title: Blood Transcriptional Biomarkers for Active Tuberculosis among Patients in the United States: a Case-Control Study with Systematic Cross-Classifier Evaluation.
abstract: Blood transcriptional signatures are promising for tuberculosis (TB) diagnosis but have not been evaluated among U.S.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
authors.affiliation: Pulmonary Section, Veterans Administration Medical Center, Denver, Colorado, USA Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Aurora, Colorado, USA Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado, USA nicholas.walter@ucdenver.edu.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Walter
authors.affiliation: Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Mikaela A
authors.initials: MA
authors.lastname: Miller
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, California, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Vasquez
authors.affiliation: Department of Medicine, Veterans Administration Medical Center, San Antonio, Texas, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Weiner
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Chapman
authors.affiliation: Department of Medicine, Veterans Administration Medical Center, San Antonio, Texas, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Engle
authors.affiliation: Denver Metro Tuberculosis Control Program, Denver, Colorado, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Higgins
authors.affiliation: Denver Health Medical Center, Denver, Colorado, USA.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Quinones
authors.affiliation: Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Rosselli
authors.affiliation: Clinical Translational Research Center, National Jewish Health, Denver, Colorado, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Canono
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, California, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Yoon
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, California, USA.
authors.forename: Adithya
authors.initials: A
authors.lastname: Cattamanchi
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, California, USA.
authors.forename: J Lucian
authors.initials: JL
authors.lastname: Davis
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Tzu
authors.initials: T
authors.lastname: Phang
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Stearman
authors.affiliation: Center for Genes, Environment, and Health, National Jewish Health, Denver, Colorado, USA.
authors.forename: Gargi
authors.initials: G
authors.lastname: Datta
authors.affiliation: Center for Genes, Environment, and Health, National Jewish Health, Denver, Colorado, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Garcia
authors.affiliation: Division of Mycobacterial and Respiratory Infections, National Jewish Health, Denver, Colorado, USA.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Daley
authors.affiliation: Center for Genes, Environment, and Health, National Jewish Health, Denver, Colorado, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Strong
authors.affiliation: Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Katerina
authors.initials: K
authors.lastname: Kechris
authors.affiliation: Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Tasha E
authors.initials: TE
authors.lastname: Fingerlin
authors.affiliation: Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado, USA Denver Metro Tuberculosis Control Program, Denver, Colorado, USA.
authors.forename: Randall
authors.initials: R
authors.lastname: Reves
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Geraci
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D055985:Latent Tuberculosis; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000502:physiology; D011014:Pneumonia / Q000097:blood / Q000175:diagnosis / Q000235:genetics; D012372:ROC Curve; D059467:Transcriptome; D014376:Tuberculosis / Q000097:blood / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D014481:United States / Q000453:epidemiology / Q000208:ethnology; D055815:Young Adult
chemical_list: D015415:Biomarkers