Transcriptional Analysis for Tuberculosis in Pregnant Women From the PRegnancy Associated Changes In Tuberculosis Immunology (PRACHITi) Study

Abstract

A new tuberculosis (TB) diagnostic cartridge assay, which detects a 3-gene TB signature in whole blood, was not diagnostic in women with maternal TB disease in India (area under the curve [AUC] = 0.72). In a cohort of pregnant women, we identified a novel gene set for TB diagnosis (AUC = 0.97) and one for TB progression (AUC = 0.96).

Keywords: RNA signature; immunology; pregnancy; transcriptomics; tuberculosis.

Conflict of interest statement

Potential conflicts of interest. A. G. receives support from the Gilead Foundation, the Makhija Foundation, and the Wyncote Foundation; reports grants or contracts unrelated to this work from NIH, Unitaid, and the Centers for Disease Control and Prevention; reports participation on a data and safety monitoring board or advisory board for the NIH/NIAID Advisory Council and Indo US Science Technology Governing Board; and reports a leadership or fiduciary role with the International Maternal Pediatric and Adolescent AIDS Clinical Trial Network TB Scientific Committee and World Health Organization Multidrug-Resistant Tuberculosis Guidelines Committee. J. S. M. reports grants or contracts unrelated to this work and support for attending meetings and/or travel from the NIH, paid to institution, and the Aurum Institute. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.

Figures

Figure 1.

Biomarker identification analysis results and tuberculosis (TB) signature comparison. The dot plots from the biomarkers identified as best classifiers from cases at the time of active TB diagnosis vs controls (diagnostic model) (A) and cases before they developed active TB vs controls(predictive model) (B). C, Receiver operating characteristic (ROC) curve from each biomarker set. The TB predictive biomarkers are colored as red, the diagnostic model in blue. The shaded areas correspond to the standard error. The area under the curve (AUC) values for each curve are noted with the same colors. Boxplots show the AUC, measured by general linear modeling, for randomForest genes (bold), differentially expressed genes (bold), and publicly available TB gene expression signatures identifying the randomForest genes as the best TB classifier in postpartum (A) and pregnancy (B). We then compared the performance of diagnostic TB signatures (D), and predictive TB signatures (E) and the randomForest gene models in the conditions classification by using linear models to measure the area under the ROC curve (AUC) of each gene set and its confidence interval. The asterisked signature is being commercially used for rapid TB diagnosis. The randomForest gene sets we identified for pregnancy (predictive) and postpartum (diagnostic) outperforms all signatures in all comparisons. Abbreviation: VST, variance-stabilizing transformation.