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Discovery and validation of a prognostic proteomic signature for tuberculosis progression : A prospective cohort study
- Source :
- PLoS Medicine, Vol 16, Iss 4, p e1002781 (2019), PLOS MEDICINE, 16(4):e1002781. PUBLIC LIBRARY SCIENCE, PLoS Medicine, PLoS medicine, vol 16, iss 4, PLoS Medicine, 16(4). Public Library of Science
- Publication Year :
- 2019
-
Abstract
- 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.
- Subjects :
- Male
Proteomics
Proteome
Tuberculosis/blood
030204 cardiovascular system & hematology
Medical and Health Sciences
Biomarkers/analysis
Cohort Studies
0302 clinical medicine
030212 general & internal medicine
Longitudinal Studies
Prospective Studies
Prospective cohort study
Child
Non-U.S. Gov't
Subclinical infection
screening and diagnosis
medicine.diagnostic_test
ACS and GC6–74 cohort study groups
Research Support, Non-U.S. Gov't
General Medicine
Prognosis
Detection
Infectious Diseases
Point-of-Care Testing
Cohort
Disease Progression
Biomarker (medicine)
HIV/AIDS
Medicine
Diagnostic Tests, Routine/methods
Female
Infection
Cohort study
4.2 Evaluation of markers and technologies
medicine.medical_specialty
Tuberculosis
Adolescent
Research Support
N.I.H
03 medical and health sciences
Rare Diseases
Research Support, N.I.H., Extramural
Tuberculosis diagnosis
Diagnostic Tests
Clinical Research
Internal medicine
General & Internal Medicine
medicine
Proteome/analysis
Journal Article
Blood test
Humans
Routine
Validation Studies
business.industry
Prevention
Extramural
medicine.disease
4.1 Discovery and preclinical testing of markers and technologies
Good Health and Well Being
Routine/methods
business
Biomarkers
Subjects
Details
- Language :
- English
- ISSN :
- 15491277
- Volume :
- 16
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- PLoS Medicine
- Accession number :
- edsair.doi.dedup.....95ba40d9ed20dd15b659c038e99adbbe