gammaMAXT: a fast multiple-testing correction algorithm
Van Lishout, François ; Gadaleta, Francesco ; 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 ▲]Detailed reference viewed: 63 (8 ULg)
High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis.
; ; et al
in Nature Genetics (2015), 47(2), 172-9
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 ▲]Detailed reference viewed: 32 (6 ULg)
Filter-free exhaustive odds ratio-based genome-wide interaction approach pinpoints evidence for interaction in the HLA region in psoriasis.
; ; et al
in BMC genetics (2015), 16(1), 11
BackgroundDeciphering the genetic architecture of complex traits is still a major challenge for human genetics. In most cases, genome-wide association studies have only partially explained the ... [more ▼]
BackgroundDeciphering the genetic architecture of complex traits is still a major challenge for human genetics. In most cases, genome-wide association studies have only partially explained the heritability of traits and diseases. Epistasis, one potentially important cause of this missing heritability, is difficult to explore at the genome-wide level. Here, we develop and assess a tool based on interactive odds ratios (IOR), Fast Odds Ratio-based sCan for Epistasis (FORCE), as a novel approach for exhaustive genome-wide epistasis search. IOR is the ratio between the multiplicative term of the odds ratio (OR) of having each variant over the OR of having both of them. By definition, an IOR that significantly deviates from 1 suggests the occurrence of an interaction (epistasis). As the IOR is fast to calculate, we used the IOR to rank and select pairs of interacting polymorphisms for P value estimation, which is more time consuming.ResultsFORCE displayed power and accuracy similar to existing parametric and non-parametric methods, and is fast enough to complete a filter-free genome-wide epistasis search in a few days on a standard computer. Analysis of psoriasis data uncovered novel epistatic interactions in the HLA region, corroborating the known major and complex role of the HLA region in psoriasis susceptibility.ConclusionsOur systematic study revealed the ability of FORCE to uncover novel interactions, highlighted the importance of exhaustiveness, as well as its specificity for certain types of interactions that were not detected by existing approaches. We therefore believe that FORCE is a valuable new tool for decoding the genetic basis of complex diseases. [less ▲]Detailed reference viewed: 12 (0 ULg)
Short-term Effect of Infliximab Is Reflected in the Clot Lysis Profile of Patients with Inflammatory Bowel Disease: A Prospective Study.
; ; et al
in Inflammatory bowel diseases (2015), 21(3), 570-8
BACKGROUND: Inflammatory bowel disease (IBD) is recognized as an independent risk factor for thrombosis. First, we investigate whether the concentration of fibrinolysis inhibitors is increased in patients ... [more ▼]
BACKGROUND: Inflammatory bowel disease (IBD) is recognized as an independent risk factor for thrombosis. First, we investigate whether the concentration of fibrinolysis inhibitors is increased in patients with IBD. Second, we investigate the effect of infliximab induction therapy on the hemostatic profile. METHODS: This prospective study included 103 patients with IBD starting infliximab therapy and 113 healthy controls. Plasma was collected before the first infliximab infusion (wk 0) and after induction therapy (wk 14). Patients not showing a clinical response on induction were considered as primary nonresponders. Fibrinolysis inhibitors were measured by enzyme-linked immunosorbent assay. Using a clot lysis assay, the area under the curve (global marker for coagulation/fibrinolysis), 50% clot lysis time (marker for fibrinolytic capacity), and amplitude (indicator for clot formation) were determined. RESULTS: Patients with IBD selected for infliximab treatment have higher area under the curve (median 29 [interquartile range, 20-38]) and amplitude (0.4 [0.3-0.5]) compared with healthy controls (18 [13-24] and 0.3 [0.2-0.3], respectively, P < 0.001). Primary nonresponders showed a decrease neither in inflammatory markers nor in hemostatic parameters, whereas in primary responders, a decrease in inflammatory markers was associated with a decrease in both area under the curve (29 [20-38] (wk 0) to 20 [14-28] (wk 14), P < 0.001) and amplitude (0.4 [0.3-0.5] (wk 0) to 0.3 [0.3-0.4] (wk 14), P < 0.001). CONCLUSIONS: This is the first prospective study demonstrating that the clot lysis profile differs between patients with IBD and healthy individuals. On infliximab induction treatment, this clot lysis profile normalizes in responders suggesting that infliximab treatment is advisable for patients with IBD with an activated hemostatic profile. [less ▲]Detailed reference viewed: 8 (1 ULg)
Withdrawal of Immunomodulators After Co-treatment Does Not Reduce Trough Level of Infliximab in Patients With Crohn's Disease.
