A trapezoidal-shaped force transducer is designed and demonstrated metrologically for static force measurement. The presented design has been investigated by finite element analysis and validated ...through experimental measurements. Metrological characterization of the force transducer is done based on guidelines of standard ISO 376: 2011, and relevant factors have been considered for evaluation of uncertainty of measurement of the force transducer. The transducer measures the force with an uncertainty of up to ± 0.05% (
k
= 2) and 0.10% (
k
= 2) in strain gauged force transducer and dial gauged force proving instrument, respectively, in the operating range (50–100% of nominal capacity). The superficial design characteristics of the transducer make it very economical for experimental and trade pacts. For a range of modern technologies, force measurement sensors and sensor-enabled industrial infrastructure play a critical role. In Industry 4.0, metrological traceability and the utilization of sensors, instruments, and machinery are in high need, and this demand will grow in the coming years.
Quantitative traits analyzed in Genome‐Wide Association Studies (GWAS) are often nonnormally distributed. For such traits, association tests based on standard linear regression are subject to reduced ...power and inflated type I error in finite samples. Applying the rank‐based inverse normal transformation (INT) to nonnormally distributed traits has become common practice in GWAS. However, the different variations on INT‐based association testing have not been formally defined, and guidance is lacking on when to use which approach. In this paper, we formally define and systematically compare the direct (D‐INT) and indirect (I‐INT) INT‐based association tests. We discuss their assumptions, underlying generative models, and connections. We demonstrate that the relative powers of D‐INT and I‐INT depend on the underlying data generating process. Since neither approach is uniformly most powerful, we combine them into an adaptive omnibus test (O‐INT). O‐INT is robust to model misspecification, protects the type I error, and is well powered against a wide range of nonnormally distributed traits. Extensive simulations were conducted to examine the finite sample operating characteristics of these tests. Our results demonstrate that, for nonnormally distributed traits, INT‐based tests outperform the standard untransformed association test, both in terms of power and type I error rate control. We apply the proposed methods to GWAS of spirometry traits in the UK Biobank. O‐INT has been implemented in the R package RNOmni, which is available on CRAN.
To examine the effects of past and current night shift work and genetic type 2 diabetes vulnerability on type 2 diabetes odds.
In the UK Biobank, we examined associations of current (
= 272,214) and ...lifetime (
= 70,480) night shift work exposure with type 2 diabetes risk (6,770 and 1,191 prevalent cases, respectively). For 180,704 and 44,141 unrelated participants of European ancestry (4,002 and 726 cases, respectively) with genetic data, we assessed whether shift work exposure modified the relationship between a genetic risk score (comprising 110 single-nucleotide polymorphisms) for type 2 diabetes and prevalent diabetes.
Compared with day workers, all current night shift workers were at higher multivariable-adjusted odds for type 2 diabetes (none or rare night shifts: odds ratio OR 1.15 95% CI 1.05-1.26; some nights: OR 1.18 95% CI 1.05-1.32; and usual nights: OR 1.44 95% CI 1.19-1.73), except current permanent night shift workers (OR 1.09 95% CI 0.93-1.27). Considering a person's lifetime work schedule and compared with never shift workers, working more night shifts per month was associated with higher type 2 diabetes odds (<3/month: OR 1.24 95% CI 0.90-1.68; 3-8/month: OR 1.11 95% CI 0.90-1.37; and >8/month: OR 1.36 95% CI 1.14-1.62;
= 0.001). The association between genetic type 2 diabetes predisposition and type 2 diabetes odds was not modified by shift work exposure.
Our findings show that night shift work, especially rotating shift work including night shifts, is associated with higher type 2 diabetes odds and that the number of night shifts worked per month appears most relevant for type 2 diabetes odds. Also, shift work exposure does not modify genetic risk for type 2 diabetes, a novel finding that warrants replication.
As a ClinGen Expert Panel (EP) we set out to adapt the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) pathogenicity criteria for classification of ...RYR1 variants as related to autosomal dominantly inherited malignant hyperthermia (MH).
We specified ACMG/AMP criteria for variant classification for RYR1 and MH. Proposed rules were piloted on 84 variants. We applied quantitative evidence calibration for several criteria using likelihood ratios based on the Bayesian framework.
