Epigenome-wide association study of incident type 2 diabetes:a meta-analysis of five prospective European cohorts

AIMS/HYPOTHESIS: Type 2 diabetes is a complex metabolic disease with increasing prevalence worldwide. Improving the prediction of incident type 2 diabetes using epigenetic markers could help tailor prevention efforts to those at the highest risk. The aim of this study was to identify predictive methylation markers for incident type 2 diabetes by combining epigenome-wide association study (EWAS) results from five prospective European cohorts.METHODS: We conducted a meta-analysis of EWASs in blood collected 7-10 years prior to type 2 diabetes diagnosis. DNA methylation was measured with Illumina Infinium Methylation arrays. A total of 1250 cases and 1950 controls from five longitudinal cohorts were included: Doetinchem, ESTHER, KORA1, KORA2 and EPIC-Norfolk. Associations between DNA methylation and incident type 2 diabetes were examined using robust linear regression with adjustment for potential confounders. Inverse-variance fixed-effects meta-analysis of cohort-level individual CpG EWAS estimates was performed using METAL. The methylGSA R package was used for gene set enrichment analysis. Confirmation of genome-wide significant CpG sites was performed in a cohort of Indian Asians (LOLIPOP, UK).RESULTS: The meta-analysis identified 76 CpG sites that were differentially methylated in individuals with incident type 2 diabetes compared with control individuals (p values &lt;1.1 × 10-7). Sixty-four out of 76 (84.2%) CpG sites were confirmed by directionally consistent effects and p values &lt;0.05 in an independent cohort of Indian Asians. However, on adjustment for baseline BMI only four CpG sites remained genome-wide significant, and addition of the 76 CpG methylation risk score to a prediction model including established predictors of type 2 diabetes (age, sex, BMI and HbA1c) showed no improvement (AUC 0.757 vs 0.753). Gene set enrichment analysis of the full epigenome-wide results clearly showed enrichment of processes linked to insulin signalling, lipid homeostasis and inflammation.CONCLUSIONS/INTERPRETATION: By combining results from five European cohorts, and thus significantly increasing study sample size, we identified 76 CpG sites associated with incident type 2 diabetes. Replication of 64 CpGs in an independent cohort of Indian Asians suggests that the association between DNA methylation levels and incident type 2 diabetes is robust and independent of ethnicity. Our data also indicate that BMI partly explains the association between DNA methylation and incident type 2 diabetes. Further studies are required to elucidate the underlying biological mechanisms and to determine potential causal roles of the differentially methylated CpG sites in type 2 diabetes development.</p

Online chemical modeling environment (OCHEM): web platform for data storage, model development and publishing of chemical information

The Online Chemical Modeling Environment is a web-based platform that aims to automate and simplify the typical steps required for QSAR modeling. The platform consists of two major subsystems: the database of experimental measurements and the modeling framework. A user-contributed database contains a set of tools for easy input, search and modification of thousands of records. The OCHEM database is based on the wiki principle and focuses primarily on the quality and verifiability of the data. The database is tightly integrated with the modeling framework, which supports all the steps required to create a predictive model: data search, calculation and selection of a vast variety of molecular descriptors, application of machine learning methods, validation, analysis of the model and assessment of the applicability domain. As compared to other similar systems, OCHEM is not intended to re-implement the existing tools or models but rather to invite the original authors to contribute their results, make them publicly available, share them with other users and to become members of the growing research community. Our intention is to make OCHEM a widely used platform to perform the QSPR/QSAR studies online and share it with other users on the Web. The ultimate goal of OCHEM is collecting all possible chemoinformatics tools within one simple, reliable and user-friendly resource. The OCHEM is free for web users and it is available online at http://www.ochem.eu

Night Shift Work Affects Urine Metabolite Profiles of Nurses with Early Chronotype

