Look who is calling: a comparison of genotype calling algorithms

In genome-wide association studies, high-level statistical analyses rely on the validity of the called genotypes, and different genotype calling algorithms (GCAs) have been proposed. We compared the GCAs Bayesian robust linear modeling using Mahalanobis distance (BRLMM), Chiamo++, and JAPL using the autosomal single-nucleotide polymorphisms (SNPs) from the 500 k Affymetrix Array Set data of the Framingham Heart Study as provided for the Genetic Analysis Workshop 16, Problem 2, and prepared standard quality control (sQC) for each algorithm. Using JAPL, most individuals were retained for the analysis. The lowest number of SNPs that successfully passed sQC was observed for BRLMM and the highest for Chiamo++. All three GCAs fulfilled all sQC criteria for 79% of the SNPs but at least one GCA failed for 18% of the SNPs. Previously undetected errors in strand coding were identified by comparing genotype concordances between GCAs. Concordance dropped with the number of GCAs failing sQC. We conclude that JAPL and Chiamo++ are the GCAs of choice if the aim is to keep as many subjects and SNPs as possible, respectively

Hic et ibi.: Raum als Parameter linguistischer Analysen

Even though spacious conditions are integral parts of the vast majority of studies in the fields of sociolinguistics and variationist linguistics, they are not always discussed as subject matters per se. The special issue In Stadt und Land – Perspektiven variations- und soziolinguistischer Forschung aims at uniting different approaches that construe spatial categories not as sheer preconditions for the assignment of linguistic features or for the drawing up of maps but as central parameters in the analyses. The contributions thus illustrate one of the current trends in sociolinguistic and variationist linguistic research to explicitly discuss, conceptualize and systematize spatial categories

ACPA: automated cluster plot analysis of genotype data

Genome-wide association studies have become standard in genetic epidemiology. Analyzing hundreds of thousands of markers simultaneously imposes some challenges for statisticians. One issue is the problem of multiplicity, which has been compared with the search for the needle in a haystack. To reduce the number of false-positive findings, a number of quality filters such as exclusion of single-nucleotide polymorphisms (SNPs) with a high missing fraction are employed. Another filter is exclusion of SNPs for which the calling algorithm had difficulties in assigning the genotypes. The only way to do this is the visual inspection of the cluster plots, also termed signal intensity plots, but this approach is often neglected. We developed an algorithm ACPA (automated cluster plot analysis), which performs this task automatically for autosomal SNPs. It is based on counting samples that lie too close to the cluster of a different genotype; SNPs are excluded when a certain threshold is exceeded. We evaluated ACPA using 1,000 randomly selected quality controlled SNPs from the Framingham Heart Study data that were provided for the Genetic Analysis Workshop 16. We compared the decision of ACPA with the decision made by two independent readers. We achieved a sensitivity of 88% (95% CI: 81%-93%) and a specificity of 86% (95% CI: 83%-89%). In a screening setting in which one aims at not losing any good SNP, we achieved 99% (95% CI: 98%-100%) specificity and still detected every second low-quality SNP

Treatment with an Anti-CD44v10-Specific Antibody Inhibits the Onset of Alopecia Areata in C3H/HeJ Mice

A murine CD44v10-neutralizing antibody has been reported to impair delayed-type hypersensitivity reactions. Because alopecia areata is characterized by a delayed-type hypersensitivity-like T cell mediated immune response, we addressed the question whether an anti-CD44v10-antibody influences the onset of alopecia areata. Therefore, we used the C3H/HeJ mouse model with the induction of alopecia areata in unaffected mice by the grafting of lesional alopecia areata mouse skin. Six grafted mice were injected (intraperitoneally) with anti-CD44v10, six grafted mice with anti-CD44standard, and six with phosphate-buffered saline only. After 11 wk phosphate-buffered saline injected animals on average had developed alopecia areata on 36.8% of their body. The onset of hair loss was slightly delayed and its extent reduced to 17.2% of their body in anti-CD44standard-treated mice. By contrast, five of six anti-CD44v10-treated mice did not show any hair loss and one mouse developed alopecia areata on only 1% of the body. Immunohistochemical examination revealed a marked reduction of perifollicular CD8+ lymphocytes and, to a lesser degree, CD4+ cells as well as a decreased expression of major histocompatibility complex class I on hair follicle epithelium in anti-CD44v10-treated mice as compared with phosphate-buffered saline or anti-CD44 standard-treated mice. Our data show that anti-CD44v10 is able to inhibit the onset of alopecia areata in C3H/HeJ mice. This might be accomplished by an anti-CD44v10-triggered impairment of immune cell homing (e.g., CD8+ T cells), resulting in a decrease of their number in target tissues

