References of "Van Steen, Kristel"
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See detailThe impact of infliximab therapy on intestinal mucosal gene expression of endothelial cell adhesion molecules in patients with inflammatory bowel disease
Arijs, I.; Quintens, R.; Lemaire, K. et al

in Gastroenterology (2010), 138(5 Suppl I), -677

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See detailA screening methodology based on Random Forests to improve the detection of gene-gene interactions
De Lobel, L.; Geurts, Pierre ULg; Baele, G. et al

in European Journal of Human Genetics (2010), 18(1127), 1132

The search for susceptibility loci in gene-gene interactions imposes a methodological and computational challenge for statisticians because of the large dimensionality inherent to the modelling of gene ... [more ▼]

The search for susceptibility loci in gene-gene interactions imposes a methodological and computational challenge for statisticians because of the large dimensionality inherent to the modelling of gene-gene interactions or epistasis. In an era in which genome-wide scans have become relatively common, new powerful methods are required to handle the huge amount of feasible gene-gene interactions and to weed out false positives and negatives from these results. One solution to the dimensionality problem is to reduce data by preliminary screening of markers to select the best candidates for further analysis. Ideally, this screening step is statistically independent of the testing phase. Initially developed for small numbers of markers, the Multifactor Dimensionality Reduction (MDR) method is a nonparametric, model-free data reduction technique to associate sets of markers with optimal predictive properties to disease. In this study, we examine the power of MDR in larger data sets and compare it with other approaches that are able to identify gene-gene interactions. Under various interaction models (purely and not purely epistatic), we use a Random Forest (RF)-based prescreening method, before executing MDR, to improve its performance. We find that the power of MDR increases when noisy SNPs are first removed, by creating a collection of candidate markers with RFs. We validate our technique by extensive simulation studies and by application to asthma data from the European Committee of Respiratory Health Study II.European Journal of Human Genetics advance online publication, 12 May 2010; doi:10.1038/ejhg.2010.48. [less ▲]

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See detailKinetics of C-Reactive Protein (CRP) following maintenance infliximab treatment in Crohn's disease identifies profiles of patients with better outcome
Jürgens, M.; Mahachie John, Jestinah ULg; Cleynen, I. et al

in Gastroenterology (2010), 138(5 (Suppl I)), -686

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See detailIn utero smoke exposure and impaired response to inhaled corticosteroids in children with asthma
Cohen, Robyn T.; Raby, Benjamin A.; Van Steen, Kristel ULg et al

in Journal of Allergy and Clinical Immunology (The) (2010), 126(3), 491-497

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See detailIntestinal mucosal gene expression of endothelial cell adhesion molecules in patients with inflammatory bowel disease and the impact of infliximab therapy.
Arijs, Ingrid; Quintens, Roel; Lemaire, Katleen et al

in Journal of Crohn’s and Colitis [=JCC] (2010)

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See detailmbmdr: an R package for exploring gene-gene interactions associated with binary or quantitative traits
Calle, M. Luz; Urrea, Victor; Van Steen, Kristel ULg

in Bioinformatics (2010), 26(17), 2198-2199

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See detailMolecular Reclassification of Crohn's Disease by Cluster Analysis of Genetic Variants
Cleynen, Isabelle; Mahachie John, Jestinah ULg; Henckaerts, Liesbet et al

in PLoS ONE (2010), 5(9), 12952

<sec> <title>Background</title> <p>Crohn's Disease (CD) has a heterogeneous presentation, and is typically classified according to extent and location of disease. The genetic susceptibility to CD is well ... [more ▼]

