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Article ; Online: Biclustering sparse binary genomic data.

van Uitert, Miranda / Meuleman, Wouter / Wessels, Lodewyk

Journal of computational biology : a journal of computational molecular cell biology

2008 Volume 15, Issue 10, Page(s) 1329–1345

Abstract: Genomic datasets often consist of large, binary, sparse data matrices. In such a dataset, one is often interested in finding contiguous blocks that (mostly) contain ones. This is a biclustering problem, and while many algorithms have been proposed to ... ...

Abstract	Genomic datasets often consist of large, binary, sparse data matrices. In such a dataset, one is often interested in finding contiguous blocks that (mostly) contain ones. This is a biclustering problem, and while many algorithms have been proposed to deal with gene expression data, only two algorithms have been proposed that specifically deal with binary matrices. None of the gene expression biclustering algorithms can handle the large number of zeros in sparse binary matrices. The two proposed binary algorithms failed to produce meaningful results. In this article, we present a new algorithm that is able to extract biclusters from sparse, binary datasets. A powerful feature is that biclusters with different numbers of rows and columns can be detected, varying from many rows to few columns and few rows to many columns. It allows the user to guide the search towards biclusters of specific dimensions. When applying our algorithm to an input matrix derived from TRANSFAC, we find transcription factors with distinctly dissimilar binding motifs, but a clear set of common targets that are significantly enriched for GO categories.
MeSH term(s)	Algorithms ; Cluster Analysis ; Computational Biology/methods ; Databases, Genetic ; Genome ; Models, Genetic ; Oligonucleotide Array Sequence Analysis/methods ; Software ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	Transcription Factors
Language	English
Publishing date	2008-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	2030900-4
ISSN	1557-8666 ; 1066-5277
ISSN (online)	1557-8666
ISSN	1066-5277
DOI	10.1089/cmb.2008.0066
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Article ; Online: Validation of the Charlson Comorbidity Index in acutely hospitalized elderly adults: a prospective cohort study.

Frenkel, Wijnanda J / Jongerius, Erika J / Mandjes-van Uitert, Miranda J / van Munster, Barbara C / de Rooij, Sophia E

Journal of the American Geriatrics Society

2014 Volume 62, Issue 2, Page(s) 342–346

Abstract: Objectives: To determine whether the Charlson Comorbidity Index (CCI) predicts short- and long-term mortality.: Design: Prospective cohort study.: Setting: The medical department of two university hospitals and one community-based hospital.: ... ...

Abstract	Objectives: To determine whether the Charlson Comorbidity Index (CCI) predicts short- and long-term mortality. Design: Prospective cohort study. Setting: The medical department of two university hospitals and one community-based hospital. Participants: Acutely hospitalized individuals aged 65 and older with a mean age of 77.8 ± 7.9, 45.8% male (n = 1,313). Measurements: In eligible persons, information on demographic characteristics, activities of daily living (modified Katz ADL Index score), and disease-related measures was collected within 48 hours after admission. Follow-up using self-reporting questionnaires was performed at 3 months and 1 year. Functional decline was defined as a decline of at least 1 point on the modified Katz ADL Index score at 12 months from baseline. Mortality data at 3 months and 1 and 5 years were collected from the municipal database. Results: Logistic regression analysis, adjusted for age and sex, showed that participants with a CCI of 5 or more had higher 3-month (odds ratio (OR) = 3.6, 95% confidence interval (CI) = 2.1-6.4), 1-year (OR = 7.1, 95% CI = 4.2-11.9), and 5-year (OR = 52.4, 95% CI = 13.3-206.4) mortality than those with a CCI of 0. Participants with CCI scores between 1 and 4 also had greater mortality risk at 3 months and 1 and 5 years. Conclusion: The CCI independently predicts short- and long-term mortality in acutely ill hospitalized elderly adults.
MeSH term(s)	Activities of Daily Living ; Acute Disease/epidemiology ; Aged ; Comorbidity ; Confidence Intervals ; Emergency Service, Hospital/statistics & numerical data ; Female ; Follow-Up Studies ; Hospitalization/statistics & numerical data ; Humans ; Length of Stay/statistics & numerical data ; Male ; Netherlands/epidemiology ; Odds Ratio ; Prognosis ; Prospective Studies ; Reproducibility of Results ; Risk Assessment/methods ; Risk Factors ; Severity of Illness Index ; Surveys and Questionnaires ; Survival Rate/trends ; Time Factors
Language	English
Publishing date	2014-02
Publishing country	United States
Document type	Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't ; Validation Studies
ZDB-ID	80363-7
ISSN	1532-5415 ; 0002-8614
ISSN (online)	1532-5415
ISSN	0002-8614
DOI	10.1111/jgs.12635
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Article ; Online: Differentially expressed genes in the pre-eclamptic placenta: a systematic review and meta-analysis.

