Rationale: Paediatric severe asthma is a heterogeneous disease suggesting that there may be discrete underlying clinical phenotypes. Objective: To generate and validate unbiased paediatric clusters in U-BIOPRED. Methods: Cross-sectional... more
Rationale: Paediatric severe asthma is a heterogeneous disease suggesting that there may be discrete underlying clinical phenotypes. Objective: To generate and validate unbiased paediatric clusters in U-BIOPRED. Methods: Cross-sectional analysis of baseline data from the European U-BIOPRED study. Demography, medical history, medication, environmental risk factors, asthma control and quality of life data were collected. External validation utilised a Dutch community paediatric-asthma cohort (PACMAN). Clinical variables were first condensed by factor analysis, followed by subsampled (10000x, proportion: 90%) partition-around-medoid clustering and stability testing by consensus distributions and Calinski & Harabasz index. Finally Classification and Regression Tree Analysis (CART) was applied to generate a prediction model. Results: 250 patients (147 male, 7.9 ±4.8 yrs) with a complete data set of 34 clinical variables were included generating 7 stable clusters (figure) with unique clinical characteristics. Clustering of the PACMAN cohort using the same variables and application of CART-model delivered 3 phenotypes, in agreement with the U-BIOPRED less severe phenotypes (P2,P3,P6). Conclusion: Unsupervised analysis based on clinical parameters revealed 7 stable clusters of paediatric asthma. Part of these clusters could be replicated in an external cohort, suggesting broad pathophysiological and clinical relevance.
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Introduction: Asthma is heterogeneous disease consisting of multiple sub-phenotypes that are poorly defined Aim: To investigate the utility of the urinary metabolome to identify sub-phenotypes of severe asthma via molecular phenotyping... more
Introduction: Asthma is heterogeneous disease consisting of multiple sub-phenotypes that are poorly defined Aim: To investigate the utility of the urinary metabolome to identify sub-phenotypes of severe asthma via molecular phenotyping Methods: Spot urine was collected from healthy controls (HC, n=108), mild-to-moderate asthmatics (MMA, n=87), severe asthmatics (SA); including both non-smokers (SAns, n=310) and smokers (SAs, n=108) from the U-BIOPRED cohort (Shaw et al, Eur Respir J. 2015; 46:1308). Metabolomics data were acquired using liquid chromatography coupled to mass spectrometry. Data were analysed using Principal Components–Canonical Variate Analysis (PC-CVA), topological data analysis (TDA), and hierarchical clustering. Results: 90 metabolites were conclusively identified, of which 44 were significantly altered with asthma (FDR Conclusions: SA evidence an altered urinary metabolic profile relative to HC. These shifts are associated with tryptophan metabolism, which may represent a useful strategy for sub-phenotyping asthma.
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BACKGROUND Exacerbation-prone asthma is a feature of severe disease. However, the basis for its persistency remains unclear. OBJECTIVES To determine the clinical and transcriptomic features of frequent exacerbators (FEs) and persistent... more
BACKGROUND Exacerbation-prone asthma is a feature of severe disease. However, the basis for its persistency remains unclear. OBJECTIVES To determine the clinical and transcriptomic features of frequent exacerbators (FEs) and persistent FEs (PFEs) in the U-BIOPRED cohort. METHODS We compared features of FE (≥2 exacerbations in past year) to infrequent exacerbators (IE, <2 exacerbations) and of PFE with repeat ≥2 exacerbations during the following year to persistent IE (PIE). Transcriptomic data in blood, bronchial and nasal epithelial brushings, bronchial biopsies and sputum cells were analysed by gene set variation analysis for 103 gene signatures. RESULTS Of 317 patients, 62.4% had FE, of whom 63.6% had PFE, while 37.6% had IE, of whom 61.3% had PIE. Using multivariate analysis, FE was associated with short-acting beta-agonist use, sinusitis and daily oral corticosteroid use, while PFE was associated with eczema, short-acting beta-agonist use and asthma control index. CEA cell adhesion molecule 5 (CEACAM5) was the only differentially expressed transcript in bronchial biopsies between PE and IE. There were no differentially expressed genes in the other four compartments. There were higher expression scores for type 2, T-helper type-17 and type 1 pathway signatures together with those associated with viral infections in bronchial biopsies from FE compared to IE, while there were higher expression scores of type 2, type 1 and steroid insensitivity pathway signatures in bronchial biopsies of PFE compared to PIE. CONCLUSION The FE group and its PFE subgroup are associated with poor asthma control while expressing higher type 1 and type 2 activation pathways compared to IE and PIE, respectively.
