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12 results on '"Wiel, M.A. van de"'

1. RNA-Seq in 296 phased trios provides a high-resolution map of genomic imprinting

Author

Jadhav, B., Monajemi, R., Gagalova, K.K., Ho, D., Draisma, H.H.M., Wiel, M.A. van de, Franke, L., Heijmans, B.T., Meurs, J. van, Jansen, R., Hoen, P.A.C. t, Sharp, A.J., Kielbasa, S.M., GoNL Consortium, BIOS Consortium, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Epidemiology and Data Science, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, and Internal Medicine

Subjects
Life Sciences & Biomedicine - Other Topics, Parent-of-origin, Physiology, Bayesian analysis, Gene Expression, Plant Science, CIRCADIAN CLOCK, Genome, 0302 clinical medicine, Structural Biology, Allele-specific expression, Imprinting (psychology), lcsh:QH301-705.5, DNA METHYLATION, Genetics, Regulation of gene expression, 0303 health sciences, CANDIDATE, Imprinting, ASSOCIATION, Uniparental disomy, DNA methylation, BIOS Consortium, General Agricultural and Biological Sciences, Life Sciences & Biomedicine, Biotechnology, Research Article, EXPRESSION, Biology, General Biochemistry, Genetics and Molecular Biology, Cell Line, 03 medical and health sciences, Genomic Imprinting, REVEALS, medicine, Humans, Gene, Ecology, Evolution, Behavior and Systematics, Alleles, GoNL Consortium, 030304 developmental biology, Science & Technology, IDENTIFICATION, Sequence Analysis, RNA, Cell Biology, 06 Biological Sciences, medicine.disease, Phased genotypes, GENE, Haplotypes, lcsh:Biology (General), SILVER, Human genome, INFERENCE, Genomic imprinting, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], 030217 neurology & neurosurgery, Blood Chemical Analysis, Developmental Biology
Abstract

Background Identification of imprinted genes, demonstrating a consistent preference towards the paternal or maternal allelic expression, is important for the understanding of gene expression regulation during embryonic development and of the molecular basis of developmental disorders with a parent-of-origin effect. Combining allelic analysis of RNA-Seq data with phased genotypes in family trios provides a powerful method to detect parent-of-origin biases in gene expression. Results We report findings in 296 family trios from two large studies: 165 lymphoblastoid cell lines from the 1000 Genomes Project and 131 blood samples from the Genome of the Netherlands (GoNL) participants. Based on parental haplotypes, we identified > 2.8 million transcribed heterozygous SNVs phased for parental origin and developed a robust statistical framework for measuring allelic expression. We identified a total of 45 imprinted genes and one imprinted unannotated transcript, including multiple imprinted transcripts showing incomplete parental expression bias that was located adjacent to strongly imprinted genes. For example, PXDC1, a gene which lies adjacent to the paternally expressed gene FAM50B, shows a 2:1 paternal expression bias. Other imprinted genes had promoter regions that coincide with sites of parentally biased DNA methylation identified in the blood from uniparental disomy (UPD) samples, thus providing independent validation of our results. Using the stranded nature of the RNA-Seq data in lymphoblastoid cell lines, we identified multiple loci with overlapping sense/antisense transcripts, of which one is expressed paternally and the other maternally. Using a sliding window approach, we searched for imprinted expression across the entire genome, identifying a novel imprinted putative lncRNA in 13q21.2. Overall, we identified 7 transcripts showing parental bias in gene expression which were not reported in 4 other recent RNA-Seq studies of imprinting. Conclusions Our methods and data provide a robust and high-resolution map of imprinted gene expression in the human genome. Electronic supplementary material The online version of this article (10.1186/s12915-019-0674-0) contains supplementary material, which is available to authorized users.

Published
2019

2. Methods for significance testing of categorical covariates in logistic regression models after multiple imputation: power and applicability analysis

Author

Eekhout, I., Wiel, M.A. van de, and Heymans, M.W.

