Publications by authors named "K Joeri van der Velde"

53 Publications

CAPICE: a computational method for Consequence-Agnostic Pathogenicity Interpretation of Clinical Exome variations.

Genome Med 2020 08 24;12(1):75. Epub 2020 Aug 24.

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Exome sequencing is now mainstream in clinical practice. However, identification of pathogenic Mendelian variants remains time-consuming, in part, because the limited accuracy of current computational prediction methods requires manual classification by experts. Here we introduce CAPICE, a new machine-learning-based method for prioritizing pathogenic variants, including SNVs and short InDels. CAPICE outperforms the best general (CADD, GAVIN) and consequence-type-specific (REVEL, ClinPred) computational prediction methods, for both rare and ultra-rare variants. CAPICE is easily added to diagnostic pipelines as pre-computed score file or command-line software, or using online MOLGENIS web service with API. Download CAPICE for free and open-source (LGPLv3) at https://github.com/molgenis/capice .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-020-00775-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446154PMC
August 2020

Novel Rare Genetic Variants Associated with Airflow Obstruction in the General Population.

Am J Respir Crit Care Med 2020 02;201(4):485-488

Department of GeneticsUniversity Medical Center GroningenUniversity of GroningenGroningen, the Netherlands.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.201909-1868LEDOI Listing
February 2020

Trismus as a Presenting Symptom in a Case of Progressive Encephalopathy with Rigidity and Myoclonus.

Case Rep Neurol 2019 Jan-Apr;11(1):132-136. Epub 2019 Apr 18.

Neurology Department, AZ Nikolaas, Sint-Niklaas, Belgium.

In this report we present a clinical case of trismus. The patient in question showed symptoms of trismus for 3 days, rapidly leading to respiratory insufficiency. Afterwards she developed myoclonus and progressive encephalopathy. Neurological workup showed no relevant abnormalities. A CT of the abdomen revealed a mass in the lower abdomen, which turned out to be an ovarian teratoma. Progressive encephalopathy with rigidity and myoclonus (PERM) was diagnosed clinically. Treatment with corticosteroids, benzodiazepines, and levetiracetam did not ameliorate the patient's condition. Only after the introduction of plasmapheresis was there a spectacular improvement in her clinical state. In this case we could not detect associated antibodies. The most likely cause of PERM is paraneoplastic disease secondary to ovarian teratoma. This type of tumor has been associated with multiple paraneoplastic neurological conditions, but this is the first case associated with PERM. To date there is only one publication on trismus as a sole presenting sign, with a quite similar disease course.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000499448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739699PMC
April 2019

Dutch genome diagnostic laboratories accelerated and improved variant interpretation and increased accuracy by sharing data.

Hum Mutat 2019 12 3;40(12):2230-2238. Epub 2019 Sep 3.

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Each year diagnostic laboratories in the Netherlands profile thousands of individuals for heritable disease using next-generation sequencing (NGS). This requires pathogenicity classification of millions of DNA variants on the standard 5-tier scale. To reduce time spent on data interpretation and increase data quality and reliability, the nine Dutch labs decided to publicly share their classifications. Variant classifications of nearly 100,000 unique variants were catalogued and compared in a centralized MOLGENIS database. Variants classified by more than one center were labeled as "consensus" when classifications agreed, and shared internationally with LOVD and ClinVar. When classifications opposed (LB/B vs. LP/P), they were labeled "conflicting", while other nonconsensus observations were labeled "no consensus". We assessed our classifications using the InterVar software to compare to ACMG 2015 guidelines, showing 99.7% overall consistency with only 0.3% discrepancies. Differences in classifications between Dutch labs or between Dutch labs and ACMG were mainly present in genes with low penetrance or for late onset disorders and highlight limitations of the current 5-tier classification system. The data sharing boosted the quality of DNA diagnostics in Dutch labs, an initiative we hope will be followed internationally. Recently, a positive match with a case from outside our consortium resulted in a more definite disease diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.23896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900155PMC
December 2019

Improving the diagnostic yield of exome- sequencing by predicting gene-phenotype associations using large-scale gene expression analysis.

Nat Commun 2019 06 28;10(1):2837. Epub 2019 Jun 28.

University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 VB, Groningen, The Netherlands.

The diagnostic yield of exome and genome sequencing remains low (8-70%), due to incomplete knowledge on the genes that cause disease. To improve this, we use RNA-seq data from 31,499 samples to predict which genes cause specific disease phenotypes, and develop GeneNetwork Assisted Diagnostic Optimization (GADO). We show that this unbiased method, which does not rely upon specific knowledge on individual genes, is effective in both identifying previously unknown disease gene associations, and flagging genes that have previously been incorrectly implicated in disease. GADO can be run on www.genenetwork.nl by supplying HPO-terms and a list of genes that contain candidate variants. Finally, applying GADO to a cohort of 61 patients for whom exome-sequencing analysis had not resulted in a genetic diagnosis, yields likely causative genes for ten cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-10649-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599066PMC
June 2019

Correction to: The 1000IBD project: multi-omics data of 1000 inflammatory bowel disease patients; data release 1.

BMC Gastroenterol 2019 03 27;19(1):44. Epub 2019 Mar 27.

Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, PO Box 30.001, 9700RB, Groningen, the Netherlands.

