Discovery and validation of a prognostic proteomic signature for tuberculosis progression: A prospective cohort study.

Authors:
Ethan G Thompson
Ethan G Thompson
The Center for Infectious Disease Research
Seattle | United States
David Sterling
David Sterling
Wake Forest University School of Medicine
United States
Stanley Kimbung Mbandi
Stanley Kimbung Mbandi
University of the Western Cape Bellville
South Africa
Michelle Fisher
Michelle Fisher
Georgia Health and Sciences University
Sara Suliman
Sara Suliman
Hospital for Sick Children Research Institute
Canada

PLoS Med 2019 Apr 16;16(4):e1002781. Epub 2019 Apr 16.

South African Tuberculosis Vaccine Initiative, Division of Immunology, Department of Pathology and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.

Background: A nonsputum blood test capable of predicting progression of healthy individuals to active tuberculosis (TB) before clinical symptoms manifest would allow targeted treatment to curb transmission. We aimed to develop a proteomic biomarker of risk of TB progression for ultimate translation into a point-of-care diagnostic.

Methods And Findings: Proteomic TB risk signatures were discovered in a longitudinal cohort of 6,363 Mycobacterium tuberculosis-infected, HIV-negative South African adolescents aged 12-18 years (68% female) who participated in the Adolescent Cohort Study (ACS) between July 6, 2005 and April 23, 2007, through either active (every 6 months) or passive follow-up over 2 years. Forty-six individuals developed microbiologically confirmed TB disease within 2 years of follow-up and were selected as progressors; 106 nonprogressors, who remained healthy, were matched to progressors. Over 3,000 human proteins were quantified in plasma with a highly multiplexed proteomic assay (SOMAscan). Three hundred sixty-one proteins of differential abundance between progressors and nonprogressors were identified. A 5-protein signature, TB Risk Model 5 (TRM5), was discovered in the ACS training set and verified by blind prediction in the ACS test set. Poor performance on samples 13-24 months before TB diagnosis motivated discovery of a second 3-protein signature, 3-protein pair-ratio (3PR) developed using an orthogonal strategy on the full ACS subcohort. Prognostic performance of both signatures was validated in an independent cohort of 1,948 HIV-negative household TB contacts from The Gambia (aged 15-60 years, 66% female), longitudinally followed up for 2 years between March 5, 2007 and October 21, 2010, sampled at baseline, month 6, and month 18. Amongst these contacts, 34 individuals progressed to microbiologically confirmed TB disease and were included as progressors, and 115 nonprogressors were included as controls. Prognostic performance of the TRM5 signature in the ACS training set was excellent within 6 months of TB diagnosis (area under the receiver operating characteristic curve [AUC] 0.96 [95% confidence interval, 0.93-0.99]) and 6-12 months (AUC 0.76 [0.65-0.87]) before TB diagnosis. TRM5 validated with an AUC of 0.66 (0.56-0.75) within 1 year of TB diagnosis in the Gambian validation cohort. The 3PR signature yielded an AUC of 0.89 (0.84-0.95) within 6 months of TB diagnosis and 0.72 (0.64-0.81) 7-12 months before TB diagnosis in the entire South African discovery cohort and validated with an AUC of 0.65 (0.55-0.75) within 1 year of TB diagnosis in the Gambian validation cohort. Signature validation may have been limited by a systematic shift in signal magnitudes generated by differences between the validation assay when compared to the discovery assay. Further validation, especially in cohorts from non-African countries, is necessary to determine how generalizable signature performance is.

Conclusions: Both proteomic TB risk signatures predicted progression to incident TB within a year of diagnosis. To our knowledge, these are the first validated prognostic proteomic signatures. Neither meet the minimum criteria as defined in the WHO Target Product Profile for a progression test. More work is required to develop such a test for practical identification of individuals for investigation of incipient, subclinical, or active TB disease for appropriate treatment and care.

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pmed.1002781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467365PMC
April 2019

Publication Analysis

Top Keywords

months diagnosis
16
year diagnosis
12
diagnosis
8
validated auc
8
south african
8
gambian validation
8
validation cohort
8
microbiologically confirmed
8
confirmed disease
8
proteomic risk
8
prognostic performance
8
risk signatures
8
cohort study
8
diagnosis gambian
8
acs training
8
prognostic proteomic
8
training set
8
signature
7
cohort
7
proteomic
6

References

(Supplied by CrossRef)
Ten challenges for TB biomarkers
THM Ottenhoff et al.
Tuberculosis (Edinb) 2012
Diagnostic performance of a seven-marker serum protein biosignature for the diagnosis of active TB disease in African primary healthcare clinic attendees with signs and symptoms suggestive of TB
NN Chegou et al.
Thorax 2016
Predictive factors for latent tuberculosis infection among adolescents in a high-burden area in South Africa
H Mahomed et al.
Int J Tuberc Lung Dis 2011

Similar Publications