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Discovery and Validation of a Six-Marker Serum Protein Signature for the Diagnosis of Active Pulmonary Tuberculosis

New non-sputum biomarker tests for active tuberculosis (TB) diagnostics are of the highest priority for global TB control. We performed in-depth proteomic analysis using the 4,000-plex SOMAscan assay on 1,470 serum samples from seven countries where TB is endemic. All samples were from patients with...

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Autores principales: De Groote, Mary A., Sterling, David G., Hraha, Thomas, Russell, Theresa M., Green, Louis S., Wall, Kirsten, Kraemer, Stephan, Ostroff, Rachel, Janjic, Nebojsa, Ochsner, Urs A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625392/
https://www.ncbi.nlm.nih.gov/pubmed/28794177
http://dx.doi.org/10.1128/JCM.00467-17
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author De Groote, Mary A.
Sterling, David G.
Hraha, Thomas
Russell, Theresa M.
Green, Louis S.
Wall, Kirsten
Kraemer, Stephan
Ostroff, Rachel
Janjic, Nebojsa
Ochsner, Urs A.
author_facet De Groote, Mary A.
Sterling, David G.
Hraha, Thomas
Russell, Theresa M.
Green, Louis S.
Wall, Kirsten
Kraemer, Stephan
Ostroff, Rachel
Janjic, Nebojsa
Ochsner, Urs A.
author_sort De Groote, Mary A.
collection PubMed
description New non-sputum biomarker tests for active tuberculosis (TB) diagnostics are of the highest priority for global TB control. We performed in-depth proteomic analysis using the 4,000-plex SOMAscan assay on 1,470 serum samples from seven countries where TB is endemic. All samples were from patients with symptoms and signs suggestive of active pulmonary TB that were systematically confirmed or ruled out for TB by culture and clinical follow-up. HIV coinfection was present in 34% of samples, and 25% were sputum smear negative. Serum protein biomarkers were identified by stability selection using L1-regularized logistic regression and by Kolmogorov-Smirnov (KS) statistics. A naive Bayes classifier using six host response markers (HR6 model), including SYWC, kallistatin, complement C9, gelsolin, testican-2, and aldolase C, performed well in a training set (area under the sensitivity-specificity curve [AUC] of 0.94) and in a blinded verification set (AUC of 0.92) to distinguish TB and non-TB samples. Differential expression was also highly significant (P < 10(−20)) for previously described TB markers, such as IP-10, LBP, FCG3B, and TSP4, and for many novel proteins not previously associated with TB. Proteins with the largest median fold changes were SAA (serum amyloid protein A), NPS-PLA2 (secreted phospholipase A2), and CA6 (carbonic anhydrase 6). Target product profiles (TPPs) for a non-sputum biomarker test to diagnose active TB for treatment initiation (TPP#1) and for a community-based triage or referral test (TPP#2) have been published by the WHO. With 90% sensitivity and 80% specificity, the HR6 model fell short of TPP#1 but reached TPP#2 performance criteria. In conclusion, we identified and validated a six-marker signature for active TB that warrants diagnostic development on a patient-near platform.
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spelling pubmed-56253922017-10-04 Discovery and Validation of a Six-Marker Serum Protein Signature for the Diagnosis of Active Pulmonary Tuberculosis De Groote, Mary A. Sterling, David G. Hraha, Thomas Russell, Theresa M. Green, Louis S. Wall, Kirsten Kraemer, Stephan Ostroff, Rachel Janjic, Nebojsa Ochsner, Urs A. J Clin Microbiol Mycobacteriology and Aerobic Actinomycetes New non-sputum biomarker tests for active tuberculosis (TB) diagnostics are of the highest priority for global TB control. We performed in-depth proteomic analysis using the 4,000-plex SOMAscan assay on 1,470 serum samples from seven countries where TB is endemic. All samples were from patients with symptoms and signs suggestive of active pulmonary TB that were systematically confirmed or ruled out for TB by culture and clinical follow-up. HIV coinfection was present in 34% of samples, and 25% were sputum smear negative. Serum protein biomarkers were identified by stability selection using L1-regularized logistic regression and by Kolmogorov-Smirnov (KS) statistics. A naive Bayes classifier using six host response markers (HR6 model), including SYWC, kallistatin, complement C9, gelsolin, testican-2, and aldolase C, performed well in a training set (area under the sensitivity-specificity curve [AUC] of 0.94) and in a blinded verification set (AUC of 0.92) to distinguish TB and non-TB samples. Differential expression was also highly significant (P < 10(−20)) for previously described TB markers, such as IP-10, LBP, FCG3B, and TSP4, and for many novel proteins not previously associated with TB. Proteins with the largest median fold changes were SAA (serum amyloid protein A), NPS-PLA2 (secreted phospholipase A2), and CA6 (carbonic anhydrase 6). Target product profiles (TPPs) for a non-sputum biomarker test to diagnose active TB for treatment initiation (TPP#1) and for a community-based triage or referral test (TPP#2) have been published by the WHO. With 90% sensitivity and 80% specificity, the HR6 model fell short of TPP#1 but reached TPP#2 performance criteria. In conclusion, we identified and validated a six-marker signature for active TB that warrants diagnostic development on a patient-near platform. American Society for Microbiology 2017-09-25 2017-10 /pmc/articles/PMC5625392/ /pubmed/28794177 http://dx.doi.org/10.1128/JCM.00467-17 Text en Copyright © 2017 De Groote et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Mycobacteriology and Aerobic Actinomycetes
De Groote, Mary A.
Sterling, David G.
Hraha, Thomas
Russell, Theresa M.
Green, Louis S.
Wall, Kirsten
Kraemer, Stephan
Ostroff, Rachel
Janjic, Nebojsa
Ochsner, Urs A.
Discovery and Validation of a Six-Marker Serum Protein Signature for the Diagnosis of Active Pulmonary Tuberculosis
title Discovery and Validation of a Six-Marker Serum Protein Signature for the Diagnosis of Active Pulmonary Tuberculosis
title_full Discovery and Validation of a Six-Marker Serum Protein Signature for the Diagnosis of Active Pulmonary Tuberculosis
title_fullStr Discovery and Validation of a Six-Marker Serum Protein Signature for the Diagnosis of Active Pulmonary Tuberculosis
title_full_unstemmed Discovery and Validation of a Six-Marker Serum Protein Signature for the Diagnosis of Active Pulmonary Tuberculosis
title_short Discovery and Validation of a Six-Marker Serum Protein Signature for the Diagnosis of Active Pulmonary Tuberculosis
title_sort discovery and validation of a six-marker serum protein signature for the diagnosis of active pulmonary tuberculosis
topic Mycobacteriology and Aerobic Actinomycetes
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625392/
https://www.ncbi.nlm.nih.gov/pubmed/28794177
http://dx.doi.org/10.1128/JCM.00467-17
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