of those at risk of death and persistent organ dysfunctions is necessary to enrich patients for future trials of sepsis therapeutics. Here, we sought to integrate endothelial and PERSEVERE biomarkers to estimate the composite risk of death or organ dysfunctions on day 7 of septic shock. We measured endothelial dysfunction markers from day 1 serum among those with existing PERSEVERE data. TreeNet® classification model was derived incorporating 22 clinical and biological variables to estimate risk. Based on relative variable importance, a simplified 6-biomarker model was developed thereafter. Among 502 patients, 49 patients died before day 7 and 124 patients had persistence of MODS on day 7 of septic shock. Area under the receiver operator characteristic curve (AUROC) for the newly derived PERSEVEREnce model to predict death or day 7 MODS was 0.93 (0.91–0.95) with a summary AUROC of 0.80 (0.76–0.84) upon tenfold cross-validation. The simplified model, based on IL-8, HSP70, ICAM-1, Angpt2/Tie2, Angpt2/Angpt1, and Thrombomodulin, performed similarly. Interaction between variables—ICAM-1 with IL-8 and Thrombomodulin with Angpt2/Angpt1—contributed to the models’ predictive capabilities. Model performance varied when estimating risk of individual organ dysfunctions with AUROCS ranging from 0.91 to 0.97 and 0.68 to 0.89 in training and test sets, respectively. The newly derived PERSEVEREnce biomarker model reliably estimates risk of death or persistent organ dysfunctions on day 7 of septic shock. If validated, this tool can be used for prognostic enrichment in future pediatric trials of sepsis therapeutics.

中文翻译：

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整合的 PERSEVERE 和内皮生物标志物风险模型预测小儿感染性休克中的死亡和持续性 MODS：一项前瞻性观察研究的二次分析

多器官功能障碍综合征 (MODS) 是儿童脓毒症发病率和死亡率的关键驱动因素。早期识别有死亡风险和持续性器官功能障碍的患者对于丰富患者进行脓毒症治疗的未来试验是必要的。在这里，我们试图整合内皮和 PERSEVERE 生物标志物，以估计感染性休克第 7 天死亡或器官功能障碍的复合风险。我们测量了具有现有 PERSEVERE 数据的第 1 天血清中的内皮功能障碍标志物。TreeNet® 分类模型包含 22 个临床和生物学变量以估计风险。基于相对变量的重要性，此后开发了一个简化的 6 生物标志物模型。在 502 名患者中，49 名患者在感染性休克第 7 天前死亡，124 名患者在感染性休克第 7 天持续存在 MODS。新推导出的 PERSEVEREnce 模型预测死亡或第 7 天 MODS 的接收者操作员特征曲线 (AUROC) 下面积为 0.93 (0.91-0.95)，经过十倍交叉验证，AUROC 为 0.80 (0.76-0.84)。基于 IL-8、HSP70、ICAM-1、Angpt2/Tie2、Angpt2/Angpt1 和 Thrombomodulin 的简化模型表现类似。变量之间的相互作用——ICAM-1 与 IL-8 和血栓调节素与 Angpt2/Angpt1——有助于模型的预测能力。在估计单个器官功能障碍的风险时，模型性能各不相同，AUROCS 在训练和测试集中的范围分别为 0.91 到 0.97 和 0.68 到 0.89。新衍生的 PERSEVEREnce 生物标志物模型可靠地估计了感染性休克第 7 天死亡或持续器官功能障碍的风险。如果经过验证，