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Asthma and chronic obstructive pulmonary disease (COPD) have overlapping clinical features and share pathobiological mechanisms but are often considered distinct disorders. Prospective, observational studies across asthma, COPD and... more
Asthma and chronic obstructive pulmonary disease (COPD) have overlapping clinical features and share pathobiological mechanisms but are often considered distinct disorders. Prospective, observational studies across asthma, COPD and asthma–COPD overlap are limited. NOVELTY is a global, prospective observational 3-year study enrolling ∼12 000 patients ≥12 years of age from primary and specialist clinical practices in 19 countries (ClinicalTrials.gov identifier: NCT02760329).NOVELTY's primary objectives are to describe patient characteristics, treatment patterns and disease burden over time, and to identify phenotypes and molecular endotypes associated with differential outcomes over time in patients with a diagnosis/suspected diagnosis of asthma and/or COPD. NOVELTY aims to recruit real-world patients, unlike clinical studies with restrictive inclusion/exclusion criteria.Data collected at yearly intervals include clinical assessments, spirometry, biospecimens, patient-reported out...
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Background: We have previously reported altered gene expression in adults with asthma compared to healthy controls from the U-BIOPRED study (Bigler, 2016). Altered transcripts may define dysregulated biological pathways and identify novel... more
Background: We have previously reported altered gene expression in adults with asthma compared to healthy controls from the U-BIOPRED study (Bigler, 2016). Altered transcripts may define dysregulated biological pathways and identify novel therapeutic targets. We hypothesised that similar dysregulation would be seen in children with asthma. Aim: To compare blood transcriptomic profiles of children and adults with asthma. Methods: Affymetrix blood transcriptomic profiles of severe asthmatic adult non-smokers, n=152, were compared to mild moderate asthmatics, n=50 (Shaw, 2015; Fleming, 2015). Profiles of school-aged children with severe asthma, n=75, were compared to mild moderate asthmatics, n=37, and in the preschool age group severe wheeze, n=62, was compared to mild moderate wheeze, n=42. Differentially expressed genes (DEG) were identified as probe sets with maximum median group intensity >log2 5, with a significant (raw P≤0.01) change ≥ 20%. Overlapping genes were determined and pathway analysis performed. Results: We found 1887 DEG comparing severe and mild moderate asthmatic adults. Only 28 DEG were found between the severe wheeze and mild pre-school age children, with a larger signature (569 DEG) in the school aged children. 480 genes were specific to school-aged children and 1801 specific to adults, with 89 DEG in common between the adults and school-aged children. Conclusions: Preschool age children were poorly defined in terms of blood transcriptomics by the clinical definitions used. While the school-aged children showed some DEG overlap with the adults, they were distinct in many DEG and pathways indicating that childhood and adult asthma may be mechanistically different.
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Research Interests: Biology and Genetic Data
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Objective: Recurrent exacerbations are a major cause of morbidity and health care expenditure in patients with severe asthma and there are a lack of effective preventive treatments. We determined the phenotypic profile of the recurrent... more
Objective: Recurrent exacerbations are a major cause of morbidity and health care expenditure in patients with severe asthma and there are a lack of effective preventive treatments. We determined the phenotypic profile of the recurrent exacerbators in the U-BIOPRED cohort. Methods: We compared clinical and inflammatory markers in patients who had experienced et al . Thorax 2011; 66: 910-7). Results: 248 patients were IE and 261 were FE. There were more severe asthmatics in the FE group (98.47% vs 66.13%, P 2 , P FE had a lower % predicted FEV 1 (65.8 vs 74.3%, P -3 /µl, P Conclusions: Patients with FE as compared to IE have more severe features of asthma with more co-morbidities, but were indistinguishable by the investigated inflammatory biomarkers. 9Omics9evaluation may yield more predictive and explanatory biomarkers.
