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See detailgammaMAXT: a fast multiple-testing correction algorithm
Van Lishout, François ULg; Gadaleta, Francesco ULg; Moore, Jason H. et al

in ERCIM 2014 Abstract Book (in press)

The purpose of the maxT algorithm (1993) is to control the family-wise error rate (FWER) when assessing significance of multiple tests jointly. However, the requirements in terms of computing time and ... [more ▼]

The purpose of the maxT algorithm (1993) is to control the family-wise error rate (FWER) when assessing significance of multiple tests jointly. However, the requirements in terms of computing time and memory of this procedure are proportional to the number of investigated hypothesis. The memory issue has been solved by Van Lishout’s implementation of maxT (2013), which makes the memory usage independent from the size of the dataset. This algorithm is implemented in MBMDR-3.0.3, a software that is able to identify genetic interactions, for a variety of SNP-SNP based epistasis model,s in an effective way. However, that implementation turned out to be less suitable for genome-wide interaction analysis studies, due to the prohibitive computational burden. Here, we present gammaMAXT, a novel algorithm which is part of MBMDR-4.2.2. We show that, in the abscence of interaction effects, test-statistics produced by the MB-MDR methodology follow a mixture distribution with a point mass at zero and a shifted gamma distribution for the top 10% of the strictly positive values. We show that the gammaMAXT algorithm has a power comparable to maxT and maintains FWER, but requires less computational resources and time. MBMDR-4.2.2 can be downloaded at http://www.statgen.ulg.ac.be. [less ▲]

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See detailHigh-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis.
Goyette, Philippe; Boucher, Gabrielle; Mallon, D et al

in Nature Genetics (2015)

Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major ... [more ▼]

Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD. [less ▲]

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See detailPractical aspects of genome-wide association interaction analysis.
Gusareva, Elena ULg; Van Steen, Kristel ULg

in Human Genetics (2014), 133(11), 1343-58

Large-scale epistasis studies can give new clues to system-level genetic mechanisms and a better understanding of the underlying biology of human complex disease traits. Though many novel methods have ... [more ▼]

Large-scale epistasis studies can give new clues to system-level genetic mechanisms and a better understanding of the underlying biology of human complex disease traits. Though many novel methods have been proposed to carry out such studies, so far only a few of them have demonstrated replicable results. Here, we propose a minimal protocol for genome-wide association interaction (GWAI) analysis to identify gene–gene interactions from large-scale genomic data. The different steps of the developed protocol are discussed and motivated, and encompass interaction screening in a hypothesis-free and hypothesisdriven manner. In particular, we examine a wide range of aspects related to epistasis discovery in the context of complex traits in humans, hereby giving practical recommendations for data quality control, variant selection or prioritization strategies and analytic tools, replication and meta-analysis, biological validation of statistical findings and other related aspects. The minimal protocol provides guidelines and attention points for anyone involved in GWAI analysis and aims to enhance the biological relevance of GWAI findings. At the same time, the protocol improves a better assessment of strengths and weaknesses of published GWAI methodologies. [less ▲]

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See detailGenome-Wide Association Interaction Analysis for Alzheimer’s Disease
Gusareva, Elena ULg; Carrasquillo, Minerva M.; Bellenguez, Céline et al

in Neurobiology of Aging (2014)

We propose a minimal protocol for exhaustive genome-wide association interaction analysis that involves screening for epistasis over large-scale genomic data combining strengths of different methods and ... [more ▼]

We propose a minimal protocol for exhaustive genome-wide association interaction analysis that involves screening for epistasis over large-scale genomic data combining strengths of different methods and statistical tools. The different steps of this protocol are illustrated on a real-life data application for Alzheimer's disease (AD) (2259 patients and 6017 controls from France). Particularly, in the exhaustive genome-wide epistasis screening we identified AD-associated interacting SNPs-pair from chromosome 6q11.1 (rs6455128, the KHDRBS2 gene) and 13q12.11 (rs7989332, the CRYL1 gene) (p = 0.006, corrected for multiple testing). A replication analysis in the independent AD cohort from Germany (555 patients and 824 controls) confirmed the discovered epistasis signal (p = 0.036). This signal was also supported by a meta-analysis approach in 5 independent AD cohorts that was applied in the context of epistasis for the first time. Transcriptome analysis revealed negative correlation between expression levels of KHDRBS2 and CRYL1 in both the temporal cortex (β = -0.19, p = 0.0006) and cerebellum (β = -0.23, p < 0.0001) brain regions. This is the first time a replicable epistasis associated with AD was identified using a hypothesis free screening approach. [less ▲]

