Blood Transcriptional Biomarkers for Active Tuberculosis among Patients in the United States: a Case-Control Study with Systematic Cross-Classifier Evaluation.
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ABSTRACT:
SUBMITTER: Walter ND
PROVIDER: S-EPMC4733166 | biostudies-literature | 2016 Feb
REPOSITORIES: biostudies-literature
Publications
Blood Transcriptional Biomarkers for Active Tuberculosis among Patients in the United States: a Case-Control Study with Systematic Cross-Classifier Evaluation.
Walter Nicholas D ND Miller Mikaela A MA Vasquez Joshua J Weiner Marc M Chapman Adam A Engle Melissa M Higgins Michael M Quinones Amy M AM Rosselli Vanessa V Canono Elizabeth E Yoon Christina C Cattamanchi Adithya A Davis J Lucian JL Phang Tzu T Stearman Robert S RS Datta Gargi G Garcia Benjamin J BJ Daley Charles L CL Strong Michael M Kechris Katerina K Fingerlin Tasha E TE Reves Randall R Geraci Mark W MW
Journal of clinical microbiology 20151118 2
<h4>Unlabelled</h4>Blood transcriptional signatures are promising for tuberculosis (TB) diagnosis but have not been evaluated among U.S.<h4>Patients</h4>To be used clinically, transcriptional classifiers need reproducible accuracy in diverse populations that vary in genetic composition, disease spectrum and severity, and comorbidities. In a prospective case-control study, we identified novel transcriptional classifiers for active TB among U.S. patients and systematically compared their accuracy ...[more]
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Project description:In a prospective case-control study, we identified novel transcriptional classifiers for TB among US patients and systematically compared their accuracy to other classifiers in published studies.
2015-11-23 | GSE73408 | GEO
Project description:In a prospective case-control study, we identified novel transcriptional classifiers for TB among US patients and systematically compared their accuracy to other classifiers in published studies. Whole blood from US patients was collected to accurately diagnose active TB in racially and ethnically diverse populations for RNA extraction and hybridization on Affymetrix microarrays.
2015-11-23 | E-GEOD-73408 | biostudies-arrayexpress
Project description:Mycobacterium tuberculosis (M. tuberculosis) infection in humans can cause active disease or latent infection. However, the factors contributing to the maintenance of latent infection vs. disease progression are poorly understood. In this study, we used a genome-wide RNA sequencing (RNA-seq) approach to identify host factors associated with M. tuberculosis infection status and a novel gene signature that can distinguish active disease from latent infection. By RNA-seq, we characterized transcriptional differences in purified protein derivative (PPD)-stimulated peripheral blood mononuclear cells (PBMCs) among three groups: patients with active tuberculosis (ATB), individuals with latent TB infection (LTBI), and TB-uninfected controls (CON). A total of 401 differentially expressed genes enabled grouping of individuals into three clusters. A validation study by quantitative real-time PCR (qRT-PCR) confirmed the differential expression of TNFRSF10C, IFNG, PGM5, EBF3, and A2ML1 between the ATB and LTBI groups. Additional clinical validation was performed to evaluate the diagnostic performance of these five biomarkers using 130 subjects. The 3-gene signature set of TNFRSF10C, EBF3, and A2ML1 enabled correct classification of 91.5% of individuals, with a high sensitivity of 86.2% and specificity of 94.9%. Diagnostic performance of the 3-gene signature set was validated using a clinical cohort of 147 subjects with suspected ATB. The sensitivity and specificity of the 3-gene set for ATB were 82.4 and 92.4%, respectively. In conclusion, we detected distinct gene expression patterns in PBMCs stimulated by PPD depending on the status of M. tuberculosis infection. Furthermore, we identified a 3-gene signature set that could distinguish ATB from LTBI, which may facilitate rapid diagnosis and treatment for more effective disease control.
