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See detailCapturing fine-level structure using unsupervised clustering method with multiple data types
Chaichoompu, Kridsadakorn ULg; Tongsima, Sissades; Shaw, Philip James et al

Poster (2016, June 17)

Several methods exist to detect shared genetic ancestry or to identify population substructure using SNP-based or haplotype-based information (Price et al. 2006, Lawson et al. 2012). Here, we propose an ... [more ▼]

Several methods exist to detect shared genetic ancestry or to identify population substructure using SNP-based or haplotype-based information (Price et al. 2006, Lawson et al. 2012). Here, we propose an unsupervised clustering method built on the ipPCA algorithm (Intarapanich et al. 2009). Our method supports both ordinal and categorical data, and it can be applied to panels of single locus and/or multiple loci data, or gene-based integrative summaries (Fouladi et al. 2015). Our method involves an iterative process using binary and ternary splits based on multivariate Gaussian mixture modeling of PCs and Clustering EM estimation as in (Lebret et al. 2015). To evaluate its performance, we examined different simulated scenarios of 2-4 populations, 500-8,000 individuals, 5,000-20,000 independent SNPs in HWE, and FST=[0.0007,0.006] (Balding and Nichols 1995), with 100 replicates for each scenario. SNPs were treated as categorical or continuous including ancestry-corrected SNPs. Haplotype-based runs used HapMap 3 data: CHB, CHD, and JPT. In simulated scenarios of extremely subtle structure (FST=[0.0009,0.006]), a population classification accuracy of 92% or greater was obtained, which was superior to ipPCA. Also in case of the HapMap populations, promising results to detect fine structure were obtained. We are convinced that our method has a potential to detect fine-level structure and it will be important in molecular reclassification studies of patients once underlying population structure has been removed. [less ▲]

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See detailA novel unsupervised clustering approach with multiple data types to reveal fine-level structure
Chaichoompu, Kridsadakorn ULg; Tongsima, Sissades; Shaw, Philip James et al

Poster (2016, May 21)

Introduction: Several methods exist to identify population substructure that is due to shared genetic ancestry or regional proximity. These may be SNP-based or haplotype-based (Price et al. 2006, Lawson ... [more ▼]

Introduction: Several methods exist to identify population substructure that is due to shared genetic ancestry or regional proximity. These may be SNP-based or haplotype-based (Price et al. 2006, Lawson et al. 2012). Here, we present a flexible unsupervised clustering approach that is built on the ipPCA machinery (Intarapanich et al. 2009). Methods: Our method supports both numeric and categorical data, and can be applied to panels of SNPs and/or haplotypes, or gene-based integrative summaries (Fouladi et al. 2015). Unlike ipPCA, our method involves an iterative process using binary and ternary splits based on multivariate Gaussian mixture modeling of PCs and Clustering EM (CEM) estimation as in (Lebret et al. 2015). To assess performance, we considered different simulated scenarios of FST=[0.0005,0.006], 5,000-20,000 independent SNPs in HWE, 500-8,000 individuals, and 2-4 populations (Balding and Nichols 1995), with 100 replicates for each scenario. SNPs were treated as categorical or continuous (including ancestry-corrected SNPs). Haplotype-based runs used HapMap 3 data: CHB-JPT (FST=0.007) and CEU-TSI (FST=0.004). Result and Conclusion: In simulated scenarios of extremely subtle structure (FST=[0.0009,0.002]), a population classification accuracy of 92.56% or greater was obtained, which was superior to ipPCA. Promising results to detect fine structure were also obtained in case of the HapMap populations. We believe that the ability of our approach to detect subtle structure, including outlier individuals, will be important in molecular reclassification studies of patients from whom underlying population patterns have been removed. Grants: KC and KVS acknowledge FNRS, AS acknowledges ANR, ST acknowledges NSTDA, and PJS acknowledges TRF. [less ▲]

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See detailIterative pruning method of unsupervised clustering for categorical data
Chaichoompu, Kridsadakorn ULg; Tongsima, Sissades; Shaw, Philip James et al

Poster (2016, April 03)