Following publication of the original article [1], the authors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12876-019-0938-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436211PMC
March 2019

The 1000IBD project: multi-omics data of 1000 inflammatory bowel disease patients; data release 1.

BMC Gastroenterol 2019 Jan 8;19(1). Epub 2019 Jan 8.

Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, PO Box 30.001, 9700RB, Groningen, the Netherlands.

Background: Inflammatory bowel disease (IBD) is a chronic complex disease of the gastrointestinal tract. Patients with IBD can experience a wide range of symptoms, but the pathophysiological mechanisms that cause these individual differences in clinical presentation remain largely unknown. In consequence, IBD is currently classified into subtypes using clinical characteristics. If we are to develop a more targeted treatment approach, molecular subtypes of IBD need to be discovered that can be used as new drug targets. To achieve this, we need multiple layers of molecular data generated from the same IBD patients.

Construction And Content: We initiated the 1000IBD project ( https://1000ibd.org ) to prospectively follow more than 1000 IBD patients from the Northern provinces of the Netherlands. For these patients, we have collected a uniquely large number of phenotypes and generated multi-omics profiles. To date, 1215 participants have been enrolled in the project and enrolment is on-going. Phenotype data collected for these participants includes information on dietary and environmental factors, drug responses and adverse drug events. Genome information has been generated using genotyping (ImmunoChip, Global Screening Array and HumanExomeChip) and sequencing (whole exome sequencing and targeted resequencing of IBD susceptibility loci), transcriptome information generated using RNA-sequencing of intestinal biopsies and microbiome information generated using both sequencing of the 16S rRNA gene and whole genome shotgun metagenomic sequencing.

Utility And Discussion: All molecular data generated within the 1000IBD project will be shared on the European Genome-Phenome Archive ( https://ega-archive.org , accession no: EGAS00001002702). The first data release, detailed in this announcement and released simultaneously with this publication, will contain basic phenotypes for 1215 participants, genotypes of 314 participants and gut microbiome data from stool samples (315 participants) and biopsies (107 participants) generated by tag sequencing the 16S gene. Future releases will comprise many more additional phenotypes and -omics data layers. 1000IBD data can be used by other researchers as a replication cohort, a dataset to test new software tools, or a dataset for applying new statistical models.

Conclusions: We report on the establishment and future development of the 1000IBD project: the first comprehensive multi-omics dataset aimed at discovering IBD biomarker profiles and treatment targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12876-018-0917-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325838PMC
January 2019

Sinonasal cysts causing dyspnoea in two cattle - case report.

Acta Vet Hung 2018 12;66(4):553-561

1 University Clinic for Ruminants, Department for Farm Animals and Veterinary Public Health, University of Veterinary Medicine Vienna , Veterinälatz 1, 1210 Vienna , Austria.

Two cattle were referred to the University Clinic for Ruminants of the University of Veterinary Medicine in Vienna. The main clinical sign in both cattle was dyspnoea with nasal stridor. Clinical examination of the upper respiratory tract was conducted, supplemented by ultrasonography, endoscopy and radiography. In addition, histological, bacteriological, and cytological examinations of different specimen materials were performed. The cow of Case 1 suffered from cystic nasal conchae, which was treated successfully by a laser technique. The cow of Case 2 also suffered from cystic nasal conchae. No surgery was performed in this case because the cyst opened spontaneously the day after diagnostic endoscopic procedures had been performed and the animal did not show any respiratory signs anymore. Pathological changes in the upper respiratory tract, such as nasal obstructions, should be included in the list of differential diagnoses in cattle showing respiratory distress.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1556/004.2018.049DOI Listing
December 2018

Cross-Cultural Adaptation and Psychometric Evaluation of the Dutch Version of the Work Rehabilitation Questionnaire (WORQ-VL).

J Occup Rehabil 2019 09;29(3):514-525

Department of Rehabilitation Sciences, Occupational Therapy, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000, Ghent, Belgium.

Purpose The Work Rehabilitation Questionnaire (WORQ) was developed to evaluate work functioning in vocational rehabilitation, but was not yet available in Dutch. The goal of this study is twofold: a description of the cross-cultural adaptation process (part 1) of the WORQ to be used in Flanders (The Dutch speaking part of Belgium, WORQ-VL) and a presentation of the first psychometric testing of the WORQ-VL (part 2). Methods For part 1, the guidelines for cross-cultural adaptation of self-report measures by Beaton et al. were used to structure the cross-cultural adaptation. For part 2, a cross-sectional study was conducted in patients with musculoskeletal disorders [sample A: hand and wrist rehabilitation (n = 21) and sample B: fibromyalgia patients (n = 93)] who completed the WORQ-VL. Internal consistency and factor structure were examined in the total sample, whereas convergent and discriminant validity of the WORQ-VL were researched in sample A. Results First results on the convergent validity and discriminant validity (small sample size) and internal consistency of the WORQ-VL are promising. The exploratory factor analysis revealed seven factors which were labeled as 'cognition', 'physical', 'mood', 'activities of daily living', 'sensory', 'emotional' and 'social'. The best evidence was found for the 'physical' subscale of the WORQ-VL: strong correlations were found with the 'physical functioning' and 'role limitations-physical' subscales of the Short-Form Health Survey, respectively r = - .84 and r = - .59, p < .01. As expected, predominantly weak correlations were found with hand grip strength, kinesiophobia, hand-related aesthetics and satisfaction (ranging between r = - .38 and r = .34, p > .05). Conclusions The WORQ-VL is a user-friendly and valuable ICF-based self-report questionnaire to evaluate work functioning. Future studies are highly needed to examine the value of the WORQ within different patient populations and settings in order to examine further the added value of this self-report measure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10926-018-9812-8DOI Listing
September 2019

MOLGENIS research: advanced bioinformatics data software for non-bioinformaticians.