; ; et al
in Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association (2015), 13(3), 514-5214
BACKGROUND & AIMS: The addition of immunomodulators increases the efficacy of maintenance therapy with infliximab for up to 1 year in patients with Crohn's disease who have not been previously treated ... [more ▼]
BACKGROUND & AIMS: The addition of immunomodulators increases the efficacy of maintenance therapy with infliximab for up to 1 year in patients with Crohn's disease who have not been previously treated with immunomodulators. However, there are questions about the effect of withdrawing immunomodulator therapy from these patients. We studied the effects of treatment with infliximab and immunomodulators (co-treatment) and then immunomodulator withdrawal on long-term outcomes of patients, as well as trough levels of infliximab and formation of anti-infliximab antibodies (ATI). METHODS: In a retrospective study with the median follow-up period of 34 months (interquartile range, 19-58 months), we analyzed data from 223 patients treated for Crohn's disease between May 1999 and December 2010 at the University Hospitals, Leuven, Belgium (65 received infliximab monotherapy, 158 received infliximab and an immunomodulator). Trough levels of infliximab and levels of ATI were measured in blood samples collected from 117 patients throughout co-treatment, as well as the time of immunomodulator withdrawal and after withdrawal. RESULTS: Patients receiving co-treatment had higher trough levels of infliximab (adjusted mean increase, 1.44-fold) than those receiving infliximab monotherapy (95% confidence interval [CI], 1.07-1.92; P = .02). A smaller percentage of patients receiving co-treatment developed ATI (35 of 158, 22%) than those receiving infliximab monotherapy (25 of 65, 38%; P = .01). Among co-treated patients, levels of infliximab remained stable after immunomodulators were withdrawn (before: 3.2 mug/mL; 95% CI, 1.6-5.8 mug/mL and after: 3.7 mug/mL; 95% CI, 1.3-6.3 mug/mL; P = .70). After withdrawal of immunomodulators, 45 of 117 patients (38%) required increasing doses of infliximab, and 21 of 117 (18%) discontinued infliximab. At the time of immunomodulator withdrawal, trough levels of infliximab and C-reactive protein were most strongly associated with response to infliximab thereafter. CONCLUSIONS: In a retrospective analysis, we confirmed that withdrawal of immunomodulators after at least 6 months (median, 13 months) of co-treatment with infliximab does not reduce the trough levels of infliximab in patients with Crohn's disease. Detectable trough levels of infliximab at the time of immunomodulator withdrawal are associated with long-term response. [less ▲]Detailed reference viewed: 7 (0 ULg)
Practical aspects of genome-wide association interaction analysis.
Gusareva, Elena ; Van Steen, Kristel
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 ▲]Detailed reference viewed: 16 (3 ULg)
Genome-Wide Association Interaction Analysis for Alzheimer’s Disease
Gusareva, Elena ; ; 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 ▲]Detailed reference viewed: 39 (10 ULg)
LD-based haplotype encoding scheme with iterative pruning principal component analysis (ipPCA) to retrieve population substructures
Chaichoompu, Kridsadakorn ; Fouladi, Ramouna ; 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)  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 . 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 ▲]Detailed reference viewed: 72 (5 ULg)
Genome-wide association interaction analysis for Alzheimer’s disease.
Gusareva, Elena ; ; et al
Poster (2014, January 27)Detailed reference viewed: 6 (0 ULg)
A comparison of multivariate genome-wide association methods.
