title: Diagnostic performance of a seven-marker serum protein biosignature for the diagnosis of active TB disease in African primary healthcare clinic attendees with signs and symptoms suggestive of TB.
abstract: User-friendly, rapid, inexpensive yet accurate TB diagnostic tools are urgently needed at points of care in resource-limited settings. We investigated host biomarkers detected in serum samples obtained from adults with signs and symptoms suggestive of TB at primary healthcare clinics in five African countries (Malawi, Namibia, South Africa, The Gambia and Uganda), for the diagnosis of TB disease.
  
  
  
  We prospectively enrolled individuals presenting with symptoms warranting investigation for pulmonary TB, prior to assessment for TB disease. We evaluated 22 host protein biomarkers in stored serum samples using a multiplex cytokine platform. Using a pre-established diagnostic algorithm comprising of laboratory, clinical and radiological findings, participants were classified as either definite TB, probable TB, questionable TB status or non-pulmonary TB.
  
  
  
  Of the 716 participants enrolled, 185 were definite and 29 were probable TB cases, 6 had questionable TB disease status, whereas 487 had no evidence of TB. A seven-marker biosignature of C reactive protein, transthyretin, IFN-γ, complement factor H, apolipoprotein-A1, inducible protein 10 and serum amyloid A identified on a training sample set (n=491), diagnosed TB disease in the test set (n=210) with sensitivity of 93.8% (95% CI 84.0% to 98.0%), specificity of 73.3% (95% CI 65.2% to 80.1%), and positive and negative predictive values of 60.6% (95% CI 50.3% to 70.1%) and 96.4% (95% CI 90.5% to 98.8%), respectively, regardless of HIV infection status or study site.
  
  
  
  We have identified a seven-marker host serum protein biosignature for the diagnosis of TB disease irrespective of HIV infection status or ethnicity in Africa. These results hold promise for the development of a field-friendly point-of-care screening test for pulmonary TB.
authors.affiliation: Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research and SAMRC Centre for Tuberculosis Research, Stellenbosch University, Cape Town, South Africa.
authors.forename: Novel N
authors.initials: NN
authors.lastname: Chegou
authors.affiliation: Vaccines and Immunity, Medical Research Council Unit, Fajara, The Gambia.
authors.forename: Jayne S
authors.initials: JS
authors.lastname: Sutherland
authors.affiliation: Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research and SAMRC Centre for Tuberculosis Research, Stellenbosch University, Cape Town, South Africa.
authors.forename: Stephanus
authors.initials: S
authors.lastname: Malherbe
authors.affiliation: Karonga Prevention Study, Chilumba, Malawi.
authors.forename: Amelia C
authors.initials: AC
authors.lastname: Crampin
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Paul L A M
authors.initials: PL
authors.lastname: Corstjens
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Geluk
authors.affiliation: Department of Medicine, Makerere University, Kampala, Uganda.
authors.forename: Harriet
authors.initials: H
authors.lastname: Mayanja-Kizza
authors.affiliation: Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research and SAMRC Centre for Tuberculosis Research, Stellenbosch University, Cape Town, South Africa.
authors.forename: Andre G
authors.initials: AG
authors.lastname: Loxton
authors.affiliation: Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research and SAMRC Centre for Tuberculosis Research, Stellenbosch University, Cape Town, South Africa.
authors.forename: Gian
authors.initials: G
authors.lastname: van der Spuy
authors.affiliation: Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research and SAMRC Centre for Tuberculosis Research, Stellenbosch University, Cape Town, South Africa.
authors.forename: Kim
authors.initials: K
authors.lastname: Stanley
authors.affiliation: Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research and SAMRC Centre for Tuberculosis Research, Stellenbosch University, Cape Town, South Africa.
authors.forename: Leigh A
authors.initials: LA
authors.lastname: Kotzé
authors.affiliation: Faculty of Health Sciences, School of Medicine, University of Namibia, Windhoek, Namibia.
authors.forename: Marieta
authors.initials: M
authors.lastname: van der Vyver
authors.affiliation: Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Ida
authors.initials: I
authors.lastname: Rosenkrands
authors.affiliation: Department of Statistics and Actuarial Sciences, Centre for Statistical Consultation, Stellenbosch University, Cape Town, South Africa.
authors.forename: Martin
authors.initials: M
authors.lastname: Kidd
authors.affiliation: Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research and SAMRC Centre for Tuberculosis Research, Stellenbosch University, Cape Town, South Africa.
authors.forename: Paul D
authors.initials: PD
authors.lastname: van Helden
authors.affiliation: Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Hazel M
authors.initials: HM
authors.lastname: Dockrell
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Tom H M
authors.initials: TH
authors.lastname: Ottenhoff
authors.affiliation: Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Stefan H E
authors.initials: SH
authors.lastname: Kaufmann
authors.affiliation: Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research and SAMRC Centre for Tuberculosis Research, Stellenbosch University, Cape Town, South Africa.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Walzl
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000175:diagnosis; D000328:Adult; D000349:Africa; D000465:Algorithms; D015415:Biomarkers / Q000097:blood; D001798:Blood Proteins / Q000032:analysis*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019095:Point-of-Care Systems; D011237:Predictive Value of Tests; D011320:Primary Health Care; D011446:Prospective Studies; D012680:Sensitivity and Specificity; D014397:Tuberculosis, Pulmonary / Q000175:diagnosis*
chemical_list: D015415:Biomarkers; D001798:Blood Proteins
keywords: Tuberculosis