Kleinrouweler, C Emily / van Uitert, Miranda / Moerland, Perry D / Ris-Stalpers, Carrie / van der Post, Joris A M / Afink, Gijs B

PloS one

2013 Volume 8, Issue 7, Page(s) e68991

Abstract: Objective: To systematically review the literature on human gene expression data of placental tissue in pre-eclampsia and to characterize a meta-signature of differentially expressed genes in order to identify novel putative diagnostic markers.: Data ... ...

Abstract	Objective: To systematically review the literature on human gene expression data of placental tissue in pre-eclampsia and to characterize a meta-signature of differentially expressed genes in order to identify novel putative diagnostic markers. Data sources: Medline through 11 February 2011 using MeSH terms and keywords related to placenta, gene expression and gene expression arrays; GEO database using the term "placent"; and reference lists of eligible primary studies, without constraints. Methods:* From 1068 studies retrieved from the search, we included original publications that had performed gene expression array analyses of placental tissue in the third trimester and that reported on differentially expressed genes in pre-eclampsia versus normotensive controls. Two reviewers independently identified eligible studies, extracted descriptive and gene expression data and assessed study quality. Using a vote-counting method based on a comparative meta-profiling algorithm, we determined a meta-signature that characterizes the significant intersection of differentially expressed genes from the collection of independent gene signatures. Results: We identified 33 eligible gene expression array studies of placental tissue in the 3(rd) trimester comprising 30 datasets on mRNA expression and 4 datasets on microRNA expression. The pre-eclamptic placental meta-signature consisted of 40 annotated gene transcripts and 17 microRNAs. At least half of the mRNA transcripts encode a protein that is secreted from the cell and could potentially serve as a biomarker. Conclusions: In addition to well-known and validated genes, we identified 14 transcripts not reported previously in relation to pre-eclampsia of which the majority is also expressed in the 1(st) trimester placenta, and three encode a secreted protein.
MeSH term(s)	Female ; Gene Expression Profiling ; Gene Expression Regulation ; Humans ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Placenta/metabolism ; Placenta/pathology ; Pre-Eclampsia/genetics ; Pregnancy ; Pregnancy Trimester, Third ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Signal Transduction/genetics
Chemical Substances	MicroRNAs ; RNA, Messenger
Language	English
Publishing date	2013-07-12
Publishing country	United States
Document type	Journal Article ; Meta-Analysis ; Review ; Systematic Review
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0068991
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Article ; Online: Meta-Analysis of Placental Transcriptome Data Identifies a Novel Molecular Pathway Related to Preeclampsia.

van Uitert, Miranda / Moerland, Perry D / Enquobahrie, Daniel A / Laivuori, Hannele / van der Post, Joris A M / Ris-Stalpers, Carrie / Afink, Gijs B

PloS one

2015 Volume 10, Issue 7, Page(s) e0132468

Abstract: Studies using the placental transcriptome to identify key molecules relevant for preeclampsia are hampered by a relatively small sample size. In addition, they use a variety of bioinformatics and statistical methods, making comparison of findings ... ...

