Volume 2, Issue 9, Pages (September 2015)

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Volume 2, Issue 9, Pages 1160-1168 (September 2015) Host Protein Biomarkers Identify Active Tuberculosis in HIV Uninfected and Co-infected Individuals  Jacqueline M. Achkar, Laetitia Cortes, Pascal Croteau, Corey Yanofsky, Marija Mentinova, Isabelle Rajotte, Michael Schirm, Yiyong Zhou, Ana Paula Junqueira-Kipnis, Victoria O. Kasprowicz, Michelle Larsen, René Allard, Joanna Hunter, Eustache Paramithiotis  EBioMedicine  Volume 2, Issue 9, Pages 1160-1168 (September 2015) DOI: 10.1016/j.ebiom.2015.07.039 Copyright © 2015 Terms and Conditions

Fig. 1 Study design outline. An initial set of HIV-samples was used to identify proteins differentially expressed in TB compared to controls (M. tuberculosis uninfected and latent M. tuberculosis infection). (A). The expression of a selected subset of 87 proteins was confirmed using an independent set of HIV− and HIV+ samples (B). Samples were excluded from the verification analysis if their HIV status remained unidentified (N=11) or if there were technical issues (N=13). The remaining samples were used to verify the protein expression in sample groups stratified by HIV status (C) as well as the ability of the biomarker candidates and their combinations to discriminate between TB and other respiratory diseases (D). The classification of TB versus other respiratory diseases was established via nested cross-validation using the classification phase sample data split at random into 5 test and training sets. TB=active tuberculosis, LTBI=latent M. tuberculosis infection, NI=non-infected, ORD=other respiratory diseases. EBioMedicine 2015 2, 1160-1168DOI: (10.1016/j.ebiom.2015.07.039) Copyright © 2015 Terms and Conditions

Fig. 2 Differentially expressed proteins in sera of HIV− subjects with active tuberculosis (TB) relative to controls (M. tuberculosis uninfected and latent M. tuberculosis infection). The differentially expressed proteins are indicated by dots and categorized by functional groups. Intensity values per protein were normalized and the ratios derived are displayed in logarithmic scale (y-axis). Mean and standard deviation of the expression ratio of TB versus controls are shown. EBioMedicine 2015 2, 1160-1168DOI: (10.1016/j.ebiom.2015.07.039) Copyright © 2015 Terms and Conditions

Fig. 3 Differential expression of candidate TB biomarkers in sera. Protein expression ratios expressed as fold change in subjects with active tuberculosis (TB) relative to uninfected controls (NI) and latent M. tuberculosis infection (LI), or relative to subjects with other respiratory diseases (ORD), in HIV+ or HIV− infected groups. The numerators and denominators per comparison and the color scale are indicated. The ratio range was from 0.2 to 6.6. The HIV− and HIV+ panel members are indicated by * and † respectively. EBioMedicine 2015 2, 1160-1168DOI: (10.1016/j.ebiom.2015.07.039) Copyright © 2015 Terms and Conditions

Fig. 4 Discrimination of active tuberculosis from other respiratory diseases. Area under the receiver operating curve (AUC) is shown for the biomarker panels in HIV− (A) and HIV+ (B) subjects. EBioMedicine 2015 2, 1160-1168DOI: (10.1016/j.ebiom.2015.07.039) Copyright © 2015 Terms and Conditions