References of "Van Steen, Kristel"
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See detailNew serological markers in inflammatory bowel disease are associated with complicated disease behavior
Ferrante, M.; Henckaerts, L.; Joossens, M. et al

in Gut (2007), 56(10), 1394-1403

OBJECTIVE: The human androgen receptor (AR) contains a polyglutamine and a polyglycine stretch which are highly polymorphic and are coded respectively by a CAG and GGN repeat in exon 1 of the AR gene ... [more ▼]

OBJECTIVE: The human androgen receptor (AR) contains a polyglutamine and a polyglycine stretch which are highly polymorphic and are coded respectively by a CAG and GGN repeat in exon 1 of the AR gene. Although the in vitro studies indicated a possible effect of the GGN repeat polymorphism on the AR gene transcription and clinical observations suggest that it might modulate the androgen action, its functional significance remains unclear. We wanted to assess whether the GGN repeat affects the serum testosterone levels in healthy men, which is the expected outcome through feedback regulation if it influences androgen action as has been shown to be the case for the CAG repeat. DESIGN AND PATIENTS: A population based cross-sectional cohort study including 1476 healthy young, middle-aged, and elderly men. MEASUREMENT: Testosterone and LH levels were determined by immunoassay; free testosterone (FT) levels were calculated. Genotyping of the GGN repeat was performed using the sequencing technique. RESULTS: The GGN repeat number was significantly associated with circulating testosterone and FT levels (P=0.017 and P=0.013 respectively). However, taking into account that age, body mass index, and CAG are already in the regression model, the GGN repeat could explain only a small part of the variation of both testosterone and FT. CONCLUSION: To our knowledge, this study is the first to demonstrate a significant positive association between the GGN repeat and androgen levels in a large cohort of healthy men. Although the present study thus adds credence to the view that the polyglycine tract in the AR can modulate AR action, this effect appears to be only small so that its clinical relevance remains questionable. [less ▲]

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See detailDoes a patient's self-reported health-related quality of life predict survival beyond key biomedical data in advanced colorectal cancer? (vol 42, pg 42, 2006)
Efficace, Fabio; Bottomley, Andrew; Coens, Corneel et al

in European Journal of Cancer (2007), 43(3), 633-633

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See detailGene expression profiling to predict the response of infliximab in patients with UC
Arijs, I.; Van Lommel, L.; Van Steen, Kristel ULg et al

in Journal of Crohn’s and Colitis [=JCC] (2007), 1(1), 34

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See detailApproaches to handling incomplete data in family-based association testing
Van Steen, Kristel ULg; Laird, N. M.; Markel, P. et al

in Annals of Human Genetics (2007), 71(Pt 2), 141-51

The high throughput of data arising from the complete sequence of the human genome has left statistical geneticists with a rich and extensive information source. The wide availability of software and the ... [more ▼]

The high throughput of data arising from the complete sequence of the human genome has left statistical geneticists with a rich and extensive information source. The wide availability of software and the increase in computing power has improved the possibilities to access and process such data. One problem is incompleteness of the data: unobserved or partially observed data points due to technical reasons or reasons associated with the patient's status or erroneous measurements of phenotype or genotype, to name a few. When not properly accounted for, these sources of incompleteness may seriously jeopardize the credibility of results from analyses. In this paper we provide some perspectives on the occurrence and analysis of different forms of incomplete data in family-based genetic association testing. [less ▲]

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See detailMucosal gene expression profiling to predict response to infliximab in patients with ulcerative colitis
Arijs, I.; Van Lommel, L.; Van Steen, Kristel ULg et al

in Gut (2007), 56(Suppl III), 19

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See detailPet ownership in eight European birth cohorts - results of a GA(2)LEN initiative
Roll, S.; Keil, T.; Eller, E. et al

in Allergy (2007), 62

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See detailGenetic markers and the risk of complicated disease behaviour in Crohn's disease patients
Henckaerts, L.; Verstreken, I.; Van Steen, Kristel ULg et al

in Gastroenterology (2007), 132(4), 17-18

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See detailFaecal bacterial molecular profiles of Crohn’s disease patients differ from their healthy relatives and matched healthy controls.
Joossens, M.; De Preter, V.; Vanhoutte, T. et al

in Gut (2007), 56(Suppl III), 5

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See detailToll-like receptor-1,-2, and-6 polymorphisms influence disease extension in inflammatory bowel diseases
Pierik, M.; Joossens, S.; Van Steen, Kristel ULg et al

in Inflammatory Bowel Diseases (2006), 12(1), 1-8

Background: Evidence that a deficient innate immune response toward the bacterial flora of the gut plays a role in the pathogenesis of inflammatory bowel disease (IBD) is growing. This is underscored by ... [more ▼]

Background: Evidence that a deficient innate immune response toward the bacterial flora of the gut plays a role in the pathogenesis of inflammatory bowel disease (IBD) is growing. This is underscored by the finding of the association between CARD15 variants and Crohn's disease (CD) and D299G in Toll-like receptor (TLR) 4 and IBD. Our aims were to study nonsynonymous polymorphisms in other TLR genes in IBD. Methods: Thirty-five single nucleotide polymorphisms (SNP) in TLR1-10 were identified from public databases. 284 IBD parent child trios and a second independent cohort of 285 IBD patients and 191 healthy controls were genotyped with polymerase chain reaction-restriction fragment length polymorphisms. Patients were pooled for genotype-phenotype analyses. Results: Although none of the SNPs was involved in disease susceptibility, a number of variants influenced the disease phenotype. A positive association between TLR1 R80T and pancolitis in UC (P = .045, OR [95% CI] 2.844 [1.026-7.844]) was found. The TLR2 R753G SNP was also associated with pancolitis (P = .027, OR [95% CI] 4.741 [1.197-18.7731). The relative risks for heterozygous patients to develop pancolitis were 5.8 and 3.3 for R80T and R753G, respectively. There was a negative association between TLR6 S249P and ulcerative colitis with proctitis only (P = .026, OR [95% CI] 0.223 [0.096-0.705]). In CD, we found a negative association between ileal disease involvement and TLR1 S6021 (P = .03, OR [95% CI] 0.522 [0.286-0.950]). Conclusion: TLR2 and its cofactors TLR1 and TLR6 are involved in the initial immune response to bacteria by recognizing peptidoglycan. An association between nonsynonymous variants in the TLR1, -2, and -6 genes and extensive colonic disease in UC and CD was found. Our findings further highlight the role of an abnormal innate immune response in the pathogenesis of IBD. [less ▲]

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See detailEotaxin polymorphisms and serum total IgE levels in children with asthma
Raby, B. A.; Van Steen, Kristel ULg; Lazarus, R. et al

in Journal of Allergy and Clinical Immunology (The) (2006), 117(2), 298-305

BACKGROUND: Eotaxin (chemokine, CC motif, ligand; CCL11) is a potent eosinophil chemoattractant strongly implicated in the pathobiology of asthma. Genetic variation at the CCL11 locus has been correlated ... [more ▼]

BACKGROUND: Eotaxin (chemokine, CC motif, ligand; CCL11) is a potent eosinophil chemoattractant strongly implicated in the pathobiology of asthma. Genetic variation at the CCL11 locus has been correlated with serum total IgE, blood eosinophil counts, and circulating eotaxin protein levels in several case-control asthma studies. Family-based association studies of CCL11 genetic variants have not been reported to date. OBJECTIVE: To evaluate 9 common CCL11 single nucleotide polymorphisms (SNPs) in nuclear families ascertained through patients with asthma participating in the Childhood Asthma Management Program study. METHODS: Single nucleotide polymorphism genotyping was performed by using minisequencing and probe hybridization platforms. Family-based association analysis for asthma and 4 asthma-related intermediate quantitative phenotypes was performed by using FBAT. RESULTS: One SNP, -384A>G, was associated with asthma among African American families (P = .01). CCL11 SNPs and haplotypes were not associated with asthma among white or Hispanic families. Two low-frequency alleles in strong pairwise linkage disequilibrium, -426C and IVS2+199A, were associated with lower serum total IgE levels (P = .0006 and P = .009, respectively) in white families, whereas 2 more common variants, -576C and g.4438C, were associated with higher IgE levels in African American families (P = .01-.04). Haplotype analysis in the white cohort provided additional evidence of association with serum total IgE, implicating 2 haplotypes. No single SNP or haplotype associations were observed with blood eosinophil levels, FEV(1), or airway responsiveness. CONCLUSION: These findings provide further evidence that genetic variation at the CCL11 locus is an important determinant of serum total IgE levels among patients with asthma. [less ▲]

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See detailDoes a patient's self-reported health-related quality of life predict survival beyond key biomedical data in advanced colorectal cancer?
Efficace, F.; Bottomley, A.; Coens, C. et al

in European Journal of Cancer (2006), 42(1), 42-9

The purpose of this study was to determine whether baseline patients' self reported health-related quality of life (HRQOL) parameters could predict survival beyond key biomedical prognostic factors in ... [more ▼]

The purpose of this study was to determine whether baseline patients' self reported health-related quality of life (HRQOL) parameters could predict survival beyond key biomedical prognostic factors in patients with metastatic colorectal cancer. The analysis was conducted on 299 patients. HRQOL baseline scores were assessed using the European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire-Core30 (EORTC QLQ-C30). The Cox proportional hazards regression model was used for both univariate and multivariate analyses of survival. In addition, a bootstrap resampling technique was used to assess the stability of the outcomes. The final multivariate Cox regression model retained four variables as independent prognostic factors for survival: white blood cell (WBC) count with a hazard ratio (HR) of 1.961 (95% CI, 1.439-2.672; P<0.001), alkaline phosphatase with HR=1.509 (95% CI, 1.126-2.022; P=0.005), number of sites involved with HR=1.108 (95% CI, 1.024-1.198; P=0.01) and the patient's score on the social functioning scale with HR=0.991 (95% CI, 0.987-0.996; P<0.001) which translates into a 9% decrease in the patient's hazard of death for any 10 point increase. The independent prognostic importance of social functioning and the stability of the final Cox regression model were also confirmed by the additional bootstrap model averaging analysis, based on 1000 bootstrap-generated samples. The results suggest that social functioning, acts as a prognostic measure of survival beyond a number of previously known biomedical parameters. [less ▲]

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See detailT-bet polymorphisms are associated with asthma and airway hyperresponsiveness
Raby, B. A.; Hwang, E. S.; Van Steen, Kristel ULg et al

in American Journal of Respiratory & Critical Care Medicine (2006), 173(1), 64-70

RATIONALE: T-bet (TBX21 or T-box 21) is a critical regulator of T-helper 1 lineage commitment and IFN-gamma production. Knockout mice lacking T-bet develop airway hyperresponsiveness (AHR) to methacholine ... [more ▼]

RATIONALE: T-bet (TBX21 or T-box 21) is a critical regulator of T-helper 1 lineage commitment and IFN-gamma production. Knockout mice lacking T-bet develop airway hyperresponsiveness (AHR) to methacholine, peribronchial eosinophilic and lymphocytic inflammation, and increased type III collagen deposition below the bronchial epithelium basement membrane, reminiscent of both acute and chronic asthma histopathology. Little is known regarding the role of genetic variation surrounding T-bet in the development of human AHR. OBJECTIVES: To assess the relationship between T-bet polymorphisms and asthma-related phenotypes using family-based association. METHODS: Single nucleotide polymorphism discovery was performed by resequencing the T-bet genomic locus in 30 individuals (including 22 patients with asthma). Sixteen variants were genotyped in 580 nuclear families ascertained through offspring with asthma from the Childhood Asthma Management Program clinical trial. Haplotype patterns were determined from this genotype data. Family-based tests of association were performed with asthma, AHR, lung function, total serum immunoglobulin E, and blood eosinophil levels. MAIN RESULTS: We identified 24 variants. Evidence of association was observed between c.-7947 and asthma in white families using both additive (p = 0.02) or dominant models (p = 0.006). c.-7947 and three other variants were also associated with AHR (log-methacholine PC(20), p = 0.02-0.04). Haplotype analysis suggested that an AHR locus is in linkage disequilibrium with variants in the 3'UTR. Evidence of association of AHR with c.-7947, but not with other 3'UTR SNPs, was replicated in an independent cohort of adult males with AHR. CONCLUSIONS: These data suggest that T-bet variation contributes to airway responsiveness in asthma. [less ▲]