| S-EPMC6930242 | biostudies-literature
Project description:BackgroundAlthough the incidence of tuberculosis (TB) has dropped substantially, it still is a serious threat to human health. And in recent years, the emergence of resistant bacilli and inadequate disease control and prevention has led to a significant rise in the global TB epidemic. It is known that the cause of TB is Mycobacterium tuberculosis infection. But it is not clear why some infected patients are active while others are latent.MethodsWe analyzed the blood gene expression profiles of 69 latent TB patients and 54 active pulmonary TB patients from GEO (Transcript Expression Omnibus) database.ResultsBy applying minimal redundancy maximal relevance and incremental feature selection, we identified 24 signature genes which can predict the TB activation. The support vector machine predictor based on these 24 genes had a sensitivity of 0.907, specificity of 0.913, and accuracy of 0.911, respectively. Although they need to be validated in a large independent dataset, the biological analysis of these 24 genes showed great promise.ConclusionWe found that cytokine production was a key process during TB activation and genes like CYBB, TSPO, CD36, and STAT1 worth further investigation.
| S-EPMC6363485 | biostudies-literature
Project description:BackgroundBlood transcriptional signatures are candidates for non-sputum triage or confirmatory tests of tuberculosis. Prospective head-to-head comparisons of their diagnostic accuracy in real-world settings are necessary to assess their clinical use. We aimed to compare the diagnostic accuracy of candidate transcriptional signatures identified by systematic review, in a setting with a high burden of tuberculosis and HIV.MethodsWe did a prospective observational study nested within a diagnostic accuracy study of sputum Xpert MTB/RIF (Xpert) and Xpert MTB/RIF Ultra (Ultra) tests for pulmonary tuberculosis. We recruited consecutive symptomatic adults aged 18 years or older self-presenting to a tuberculosis clinic in Cape Town, South Africa. Participants provided blood for RNA sequencing, and sputum samples for liquid culture and molecular testing using Xpert and Ultra. We assessed the diagnostic accuracy of candidate blood transcriptional signatures for active tuberculosis (including those intended to distinguish active tuberculosis from other diseases) identified by systematic review, compared with culture or Xpert MTB/RIF positivity as the standard reference. In our primary analysis, patients with tuberculosis were defined as those with either a positive liquid culture or Xpert result. Patients with missing blood RNA or sputum results were excluded. Our primary objective was to benchmark the diagnostic accuracy of candidate transcriptional signatures against the WHO target product profile (TPP) for a tuberculosis triage test.FindingsBetween Feb 12, 2016, and July 18, 2017, we obtained paired sputum and RNA sequencing data from 181 participants, 54 (30%) of whom had confirmed pulmonary tuberculosis. Of 27 eligible signatures identified by systematic review, four achieved the highest diagnostic accuracy with similar area under the receiver operating characteristic curves (Sweeney3: 90·6% [95% CI 85·6-95·6]; Kaforou25: 86·9% [80·9-92·9]; Roe3: 86·9% [80·3-93·5]; and BATF2: 86·8% [80·6-93·1]), independent of age, sex, HIV status, previous tuberculosis, or sputum smear result. At test thresholds that gave 70% specificity (the minimum WHO TPP specificity for a triage test), these four signatures achieved sensitivities between 83·3% (95% CI 71·3-91·0) and 90·7% (80·1-96·0). No signature met the optimum criteria, of 95% sensitivity and 80% specificity proposed by WHO for a triage test, or the minimum criteria (of 65% sensitivity and 98% specificity) for a confirmatory test, but all four correctly identified Ultra-positive, culture-negative patients.InterpretationSelected blood transcriptional signatures met the minimum WHO benchmarks for a tuberculosis triage test but not for a confirmatory test. Further development of the signatures is warranted to investigate their possible effects on clinical and health economic outcomes as part of a triage strategy, or when used as add-on confirmatory test in conjunction with the highly sensitive Ultra test for Mycobacterium tuberculosis DNA.FundingRoyal Society Newton Advanced Fellowship, Wellcome Trust, National Institute of Health Research, and UK Medical Research Council.