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See detailLD-based haplotype encoding scheme with iterative pruning principal component analysis (ipPCA) to retrieve population substructures
Chaichoompu, Kridsadakorn ULg; Fouladi, Ramouna ULg; Wangkumhang, Pongsakorn et al

Poster (2014, April 29)

Objective To identify and differentiate between subpopulations using a rich set of genetic markers, as using reduced sets of genetic markers for these purposes can become challenging, especially when ... [more ▼]

Objective To identify and differentiate between subpopulations using a rich set of genetic markers, as using reduced sets of genetic markers for these purposes can become challenging, especially when similar geographic regions are involved or when spurious patterns are likely to exist. Method Single Nucleotide Polymorphisms (SNPs) are commonly used to capture variations between populations and often genome-wide SNP data are pruned based on linkage disequilibrium (LD) patterns. Notably, haplotype composition and the pattern of LD between markers may vary between larger populations but may also play a role within more confined geographic regions. Indeed, knowledge about haplotypes in unrelated individuals can reveal useful information about genetic ancestry. Here, we use iterative pruning principal component analysis (ipPCA) [1] to identify and characterize subpopulations in an unsupervised way. As input data, either pruned genome-wide SNP data are used (using PLINK 1.9 with the "indep-pairwise" option, window size = 100k, r2 < 0.25) or multilocus haplotype information derived from the genome-wide SNP panel (using BEAGLE 3.3.2 to infer haplotype). These approaches are applied to real-life data from 992 Thai individuals [2]. Result Preliminary results indicate that ipPCA applied to pruned SNP data or ipPCA that explicitly uses multilocus information (haplotypes) give complementary information about population substructure for geographically confined populations such as the Thai samples in this study. Both methods address different aspects of population structure. Detailed simulation studies are needed to identify the optimal scenarios for haplotype-based ipPCA. Conclusion In this work, we propose to combine an LD-based haplotype encoding scheme with the ipPCA machinery to retrieve fine population substructures. Despite the complexities that are associated with haplotype inference, added value can be obtained when the LD structure between SNPs is exploited in the search for relevant population strata. References 1. Intarapanich, A., et al., Iterative pruning PCA improves resolution of highly structured populations. BMC Bioinformatics, 2009. 10: p. 382. 2. Wangkumhang, P., et al., Insight into the peopling of Mainland Southeast Asia from Thai population genetic structure. PLoS One, 2013. 8(11): p. e79522. [less ▲]

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See detailGenome-wide association interaction analysis for Alzheimer’s disease.
Gusareva, Elena ULg; Bellenguez, C; Cuyvers, E et al

Poster (2014, January 27)

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See detailAssociation of IL33-IL-1 receptor-like 1 (IL1RL1) pathway polymorphisms with wheezing phenotypes and asthma in childhood.
Savenije, Olga E.; Mahachie John, Jestinah ULg; Granell, Raquel et al

in The Journal of allergy and clinical immunology (2014)

BACKGROUND: Genome-wide association studies identified IL33 and IL-1 receptor-like 1 (IL1RL1)/IL18R1 as asthma susceptibility loci. IL33 and IL1RL1 constitute a single ligand-receptor pathway. OBJECTIVE ... [more ▼]

