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Multivariate time-series analysis of biomarkers from a dengue cohort offers new approaches for diagnosis and prognosis.

登革热队列生物标志物的多变量时间序列分析为诊断和预后提供了新的方法。

  • 影响因子:4.33
  • DOI:10.1371/journal.pntd.0008199
  • 作者列表:"Vasey B","Shankar AH","Herrera BB","Becerra A","Xhaja K","Echenagucia M","Machado SR","Caicedo D","Miller J","Amedeo P","Naumova EN","Bosch I","Norma Blumenfeld deBosch.
  • 发表时间:2020-06-16
Abstract

:Dengue is a major public health problem worldwide with distinct clinical manifestations: an acute presentation (dengue fever, DF) similar to other febrile illnesses (OFI) and a more severe, life-threatening form (severe dengue, SD). Due to nonspecific clinical presentation during the early phase of dengue infection, differentiating DF from OFI has remained a challenge, and current methods to determine severity of dengue remain poor early predictors. We present a prospective clinical cohort study conducted in Caracas, Venezuela from 2001-2005, designed to determine whether clinical and hematological parameters could distinguish DF from OFI, and identify early prognostic biomarkers of SD. From 204 enrolled suspected dengue patients, there were 111 confirmed dengue cases. Piecewise mixed effects regression and nonparametric statistics were used to analyze longitudinal records. Decreased serum albumin and fibrinogen along with increased D-dimer, thrombin-antithrombin complex, activated partial thromboplastin time and thrombin time were prognostic of SD on the day of defervescence. In the febrile phase, the day-to-day rates of change in serum albumin and fibrinogen concentration, along with platelet counts, were significantly decreased in dengue patients compared to OFI, while the day-to-day rates of change of lymphocytes (%) and thrombin time were increased. In dengue patients, the absolute lymphocytes to neutrophils ratio showed specific temporal increase, enabling classification of dengue patients entering the critical phase with an area under the ROC curve of 0.79. Secondary dengue patients had elongation of Thrombin time compared to primary cases while the D-dimer formation (fibrinolysis marker) remained always lower for secondary compared to primary cases. Based on partial analysis of 31 viral complete genomes, a high frequency of C-to-T transitions located at the third codon position was observed, suggesting deamination events with five major hot spots of amino acid polymorphic sites outside in non-structural proteins. No association of severe outcome was statistically significant for any of the five major polymorphic sites found. This study offers an improved understanding of dengue hemostasis and a novel way of approaching dengue diagnosis and disease prognosis using piecewise mixed effect regression modeling. It also suggests that a better discrimination of the day of disease can improve the diagnostic and prognostic classification power of clinical variables using ROC curve analysis. The piecewise mixed effect regression model corroborated key early clinical determinants of disease, and offers a time-series approach for future vaccine and pathogenesis clinical studies.

摘要

: 登革热是世界范围内的主要公共卫生问题,具有独特的临床表现: 类似于其他发热性疾病 (OFI) 的急性表现 (登革热,DF) 和更严重的危及生命的形式 (严重登革热,SD)。由于登革热感染早期的非特异性临床表现,区分DF和OFI仍然是一个挑战,目前确定登革热严重程度的方法仍然是不良的早期预测因子。我们提出了2001-2005在委内瑞拉加拉加斯进行的一项前瞻性临床队列研究,旨在确定临床和血液学参数是否可以区分DF和OFI,并确定SD的早期预后生物标志物。在纳入的204例疑似登革热患者中,有111例确诊登革热病例。采用分段混合效应回归和非参数统计分析纵向记录。血清白蛋白和纤维蛋白原降低以及D-二聚体、凝血酶-抗凝血酶复合物、活化部分凝血活酶时间和凝血酶时间升高是SD退热当天的预后。在发热期,与OFI相比,登革热患者血清白蛋白和纤维蛋白原浓度的每日变化率以及血小板计数显著降低,而淋巴细胞 (%) 和凝血酶时间的每日变化率增加。在登革热患者中,绝对淋巴细胞与嗜中性粒细胞的比率显示特定的时间增加,使得能够对进入危险期的登革热患者进行分类,ROC曲线下面积为0.79。与原发性病例相比,继发性登革热患者的凝血酶时间延长,而与原发性病例相比,继发性登革热患者的D-二聚体形成 (纤维蛋白溶解标志物) 始终保持较低。基于对31个病毒完整基因组的部分分析,观察到位于第三密码子位置的高频率的C-to-T转换,表明在非结构蛋白中具有5个氨基酸多态性位点外部的主要热点的脱氨基事件。对于发现的五个主要多态性位点中的任何一个,没有严重结果的关联在统计学上是显著的。本研究提供了对登革热止血的改进理解,以及使用分段混合效应回归建模接近登革热诊断和疾病预后的新方法。这也表明,更好地区分疾病日可以使用ROC曲线分析提高临床变量的诊断和预后分类能力。分段混合效应回归模型证实了疾病的关键早期临床决定因素,并为未来的疫苗和发病机制临床研究提供了时间序列方法。

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临床化学检测方向

临床化学检测,用于诊断或治疗疾病的实验室检测,常用的检查物有:血液、尿液、组织和体液等。

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