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The HLA-DRB1 locus within the major histocompatibility complex (MHC) at 6p21.3 has been identified as a susceptibility gene for rheumatoid arthritis (RA); however, there is increasing evidence of additional susceptibility genes in the MHC... more
The HLA-DRB1 locus within the major histocompatibility complex (MHC) at 6p21.3 has been identified as a susceptibility gene for rheumatoid arthritis (RA); however, there is increasing evidence of additional susceptibility genes in the MHC region. The aim of this study was to estimate their number and location. A case-control study was performed involving 977 control subjects and 855 RA patients. The HLA-DRB1 locus was genotyped together with 2,360 single-nucleotide polymorphisms in the MHC region. Logistic regression was used to detect DRB1-independent effects. After adjusting for the effect of HLA-DRB1, 18 markers in 14 genes were strongly associated with RA (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;10(-4)). Multivariate logistic regression analysis of these markers and DRB1 led to a model containing DRB1 plus the following 3 markers: rs4678, a nonsynonymous change in the VARS2L locus, approximately 1.7 Mb telomeric of DRB1; rs2442728, upstream of HLA-B, approximately 1.2 Mb telomeric of DRB1; and rs17499655, located in the 5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-untranslated region of DQA2, only 0.1 Mb centromeric of DRB1. In-depth investigation of the DQA2 association, however, suggested that it arose through cryptic linkage disequilibrium with an allele of DRB1. Two non-shared epitope alleles were also strongly associated with RA (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;10(-4)): *0301 with anti- cyclic citrullinated peptide-negative RA and *0701 independently of autoantibody status. These results confirm the polygenic contribution of the MHC to RA and implicate 2 additional non-DRB1 susceptibility loci. The role of the HLA-DQ locus in RA has been a subject of controversy, but in our data, it appears to be spurious.
Research Interests: Genetics, Immunology, Biology, Adolescent, Humans, and 15 moreFemale, Male, Arthritis, Clinical Sciences, Aged, Genotype, Adult, Major histocompatibility complex, Linkage Disequilibrium, Genetic Association, Allele, Logistic Models, Case Control Studies, Human leukocyte antigen, and Genetic predisposition to disease
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BackgroundAn objective of the Severe Heterogeneous Asthma Registry, Patient-centered (SHARP) is to produce real-world evidence on a pan-European scale by linking nonstandardised, patient-level registry data. Mepolizumab has shown clinical... more
BackgroundAn objective of the Severe Heterogeneous Asthma Registry, Patient-centered (SHARP) is to produce real-world evidence on a pan-European scale by linking nonstandardised, patient-level registry data. Mepolizumab has shown clinical efficacy in randomised controlled trials and prospective real-world studies and could therefore serve as a proof of principle for this novel approach. The aim of the present study was to harmonise data from 10 national severe asthma registries and characterise patients receiving mepolizumab, assess its effectiveness on annual exacerbations and maintenance oral glucocorticoid (OCS) use, and evaluate treatment patterns.MethodsIn this observational cohort study, registry data (5871 patients) were extracted for harmonisation. Where harmonisation was possible, patients who initiated mepolizumab between 1 January 2016 and 31 December 2021 were examined. Changes of a 12-month (range 11–18 months) period in frequent (two or more) exacerbations, maintenance...
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IntroductionWe sought to explore biomarkers of coronary atherosclerosis in an unbiased fashion.MethodsWe analyzed 665 patients (mean ± SD age, 56 ± 11 years; 47% male) from the GLOBAL clinical study (NCT01738828). Cases were defined by... more
IntroductionWe sought to explore biomarkers of coronary atherosclerosis in an unbiased fashion.MethodsWe analyzed 665 patients (mean ± SD age, 56 ± 11 years; 47% male) from the GLOBAL clinical study (NCT01738828). Cases were defined by the presence of any discernable atherosclerotic plaque based on comprehensive cardiac computed tomography (CT). De novo Bayesian networks built out of 37,000 molecular measurements and 99 conventional biomarkers per patient examined the potential causality of specific biomarkers.ResultsMost highly ranked biomarkers by gradient boosting were interleukin-6, symmetric dimethylarginine, LDL-triglycerides [LDL-TG], apolipoprotein B48, palmitoleic acid, small dense LDL, alkaline phosphatase, and asymmetric dimethylarginine. In Bayesian analysis, LDL-TG was directly linked to atherosclerosis in over 95% of the ensembles. Genetic variants in the genomic region encoding hepatic lipase (LIPC) were associated with LIPC gene expression, LDL-TG levels and with ath...
