Model-Based Relationship between the Molecular Bacterial Load Assay and Time to Positivity in Liquid Culture
Model-Based Relationship between the Molecular Bacterial Load Assay and Time to Positivity in Liquid Culture
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DOI：
10.1128/aac.00652-19
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发表时间：
2019-10-01
影响因子：
4.9
通讯作者：
Simonsson, Ulrika S. H.
中科院分区：
文献类型：
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作者：
Svensson, Robin J.;Sabiiti, Wilber;Simonsson, Ulrika S. H.
分子细菌负荷（MBL）检测是一种新的结核病生物标志物，可在4小时内提供结果。MBL和阳性时间（TTP）之间的关系尚未得到彻底研究，也不存在预测模型。我们的目的是建立一个MBL模型，并确定患者的MBL-TTP关系。该模型是根据来自马拉维、莫桑比克和坦桑尼亚的105名结核病患者的数据开发的，这些患者的痰液收集了12周，联合MBL和TTP观察结果被量化。使用分枝杆菌生长指示管（MGIT）960系统，使用分枝杆菌RNA和TTP的PCR定量MBL。治疗包括标准剂量的异烟肼、吡嗪酰胺和乙胺丁醇以及10或35 mg/kg体重的利福平。开发的MBLTTP模型包括几个相关的子模型，一个描述痰液中细菌负荷下降的组件，另一个描述液体培养物中生长的组件，以及将细菌生长转化为TIP信号的危险模型。包括污染和阴性TIP样品的其他组分。使用开发的模型进行的视觉预测检查得到了很好的描述所观察到的数据。由于污染和阴性样品，该模型预测TTP的总样品损失大于MBL。该模型检测到35 mg/kg与10 mg/kg利福平的细菌杀灭增加（P = 0.002）。总之，MBL和TIP的组合模型，描述了MBL-TIP的关系。分别使用完整的MBL-TTP模型或每个子模型。第二，该模型可用于在历史或未来试验中预测给定TTP数据的MBL的生物标志物响应，反之亦然。
The molecular bacterial load (MBL) assay is a new tuberculosis biomarker which provides results in similar to 4 hours. The relationship between MBL and timeto-positivity (TTP) has not been thoroughly studied, and predictive models do not exist. We aimed to develop a model for MBL and identify the MBL-TTP relationship in patients. The model was developed on data from 105 tuberculosis patients from Malawi, Mozambique, and Tanzania with joint MBL and TTP observations quantified from patient sputum collected for 12 weeks. MBL was quantified using PCR of mycobacterial RNA and TTP using the mycobacterial growth indicator tube (MGIT) 960 system. Treatment consisted of isoniazid, pyrazinamide, and ethambutol in standard doses together with rifampin 10 or 35 mg/kg of body weight. The developed MBLTTP model included several linked submodels, a component describing decline of bacterial load in sputum, another component describing growth in liquid culture, and a hazard model translating bacterial growth into a TIP signal. Additional components for contaminated and negative TIP samples were included. Visual predictive checks performed using the developed model gave good description of the observed data. The model predicted greater total sample loss for TTP than MBL due to contamination and negative samples. The model detected an increase in bacterial killing for 35 versus 10 mg/kg rifampin (P = 0.002). In conclusion, a combined model for MBL and TIP was developed that described the MBL-TIP relationship. The full MBL-TTP model or each submodel was used separately. Second, the model can be used to predict biomarker response for MBL given TTP data or vice versa in historical or future trials.