BACKGROUND: Genome-wide association studies identified IL33 and IL-1 receptor-like 1 (IL1RL1)/IL18R1 as asthma susceptibility loci. IL33 and IL1RL1 constitute a single ligand-receptor pathway. OBJECTIVE: In 2 birth cohorts, the Prevalence and Incidence of Asthma and Mite Allergy (PIAMA) study and Avon Longitudinal Study of Parents and Children (ALSPAC), we analyzed associations of longitudinal wheezing phenotypes and asthma with single nucleotide polymorphisms (SNPs) of 8 genes encoding IL-33, IL1RL1, its coreceptor IL1RAcP, its adaptors myeloid differentiation primary response gene 88 (MyD88) and Toll-IL-11 receptor domain containing adaptor protein (TIRAP), and the downstream IL-1 receptor-associated kinase 1, IL-1 receptor-associated kinase 4, and TNF receptor-associated factor 6 (TRAF6). Furthermore, we investigated whether SNPs in this pathway show replicable evidence of gene-gene interaction. METHODS: Ninety-four SNPs were investigated in 2007 children in the PIAMA study and 7247 children in ALSPAC. Associations with wheezing phenotypes and asthma at 8 years of age were analyzed in each cohort and subsequently meta-analyzed. Gene-gene interactions were assessed through model-based multifactor dimensionality reduction in the PIAMA study, and gene-gene interactions of 10 SNP pairs were further evaluated. RESULTS: Intermediate-onset wheeze was associated with SNPs in several genes in the IL33-IL1RL1 pathway after applying multiple testing correction in the meta-analysis: 2 IL33 SNPs (rs4742170 and rs7037276), 1 IL-1 receptor accessory protein (IL1RAP) SNP (rs10513854), and 1 TRAF6 SNP (rs5030411). Late-onset wheeze was associated with 2 IL1RL1 SNPs (rs10208293 and rs13424006), and persistent wheeze was associated with 1 IL33 SNP (rs1342326) and 1 IL1RAP SNP (rs9290936). IL33 and IL1RL1 SNPs were nominally associated with asthma. Three SNP pairs showed interaction for asthma in the PIAMA study but not in ALSPAC. CONCLUSIONS: IL33-IL1RL1 pathway polymorphisms are associated with asthma and specific wheezing phenotypes; that is, most SNPs are associated with intermediate-onset wheeze, a phenotype closely associated with sensitization. We speculate that IL33-IL1RL1 pathway polymorphisms affect development of wheeze and subsequent asthma through sensitization in early childhood. [less ▲]

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See detailGenome-wide environmental interaction analysis using multidimensional data reduction principles to identify asthma pharmacogenetic loci in relation to corticosteroid therapy
Van Lishout, François ULg; Bessonov, Kyrylo ULg; Duan, Quingling et al

Poster (2013, October 25)

Genome-wide gene-environment (GxE) and gene-gene (GxG) interaction studies share a lot of challenges via the common genetic component they involve. GWEI studies may therefore benefit from the abundance of ... [more ▼]

Genome-wide gene-environment (GxE) and gene-gene (GxG) interaction studies share a lot of challenges via the common genetic component they involve. GWEI studies may therefore benefit from the abundance of methodologies that are available in the context of genome-wide epistasis detection methods. One of these is Model-Based Multifactor Dimensionality Reduction (MB-MDR), which does not make any assumption about the genetic inheritance model. MB-MDR involves reducing a high-dimensional GxE space to GxE factor levels that either exhibit high or low or no evidence for their association to disease outcome. In contrast to logistic regression and random forests, MB-MDR can be used to detect GxE interactions in the absence of any main effects or when sample sizes are too small to be able to model all main and GxE interaction effects. In this ongoing study, we demonstrate the opportunities and challenges of MB-MDR for genome-wide GxE interaction analysis and analyzed the difference in prebronchodilator FEV1 following 8 weeks of inhaled corticosteroid therapy, for 565 pediatric Caucasian CAMP (ages 5-12) from the SHARE project. [less ▲]

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See detailGenome-wide association interaction analysis for Alzheimer’s disease.
Gusareva, Elena ULg; Bellenguez, C; Cuyvers, E et al

Poster (2013, October)

Identification of epistasis is a challenging task that when successful gives new clues to systems-level genetics where the complexity of underling biology of human disease can be better understood. Though ... [more ▼]

Identification of epistasis is a challenging task that when successful gives new clues to systems-level genetics where the complexity of underling biology of human disease can be better understood. Though many novel methods for detecting epistasis have been proposed and many studies for epistasis detection have been conducted, so far few studies can demonstrate replicable epistasis. In the present work, we propose a minimal protocol for exhaustive genome-wide association interaction (GWAI) analysis that involves screening for epistasis over large-scale genomic data combining strengths of different methods and statistical tools. The different steps of this protocol are illustrated on a real-life data application for Alzheimer’s disease (a large cohort of 2259 patients and 6017 controls from France). Using this protocol, we identified AD-associated interacting SNPs-pair from chromosome 6q11.1 (rs6455128, the KHDRBS2 gene) and 13q12.11 (rs7989332, the CRYL1 gene) and male-specific epistasis between SNPs from chromosome 5q34 (rs729149 and rs3733980, the WWC1 gene) and 15q22.2 (rs9806612, rs9302230 and rs7175766, the TLN2 gene). The transcriptome analysis revealed negative correlation between expression levels of KHDRBS2 and CRYL1 in both the temporal cortex and cerebellum brain regions and positive correlation between the expression levels of CRYL1 and WWC1 in the temporal cortex brain region. A replication analysis strategy and a meta-analysis approach in independent data confirmed effects of some of the discovered interactions. [less ▲]