Bioinformatics 2019 03;35(6):1076-1078

Genomics Coordination Center, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.

Motivation: The volume and complexity of biological data increases rapidly. Many clinical professionals and biomedical researchers without a bioinformatics background are generating big '-omics' data, but do not always have the tools to manage, process or publicly share these data.

Results: Here we present MOLGENIS Research, an open-source web-application to collect, manage, analyze, visualize and share large and complex biomedical datasets, without the need for advanced bioinformatics skills.

Availability And Implementation: MOLGENIS Research is freely available (open source software). It can be installed from source code (see http://github.com/molgenis), downloaded as a precompiled WAR file (for your own server), setup inside a Docker container (see http://molgenis.github.io), or requested as a Software-as-a-Service subscription. For a public demo instance and complete installation instructions see http://molgenis.org/research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/bioinformatics/bty742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6419911PMC
March 2019

No major role for rare plectin variants in arrhythmogenic right ventricular cardiomyopathy.

PLoS One 2018 30;13(8):e0203078. Epub 2018 Aug 30.

Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Aims: Likely pathogenic/pathogenic variants in genes encoding desmosomal proteins play an important role in the pathophysiology of arrhythmogenic right ventricular cardiomyopathy (ARVC). However, for a substantial proportion of ARVC patients, the genetic substrate remains unknown. We hypothesized that plectin, a cytolinker protein encoded by the PLEC gene, could play a role in ARVC because it has been proposed to link the desmosomal protein desmoplakin to the cytoskeleton and therefore has a potential function in the desmosomal structure.

Methods: We screened PLEC in 359 ARVC patients and compared the frequency of rare coding PLEC variants (minor allele frequency [MAF] <0.001) between patients and controls. To assess the frequency of rare variants in the control population, we evaluated the rare coding variants (MAF <0.001) found in the European cohort of the Exome Aggregation Database. We further evaluated plectin localization by immunofluorescence in a subset of patients with and without a PLEC variant.

Results: Forty ARVC patients carried one or more rare PLEC variants (11%, 40/359). However, rare variants also seem to occur frequently in the control population (18%, 4754/26197 individuals). Nor did we find a difference in the prevalence of rare PLEC variants in ARVC patients with or without a desmosomal likely pathogenic/pathogenic variant (14% versus 8%, respectively). However, immunofluorescence analysis did show decreased plectin junctional localization in myocardial tissue from 5 ARVC patients with PLEC variants.

Conclusions: Although PLEC has been hypothesized as a promising candidate gene for ARVC, our current study did not show an enrichment of rare PLEC variants in ARVC patients compared to controls and therefore does not support a major role for PLEC in this disorder. Although rare PLEC variants were associated with abnormal localization in cardiac tissue, the confluence of data does not support a role for plectin abnormalities in ARVC development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0203078PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117038PMC
February 2019

Cytokine-induced interleukin-1 receptor antagonist protein expression in genetically engineered equine mesenchymal stem cells for osteoarthritis treatment.

J Gene Med 2018 05 22;20(5):e3021. Epub 2018 Apr 22.

Institute of Pathology and Forensic Veterinary Medicine, Working Group Histology and Embryology, University of Veterinary Medicine Vienna, Vienna, Austria.

Background: A combination of tissue engineering methods employing mesenchymal stem cells (MSCs) together with gene transfer takes advantage of innovative strategies and highlights a new approach for targeting osteoarthritis (OA) and other cartilage defects. Furthermore, the development of systems allowing tunable transgene expression as regulated by natural disease-induced substances is highly desirable.

Methods: Bone marrow-derived equine MSCs were transduced with a lentiviral vector expressing interleukin-1 receptor antagonist (IL-1Ra) gene under the control of an inducible nuclear factor-kappa B-responsive promoter and IL-1Ra production upon pro-inflammatory cytokine stimulation [tumor necrosis factor (TNF)α, interleukin (IL)-1β] was analysed. To assess the biological activity of the IL-1Ra protein that was produced and the therapeutic effect of IL-1Ra-expressing MSCs (MSC/IL-1Ra), cytokine-based two- and three-dimensional in vitro models of osteoarthritis using equine chondrocytes were established and quantitative real-time polymerase chain reaction (PCR) analysis was used to measure the gene expression of aggrecan, collagen IIA1, interleukin-1β, interleukin-6, interleukin-8, matrix metalloproteinase-1 and matrix metalloproteinase-13.

Results: A dose-dependent increase in IL-1Ra expression was found in MSC/IL-1Ra cells upon TNFα administration, whereas stimulation using IL-1β did not lead to IL-1Ra production above the basal level observed in nonstimulated cells as a result of the existing feedback loop. Repeated cycles of induction allowed on/off modulation of transgene expression. In vitro analyses revealed that IL-1Ra protein present in the conditioned medium from MSC/IL-1Ra cells blocks OA onset in cytokine-treated equine chondrocytes and co-cultivation of MSC/IL-1Ra cells with osteoarthritic spheroids alleviates the severity of the osteoarthritic changes.

Conclusions: Thus, pro-inflammatory cytokine induced IL-1Ra protein expression from genetically modified MSCs might represent a promising strategy for osteoarthritis treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jgm.3021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6001542PMC
May 2018

MYO5B, STX3, and STXBP2 mutations reveal a common disease mechanism that unifies a subset of congenital diarrheal disorders: A mutation update.

Hum Mutat 2018 03 17;39(3):333-344. Epub 2018 Jan 17.

Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Microvillus inclusion disease (MVID) is a rare but fatal autosomal recessive congenital diarrheal disorder caused by MYO5B mutations. In 2013, we launched an open-access registry for MVID patients and their MYO5B mutations (www.mvid-central.org). Since then, additional unique MYO5B mutations have been identified in MVID patients, but also in non-MVID patients. Animal models have been generated that formally prove the causality between MYO5B and MVID. Importantly, mutations in two other genes, STXBP2 and STX3, have since been associated with variants of MVID, shedding new light on the pathogenesis of this congenital diarrheal disorder. Here, we review these additional genes and their mutations. Furthermore, we discuss recent data from cell studies that indicate that the three genes are functionally linked and, therefore, may constitute a common disease mechanism that unifies a subset of phenotypically linked congenital diarrheal disorders. We present new data based on patient material to support this. To congregate existing and future information on MVID geno-/phenotypes, we have updated and expanded the MVID registry to include all currently known MVID-associated gene mutations, their demonstrated or predicted functional consequences, and associated clinical information.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.23386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5838515PMC
March 2018

reGenotyper: Detecting mislabeled samples in genetic data.

PLoS One 2017 13;12(2):e0171324. Epub 2017 Feb 13.

Groningen Bioinformatics Centre, University of Groningen, Groningen, The Netherlands.

In high-throughput molecular profiling studies, genotype labels can be wrongly assigned at various experimental steps; the resulting mislabeled samples seriously reduce the power to detect the genetic basis of phenotypic variation. We have developed an approach to detect potential mislabeling, recover the "ideal" genotype and identify "best-matched" labels for mislabeled samples. On average, we identified 4% of samples as mislabeled in eight published datasets, highlighting the necessity of applying a "data cleaning" step before standard data analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0171324PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5305221PMC
August 2017

GAVIN: Gene-Aware Variant INterpretation for medical sequencing.

Genome Biol 2017 01 16;18(1). Epub 2017 Jan 16.

University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, The Netherlands.

We present Gene-Aware Variant INterpretation (GAVIN), a new method that accurately classifies variants for clinical diagnostic purposes. Classifications are based on gene-specific calibrations of allele frequencies from the ExAC database, likely variant impact using SnpEff, and estimated deleteriousness based on CADD scores for >3000 genes. In a benchmark on 18 clinical gene sets, we achieve a sensitivity of 91.4% and a specificity of 76.9%. This accuracy is unmatched by 12 other tools. We provide GAVIN as an online MOLGENIS service to annotate VCF files and as an open source executable for use in bioinformatic pipelines. It can be found at http://molgenis.org/gavin .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13059-016-1141-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5240400PMC
January 2017

Enzymatically Modified Starch Favorably Modulated Intestinal Transit Time and Hindgut Fermentation in Growing Pigs.

PLoS One 2016 9;11(12):e0167784. Epub 2016 Dec 9.

Research Cluster "Animal Gut Health", Department for Farm Animals and Veterinary Public Health, University of Veterinary Medicine Vienna, Vienna, Austria.

Aside from being used as stabilizing agents in many processed foods, chemically modified starches may act as functional dietary ingredients. Therefore, development of chemically modified starches that are less digestible in the upper intestinal segments and promote fermentation in the hindgut receives considerable attention. This study aimed to investigate the impact of an enzymatically modified starch (EMS) on nutrient flow, passage rate, and bacterial activity at ileal and post-ileal level. Eight ileal-cannulated growing pigs were fed 2 diets containing 72% purified starch (EMS or waxy cornstarch as control) in a cross-over design for 10 d, followed by a 4-d collection of feces and 2-d collection of ileal digesta. On d 17, solid and liquid phase markers were added to the diet to determine ileal digesta flow for 8 h after feeding. Reduced small intestinal digestion after the consumption of the EMS diet was indicated by a 10%-increase in ileal flow and fecal excretion of dry matter and energy compared to the control diet (P<0.05). Moreover, EMS feeding reduced ileal transit time of both liquid and solid fractions compared to the control diet (P<0.05). The greater substrate flow to the large intestine with the EMS diet increased the concentrations of total and individual short-chain fatty acids (SCFA) in feces (P<0.05). Total bacterial 16S rRNA gene abundance was not affected by diet, whereas the relative abundance of the Lactobacillus group decreased (P<0.01) by 50% and of Enterobacteriaceae tended (P<0.1) to increase by 20% in ileal digesta with the EMS diet compared to the control diet. In conclusion, EMS appears to resemble a slowly digestible starch by reducing intestinal transit and increasing SCFA in the distal large intestine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167784PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5147999PMC
July 2017

Inflammation-induced transgene expression in genetically engineered equine mesenchymal stem cells.

J Gene Med 2016 Aug;18(8):154-64

Institute of Anatomy, Histology and Embryology, University of Veterinary Medicine Vienna, Vienna, Austria.

Background: Osteoarthritis, a chronic and progressive degenerative joint disorder, ranks amongst the top five causes of disability. Given the high incidence, associated socioeconomic costs and the absence of effective disease-modifying therapies of osteoarthritis, cell-based treatments offer a promising new approach. Owing to their paracrine, differentiation and self-renewal abilities, mesenchymal stem cells (MSCs) have great potential for regenerative medicine, which might be further enhanced by targeted gene therapy. Hence, the development of systems allowing transgene expression, particularly when regulated by natural disease-dependent occuring substances, is of high interest.

Methods: Bone marrow-isolated equine MSCs were stably transduced with an HIV-1 based lentiviral vector expressing the luciferase gene under control of an inducible nuclear factor κB (NFκB)-responsive promoter. Marker gene expression was analysed by determining luciferase activity in transduced cells stimulated with different concentrations of interleukin (IL)-1β or tumour necrosis factor (TNF)α.

Results: A dose-dependent increase in luciferase expression was observed in transduced MSCs upon cytokine stimulation. The induction effect was more potent in cells treated with TNFα compared to those treated with IL-1β. Maximum transgene expression was obtained after 48 h of stimulation and the same time was necessary to return to baseline luciferase expression levels after withdrawal of the stimulus. Repeated cycles of induction allowed on-off modulation of transgene expression without becoming refractory to induction. The NFκB-responsive promoter retained its inducibility also in chondrogenically differentiated MSC/Luc cells.

Conclusions: The results of the present study demonstrate that on demand transgene expression from the NFκB-responsive promoter using naturally occurring inflammatory cytokines can be induced in undifferentiated and chondrogenically differentiated equine MSCs. Copyright © 2016 John Wiley & Sons, Ltd.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jgm.2888DOI Listing
August 2016

MOLGENIS/connect: a system for semi-automatic integration of heterogeneous phenotype data with applications in biobanks.

Bioinformatics 2016 07 21;32(14):2176-83. Epub 2016 Mar 21.

Department of Genetics, University Medical Center Groningen, Genomics Coordination Center, University of Groningen, Groningen, The Netherlands Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Motivation: While the size and number of biobanks, patient registries and other data collections are increasing, biomedical researchers still often need to pool data for statistical power, a task that requires time-intensive retrospective integration.

Results: To address this challenge, we developed MOLGENIS/connect, a semi-automatic system to find, match and pool data from different sources. The system shortlists relevant source attributes from thousands of candidates using ontology-based query expansion to overcome variations in terminology. Then it generates algorithms that transform source attributes to a common target DataSchema. These include unit conversion, categorical value matching and complex conversion patterns (e.g. calculation of BMI). In comparison to human-experts, MOLGENIS/connect was able to auto-generate 27% of the algorithms perfectly, with an additional 46% needing only minor editing, representing a reduction in the human effort and expertise needed to pool data.

Availability And Implementation: Source code, binaries and documentation are available as open-source under LGPLv3 from http://github.com/molgenis/molgenis and www.molgenis.org/connect

Contact: : m.a.swertz@rug.nl

Supplementary Information: Supplementary data are available at Bioinformatics online.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/bioinformatics/btw155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4937195PMC
July 2016

Association between nutritional status and subjective health status in chronically ill children attending special schools.

Qual Life Res 2016 Apr 11;25(4):969-77. Epub 2015 Sep 11.

Department of Pediatrics, Pediatric Intensive Care, Erasmus MC - Sophia Children's Hospital, Dr. Molewaterplein 60, 3015 GJ, Rotterdam, The Netherlands.

Purpose: In hospitalized children with a chronic disease, malnutrition was associated with a lower subjective health status. In outpatient children with a chronic disease attending special schools, this association has never been studied. The aim of this study was to assess the association between nutritional status and subjective health status in chronically ill children attending special schools.

Methods: Overall, 642 children, median age 9.8 years (IQR 7.7-11.5), 60 % male, 72 % Caucasian, were included in this prospective study in nine special schools for chronically ill children in the Netherlands. Overall malnutrition was assessed as: acute malnutrition (<-2 SDS for weight for height (WFH)) and chronic malnutrition (<-2 SDS for height for age). The malnutrition risk was assessed with the nutritional risk-screening tool STRONGkids. Subjective health status was assessed with EQ-5D.

Results: Overall, 16 % of the children had overall malnutrition: 3 % acute and 13 % chronic malnutrition. Nurses reported 'some/severe problems' on the health status dimensions mobility (15 %), self-care (17 %), usual activities (19 %), pain/discomfort (22 %), and anxiety/depression (22 %) in chronically ill children. Their mean visual analogue scale score (VAS) was 73.0 (SD 11.1). Malnutrition, medication usage, and younger age explained 38 % of the variance of the VAS score.

Conclusions: The presence of overall malnutrition in chronically ill children attending special schools was associated with lower subjective health status, especially in younger children and in those with chronic medication usage. Therefore, it is important to develop and use profile-screening tools to identify these children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11136-015-1130-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830861PMC
April 2016

Calling genotypes from public RNA-sequencing data enables identification of genetic variants that affect gene-expression levels.

Genome Med 2015 27;7(1):30. Epub 2015 Mar 27.

University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 RB Groningen, The Netherlands.

Background: RNA-sequencing (RNA-seq) is a powerful technique for the identification of genetic variants that affect gene-expression levels, either through expression quantitative trait locus (eQTL) mapping or through allele-specific expression (ASE) analysis. Given increasing numbers of RNA-seq samples in the public domain, we here studied to what extent eQTLs and ASE effects can be identified when using public RNA-seq data while deriving the genotypes from the RNA-sequencing reads themselves.

Methods: We downloaded the raw reads for all available human RNA-seq datasets. Using these reads we performed gene expression quantification. All samples were jointly normalized and subjected to a strict quality control. We also derived genotypes using the RNA-seq reads and used imputation to infer non-coding variants. This allowed us to perform eQTL mapping and ASE analyses jointly on all samples that passed quality control. Our results were validated using samples for which DNA-seq genotypes were available.

Results: 4,978 public human RNA-seq runs, representing many different tissues and cell-types, passed quality control. Even though these data originated from many different laboratories, samples reflecting the same cell type clustered together, suggesting that technical biases due to different sequencing protocols are limited. In a joint analysis on the 1,262 samples with high quality genotypes, we identified cis-eQTLs effects for 8,034 unique genes (at a false discovery rate ≤0.05). eQTL mapping on individual tissues revealed that a limited number of samples already suffice to identify tissue-specific eQTLs for known disease-associated genetic variants. Additionally, we observed strong ASE effects for 34 rare pathogenic variants, corroborating previously observed effects on the corresponding protein levels.

Conclusions: By deriving and imputing genotypes from RNA-seq data, it is possible to identify both eQTLs and ASE effects. Given the exponential growth of the number of publicly available RNA-seq samples, we expect this approach will become especially relevant for studying the effects of tissue-specific and rare pathogenic genetic variants to aid clinical interpretation of exome and genome sequencing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-015-0152-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423486PMC
May 2015

Evaluation of CADD Scores in Curated Mismatch Repair Gene Variants Yields a Model for Clinical Validation and Prioritization.

Hum Mutat 2015 Jul 20;36(7):712-9. Epub 2015 May 20.

Genomics Coordination Center, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Next-generation sequencing in clinical diagnostics is providing valuable genomic variant data, which can be used to support healthcare decisions. In silico tools to predict pathogenicity are crucial to assess such variants and we have evaluated a new tool, Combined Annotation Dependent Depletion (CADD), and its classification of gene variants in Lynch syndrome by using a set of 2,210 DNA mismatch repair gene variants. These had already been classified by experts from InSiGHT's Variant Interpretation Committee. Overall, we found CADD scores do predict pathogenicity (Spearman's ρ = 0.595, P < 0.001). However, we discovered 31 major discrepancies between the InSiGHT classification and the CADD scores; these were explained in favor of the expert classification using population allele frequencies, cosegregation analyses, disease association studies, or a second-tier test. Of 751 variants that could not be clinically classified by InSiGHT, CADD indicated that 47 variants were worth further study to confirm their putative pathogenicity. We demonstrate CADD is valuable in prioritizing variants in clinically relevant genes for further assessment by expert classification teams.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.22798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973827PMC
July 2015

Genotype harmonizer: automatic strand alignment and format conversion for genotype data integration.

BMC Res Notes 2014 Dec 11;7:901. Epub 2014 Dec 11.

University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, the Netherlands.

Background: To gain statistical power or to allow fine mapping, researchers typically want to pool data before meta-analyses or genotype imputation. However, the necessary harmonization of genetic datasets is currently error-prone because of many different file formats and lack of clarity about which genomic strand is used as reference.

Findings: Genotype Harmonizer (GH) is a command-line tool to harmonize genetic datasets by automatically solving issues concerning genomic strand and file format. GH solves the unknown strand issue by aligning ambiguous A/T and G/C SNPs to a specified reference, using linkage disequilibrium patterns without prior knowledge of the used strands. GH supports many common GWAS/NGS genotype formats including PLINK, binary PLINK, VCF, SHAPEIT2 & Oxford GEN. GH is implemented in Java and a large part of the functionality can also be used as Java 'Genotype-IO' API. All software is open source under license LGPLv3 and available from http://www.molgenis.org/systemsgenetics.

Conclusions: GH can be used to harmonize genetic datasets across different file formats and can be easily integrated as a step in routine meta-analysis and imputation pipelines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1756-0500-7-901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4307387PMC
December 2014

Case report: Hyperthermia and diminished consciousness in an elderly woman following an accidental overdose of scopolamine.

Acta Neurol Belg 2015 Sep 14;115(3):517-8. Epub 2014 Nov 14.

Department of Neurology, AZ Nikolaas, Sint Niklaas, Belgium,

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13760-014-0385-9DOI Listing
September 2015

BiobankConnect: software to rapidly connect data elements for pooled analysis across biobanks using ontological and lexical indexing.

J Am Med Inform Assoc 2015 Jan 31;22(1):65-75. Epub 2014 Oct 31.

Department of Genetics, Genomics Coordination Center, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands Groningen Bioinformatics Center, University of Groningen, Groningen, The Netherlands.

Objective: Pooling data across biobanks is necessary to increase statistical power, reveal more subtle associations, and synergize the value of data sources. However, searching for desired data elements among the thousands of available elements and harmonizing differences in terminology, data collection, and structure, is arduous and time consuming.

Materials And Methods: To speed up biobank data pooling we developed BiobankConnect, a system to semi-automatically match desired data elements to available elements by: (1) annotating the desired elements with ontology terms using BioPortal; (2) automatically expanding the query for these elements with synonyms and subclass information using OntoCAT; (3) automatically searching available elements for these expanded terms using Lucene lexical matching; and (4) shortlisting relevant matches sorted by matching score.

Results: We evaluated BiobankConnect using human curated matches from EU-BioSHaRE, searching for 32 desired data elements in 7461 available elements from six biobanks. We found 0.75 precision at rank 1 and 0.74 recall at rank 10 compared to a manually curated set of relevant matches. In addition, best matches chosen by BioSHaRE experts ranked first in 63.0% and in the top 10 in 98.4% of cases, indicating that our system has the potential to significantly reduce manual matching work.

Conclusions: BiobankConnect provides an easy user interface to significantly speed up the biobank harmonization process. It may also prove useful for other forms of biomedical data integration. All the software can be downloaded as a MOLGENIS open source app from http://www.github.com/molgenis, with a demo available at http://www.biobankconnect.org.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/amiajnl-2013-002577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433361PMC
January 2015

WormQTLHD--a web database for linking human disease to natural variation data in C. elegans.

Nucleic Acids Res 2014 Jan 11;42(Database issue):D794-801. Epub 2013 Nov 11.

Genomics Coordination Center, University of Groningen, University Medical Center Groningen, P.O. Box 30001, 9700 RB Groningen, The Netherlands, Groningen Bioinformatics Center, University of Groningen, P.O. Box 11103, 9700 CC Groningen, The Netherlands, Department of Genetics, University of Groningen, University Medical Center Groningen, P.O. Box 30001, 9700 RB Groningen, The Netherlands, Department of Bioinformatics, Hanze University of Applied Sciences, Groningen, Zernikeplein 11, 9747 AS, The Netherlands and Laboratory of Nematology, Wageningen University, 6708 PB Wageningen, The Netherlands.

Interactions between proteins are highly conserved across species. As a result, the molecular basis of multiple diseases affecting humans can be studied in model organisms that offer many alternative experimental opportunities. One such organism-Caenorhabditis elegans-has been used to produce much molecular quantitative genetics and systems biology data over the past decade. We present WormQTL(HD) (Human Disease), a database that quantitatively and systematically links expression Quantitative Trait Loci (eQTL) findings in C. elegans to gene-disease associations in man. WormQTL(HD), available online at http://www.wormqtl-hd.org, is a user-friendly set of tools to reveal functionally coherent, evolutionary conserved gene networks. These can be used to predict novel gene-to-gene associations and the functions of genes underlying the disease of interest. We created a new database that links C. elegans eQTL data sets to human diseases (34 337 gene-disease associations from OMIM, DGA, GWAS Central and NHGRI GWAS Catalogue) based on overlapping sets of orthologous genes associated to phenotypes in these two species. We utilized QTL results, high-throughput molecular phenotypes, classical phenotypes and genotype data covering different developmental stages and environments from WormQTL database. All software is available as open source, built on MOLGENIS and xQTL workbench.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/nar/gkt1044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3965109PMC
January 2014

An overview and online registry of microvillus inclusion disease patients and their MYO5B mutations.

Hum Mutat 2013 Dec 16;34(12):1597-605. Epub 2013 Oct 16.

Genomics Coordination Center, Department of Genetics, University Medical Center Groningen, University of Groningen, The Netherlands.

Microvillus inclusion disease (MVID) is one of the most severe congenital intestinal disorders and is characterized by neonatal secretory diarrhea and the inability to absorb nutrients from the intestinal lumen. MVID is associated with patient-, family-, and ancestry-unique mutations in the MYO5B gene, encoding the actin-based motor protein myosin Vb. Here, we review the MYO5B gene and all currently known MYO5B mutations and for the first time methodologically categorize these with regard to functional protein domains and recurrence in MYO7A associated with Usher syndrome and other myosins. We also review animal models for MVID and the latest data on functional studies related to the myosin Vb protein. To congregate existing and future information on MVID geno-/phenotypes and facilitate its quick and easy sharing among clinicians and researchers, we have constructed an online MOLGENIS-based international patient registry (www.MVID-central.org). This easily accessible database currently contains detailed information of 137 MVID patients together with reported clinical/phenotypic details and 41 unique MYO5B mutations, of which several unpublished. The future expansion and prospective nature of this registry is expected to improve disease diagnosis, prognosis, and genetic counseling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.22440DOI Listing
December 2013

How securely is the testicular artery occluded in the spermatic cord by using a ligature?