Single Nucleotide Polymorphisms (SNPs) are commonly used to identify population structures. Iterative pruning Principal Component Analysis (ipPCA) utilizes SNP profiles to assign individuals to ... [more ▼]

Single Nucleotide Polymorphisms (SNPs) are commonly used to identify population structures. Iterative pruning Principal Component Analysis (ipPCA) utilizes SNP profiles to assign individuals to subpopulations without making assumptions about ancestry. The strategy can be extrapolated to patient samples to identify molecular classes of patients. It is challenging to investigate the utility of substructure detection using profiles based on pre-defined genomic regions-of-interest rather than profiles based on SNPs. Using principles outlined in Fouladi, 2015, we can construct gene-based categorical variables representing different summary gene profiles in a region. These gene-based new constructs no longer have an equal number of unordered category levels. Here, we present C-PCA, an extension of ipPCA to target perform iterative pruning for categorical variables using optimal scaling. It allows performing non-linear principal component analyses to handle possibly non-linearly related variables with different measurement levels. To show the power of C-PCA compared to ipPCA, we simulated 500 individuals and assigned them to two populations of equal size. We considered genetic population distances using Fixation Index from 0.001 to 0.006. For each dataset, we simulated 10,000 independent random SNPs for 100 replicates using the Balding–Nichols model. These were used numerically in ipPCA and as categorical in C-PCA analysis. In conclusion, like ipPCA, we expect C-PCA to perform well in the presence of fine substructures. This paves the way to apply C-PCA to DNA-seq data and input categorical variable derived from genomic regions-of-interest to which common and rare variants are mapped. We foresee additional advantages of C-PCA in this context since region-based categorical variables are likely to be non-linearly associated at the background of underlying gene-gene interaction networks. C-PCA is implemented in R. [less ▲]

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See detailA roadmap to multifactor dimensionality reduction methods.
Gola, Damian; Mahachie John, Jestinah M.; Van Steen, Kristel ULg et al

in Briefings in Bioinformatics (2016), 17(2), 293-308

Complex diseases are defined to be determined by multiple genetic and environmental factors alone as well as in interactions. To analyze interactions in genetic data, many statistical methods have been ... [more ▼]

Complex diseases are defined to be determined by multiple genetic and environmental factors alone as well as in interactions. To analyze interactions in genetic data, many statistical methods have been suggested, with most of them relying on statistical regression models. Given the known limitations of classical methods, approaches from the machine-learning community have also become attractive. From this latter family, a fast-growing collection of methods emerged that are based on the Multifactor Dimensionality Reduction (MDR) approach. Since its first introduction, MDR has enjoyed great popularity in applications and has been extended and modified multiple times. Based on a literature search, we here provide a systematic and comprehensive overview of these suggested methods. The methods are described in detail, and the availability of implementations is listed. Most recent approaches offer to deal with large-scale data sets and rare variants, which is why we expect these methods to even gain in popularity. [less ▲]

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See detailIntegration Analysis of Three Omics Data Using Penalized Regression Methods: An Application to Bladder Cancer
Pineda San Juan, Silvia ULg; Real, Francisco X; Kogevinas, Manolis et al

in PLoS Genetics (2015)

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

in BioData Mining (2015), 8(36),

Background: The purpose of the maxT algorithm is to provide a significance test algorithm that controls the family-wise error rate (FWER) during simultaneous hypothesis testing. However, the requirements ... [more ▼]

Background: The purpose of the maxT algorithm is to provide a significance test algorithm that controls the family-wise error rate (FWER) during simultaneous hypothesis testing. However, the requirements in terms of computing time and memory of this procedure are proportional to the number of investigated hypotheses. The memory issue has been solved in 2013 by Van Lishout’s implementation of MaxT, 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 models effectively. On the other hand, that implementation turned out to be less suitable for genome-wide interaction analysis studies, due to the prohibitive computational burden. Results: In this work we introduce gammaMAXT, a novel implementation of the maxT algorithm for multiple testing correction. The algorithm was implemented in software MBMDR-4.2.2, as part of the MB-MDR framework to screen for SNP-SNP, SNP-environment or SNP-SNP-environment interactions at a genome-wide level. We show that, in the absence 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. We analyze a dataset composed of 106 SNPs and 1000 individuals within one day on a 256-core computer cluster. The same analysis would take about 104 times longer with MBMDR-3.0.3. Conclusions: These results are promising for future GWAIs.However, the proposed gammaMAXT algorithm offers a general significance assessment and multiple testing approach, applicable to any context that requires performing hundreds of thousands of tests. It offers new perspectives for fast and efficient permutation-based significance assessment in large-scale (integrated) omics studies. [less ▲]