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See detailReplication of large-scale epistasis studies: an example on ankylosing spondylitis
Bessonov, Kyrylo ULg; Van Steen, Kristel ULg

Poster (2013, September 17)

Ankylosing spondylitis (AS) is a common form of inflammatory arthritis occurring in approximately 5 out of 1,000 adults of European descent. Recently, the Australo-Anglo-American Spondyloarthritis ... [more ▼]

Ankylosing spondylitis (AS) is a common form of inflammatory arthritis occurring in approximately 5 out of 1,000 adults of European descent. Recently, the Australo-Anglo-American Spondyloarthritis Consortium and the WTCCC2 showed that polymorphisms of ERAP1 only affect AS risk in HLA-B27-positive individuals, hereby establishing an interaction between ERAP1 and HLA in the TASC, WTCCC2 and replication datasets [2,5]. We were able to confirm this interaction although using other SNPs. In this study, we use the aforementioned data from WTTCC2 on AS to address unresolved issues when performing large-scale SNP-SNP interaction studies, so as to better guarantee “stable” and “truly replicable” results. These issues are 1) the choice of variable selection method (e.g., of known loci mapping to genes part of know pathways), 2) the choice of SNPs representing a genomic region (e.g., SNPs with modest versus negligible LD between them), 3) the choice of analysis method (e.g., regression-based versus data-reduction (non-parametric) based), 4) different adjustment schemes for lower-order effects (using additive/co-dominant genetic models). We show that even modest changes in 1)-4) may give rise to quite varying epistasis findings for AS, and motivate some “optimal” choices via extensive simulation studies. In this work we rely on a minimal GWAI protocol for genome-wide epistasis detection using SNPs, as developed in our lab [6][9], using the advanced non-parametric Model-Based Multifactor Dimensionality Reduction (MB-MDR) method [1] and an adapted [*] BOolean Operation-based Screening and Testing (BOOST) algorithm [4]. [*] A BOOST [4] like implementation based on the original BOOST algorithm which accounts for missing genotypes [less ▲]

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See detailTherapeutic Strategy and Patient Outcome during the First 2 Years of Pediatric Crohn’s Disease
Veereman, G; Mahachie John, Jestinah ULg; De Greef, E et al

in Journal of Pediatric Gastroenterology and Nutrition (2013, May)

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See detailAn efficient algorithm to perform multiple testing in epistasis screening
Van Lishout, François ULg; Mahachie John, Jestinah ULg; Gusareva, Elena ULg et al

in BMC Bioinformatics (2013), 14

Background: Research in epistasis or gene-gene interaction detection for human complex traits has grown over the last few years. It has been marked by promising methodological developments, improved ... [more ▼]

Background: Research in epistasis or gene-gene interaction detection for human complex traits has grown over the last few years. It has been marked by promising methodological developments, improved translation efforts of statistical epistasis to biological epistasis and attempts to integrate different omics information sources into the epistasis screening to enhance power. The quest for gene-gene interactions poses severe multiple-testing problems. In this context, the maxT algorithm is one technique to control the false-positive rate. However, the memory needed by this algorithm rises linearly with the amount of hypothesis tests. Gene-gene interaction studies will require a memory proportional to the squared number of SNPs. A genome-wide epistasis search would therefore require terabytes of memory. Hence, cache problems are likely to occur, increasing the computation time. In this work we present a new version of maxT, requiring an amount of memory independent from the number of genetic effects to be investigated. This algorithm was implemented in C++ in our epistasis screening software MBMDR-3.0.3. We evaluate the new implementation in terms of memory efficiency and speed using simulated data. The software is illustrated on real-life data for Crohn's disease. Results: In the case of a binary (affected/unaffected) trait, the parallel workflow of MBMDR-3.0.3 analyzes all gene-gene interactions with a dataset of 100,000 SNPs typed on 1000 individuals within 4 days and 9 hours, using 999 permutations of the trait to assess statistical significance, on a cluster composed of 10 blades, containing each four Quad-Core AMD Opteron Processor 2352 2.1 GHz. In the case of a continuous trait, a similar run takes 9 days. Our program found 14 SNP-SNP interactions with a multiple-testing corrected p-value of less than 0.05 on real-life Crohn's disease data. Conclusions: Our software is the first implementation of the MB-MDR methodology able to solve large-scale SNP-SNP interactions problems within a few days, without using much memory, while adequately controlling the type I error rates. A new implementation to reach genome-wide epistasis screening is under construction. In the context of Crohn's disease, MBMDR-3.0.3 could identify epistasis involving regions that are well known in the field and could be explained from a biological point of view. This demonstrates the power of our software to find relevant phenotype-genotype higher-order associations. [less ▲]

