scholarly journals Integration of metabolomics and transcriptomics reveals novel biomarkers in the blood for tuberculosis diagnosis in children

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Noton K. Dutta ◽  
Jeffrey A. Tornheim ◽  
Kiyoshi F. Fukutani ◽  
Mandar Paradkar ◽  
Rafael T. Tiburcio ◽  
...  
Keyword(s):  
Treatment Response ◽  
Characteristic Curve ◽  
Lymphoid Cells ◽  
Mitochondrial Translation ◽  
Indian Children ◽  
Metabolomic Data ◽  
Pediatric Tb ◽  
Novel Biomarkers ◽  
Pediatric Tuberculosis ◽  
Plasma Metabolite

Abstract Pediatric tuberculosis (TB) remains a major global health problem. Improved pediatric diagnostics using readily available biosources are urgently needed. We used liquid chromatography-mass spectrometry to analyze plasma metabolite profiles of Indian children with active TB (n = 16) and age- and sex-matched, Mycobacterium tuberculosis-exposed but uninfected household contacts (n = 32). Metabolomic data were integrated with whole blood transcriptomic data for each participant at diagnosis and throughout treatment for drug-susceptible TB. A decision tree algorithm identified 3 metabolites that correctly identified TB status at distinct times during treatment. N-acetylneuraminate achieved an area under the receiver operating characteristic curve (AUC) of 0.66 at diagnosis. Quinolinate achieved an AUC of 0.77 after 1 month of treatment, and pyridoxate achieved an AUC of 0.87 after successful treatment completion. A set of 4 metabolites (gamma-glutamylalanine, gamma-glutamylglycine, glutamine, and pyridoxate) identified treatment response with an AUC of 0.86. Pathway enrichment analyses of these metabolites and corresponding transcriptional data correlated N-acetylneuraminate with immunoregulatory interactions between lymphoid and non-lymphoid cells, and correlated pyridoxate with p53-regulated metabolic genes and mitochondrial translation. Our findings shed new light on metabolic dysregulation in children with TB and pave the way for new diagnostic and treatment response markers in pediatric TB.

scholarly journals The Kynurenine/Tryptophan Ratio Is a Sensitive Biomarker for the Diagnosis of Pediatric Tuberculosis Among Indian Children

2022 ◽  
Vol 12 ◽  
Author(s):  
Jeffrey A. Tornheim ◽  
Mandar Paradkar ◽  
Henry Zhao ◽  
Vandana Kulkarni ◽  
Neeta Pradhan ◽  
...  
Keyword(s):  
Treatment Response ◽  
Characteristic Curve ◽  
Receiver Operator Characteristic Curve ◽  
Group Differences ◽  
Indian Children ◽  
Tb Treatment ◽  
Potential Biomarker ◽  
Pediatric Tb ◽  
Metabolome Profiling ◽  
Pediatric Tuberculosis

ObjectivesPediatric tuberculosis (TB) remains difficult to diagnose. The plasma kynurenine to tryptophan ratio (K/T ratio) is a potential biomarker for TB diagnosis and treatment response but has not been assessed in children.MethodsWe performed a targeted diagnostic accuracy analysis of four biomarkers: kynurenine abundance, tryptophan abundance, the K/T ratio, and IDO-1 gene expression. Data were obtained from transcriptome and metabolome profiling of children with confirmed tuberculosis and age- and sex-matched uninfected household contacts of pulmonary tuberculosis patients. Each biomarker was assessed as a baseline diagnostic and in response to successful TB treatment.ResultsDespite non-significant between-group differences in unbiased analysis, the K/T ratio achieved an area under the receiver operator characteristic curve (AUC) of 0.667 and 81.5% sensitivity for TB diagnosis. Kynurenine, tryptophan, and IDO-1 demonstrated diagnostic AUCs of 0.667, 0.602, and 0.463, respectively. None of these biomarkers demonstrated high AUCs for treatment response. The AUC of the K/T ratio was lower than biomarkers identified in unbiased analysis, but improved sensitivity over existing commercial assays for pediatric TB diagnosis.ConclusionsPlasma kynurenine and the K/T ratio may be useful biomarkers for pediatric TB. Ongoing studies in geographically diverse populations will determine optimal use of these biomarkers worldwide.