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See detailEpistasis associated to inflammatory bowel disease (IBD) in humans
Gusareva, Elena ULg; Wei, Zhi; Traherne, J.A. et al

Poster (2015, October 05)

Gene-gene interactions underlie biochemical pathways and have been well demonstrated in model organisms. Very few examples exist on replicated epistasis in humans. Here, we performed genome-wide scans to ... [more ▼]

Gene-gene interactions underlie biochemical pathways and have been well demonstrated in model organisms. Very few examples exist on replicated epistasis in humans. Here, we performed genome-wide scans to detect epistasis associated to Crohn’s disease (CD) and ulcerative colitis (UC). We used extensive data of the IIBDGC consisting of 18277 and 14224 CD and UC patients, respectively, and ~34050 healthy controls from 15 European countries typed on the Immunochip. At first, we removed rare variants at MAF<0.05 and filtered common variants at linkage disequilibrium (LD) of r2>0.75. To limit our results to independent effects, SNPs on chromosome 6 (which contains the HLA locus), were furthermore pruned to ensure an LD of r2<0.35. We adjusted the binary traits, CD and UC, for population stratification by regressing out the first 5 principal components in R-3.0.1. The study cohorts were randomly stratified into two subgroups (referred as discovery and replication). We then performed screenings for epistatic interactions with new adjusted trait values in the two subgroups using multidimensional reduction tool MB-MDR with permutation-based (step-down MaxT) multiple testing correction and significance assessment at 0.05. We identified 14 and 6 SNP-pairs associated to CD and UC, respectively, which were concordant between the discovery and replication groups. All SNP-pairs involved concomitant variants located on the same chromosomes (for CD at 1p31.3, 5p13.1, 16q12.1 and for UC at 1p31.3, 6p21.3). A more detailed investigation of these findings, as well as the implementation of different analysis protocols, will further increase our understanding of possible epistatic mechanisms underpinning IBD. [less ▲]

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See detailDetecting patient subgroups using reduced set of disease-related markers with iterative pruning Principal Component Analysis (ipPCA)
Chaichoompu, Kridsadakorn ULg; Cleynen, Isabelle; Fouladi, Ramouna ULg et al

Poster (2015, October 03)

Genetic markers such as Single Nucleotide Polymorphisms (SNPs) can be used to find subgroups of populations or patients with carefully selected clustering algorithms. The iterative pruning principal ... [more ▼]

Genetic markers such as Single Nucleotide Polymorphisms (SNPs) can be used to find subgroups of populations or patients with carefully selected clustering algorithms. The iterative pruning principal component analysis (ipPCA) has been shown to be a powerful tool to identify fine substructures within general populations based on SNP profiles. Usually, SNPs contributing to such profiles have passed rigorous quality control procedures, similar to the ones used for GWAs. Alternatively, attention is restricted to a smaller subset such as PCA-correlated SNPs. Here, we applied ipPCA on real-life data consisting of the 163 known inflammatory-bowel disease (IBD) associated loci in 13,400 healthy individuals and 29,500 IBD (16,902 Crohn’s disease (CD), and 12,598 ulcerative colitis (UC)) patients from the IIBDGC. Prior to clustering by ipPCA, in each group separately, we regressed out the first five Principal Components (PCs) that were computed from a filtered panel of genome-wide SNPs, to account for general population strata. Next, we applied ipPCA on the healthy group, to learn about the presence of a population-specific partitioning in controls. Then we performed three subphenotype analyses: CD only, UC only and the combined group of CD and UC patients (IBD). For each patient subgroup analysis and for the ipPCA analysis on controls, we highlighted and compared the key SNP drivers. CD patients could be molecularly reclassified in two groups, and similar for UC patients. The combined patient group could be subdivided in four groups. Finally, we compared demographic and clinical features among the different groups and looked for meaningful characterizations of adjusted patient clusters by performing pathway analysis on driver genes. [less ▲]