<sec> <title>Background</title> <p>Crohn's Disease (CD) has a heterogeneous presentation, and is typically classified according to extent and location of disease. The genetic susceptibility to CD is well known and genome-wide association scans (GWAS) and meta-analysis thereof have identified over 30 susceptibility loci. Except for the association between ileal CD and <italic>NOD2</italic> mutations, efforts in trying to link CD genetics to clinical subphenotypes have not been very successful. We hypothesized that the large number of confirmed genetic variants enables (better) classification of CD patients.</p> </sec><sec> <title>Methodology/Principal Findings</title> <p>To look for genetic-based subgroups, genotyping results of 46 SNPs identified from CD GWAS were analyzed by Latent Class Analysis (LCA) in CD patients and in healthy controls. Six genetic-based subgroups were identified in CD patients, which were significantly different from the five subgroups found in healthy controls. The identified CD-specific clusters are therefore likely to contribute to disease behavior. We then looked at whether we could relate the genetic-based subgroups to the currently used clinical parameters. Although modest differences in prevalence of disease location and behavior could be observed among the CD clusters, Random Forest analysis showed that patients could not be allocated to one of the 6 genetic-based subgroups based on the typically used clinical parameters alone. This points to a poor relationship between the genetic-based subgroups and the used clinical subphenotypes.</p> </sec><sec> <title>Conclusions/Significance</title> <p>This approach serves as a first step to reclassify Crohn's disease. The used technique can be applied to other common complex diseases as well, and will help to complete patient characterization, in order to evolve towards personalized medicine.</p> </sec> [less ▲]

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See detailFAM-MDR: A Flexible Family-Based Multifactor Dimensionality Reduction Technique to Detect Epistasis Using Related Individuals
Cattaert, Tom ULg; Urrea, V.; Naj, A. C. et al

in PLoS ONE (2010), 5(4), -

We propose a novel multifactor dimensionality reduction method for epistasis detection in small or extended pedigrees, FAM-MDR. It combines features of the Genome-wide Rapid Association using Mixed Model ... [more ▼]

We propose a novel multifactor dimensionality reduction method for epistasis detection in small or extended pedigrees, FAM-MDR. It combines features of the Genome-wide Rapid Association using Mixed Model And Regression approach (GRAMMAR) with Model-Based MDR (MB-MDR). We focus on continuous traits, although the method is general and can be used for outcomes of any type, including binary and censored traits. When comparing FAM-MDR with Pedigree-based Generalized MDR (PGMDR), which is a generalization of Multifactor Dimensionality Reduction (MDR) to continuous traits and related individuals, FAM-MDR was found to outperform PGMDR in terms of power, in most of the considered simulated scenarios. Additional simulations revealed that PGMDR does not appropriately deal with multiple testing and consequently gives rise to overly optimistic results. FAM-MDR adequately deals with multiple testing in epistasis screens and is in contrast rather conservative, by construction. Furthermore, simulations show that correcting for lower order (main) effects is of utmost importance when claiming epistasis. As Type 2 Diabetes Mellitus (T2DM) is a complex phenotype likely influenced by gene-gene interactions, we applied FAM-MDR to examine data on glucose area-under-the-curve (GAUC), an endophenotype of T2DM for which multiple independent genetic associations have been observed, in the Amish Family Diabetes Study (AFDS). This application reveals that FAM-MDR makes more efficient use of the available data than PGMDR and can deal with multi-generational pedigrees more easily. In conclusion, we have validated FAM-MDR and compared it to PGMDR, the current state-of-the-art MDR method for family data, using both simulations and a practical dataset. FAM-MDR is found to outperform PGMDR in that it handles the multiple testing issue more correctly, has increased power, and efficiently uses all available information. [less ▲]

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See detailReanalysis of death risk in long-term follow-up in infliximab patients versus controls
Fidder, H.; Van Steen, Kristel ULg; Van Assche, G. et al

in Gut (2010), 59

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See detailIntestinal mucosal expression of matrix metalloproteinase and ADAM genes in patients with inflammatory bowel disease and the impact of infliximab therapy
Arijs, Ingrid; Quintens, R.; Lemaire, K. et al

in Gastroenterology (2010), 138(5), 677

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See detailImmortal time bias and infliximab-related mortality and malignancy incidence
Fidder, H.; Van Steen, Kristel ULg; Van Assche, G. et al

in Gut (2010), 59

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See detailColonic mucosal expression of barrier genes in patients with inflammatory bowel disease before and after first infliximab treatmen
Arijs, I.; Van Lommel, L.; Van Steen, Kristel ULg et al

in Acta Gastro-Enterologica Belgica (2009)

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See detailSelecting multiple epistatic models using MB-MDR
Cattaert, Tom ULg; De Wit, V.; Mahachie John, Jestinah ULg et al

in Conference Abstract Book (2009)