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To identify new genes involved in the cellular uptake of low-density lipoprotein (LDL), we applied a novel whole genome CRISPR/Cas9 knockout-screen on HepG2 cell lines. We identifiedTAGLN(transgelin), an actin-binding protein, as a new... more
To identify new genes involved in the cellular uptake of low-density lipoprotein (LDL), we applied a novel whole genome CRISPR/Cas9 knockout-screen on HepG2 cell lines. We identifiedTAGLN(transgelin), an actin-binding protein, as a new gene involved in LDL endocytosis.In silicovalidation demonstrated that genetically predicted differences in expression ofTAGLNin human populations were associated with plasma lipids (triglycerides, total cholesterol, HDL, and LDL cholesterol) in the Global Lipids Genetics Consortium and lipid-related phenotypes in the UK Biobank. Decreased cellular LDL uptake observed inTAGLN-knockout cells due to decreased LDL receptor internalization, led to alterations in cellular cholesterol content and compensatory changes in cholesterol biosynthesis. Transgelin was also shown to be involved in the actin-dependent phase of clathrin-mediated endocytosis of other cargo besides LDL. The identification of novel genes involved in LDL uptake may improve the diagnosis o...
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Research Interests: Respiratory Medicine, Gastroenterology, Risk, Asthma, Macrophages, and 13 moreMedicine, Internal Medicine, Symptoms, Metaanalysis, Clinical Sciences, Prevalence, Respiratory System, Science Technology, Phenotypes, Sputum, Inhibitors, Life Sciences & Biomedicine, and Cardiovascular medicine and haematology
Background: Asthma is now recognized as a heterogeneous collection of distinct phenotypes. We aimed to uncover potential asthma phenotypes through clustering of clinical variables in the pan-European U-BIOPRED cohort. Methods: Clinical... more
Background: Asthma is now recognized as a heterogeneous collection of distinct phenotypes. We aimed to uncover potential asthma phenotypes through clustering of clinical variables in the pan-European U-BIOPRED cohort. Methods: Clinical data from subjects classified as severe (n=209) or non-severe (n=51) asthmatics [Bel et al. Thorax 2011] were analyzed through hierarchical clustering, k-means or partitioning around medoids. Quality of the results was assessed by bootstrapping analysis, also known as consensus clustering [Monti et al.Machine Learning 2003]. Results: Using a reduced set of 16 clinical variables, stable preliminary results were obtained, indicative of potentially new asthma phenotypes. K-means analysis of the 260 mild to severe asthma subjects identified 4 stable clusters (Table), defined mainly by baseline lung function, bronchodilator response and asthma control. View this table: Table: U-BIOPRED clusters with the most discriminating variables Conclusion: This preliminary analysis shows that clinical variables from the U-BIOPRED cohort can be used to derive phenotypic asthma clusters that are similar but not identical to previously published ones. The significance and stability of these clusters are being benchmarked through topology data analysis and will be further examined in an unrelated asthma cohort, ADEPT. Funded by the Innovative Medicines Initiative (U-BIOPRED n°115010; eTRIKS n°115446).
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Research Interests: Genetics, Biology, Adolescent, Medicine, Biological Sciences, and 15 moreHumans, Female, Bone Density, Pedigree, Aged, Middle Aged, Human Genome, Adult, Bone Mineral Density, Quantitative Trait Loci, Reproducibility of Results, Cohort Studies, lumbar vertebrae, Medical and Health Sciences, and Positional Cloning
BackgroundStudies of asthma and chronic obstructive pulmonary disease (COPD) typically focus on these diagnoses separately, limiting understanding of disease mechanisms and treatment options. NOVELTY is a global, 3-year, prospective... more
BackgroundStudies of asthma and chronic obstructive pulmonary disease (COPD) typically focus on these diagnoses separately, limiting understanding of disease mechanisms and treatment options. NOVELTY is a global, 3-year, prospective observational study of patients with asthma and/or COPD from real-world clinical practice. We investigated heterogeneity and overlap by diagnosis and severity in this cohort.MethodsPatients with physician-assigned asthma, COPD or both (asthma+COPD) were enrolled, and stratified by diagnosis and severity. Baseline characteristics were reported descriptively by physician-assigned diagnosis and/or severity. Factors associated with physician-assessed severity were evaluated using ordinal logistic regression analysis.ResultsOf 11 243 patients, 5940 (52.8%) had physician-assigned asthma, 1396 (12.4%) had asthma+COPD and 3907 (34.8%) had COPD; almost half were from primary care. Symptoms, health-related quality of life and spirometry showed substantial heteroge...
