References of "Van Steen, Kristel"
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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 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 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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See detailFramework for the integration of genomics, epigenomics, and transcriptomics in complex diseases
Pineda San Juan, Silvia ULg; Gómez-Rubio, Paulina; Antoni, Picornell et al

in Human Heredity (2015)

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See detailFilter-free exhaustive odds ratio-based genome-wide interaction approach pinpoints evidence for interaction in the HLA region in psoriasis.
Grange, Laura; Bureau, Jean-Francois; Nikolayeva, Iryna 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 ▲]

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See detailShort-term Effect of Infliximab Is Reflected in the Clot Lysis Profile of Patients with Inflammatory Bowel Disease: A Prospective Study.
Bollen, Lize; Vande Casteele, Niels; Peeters, Miet 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 ▲]

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See detailWithdrawal of Immunomodulators After Co-treatment Does Not Reduce Trough Level of Infliximab in Patients With Crohn's Disease.
Drobne, David; Bossuyt, Peter; Breynaert, Christine 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 ▲]

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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 (2014, November 12)

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 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 detailDiscovering main genetic interactions with LABNet LAsso-based network inference.
Gadaleta, Francesco ULg; Van Steen, Kristel ULg

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 ▲]

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