| S-EPMC7113842 | biostudies-literature
Project description:This series regroups different datasets (training set, test set, validation set, longitudinal set, separated cell set) to identify and characterise a specific transcriptional signature for patients with active TB, distinct from patients with latent TB and healthy controls. The training set dataset was used to identify a whole blood transcriptional signature for active TB patients in London, across a range of ethnicity. This signature was then validated in an independent cohort of patients, also recruited in London (the test set), and then further confirmed in an additional independent cohort recruited in Cape Town, South Africa (validation set), in order to confirm that the defined signature was present in both high (Cape Town, South Africa) and medium incidence regions (London, UK). The longitudinal dataset was then used to explore how successful TB treatment modifies this transcriptional signature. The separated cell set compares the transcriptional profiles in purified cell subsets (neutrophils, monocytes and T cells) to assess which cell types are contributing to the whole blood signature, and in what way. These studies may ultimately help to improve the diagnosis of active tuberculosis which normally relies on culture of the bacilli, which can take up to 6 weeks, and sometimes the bacilli cannot be obtained from sputum thus requiring invasive techniques such as bronchoalveolar lavage (BAL). In some cases (30%) the bacill cannot be grown from sputum or BAL. Any diagnostic tool would need to be valid across a range of ethnicities, and be valid in both high and low incidence countries. A further aim was to determine whether latent TB patients have a distinct homogeneous or heterogeneous signature, since it is not currently possible to determine using present tests (Tuberculin skin test - TST - or MTb antigen responsiveness of blood cells to produce IFN-gamma - IGRA assay) whether the mycobacteria have been cleared, are still present but are controlled by an active immune response, or to predict which patients will develop active TB. Defining heterogeneity in the latent TB patients would be an important step in developing diagnostics which could detect those most at risk of developing active TB, and thus enable targeted preventive therapy. The latter situation may be determined if Latent patients have a blood transcriptional signature similar to that in Active patients. The transcriptional signature in whole blood and cell subsets from Active TB patients may also provide information as to the factors leading to immunopathogenesis, thus possibly identifying therapeutic targets. The transcriptional profile in latent TB may give information regarding protective factors controlling the infection, important for vaccine development. Finally, definition of a transcriptional signature which responds to therapy could facilitate the development of surrogate biomarkers for drug or vaccine studies. Since any active TB signature may reflect common inflammatory responses evoked during many diseases, we also performed analysis of significance, comparing transcriptional profiles from patients with TB to those from patients with other bacterial and inflammatory diseases to identify a TB specific signature. The resulting signature was then tested against patients normalized to their own controls from 7 independent datasets: TB (Training and Validation Sets), Staphylococcus infection, Group A Streptococcus infection, Still's disease, and adult and pediatric SLE. This SuperSeries is composed of the SubSeries listed below.
