Behind the (impedance) baseline in children.
; ; Van Steen, Kristel et al
in Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus / I.S.D.E (2013)
Impedance baseline is a new parameter recently related to esophageal integrity. The aim of this study was to assess the effect of different factors on impedance baseline in pediatric patients. We analyzed ... [more ▼]
Impedance baseline is a new parameter recently related to esophageal integrity. The aim of this study was to assess the effect of different factors on impedance baseline in pediatric patients. We analyzed the impedance baseline of 800 children with symptoms of gastroesophageal reflux. Mean impedance baseline was automatically calculated throughout 24-hour tracings. The presence of different age groups and of esophagitis was evaluated. Unpaired t-test, Spearman rank correlation, polynomial, and regression plot were used for statistical analysis. Age-related percentile curves were created. We considered a P-value <0.05 as statistically significant. Impedance baseline was significantly (P < 0.001) lower in younger compared to older children up to 48 months. The mean increase of baseline per month was much higher in the first 36 months of life (47.5 vs. 2.9 Ohm in Channel 1 and 29.9 vs. 2.3 Ohm in Channel 6, respectively) than in older ages. Patients with esophagitis showed significantly decreased impedance baseline (P < 0.05). Infants (especially in the first months of life) and young children present a significantly lower impedance baseline compared to older children both in proximal and distal esophagus. The presence of esophagitis may also determine a decreased impedance baseline regardless of the age of the patients. [less ▲]Detailed reference viewed: 16 (1 ULg)
Esophageal impedance baseline is age dependent.
; ; et al
in Journal of pediatric gastroenterology and nutrition (2013), 57(4), 506-13
OBJECTIVE: Esophageal impedance (multichannel intraluminal impedance [MII]) baseline (impedance baseline [IB]) has been recently considered to be related to esophageal integrity. The aim of this study was ... [more ▼]
OBJECTIVE: Esophageal impedance (multichannel intraluminal impedance [MII]) baseline (impedance baseline [IB]) has been recently considered to be related to esophageal integrity. The aim of this study was to analyze the age effect on IB in a large population of pediatric patients. DESIGN: A total of 816 children with symptoms of gastroesophageal reflux and submitted to MII were included. Mean IB was automatically calculated in the different MII channels (Chs) throughout 24-hour tracings by the specific software without removing any episode of increased/decreased IB. Acid and nonacid reflux parameters and age subgroups analysis were performed. Unpaired t test, Spearman rank correlation, polynomial and regression plot, multiple regression analysis, factorial analysis of variance, and the least mean squares method were used for statistical analysis and age-related percentile curves. P < 0.05 was considered as statistically significant. RESULTS: Mean IB was significantly (P < 0.001) lower in younger compared with older children up to 48 months. The mean increase of IB per month was 2.9 Omega in Ch 1 and 2.3 Omega in Ch 6, but much higher in the first 36 months of life (47.5 Omega in Ch 1 and 29.9 Omega in Ch 6, respectively). From 48 months onward, there was no significant increase of the mean IB (P = 0.73). In the multiple regression analysis, only age and reflux index (but no other reflux parameters) significantly correlated with IB. Distal IB was significantly (P < 0.05) lower in patients with esophagitis and in subjects taking proton pump inhibitors compared with subjects off (any) treatment. Percentiles of IB in proximal and distal Chs were provided according to different age groups. CONCLUSIONS: IB is significantly lower in infants (especially in the first months of life) compared with older children. Low IB in both proximal and distal esophagus in young infants may be related to anatomical and functional difference other than the presence of esophagitis. [less ▲]Detailed reference viewed: 38 (1 ULg)
EU Pancreas: An Integrated European Platform for Pancreas Cancer Research - from Basic Science to Clinical and Public Health Interventions for a Rare Disease.