Seven ACMG/AMP criteria were adopted without changes, nine were adopted with RYR1-specific modifications, and ten were dropped. The in silico (PP3 and BP4) and hotspot criteria (PM1) were evaluated quantitatively. REVEL gave an odds ratio (OR) of 23:1 for PP3 and 14:1 for BP4 using trichotomized cutoffs of ≥0.85 (pathogenic) and ≤0.5 (benign). The PM1 hotspot criterion had an OR of 24:1. PP3 and PM1 were implemented at moderate strength. Applying the revised ACMG/AMP criteria to 44 recognized MH variants, 29 were classified as pathogenic, 13 as likely pathogenic, and 2 as variants of uncertain significance.
Curation of these variants will facilitate classification of RYR1/MH genomic testing results, which is especially important for secondary findings analyses. Our approach to quantitatively calibrating criteria is generalizable to other variant curation expert panels.
Preeclampsia risk is influenced by both the mother’s genetic background and the genetics of her fetus; however, the specific genes responsible for conferring preeclampsia risk have largely remained ...elusive. Evidence that preeclampsia has a genetic predisposition was first detailed in the early 1960s, and overall preeclampsia heritability is estimated at ∼55%. Many traditional gene discovery approaches have been used to investigate the specific genes that contribute to preeclampsia risk, but these have largely not been successful or reproducible. Over the past decade, genome-wide association studies have allowed for significant advances in the understanding of the genetic basis of many common diseases. Genome-wide association studies are predicated on the idea that the genetic basis of many common diseases are complex and polygenic with many variants, each with modest effects that contribute to disease risk. Using this approach in preeclampsia, a large genome-wide association study recently identified and replicated the first robust fetal genomic region associated with excess risk. A screen of >7 million genetic variants in 2658 offspring from preeclamptic women and 308,292 population controls identified a single association signal close to the Fms-like tyrosine kinase 1 gene, on chromosome 13. Fms-like tyrosine kinase 1 encodes soluble Fms-like tyrosine kinase 1, a splice variant of the vascular endothelial growth factor receptor that exerts antiangiogenic activity by inhibiting signaling of proangiogenic factors. The Fms-like tyrosine kinase 1 pathway is central in preeclampsia pathogenesis because excess circulating soluble Fms-like tyrosine kinase 1 in the maternal plasma leads to the hallmark clinical features of preeclampsia, including hypertension and proteinuria. The success of this landmark fetal preeclampsia genome-wide association study suggests that well-powered, larger maternal and fetal genome-wide association study will be fruitful in identifying additional common variants that implicate causal preeclampsia genes and pathways. Such efforts will rely on the continued development of large preeclampsia consortia focused on preeclampsia genetics to obtain adequate sample sizes, detailed clinical phenotyping, and matched maternal-fetal samples. In summary, the fetal preeclampsia genome-wide association study represents an exciting advance in preeclampsia biology, suggesting that dysregulation at the Fms-like tyrosine kinase 1 locus in the fetal genome (likely in the placenta) is a fundamental molecular defect in preeclampsia.
The diversity in our genome is crucial to understanding the demographic history of worldwide populations. However, we have yet to know whether subtle genetic differences within a population can be ...disentangled, or whether they have an impact on complex traits. Here we apply dimensionality reduction methods (PCA, t-SNE, PCA-t-SNE, UMAP, and PCA-UMAP) to biobank-derived genomic data of a Japanese population (n = 169,719). Dimensionality reduction reveals fine-scale population structure, conspicuously differentiating adjacent insular subpopulations. We further enluciate the demographic landscape of these Japanese subpopulations using population genetics analyses. Finally, we perform phenome-wide polygenic risk score (PRS) analyses on 67 complex traits. Differences in PRS between the deconvoluted subpopulations are not always concordant with those in the observed phenotypes, suggesting that the PRS differences might reflect biases from the uncorrected structure, in a trait-dependent manner. This study suggests that such an uncorrected structure can be a potential pitfall in the clinical application of PRS.
