The effect of host factors on discriminatory performance of a transcriptomic signature of tuberculosis risk
Humphrey Mulenga,
Andrew Fiore-Gartland,
Simon C. Mendelsohn,
Adam Penn-Nicholson,
Stanley Kimbung Mbandi,
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, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, 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, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, University of Cape Town, Anzio Road, Observatory, 7925, South Africa
Adam Penn-Nicholson
South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, University of Cape Town, Anzio Road, Observatory, 7925, South Africa
Stanley Kimbung Mbandi
South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, 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, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, University of Cape Town, Anzio Road, Observatory, 7925, South Africa
Michèle Tameris
South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, 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 Dr, Parow, 7505, South Africa
Kogieleum Naidoo
Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, 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, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, University of Cape Town, Anzio Road, Observatory, 7925, South Africa
Mark Hatherill
South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, University of Cape Town, Anzio Road, Observatory, 7925, South Africa; Corresponding author.
Summary: Background: We aimed to understand host factors that affect discriminatory performance of a transcriptomic signature of tuberculosis risk (RISK11). Methods: HIV-negative adults aged 18–60 years were evaluated in a prospective study of RISK11 and surveilled for tuberculosis through 15 months. Generalised linear models and receiver-operating characteristic (ROC) regression were used to estimate effect of host factors on RISK11 score (%marginal effect) and on discriminatory performance for tuberculosis disease (area under the curve, AUC), respectively. Findings: Among 2923 participants including 74 prevalent and 56 incident tuberculosis cases, percentage marginal effects on RISK11 score were increased among those with prevalent tuberculosis (+18·90%, 95%CI 12·66−25·13), night sweats (+14·65%, 95%CI 5·39−23·91), incident tuberculosis (+7·29%, 95%CI 1·46−13·11), flu-like symptoms (+5·13%, 95%CI 1·58−8·68), and smoking history (+2·41%, 95%CI 0·89−3·93) than those without; and reduced in males (−6·68%, 95%CI −8·31−5·04) and with every unit increase in BMI (−0·13%, −95%CI −0·25−0·01). Adjustment for host factors affecting controls did not change RISK11 discriminatory performance. Cough was associated with 72·55% higher RISK11 score in prevalent tuberculosis cases. Stratification by cough improved diagnostic performance from AUC = 0·74 (95%CI 0·67−0·82) overall, to 0·97 (95%CI 0·90−1·00, p < 0·001) in cough-positive participants. Combining host factors with RISK11 improved prognostic performance, compared to RISK11 alone, (AUC = 0·76, 95%CI 0·69−0·83 versus 0·56, 95%CI 0·46−0·68, p < 0·001) over a 15-month predictive horizon. Interpretation: Several host factors affected RISK11 score, but only adjustment for cough affected diagnostic performance. Combining host factors with RISK11 should be considered to improve prognostic performance. Funding: Bill and Melinda Gates Foundation, South African Medical Research Council.