; ; Van Steen, Kristel et al
in Public health genomics (2013), 16(6), 305-12
Background: Large-scale international collaboration is essential to decipher relevant information in the context of omics-scale interrogations in cancer research. This is even more important for rare and ... [more ▼]
Background: Large-scale international collaboration is essential to decipher relevant information in the context of omics-scale interrogations in cancer research. This is even more important for rare and fatal diseases like pancreas cancer (PC). Methods: The COST Action BM1204 is a unique platform to facilitate the collaboration of a broad range of European and international PC multidisciplinary research groups in order to: (1) integrate knowledge and experience in a multidisciplinary way 'from cell to society', (2) promote the application of uniform study tools and protocols, (3) foster their optimal use by early-stage researchers, (4) enhance the mobility and training of researchers, and (5) disseminate the results produced to the broader society. Results: This Action will develop novel interdisciplinary tools for collaborative research to improve our understanding of PC and its prevention, diagnosis and treatment. It also aims to answer questions related to the etiology, early detection, evidence-based and personalized treatment, and health management for PC. Furthermore, the Action will contribute to new insights into PC personalized medicine and beyond as well as to the understanding of complex and rare diseases taking PC as a best practice example. The Action aims at attracting young scholars across a range of disciplines in collaboration with more experienced researchers and enhancing active European participation in the international scenario of PC research. Conclusion: The ultimate aim is to foster PC research in Europe and to coordinate this effort with other international initiatives to reduce disease mortality. (c) 2013 S. Karger AG, Basel. [less ▲]Detailed reference viewed: 29 (6 ULg)
Molecular reclassification of Crohn's disease: a cautionary note on population stratification.
; ; Mahachie John, Jestinah et al
in PloS one (2013), 8(10), 77720
Complex human diseases commonly differ in their phenotypic characteristics, e.g., Crohn's disease (CD) patients are heterogeneous with regard to disease location and disease extent. The genetic ... [more ▼]
Complex human diseases commonly differ in their phenotypic characteristics, e.g., Crohn's disease (CD) patients are heterogeneous with regard to disease location and disease extent. The genetic susceptibility to Crohn's disease is widely acknowledged and has been demonstrated by identification of over 100 CD associated genetic loci. However, relating CD subphenotypes to disease susceptible loci has proven to be a difficult task. In this paper we discuss the use of cluster analysis on genetic markers to identify genetic-based subgroups while taking into account possible confounding by population stratification. We show that it is highly relevant to consider the confounding nature of population stratification in order to avoid that detected clusters are strongly related to population groups instead of disease-specific groups. Therefore, we explain the use of principal components to correct for population stratification while clustering affected individuals into genetic-based subgroups. The principal components are obtained using 30 ancestry informative markers (AIM), and the first two PCs are determined to discriminate between continental origins of the affected individuals. Genotypes on 51 CD associated single nucleotide polymorphisms (SNPs) are used to perform latent class analysis, hierarchical and Partitioning Around Medoids (PAM) cluster analysis within a sample of affected individuals with and without the use of principal components to adjust for population stratification. It is seen that without correction for population stratification clusters seem to be influenced by population stratification while with correction clusters are unrelated to continental origin of individuals. [less ▲]Detailed reference viewed: 19 (1 ULg)
Unique gene expression and MR T2 relaxometry patterns define chronic murine dextran sodium sulphate colitis as a model for connective tissue changes in human Crohn's disease.
; ; et al
in PloS one (2013), 8(7), 68876
INTRODUCTION: Chronically relapsing inflammation, tissue remodeling and fibrosis are hallmarks of inflammatory bowel diseases. The aim of this study was to investigate changes in connective tissue in a ... [more ▼]
INTRODUCTION: Chronically relapsing inflammation, tissue remodeling and fibrosis are hallmarks of inflammatory bowel diseases. The aim of this study was to investigate changes in connective tissue in a chronic murine model resulting from repeated cycles of dextran sodium sulphate (DSS) ingestion, to mimic the relapsing nature of the human disease. MATERIALS AND METHODS: C57BL/6 mice were exposed to DSS in drinking water for 1 week, followed by a recovery phase of 2 weeks. This cycle of exposure was repeated for up to 3 times (9 weeks in total). Colonic inflammation, fibrosis, extracellular matrix proteins and colonic gene expression were studied. In vivo MRI T 2 relaxometry was studied as a potential non-invasive imaging tool to evaluate bowel wall inflammation and fibrosis. RESULTS: Repeated cycles of DSS resulted in a relapsing and remitting disease course, which induced a chronic segmental, transmural colitis after 2 and 3 cycles of DSS with clear induction of fibrosis and remodeling of the muscular layer. Tenascin expression mirrored its expression in Crohn's colitis. Microarray data identified a gene expression profile different in chronic colitis from that in acute colitis. Additional recovery was associated with upregulation of unique genes, in particular keratins, pointing to activation of molecular pathways for healing and repair. In vivo MRI T2 relaxometry of the colon showed a clear shift towards higher T2 values in the acute stage and a gradual regression of T2 values with increasing cycles of DSS. CONCLUSIONS: Repeated cycles of DSS exposure induce fibrosis and connective tissue changes with typical features, as occurring in Crohn's disease. Colonic gene expression analysis revealed unique expression profiles in chronic colitis compared to acute colitis and after additional recovery, pointing to potential new targets to intervene with the induction of fibrosis. In vivo T2 relaxometry is a promising non-invasive assessment of inflammation and fibrosis. [less ▲]Detailed reference viewed: 16 (2 ULg)
Genetic and microbial factors modulating the ubiquitin proteasome system in inflammatory bowel disease.