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See detailBiological validation of statistical epistasis signals.
Gusareva, Elena ULg; van der Lee, Sven; Katsumata, Yuriko et al

Speech/Talk (2015)

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See detailA cautionary note on the impact of protocol changes for Genome-Wide Association SNP x SNP Interaction studies: an example on ankylosing spondylitis
Bessonov, Kyrylo ULg; Gusareva, Elena ULg; Van Steen, Kristel ULg

in Human Genetics (2015)

Genome-wide association interaction (GWAI) studies have increased in popularity. Yet to date, no standard protocol exists. In practice, any GWAI workflow involves making choices about quality control ... [more ▼]

Genome-wide association interaction (GWAI) studies have increased in popularity. Yet to date, no standard protocol exists. In practice, any GWAI workflow involves making choices about quality control strategy, SNP filtering, linkage disequilibrium (LD) pruning, analytic tool to model or to test for genetic interactions. Each of these can have an impact on the final epistasis findings and may affect their reproducibility in follow-up analyses. Choosing an analytic tool is not straightforward, as different such tools exist and current understanding about their performance is based on often very particular simulation settings. In the present study, we wish to create awareness for the impact of (minor) changes in a GWAI analysis protocol can have on final epistasis findings. In particular, we investigate the influence of marker selection and marker prioritization strategies, LD pruning and the choice of epistasis detection analytics on study results, giving rise to 8 GWAI protocols. Discussions are made in the context of the ankylosing spondylitis (AS) data obtained via the Wellcome Trust Case Control Consortium (WTCCC2). As expected, the largest impact on AS epistasis findings is caused by the choice of marker selection criterion, followed by marker coding and LD pruning. In MB-MDR, co-dominant coding of main effects is more robust to the effects of LD pruning than additive coding. We were able to reproduce previously reported epistasis involvement of HLA-B and ERAP1 in AS pathology. In addition, our results suggest involvement of MAGI3 and PARK2, responsible for cell adhesion and cellular trafficking. Gene Ontology (GO) biological function enrichment analysis across the 8 considered GWAI protocols also suggested that AS could be associated to the Central Nervous System (CNS) malfunctions, specifically, in nerve impulse propagation and in neurotransmitters metabolic processes. [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, Dermot 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 ▲]

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See detailPerspectives on Data Integration in Human Complex Disease Analysis
Van Steen, Kristel ULg; Malats, Nuria

in Big Data Analytics in Bioinformatics and Healthcare (2015)

The identification of causal or predictive variants/genes/mechanisms for disease-associated traits is characterized by “complex” networks of molecular phenotypes. Present technology and computer power ... [more ▼]

The identification of causal or predictive variants/genes/mechanisms for disease-associated traits is characterized by “complex” networks of molecular phenotypes. Present technology and computer power allow building and processing large collections of these data types. However, the super-rapid data generation is counterweighted by a slow-pace for data integration methods development. Most currently available integrative analytic tools pertain to pairing omics data and focus on between-data source relationships, making strong assumptions about within-data source architectures. A limited number of initiatives exist aiming to find the most optimal ways to analyze multiple, possibly related, omics databases, and fully acknowledge the specific characteristics of each data type. A thorough understanding of the underlying assumptions of integrative methods is needed to draw sound conclusions afterwards. In this chapter, the authors discuss how the field of “integromics” has evolved and give pointers towards essential research developments in this context. [less ▲]

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See detailRestoration of Foxp3+ Regulatory T-cell Subsets and Foxp3- Type 1 Regulatory-like T Cells in Inflammatory Bowel Diseases During Anti-tumor Necrosis Factor Therapy.
Li, Zhe; Vermeire, Severine; Bullens, Dominique et al

in Inflammatory Bowel Diseases (2015), 21(10), 2418-28

BACKGROUND: A defect in regulatory T cells (Tregs) may be involved in the pathogenesis of inflammatory bowel diseases (IBD). Several subsets of human Foxp3+ Tregs (activated and resting Tregs) have now ... [more ▼]