scholarly journals Quantitative Assessment of the Echogenicity of a Breast Tumor Predicts the Response to Neoadjuvant Chemotherapy

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3546
Author(s):  
Katarzyna Sylwia Dobruch-Sobczak ◽  
Hanna Piotrzkowska-Wróblewska ◽  
Piotr Karwat ◽  
Ziemowit Klimonda ◽  
Ewa Markiewicz-Grodzicka ◽  
...  
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Treatment Response ◽  
Roc Analysis ◽  
Operating Characteristic ◽  
Characteristic Curve ◽  
Quantitative Measure ◽  
Malignant Cell ◽  
Breast Cancer Patients ◽  
The Third ◽  
Leibler Divergence

The aim of the study was to improve monitoring the treatment response in breast cancer patients undergoing neoadjuvant chemotherapy (NAC). The IRB approved this prospective study. Ultrasound examinations were performed prior to treatment and 7 days after four consecutive NAC cycles. Residual malignant cell (RMC) measurement at surgery was the standard of reference. Alteration in B-mode ultrasound (tumor echogenicity and volume) and the Kullback-Leibler divergence (kld), as a quantitative measure of amplitude difference, were used. Correlations of these parameters with RMC were assessed and Receiver Operating Characteristic curve (ROC) analysis was performed. Thirty-nine patients (mean age 57 y.) with 50 tumors were included. There was a significant correlation between RMC and changes in quantitative parameters (KLD) after the second, third and fourth course of NAC, and alteration in echogenicity after the third and fourth course. Multivariate analysis of the echogenicity and KLD after the third NAC course revealed a sensitivity of 91%, specificity of 92%, PPV = 77%, NPV = 97%, accuracy = 91%, and AUC of 0.92 for non-responding tumors (RMC ≥ 70%). In conclusion, monitoring the echogenicity and KLD parameters made it possible to accurately predict the treatment response from the second course of NAC.

Developing National Genotype-Independent Indicators for Recent Mycobacterium Tuberculosis Transmission Using Pediatric Cases—United States, 2011-2017

2021 ◽  
pp. 003335492098521
Author(s):  
Alexia V. Harrist ◽  
Clinton J. McDaniel ◽  
Jonathan M. Wortham ◽  
Sandy P. Althomsons
Keyword(s):  
United States ◽  
Mycobacterium Tuberculosis ◽  
Statistical Model ◽  
Moving Average ◽  
The United States ◽  
Tuberculosis Transmission ◽  
Average Proportion ◽  
Pediatric Tb ◽  
Case Rate ◽  
Pediatric Tuberculosis

Introduction Pediatric tuberculosis (TB) cases are sentinel events for Mycobacterium tuberculosis transmission in communities because children, by definition, must have been infected relatively recently. However, these events are not consistently identified by genotype-dependent surveillance alerting methods because many pediatric TB cases are not culture-positive, a prerequisite for genotyping. Methods We developed 3 potential indicators of ongoing TB transmission based on identifying counties in the United States with relatively high pediatric (aged <15 years) TB incidence: (1) a case proportion indicator: an above-average proportion of pediatric TB cases among all TB cases; (2) a case rate indicator: an above-average pediatric TB case rate; and (3) a statistical model indicator: a statistical model based on a significant increase in pediatric TB cases from the previous 8-quarter moving average. Results Of the 249 US counties reporting ≥2 pediatric TB cases during 2009-2017, 240 and 249 counties were identified by the case proportion and case rate indicators, respectively. The statistical model indicator identified 40 counties with a significant increase in the number of pediatric TB cases. We compared results from the 3 indicators with an independently generated list of 91 likely transmission events involving ≥2 pediatric cases (ie, known TB outbreaks or case clusters with reported epidemiologic links). All counties with likely transmission events involving multiple pediatric cases were identified by ≥1 indicator; 23 were identified by all 3 indicators. Practice Implications This retrospective analysis demonstrates the feasibility of using routine TB surveillance data to identify counties where ongoing TB transmission might be occurring, even in the absence of available genotyping data.

scholarly journals Breath can discriminate tuberculosis from other lower respiratory illness in children