Abstract	Studies using the placental transcriptome to identify key molecules relevant for preeclampsia are hampered by a relatively small sample size. In addition, they use a variety of bioinformatics and statistical methods, making comparison of findings challenging. To generate a more robust preeclampsia gene expression signature, we performed a meta-analysis on the original data of 11 placenta RNA microarray experiments, representing 139 normotensive and 116 preeclamptic pregnancies. Microarray data were pre-processed and analyzed using standardized bioinformatics and statistical procedures and the effect sizes were combined using an inverse-variance random-effects model. Interactions between genes in the resulting gene expression signature were identified by pathway analysis (Ingenuity Pathway Analysis, Gene Set Enrichment Analysis, Graphite) and protein-protein associations (STRING). This approach has resulted in a comprehensive list of differentially expressed genes that led to a 388-gene meta-signature of preeclamptic placenta. Pathway analysis highlights the involvement of the previously identified hypoxia/HIF1A pathway in the establishment of the preeclamptic gene expression profile, while analysis of protein interaction networks indicates CREBBP/EP300 as a novel element central to the preeclamptic placental transcriptome. In addition, there is an apparent high incidence of preeclampsia in women carrying a child with a mutation in CREBBP/EP300 (Rubinstein-Taybi Syndrome). The 388-gene preeclampsia meta-signature offers a vital starting point for further studies into the relevance of these genes (in particular CREBBP/EP300) and their concomitant pathways as biomarkers or functional molecules in preeclampsia. This will result in a better understanding of the molecular basis of this disease and opens up the opportunity to develop rational therapies targeting the placental dysfunction causal to preeclampsia.
MeSH term(s)	Female ; Gene Expression Profiling/methods ; Humans ; Placenta/metabolism ; Pre-Eclampsia/genetics ; Pre-Eclampsia/metabolism ; Pregnancy ; Protein Interaction Mapping
Language	English
Publishing date	2015-07-14
Publishing country	United States
Document type	Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0132468
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Book: Series expansions for finite-state Markov chains

Heidergott, Bernd / Hordijk, Arie / Uitert, Miranda van

(Discussion paper / Tinbergen Institute : 4, Econometrics ; 2005-086)

2005

Author's details	Bernd Heidergott, Arie Hordijk, Miranda van Uitert
Series title	Discussion paper / Tinbergen Institute : 4, Econometrics ; 2005-086
Keywords	24#34#60#81
Language	English
Size	22 S, graph. Darst
Publishing place	Amsterdam u.a.
Document type	Book
Database	ECONomics Information System

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Article ; Online: Meta-Analysis of Placental Transcriptome Data Identifies a Novel Molecular Pathway Related to Preeclampsia.

Miranda van Uitert / Perry D Moerland / Daniel A Enquobahrie / Hannele Laivuori / Joris A M van der Post / Carrie Ris-Stalpers / Gijs B Afink

PLoS ONE, Vol 10, Iss 7, p e

2015 Volume 0132468

Abstract	Studies using the placental transcriptome to identify key molecules relevant for preeclampsia are hampered by a relatively small sample size. In addition, they use a variety of bioinformatics and statistical methods, making comparison of findings challenging. To generate a more robust preeclampsia gene expression signature, we performed a meta-analysis on the original data of 11 placenta RNA microarray experiments, representing 139 normotensive and 116 preeclamptic pregnancies. Microarray data were pre-processed and analyzed using standardized bioinformatics and statistical procedures and the effect sizes were combined using an inverse-variance random-effects model. Interactions between genes in the resulting gene expression signature were identified by pathway analysis (Ingenuity Pathway Analysis, Gene Set Enrichment Analysis, Graphite) and protein-protein associations (STRING). This approach has resulted in a comprehensive list of differentially expressed genes that led to a 388-gene meta-signature of preeclamptic placenta. Pathway analysis highlights the involvement of the previously identified hypoxia/HIF1A pathway in the establishment of the preeclamptic gene expression profile, while analysis of protein interaction networks indicates CREBBP/EP300 as a novel element central to the preeclamptic placental transcriptome. In addition, there is an apparent high incidence of preeclampsia in women carrying a child with a mutation in CREBBP/EP300 (Rubinstein-Taybi Syndrome). The 388-gene preeclampsia meta-signature offers a vital starting point for further studies into the relevance of these genes (in particular CREBBP/EP300) and their concomitant pathways as biomarkers or functional molecules in preeclampsia. This will result in a better understanding of the molecular basis of this disease and opens up the opportunity to develop rational therapies targeting the placental dysfunction causal to preeclampsia.
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2015-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: Computational identification of insertional mutagenesis targets for cancer gene discovery.

de Jong, Johann / de Ridder, Jeroen / van der Weyden, Louise / Sun, Ning / van Uitert, Miranda / Berns, Anton / van Lohuizen, Maarten / Jonkers, Jos / Adams, David J / Wessels, Lodewyk F A

Nucleic acids research

2011 Volume 39, Issue 15, Page(s) e105

Abstract: Insertional mutagenesis is a potent forward genetic screening technique used to identify candidate cancer genes in mouse model systems. An important, yet unresolved issue in the analysis of these screens, is the identification of the genes affected by ... ...

