User considerations in assessing pharmacogenomic tests and their clinical support tools

Pharmacogenomic (PGx) testing is gaining recognition from physicians, pharmacists and patients as a tool for evidence-based medication management. However, seemingly similar PGx testing panels (and PGx-based decision support tools) can diverge in their technological specifications, as well as the genetic factors that determine test specificity and sensitivity, and hence offer different values for users. Reluctance to embrace PGx testing is often the result of unfamiliarity with PGx technology, a lack of knowledge about the availability of curated guidelines/evidence for drug dosing recommendations, and an absence of wide-spread institutional implementation efforts and educational support. Demystifying an often confusing and variable PGx marketplace can lead to greater acceptance of PGx as a standard-of-care practice that improves drug outcomes and provides a lifetime value for patients. Here, we highlight the key underlying factors of a PGx test that should be considered, and discuss the current progress of PGx implementation

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Variation in the Glucose Transporter gene <i>SLC2A2 </i>is associated with glycaemic response to metformin

Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear1. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (P = 6.6 × 10−14) greater metformin-induced reduction in hemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 was the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550 mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine

Description of the thermo-mechanical properties of a Sn-based solder alloy by a unified viscoplastic material model for finite element calculations

Automotive electronic devices are exposed to substantially harsher thermo-mechanical loads compared to commercial consumer electronic products. As a consequence, solder joints carrying out the electrical interconnection between the components undergo deformation and degradation under thermal cycling, which can determine the lifetime of the electronic assembly in long term operation. In the past decade, lifetime prediction methods for solder joints based on finite element (FE) simulations are increasingly employed in the process of product design. However, constitutive FE models for solder alloys capable of describing their mechanical behavior at the relevant conditions of automotive applications are still not widely established. Here, we employ a unified viscoplastic material model initially proposed by Chaboche et al. in order to address the mechanical properties of an as-casted Sn-based solder alloy under a cyclic mechanical load. Extensive experimental investigations at temperatures from -40°C up to +150°C reveal a complex nonlinear interplay between hardening, recovery and thermally activated inelastic deformation processes in the material studied. We identified the necessary constitutive model terms and performed parameter calibration according to their specific functionality. A very good agreement between the numerical calculations and experimental data is achieved, which renders the constitutive model used a very promising approach for a wide use in FE simulations of lead-free solder alloys

Experimental investigation of the visco-plastic mechanical properties of a Sn-based solder alloy for material modelling in Finite Element calculations of automotive electronics

Here, we present an advanced experimental procedure for determining the properties of a SnAg3.5 solder alloy in the strain range of primary creep under cyclic load and isothermal conditions. The challenge in this experiment is the accurate high-resolution measurement of sample elongation used for a closed-loop control, as well as avoiding the influence of sensor and specimen clamping. We realized reproducible strain rate control within a total specimen elongation of 60 μm. The tensile-compression experiment comprises strain rate variation for three strain amplitudes with integrated relaxation stages followed by a measurement of cyclic fatigue. The strain rate at every strain stage was varied in the range of 1E-3 to 1E-6 per second. At the end of every strain stage a time-limited relaxation experiment is performed, where the specimen's length is kept constant, while the stress evolution is recorded. Finally, the specimen is subjected to cyclic fatigue until a drop of 50 % of the initial materials strength is reached. The total procedure is performed in a temperature range from -40 to 150 °C. We prove the capability of common creep models to map the observed cyclic stress-strain hysteresis as well as stress dependency on strain rate. The results reveal substantial limitations of common stationary creep models and strongly suggest the application of advanced visco-plastic material models for an accurate description of the solder alloy properties. The experimental data presented can be used for the calibration of unified visco-plastic constitutive models initially proposed by Chaboché et al. and further extended during the past two decades