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Carly A. Bobak ◽  
Lili Kang ◽  
Lesley Workman ◽  
Lindy Bateman ◽  
Mohammad S. Khan ◽  
...  
Keyword(s):  
Machine Learning ◽  
Lower Respiratory Tract ◽  
Cross Validation ◽  
Pediatric Patients ◽  
Respiratory Illness ◽  
Health Crisis ◽  
Machine Learning Model ◽  
Childhood Tb ◽  
Pediatric Tb ◽  
Pediatric Tuberculosis

AbstractPediatric tuberculosis (TB) remains a global health crisis. Despite progress, pediatric patients remain difficult to diagnose, with approximately half of all childhood TB patients lacking bacterial confirmation. In this pilot study (n = 31), we identify a 4-compound breathprint and subsequent machine learning model that accurately classifies children with confirmed TB (n = 10) from children with another lower respiratory tract infection (LRTI) (n = 10) with a sensitivity of 80% and specificity of 100% observed across cross validation folds. Importantly, we demonstrate that the breathprint identified an additional nine of eleven patients who had unconfirmed clinical TB and whose symptoms improved while treated for TB. While more work is necessary to validate the utility of using patient breath to diagnose pediatric TB, it shows promise as a triage instrument or paired as part of an aggregate diagnostic scheme.

scholarly journals Uncovering reasons for treatment initiation delays among children with TB in Lima, Peru

2020 ◽  
Vol 24 (12) ◽  
pp. 1254-1260
Author(s):  
J. Coit ◽  
M. Wong ◽  
J. T. Galea ◽  
M. Mendoza ◽  
H. Marin ◽  
...  
Keyword(s):  
Treatment Initiation ◽  
Complex Interventions ◽  
Diagnostic Tools ◽  
Diagnostic Study ◽  
Burden Of Care ◽  
Structured Interviews ◽  
Tb Treatment ◽  
Pediatric Tb ◽  
Field Workers ◽  
Pediatric Tuberculosis

BACKGROUND: Timely diagnosis and treatment of pediatric tuberculosis (TB) is critical to reducing mortality but remains challenging in the absence of adequate diagnostic tools. Even once a TB diagnosis is made, delays in treatment initiation are common, but for reasons that are not well understood.METHODS: To examine reasons for delay post-diagnosis, we conducted semi-structured interviews with Ministry of Health (MoH) physicians and field workers affiliated with a pediatric TB diagnostic study, and caregivers of children aged 0–14 years who were diagnosed with pulmonary TB in Lima, Peru. Interviews were analyzed using systematic comparative and descriptive content analysis.RESULTS: We interviewed five physicians, five field workers and 26 caregivers with children who initiated TB treatment < 7 days after diagnosis (n = 15) or who experienced a delay of ≥7 days (n = 11). Median time in delay from diagnosis to treatment initiation was 26 days (range 7–117). Reasons for delay included: health systems challenges (administrative hurdles, medication stock, clinic hours), burden of care on families and caregiver perceptions of disease severity.CONCLUSION: Reasons for delay in treatment initiation are complex. Interventions to streamline administrative processes and tools to identify and support families at risk for delays in treatment initiation are urgently needed.

scholarly journals Discovery and Validation of a Three-Cytokine Plasma Signature as a Biomarker for Diagnosis of Pediatric Tuberculosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Nathella Pavan Kumar ◽  
Syed Hissar ◽  
Kannan Thiruvengadam ◽  
Velayuthum V. Banurekha ◽  
N. Suresh ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Validation Cohort ◽  
Diagnostic Study ◽  
Operating Characteristics ◽  
Discovery Cohort ◽  
Roc Curve Analysis ◽  
Immune Biomarkers ◽  
Cytokine Plasma ◽  
Pediatric Tb ◽  
Pediatric Tuberculosis

Pediatric TB poses challenge in diagnosis due to the paucibacillary nature of the disease. We conducted a prospective diagnostic study to identify immune biomarkers of pediatric TB and controls (discovery cohort) and obtained a separate “validation” cohort of confirmed cases of pediatric TB and controls. Multiplex ELISA was performed to examine the plasma levels of cytokines. Discovery and validation cohorts revealed that baseline plasma levels of IFNγ, TNFα, IL-2, and IL-17A were significantly higher in active TB (confirmed TB and unconfirmed TB) in comparison to unlikely TB children. Receiver operating characteristics (ROC) curve analysis revealed that IFNγ, IL-2, TNFα, and IL-17A (in the discovery cohort) and TNFα and IL-17A (in the validation cohort) could act as biomarkers distinguishing confirmed or unconfirmed TB from unlikely TB with the sensitivity and specificity of more than 90%. In the discovery cohort, cytokines levels were significantly diminished following anti-tuberculosis treatment. In both the cohorts, combiROC models offered 100% sensitivity and 98% to 100% specificity for a three-cytokine signature of TNFα, IL-2, and IL-17A, which can distinguish confirmed or unconfirmed TB children from unlikely TB. Thus, a baseline cytokine signature of TNFα, IL-2, and IL-17A could serve as an accurate biomarker for the diagnosis of pediatric tuberculosis.