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See detailGenome-wide association interaction analysis for complex diseases: an example on Alzheimer’s disease.
Gusareva, Elena ULg; Cuyvers, E; Colon, S et al

Poster (2013, April)

Objectives: Common genetic mutations that can be detected via a genome-wide association (GWA) study and at the same time have a strong contribution to disease risk are fairly limited. Some of the genetic ... [more ▼]

Objectives: Common genetic mutations that can be detected via a genome-wide association (GWA) study and at the same time have a strong contribution to disease risk are fairly limited. Some of the genetic variants in humans are either rare, thus more difficult to be identified, or they are common, but exert relatively small or even no individual effects that are masked or enhanced by one or several genes. The discovery of interacting genetic variants, possibly explaining part of the hidden genetic heritability, requires the development of sophisticated strategies and bioinformatics tools. Methods: In the present study, we propose a minimal protocol for genome-wide association interaction (GWAI) analysis that involves screening over large-scale genomic data in the search for epistatic or synergetic effects. The different steps of this minimal protocol are illustrated on a real-life data application for Alzheimer disease (AlzD) (large human cohort of 2,259 cases and 6,017 controls from France) and the pros and cons of the approaches are discussed. Results: Using the protocol, we identified two pairs of AlzD-associated interacting SNPs: from chromosome 6q11.1 and 13q12.11 and male-specific epistasis between SNPs from chromosome 5q34 and 15q22.2. Conclusion: In the present work we developed and applied an epistasis detection protocol to perform a comprehensive genome-wide search for AlzD-associated epistatic effects, hereby combining the strengths of different strategies, methods and statistical tools. It is the first time an epistasis study of this magnitude has been conducted in the context of AlzD. We show the advantages of viewing and analyzing data from different angles. A replication analysis strategy adapted to the epistasis detection context, as well as a meta-analytic approach confirmed effects of the discovered interactions. Apart from the biological and clinical importance, the present work offers a roadmap for future investigations in the field of epistasis detection and interpretation. [less ▲]

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See detailGenome-wide Epistasis Screening for Alzheimer‘s Disease
Gusareva, Elena ULg; Bellenguez, C; Sleegers, K et al

Poster (2013, March)

Objectives: Alzheimer disease (AlzD) is a complex, progressive neurodegenerative disease where dementia symptoms (memory and other intellectual abilities loss) gradually worsen over a number of years. The ... [more ▼]

Objectives: Alzheimer disease (AlzD) is a complex, progressive neurodegenerative disease where dementia symptoms (memory and other intellectual abilities loss) gradually worsen over a number of years. The disease is characterized by the neuropathologic findings of neurofibrillary tangles and amyloid plaques that accumulate in vulnerable brain regions. AlzD is inherited as complex trait and appears to be highly heritable with 58-79 percent attributable to genetic factors. So far, although a number of main-effect genes have been identified, only a fraction of AlzD cases can be explained by specific gene mutations. In our study we performed an exhaustive and selective genome-wide screening for SNP-SNP interactions associated with AlzD in a large case/control cohort to reveal hidden heritability that can be accounted for by epistasis. Methods: We developed a minimal protocol for genome-wide association interaction (GWAI) analysis that involves screening over large-scale genomic data in the search for epistatic or synergetic effects. The protocol was applied on a large human cohort of 2,259 cases AlzD cases and 6,017 healthy controls from France to search for AlzD-associated epistasic effects. Results: In the exhaustive genome-wide screening, we identified two pairs of AlzD-associated interacting SNPs from chromosomes 6q11.1 and 13q12.11, and male-specific epistasis between SNPs from chromosomes 5q34 and 15q22.2. In the selective epistasis search, screening over the candidate genes for AlzD previously reported to be in interaction, we replicated seven out of twelve AlzD-associated gene pairs (INS / PPARA, IL1A / PPARA, IL10 / PPARA, TF / HFE, MTHFR / IL6, ABCA1 / NPC1, LRP1 / MAPT). Conclusion: It is the first time an epistasis study of this magnitude has been conducted in the context of AlzD. We show the advantages of viewing and analyzing data from different angles. A replication analysis strategy adapted to the epistasis detection context, as well as a meta-analytic approach confirmed effects of the discovered interactions. Apart from the biological and clinical importance, the present work offers a roadmap for future investigations in the field of epistasis detection and interpretation. [less ▲]