Night shift work can have a serious impact on health. Here, we assess whether and how night shift work influences the metabolite profiles, specifically with respect to different chronotype classes. We have recruited 100 women including 68 nurses working both, day shift and night shifts for up to 5 consecutive days and collected 3640 spontaneous urine samples. About 424 waking-up urine samples were measured using a targeted metabolomics approach. To account for urine dilution, we applied three methods to normalize the metabolite values: creatinine-, osmolality- and regression-based normalization. Based on linear mixed effect models, we found 31 metabolites significantly (false discovery rate <0.05) affected in nurses working in night shifts. One metabolite, acylcarnitine C10:2, was consistently identified with all three normalization methods. We further observed 11 and 4 metabolites significantly associated with night shift in early and late chronotype classes, respectively. Increased levels of medium- and long chain acylcarnitines indicate a strong impairment of the fatty acid oxidation. Our results show that night shift work influences acylcarnitines and BCAAs, particularly in nurses in the early chronotype class. Women with intermediate and late chronotypes appear to be less affected by night shift work

Effect of Insulin Resistance on Monounsaturated Fatty Acid Levels : A Multi-cohort Non-targeted Metabolomics and Mendelian Randomization Study

Insulin resistance (IR) and impaired insulin secretion contribute to type 2 diabetes and cardiovascular disease. Both are associated with changes in the circulating metabolome, but causal directions have been difficult to disentangle. We combined untargeted plasma metabolomics by liquid chromatography/mass spectrometry in three non-diabetic cohorts with Mendelian Randomization (MR) analysis to obtain new insights into early metabolic alterations in IR and impaired insulin secretion. In up to 910 elderly men we found associations of 52 metabolites with hyperinsulinemic-euglycemic clamp-measured IR and/or beta-cell responsiveness (disposition index) during an oral glucose tolerance test. These implicated bile acid, glycerophospholipid and caffeine metabolism for IR and fatty acid biosynthesis for impaired insulin secretion. In MR analysis in two separate cohorts (n = 2,613) followed by replication in three independent studies profiled on different metabolomics platforms (n = 7,824 / 8,961 / 8,330), we discovered and replicated causal effects of IR on lower levels of palmitoleic acid and oleic acid. A trend for a causal effect of IR on higher levels of tyrosine reached significance only in meta-analysis. In one of the largest studies combining "gold standard" measures for insulin responsiveness with non-targeted metabolomics, we found distinct metabolic profiles related to IR or impaired insulin secretion. We speculate that the causal effects on monounsaturated fatty acid levels could explain parts of the raised cardiovascular disease risk in IR that is independent of diabetes development.Peer reviewe

Sequence-Based Prediction of Type III Secreted Proteins

The type III secretion system (TTSS) is a key mechanism for host cell interaction used by a variety of bacterial pathogens and symbionts of plants and animals including humans. The TTSS represents a molecular syringe with which the bacteria deliver effector proteins directly into the host cell cytosol. Despite the importance of the TTSS for bacterial pathogenesis, recognition and targeting of type III secreted proteins has up until now been poorly understood. Several hypotheses are discussed, including an mRNA-based signal, a chaperon-mediated process, or an N-terminal signal peptide. In this study, we systematically analyzed the amino acid composition and secondary structure of N-termini of 100 experimentally verified effector proteins. Based on this, we developed a machine-learning approach for the prediction of TTSS effector proteins, taking into account N-terminal sequence features such as frequencies of amino acids, short peptides, or residues with certain physico-chemical properties. The resulting computational model revealed a strong type III secretion signal in the N-terminus that can be used to detect effectors with sensitivity of ∼71% and selectivity of ∼85%. This signal seems to be taxonomically universal and conserved among animal pathogens and plant symbionts, since we could successfully detect effector proteins if the respective group was excluded from training. The application of our prediction approach to 739 complete bacterial and archaeal genome sequences resulted in the identification of between 0% and 12% putative TTSS effector proteins. Comparison of effector proteins with orthologs that are not secreted by the TTSS showed no clear pattern of signal acquisition by fusion, suggesting convergent evolutionary processes shaping the type III secretion signal. The newly developed program EffectiveT3 (http://www.chlamydiaedb.org) is the first universal in silico prediction program for the identification of novel TTSS effectors. Our findings will facilitate further studies on and improve our understanding of type III secretion and its role in pathogen–host interactions

Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density.

