Dataset Information

A Novel, 5-Transcript, Whole-blood Gene-expression Signature for Tuberculosis Screening Among People Living With Human Immunodeficiency Virus.

ABSTRACT: BACKGROUND:Gene-expression profiles have been reported to distinguish between patients with and without active tuberculosis (TB), but no prior study has been conducted in the context of TB screening. METHODS:We included all the patients (n = 40) with culture-confirmed TB and time-matched controls (n = 80) enrolled between July 2013 and April 2015 in a TB screening study among people living with human immunodeficiency virus (PLHIV) in Kampala, Uganda. We randomly split the patients into training (n = 80) and test (n = 40) datasets. We used the training dataset to derive candidate signatures that consisted of 1 to 5 differentially-expressed transcripts (P ? .10) and compared the performance of our candidate signatures with 4 published TB gene-expression signatures, both on the independent test dataset and in 2 external datasets. RESULTS:We identified a novel, 5-transcript signature that met the accuracy thresholds recommended for a TB screening test. On the independent test dataset, our signature had an area under the curve (AUC) of 0.87 (95% confidence interval [CI] 0.72-0.98), with sensitivity of 94% and specificity of 75%. None of the 4 published TB signatures achieved desired accuracy thresholds. Our novel signature performed well in external datasets from both high (AUC 0.81, 95% CI 0.74-0.88) and low (0.81, 95% CI 0.77-0.85) TB burden settings. CONCLUSIONS:We identified the first gene-expression signature for TB screening. Our signature has the potential to be translated into a point-of-care test to facilitate systematic TB screening among PLHIV and other high-risk populations.

SUBMITTER: Rajan JV

PROVIDER: S-EPMC6579960 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A Novel, 5-Transcript, Whole-blood Gene-expression Signature for Tuberculosis Screening Among People Living With Human Immunodeficiency Virus.

Rajan Jayant V JV Semitala Fred C FC Mehta Tejas T Seielstad Mark M Montalvo Lani L Andama Alfred A Asege Lucy L Nakaye Martha M Katende Jane J Mwebe Sandra S Kamya Moses R MR Yoon Christina C Cattamanchi Adithya A

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20190601 1

<h4>Background</h4>Gene-expression profiles have been reported to distinguish between patients with and without active tuberculosis (TB), but no prior study has been conducted in the context of TB screening.<h4>Methods</h4>We included all the patients (n = 40) with culture-confirmed TB and time-matched controls (n = 80) enrolled between July 2013 and April 2015 in a TB screening study among people living with human immunodeficiency virus (PLHIV) in Kampala, Uganda. We randomly split the patients ...[more]

PMID: 30462176

Similar Datasets

Project description:BACKGROUND:Extrapulmonary tuberculosis is an emerging public health problem among HIV positives compared to the general population. This study aimed to assess the incidence and predictors of extrapulmonary tuberculosis among people living with HIV in selected health facilities in Addis Ababa, Ethiopia, from 01 January 2013 up to 31 December 2018. METHODS:A retrospective cohort study design was employed based on data collected from 566 HIV positive individuals. Data were entered using EpiInfo version 7.1 and analyzed by SPSS version 20. The incidence rate was determined per 100 person-years. Kaplan-Meier estimates used to estimate survivor and the hazard function, whereas log-rank tests used to compare survival curves and hazard across different categories. Cox proportional hazard model was used to identify the predictors and 95%CI of the hazard ratio were computed. P-value<0.05 in the multivariable analysis was considered statistically significant. RESULTS:Five hundred sixty-six HIV positive individuals were followed for 2140.08 person-years. Among them, 72 developed extrapulmonary tuberculosis that gives an incidence rate of 3.36/100 person-years (95%CI = 2.68-4.22). The most frequent forms of extrapulmonary tuberculosis were; lymph node tuberculosis (56%, 41) followed equally by pleural tuberculosis (15%, 11) and disseminated tuberculosis (15%, 11). The majority (70.83%) of the cases occurred within the first year of follow-up. In multivariable Cox regression analysis, baseline WHO stage III/IV (AHR = 2.720, 95%CI = 1.575-4.697), baseline CD4 count<50cells/μl (AHR = 4.073, 95%CI = 2.064-8.040), baseline CD4 count 50-200 cells/μl (AHR = 2.360, 95%CI = 1.314-4.239) and baseline Hgb<10 mg/dl (AHR = 1.979, 95%CI = 1.091-3.591) were the independent risk factors. While isoniazid prophylaxis (AHR = 0.232, 95%CI = 0.095-0.565) and taking antiretroviral drugs (AHR = 0.134, 95%CI = 0.075-0.238) had a protective benefit. CONCLUSION:Extrapulmonary tuberculosis co-infection was common among HIV positive individuals, and mostly occurred in those with advanced immune suppression. The risk decreases in those taking antiretroviral therapy and took isoniazid preventive treatment. Screening of HIV positives for extrapulmonary tuberculosis throughout their follow-up would be important.