Subjects
Pooling, Simulation study, Life, Health, CH - Child Health, Categorical covariates, Multiple imputation, Logistic regression, Significance test, ELSS - Earth, Life and Social Sciences, Healthy for Life, Healthy Living
Abstract

Background. Multiple imputation is a recommended method to handle missing data. For significance testing after multiple imputation, Rubin’s Rules (RR) are easily applied to pool parameter estimates. In a logistic regression model, to consider whether a categorical covariate with more than two levels significantly contributes to the model, different methods are available. For example pooling chi-square tests with multiple degrees of freedom, pooling likelihood ratio test statistics, and pooling based on the covariance matrix of the regression model. These methods are more complex than RR and are not available in all mainstream statistical software packages. In addition, they do not always obtain optimal power levels. We argue that the median of the p-values from the overall significance tests from the analyses on the imputed datasets can be used as an alternative pooling rule for categorical variables. The aim of the current study is to compare different methods to test a categorical variable for significance after multiple imputation on applicability and power. Methods. In a large simulation study, we demonstrated the control of the type I error and power levels of different pooling methods for categorical variables. Results. This simulation study showed that for non-significant categorical covariates the type I error is controlled and the statistical power of the median pooling rule was at least equal to current multiple parameter tests. An empirical data example showed similar results. Conclusions. It can therefore be concluded that using the median of the p-values from the imputed data analyses is an attractive and easy to use alternative method for significance testing of categorical variables.

Published
2017

3. Testing for association between RNA-Seq and high-dimensional data

Author

Rauschenberger, A., Jonker, M.A., Wiel, M.A. van de, Menezes, R.X. de, Rauschenberger, A., Jonker, M.A., Wiel, M.A. van de, and Menezes, R.X. de

Abstract

Contains fulltext : 171636.pdf (publisher's version ) (Open Access), BACKGROUND: Testing for association between RNA-Seq and other genomic data is challenging due to high variability of the former and high dimensionality of the latter. RESULTS: Using the negative binomial distribution and a random-effects model, we develop an omnibus test that overcomes both difficulties. It may be conceptualised as a test of overall significance in regression analysis, where the response variable is overdispersed and the number of explanatory variables exceeds the sample size. CONCLUSIONS: The proposed test can detect genetic and epigenetic alterations that affect gene expression. It can examine complex regulatory mechanisms of gene expression. The R package globalSeq is available from Bioconductor.

Published
2016

4. High Prevalence and Clinical Relevance of Genes Affected by Chromosomal Breaks in Colorectal Cancer

Author

Broek, E. van den, Dijkstra, M.J., Krijgsman, O., Sie, D., Haan, J.C., Traets, J.J., Wiel, M.A. van de, Nagtegaal, I.D., Punt, C.J.A., Carvalho, B., Ylstra, B., Abeln, S., Meijer, G.A., Fijneman, R.J., Broek, E. van den, Dijkstra, M.J., Krijgsman, O., Sie, D., Haan, J.C., Traets, J.J., Wiel, M.A. van de, Nagtegaal, I.D., Punt, C.J.A., Carvalho, B., Ylstra, B., Abeln, S., Meijer, G.A., and Fijneman, R.J.

Abstract

Contains fulltext : 152977.PDF (publisher's version ) (Open Access), BACKGROUND: Cancer is caused by somatic DNA alterations such as gene point mutations, DNA copy number aberrations (CNA) and structural variants (SVs). Genome-wide analyses of SVs in large sample series with well-documented clinical information are still scarce. Consequently, the impact of SVs on carcinogenesis and patient outcome remains poorly understood. This study aimed to perform a systematic analysis of genes that are affected by CNA-associated chromosomal breaks in colorectal cancer (CRC) and to determine the clinical relevance of recurrent breakpoint genes. METHODS: Primary CRC samples of patients with metastatic disease from CAIRO and CAIRO2 clinical trials were previously characterized by array-comparative genomic hybridization. These data were now used to determine the prevalence of CNA-associated chromosomal breaks within genes across 352 CRC samples. In addition, mutation status of the commonly affected APC, TP53, KRAS, PIK3CA, FBXW7, SMAD4, BRAF and NRAS genes was determined for 204 CRC samples by targeted massive parallel sequencing. Clinical relevance was assessed upon stratification of patients based on gene mutations and gene breakpoints that were observed in >3% of CRC cases. RESULTS: In total, 748 genes were identified that were recurrently affected by chromosomal breaks (FDR <0.1). MACROD2 was affected in 41% of CRC samples and another 169 genes showed breakpoints in >3% of cases, indicating that prevalence of gene breakpoints is comparable to the prevalence of well-known gene point mutations. Patient stratification based on gene breakpoints and point mutations revealed one CRC subtype with very poor prognosis. CONCLUSIONS: We conclude that CNA-associated chromosomal breaks within genes represent a highly prevalent and clinically relevant subset of SVs in CRC.