Abstract	Insertional mutagenesis is a potent forward genetic screening technique used to identify candidate cancer genes in mouse model systems. An important, yet unresolved issue in the analysis of these screens, is the identification of the genes affected by the insertions. To address this, we developed Kernel Convolved Rule Based Mapping (KC-RBM). KC-RBM exploits distance, orientation and insertion density across tumors to automatically map integration sites to target genes. We perform the first genome-wide evaluation of the association of insertion occurrences with aberrant gene expression of the predicted targets in both retroviral and transposon data sets. We demonstrate the efficiency of KC-RBM by showing its superior performance over existing approaches in recovering true positives from a list of independently, manually curated cancer genes. The results of this work will significantly enhance the accuracy and speed of cancer gene discovery in forward genetic screens. KC-RBM is available as R-package.
MeSH term(s)	Animals ; Chromosome Mapping/methods ; Computational Biology/methods ; DNA Transposable Elements ; Gene Expression ; Genes, Neoplasm ; Leukemia Virus, Murine/genetics ; Mice ; Mutagenesis, Insertional
Chemical Substances	DNA Transposable Elements
Language	English
Publishing date	2011-06-07
Publishing country	England
Document type	Evaluation Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkr447
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Article ; Online: Rest-activity patterns in patients with delirium.

van Uitert, Miranda / de Jonghe, Annemarieke / de Gijsel, Swana / van Someren, Eus J W / de Rooij, Sophia E J A / van Munster, Barbara C

Rejuvenation research

2011 Volume 14, Issue 5, Page(s) 483–490

Abstract: Objective: Delirium is a frequent syndrome in elderly hospital patients. Symptoms typically show a fluctuating course during the day, with patients exhibiting disturbances of their sleep-wake rhythm. Delirium is frequently underdiagnosed, especially the ...

Abstract	Objective: Delirium is a frequent syndrome in elderly hospital patients. Symptoms typically show a fluctuating course during the day, with patients exhibiting disturbances of their sleep-wake rhythm. Delirium is frequently underdiagnosed, especially the so-called hypoactive subtype. Devices measuring 24-hr motor patterns could contribute to the recognition of delirium. The purpose of this paper is two-fold. First, the results of a pilot study are presented, in which 24-hr motor patterns of delirious patients are measured with a wrist-actigraph. Second, studies reporting 24-hr motor patterns in delirious patients are systematically reviewed. Methods: The pilot study included 9 patients, 65 years or older, with a hip fracture in need of surgical repair. For the review, MEDLINE and Embase were searched for studies on motor activity assessment in delirious patients. Results: In the pilot study, the 24-hr activity rhythm was severely disturbed during delirium, and most actigraphic sleep parameter estimates indicated significantly worse sleep during delirious nights. The systematic search resulted in 10 papers. In 3 papers, the sleep-wake rhythm of delirious patients was significantly different from that of nondelirious patients. In 5 papers, delirious patients could be classified into delirium subtypes. In the 2 remaining papers, 24-hr motor patterns of delirium subtypes were not significantly different. Conclusion: Activity patterns revealed differences between delirious and nondelirious patients and between the different subtypes, even in small samples of patients. Future studies, with preferably larger sample sizes, should confirm the potential of activity pattern measuring devices in the early detection of delirium.
MeSH term(s)	Aged ; Aged, 80 and over ; Delirium/physiopathology ; Female ; Humans ; Male ; Pilot Projects ; Rest/physiology
Language	English
Publishing date	2011-10
Publishing country	United States
Document type	Journal Article ; Meta-Analysis
ZDB-ID	2150779-X
ISSN	1557-8577 ; 1549-1684
ISSN (online)	1557-8577
ISSN	1549-1684
DOI	10.1089/rej.2011.1181
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Article ; Online: Differentially expressed genes in the pre-eclamptic placenta

C Emily Kleinrouweler / Miranda van Uitert / Perry D Moerland / Carrie Ris-Stalpers / Joris A M van der Post / Gijs B Afink

PLoS ONE, Vol 8, Iss 7, p e

a systematic review and meta-analysis.

