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CXCL1: A new diagnostic biomarker for human tuberculosis discovered using Diversity Outbred mice

More humans have died of tuberculosis (TB) than any other infectious disease and millions still die each year. Experts advocate for blood-based, serum protein biomarkers to help diagnose TB, which afflicts millions of people in high-burden countries. However, the protein biomarker pipeline is small....

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Autores principales: Koyuncu, Deniz, Niazi, Muhammad Khalid Khan, Tavolara, Thomas, Abeijon, Claudia, Ginese, Melanie L., Liao, Yanghui, Mark, Carolyn, Specht, Aubrey, Gower, Adam C., Restrepo, Blanca I., Gatti, Daniel M., Kramnik, Igor, Gurcan, Metin, Yener, Bülent, Beamer, Gillian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423361/
https://www.ncbi.nlm.nih.gov/pubmed/34403447
http://dx.doi.org/10.1371/journal.ppat.1009773
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author Koyuncu, Deniz
Niazi, Muhammad Khalid Khan
Tavolara, Thomas
Abeijon, Claudia
Ginese, Melanie L.
Liao, Yanghui
Mark, Carolyn
Specht, Aubrey
Gower, Adam C.
Restrepo, Blanca I.
Gatti, Daniel M.
Kramnik, Igor
Gurcan, Metin
Yener, Bülent
Beamer, Gillian
author_facet Koyuncu, Deniz
Niazi, Muhammad Khalid Khan
Tavolara, Thomas
Abeijon, Claudia
Ginese, Melanie L.
Liao, Yanghui
Mark, Carolyn
Specht, Aubrey
Gower, Adam C.
Restrepo, Blanca I.
Gatti, Daniel M.
Kramnik, Igor
Gurcan, Metin
Yener, Bülent
Beamer, Gillian
author_sort Koyuncu, Deniz
collection PubMed
description More humans have died of tuberculosis (TB) than any other infectious disease and millions still die each year. Experts advocate for blood-based, serum protein biomarkers to help diagnose TB, which afflicts millions of people in high-burden countries. However, the protein biomarker pipeline is small. Here, we used the Diversity Outbred (DO) mouse population to address this gap, identifying five protein biomarker candidates. One protein biomarker, serum CXCL1, met the World Health Organization’s Targeted Product Profile for a triage test to diagnose active TB from latent M.tb infection (LTBI), non-TB lung disease, and normal sera in HIV-negative, adults from South Africa and Vietnam. To find the biomarker candidates, we quantified seven immune cytokines and four inflammatory proteins corresponding to highly expressed genes unique to progressor DO mice. Next, we applied statistical and machine learning methods to the data, i.e., 11 proteins in lungs from 453 infected and 29 non-infected mice. After searching all combinations of five algorithms and 239 protein subsets, validating, and testing the findings on independent data, two combinations accurately diagnosed progressor DO mice: Logistic Regression using MMP8; and Gradient Tree Boosting using a panel of 4: CXCL1, CXCL2, TNF, IL-10. Of those five protein biomarker candidates, two (MMP8 and CXCL1) were crucial for classifying DO mice; were above the limit of detection in most human serum samples; and had not been widely assessed for diagnostic performance in humans before. In patient sera, CXCL1 exceeded the triage diagnostic test criteria (>90% sensitivity; >70% specificity), while MMP8 did not. Using Area Under the Curve analyses, CXCL1 averaged 94.5% sensitivity and 88.8% specificity for active pulmonary TB (ATB) vs LTBI; 90.9% sensitivity and 71.4% specificity for ATB vs non-TB; and 100.0% sensitivity and 98.4% specificity for ATB vs normal sera. Our findings overall show that the DO mouse population can discover diagnostic-quality, serum protein biomarkers of human TB.
