Blood transcriptional biomarkers for active tuberculosis among patients in the United States: A case-control study with systematic cross-classifier evaluation

Nicholas D. Walter, Mikaela A. Miller, Joshua Vasquez, Marc Weiner, Adam Chapman, Melissa Engle, Michael Higgins, Amy M. Quinones, Vanessa Rosselli, Elizabeth Canono, Christina Yoon, Adithya Cattamanchi, J. Lucian Davis, Tzu Phang, Robert S. Stearman, Gargi Datta, Benjamin J. Garcia, Charles L. Daley, Michael Strong, Katerina KechrisTasha E. Fingerlin, Randall Reves, Mark W. Geraci

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Blood transcriptional signatures are promising for tuberculosis (TB) diagnosis but have not been evaluated among U.S. patients. To be used clinically, transcriptional classifiers need reproducible accuracy in diverse populations that vary in genetic composition, disease spectrum and severity, and comorbidities. In a prospective case-control study, we identified novel transcriptional classifiers for active TB among U.S. patients and systematically compared their accuracy to classifiers from published studies. Blood samples from HIV-uninfected U.S. adults with active TB, pneumonia, or latent TB infection underwent whole-Transcriptome microarray. We used support vector machines to classify disease state based on transcriptional patterns. We externally validated our classifiers using data from sub-Saharan African cohorts and evaluated previously published transcriptional classifiers in our population. Our classifier distinguishing active TB from pneumonia had an area under the concentration-Time curve (AUC) of 96.5% (95.4% to 97.6%) among U.S. patients, but the AUC was lower (90.6% [89.6% to 91.7%]) in HIV-uninfected Sub-Saharan Africans. Previously published comparable classifiers had AUC values of 90.0% (87.7% to 92.3%) and 82.9% (80.8% to 85.1%) when tested in U.S. patients. Our classifier distinguishing active TB from latent TB had AUC values of 95.9% (95.2% to 96.6%) among U.S. patients and 95.3% (94.7% to 96.0%) among Sub-Saharan Africans. Previously published comparable classifiers had AUC values of 98.0% (97.4% to 98.7%) and 94.8% (92.9% to 96.8%) when tested in U.S. patients. Blood transcriptional classifiers accurately detected active TB among U.S. adults. The accuracy of classifiers for active TB versus that of other diseases decreased when tested in new populations with different disease controls, suggesting additional studies are required to enhance generalizability. Classifiers that distinguish active TB from latent TB are accurate and generalizable across populations and can be explored as screening assays.

Original languageEnglish (US)
Pages (from-to)274-282
Number of pages9
JournalJournal of clinical microbiology
Volume54
Issue number2
DOIs
StatePublished - Feb 2016

ASJC Scopus subject areas

  • Microbiology (medical)

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    Walter, N. D., Miller, M. A., Vasquez, J., Weiner, M., Chapman, A., Engle, M., Higgins, M., Quinones, A. M., Rosselli, V., Canono, E., Yoon, C., Cattamanchi, A., Lucian Davis, J., Phang, T., Stearman, R. S., Datta, G., Garcia, B. J., Daley, C. L., Strong, M., ... Geraci, M. W. (2016). Blood transcriptional biomarkers for active tuberculosis among patients in the United States: A case-control study with systematic cross-classifier evaluation. Journal of clinical microbiology, 54(2), 274-282. https://doi.org/10.1128/JCM.01990-15