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See detailTherapeutic Strategy and Patient Outcome during the First 2 Years of Pediatric Crohn’s Disease
Veereman, G; Mahachie John, Jestinah ULg; De Greef, E et al

in Acta Gastro-Enterologica Belgica (2013)

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See detailProfile of pediatric Crohn's disease in Belgium.
De Greef, E.; Mahachie John, Jestinah ULg; Hoffman, I. et al

in Journal of Crohn's & colitis (2013), 7(11), 588-98

AIM: A Belgian registry for pediatric Crohn's disease, BELCRO, was created. This first report aims at describing disease presentation and phenotype and determining associations between variables at ... [more ▼]

AIM: A Belgian registry for pediatric Crohn's disease, BELCRO, was created. This first report aims at describing disease presentation and phenotype and determining associations between variables at diagnosis and registration in the database. METHODS: Through a collaborative network, children with previously established Crohn's disease and newly diagnosed children and adolescents (under 18 y of age) were recruited over a 2 year period. Data were collected by 23 centers and entered in a database. Statistical association tests analyzed relationships between variables of interest at diagnosis. RESULTS: Two hundred fifty-five patients were included. Median age at diagnosis was 12.5 y (range: 1.6-18 y); median duration of symptoms prior to diagnosis was 3 m (range: 1-12 m). Neonatal history and previous medical history did not influence disease onset nor disease behavior. Fifty three % of these patients presented with a BMI z-score < -1. CRP was an independent predictor of disease severity. Steroids were widely used as initial treatment in moderate to severe and extensive disease. Over time, immunomodulators and biological were prescribed more frequently, reflecting a lower prescription rate for steroids and 5-ASA. A positive family history was the sole significant determinant for earlier use of immunosuppression. CONCLUSION: In Belgium, the median age of children presenting with Crohn's disease is 12.5 y. Faltering growth, extensive disease and upper GI involvement are frequent. CRP is an independent predictive factor of disease activity. A positive family history appears to be the main determinant for initial treatment choice. [less ▲]

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See detailGenetic association and functional role of Crohn disease risk alleles involved in microbial sensing, autophagy, and endoplasmic reticulum (ER) stress.
Hoefkens, Eveline; Nys, Kris; John, Jestinah M. et al

in Autophagy (2013), 9(12), 2046-55

Genome-wide association studies have identified several genes implicated in autophagy (ATG16L1, IRGM, ULK1, LRRK2, and MTMR3), intracellular bacterial sensing (NOD2), and endoplasmic reticulum (ER) stress ... [more ▼]

Genome-wide association studies have identified several genes implicated in autophagy (ATG16L1, IRGM, ULK1, LRRK2, and MTMR3), intracellular bacterial sensing (NOD2), and endoplasmic reticulum (ER) stress (XBP1 and ORMDL3) to be associated with Crohn disease (CD). We studied the known CD-associated variants in these genes in a large cohort of 3451 individuals (1744 CD patients, 793 ulcerative colitis (UC) patients and 914 healthy controls). We also investigated the functional phenotype linked to these genetic variants. Association with CD was confirmed for NOD2, ATG16L1, IRGM, MTMR3, and ORMDL3. The risk for developing CD increased with an increasing number of risk alleles for these genes (P<0.001, OR 1.26 [1.20 to 1.32]). Three times as many (34.8%) CD patients carried a risk allele in all three pathways, in contrast to 13.3% of the controls (P<0.0001, OR = 3.46 [2.77 to 4.32]). For UC, no significant association for one single nucleotide polymorphism (SNP) was found, but the risk for development of UC increased with an increasing total number of risk alleles (P = 0.001, OR = 1.10 [1.04 to 1.17]). We found a genetic interaction between reference SNP (rs)2241880 (ATG16L1) and rs10065172 (IRGM) in CD. Functional experiments hinted toward an association between an increased genetic risk and an augmented inflammatory status, highlighting the relevance of the genetic findings. [less ▲]

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See detailBehind the (impedance) baseline in children.
Salvatore, S.; Salvatoni, A.; Van Steen, Kristel ULg 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 ▲]

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See detailEsophageal impedance baseline is age dependent.
Salvatore, Silvia; Salvatoni, Alessandro; Van Berkel, Marieke 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 ▲]

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See detailEU Pancreas: An Integrated European Platform for Pancreas Cancer Research - from Basic Science to Clinical and Public Health Interventions for a Rare Disease.
Milne, R.; La Vecchia, C.; Van Steen, Kristel ULg 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 ▲]

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