2010-08-11 | GSE19491 | GEO
Project description:ImportanceActive tuberculosis (TB) disease leads to substantial mortality but is preventable through screening and treatment for latent TB infection. Early mortality after TB diagnosis (≤1 year) is well described, but delayed mortality (>1 year) among patients with active TB is poorly understood.ObjectiveTo compare early and delayed mortality and years of potential life (YPL) lost among patients with active TB disease vs an age-, sex-, and year of diagnosis-matched comparison cohort without active TB disease.Design, setting, and participantsThis retrospective cohort study, conducted in the integrated health system of Kaiser Permanente Northern California, included patients with microbiologically confirmed active TB disease from January 1, 1997, to December 31, 2017, and a control cohort matched by age, sex, and year of diagnosis. Multivariable models were used to adjust for demographic and clinical characteristics. Patients with active TB disease prior to 1997 were excluded. Data were analyzed from January 1, 2019, to January 31, 2020.ExposureMicrobiologically confirmed TB disease.Main outcomes and measuresEarly (≤1 year after TB diagnosis) and delayed (>1 year after TB diagnosis) all-cause mortality.ResultsA total of 2522 patients who had active TB from 1997 to 2017 were identified, with 17 166 person-years of follow-up. The comparison cohort included 100 880 persons with 735 726 person-years of follow-up. In the active TB and comparison cohorts, similar percentages of persons were male (56.3% vs 55.6%), aged 45 to 64 years (33.7% vs 33.7%), and aged 65 years or older (24.7% vs 24.7%). Both early mortality (7.0%) and delayed mortality (16.3%) were higher among patients with active TB disease compared with those without active TB disease (1.1% and 12.0%, respectively). Patients with active TB disease had a significantly higher risk for early (adjusted hazard ratio [aHR], 7.29; 95% CI, 6.08-8.73) and delayed (aHR, 1.78; 95% CI, 1.61-1.98) mortality compared with the comparison cohort (P < .001). Active TB disease was associated with an adjusted -7.0 (95% CI, -8.4 to -5.5) YPL lost compared with the comparison cohort.Conclusions and relevanceIn this study, patients with active TB disease had significantly higher early and delayed all-cause mortality when adjusting for demographic and clinical characteristics. These findings suggest that TB prevention through screening and treatment of latent TB infection could reduce mortality and YPL lost due to active TB disease.
| S-EPMC7512053 | biostudies-literature
Project description:This series regroups different datasets (training set, test set, validation set, longitudinal set, separated cell set) to identify and characterise a specific transcriptional signature for patients with active TB, distinct from patients with latent TB and healthy controls. The training set dataset was used to identify a whole blood transcriptional signature for active TB patients in London, across a range of ethnicity. This signature was then validated in an independent cohort of patients, also recruited in London (the test set), and then further confirmed in an additional independent cohort recruited in Cape Town, South Africa (validation set), in order to confirm that the defined signature was present in both high (Cape Town, South Africa) and medium incidence regions (London, UK). The longitudinal dataset was then used to explore how successful TB treatment modifies this transcriptional signature. The separated cell set compares the transcriptional profiles in purified cell subsets (neutrophils, monocytes and T cells) to assess which cell types are contributing to the whole blood signature, and in what way. These studies may ultimately help to improve the diagnosis of active tuberculosis which normally relies on culture of the bacilli, which can take up to 6 weeks, and sometimes the bacilli cannot be obtained from sputum thus requiring invasive techniques such as bronchoalveolar lavage (BAL). In some cases (30%) the bacill cannot be grown from sputum or BAL. Any diagnostic tool would need to be valid across a range of ethnicities, and be valid in both high and low incidence countries. A further aim was to determine whether latent TB patients have a distinct homogeneous or heterogeneous signature, since it is not currently possible to determine using present tests (Tuberculin skin test - TST - or MTb antigen responsiveness of blood cells to produce IFN-gamma - IGRA assay) whether the mycobacteria have been cleared, are still present but are controlled by an active immune response, or to predict which patients will develop active TB. Defining heterogeneity in the latent TB patients would be an important step in developing diagnostics which could detect those most at risk of developing active TB, and thus enable targeted