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See detailPermutation based methods for comparing quality of life between observed treatments
Moerkerke, Beatrijs; Goetghebeur, Els; Van Steen, Kristel ULg et al

in Statistics in Medicine (2005), 24(24), 4055-66

Quality of life is becoming an important outcome for the comparison of aggressive therapies. To measure quality of life (QOL), questionnaires have been designed that ask patients about symptoms and ... [more ▼]

Quality of life is becoming an important outcome for the comparison of aggressive therapies. To measure quality of life (QOL), questionnaires have been designed that ask patients about symptoms and functionality in several aspects of daily life. Primary analyses of such questionnaires typically focus on a summary statistic, such as a sum score or a single global question. This avoids inflated type I errors or loss of power due to multiple testing of individual items. In return, specific questions and answers that initially mattered to the patient may unfortunately get buried. To avoid reduced specificity and interpretability for both patients and physicians, we propose to also analyse all original questions. In this paper, we seek to detect items of the QOL questionnaire that differ significantly over observed treatments even in the face of multiple testing. We sequentially build a model that combines features which additionally discriminate between treatments. To achieve this, we draw on insights gained in the field of statistical genetics where one is often confronted with a vast amount of predictors, e.g. of a genotypic nature. Specifically, we adopt a permutation based approach to evaluate the null distribution of the maximum of many correlated test statistics and use it to build a regression model that explains QOL differences between treatment arms. We apply the new methodology to analyse QOL data in an observational study of four different treatments of breast cancer. We discover that a single question captures most of the observed treatment differences in this population. [less ▲]

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See detailThe value of patient-reported symptoms as prognostic factors for survival in advanced colorectal cancer.
Efficace, F.; Bottomley, A.; Coens, C. et al

in Journal of Clinical Oncology (2005), 23(16S), 267

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See detailA bootstrap model averaging technique to investigate the prognostic value for survival of quality of life information.
Bottomley, A.; Efficace, F.; Stuppe, R. et al

in Quality of Life Research (2005), 14(9), 21361022

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See detailGenomic screening in family-based association testing and the multiple testing problem
Van Steen, Kristel ULg; McQueen, M. B.; Herbert, A. et al

in Genetic Epidemiology. Supplement (2005), 28

The Human Genome Project and its spin- offs are making it increasingly feasible to determine the genetic basis of complex traits using genome- wide association studies. The statistical challenge of ... [more ▼]

The Human Genome Project and its spin- offs are making it increasingly feasible to determine the genetic basis of complex traits using genome- wide association studies. The statistical challenge of analyzing such studies stems from the severe multiple-comparison problem resulting from the analysis of thousands of SNPs. Our methodology for genome- wide family- based association studies, using single SNPs or haplotypes, can identify associations that achieve genome- wide significance. In relation to developing guidelines for our screening tools, we determined lower bounds for the estimated power to detect the gene underlying the disease- susceptibility locus, which hold regardless of the linkage disequilibrium structure present in the data. We also assessed the power of our approach in the presence of multiple disease- susceptibility loci. Our screening tools accommodate genomic control and use the concept of haplotype- tagging SNPs. Our methods use the entire sample and do not require separate screening and validation samples to establish genome- wide significance, as population- based designs do. [less ▲]

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See detailPaternal history of asthma and airway responsiveness in children with asthma
Raby, B. A.; Van Steen, Kristel ULg; Celedon, J. C. et al

in American Journal of Respiratory & Critical Care Medicine (2005), 172(5), 552-8

RATIONALE: Little is known regarding the relationship between parental history of asthma and subsequent airway hyperresponsiveness (AHR) in children with asthma. OBJECTIVES: We evaluated this relationship ... [more ▼]