2013 Volume 68991

Abstract: OBJECTIVE: To systematically review the literature on human gene expression data of placental tissue in pre-eclampsia and to characterize a meta-signature of differentially expressed genes in order to identify novel putative diagnostic markers. DATA ... ...

Abstract	OBJECTIVE: To systematically review the literature on human gene expression data of placental tissue in pre-eclampsia and to characterize a meta-signature of differentially expressed genes in order to identify novel putative diagnostic markers. DATA SOURCES: Medline through 11 February 2011 using MeSH terms and keywords related to placenta, gene expression and gene expression arrays; GEO database using the term "placent*"; and reference lists of eligible primary studies, without constraints. METHODS: From 1068 studies retrieved from the search, we included original publications that had performed gene expression array analyses of placental tissue in the third trimester and that reported on differentially expressed genes in pre-eclampsia versus normotensive controls. Two reviewers independently identified eligible studies, extracted descriptive and gene expression data and assessed study quality. Using a vote-counting method based on a comparative meta-profiling algorithm, we determined a meta-signature that characterizes the significant intersection of differentially expressed genes from the collection of independent gene signatures. RESULTS: We identified 33 eligible gene expression array studies of placental tissue in the 3(rd) trimester comprising 30 datasets on mRNA expression and 4 datasets on microRNA expression. The pre-eclamptic placental meta-signature consisted of 40 annotated gene transcripts and 17 microRNAs. At least half of the mRNA transcripts encode a protein that is secreted from the cell and could potentially serve as a biomarker. CONCLUSIONS: In addition to well-known and validated genes, we identified 14 transcripts not reported previously in relation to pre-eclampsia of which the majority is also expressed in the 1(st) trimester placenta, and three encode a secreted protein.
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2013-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Large-scale mutagenesis in p19(ARF)- and p53-deficient mice identifies cancer genes and their collaborative networks.

Uren, Anthony G / Kool, Jaap / Matentzoglu, Konstantin / de Ridder, Jeroen / Mattison, Jenny / van Uitert, Miranda / Lagcher, Wendy / Sie, Daoud / Tanger, Ellen / Cox, Tony / Reinders, Marcel / Hubbard, Tim J / Rogers, Jane / Jonkers, Jos / Wessels, Lodewyk / Adams, David J / van Lohuizen, Maarten / Berns, Anton

Cell

2008 Volume 133, Issue 4, Page(s) 727–741

Abstract: p53 and p19(ARF) are tumor suppressors frequently mutated in human tumors. In a high-throughput screen in mice for mutations collaborating with either p53 or p19(ARF) deficiency, we identified 10,806 retroviral insertion sites, implicating over 300 loci ... ...

Abstract	p53 and p19(ARF) are tumor suppressors frequently mutated in human tumors. In a high-throughput screen in mice for mutations collaborating with either p53 or p19(ARF) deficiency, we identified 10,806 retroviral insertion sites, implicating over 300 loci in tumorigenesis. This dataset reveals 20 genes that are specifically mutated in either p19(ARF)-deficient, p53-deficient or wild-type mice (including Flt3, mmu-mir-106a-363, Smg6, and Ccnd3), as well as networks of significant collaborative and mutually exclusive interactions between cancer genes. Furthermore, we found candidate tumor suppressor genes, as well as distinct clusters of insertions within genes like Flt3 and Notch1 that induce mutants with different spectra of genetic interactions. Cross species comparative analysis with aCGH data of human cancer cell lines revealed known and candidate oncogenes (Mmp13, Slamf6, and Rreb1) and tumor suppressors (Wwox and Arfrp2). This dataset should prove to be a rich resource for the study of genetic interactions that underlie tumorigenesis.
MeSH term(s)	Animals ; Cell Line, Tumor ; Cloning, Molecular ; Cyclin-Dependent Kinase Inhibitor p16/genetics ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Gene Regulatory Networks ; Genes, Tumor Suppressor ; Genes, p53 ; Genomics/methods ; Humans ; Mice ; Mice, Knockout ; Mutagenesis, Insertional ; Neoplasms/genetics ; Neoplasms/metabolism ; Sequence Analysis, DNA ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	Cdkn2a protein, mouse ; Cyclin-Dependent Kinase Inhibitor p16 ; Tumor Suppressor Protein p53
Language	English
Publishing date	2008-05-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2008.03.021
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