; Van Steen, Kristel ; et al
in PloS one (2014), 9(4), 95923
Joint association analysis of multiple traits in a genome-wide association study (GWAS), i.e. a multivariate GWAS, offers several advantages over analyzing each trait in a separate GWAS. In this study we ... [more ▼]
Joint association analysis of multiple traits in a genome-wide association study (GWAS), i.e. a multivariate GWAS, offers several advantages over analyzing each trait in a separate GWAS. In this study we directly compared a number of multivariate GWAS methods using simulated data. We focused on six methods that are implemented in the software packages PLINK, SNPTEST, MultiPhen, BIMBAM, PCHAT and TATES, and also compared them to standard univariate GWAS, analysis of the first principal component of the traits, and meta-analysis of univariate results. We simulated data (N = 1000) for three quantitative traits and one bi-allelic quantitative trait locus (QTL), and varied the number of traits associated with the QTL (explained variance 0.1%), minor allele frequency of the QTL, residual correlation between the traits, and the sign of the correlation induced by the QTL relative to the residual correlation. We compared the power of the methods using empirically fixed significance thresholds (alpha = 0.05). Our results showed that the multivariate methods implemented in PLINK, SNPTEST, MultiPhen and BIMBAM performed best for the majority of the tested scenarios, with a notable increase in power for scenarios with an opposite sign of genetic and residual correlation. All multivariate analyses resulted in a higher power than univariate analyses, even when only one of the traits was associated with the QTL. Hence, use of multivariate GWAS methods can be recommended, even when genetic correlations between traits are weak. [less ▲]Detailed reference viewed: 11 (0 ULg)
Diagnosing and treating pediatric Crohn's disease patients: is there a difference between adult and pediatric gastroenterologist's practices ? Results of the BELCRO cohort.
; ; et al
in Acta gastro-enterologica Belgica (2014), 77(1), 25-9Detailed reference viewed: 7 (0 ULg)
Letter to the Editor: On the term 'interaction' and related phrases in the literature on Random Forests.
; ; et al
in Briefings in bioinformatics (2014)
In an interesting and quite exhaustive review on Random Forests (RF) methodology in bioinformatics Touw et al. address-among other topics-the problem of the detection of interactions between variables ... [more ▼]
In an interesting and quite exhaustive review on Random Forests (RF) methodology in bioinformatics Touw et al. address-among other topics-the problem of the detection of interactions between variables based on RF methodology. We feel that some important statistical concepts, such as 'interaction', 'conditional dependence' or 'correlation', are sometimes employed inconsistently in the bioinformatics literature in general and in the literature on RF in particular. In this letter to the Editor, we aim to clarify some of the central statistical concepts and point out some confusing interpretations concerning RF given by Touw et al. and other authors. [less ▲]Detailed reference viewed: 9 (0 ULg)
Risk of malignancies in patients with inflammatory bowel disease treated with thiopurines or anti-TNF alpha antibodies.
; ; et al
in Pharmacoepidemiology and drug safety (2014), 23(7), 735-44
PURPOSE: We aimed to analyse malignancy rates and predictors for the development of malignancies in a large German inflammatory bowel disease (IBD) cohort treated with thiopurines and/or anti-tumour ... [more ▼]
PURPOSE: We aimed to analyse malignancy rates and predictors for the development of malignancies in a large German inflammatory bowel disease (IBD) cohort treated with thiopurines and/or anti-tumour necrosis factor (TNF) antibodies. METHODS: De novo malignancies in 666 thiopurine-treated and/or anti-TNF-treated IBD patients were analysed. Patients (n = 262) were treated with thiopurines alone and never exposed to anti-TNF antibodies (TP group). In addition, patients (n = 404) were exposed to anti-TNF antibodies (TNF+ group) with no (7.4%), discontinued (80.4%) or continued (12.1%) thiopurine therapy. RESULTS: In the TP group, 20 malignancies were observed in 18 patients compared with 8 malignancies in 7 patients in the TNF+ group (hazard ratio 4.15; 95% CI 1.82-9.44; p = 0.0007; univariate Cox regression). Moreover, 18.2% of all patients in the TP group >/=50 years of age developed a malignancy, compared with 3.8% of all patients <50 years of age (p = 0.0008). In the TNF+ group, 6.5% of all patients >/=50 years of age developed malignancies compared with 0.3% of all patients <50 years of age (p = 0.0007). In both groups combined, thiopurine treatment duration >/=4 years was associated with the risk for skin cancer (p = 0.0024) and lymphoma (p = 0.0005). CONCLUSIONS: Our data demonstrate an increased risk for the development of malignancies in IBD patients treated with thiopurines in comparison with patients treated with anti-TNF antibodies with or without thiopurines. [less ▲]Detailed reference viewed: 10 (0 ULg)
Discovering main genetic interactions with LABNet LAsso-based network inference.