The Rise of Welfare Service States – Conceptual challenges of an ambiguous welfare settlement and the need for new policy research

Bonvin J-M, Otto H-U, Wohlfarth A, Ziegler H. The Rise of Welfare Service States – Conceptual challenges of an ambiguous welfare settlement and the need for new policy research. Social Work & Society. 2018;16(2).This paper sums up the reasoning for a Welfare Service State and offers an outline of conceptual challenges associated with a service-based welfare architecture

BiomarCaRE: rationale and design of the European BiomarCaRE project including 300,000 participants from 13 European countries

Biomarkers are considered as tools to enhance cardiovascular risk estimation. However, the value of biomarkers on risk estimation beyond European risk scores, their comparative impact among different European regions and their role towards personalised medicine remains uncertain. Biomarker for Cardiovascular Risk Assessment in Europe (BiomarCaRE) is an European collaborative research project with the primary objective to assess the value of established and emerging biomarkers for cardiovascular risk prediction. BiomarCaRE integrates clinical and epidemiological biomarker research and commercial enterprises throughout Europe to combine innovation in biomarker discovery for cardiovascular disease prediction with consecutive validation of biomarker effectiveness in large, well-defined primary and secondary prevention cohorts including over 300,000 participants from 13 European countries. Results from this study will contribute to improved cardiovascular risk prediction across different European populations. The present publication describes the rationale and design of the BiomarCaRE project. Electronic supplementary material The online version of this article (doi:10.1007/s10654-014-9952-x) contains supplementary material, which is available to authorized users

Thymosin beta 4 Improves Differentiation and Vascularization of EHTs

Induced pluripotent stem cells (iPSC) constitute a powerful tool to study cardiac physiology and represents a promising treatment strategy to tackle cardiac disease. However, iPSCs remain relatively immature after differentiation. Additionally, engineered heart tissue (EHT) has been investigated as a therapy option in preclinical disease models with promising results, although their vascularization and functionality leave room for improvement. Thymosin beta 4 (T beta 4) has been shown to promote the differentiation of progenitor cell lines to cardiomyocytes while it also induces angiogenic sprouting and vascular maturation. We examined the potential impact of T beta 4 to enhance maturation of cardiomyocytes from iPSCs. Assessing the expression of transcription factors associated with cardiac differentiation, we were able to demonstrate the increased generation of cells displaying cardiomyocyte characteristics in vitro. Furthermore, we demonstrated, in a zebrafish model of embryonic vascular development, that T beta 4 is crucial for the proper execution of lymphatic and angiogenic vessel sprouting. Finally, utilizing T beta 4-transduced EHTs generated from mice genetically engineered to label endothelial cells in vitro, we show that treatment with T beta 4 promotes vascularization and contractility in EHTs, highlighting T beta 4 as a growth factor improving the formation of cardiomyocytes from iPSC and enhancing the performance of EHTs generated from neonatal cardiomyocytes

Comprehensive exploration of the effects of miRNA SNPs on monocyte gene expression

We aimed to assess whether pri-miRNA SNPs (miSNPs) could influence monocyte gene expression, either through marginal association or by interacting with polymorphisms located in 3'UTR regions (3utrSNPs). We then conducted a genome-wide search for marginal miSNPs effects and pairwise miSNPs × 3utrSNPs interactions in a sample of 1,467 individuals for which genome-wide monocyte expression and genotype data were available. Statistical associations that survived multiple testing correction were tested for replication in an independent sample of 758 individuals with both monocyte gene expression and genotype data. In both studies, the hsa-mir-1279 rs1463335 was found to modulate in cis the expression of LYZ and in trans the expression of CNTN6, CTRC, COPZ2, KRT9, LRRFIP1, NOD1, PCDHA6, ST5 and TRAF3IP2 genes, supporting the role of hsa-mir-1279 as a regulator of several genes in monocytes. In addition, we identified two robust miSNPs × 3utrSNPs interactions, one involving HLA-DPB1 rs1042448 and hsa-mir-219-1 rs107822, the second the H1F0 rs1894644 and hsa-mir-659 rs5750504, modulating the expression of the associated genes. As some of the aforementioned genes have previously been reported to reside at disease-associated loci, our findings provide novel arguments supporting the hypothesis that the genetic variability of miRNAs could also contribute to the susceptibility to human diseases

Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10 -8). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events