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Host Blood RNA Transcript and Protein Signatures for Sputum-Independent Diagnostics of Tuberculosis in Adults

To achieve the ambitious targets for tuberculosis (TB) prevention, care, and control stated by the End TB Strategy, new health care strategies, diagnostic tools are warranted. Host-derived biosignatures are explored for their TB diagnostic potential in accordance with the WHO target product profiles...

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Autores principales: Sivakumaran, Dhanasekaran, Ritz, Christian, Gjøen, John Espen, Vaz, Mario, Selvam, Sumithra, Ottenhoff, Tom H. M., Doherty, Timothy Mark, Jenum, Synne, Grewal, Harleen M. S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891042/
https://www.ncbi.nlm.nih.gov/pubmed/33613569
http://dx.doi.org/10.3389/fimmu.2020.626049
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author Sivakumaran, Dhanasekaran
Ritz, Christian
Gjøen, John Espen
Vaz, Mario
Selvam, Sumithra
Ottenhoff, Tom H. M.
Doherty, Timothy Mark
Jenum, Synne
Grewal, Harleen M. S.
author_facet Sivakumaran, Dhanasekaran
Ritz, Christian
Gjøen, John Espen
Vaz, Mario
Selvam, Sumithra
Ottenhoff, Tom H. M.
Doherty, Timothy Mark
Jenum, Synne
Grewal, Harleen M. S.
author_sort Sivakumaran, Dhanasekaran
collection PubMed
description To achieve the ambitious targets for tuberculosis (TB) prevention, care, and control stated by the End TB Strategy, new health care strategies, diagnostic tools are warranted. Host-derived biosignatures are explored for their TB diagnostic potential in accordance with the WHO target product profiles (TPPs) for point-of-care (POC) testing. We aimed to identify sputum-independent TB diagnostic signatures in newly diagnosed adult pulmonary-TB (PTB) patients recruited in the context of a prospective household contact cohort study conducted in Andhra Pradesh, India. Whole-blood mRNA samples from 158 subjects (PTB, n = 109; age-matched household controls, n = 49) were examined by dual-color Reverse-Transcriptase Multiplex Ligation-dependent Probe-Amplification (dcRT-MLPA) for the expression of 198 pre-defined genes and a Mesoscale discovery assay for the concentration of 18 cytokines/chemokines in TB-antigen stimulated QuantiFERON supernatants. To identify signatures, we applied a two-step approach; in the first step, univariate filtering was used to identify and shortlist potentially predictive biomarkers; this step may be seen as removing redundant biomarkers. In the second step, a logistic regression approach was used such that group membership (PTB vs. household controls) became the binary response in a Lasso regression model. We identified an 11-gene signature that distinguished PTB from household controls with AUCs of ≥0.98 (95% CIs: 0.94–1.00), and a 4-protein signature (IFNγ, GMCSF, IL7 and IL15) that differentiated PTB from household controls with AUCs of ≥0.87 (95% CIs: 0.75–1.00), in our discovery cohort. Subsequently, we evaluated the performance of the 11-gene signature in two external validation data sets viz, an independent cohort at the Glenfield Hospital, University Hospitals of Leicester NHS Trust, Leicester, UK (GSE107994 data set), and the Catalysis treatment response cohort (GSE89403 data set) from South Africa. The 11-gene signature validated and distinguished PTB from healthy and asymptomatic M. tuberculosis infected household controls in the GSE107994 data set, with an AUC of 0.95 (95% CI: 0.91–0.98) and 0.94 (95% CI: 0.89–0.98). More interestingly in the GSE89403 data set, the 11-gene signature distinguished PTB from household controls and patients with other lung diseases with an AUC of 0.93 (95% CI: 0.87–0.99) and 0.73 (95% CI: 0.56–0.89). These criteria meet the WHO TTP benchmarks for a non–sputum-based triage test for TB diagnosis. We suggest that further validation is required before clinical implementation of the 11-gene signature we have identified markers will be possible.