; ; et al
in Gut (2013)
OBJECTIVE: Altered microbiota composition, changes in immune responses and impaired intestinal barrier functions are observed in IBD. Most of these features are controlled by proteases and their ... [more ▼]
OBJECTIVE: Altered microbiota composition, changes in immune responses and impaired intestinal barrier functions are observed in IBD. Most of these features are controlled by proteases and their inhibitors to maintain gut homeostasis. Unrestrained or excessive proteolysis can lead to pathological gastrointestinal conditions. The aim was to validate the identified protease IBD candidates from a previously performed systematic review through a genetic association study and functional follow-up. DESIGN: We performed a genetic association study in a large multicentre cohort of patients with Crohn's disease (CD) and UC from five European IBD referral centres in a total of 2320 CD patients, 2112 UC patients and 1796 healthy controls. Subsequently, we did an extensive functional assessment of the candidate genes to explore their causality in IBD pathogenesis. RESULTS: Ten single nucleotide polymorphisms (SNPs) in four genes were significantly associated with CD: CYLD, USP40, APEH and USP3. CYLD was the most significant gene with the intronically located rs12324931 the strongest associated SNP (pFDR=1.74e-17, OR=2.24 (1.83 to 2.74)). Five SNPs in four genes were significantly associated with UC: USP40, APEH, DAG1 and USP3. CYLD, as well as some of the other associated genes, is part of the ubiquitin proteasome system (UPS). We therefore determined if the IBD-associated adherent-invasive Escherichia coli (AIEC) can modulate the UPS functioning. Infection of intestinal epithelial cells with the AIEC LF82 reference strain modulated the UPS turnover by reducing poly-ubiquitin conjugate accumulation, increasing 26S proteasome activities and decreasing protein levels of the NF-kappaB regulator CYLD. This resulted in IkappaB-alpha degradation and NF-kappaB activation. This activity was very important for the pathogenicity of AIEC since decreased CYLD resulted in increased ability of AIEC LF82 to replicate intracellularly. CONCLUSIONS: Our results reveal the UPS, and CYLD specifically, as an important contributor to IBD pathogenesis, which is favoured by both genetic and microbial factors. [less ▲]Detailed reference viewed: 55 (2 ULg)
Genetic variations in toll-like receptor pathway and lung function decline in Cystic fibrosis patients.
; Mahachie John, Jestinah ; Van Steen, Kristel et al
in Human immunology (2013), 74(12), 1649-55
The toll-like receptor (TLR) family maintains pulmonary homeostasis by pathogen recognition, clearance and regulation of inflammation. Genes affecting inflammation response play a key role in modifying ... [more ▼]
The toll-like receptor (TLR) family maintains pulmonary homeostasis by pathogen recognition, clearance and regulation of inflammation. Genes affecting inflammation response play a key role in modifying Cystic fibrosis (CF) lung disease severity. We assessed the impact of single nucleotide polymorphisms (SNPs) of TLR genes (TLR1 to TLR10, CD14, lipopolyssacharide-binding protein (LBP)) on lung function in CF patients. Each SNP was tested for time-dependent effect on FEV1, using six genetic models. In addition, we investigated associations between SNP genotypes and extreme subject specific slopes of FEV1 decline. Variant alleles of polymorphisms of TLR2 rs1898830, rs5743708, and rs3804100 demonstrated a consistent association with lung disease severity (p = 0.008, p = 0.006 and p = 0.029 respectively). Patients homozygous for variant C allele of TLR5 polymorphism rs5744174 are more frequently associated with extreme fast FEV1 decline (OR: 20 (95% Confidence Interval:1.85-216.18)). Patients homozygous AA for TLR1 polymorphism rs5743551 are more frequently associated with faster decline of FEV1 compared to heterozygous genotype (OR:7.33 (95% CI:1.63-33.11). Our findings indicate that variations in TLR1, TLR2 and TLR5 genes may influence CF lung function decline. Further functional analysis is required to provide new insights into the pathogenesis of TLRs in CF lung disease severity. [less ▲]Detailed reference viewed: 19 (4 ULg)
Large Sample Size, Wide Variant Spectrum, and Advanced Machine-Learning Technique Boost Risk Prediction for Inflammatory Bowel Disease.