Published
2015

5. Spatial and temporal evolution of distal 10q deletion, a prognostically unfavorable event in diffuse low-grade gliomas

Author

Thuijl, H.F. van, Scheinin, I., Sie, D., Alentorn, A., Essen, H.F. van, Cordes, M., Fleischeuer, R., Gijtenbeek, A., Beute, G., Brink, W.A. van den, Meijer, G.A., Havenith, M., Idbaih, A., Hoang-Xuan, K., Mokhtari, K., Verhaak, R., Valk, P. van der, Wiel, M.A. van de, Heimans, J.J., Aronica, E., Reijneveld, J.C., Wesseling, P., Ylstra, B., Thuijl, H.F. van, Scheinin, I., Sie, D., Alentorn, A., Essen, H.F. van, Cordes, M., Fleischeuer, R., Gijtenbeek, A., Beute, G., Brink, W.A. van den, Meijer, G.A., Havenith, M., Idbaih, A., Hoang-Xuan, K., Mokhtari, K., Verhaak, R., Valk, P. van der, Wiel, M.A. van de, Heimans, J.J., Aronica, E., Reijneveld, J.C., Wesseling, P., and Ylstra, B.

Abstract

Contains fulltext : 136086.pdf (publisher's version ) (Open Access), BackgroundThe disease course of patients with diffuse low-grade glioma is notoriously unpredictable. Temporal and spatially distinct samples may provide insight into the evolution of clinically relevant copy number aberrations (CNAs). The purpose of this study is to identify CNAs that are indicative of aggressive tumor behaviour and can thereby complement the prognostically favorable 1p/19q co-deletion.ResultsGenome-wide, 50 base pair single-end, sequencing was performed to detect CNAs in a clinically well-characterized cohort of 98 formalin-fixed paraffin-embedded low-grade gliomas. CNAs are correlated with overall survival as an endpoint. Seventy-five additional samples from spatially distinct regions and paired recurrent tumors of the discovery cohort were analysed to interrogate the intratumoral heterogeneity and spatial evolution. Loss of 10q25.2-qter is a frequent subclonal event and significantly correlates with an unfavorable prognosis. A significant correlation is furthermore observed in a validation set of 126 and confirmation set of 184 patients. Loss of 10q25.2-qter arises in a longitudinal manner in paired recurrent tumor specimens, whereas the prognostically favorable 1p/ 19q co-deletion is the only CNA that is stable across spatial regions and recurrent tumors.ConclusionsCNAs in low-grade gliomas display extensive intratumoral heterogeneity. Distal loss of 10q is a late onset event and a marker for reduced overall survival in low-grade glioma patients. Intratumoral heterogeneity and higher frequencies of distal 10q loss in recurrences suggest this event is involved in outgrowth to the recurrent tumor.

Published
2014

6. Genomic landscape of metastatic colorectal cancer

Author

Haan, J.C., Labots, M., Rausch, C., Koopman, M., Tol, J., Mekenkamp, L.J., Wiel, M.A. van de, Israeli, D., Essen, H.F. van, Grieken, N.C. van, Voorham, Q.J., Bosch, L.J., Qu, X., Kabbarah, O., Verheul, H.M., Nagtegaal, I.D., Punt, C.J.A., Ylstra, B., Meijer, G.A., Haan, J.C., Labots, M., Rausch, C., Koopman, M., Tol, J., Mekenkamp, L.J., Wiel, M.A. van de, Israeli, D., Essen, H.F. van, Grieken, N.C. van, Voorham, Q.J., Bosch, L.J., Qu, X., Kabbarah, O., Verheul, H.M., Nagtegaal, I.D., Punt, C.J.A., Ylstra, B., and Meijer, G.A.

Abstract

Contains fulltext : 139110.pdf (publisher's version ) (Open Access), Response to drug therapy in individual colorectal cancer (CRC) patients is associated with tumour biology. Here we describe the genomic landscape of tumour samples of a homogeneous well-annotated series of patients with metastatic CRC (mCRC) of two phase III clinical trials, CAIRO and CAIRO2. DNA copy number aberrations of 349 patients are determined. Within three treatment arms, 194 chromosomal subregions are associated with progression-free survival (PFS; uncorrected single-test P-values <0.005). These subregions are filtered for effect on messenger RNA expression, using an independent data set from The Cancer Genome Atlas which returned 171 genes. Three chromosomal regions are associated with a significant difference in PFS between treatment arms with or without irinotecan. One of these regions, 6q16.1-q21, correlates in vitro with sensitivity to SN-38, the active metabolite of irinotecan. This genomic landscape of mCRC reveals a number of DNA copy number aberrations associated with response to drug therapy.