Project description:BackgroundUndiagnosed tuberculosis (TB) remains a major threat for people living with HIV (PLHIV). Multiple blood transcriptomic biomarkers have shown promise for TB diagnosis. We sought to evaluate their diagnostic accuracy and clinical utility for systematic pre-antiretroviral therapy (ART) TB screening.MethodsWe enrolled consecutive adults referred to start ART at a community health centre in Cape Town, South Africa, irrespective of symptoms. Sputa were obtained (using induction if required) for two liquid cultures. Whole-blood RNA samples underwent transcriptional profiling using a custom Nanostring gene-panel. We measured the diagnostic accuracy of seven candidate RNA biomarkers for the reference standard of Mycobacterium tuberculosis culture status, using area under the receiver-operating characteristic curve (AUROC) analysis, and sensitivity/specificity at pre-specified thresholds (two standard scores above the mean of healthy controls; Z2). Clinical utility was assessed using decision curve analysis. We compared performance to CRP (threshold ≥5mg/L), World Health Organisation (WHO) four-symptom screen (W4SS) and the WHO target product profile for TB triage tests.ResultsA total of 707 PLHIV were included, with median CD4 count 306 cells/mm3. Of 676 with available sputum culture results, 89 (13%) had culture-confirmed TB. The seven RNA biomarkers were moderately to highly correlated (Spearman rank coefficients 0.42-0.93) and discriminated TB culture-positivity with similar AUROCs (0.73-0.80), but none statistically better than CRP (AUROC 0.78; 95% CI 0.72-0.83). Diagnostic accuracy was similar across CD4 count strata, but lower among W4SS-negative (AUROCs 0.56-0.65) compared to W4SS-positive participants (AUROCs 0.75-0.84). The RNA biomarker with highest AUROC point estimate was a 4-gene signature (Suliman4; AUROC 0.80; 95% CI 0.75-0.86), with sensitivity 0.83 (0.74-0.90) and specificity 0.59 (0.55-0.63) at Z2 threshold. In decision curve analysis, Suliman4 and CRP had similar clinical utility to guide confirmatory TB testing, but both had higher net benefit than W4SS. In exploratory analyses, an approach combining CRP (≥5mg/L) and Suliman4 (≥Z2) had sensitivity of 0.80 (0.70-0.87), specificity of 0.70 (0.66-0.74) and higher net benefit than either biomarker alone.InterpretationRNA biomarkers showed better clinical utility to guide confirmatory TB testing for PLHIV prior to ART initiation than symptom-based screening, but their performance did not exceed that of CRP, and fell short of WHO recommended targets. Interferon-independent approaches may be required to improve accuracy of host-response biomarkers to support TB screening pre-ART initiation.FundingSouth African MRC, EDCTP2, NIH/NIAID, Wellcome Trust, NIHR, Royal College of Physicians London.

Dataset Information

A Novel, 5-Transcript, Whole-blood Gene-expression Signature for Tuberculosis Screening Among People Living With Human Immunodeficiency Virus.

Publications

A Novel, 5-Transcript, Whole-blood Gene-expression Signature for Tuberculosis Screening Among People Living With Human Immunodeficiency Virus.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets