A roadmap to multifactor dimensionality reduction methods.
; ; Van Steen, Kristel 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 ▲]Detailed reference viewed: 7 (2 ULg)
Integration Analysis of Three Omics Data Using Penalized Regression Methods: An Application to Bladder Cancer
Pineda San Juan, Silvia ; ; et al
in PLoS Genetics (2015)Detailed reference viewed: 35 (5 ULg)
gammaMAXT: a fast multiple-testing correction algorithm
Van Lishout, François ; ; 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 ▲]Detailed reference viewed: 38 (7 ULg)
Epistasis associated to inflammatory bowel disease (IBD) in humans
Gusareva, Elena ; ; 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 ▲]Detailed reference viewed: 28 (4 ULg)
Biological validation of statistical epistasis signals.
Gusareva, Elena ; ; et al
Speech/Talk (2015)Detailed reference viewed: 21 (1 ULg)
Model-Based Multifactor Dimensionality Reduction for Rare Variant Association Analysis
Fouladi, Ramouna ; Bessonov, Kyrylo ; Van Lishout, François et al
in Human Heredity (2015), 79Detailed reference viewed: 23 (4 ULg)
A cautionary note on the impact of protocol changes for Genome-Wide Association SNP x SNP Interaction studies: an example on ankylosing spondylitis
Bessonov, Kyrylo ; Gusareva, Elena ; Van Steen, Kristel
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 ▲]Detailed reference viewed: 87 (36 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: 64 (17 ULg)
Restoration of Foxp3+ Regulatory T-cell Subsets and Foxp3- Type 1 Regulatory-like T Cells in Inflammatory Bowel Diseases During Anti-tumor Necrosis Factor Therapy.
; ; 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 ▲]Detailed reference viewed: 15 (1 ULg)
Anti-Tumor Necrosis Factor Therapy Restores Peripheral Blood B-cell Subsets and CD40 Expression in Inflammatory Bowel Diseases.
; ; 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 ▲]Detailed reference viewed: 9 (1 ULg)
Specific members of the predominant gut microbiota predict pouchitis following colectomy and IPAA in UC.
; ; 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 ▲]Detailed reference viewed: 12 (1 ULg)
Framework for the Integration of Genomics, Epigenomics and Transcriptomics in Complex Diseases.
; ; 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 ▲]Detailed reference viewed: 11 (1 ULg)
Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease.
; ; 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 ▲]Detailed reference viewed: 17 (1 ULg)
Statistical Analysis of High-Dimensional Genetic Data in Complex Traits.
; Van Steen, Kristel ; et al
in BioMed Research International (2015), 2015Detailed reference viewed: 9 (1 ULg)
Genome-Wide Copy Number Variation Scan Identifies Complement Component C4 as Novel Susceptibility Gene for Crohn's Disease.
; ; 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 ▲]Detailed reference viewed: 33 (4 ULg)
Framework for the integration of genomics, epigenomics, and transcriptomics in complex diseases
Pineda San Juan, Silvia ; ; et al
in Human Heredity (2015)Detailed reference viewed: 163 (14 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: 17 (1 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: 26 (3 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: 24 (0 ULg)
Integration analysis of ‘OMICS’ data using penalized regression methods: An application to bladder cancer
Pineda San Juan, Silvia ; ; Van Steen, Kristel
Conference (2014, November 24)Detailed reference viewed: 26 (4 ULg)