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In a multicentre, genome‐wide association study to identify host genetic factors associated with treatment response in adult chronic hepatitis B patients, genotype data were obtained by microarray analysis from 1669 patients who received... more
In a multicentre, genome‐wide association study to identify host genetic factors associated with treatment response in adult chronic hepatitis B patients, genotype data were obtained by microarray analysis from 1669 patients who received peginterferon alfa‐2a for ≥ 24 weeks with/without a nucleos(t)ide analog. Treatment response was assessed at least 24 weeks post‐treatment, using serological and/or virological endpoints. Thirty‐six single‐marker analyses and a gene‐by‐gene analysis were conducted. No single nucleotide polymorphisms (SNPs) achieved genome‐wide significance (P < 5 × 10−8) in single‐marker analyses, but suggestive associations (P < 1 × 10−5) were identified for 116 SNPs. In gene‐by‐gene analyses, one gene, FCER1A (rs7549785), reached genome‐wide significance (P = 2.65 × 10−8) in East Asian patients for hepatitis B surface antigen (HBsAg) clearance, with a moderate effect size (odds ratio = 4.74). Eleven of 44 carriers (25%) of the A allele at rs7549785 achieved ...
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KULeuven. ...
Research Interests: European and Bevacizumab
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Background: Determinates of how physicians assign severity in asthma or COPD are poorly understood. The NOVEL observational longiTudinal studY NOVELTY (NCT02760329) is a global, prospective, 3-year observational study of patients with a... more
Background: Determinates of how physicians assign severity in asthma or COPD are poorly understood. The NOVEL observational longiTudinal studY NOVELTY (NCT02760329) is a global, prospective, 3-year observational study of patients with a physician-assigned diagnosis or suspected diagnosis of asthma, asthma+COPD or COPD. Objective: To identify factors associated with physician-assigned severity of either asthma or COPD in the NOVELTY population. Methods: Ordinal regression analysis was used to identify factors associated with higher physician-assigned severity (severe vs mild or moderate; moderate vs mild) at baseline in patients with asthma (n=4,361) or COPD (n=2,931). Results: Factors associated with higher levels of physician-assigned severity are shown in the figure. Clinical features including exacerbation history in the past year, lower post-bronchodilator FEV1 % predicted, or FEV1/FVC ratio, reversibility and higher mMRC dyspnoea score were associated with greater severity for ...
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Longitudinal Replication Of Severe Asthma Exhaled Breath Phenotypes By The U-Biopred Electronic Nose Platform
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Rationale: Severe asthma (SA)cohorts now exist worldwide. Comparing them will enable validation of initial findings from bio-clinical phenotyping of the cohorts. Aims: The aim of the study was to compare SA from Brazil (ProAR cohort)and... more
Rationale: Severe asthma (SA)cohorts now exist worldwide. Comparing them will enable validation of initial findings from bio-clinical phenotyping of the cohorts. Aims: The aim of the study was to compare SA from Brazil (ProAR cohort)and from Europe(U-BIOPRED cohort) Methods: The U-BIOPRED adult SA cohort was collected from 11 European countries.ProAR cohort is comprised of adults with previously untreated SA followed up for several years in one reference centre in Brazil.Data collection was harmonized when possible. In ProAR there was a subgroup of subjects with a typical history of asthma but no spirometric reversibility whereas in U-BIOPRED, those with no reversibility were required to fulfil other criteria eg.hyperresponsiveness to methacholine. Results: Similarities and differences between U-BIOPRED and ProAR cohorts of SA. Figure 1 Summary: These two cohorts, which markedly differ in their environment and ethnicity, have striking similarities on their mean age and FEV1.Age of onset was higher in U-BIOPRED and the proportion of females was greater in ProAR. The use of oral corticosteroids daily was frequent in U-BIOPRED, and still they had more exacerbations and higher ACQ scores. Regular use of oral corticosteroids was not observed in ProAR, after several years of tapering down. Comparisons between these two cohorts, however diverse they are, will provide the basis of global, external validation of SA phenotypes.
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Oxidative stress is believed to be a major driver of inflammation in smoking asthmatics. The U-BIOPRED project recruited a cohort of Severe Asthma smokers/ex-smokers (SAs/ex) and non-smokers (SAn) with extensive clinical and biomarker... more
Oxidative stress is believed to be a major driver of inflammation in smoking asthmatics. The U-BIOPRED project recruited a cohort of Severe Asthma smokers/ex-smokers (SAs/ex) and non-smokers (SAn) with extensive clinical and biomarker information enabling characterization of these subjects. We investigated oxidative stress in severe asthma subjects by analysing urinary 8-iso-PGF2α and the mRNA-expression of the main pro-oxidant (NOX2; NOSs) and anti-oxidant (SODs; CAT; GPX1) enzymes in the airways of SAs/ex and SAn. All the severe asthma U-BIOPRED subjects were further divided into current smokers with severe asthma (CSA), ex-smokers with severe asthma (ESA) and non-smokers with severe asthma (NSA) to deepen the effect of active smoking. Clinical data, urine and sputum were obtained from severe asthma subjects. A bronchoscopy to obtain bronchial biopsy and brushing was performed in a subset of subjects. The main clinical data were analysed for each subset of subjects (urine-8-iso-PG...
Research Interests: Gastroenterology, Asthma, Lung Inflammation, Medicine, Multidisciplinary, and 15 morePathophysiology, Internal Medicine, Nitric oxide, Mechanisms, Urine, Cohort, Superoxide Dismutase, PLoS one, Biomarker, Redox Regulation, Science Technology, Sputum, Multidisciplinary Sciences, Creatinine, and Cigarette Smoke
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Introduction In order to gain new insights into the biology of severe asthma, correlation analysis was performed between clinical and transcriptome data obtained from biopsies and bronchial brushings in the U-BIOPRED cohorts. Objective... more
Introduction In order to gain new insights into the biology of severe asthma, correlation analysis was performed between clinical and transcriptome data obtained from biopsies and bronchial brushings in the U-BIOPRED cohorts. Objective Discovering transcriptomic fingerprints associated with clinically relevant traits of severe asthma. Methods Gene expression data obtained from bronchial biopsies and brushing samples from severe asthma subjects and normal healthy volunteers (52 vs 41 and 60 vs 46 samples respectively) were compared using the R package WGCNA (Langfelder & Horvath, BMC Bioinformatics, 2008; 9, 559) and correlated to the clinical data. Groups of genes (modules) were determined by topological overlap matrix analysis. Results Significant correlations were found between specific modules and severe asthma clinical traits in both biopsies (see table) and brushings. Interestingly, 214 genes (module 1) were correlated to the number of exacerbations in the previous year. In addition, 19 significant correlations were identified between gene modules and clinical traits from analysis of the brushing transcriptome. Conclusions A cutting-edge bioinformatics methodology was adapted for the analysis of severe asthma transcriptomes. Several gene modules were found to be correlated with specific clinical traits and will be presented. Funded by the Innovative Medicines Initiative (U-BIOPRED: IMI n°115010; eTRIKS: IMI n°115446).
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Rationale: Smoking results in deteriorated clinical and inflammatory outcomes in severe asthma [Thomson et al; JACI 2013]. We aimed to compare clinical, inflammatory and histological characteristics between smoking and non-smoking severe... more
Rationale: Smoking results in deteriorated clinical and inflammatory outcomes in severe asthma [Thomson et al; JACI 2013]. We aimed to compare clinical, inflammatory and histological characteristics between smoking and non-smoking severe asthma patients. Methods: This was a cross-sectional analysis of the U-BIOPRED adult severe asthma cohort. Clinical, sputum and endobronchial biopsy (immunohistochemistry) data were collected. Group comparisons were undertaken between smokers, ex-smokers and non-smokers and between (ex-)smokers and non-smokers with one-way ANOVA, independent T-test, Mann-Whitney U and Chi-square analyses. Results: Current smokers had significantly lower post-salbutamol FEV1/FVC %predicted (mean±SD; 75.8±13.2%) than ex-smokers and non-smokers (84.6±15.1 and 84.7±16.2; p=0.014 ). There was a significantly higher number of mast cells within the airway smooth muscle layer in (ex-)smokers compared with non-smokers (median(interquartile range); 18.4(9.6-35.8)cells/mm2 versus 10.3(3.0-14.2); p=0.044 ), in contrast to the mast cells in the epithelium and submucosa ( p=0.113 and p=0.787 ). The lamina reticularis was thicker in (ex-)smokers compared with non-smokers (9.7±2.0µm versus 8.5±1.4; p=0.006) and thicker in current smokers compared with ex-smokers and non-smokers (10.4±2.8µm versus 9.4±1.5 versus 8.6±1.4; p=0.010 ). Conclusion: Severe asthma patients who smoke have lower post-bronchodilator lung function than ex-smokers and non-smokers. Notably, smokers and ex-smokers also exhibit a greater number of mast cells within the airway smooth muscle layer and a thicker lamina reticularis suggesting more prominent airway remodeling by smoking in severe asthma.
