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

Discovery and Validation of a Six-Marker Serum Protein Signature for the Diagnosis of Active Pulmonary Tuberculosis.
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De Groote MA, Sterling DG, Hraha T, Russell T, Green LS, Wall K, Kraemer S, Ostroff R, Janjic N, Ochsner UA,


De Groote MA, Sterling DG, Hraha T, Russell T, Green LS, Wall K, Kraemer S, Ostroff R, Janjic N, Ochsner UA, (click to view)

De Groote MA, Sterling DG, Hraha T, Russell T, Green LS, Wall K, Kraemer S, Ostroff R, Janjic N, Ochsner UA,

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Journal of clinical microbiology 2017 08 09() pii 10.1128/JCM.00467-17

Abstract

New non-sputum biomarker tests for active tuberculosis (TB) diagnostics are of highest priority for global TB control. We performed in-depth proteomic analysis using the 4000-plex SOMAscan assay on 1470 serum samples from seven TB-endemic countries. 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%and 22% were sputum smear-negative. Serum protein biomarkers were identified by stability selection using L1-regularized logistic regression and by Kolmogorov-Smirnov (KS) statistics. A naïve 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 (AUC=0.94) and in a blinded verification set (AUC=0.92) to distinguish TB and non-TB. 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-change 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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