Abstract Background and aims Late-night-dinner eating is associated with increased risk for type-2-diabetes. The underlying mechanism is unclear. One explanatory hypothesis is that the concurrence of ...elevated circulating melatonin and high glucose concentrations (characterizing late-eating) leads to impaired glucose-tolerance. However, to date no study has tested the influence of physiological melatonin concentrations on glucose-tolerance. The discovery of melatonin receptor MTNR1B as a diabetes risk gene provides evidence for a role of physiological levels of melatonin in glucose control. The aim of our study was to test the hypothesis that endogenous melatonin worsens glucose control when eating-late. Registered under ClinicalTrials.gov Identifier no. NCT03003936 Methods We performed a randomized, cross-over trial to compare glucose-tolerance in the presence (late-dinner) or absence (early-dinner) of physiological melatonin and we compared the results between homozygous carriers and non-carriers of the MTNR1B risk allele. Results The concurrence of meal timing with elevated endogenous melatonin concentrations resulted in impaired glucose-tolerance. This effect was stronger in MTNR1B risk-carriers than in non-carriers. Furthermore, eating-late significantly impaired glucose tolerance only in risk-carriers and not in the non-risk carriers. Conclusions The interaction of dinner timing with MTNR1B supports a causal role of endogenous melatonin in the impairment of glucose-tolerance. These results suggest that moving the dinner to an earlier time may result in better glucose-tolerance specially in MTNR1B carriers. Clinical Trial Registration https://clinicaltrials.gov/ct2/show/NCT03003936
Poor dietary choices may underlie known associations between having an evening diurnal preference and cardiometabolic diseases. Assessing causal links between diurnal preference and food intake is ...now possible in Mendelian randomization (MR) analyses.
We aimed to use a 2-sample MR to determine potential causal effects of genetic liability to a morning preference on food intake. We also examined potential causal effects of a morning preference on objectively captured response performances to email-administered 24-h diet recalls.
We used genetic variants associated with a morning preference from a published genome-wide association meta-analysis. Our outcomes included 61 food items with estimates from a food-frequency questionnaire in the UK Biobank (n = 361,194). For significant findings, we repeated the analysis using intake estimates from modified 24-h diet recalls in a subset of overlapping participants (n = 146,086). In addition, we examined 7 response performance outcomes, including the time and duration of responses to 24-h diet recalls (n = 123,035). MR effects were estimated using an inverse-variance weighted analysis.
Genetic liability to a morning preference was associated with increased intake of 6 food items (fresh fruit, alcohol with meals, bran cereal, cereals, dried fruit, and water), decreased intake of 4 food items (beer plus cider, processed meat, other cereals e.g., corn or frosted flakes, and full cream milk), increased temperature of hot drinks, and decreased variation in diet (PFalse Discovery Rate < 0.05). There was no evidence for an effect on coffee or tea intake. Findings for fresh fruit, beer plus cider, bran cereal, and cereal were consistent when intakes were estimated by 24-h diet recalls (P < 0.05). We also identified potential causal links between a morning preference with earlier timing and a shorter duration for completing email-administered 24-h diet recalls.
Our findings provide evidence for a potentially causal effect of a morning preference with the increased intake of foods known to constitute a healthy diet, suggesting possible health benefits of adopting a more morning diurnal preference.
Our sleep timing preference, or chronotype, is a manifestation of our internal biological clock. Variation in chronotype has been linked to sleep disorders, cognitive and physical performance, and ...chronic disease. Here we perform a genome-wide association study of self-reported chronotype within the UK Biobank cohort (n=100,420). We identify 12 new genetic loci that implicate known components of the circadian clock machinery and point to previously unstudied genetic variants and candidate genes that might modulate core circadian rhythms or light-sensing pathways. Pathway analyses highlight central nervous and ocular systems and fear-response-related processes. Genetic correlation analysis suggests chronotype shares underlying genetic pathways with schizophrenia, educational attainment and possibly BMI. Further, Mendelian randomization suggests that evening chronotype relates to higher educational attainment. These results not only expand our knowledge of the circadian system in humans but also expose the influence of circadian characteristics over human health and life-history variables such as educational attainment.
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