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spelling pubmed-84233612021-09-08 CXCL1: A new diagnostic biomarker for human tuberculosis discovered using Diversity Outbred mice Koyuncu, Deniz Niazi, Muhammad Khalid Khan Tavolara, Thomas Abeijon, Claudia Ginese, Melanie L. Liao, Yanghui Mark, Carolyn Specht, Aubrey Gower, Adam C. Restrepo, Blanca I. Gatti, Daniel M. Kramnik, Igor Gurcan, Metin Yener, Bülent Beamer, Gillian PLoS Pathog Research Article More humans have died of tuberculosis (TB) than any other infectious disease and millions still die each year. Experts advocate for blood-based, serum protein biomarkers to help diagnose TB, which afflicts millions of people in high-burden countries. However, the protein biomarker pipeline is small. Here, we used the Diversity Outbred (DO) mouse population to address this gap, identifying five protein biomarker candidates. One protein biomarker, serum CXCL1, met the World Health Organization’s Targeted Product Profile for a triage test to diagnose active TB from latent M.tb infection (LTBI), non-TB lung disease, and normal sera in HIV-negative, adults from South Africa and Vietnam. To find the biomarker candidates, we quantified seven immune cytokines and four inflammatory proteins corresponding to highly expressed genes unique to progressor DO mice. Next, we applied statistical and machine learning methods to the data, i.e., 11 proteins in lungs from 453 infected and 29 non-infected mice. After searching all combinations of five algorithms and 239 protein subsets, validating, and testing the findings on independent data, two combinations accurately diagnosed progressor DO mice: Logistic Regression using MMP8; and Gradient Tree Boosting using a panel of 4: CXCL1, CXCL2, TNF, IL-10. Of those five protein biomarker candidates, two (MMP8 and CXCL1) were crucial for classifying DO mice; were above the limit of detection in most human serum samples; and had not been widely assessed for diagnostic performance in humans before. In patient sera, CXCL1 exceeded the triage diagnostic test criteria (>90% sensitivity; >70% specificity), while MMP8 did not. Using Area Under the Curve analyses, CXCL1 averaged 94.5% sensitivity and 88.8% specificity for active pulmonary TB (ATB) vs LTBI; 90.9% sensitivity and 71.4% specificity for ATB vs non-TB; and 100.0% sensitivity and 98.4% specificity for ATB vs normal sera. Our findings overall show that the DO mouse population can discover diagnostic-quality, serum protein biomarkers of human TB. Public Library of Science 2021-08-17 /pmc/articles/PMC8423361/ /pubmed/34403447 http://dx.doi.org/10.1371/journal.ppat.1009773 Text en © 2021 Koyuncu et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Koyuncu, Deniz
Niazi, Muhammad Khalid Khan
Tavolara, Thomas
Abeijon, Claudia
Ginese, Melanie L.
Liao, Yanghui
Mark, Carolyn
Specht, Aubrey
Gower, Adam C.
Restrepo, Blanca I.
Gatti, Daniel M.
Kramnik, Igor
Gurcan, Metin
Yener, Bülent
Beamer, Gillian
CXCL1: A new diagnostic biomarker for human tuberculosis discovered using Diversity Outbred mice
title CXCL1: A new diagnostic biomarker for human tuberculosis discovered using Diversity Outbred mice
title_full CXCL1: A new diagnostic biomarker for human tuberculosis discovered using Diversity Outbred mice
title_fullStr CXCL1: A new diagnostic biomarker for human tuberculosis discovered using Diversity Outbred mice
title_full_unstemmed CXCL1: A new diagnostic biomarker for human tuberculosis discovered using Diversity Outbred mice
title_short CXCL1: A new diagnostic biomarker for human tuberculosis discovered using Diversity Outbred mice
title_sort cxcl1: a new diagnostic biomarker for human tuberculosis discovered using diversity outbred mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423361/
https://www.ncbi.nlm.nih.gov/pubmed/34403447
http://dx.doi.org/10.1371/journal.ppat.1009773
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