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Robust Bayesian nonlinear mixed‐effects modeling of time to positivity in tuberculosis trials
Author(s) -
Burger Divan Aristo,
Schall Robert,
Chen DingGeng
Publication year - 2018
Publication title -
pharmaceutical statistics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.421
H-Index - 38
eISSN - 1539-1612
pISSN - 1539-1604
DOI - 10.1002/pst.1877
Subject(s) - outlier , bayesian probability , robustness (evolution) , statistics , robust statistics , econometrics , linear regression , robust regression , regression , bayesian inference , linear model , identification (biology) , computer science , mathematics , medicine , biology , biochemistry , gene , botany
Early phase 2 tuberculosis (TB) trials are conducted to characterize the early bactericidal activity (EBA) of anti‐TB drugs. The EBA of anti‐TB drugs has conventionally been calculated as the rate of decline in colony forming unit (CFU) count during the first 14 days of treatment. The measurement of CFU count, however, is expensive and prone to contamination. Alternatively to CFU count, time to positivity (TTP), which is a potential biomarker for long‐term efficacy of anti‐TB drugs, can be used to characterize EBA. The current Bayesian nonlinear mixed‐effects (NLME) regression model for TTP data, however, lacks robustness to gross outliers that often are present in the data. The conventional way of handling such outliers involves their identification by visual inspection and subsequent exclusion from the analysis. However, this process can be questioned because of its subjective nature. For this reason, we fitted robust versions of the Bayesian nonlinear mixed‐effects regression model to a wide range of TTP datasets. The performance of the explored models was assessed through model comparison statistics and a simulation study. We conclude that fitting a robust model to TTP data obviates the need for explicit identification and subsequent “deletion” of outliers but ensures that gross outliers exert no undue influence on model fits. We recommend that the current practice of fitting conventional normal theory models be abandoned in favor of fitting robust models to TTP data.