Published
2014

7. DNA copy number analysis of fresh and formalin-fixed specimens by shallow whole-genome sequencing with identification and exclusion of problematic regions in the genome assembly

Author

Scheinin, I., Sie, D., Bengtsson, H., Wiel, M.A. van de, Olshen, A.B., Thuijl, H.F. van, Essen, H.F. van, Eijk, P.P., Rustenburg, F., Meijer, G.A., Reijneveld, J.C., Wesseling, P., Pinkel, D., Albertson, D.G., Ylstra, B., Scheinin, I., Sie, D., Bengtsson, H., Wiel, M.A. van de, Olshen, A.B., Thuijl, H.F. van, Essen, H.F. van, Eijk, P.P., Rustenburg, F., Meijer, G.A., Reijneveld, J.C., Wesseling, P., Pinkel, D., Albertson, D.G., and Ylstra, B.

Abstract

Contains fulltext : 139379.pdf (publisher's version ) (Open Access), Detection of DNA copy number aberrations by shallow whole-genome sequencing (WGS) faces many challenges, including lack of completion and errors in the human reference genome, repetitive sequences, polymorphisms, variable sample quality, and biases in the sequencing procedures. Formalin-fixed paraffin-embedded (FFPE) archival material, the analysis of which is important for studies of cancer, presents particular analytical difficulties due to degradation of the DNA and frequent lack of matched reference samples. We present a robust, cost-effective WGS method for DNA copy number analysis that addresses these challenges more successfully than currently available procedures. In practice, very useful profiles can be obtained with approximately 0.1x genome coverage. We improve on previous methods by first implementing a combined correction for sequence mappability and GC content, and second, by applying this procedure to sequence data from the 1000 Genomes Project in order to develop a blacklist of problematic genome regions. A small subset of these blacklisted regions was previously identified by ENCODE, but the vast majority are novel unappreciated problematic regions. Our procedures are implemented in a pipeline called QDNAseq. We have analyzed over 1000 samples, most of which were obtained from the fixed tissue archives of more than 25 institutions. We demonstrate that for most samples our sequencing and analysis procedures yield genome profiles with noise levels near the statistical limit imposed by read counting. The described procedures also provide better correction of artifacts introduced by low DNA quality than prior approaches and better copy number data than high-resolution microarrays at a substantially lower cost.

Published
2014

8. Small bowel adenocarcinoma copy number profiles are more closely related to colorectal than to gastric cancers.

Author

Haan, J.C., Buffart, T.E., Eijk, P.P., Wiel, M.A. van de, Wieringen, W.N. van, Howdle, P.D., Mulder, C.J., Velde, C.J. van de, Quirke, P., Nagtegaal, I.D., Grieken, N.C. van, Grabsch, H., Meijer, G.A., Ylstra, B., Haan, J.C., Buffart, T.E., Eijk, P.P., Wiel, M.A. van de, Wieringen, W.N. van, Howdle, P.D., Mulder, C.J., Velde, C.J. van de, Quirke, P., Nagtegaal, I.D., Grieken, N.C. van, Grabsch, H., Meijer, G.A., and Ylstra, B.

Abstract

1 februari 2012, Contains fulltext : 109554pub.pdf (publisher's version ) (Closed access), BACKGROUND: Small bowel adenocarcinoma (SBA) is a rare cancer and consequently, the options for clinical trials are limited. As they are treated according to either a colorectal or a gastric cancer regimen and the molecular biology of a tumor is a pivotal determinant for therapy response, chromosomal copy number aberrations were compared with the colorectal and gastric adenocarcinomas. Materials and methods: A total of 85 microsatellite stable (MSS) adenocarcinomas from the stomach, colorectum and small bowel were selected from existing array comparative genomic hybridization (aCGH) datasets. We compared the aCGH profiles of the three tumor sites by supervised analysis and hierarchical clustering. RESULTS: Hierarchical clustering revealed substantial overlap of 27 SBA copy number profiles with matched colorectal adenocarcinomas but less overlap with profiles of gastric adenocarcinomas. DNA copy number aberrations located at chromosomes 1p36.3-p34.3, 4p15.3-q35.2, 9p24.3-p11.1, 13q13.2-q31.3 and 17p13.3-p13.2 were the strongest features discriminating SBAs and colorectal adenocarcinomas from gastric adenocarcinomas. CONCLUSIONS: We show that MSS SBAs are more similar to colorectal than to gastric cancer, based on the 27 genome-wide DNA copy number profiles that are currently available. These molecular similarities provide added support for treatment of MSS small bowel cancers according to colorectal cancer regimens.