Equine Vet J 2013 Sep 7;45(5):649-52. Epub 2013 Jan 7.

Veterinary Clinic Duurstede, Wijk bij Duurstede, The Netherlands.

Reasons For Performing Study: There are no studies on the ideal ligature technique for the spermatic cord.

Objectives: To compare the maximal resistance pressure in the testicular artery and the maximal tensile forces to produce failure of 2 different ligature techniques used for ligation of the equine spermatic cord.

Methods: The capabilities of 2 types of ligatures, single knot loop and double knot loop, were assessed using a pressure-resistance test in testicular arteries and with an in vitro mechanical evaluation of the tensile strength by single cycle-to-failure testing.

Results: In the pressure-resistance test, the mean ± s.d. peak force at failure of the single knot loop was 354.4 ± 91.7 mmHg and for the double knot loop 303.2 ± 62.0 mmHg. There was no significant difference between the maximal load to failure of the single knot loop and double knot loop technique. The pressure needed for rupture was significantly higher (P = 0.001) than for leakage. The maximal tensile force at failure of the single knot loop was significantly higher than the double knot loop (P = 0.028). There was no significant difference in load elongation properties to failure between the single knot loop and double knot loop.

Conclusions: Although no significant differences were obtained in the pressure-resistance test, the single knot loop sustained significantly greater load to failure than the double knot loop in single cycle-to-failure testing. Based on these findings, it would appear that the performance of the single knot loop should be superior to the double knot loop.

Potential Relevance: Both ligature techniques are able to withstand the normal physiological intravascular pressure. The single knot loop has the greater breaking strength of the 2 ligatures tested and is less time consuming to perform and may therefore have advantages during equine castration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/evj.12016DOI Listing
September 2013

WormQTL--public archive and analysis web portal for natural variation data in Caenorhabditis spp.

Nucleic Acids Res 2013 Jan 24;41(Database issue):D738-43. Epub 2012 Nov 24.

Laboratory of Nematology, Wageningen University, Wageningen 6708 PB, The Netherlands.

Here, we present WormQTL (http://www.wormqtl.org), an easily accessible database enabling search, comparative analysis and meta-analysis of all data on variation in Caenorhabditis spp. Over the past decade, Caenorhabditis elegans has become instrumental for molecular quantitative genetics and the systems biology of natural variation. These efforts have resulted in a valuable amount of phenotypic, high-throughput molecular and genotypic data across different developmental worm stages and environments in hundreds of C. elegans strains. WormQTL provides a workbench of analysis tools for genotype-phenotype linkage and association mapping based on but not limited to R/qtl (http://www.rqtl.org). All data can be uploaded and downloaded using simple delimited text or Excel formats and are accessible via a public web user interface for biologists and R statistic and web service interfaces for bioinformaticians, based on open source MOLGENIS and xQTL workbench software. WormQTL welcomes data submissions from other worm researchers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/nar/gks1124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3531126PMC
January 2013

Guttural pouch mycosis in horses: a retrospective study of 28 cases.

Vet Rec 2012 Dec 31;171(22):561. Epub 2012 Oct 31.

Equine Clinic, University of Veterinary and Pharmaceutical Sciences Brno, Brno, Czech Republic.

The medical records of 28 horses with guttural pouch mycosis were reviewed. The most commonly observed clinical signs were nasal discharge, epistaxis, dysphagia and/or cough. All 28 horses had the disease unilaterally, however, in five of them, it had spread into the contralateral pouch via the mesial septum. Three horses were treated medically, 11 horses underwent surgery and seven horses were treated both medically and surgically. Fifty percent of horses (14/28) were euthanased or died, fifty percent of horses (14/28) survived. There was no significant correlation between treatment method (medical, surgical, combination) and survival rate. The most common reason for euthanasia was dysphagia due to pharyngeal dysfunction. There was a highly significant correlation between the presence of dysphagia and non-survival (p=0.008).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/vr.100700DOI Listing
December 2012

Observ-OM and Observ-TAB: Universal syntax solutions for the integration, search, and exchange of phenotype and genotype information.

Hum Mutat 2012 May 4;33(5):867-73. Epub 2012 Apr 4.

EU-GEN2PHEN, and European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, United Kingdom.

Genetic and epidemiological research increasingly employs large collections of phenotypic and molecular observation data from high quality human and model organism samples. Standardization efforts have produced a few simple formats for exchange of these various data, but a lightweight and convenient data representation scheme for all data modalities does not exist, hindering successful data integration, such as assignment of mouse models to orphan diseases and phenotypic clustering for pathways. We report a unified system to integrate and compare observation data across experimental projects, disease databases, and clinical biobanks. The core object model (Observ-OM) comprises only four basic concepts to represent any kind of observation: Targets, Features, Protocols (and their Applications), and Values. An easy-to-use file format (Observ-TAB) employs Excel to represent individual and aggregate data in straightforward spreadsheets. The systems have been tested successfully on human biobank, genome-wide association studies, quantitative trait loci, model organism, and patient registry data using the MOLGENIS platform to quickly setup custom data portals. Our system will dramatically lower the barrier for future data sharing and facilitate integrated search across panels and species. All models, formats, documentation, and software are available for free and open source (LGPLv3) at http://www.observ-om.org.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.22070DOI Listing
May 2012