; ; et al
in American Journal of Human Genetics (2013)
We performed risk assessment for Crohn's disease (CD) and ulcerative colitis (UC), the two common forms of inflammatory bowel disease (IBD), by using data from the International IBD Genetics Consortium's ... [more ▼]
We performed risk assessment for Crohn's disease (CD) and ulcerative colitis (UC), the two common forms of inflammatory bowel disease (IBD), by using data from the International IBD Genetics Consortium's Immunochip project. This data set contains ?17,000 CD cases, ?13,000 UC cases, and ?22,000 controls from 15 European countries typed on the Immunochip. This custom chip provides a more comprehensive catalog of the most promising candidate variants by picking up the remaining common variants and certain rare variants that were missed in the first generation of GWAS. Given this unprecedented large sample size and wide variant spectrum, we employed the most recent machine-learning techniques to build optimal predictive models. Our final predictive models achieved areas under the curve (AUCs) of 0.86 and 0.83 for CD and UC, respectively, in an independent evaluation. To our knowledge, this is the best prediction performance ever reported for CD and UC to date. [less ▲]Detailed reference viewed: 35 (1 ULg)
A robustness study to investigate the performance of parametric and non-parametric tests used in Model-Based Multifactor Dimensionality Reduction Epistasis Detection
Mahachie John, Jestinah ; Gusareva, Elena ; Van Lishout, François et al
in BioData Mining (2013)Detailed reference viewed: 22 (5 ULg)
Crohn’s disease susceptibility genes involved in microbial sensing, autophagy and endoplasmic reticulum (er) stress and their interaction
; Mahachie John, Jestinah ; Van Steen, Kristel et al
in Autophagy (2013)Detailed reference viewed: 44 (5 ULg)
Survival analysis: finding relevant epistatic SNP pairs using Model- Based Multifactor Dimensionality Reduction
Van Lishout, François ; ; et al
Conference (2012, December 03)
Analyzing the combined effects of genes (and/or environmental factors) on the development of complex diseases is quite challenging, both from the statistical and computational perspective, even using a ... [more ▼]
Analyzing the combined effects of genes (and/or environmental factors) on the development of complex diseases is quite challenging, both from the statistical and computational perspective, even using a relatively small number of genetic and non-genetic exposures. Several data-mining methods have been proposed for interaction analysis, among them, the Multifactor Dimensionality Reduction Method (MDR). Model-Based Multifactor Dimensionality Reduction (MB-MDR), a relatively new dimensionality reduction technique, is able to unify the best of both nonparametric and parametric worlds, and has proven its utility in a variety of theoretical and practical settings. Until now, MB-MDR software has only accommodated traits that are measured on a binary or interval scale. Time-to-event data could therefore not be analyzed with the MB-MDR methodology. MB-MDR-3.0.0 overcomes this shortcoming of earlier versions. We show the added value of MB-MDR for censored traits by comparing the implemented strategies with more classical methods such as those based on a parametric regression paradigm. The simulation results are supplemented with an application to real-life data. [less ▲]Detailed reference viewed: 74 (8 ULg)
Prognostic Value of Serologic and Histologic Markers on Clinical Relapse in Ulcerative Colitis Patients With Mucosal Healing
; ; et al
in American Journal of Gastroenterology (2012), 11(107), 1684-92Detailed reference viewed: 65 (5 ULg)
Active Foxp3 (+) Regulatory T Cells Rather Than Other Foxp3 (+) T Cells Subsets CorrelateWith Clinical Response To Infliximab Therapy For IBD
; ; et al
Poster (2012, October)Detailed reference viewed: 6 (1 ULg)
Restoration Of B Cells Correlates With Clinical Response To Anti-Tnf Therapy
; ; et al
Poster (2012, October)Detailed reference viewed: 11 (1 ULg)
Integrating biological information in genome-wide association interaction (GWAI) studies.