BACKGROUND: A defect in regulatory T cells (Tregs) may be involved in the pathogenesis of inflammatory bowel diseases (IBD). Several subsets of human Foxp3+ Tregs (activated and resting Tregs) have now been identified, as well as an IL-10 and IFN-gamma double producing Foxp3 type 1 regulatory-like T cell (Tr1L). We have quantified these Tregs in patients with active IBD and during therapy with infliximab (IFX). METHODS: Blood samples were obtained from healthy controls (n = 54) and patients with active IBD, either before (n = 62) or during IFX therapy (n = 75). Tregs were identified by immunofluorescent staining and flow cytometry analysis. Resting and activated Foxp3+ Tregs can be differentiated from Foxp3+ effector T cells (Foxp3+ Teff) by the expression of CD45RA. Tr1L are identified as CD4+CD45RA-CD25-CD127-Foxp3- T cells. RESULTS: A numerical deficiency of circulating resting Tregs, activated Treg cells, and Tr1L was documented in patients with active IBD. Baseline levels of these Treg subsets predicted clinical responses to IFX. We documented an upregulation of all 3 subsets during IFX therapy. Moreover, after therapy, significant differences in Treg subsets were seen between responders and nonresponders to IFX. Restoration of Tregs correlated with the clinical and biological response to IFX therapy. Trough serum levels of IFX positively correlated with the proportion of activated Treg cells and Tr1L during therapy. CONCLUSIONS: IFX therapy, when successful, results in upmodulation of the different types of Treg cells in the blood of patients with IBD. This effect might be relevant for understanding the mechanism of action of anti-TNF agents. [less ▲]

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See detailAnti-Tumor Necrosis Factor Therapy Restores Peripheral Blood B-cell Subsets and CD40 Expression in Inflammatory Bowel Diseases.
Li, Zhe; Vermeire, Severine; Bullens, Dominique et al

in Inflammatory Bowel Diseases (2015), 21(12), 2787-96

BACKGROUND: Anti-tumor necrosis factor (TNF) therapy has become a standard therapy for severe inflammatory bowel diseases (IBD), but its effect on B lymphocytes is largely unexplored. In this study we ... [more ▼]

BACKGROUND: Anti-tumor necrosis factor (TNF) therapy has become a standard therapy for severe inflammatory bowel diseases (IBD), but its effect on B lymphocytes is largely unexplored. In this study we investigated peripheral blood B cells, B-cell subsets, and CD40 expression in patients with IBD before and during anti-TNF therapy with infliximab (IFX). METHODS: Blood was taken from healthy controls (n = 52) and patients with active IBD before (n = 46) and/or during anti-TNF therapy (n = 55). B-cell markers were detected by immunofluorescent staining and FACS analysis. Patients were classified as responders or nonresponders to anti-TNF therapy. RESULTS: We found a numerical deficiency of circulating CD19 B cells, a lower activation state (CD40 expression) and lower proportions of CD5 B cells and IgMIgDCD27 preswitched memory cells among B cells in active patients with IBD before IFX therapy compared with healthy controls. IFX treatment increased CD19 B-cell numbers as well as the proportions of named B-cell subsets in responders but not in nonresponders. IFX more effectively upregulated CD40 expression in responders than in nonresponders. Restoration of B cells correlated with the biological response to therapy (C-reactive protein). Trough serum levels of IFX correlated with the number of B cells during therapy. CONCLUSIONS: A lower number of circulating B cells, a low CD40 expression, and a decrease in the proportion of CD5 and in the preswitched memory subset characterize active IBD. Restoration of these abnormalities correlates with the clinical response to anti-TNF therapy. The mechanism for this effect on B cells should be further explored. [less ▲]

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See detailSpecific members of the predominant gut microbiota predict pouchitis following colectomy and IPAA in UC.
Machiels, Kathleen; Sabino, Joao; Vandermosten, Leen et al

in Gut (2015)

