Evaluation of a transcriptomic signature of tuberculosis risk in combination with an interferon gamma release assay: A diagnostic test accuracy study

Humphrey Mulenga; Andrew Fiore-Gartland; Simon C. Mendelsohn; Adam Penn-Nicholson; Stanley Kimbung Mbandi; Elisa Nemes; Bhavesh Borate; Munyaradzi Musvosvi; Michèle Tameris; Gerhard Walzl; Kogieleum Naidoo; Gavin Churchyard; Thomas J. Scriba; Mark Hatherill

EClinicalMedicine (May 2022)

Evaluation of a transcriptomic signature of tuberculosis risk in combination with an interferon gamma release assay: A diagnostic test accuracy study

Humphrey Mulenga,
Andrew Fiore-Gartland,
Simon C. Mendelsohn,
Adam Penn-Nicholson,
Stanley Kimbung Mbandi,
Elisa Nemes,
Bhavesh Borate,
Munyaradzi Musvosvi,
Michèle Tameris,
Gerhard Walzl,
Kogieleum Naidoo,
Gavin Churchyard,
Thomas J. Scriba,
Mark Hatherill

Affiliations

Humphrey Mulenga: South African Tuberculosis Vaccine Initiative, Department of Pathology, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, University of Cape Town, Anzio Road, Observatory 7925, South Africa
Andrew Fiore-Gartland: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Fairview Ave. N., Seattle, WA 98109-1024, USA
Simon C. Mendelsohn: South African Tuberculosis Vaccine Initiative, Department of Pathology, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, University of Cape Town, Anzio Road, Observatory 7925, South Africa
Adam Penn-Nicholson: South African Tuberculosis Vaccine Initiative, Department of Pathology, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, University of Cape Town, Anzio Road, Observatory 7925, South Africa
Stanley Kimbung Mbandi: South African Tuberculosis Vaccine Initiative, Department of Pathology, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, University of Cape Town, Anzio Road, Observatory 7925, South Africa
Elisa Nemes: South African Tuberculosis Vaccine Initiative, Department of Pathology, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, University of Cape Town, Anzio Road, Observatory 7925, South Africa
Bhavesh Borate: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Fairview Ave. N., Seattle, WA 98109-1024, USA
Munyaradzi Musvosvi: South African Tuberculosis Vaccine Initiative, Department of Pathology, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, University of Cape Town, Anzio Road, Observatory 7925, South Africa
Michèle Tameris: South African Tuberculosis Vaccine Initiative, Department of Pathology, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, University of Cape Town, Anzio Road, Observatory 7925, South Africa
Gerhard Walzl: DST/NRF Centre of Excellence for Biomedical TB Research and SAMRC Centre for TB Research, Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Francie Van Zijl Drive, Parow 7505, South Africa
Kogieleum Naidoo: Centre for the AIDS Programme of Research in South Africa (CAPRISA), Doris Duke Medical Research Institute, University of KwaZulu-Natal, 719 Umbilo Road, Durban 4001, South Africa; MRC-CAPRISA HIV-TB Pathogenesis and Treatment Research Unit, Doris Duke Medical Research Institute, University of KwaZulu-Natal, 719 Umbilo Road, Durban 4001, South Africa
Gavin Churchyard: The Aurum Institute, 29 Queens Rd, Parktown, Johannesburg, Gauteng 2194, South Africa; School of Public Health, University of Witwatersrand, 27 St Andrews Road, Parktown, Johannesburg 2193, South Africa; Department of Medicine, Vanderbilt University, Nashville, TN, USA
Thomas J. Scriba: South African Tuberculosis Vaccine Initiative, Department of Pathology, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, University of Cape Town, Anzio Road, Observatory 7925, South Africa
Mark Hatherill: South African Tuberculosis Vaccine Initiative, Department of Pathology, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, University of Cape Town, Anzio Road, Observatory 7925, South Africa; Corresponding author.

Journal volume & issue: Vol. 47
p. 101396

Abstract

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Summary: Background: We evaluated the diagnostic and prognostic performance of a transcriptomic signature of tuberculosis (TB) risk (RISK11) and QuantiFERON-TB Gold-plus (QFTPlus) as combination biomarkers of TB risk. Methods: Healthy South Africans who were HIV-negative aged 18–60 years with baseline RISK11 and QFTPlus results were evaluated in a prospective cohort study conducted between Sept 20, 2016 and Dec 20, 2019. Prevalence and incidence-rate ratios were used to evaluate risk of TB. Positive (LR+) and negative (LR–) likelihood ratios were used to compare individual tests versus Both-Positive (RISK11+/QFTPlus+) and Either-Positive (RISK11+ or QFTPlus+) combinations. Findings: Among 2912 participants, prevalent TB in RISK11+/QFTPlus+ participants was 13·3-fold (95% CI 4·2–42·7) higher than RISK11–/QFTPlus–; 2·4–fold (95% CI 1·2–4·8) higher than RISK11+/QFTPlus–; and 4·5-fold (95% CI 2·5–8·0) higher than RISK11–/QFTPlus+ participants. Risk of incident TB in RISK11+/QFTPlus+ participants was 8·3-fold (95% CI 2·5–27·0) higher than RISK11–/QFTPlus–; 2·5-fold (95% CI 1·0–6·6) higher than RISK11+/QFTPlus–; and 2·1-fold (95% CI 1·2–3·4) higher than RISK11–/QFTPlus+ participants, respectively. Compared to QFTPlus, the Both-Positive test combination increased diagnostic LR+ from 1·3 (95% CI 1·2–1·5) to 4·7 (95% CI 3·2–7·0), and prognostic LR+ from 1·4 (95% CI 1·2–1·5) to 2·8 (95% CI 1·5–5·1), but did not improve upon RISK11 alone. Compared with RISK11, the Either-Positive test combination decreased diagnostic LR– from 0·7 (95% CI 0·6–0·9) to 0·3 (95% CI 0·2–0·6), and prognostic LR– from 0·9 (95% CI 0·8–1·0) to 0·3 (0·1–0·7), but did not improve upon QFTPlus alone. Interpretation: Combining two tests such as RISK11 and QFTPlus, with discordant individual performance characteristics does not improve overall discriminatory performance, relative to the individual tests. Funding: Bill and Melinda Gates Foundation, South African Medical Research Council.

Published in EClinicalMedicine

ISSN: 2589-5370 (Online)
Publisher: Elsevier
Country of publisher: United Kingdom
LCC subjects: Medicine: Medicine (General)
Website: https://www.thelancet.com/journals/eclinm/home

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