Gusareva, Elena ; Van Steen, Kristel
Genome-wide association (GWA) studies of Crohn's disease have identified numerous genes. However, a substantial portion of the heritability of this disease remains unexplained. Some gene variants, not ... [more ▼]
Genome-wide association (GWA) studies of Crohn's disease have identified numerous genes. However, a substantial portion of the heritability of this disease remains unexplained. Some gene variants, not detectable via main effects GWA study, may manifest themselves only in interaction with other variants. To search for interacting genes involved in the regulation of Crohn's disease, we performed GWA epistasis screening in a large human cohort (1851 cases/2938 controls) belonging to the Wellcome Trust Case Control Consortium (WTCCC). All subjects were genotyped with the GeneChip 500K Mapping Array Set (Affymetrix chip). SNPs that passed our quality control (359,479 SNPs) were processed in Biofilter (a software package that looks for candidate epistatic genes contributing to disease risk) giving rise to 14,185 SNPs. Subsequent MB-MDR epistasis screening, highlighted evidence for statistical epistasis for 6 SNP pairs. Four of these pairs involve interaction on between the HTR3B and USP28 genes (chromosome 11). One pair involves an interaction between the SLED1 and ACSL1 genes (chromosome 4). Another pair involves an interaction between PTPN22 (chromosome 1) and a SNP located between USPL1 and ALOX5AP (chromosome 13). Notably, when mapped to the same genomic regions, the interacting SNPs were not in linkage disequilibrium (r^2 < 0.11). All results were corrected for potential main SNP effects and were corrected for multiple testing on 7072 SNPs (i.e., 25,003,056 pairs). We investigated the consistency of these findings using different methodologies, including information-based, LD comparison-based and regression-based approaches. We also investigated the utility of using prior information from biological interaction data bases in novel epistasis discoveries, as well as the utility of biological data bases in interpreting a posterior identified statistical epistasis pairs. Our findings may provide new leads on important pathways involved in Crohn's disease. [less ▲]Detailed reference viewed: 17 (1 ULg)
Factors determining therapeutic strategy at diagnosis and evolution of disease severity in a cohort of Belgian pediatric Crohn's disease patients (BELCRO)
; ; et al
in Gastroenterology (2012)Detailed reference viewed: 26 (4 ULg)
Sequential T2 Relaxometry as a Non-Invasive Assessment of Transmural Inflammation in a Murine Model of Chronically Relapsing Colitis
; ; et al
Poster (2012, May)Detailed reference viewed: 10 (2 ULg)
Repeated cycles of DSS inducing a chronically relapsing inflammation: a novel model to study fibrosis using in vivo MRI T2 relaxometry
; ; et al
Poster (2012, May)Detailed reference viewed: 13 (2 ULg)
Application of mixed polygenic model to control for cryptic/genuine relatedness and population stratification.
Gusareva, Elena ; Mahachie John, Jestinah ; et al
Poster (2012, March 12)
In genome-wide association studies (GWAs), population stratification may cause inflated type I errors and overly-optimistic test results, when not properly corrected for. During the past decade, several ... [more ▼]
In genome-wide association studies (GWAs), population stratification may cause inflated type I errors and overly-optimistic test results, when not properly corrected for. During the past decade, several methods have been proposed for association testing in the presence of population stratification. Among these, principal components-based approaches are the most popular. Principal component analysis (PCA) allows data transformation to a new coordinate system such that the projection of the data along the first new coordinate (called the PC1) has the largest variance; the second PC has the second largest variance, and so on. In practice, two components are usually enough to adjust or to control for population stratification. They can easily be included in parametric association models as covariates. Despite the success of this strategy, there are still some caveats which need further attention. Among these are that principal component-based methods generally do not account for cryptic relatedness (kinship) between supposedly unrelated individuals, are not straightforwardly adapted to accommodate family-based designs or mixtures of families and unrelated individuals, and do not always take proper account of the trait under investigation. In this work, we present an easy-to-use alternative that addresses the aforementioned issues. For quantitative traits, we propose to first use the mixed polygenic model (possibly taking into account important non-genetic confounders as covariates), second to derive “polygenic” residuals from this model – hereby removing genomic kinship relationships, and third to consider these residuals as new traits in a classical genome-wide QTL analysis for “unrelated individuals”. The polygenic component of the aforementioned mixed polygenic model describes the contribution from multiple independently segregating genes, all having a small additive effect on the trait under investigation. Via an extensive simulation study, with various settings of population stratification and admixture, we show that this approach not only removes most of the “relatedness” between individuals (cryptic relatedness or known relatedness), but also removes most of the remaining substructures caused by population stratification or admixture. As a proof of concept, we demonstrate the efficiency of this robust method to control for population stratification on real-life genome-scale data from the SNP Health Association Resource (SHARe) Asthma Resource project (SHARP) (dbGaP accession number phs000166.v2.p1). We also provide leads to extend this method to dichotomous traits. [less ▲]Detailed reference viewed: 85 (18 ULg)
Genetic and functional evidence for a role of CYLD in Crohn’s Disease: results from a European consortium
; ; et al
in Journal of Crohn’s and Colitis [=JCC] (2012)Detailed reference viewed: 35 (5 ULg)