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Rationale: Children with asthma or pre-school wheeze represent a heterogeneous group, characterized by a variety of underlying pathophysiological molecular mechanisms. Recent 9omics9 technologies provide composite molecular samples in... more
Rationale: Children with asthma or pre-school wheeze represent a heterogeneous group, characterized by a variety of underlying pathophysiological molecular mechanisms. Recent 9omics9 technologies provide composite molecular samples in inflammatory airway diseases [Wheelock ERJ 2013]. This includes breathomics, non-invasive metabolomics in exhaled air. Aim: To reveal phenotypes by unbiased cluster analysis based on metabolomic fingerprints from exhaled breath by electronic nose (eNose) in children with asthma or pre-school wheeze. Methods: This was a cross-sectional analysis from a subset of the paediatric U-BIOPRED cohort. Exhaled volatile organic compounds trapped on adsorption tubes were analyzed by an centralized eNose platform [Brinkman ERS 2012 A4307]. Ward clustering based on Similarity Profile Analysis [Clarke JEMBE 2008] was performed on eNose platform data, followed by ANOVA and chi-square tests. Results: 106 children were included (age (IQR)7.6 (4.0-13.0)yrs, 62% male, skin prick test (SPT) positive 54%). Five clusters were delineated that differed significantly regarding age, asthma control, asthma related quality of life, SPT. Conclusion: In this preliminary analysis, unbiased fingerprinting by eNose provides clinical clusters of children with asthma or pre-school wheeze. This suggests that metabolomics in exhaled air is suitable for phenotyping of airways disease in childhood.
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Rationale: U-BIOPRED aims to sub-phenotype SA through the life course of the disease, using an innovative systems biology approach Methods: Children with SA and SPSW (defined in Thorax 2011;66:910) and mild-moderate controls were... more
Rationale: U-BIOPRED aims to sub-phenotype SA through the life course of the disease, using an innovative systems biology approach Methods: Children with SA and SPSW (defined in Thorax 2011;66:910) and mild-moderate controls were recruited. Data regarding demographics, exacerbations, quality of life (QoL), asthma control, lung function and FENO were collected. Results: 272 children were enrolled. QoL scores were lowest in the SPSW cohort. They also had frequent exacerbations. Urinary cotinine was more often positive in children with SPSW compared to controls (20% vs 2.3% p=0.006) and their mothers were more likely to have smoked during pregnancy (13.8% vs 0% p=0.006). Conclusions: These preliminary data confirm that severe paediatric cohorts have poor QOL despite significant treatment and are frequently exposed to tobacco smoke. There arevclear unmet needs in the management of these children. Integration of the clinical with high dimensional datasets will help to define sub-phenotypes.
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DIABLO sPLSDA model results. (DOCX 18966 kb)
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Table S7. Estimated accuracy and standard deviation of the RFE procedure. Table S8. Accuracy and Kappa values of the Random Forest models in the training set. Table S9. Performances values for the Random Forest model in the testing set.... more
Table S7. Estimated accuracy and standard deviation of the RFE procedure. Table S8. Accuracy and Kappa values of the Random Forest models in the training set. Table S9. Performances values for the Random Forest model in the testing set. Figure S11. Relative importance of the top 20 predictors building the final model of the RF. The importance axis is scaled, with the mRNA expression of CD3D scaled to 100% and the methylation state of POLA2 to 0% (not shown). (DOCX 18 kb)
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AUC of consensus clustering. (XLSX 13 kb)