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spelling pubmed-78910422021-02-19 Host Blood RNA Transcript and Protein Signatures for Sputum-Independent Diagnostics of Tuberculosis in Adults Sivakumaran, Dhanasekaran Ritz, Christian Gjøen, John Espen Vaz, Mario Selvam, Sumithra Ottenhoff, Tom H. M. Doherty, Timothy Mark Jenum, Synne Grewal, Harleen M. S. Front Immunol Immunology To achieve the ambitious targets for tuberculosis (TB) prevention, care, and control stated by the End TB Strategy, new health care strategies, diagnostic tools are warranted. Host-derived biosignatures are explored for their TB diagnostic potential in accordance with the WHO target product profiles (TPPs) for point-of-care (POC) testing. We aimed to identify sputum-independent TB diagnostic signatures in newly diagnosed adult pulmonary-TB (PTB) patients recruited in the context of a prospective household contact cohort study conducted in Andhra Pradesh, India. Whole-blood mRNA samples from 158 subjects (PTB, n = 109; age-matched household controls, n = 49) were examined by dual-color Reverse-Transcriptase Multiplex Ligation-dependent Probe-Amplification (dcRT-MLPA) for the expression of 198 pre-defined genes and a Mesoscale discovery assay for the concentration of 18 cytokines/chemokines in TB-antigen stimulated QuantiFERON supernatants. To identify signatures, we applied a two-step approach; in the first step, univariate filtering was used to identify and shortlist potentially predictive biomarkers; this step may be seen as removing redundant biomarkers. In the second step, a logistic regression approach was used such that group membership (PTB vs. household controls) became the binary response in a Lasso regression model. We identified an 11-gene signature that distinguished PTB from household controls with AUCs of ≥0.98 (95% CIs: 0.94–1.00), and a 4-protein signature (IFNγ, GMCSF, IL7 and IL15) that differentiated PTB from household controls with AUCs of ≥0.87 (95% CIs: 0.75–1.00), in our discovery cohort. Subsequently, we evaluated the performance of the 11-gene signature in two external validation data sets viz, an independent cohort at the Glenfield Hospital, University Hospitals of Leicester NHS Trust, Leicester, UK (GSE107994 data set), and the Catalysis treatment response cohort (GSE89403 data set) from South Africa. The 11-gene signature validated and distinguished PTB from healthy and asymptomatic M. tuberculosis infected household controls in the GSE107994 data set, with an AUC of 0.95 (95% CI: 0.91–0.98) and 0.94 (95% CI: 0.89–0.98). More interestingly in the GSE89403 data set, the 11-gene signature distinguished PTB from household controls and patients with other lung diseases with an AUC of 0.93 (95% CI: 0.87–0.99) and 0.73 (95% CI: 0.56–0.89). These criteria meet the WHO TTP benchmarks for a non–sputum-based triage test for TB diagnosis. We suggest that further validation is required before clinical implementation of the 11-gene signature we have identified markers will be possible. Frontiers Media S.A. 2021-02-04 /pmc/articles/PMC7891042/ /pubmed/33613569 http://dx.doi.org/10.3389/fimmu.2020.626049 Text en Copyright © 2021 Sivakumaran, Ritz, Gjøen, Vaz, Selvam, Ottenhoff, Doherty, Jenum and Grewal http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Sivakumaran, Dhanasekaran
Ritz, Christian
Gjøen, John Espen
Vaz, Mario
Selvam, Sumithra
Ottenhoff, Tom H. M.
Doherty, Timothy Mark
Jenum, Synne
Grewal, Harleen M. S.
Host Blood RNA Transcript and Protein Signatures for Sputum-Independent Diagnostics of Tuberculosis in Adults
title Host Blood RNA Transcript and Protein Signatures for Sputum-Independent Diagnostics of Tuberculosis in Adults
title_full Host Blood RNA Transcript and Protein Signatures for Sputum-Independent Diagnostics of Tuberculosis in Adults
title_fullStr Host Blood RNA Transcript and Protein Signatures for Sputum-Independent Diagnostics of Tuberculosis in Adults
title_full_unstemmed Host Blood RNA Transcript and Protein Signatures for Sputum-Independent Diagnostics of Tuberculosis in Adults
title_short Host Blood RNA Transcript and Protein Signatures for Sputum-Independent Diagnostics of Tuberculosis in Adults
title_sort host blood rna transcript and protein signatures for sputum-independent diagnostics of tuberculosis in adults
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891042/
https://www.ncbi.nlm.nih.gov/pubmed/33613569
http://dx.doi.org/10.3389/fimmu.2020.626049
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