RATIONALE: Little is known regarding the relationship between parental history of asthma and subsequent airway hyperresponsiveness (AHR) in children with asthma. OBJECTIVES: We evaluated this relationship in 1,041 children with asthma participating in a randomized trial of antiinflammatory medications (the Childhood Asthma Management Program [CAMP]). METHODS: Methacholine challenge testing was performed before treatment randomization and once per year over an average of 4.5 years postrandomization. Cross-sectional and longitudinal repeated measures analyses were performed to model the relationship between PC20 (the methacholine concentration causing a 20% fall in FEV1) with maternal, paternal, and joint parental histories of asthma. Models were adjusted for potential confounders. MEASUREMENTS AND MAIN RESULTS: At baseline, AHR was strongly associated with a paternal history of asthma. Children with a paternal history of asthma demonstrated significantly greater AHR than those without such history (median log(e)PC20, 0.84 vs. 1.13; p = 0.006). Although maternal history of asthma was not associated with AHR, children with two parents with asthma had greater AHR than those with no parents with asthma (median log(e)PC20, 0.52 vs. 1.17; p = 0.0008). Longitudinal multivariate analysis of the relation between paternal history of asthma and AHR using repeated PC20 measurements over 44 months postrandomization confirmed a significant association between paternal history of asthma and AHR among children in CAMP. CONCLUSIONS: Our findings suggest that the genetic contribution of the father is associated with AHR, an important determinant of disease severity among children with asthma. [less ▲]

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See detailPBAT: a comprehensive software package for genome-wide association analysis of complex family-based studies
Van Steen, Kristel ULg; Lange, C.

in Human Genomics (2005), 2(1), 67-9

The PBAT software package (v2.5) provides a unique set of tools for complex family-based association analysis at a genome-wide level. PBAT can handle nuclear families with missing parental genotypes ... [more ▼]

The PBAT software package (v2.5) provides a unique set of tools for complex family-based association analysis at a genome-wide level. PBAT can handle nuclear families with missing parental genotypes, extended pedigrees with missing genotypic information, analysis of single nucleotide polymorphisms (SNPs), haplotype analysis, quantitative traits, multivariate/longitudinal data and time to onset phenotypes. The data analysis can be adjusted for covariates and gene/environment interactions. Haplotype-based features include sliding windows and the reconstruction of the haplotypes of the probands. PBAT's screening tools allow the user successfully to handle the multiple comparisons problem at a genome-wide level, even for 100,000 SNPs and more. Moreover, PBAT is computationally fast. A genome scan of 300,000 SNPs in 2,000 trios takes 4 central processing unit (CPU)-days. PBAT is available for Linux, Sun Solaris and Windows XP. [less ▲]

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See detailGenomic screening in family-based association testing
Murphy, A.; McGueen, M. B.; Su, J. et al

in Genetic Epidemiology. Supplement (2005), 29

Due to the recent gains in the availability of single-nucleotide polymorphism data, genome-wide association testing has become feasible. It is hoped that this additional data may confirm the presence of ... [more ▼]

Due to the recent gains in the availability of single-nucleotide polymorphism data, genome-wide association testing has become feasible. It is hoped that this additional data may confirm the presence of disease susceptibility loci, and identify new genetic determinants of disease. However, the problem of multiple comparisons threatens to diminish any potential gains from this newly available data. To circumvent the multiple comparisons issue, we utilize a recently developed screening technique using family-based association testing. This screening methodology allows for the identification of the most promising single-nucleotide polymorphisms for testing without biasing the nominal significance level of our test statistic. We compare the results of our screening technique across univariate and multivariate family-based association tests. From our analyses, we observe that the screening technique, applied to different settings, is fairly consistent in identifying optimal markers for testing. One of the identified markers, TSC0047225, was significantly associated with both the ttth1 (p=0.004) and ttth1-ttth4 (p=0.004) phenotype(s). We find that both univariate- and multivariate-based screening techniques are powerful tools for detecting an association. [less ▲]

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See detailThe prognostic value of health related quality of life in colorectal cancer patients: A multivariate analysis using a bootstrap model-averaging approach
Efficace, F.; Bottomley, A.; Coens, C. et al

in Quality of Life Research (2005), 14(9), 21371030

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