OBJECTIVE: Pouchitis is the most common complication after colectomy with ileal pouch-anal anastomosis (IPAA) for UC and the risk is the highest within the 1st year after surgery. The pathogenesis is not ... [more ▼]

OBJECTIVE: Pouchitis is the most common complication after colectomy with ileal pouch-anal anastomosis (IPAA) for UC and the risk is the highest within the 1st year after surgery. The pathogenesis is not completely understood but clinical response to antibiotics suggests a role for gut microbiota. We hypothesised that the risk for pouchitis can be predicted based on the faecal microbial composition before colectomy. DESIGN: Faecal samples from 21 patients with UC undergoing IPAA were prospectively collected before colectomy and at predefined clinical visits at 1 month, 3 months, 6 months and 12 months after IPAA. The predominant microbiota was analysed using community profiling with denaturing gradient gel electrophoresis followed by quantitative real-time PCR validation. RESULTS: Cluster analysis before colectomy distinguished patients with pouchitis from those with normal pouch during the 1st year of follow-up. In patients developing pouchitis, an increase of Ruminococcus gnavus (p<0.001), Bacteroides vulgatus (p=0.043), Clostridium perfringens (p=0.011) and a reduction of two Lachnospiraceae genera (Blautia (p=0.04), Roseburia (p=0.008)) was observed. A score combining these five bacterial risk factors was calculated and presence of at least two risk factors showed a sensitivity and specificity of 100% and 63.6%, respectively. CONCLUSIONS: Presence of R. gnavus, B. vulgatus and C. perfringens and absence of Blautia and Roseburia in faecal samples of patients with UC before surgery is associated with a higher risk of pouchitis after IPAA. Our findings suggest new predictive and therapeutic strategies in patients undergoing colectomy with IPAA. [less ▲]

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See detailFramework for the Integration of Genomics, Epigenomics and Transcriptomics in Complex Diseases.
Pineda, Silvia; Gomez-Rubio, Paulina; Picornell, Antonio et al

in Human Heredity (2015), 79(3-4), 124-36

OBJECTIVES: Different types of '-omics' data are becoming available in the post-genome era; still a single -omics assessment provides limited insights to understand the biological mechanism of complex ... [more ▼]

OBJECTIVES: Different types of '-omics' data are becoming available in the post-genome era; still a single -omics assessment provides limited insights to understand the biological mechanism of complex diseases. Genomics, epigenomics and transcriptomics data provide insight into the molecular dysregulation of neoplastic diseases, among them urothelial bladder cancer (UBC). Here, we propose a detailed analytical framework necessary to achieve an adequate integration of the three sets of -omics data to ultimately identify previously hidden genetic mechanisms in UBC. METHODS: We built a multi-staged framework to study possible pair-wise combinations and integrated the data in three-way relationships. SNP genotypes, CpG methylation levels and gene expression levels were determined for a total of 70 individuals with UBC and with fresh tumour tissue available. RESULTS: We suggest two main hypothesis-based scenarios for gene regulation based on the -omics integration analysis, where DNA methylation affects gene expression and genetic variants co-regulate gene expression and DNA methylation. We identified several three-way trans-association 'hotspots' that are found at the molecular level and that deserve further studies. CONCLUSIONS: The proposed integrative framework allowed us to identify relationships at the whole-genome level providing some new biological insights and highlighting the importance of integrating -omics data. [less ▲]

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See detailTrough concentrations of infliximab guide dosing for patients with inflammatory bowel disease.
Vande Casteele, Niels; Ferrante, Marc; Van Assche, Gert et al

in Gastroenterology (2015), 148(7), 1320-93

BACKGROUND & AIMS: Infliximab, a tumor necrosis factor antagonist, is effective for treating patients with Crohn's disease (CD) and ulcerative colitis (UC). We aimed to determine whether dosing based on ... [more ▼]

