title: Blood transcriptomic diagnosis of pulmonary and extrapulmonary tuberculosis.
abstract: BACKGROUND.Novel rapid diagnostics for active tuberculosis (TB) are required to overcome the time delays and inadequate sensitivity of current microbiological tests that are critically dependent on sampling the site of disease. Multiparametric blood transcriptomic signatures of TB have been described as potential diagnostic tests. We sought to identify the best transcript candidates as host biomarkers for active TB, extend the evaluation of their specificity by comparison with other infectious diseases, and to test their performance in both pulmonary and extrapulmonary TB.METHODS.Support vector machine learning, combined with feature selection, was applied to new and previously published blood transcriptional profiles in order to identify the minimal TB‑specific transcriptional signature shared by multiple patient cohorts including pulmonary and extrapulmonary TB, and individuals with and without HIV-1 coinfection.RESULTS.We identified and validated elevated blood basic leucine zipper transcription factor 2 (BATF2) transcript levels as a single sensitive biomarker that discriminated active pulmonary and extrapulmonary TB from healthy individuals, with receiver operating characteristic (ROC) area under the curve (AUC) scores of 0.93 to 0.99 in multiple cohorts of HIV-1-negative individuals, and 0.85 in HIV-1-infected individuals. In addition, we identified and validated a potentially novel 4-gene signature comprising CD177, haptoglobin, immunoglobin J chain, and galectin 10 that discriminated active pulmonary and extrapulmonary TB from other febrile infections, giving ROC AUCs of 0.94 to 1.CONCLUSIONS.Elevated bloodBATF2transcript levels provide a sensitive biomarker that discriminates active TB from healthy individuals, and a potentially novel 4-gene transcriptional signature differentiates between active TB and other infectious diseases in individuals presenting with fever.FUNDING.MRC, Wellcome Trust, Rosetrees Trust, British Lung Foundation, NIHR.
authors.affiliation: Division of Infection and Immunity, University College London, London, United Kingdom.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Roe
authors.affiliation: Division of Infection and Immunity, University College London, London, United Kingdom.
authors.forename: Niclas
authors.initials: N
authors.lastname: Thomas
authors.affiliation: Division of Infection and Immunity, University College London, London, United Kingdom.
authors.forename: Eliza
authors.initials: E
authors.lastname: Gil
authors.affiliation: Division of Infection and Immunity, University College London, London, United Kingdom.
authors.forename: Katharine
authors.initials: K
authors.lastname: Best
authors.affiliation: Division of Infection and Immunity, University College London, London, United Kingdom.
authors.forename: Evdokia
authors.initials: E
authors.lastname: Tsaliki
authors.affiliation: Department of Microbiology, University College London Hospitals NHS Trust, London, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Morris-Jones
authors.affiliation: Division of Infection and Immunity, University College London, London, United Kingdom.
authors.forename: Sian
authors.initials: S
authors.lastname: Stafford
authors.affiliation: Division of Infection and Immunity, University College London, London, United Kingdom.
authors.forename: Nandi
authors.initials: N
authors.lastname: Simpson
authors.affiliation: Blizard Institute, Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London, United Kingdom.
authors.forename: Karolina D
authors.initials: KD
authors.lastname: Witt
authors.affiliation: Division of Infection and Immunity, University College London, London, United Kingdom.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Chain
authors.affiliation: Research Department of Infection and Population Health, University College London, London, United Kingdom.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Miller
authors.affiliation: Blizard Institute, Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London, United Kingdom.
authors.forename: Adrian
authors.initials: A
authors.lastname: Martineau
authors.affiliation: Division of Infection and Immunity, University College London, London, United Kingdom.|National Institute for Health Research University College London Hospitals Biomedical Research Centre, London, United Kingdom.
authors.forename: Mahdad
authors.initials: M
authors.lastname: Noursadeghi
mesh_terms: D000328:Adult; D019540:Area Under Curve; D050976:Basic-Leucine Zipper Transcription Factors / Q000097:blood; D015415:Biomarkers / Q000097:blood; D005260:Female; D006801:Humans; D008297:Male; D009169:Mycobacterium tuberculosis; D012372:ROC Curve; D012680:Sensitivity and Specificity; D060388:Support Vector Machine; D059467:Transcriptome; D014376:Tuberculosis / Q000097:blood / Q000175:diagnosis*; D014397:Tuberculosis, Pulmonary / Q000097:blood / Q000175:diagnosis*; D025521:Tumor Suppressor Proteins / Q000097:blood
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; C569485:Batf2 protein, human; D015415:Biomarkers; D025521:Tumor Suppressor Proteins