Sepsis is a heterogeneous syndrome, and the identification of clinical subphenotypes is essential. Although organ dysfunction is a defining element of sepsis, subphenotypes of differential trajectory are not well studied. We sought to identify distinct Sequential Organ Failure Assessment (SOFA) score trajectory-based subphenotypes in sepsis. We created 72-h SOFA score trajectories in patients with sepsis from four diverse intensive care unit (ICU) cohorts. We then used dynamic time warping (DTW) to compute heterogeneous SOFA trajectory similarities and hierarchical agglomerative clustering (HAC) to identify trajectory-based subphenotypes. Patient characteristics were compared between subphenotypes and a random forest model was developed to predict subphenotype membership at 6 and 24 h after being admitted to the ICU. The model was tested on three validation cohorts. Sensitivity analyses were performed with alternative clustering methodologies. A total of 4678, 3665, 12,282, and 4804 unique sepsis patients were included in development and three validation cohorts, respectively. Four subphenotypes were identified in the development cohort: Rapidly Worsening (n = 612, 13.1%), Delayed Worsening (n = 960, 20.5%), Rapidly Improving (n = 1932, 41.3%), and Delayed Improving (n = 1174, 25.1%). Baseline characteristics, including the pattern of organ dysfunction, varied between subphenotypes. Rapidly Worsening was defined by a higher comorbidity burden, acidosis, and visceral organ dysfunction. Rapidly Improving was defined by vasopressor use without acidosis. Outcomes differed across the subphenotypes, Rapidly Worsening had the highest in-hospital mortality (28.3%, P-value < 0.001), despite a lower SOFA (mean: 4.5) at ICU admission compared to Rapidly Improving (mortality:5.5%, mean SOFA: 5.5). An overall prediction accuracy of 0.78 (95% CI, [0.77, 0.8]) was obtained at 6 h after ICU admission, which increased to 0.87 (95% CI, [0.86, 0.88]) at 24 h. Similar subphenotypes were replicated in three validation cohorts. The majority of patients with sepsis have an improving phenotype with a lower mortality risk; however, they make up over 20% of all deaths due to their larger numbers. Four novel, clinically-defined, trajectory-based sepsis subphenotypes were identified and validated. Identifying trajectory-based subphenotypes has immediate implications for the powering and predictive enrichment of clinical trials. Understanding the pathophysiology of these differential trajectories may reveal unanticipated therapeutic targets and identify more precise populations and endpoints for clinical trials.

中文翻译：

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基于器官功能障碍轨迹的脓毒症亚表型

脓毒症是一种异质性综合征，临床亚型的鉴定至关重要。尽管器官功能障碍是脓毒症的一个决定因素，但差异轨迹的亚表型尚未得到很好的研究。我们试图在脓毒症中识别不同的序贯器官衰竭评估 (SOFA) 评分轨迹亚表型。我们为来自四个不同重症监护病房 (ICU) 队列的脓毒症患者创建了 72 小时 SOFA 评分轨迹。然后，我们使用动态时间扭曲 (DTW) 来计算异质 SOFA 轨迹相似度，并使用层次凝聚聚类 (HAC) 来识别基于轨迹的子表型。比较亚表型之间的患者特征，并开发了随机森林模型来预测入住 ICU 后 6 小时和 24 小时的亚表型成员。该模型在三个验证队列中进行了测试。使用替代聚类方法进行敏感性分析。共有 4678 名、3665 名、12282 名和 4804 名独特的脓毒症患者分别被纳入开发队列和三个验证队列。在发育队列中确定了四种亚表型：快速恶化（n = 612，13.1%）、延迟恶化（n = 960，20.5%）、快速改善（n = 1932，41.3%）和延迟改善（n = 1174， 25.1%)。基线特征，包括器官功能障碍的模式，在亚表型之间有所不同。快速恶化的定义是更高的合并症负担、酸中毒和内脏器官功能障碍。快速改善定义为在没有酸中毒的情况下使用升压药。不同亚表型的结果不同，快速恶化的住院死亡率最高（28.3%，P 值 < 0.001），尽管与快速改善（死亡率：5.5%，平均 SOFA：5.5）相比，入住 ICU 时 SOFA 较低（平均：4.5）。入住 ICU 后 6 小时获得的总体预测准确度为 0.78（95% CI，[0.77，0.8]），在 24 小时增加到 0.87（95% CI，[0.86，0.88]）。在三个验证队列中复制了相似的亚表型。大多数脓毒症患者的表型有所改善，死亡风险较低；然而，由于数量较多，它们占所有死亡人数的 20% 以上。鉴定并验证了四种新的、临床定义的、基于轨迹的脓毒症亚表型。识别基于轨迹的亚表型对临床试验的动力和预测丰富具有直接影响。