BACKGROUND & AIMS: Infliximab, a tumor necrosis factor antagonist, is effective for treating patients with Crohn's disease (CD) and ulcerative colitis (UC). We aimed to determine whether dosing based on therapeutic drug monitoring increases rate of remission and whether continued concentration-based dosing is superior to clinically based dosing of infliximab for maintaining remission in patients with CD and UC. METHODS: We performed a 1-year randomized controlled trial at a tertiary referral center, including 263 adults (178 with CD and 85 with UC) with stable responses to maintenance infliximab therapy. Doses were escalated or reduced using an algorithm to reach a target trough concentration (TC) of 3-7 mug/mL in all patients (optimization phase). Patients were randomly assigned (1:1) to groups that received infliximab dosing based on their clinical features (n = 123) or continued dosing based on TCs (n = 128) (maintenance phase). The primary end point was clinical and biochemical remission at 1 year after the optimization phase. RESULTS: At screening, 115 of 263 patients had a TC of infliximab of 3-7 mug/mL (43.7%). Of 76 patients with TCs <3 mug/mL, 69 patients (91%) achieved TCs of 3-7 mug/mL after dose escalation. This resulted in a higher proportion of CD patients in remission than before dose escalation (88% vs 65%; P = .020) and a decrease in the median concentration of C-reactive protein, compared with before the dose increase (3.2 vs 4.3 mg/L; P < .001); these changes were not observed in patients with UC. Of 72 patients with TCs >7 mug/mL, 67 patients (93%) achieved TCs of 3-7 mug/mL after dose reduction. This resulted in a 28% reduction in drug cost from before dose reduction (P < .001). Sixty-six percent of patients whose dosing was based on clinical features and 69% whose dosing was based on TC achieved remission, the primary end point (P = .686). Disease relapsed in 21 patients who received clinically based dosing (17%) and 9 patients who received concentration-based dosing (7%) (P = .018). CONCLUSIONS: Targeting patients' infliximab TCs to 3-7 mug/mL results in a more efficient use of the drug. After dose optimization, continued concentration-based dosing was not superior to clinically based dosing for achieving remission after 1 year, but was associated with fewer flares during the course of treatment. ClinicalTrialsRegister.eu number: 2011-002061-38. [less ▲]

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See detailStatistical Analysis of High-Dimensional Genetic Data in Complex Traits.
Park, Taesung; Van Steen, Kristel ULg; Lou, Xiang-Yang et al

in BioMed Research International (2015), 2015

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See detailGenome-Wide Copy Number Variation Scan Identifies Complement Component C4 as Novel Susceptibility Gene for Crohn's Disease.
Cleynen, Isabelle; Konings, Peter; Robberecht, Caroline et al

in Inflammatory bowel diseases (2015)

BACKGROUND: The genetic component of Crohn's disease (CD) is well known, with 140 susceptibility loci identified so far. In addition to single nucleotide polymorphisms typically studied in genome-wide ... [more ▼]

BACKGROUND: The genetic component of Crohn's disease (CD) is well known, with 140 susceptibility loci identified so far. In addition to single nucleotide polymorphisms typically studied in genome-wide scans, copy number variation is responsible for a large proportion of human genetic variation. METHODS: We performed a genome-wide search for copy number variants associated with CD using array comparative genomic hybridization. One of the found regions was validated independently through real-time PCR. Serum levels of the found gene were measured in patients and control subjects. RESULTS: We found copy number differences for the C4S and C4L gene variants of complement component C4 in the central major histocompatibility complex region on chromosome 6p21. Specifically, we saw that CD patients tend to have lower C4L and higher C4S copies than control subjects (P = 5.00 x 10 and P = 9.11 x 10), which was independent of known associated classical HLA I and II alleles (P = 7.68 x 10 and P = 6.29 x 10). Although C4 serum levels were not different between patients and control subjects, the relationship between C4 copy number and serum level was different for patients and control subjects with higher copy numbers leading to higher serum concentrations in control subjects, compared with CD patients (P < 0.001). CONCLUSIONS: C4 is part of the classical activation pathway of the complement system, which is important for (auto)immunity. Low C4L or high C4S copy number, and corresponding effects on C4 serum level, could lead to an exaggerated response against infections, possibly leading to (auto)immune disease. [less ▲]

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