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See detailGENESTAT: an information portal for design and analysis of genetic association studies
Ripatti, Samuli; Becker, Tim; Bickeboller, Heike et al

in European Journal of Human Genetics (2009), 17(4), 533-6

We present the rationale, the background and the structure for version 2.0 of the GENESTAT information portal (www.genestat.org) for statistical genetics. The fast methodological advances, coupled with a ... [more ▼]

We present the rationale, the background and the structure for version 2.0 of the GENESTAT information portal (www.genestat.org) for statistical genetics. The fast methodological advances, coupled with a range of standalone software, makes it difficult for expert as well as non-expert users to orientate when designing and analysing their genetic studies. The ultimate ambition of GENESTAT is to guide on statistical methodology related to the broad spectrum of research in genetic epidemiology. GENESTAT 2.0 focuses on genetic association studies. Each entry provides a summary of a topic and gives links to key papers, websites and software. The flexibility of the internet is utilised for cross-referencing and for open editing. This paper gives an overview of GENESTAT and gives short introductions to the current main topics in GENESTAT, with additional entries on the website. Methods and software developers are invited to contribute to the portal, which is powered by a Wikipedia-type engine and allows easy additions and editing. [less ▲]

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See detailCluster analysis of genetic variants enables reclassification of Crohn’s disease at the molecular level
Cleynen, I.; Van Moerkercke, W.; Mahachie John, Jestinah ULg et al

in Gut (2009)

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See detailImportin-13 genetic variation is associated with improved airway responsiveness in childhood asthma
Raby, B. A.; Van Steen, Kristel ULg; Lasky-Su, J. et al

in Respiratory Research (2009), 10

BACKGROUND: Glucocorticoid function is dependent on efficient translocation of the glucocorticoid receptor (GR) from the cytoplasm to the nucleus of cells. Importin-13 (IPO13) is a nuclear transport ... [more ▼]

BACKGROUND: Glucocorticoid function is dependent on efficient translocation of the glucocorticoid receptor (GR) from the cytoplasm to the nucleus of cells. Importin-13 (IPO13) is a nuclear transport receptor that mediates nuclear entry of GR. In airway epithelial cells, inhibition of IPO13 expression prevents nuclear entry of GR and abrogates anti-inflammatory effects of glucocorticoids. Impaired nuclear entry of GR has been documented in steroid-non-responsive asthmatics. We hypothesize that common IPO13 genetic variation influences the anti-inflammatory effects of inhaled corticosteroids for the treatment of asthma, as measured by change in methacholine airway hyperresponsiveness (AHR-PC20). METHODS: 10 polymorphisms were evaluated in 654 children with mild-to-moderate asthma participating in the Childhood Asthma Management Program (CAMP), a clinical trial of inhaled anti-inflammatory medications (budesonide and nedocromil). Population-based association tests with repeated measures of PC20 were performed using mixed models and confirmed using family-based tests of association. RESULTS: Among participants randomized to placebo or nedocromil, IPO13 polymorphisms were associated with improved PC20 (i.e. less AHR), with subjects harboring minor alleles demonstrating an average 1.51-2.17 fold increase in mean PC20 at 8-months post-randomization that persisted over four years of observation (p = 0.01-0.005). This improvement was similar to that among children treated with long-term inhaled corticosteroids. There was no additional improvement in PC20 by IPO13 variants among children treated with inhaled corticosteroids. CONCLUSION: IPO13 variation is associated with improved AHR in asthmatic children. The degree of this improvement is similar to that observed with long-term inhaled corticosteroid treatment, suggesting that IPO13 variation may improve nuclear bioavailability of endogenous glucocorticoids. [less ▲]

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See detailMucosal gene signatures to predict response to infliximab in patients with ulcerative colitis
Arijs, I.; Li, K.; Toedter, G. et al

in Gut (2009), 58(12), 1612-9

BACKGROUND AND AIMS: Infliximab is an effective treatment for ulcerative colitis with over 60% of patients responding to treatment and up to 30% reaching remission. The mechanism of resistance to anti ... [more ▼]