scholarly journals Urine TWEAK level as a biomarker for early response to treatment in active lupus nephritis: a prospective multicentre study

2019 ◽  
Vol 6 (1) ◽  
pp. e000298 ◽  
Author(s):  
Thitima Benjachat Suttichet ◽  
Wonngarm Kittanamongkolchai ◽  
Chutipha Phromjeen ◽  
Sirirat Anutrakulchai ◽  
Thanachai Panaput ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Treatment Response ◽  
Induction Therapy ◽  
Characteristic Curve ◽  
Predictive Performance ◽  
Complete Response ◽  
Early Response ◽  
Response To Treatment ◽  
Urine Protein ◽  
Spot Urine

BackgroundTNF-like weak inducer of apoptosis (TWEAK) is a proinflammatory molecule that plays a key role in active inflammation of lupus nephritis (LN). Urine TWEAK (uTWEAK) levels were found to be associated with renal disease activity among patients with LN. Here, we determined whether serial measurements of uTWEAK during induction therapy could predict treatment response or not.MethodsSpot urine samples were collected from patients with biopsy-proven active LN at time of flare, and 3 and 6 months after flare to assess the uTWEAK levels. All patients received standard immunosuppressive therapy and treatment response was evaluated at 6 months. The performance of uTWEAK as a predictor for treatment response was compared with clinically used biomarkers for patients with LN.ResultsAmong 110 patients with LN, there were 29% complete responders (CR), 34% partial responders (PR) and 37% non-responders (NR). On average, uTWEAK level was consistently low in CR, trended down by 3 months in PR and persistently elevated in NR. uTWEAK levels at month 3 were able to predict complete response at month 6 (OR adjusted for age, sex and creatinine=0.34 [95% CI 0.15 to 0.80], the area under the receiver operating characteristic curve [ROC-AUC]=0.68, p=0.02). The optimal threshold for uTWEAK level at month 3 was 0.46 pg/mgCr, discriminating complete response with 70% sensitivity and 63% specificity. Combining uTWEAK and urine protein at month 3 improved predictive performance for complete response at 6 months (ROC-AUC 0.83, p<0.001).ConclusionsIn addition to urine protein, uTWEAK level at 3 months after flare can improve the accuracy in predicting complete response at 6 months of induction therapy.

Immunobiology of Pediatric Tuberculosis: Lessons Learned and Implications for an Improved TB-Vaccine

2017 ◽  
Vol 13 (02) ◽  
pp. 113-121 ◽  
Author(s):  
Mardi Boer ◽  
Deborah Lewinsohn ◽  
Christina Lancioni
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
Mycobacterial Infection ◽  
Lessons Learned ◽  
Bacillus Calmette Guerin ◽  
Partial Protection ◽  
Young Infants ◽  
Pediatric Tb ◽  
Pediatric Tuberculosis ◽  
Disseminated Disease

AbstractChildren, especially neonates and young infants, are uniquely vulnerable to tuberculosis (TB) and frequently present with primary progressive pulmonary or disseminated disease. There is an urgent need to understand the unique immunobiology of Mycobacterium tuberculosis (Mtb) in young infants and to identify protective infant immune responses. The existing vaccine against TB, Mycobacterium bovis bacillus Calmette–Guérin (M. bovis BCG), provides a partial protection against TB disease and disseminated forms of TB in infants; however, it is unknown how this partial protection is mediated. To end pediatric TB morbidity and mortality, a fully efficacious next-generation TB-vaccine is needed. Here, we focus on our current understanding of TB immunobiology as it pertains to young infants, and we evaluate what BCG-vaccination, as well as recently trialed novel TB-vaccines, has taught us about the immunobiology of mycobacterial infection in this population.

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