Published
2012

10. Differential effects of amlodipine and atorvastatin treatment and their combination on atherosclerosis in ApoE*3-Leiden transgenic mice

Author

Delsing, D.J.M., Jukema, J.W., Wiel, M.A. van de, Emeis, J.J., Laarse, A. van der, Havekes, L.M., Princen, H.M.G., Delsing, D.J.M., Jukema, J.W., Wiel, M.A. van de, Emeis, J.J., Laarse, A. van der, Havekes, L.M., and Princen, H.M.G.

Abstract

This study was designed to investigate the potential antiatherosclerotic effects of the calcium antagonist amlodipine as compared with the HMG-CoA reductase inhibitor atorvastatin and the combination of both in ApoE*3-Leiden transgenic mice. Four groups of 15 ApoE*3-Leiden mice were put on a high-cholesterol diet. One group received 0.002% (wt/wt) amlodipine in the diet, which had no effect on plasma cholesterol levels. Another group received 0.01% (wt/wt) atorvastatin, resulting in a decrease of plasma cholesterol by 50% by a reduction in very low density lipoprotein production. The combination group received both amlodipine and atorvastatin. After 28 weeks, atherosclerosis in the aortic root was quantified. Treatment with amlodipine had no significant effect on atherosclerotic lesion area, whereas atorvastatin markedly reduced atherosclerosis by 77% compared with the control group. Atorvastatin also reduced inflammation markers. The combination of amlodipine and atorvastatin tended to reduce lesion area by 61% compared with the atorvastatinonly group; however, this effect did not reach statistical significance. Amlodipine treatment significantly reduced calcification in the lesions, whereas atorvastatin alone had no effect. The combination of amlodipine and atorvastatin resulted in a near absence of calcium deposits in the lesions. This study demonstrates that amlodipine treatment alone does not significantly reduce atherosclerotic lesion development. Atorvastatin was shown to have strong antiatherosclerotic effects, and cotreatment with amlodipine may potentiate the antiatherosclerotic effect of atorvastatin.

Published
2003

11. Empirical Bayes applications in biomedical high-dimensional prediction

Author

Münch, M.M., Wiel, M.A. van de, Vaart, A.W. van der, Peeters, C.F.W., Houwing-Duistermaat, J.J., Richardson, S., Mertens, B.J.A., Szabó, B., Edixhoven, S.J., Duijn Schouten, F.A. van der, and Leiden University

Subjects
Omics data, High-dimensional prediction, Empirical Bayes, Variational Bayes
Abstract

The thesis introduces three methods for high-dimensional prediction problems in the biomedical field. The methods make use of empirical and variational Bayes in the estimation. Several applications show that the proposed methods are competitive to existing methods.

Published
2021

12. Permutation-based inference for high-dimensional data

Author

Hemerik, J., Goeman, J.J., Solari, A., Cessie, S. le, Vaart, A.W. van der, Wiel, M.A. van de, and Leiden University

Subjects
Semi-parametric, SAM, Permutation', Significance analysis of microarrays, False discovery rate, False discovery proportion, Confidence bound, Multiple testing, Robust test, Non-parametric test
Abstract

The thesis provides novel statistical (multiple) testing methods based on permutations or other transformations of data. Permutation-based multiple testing methods tend to have relatively high power, because they take into account the observed dependence structure of the data (without requiring assumptions on that structure). This thesis places particular emphasis on confidence upper bounds for the false discovery proportion: the proportion of false positives among all rejected hypotheses. Moreover, a novel semi-parametric method is presented for robust testing in generalized linear models. This test is related to the score test and the permutation test and is based on sign-flipping individual score contributions.

Published
2018

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