Dufault Suzanne M, Davies Geraint R, Svensson Elin M, Sloan Derek J, McCallum Andrew D, Patel Anu, Van Brantegem Pieter, Denti Paolo, Phillips Patrick P J
Division of Biostatistics, University of California, San Francisco, San Francisco, California, USA; UCSF Center for Tuberculosis, University of California, San Francisco, San Francisco, California, USA.
Institute of Infection and Global Health, University of Liverpool, Liverpool, UK.
Int J Antimicrob Agents. 2025 Feb;65(2):107404. doi: 10.1016/j.ijantimicag.2024.107404. Epub 2024 Dec 7.
The BACTEC Mycobacteria Growth Indicator Tube (MGIT) machine is the standard globally for detecting viable mycobacteria in patients' sputum. Samples are observed for no longer than 42 days, at which point the sample is declared 'negative' for tuberculosis (TB). This time to detection of bacterial growth, referred to as time-to-positivity (TTP), is increasingly of interest, not solely as a diagnostic tool but also as a continuous biomarker wherein change in TTP can be used for comparing the bactericidal activity of different TB treatments. However, as a continuous measure, there are oddities in the distribution of TTP values observed, particularly at higher values.
We explored whether there is evidence to suggest setting an upper limit of quantification for modeling purposes (ULOQ) lower than the diagnostic limit of detection (LOD) using data from several TB-PACTS randomized clinical trials and PanACEA MAMS-TB.
Across all trials, less than 7.1% of weekly samples returned TTP measurements between 25 and 42 days. Further, the relative absolute prediction error (%) was highest in this range. When modelling with ULOQs of 25 and 30 days, estimator precision improved for 23 of 25 regimen-level slopes compared to models using the LOD. Discrimination between regimens based on Bayesian posteriors also improved.
Although TTP measurements between 25 days and the diagnostic LOD may be important for diagnostic purposes, TTP values in this range may not contribute meaningfully to its use as a quantitative measure, particularly when assessing treatment response, and may lead to underpowered clinical trials.
BACTEC分枝杆菌生长指示管（MGIT）仪器是全球检测患者痰液中活分枝杆菌的标准仪器。样本观察时间不超过42天，届时样本被判定为肺结核（TB）“阴性”。这种检测细菌生长的时间，即阳性时间（TTP），越来越受到关注，这不仅是作为一种诊断工具，而且还是作为一种连续生物标志物，其中TTP的变化可用于比较不同结核病治疗的杀菌活性。然而，作为一种连续测量方法，观察到的TTP值分布存在异常，特别是在较高值时。
我们利用来自几项结核病加速临床试验（TB-PACTS）和泛美临床评估与监测系统结核病研究（PanACEA MAMS-TB）的数据，探讨是否有证据表明为建模目的设定的定量上限（ULOQ）低于检测诊断限（LOD）。
在所有试验中，每周样本中不到7.1%的TTP测量值在25至42天之间。此外，这个范围内的相对绝对预测误差（%）最高。当使用25天和30天的ULOQ进行建模时，与使用LOD的模型相比，25个方案水平斜率中的23个的估计精度有所提高。基于贝叶斯后验概率的方案间区分也有所改善。
虽然25天至诊断LOD之间的TTP测量值对于诊断目的可能很重要，但该范围内的TTP值作为定量测量可能没有显著意义，特别是在评估治疗反应时，并且可能导致临床试验效能不足。