BACKGROUND AND AIMS: Infliximab is an effective treatment for ulcerative colitis with over 60% of patients responding to treatment and up to 30% reaching remission. The mechanism of resistance to anti-tumour necrosis factor alpha (anti-TNFalpha) is unknown. This study used colonic mucosal gene expression to provide a predictive response signature for infliximab treatment in ulcerative colitis. METHODS: Two cohorts of patients who received their first treatment with infliximab for refractory ulcerative colitis were studied. Response to infliximab was defined as endoscopic and histological healing. Total RNA from pre-treatment colonic mucosal biopsies was analysed with Affymetrix Human Genome U133 Plus 2.0 Arrays. Quantitative RT-PCR was used to confirm microarray data. RESULTS: For predicting response to infliximab treatment, pre-treatment colonic mucosal expression profiles were compared for responders and non-responders. Comparative analysis identified 179 differentially expressed probe sets in cohort A and 361 in cohort B with an overlap of 74 probe sets, representing 53 known genes, between both analyses. Comparative analysis of both cohorts combined, yielded 212 differentially expressed probe sets. The top five differentially expressed genes in a combined analysis of both cohorts were osteoprotegerin, stanniocalcin-1, prostaglandin-endoperoxide synthase 2, interleukin 13 receptor alpha 2 and interleukin 11. All proteins encoded by these genes are involved in the adaptive immune response. These markers separated responders from non-responders with 95% sensitivity and 85% specificity. CONCLUSION: Gene array studies of ulcerative colitis mucosal biopsies identified predictive panels of genes for (non-)response to infliximab. Further study of the pathways involved should allow a better understanding of the mechanisms of resistance to infliximab therapy in ulcerative colitis. ClinicalTrials.gov number, NCT00639821. [less ▲]

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See detailPredictive Value of C-Reactive Protein Level Changes On the Long Term Outcome of Infliximab in Crohn's Disease
Jürgens, M.; Schnitzler, F.; Van Steen, Kristel ULg et al

in Gastroenterology (2009), 136(5), 171

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See detailGenetic risk profiling and prediction of disease course in Crohn's disease patients.
Henckaerts, Liesbet; Van Steen, Kristel ULg; Verstreken, Isabel et al

in Clinical Gastroenterology and Hepatology : the Official Clinical Practice Journal of The American Gastroenterological Association (2009), 7(9), 972-9802

BACKGROUND & AIMS: Clinical presentation at diagnosis and disease course of Crohn's disease (CD) are heterogeneous and variable over time. Early introduction of immunomodulators and/or biologicals might ... [more ▼]

BACKGROUND & AIMS: Clinical presentation at diagnosis and disease course of Crohn's disease (CD) are heterogeneous and variable over time. Early introduction of immunomodulators and/or biologicals might be justified in patients at risk for disease progression, so it is important to identify these patients as soon as possible. We examined the influence of recently discovered CD-associated susceptibility loci on changes in disease behavior and evaluated whether a genetic risk model for disease progression could be generated. METHODS: Complete medical data were available for 875 CD patients (median follow-up time, 14 years; interquartile range, 7-22). Fifty CD-associated polymorphisms were genotyped. Kaplan-Meier survival analyses, multiple logistic regression, and generalized multifactor dimensionality reduction analyses (GMDR) were performed, correcting for follow-up time. RESULTS: Homozygosity for the rs1363670 G-allele in a gene encoding a hypothetical protein near the IL12B gene was independently associated with stricturing disease behavior (odds ratio [OR], 5.48; 95% confidence interval [CI], 1.60-18.83; P = .007) and with shorter time to strictures (P = .01), especially in patients with ileal involvement (P = .0002). Male patients carrying at least one rs12704036 T-allele in a gene desert had the shortest time to non-perianal fistula (P < .0001). The presence of a C-allele at the CDKAL1 single nucleotide polymorphism rs6908425 and the absence of NOD2 variants were independently associated with development of perianal fistula (OR, 8.86; 95% CI, 1.13-69.78; P = .04 and OR, 0.56; 95% CI, 0.38-0.83; P = .004, respectively), particularly when colonic involvement and active smoking were present. CONCLUSIONS: CD-associated polymorphisms play a role in disease progression and might be useful in identifying patients who could benefit from an early top-down treatment approach. [less ▲]

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