The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease

Methoden der statistischen Versuchsplanung zur Verbesserung der Qualität von in silico Modellen

Applications, such as risk assessment within REACH or drug discovery (ADME) require reliable methods for the design of experiments and efficient testing strategies. With a large initial set of compounds, experimental design techniques select a representative subset for testing. Once measured, these compounds can be used to build QSAR models to predict properties of the remaining compounds. This thesis describes several newly developed step-wise adaptive experimental design approaches to support the calculation of prediction models in chemoinformatics. The approaches utilize the accumulating information about the analyzed properties to enable a refined representation of the chemical search space. A statistical evaluation, carried out on five regression datasets with chemical endpoints shows that the proposed approaches are more efficient and contribute to the development of more reliable models.Bei der Risikobewertung im Rahmen von REACH oder der Entwicklung neuer Medikamente (ADME) werden effiziente Teststrategien und zuverlässige Methoden zur statistischen Versuchsplanung (Experimental Design) benötigt. Ausgehend von einer größeren Sammlung relevanter Molekülen wählen die Methoden des Experimental Designs repräsentative Stichproben. Sobald diese Chemikalien getestet wurden, können die Messwerte benutzt werden um QSAR Modelle zur Vorhersage der Eigenschaften der verbleibenden Chemikalien zu berechnen. Für diese Dissertation wurden verschiedene schrittweise, adaptive Verfahren zur statistischen Versuchsplanung im chemoinformatischen Bereich entwickelt. Diese Verfahren nutzen die Zielvariable, um eine verfeinerte Darstellung des chemischen Suchraumes zu ermöglichen. Die statistische Auswertung durch fünf Regressionsdatensätzen mit chemischen Endpunkten zeigt, dass die vorgeschlagenen Verfahren effizienter sind und die Entwicklung zuverlässigerer Modelle ermöglichen

Assessing rigor and impact of research software for hiring and promotion in psychology: A comment on Gärtner et al. (2022)

Based on four principles of a more responsible research assessment in academic hiring and promotion processes, Gärtner, Leising, and Schönbrodt (2022) suggested an evaluation scheme for published manuscripts, reusable data sets, and research software. This commentary responds to the proposed indicators for the evaluation of research software contributions in academic hiring and promotion processes. Acknowledging the significance of research software as a critical component of modern science, we propose that an evaluation scheme must emphasize the two major dimensions of rigor and impact. Generally, we believe that research software should be recognized as valuable scientific output in academic hiring and promotion, with the hope that this incentivizes the development of more open and better research software

A Note on the Connection Between Trek Rules and Separable Nonlinear Least Squares in Linear Structural Equation Models

We show that separable nonlinear least squares (SNLLS) estimation is applicable to all linear structural equation models (SEMs) that can be specified in RAM notation. SNLLS is an estimation technique that has successfully been applied to a wide range of models, for example neural networks and dynamic systems, often leading to improvements in convergence and computation time. It is applicable to models of a special form, where a subset of parameters enters the objective linearly. Recently, Kreiberg et al. (2021) have shown that this is also the case for factor analysis models. We generalize this result to all linear SEMs. To that end, we show that undirected effects (variances and covariances) and mean parameters enter the objective linearly and therefore, in the least squares estimation of structural equation models, only the directed effects have to be obtained iteratively. For model classes without unknown directed effects SNLLS can be used to analytically compute least squares estimates. To provide deeper insight into the nature of this result, we employ trek rules that link graphical representations of structural equation models to their covariance parametrization. We further give an efficient expression for the gradient, which is crucial to make a fast implementation possible. Results from our simulation indicate that SNLLS leads to improved convergence rates and a reduced number of iterations