Gadaleta, Francesco ; Van Steen, Kristel
in PloS one (2014), 9(11), 110451
Genome-wide association studies can potentially unravel the mechanisms behind complex traits and common genetic diseases. Despite the valuable results produced thus far, many questions remain unanswered ... [more ▼]
Genome-wide association studies can potentially unravel the mechanisms behind complex traits and common genetic diseases. Despite the valuable results produced thus far, many questions remain unanswered. For instance, which specific genetic compounds are linked to the risk of the disease under investigation; what biological mechanism do they act through; or how do they interact with environmental and other external factors? The driving force of computational biology is the constantly growing amount of big data generated by high-throughput technologies. A practical framework that can deal with this abundance of information and that consent to discovering genetic associations and interactions is provided by means of networks. Unfortunately, high dimensionality, the presence of noise and the geometry of data can make the aforementioned problem extremely challenging. We propose a penalised linear regression approach that can deal with the aforementioned issues that affect genetic data. We analyse the gene expression profiles of individuals with a common trait to infer the network structure of interactions among genes. The permutation-based approach leads to more stable and reliable networks inferred from synthetic microarray data. We show that a higher number of permutations determines the number of predicted edges, improves the overall sensitivity and controls the number of false positives. [less ▲]Detailed reference viewed: 55 (0 ULg)
Neutrophil gelatinase B-associated lipocalin and matrix metalloproteinase-9 complex as a surrogate serum marker of mucosal healing in ulcerative colitis.
; ; et al
in Inflammatory bowel diseases (2014), 20(7), 1198-207
BACKGROUND: The current standard for the assessment of mucosal healing after therapy in inflammatory bowel diseases is endoscopy. However, a high need exists for noninvasive, accurate surrogate markers ... [more ▼]
BACKGROUND: The current standard for the assessment of mucosal healing after therapy in inflammatory bowel diseases is endoscopy. However, a high need exists for noninvasive, accurate surrogate markers. METHODS: In 2 independent cohorts, levels of serum neutrophil gelatinase B-associated lipocalin and matrix metalloproteinase-9 complex (NGAL-MMP-9) from patients with active ulcerative colitis (UC) before and after first treatment with infliximab and from healthy controls (HC) were determined with zymography and sandwich enzyme-linked immunosorbent assay. The response to infliximab was defined as complete mucosal healing (Mayo endoscopic subscore 0-1) at control endoscopy. Data were analyzed with SPSS, and P values <0.05 were considered significant. RESULTS: In cohort 1 (n = 66; median age, 30 yr; 38% female), serum NGAL-MMP-9 levels significantly increased at baseline in UC patients versus HC (103.8 versus 42.4 ng/mL; P < 0.0001), whereas 55% of the patients had normal C-reactive protein levels. NGAL-MMP-9 levels significantly decreased after therapy in UC responders (from 116.3 ng/mL to 32.0 ng/mL; P < 0.0001) and in nonresponders (from 94.7 ng/mL to 54.1 ng/mL; P = 0.047). In cohort 2 (n = 132; median age, 39 yr; 53% female), NGAL-MMP-9 levels increased at baseline in active UC patients versus HC (86.5 versus 60.4 ng/mL; P = 0.10), whereas 45% of the patients had normal C-reactive protein levels. NGAL-MMP-9 levels significantly decreased after therapy in responders (from 87.5 ng/mL to 16.3 ng/mL; P < 0.0001) but not in nonresponders (from 82.7 ng/mL to 57.8 ng/mL; P = 0.19). After pooling the data, a cutoff value of 97.7 ng/mL for NGAL-MMP-9 complex was determined to predict complete mucosal healing with high specificity (91%). CONCLUSIONS: Serum NGAL-MMP-9 is suggested as a new surrogate marker for the assessment of mucosal healing in UC patients treated with infliximab. [less ▲]Detailed reference viewed: 10 (0 ULg)
Active PAI-1 as marker for venous thromboembolism: case-control study using a comprehensive panel of PAI-1 and TAFI assays.