preventive therapy. The latter situation may be determined if Latent patients have a blood transcriptional signature similar to that in Active patients. The transcriptional signature in whole blood and cell subsets from Active TB patients may also provide information as to the factors leading to immunopathogenesis, thus possibly identifying therapeutic targets. The transcriptional profile in latent TB may give information regarding protective factors controlling the infection, important for vaccine development. Finally, definition of a transcriptional signature which responds to therapy could facilitate the development of surrogate biomarkers for drug or vaccine studies. Since any active TB signature may reflect common inflammatory responses evoked during many diseases, we also performed analysis of significance, comparing transcriptional profiles from patients with TB to those from patients with other bacterial and inflammatory diseases to identify a TB specific signature. The resulting signature was then tested against patients normalized to their own controls from 7 independent datasets: TB (Training and Validation Sets), Staphylococcus infection, Group A Streptococcus infection, Still's disease, and adult and pediatric SLE. This SuperSeries is composed of the following subset Series: GSE19435: Transcriptional profiles in Blood of patients with Tuberculosis - Longitudinal Study GSE19439: Blood Transcriptional Profiles in Active and Latent Tuberculosis UK (Training Set) GSE19442: Blood Transcriptional Profiles of TB in South Africa GSE19443: Blood Transcriptional Profiles of Active TB (UK Test Set Separated) GSE19444: Blood Transcriptional Profiles of Active and Latent TB (UK Test Set) GSE22098: Whole blood transcriptional profiles of patients with active tuberculosis (TB) and other inflammatory and infectious diseases Active Pulmonary TB: PTB - All patients were confirmed by isolation of Mycobacterium Tuberculosis on culture of sputum or bronchoalvelolar lavage fluid. Latent TB: LTB - All patients were screened at a tuberculosis clinic, being either new entrants to the UK from endemic countries or being household contacts of infectious cases, or in the case of the validation set recruited in South Africa, were residents of a high incidence country. All UK patients were positive by tuberculin skin test (>14mm if BCG vaccinated, >5mm if not vaccinated) and were also positive by Interferon-Gamma Release assay(IGRA); specifically Quantiferon Gold In-Tube Assay (Cellestis, Australia). The South African latent TB patients were all positive by Interferon-Gamma Release assay (IGRA); specifically Quantiferon Gold In-Tube Assay. Latent patients had no clinical, radiological or microbiological evidence of active infection and were asymptomatic. Healthy controls - these were volunteers without exposure to TB who were negative by both tuberculin skin test (<15mm if BCG vaccinated, <6mm if unvaccinated); and IGRA (as described above). Experimental variables : Patient group: Active PTB; Latent TB, Healthy controls (BCG vaccinated and unvaccinated). Ethnicity - a wide range of ethnic groups is represented. The active PTB group incorporates a range of smear positive and smear negative disease and a spectrum of disease extent/severity. Experimental methods: Whole blood was collected into Tempus tubes (Applied Biosystems, Foster City, CA, USA) and stored between -20degrees Celsius and -80 degrees Celsius before RNA extraction. For the training set cohort, and the active TB patients baseline samples in the longitudinal cohort, total RNA was isolated from whole blood using the PerfectPure RNA Blood kit (5 PRIME Inc, Gaithersburg, MD, USA). For the separated cell samples, total RNA was isolated using the Qiagen RNeasy Mini Kit. For all other cohorts Total RNA was isolated from whole blood using the MagMAX 96 well RNA isolation kit (Applied Biosystems, Foster City, CA, USA). Isolated total RNA was then globin reduced using the GLOBINclear 96-well format kit (Ambion, Austin, TX, USA) according to the manufacturer's instructions. Total and globin-reduced RNA integrity was assessed using an Agilent 2100 Bioanalyzer (Agilent, Palo Alto, CA). Biotinylated, amplified RNA targets (cRNA) were then prepared from the globin-reduced RNA using the Illumina CustomPrep RNA amplification kit (Ambion, Austin, TX, USA). Labeled cRNA was hybridized overnight to Sentrix HT12 V3 BeadChip arrays (>48,000 probes, Illumina Inc, San Diego, CA, USA), washed, blocked, stained and scanned on an Illumina BeadStation 500 following the manufacturer's protocols. Illumina's BeadStudio version 2 software was used to generate signal intensity values from the scans, substract background, and scale each microarray to the median average intensity for all samples (per-chip normalisation). This normalised data was used for all subsequent data analysis.