; ; et al
in Thrombosis research (2014), 134(5), 1097-102
BACKGROUND: Both activated Thrombin Activatable Fibrinolysis Inhibitor (TAFI) and active Plasminogen Activator Inhibitor-1 (PAI-1) attenuate fibrinolysis and may therefore contribute to the ... [more ▼]
BACKGROUND: Both activated Thrombin Activatable Fibrinolysis Inhibitor (TAFI) and active Plasminogen Activator Inhibitor-1 (PAI-1) attenuate fibrinolysis and may therefore contribute to the pathophysiology of Venous ThromboEmbolism (VTE). Whether increased TAFI and/or PAI-1 concentrations are associated with VTE is unclear. OBJECTIVE: To study an association of impaired fibrinolysis and VTE using a comprehensive panel of in-house developed assays measuring intact TAFI, activation peptide of TAFI (AP-TAFI), PAI-1 antigen, endogenous PAI-1:t-PA complex (PAI-1:t-PA) and active PAI-1 levels in 102 VTE patients and in 113 healthy controls (HC). RESULTS: Active PAI-1 was significantly higher in VTE patients compared to HC (20.9 [9.6-37.8] ng/ml vs. 6.2 [3.5-9.7] ng/ml, respectively). Active PAI-1 was the best discriminator with an area under the ROC curve and 95% confidence interval (AUROC [95%CI]) of 0.84 [0.79-0.90] compared to 0.75 [0.68-0.72] for PAI-1:t-PA, 0.65 [0.58-0.73] for PAI-1 antigen, 0.62 [0.54-0.69] for AP-TAFI and 0.51 [0.44-0.59] for intact TAFI. Using ROC analysis, we defined an optimal cut-off of 12.8 ng/ml for active PAI-1, with corresponding sensitivity of 71 [61-79] % and specificity of 89 [82-94] %. A lack of association with the time between VTE event and sample collection or with the intake of anticoagulant treatment suggests that active PAI-1 levels are sustainable high in VTE patients. CONCLUSIONS: This case-control study emphasizes the clinical importance of measuring active PAI-1 instead of PAI-1 antigen and identifies active PAI-1 as a potential marker of VTE. Prognostic studies will need to address the clinical significance of active PAI-1 as biomarker. [less ▲]Detailed reference viewed: 12 (0 ULg)
Association of IL33-IL-1 receptor-like 1 (IL1RL1) pathway polymorphisms with wheezing phenotypes and asthma in childhood.
; Mahachie John, Jestinah ; 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 ▲]Detailed reference viewed: 24 (3 ULg)
Genome-wide environmental interaction analysis using multidimensional data reduction principles to identify asthma pharmacogenetic loci in relation to corticosteroid therapy
Van Lishout, François ; Bessonov, Kyrylo ; 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 ▲]Detailed reference viewed: 49 (11 ULg)
Genome-wide association interaction analysis for Alzheimer’s disease.
Gusareva, Elena ; ; 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 ▲]Detailed reference viewed: 5 (0 ULg)
Replication of large-scale epistasis studies: an example on ankylosing spondylitis
Bessonov, Kyrylo ; Van Steen, Kristel
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 , using the advanced non-parametric Model-Based Multifactor Dimensionality Reduction (MB-MDR) method  and an adapted [*] BOolean Operation-based Screening and Testing (BOOST) algorithm . [*] A BOOST  like implementation based on the original BOOST algorithm which accounts for missing genotypes [less ▲]Detailed reference viewed: 26 (3 ULg)