2010-08-11 | E-GEOD-19491 | biostudies-arrayexpress
Project description:Epidemiological studies have used various measures to characterize trihalomethane (THM) exposures, but the relationship of these indicators to exposure biomarkers remains unclear.We examined temporal and spatial variability in baseline blood THM concentrations and assessed the relationship between these concentrations and several exposure indicators (tap water concentration, water-use activities, multiroute exposure metrics).We measured water-use activity and THM concentrations in blood and residential tap water from 150 postpartum women from three U.S. locations.Blood ?THM [sum of chloroform (TCM), bromodichloromethane (BDCM), dibromo-chloromethane (DBCM), and bromoform (TBM)] concentrations varied by site and season. As expected based on variable tap water concentrations and toxicokinetic properties, the proportion of brominated species (BDCM, DBCM, and TBM) in blood varied by site (site 1, 24%; site 2, 29%; site 3, 57%) but varied less markedly than in tap water (site 1, 35%; site 2, 75%; site 3, 68%). The blood-water ?THM Spearman rank correlation coefficient was 0.36, with correlations higher for individual brominated species (BDCM, 0.62; DBCM, 0.53; TBM, 0.54) than for TCM (0.37). Noningestion water activities contributed more to the total exposure metric than did ingestion, but tap water THM concentrations were more predictive of blood THM levels than were metrics that incorporated water use.Spatial and temporal variability in THM concentrations was greater in water than in blood. We found consistent blood-water correlations across season and site for BDCM and DBCM, and multivariate regression results suggest that water THM concentrations may be an adequate surro-gate for baseline blood levels.
| S-EPMC3346785 | biostudies-other
Project description:BackgroundThere is a need to identify scalable tuberculosis screening strategies among high burden populations. The WHO has identified a non-sputum-based triage test as a development priority.MethodsWe performed a diagnostic case-control study of point-of-care C-reactive protein (CRP) and Prototype-Xpert-MTB-Host-Response (Xpert-MTB-HR) assays in the context of a mass screening program for tuberculosis in two prisons in Brazil. All incarcerated individuals irrespective of symptoms were screened by sputum Xpert MTB/RIF and sputum culture. Among consecutive, Xpert MTB/RIF or culture-confirmed cases and Xpert MTB/RIF and culture-negative controls, CRP was quantified in serum by a point-of-care assay (iChroma-II) and a 3-gene expression score was quantified from whole blood using the Xpert-MTB-HR cartridge. We evaluated receiver operating characteristic area under the curve (AUC) and assessed specificity at 90% sensitivity and sensitivity at 70% specificity, consistent with WHO target product profile (TPP) benchmarks.FindingsTwo hundred controls (no TB) and 100 culture- or Xpert MTB/RIF-positive tuberculosis cases were included. Half of tuberculosis cases and 11% of controls reported any tuberculosis symptoms. AUC for CRP was 0·79 (95% CI: 0·73-0·84) and for Xpert-MTB-HR was 0·84 (95% CI: 0·79-0·89). At 90% sensitivity, Xpert-MTB-HR had significantly higher specificity (53·0%, 95% CI: 45·0-69·0%) than CRP (28·1%, 95% CI: 20·2-41·8%) (p = 0·003), both well below the TPP benchmark of 70%. Among individuals with medium or high sputum Xpert MTB/RIF semi-quantitative load, sensitivity (at 70% specificity) of CRP (90·3%, 95% CI: 74·2-98·0) and Xpert-MTB-HR (96·8%, 95% CI: 83·3-99·9%) was higher.InterpretationFor active case finding in this high tuberculosis-burden setting, CRP and Xpert-MTB-HR did not meet TPP benchmarks for a triage test. However, Xpert-MTB-HR was highly sensitive in detecting individuals with medium or high sputum bacillary burden.FundingNational Institutes of Health (R01 AI130058 and R01 AI149620) and Brazilian National Council for Scientific and Technological Development (CNPq-404182/2019-4).
| S-EPMC8020164 | biostudies-literature