metaboprep: an R package for preanalysis data description and processing.

MOTIVATION: Metabolomics is an increasingly common part of health research and there is need for preanalytical data processing. Researchers typically need to characterize the data and to exclude errors within the context of the intended analysis. Whilst some preprocessing steps are common, there is currently a lack of standardization and reporting transparency for these procedures. RESULTS: Here, we introduce metaboprep, a standardized data processing workflow to extract and characterize high quality metabolomics datasets. The package extracts data from preformed worksheets, provides summary statistics and enables the user to select samples and metabolites for their analysis based on a set of quality metrics. A report summarizing quality metrics and the influence of available batch variables on the data are generated for the purpose of open disclosure. Where possible, we provide users flexibility in defining their own selection thresholds. AVAILABILITY AND IMPLEMENTATION: metaboprep is an open-source R package available at https://github.com/MRCIEU/metaboprep. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Sex-specific associations of adiposity with cardiometabolic traits in the UK: A multi-life stage cohort study with repeat metabolomics.

BACKGROUND: Sex differences in cardiometabolic disease risk are commonly observed across the life course but are poorly understood and may be due to different associations of adiposity with cardiometabolic risk in females and males. We examined whether adiposity is differently associated with cardiometabolic trait levels in females and males at 3 different life stages. METHODS AND FINDINGS: Data were from 2 generations (offspring, Generation 1 [G1] born in 1991/1992 and their parents, Generation 0 [G0]) of a United Kingdom population-based birth cohort study, the Avon Longitudinal Study of Parents and Children (ALSPAC). Follow-up continues on the cohort; data up to 25 y after recruitment to the study are included in this analysis. Body mass index (BMI) and total fat mass from dual-energy X-ray absorptiometry (DXA) were measured at mean age 9 y, 15 y, and 18 y in G1. Waist circumference was measured at 9 y and 15 y in G1. Concentrations of 148 cardiometabolic traits quantified using nuclear magnetic resonance spectroscopy were measured at 15 y, 18 y, and 25 y in G1. In G0, all 3 adiposity measures and the same 148 traits were available at 50 y. Using linear regression models, sex-specific associations of adiposity measures at each time point (9 y, 15 y, and 18 y) with cardiometabolic traits 3 to 6 y later were examined in G1. In G0, sex-specific associations of adiposity measures and cardiometabolic traits were examined cross-sectionally at 50 y. A total of 3,081 G1 and 4,887 G0 participants contributed to analyses. BMI was more strongly associated with key atherogenic traits in males compared with females at younger ages (15 y to 25 y), and associations were more similar between the sexes or stronger in females at 50 y, particularly for apolipoprotein B-containing lipoprotein particles and lipid concentrations. For example, a 1 standard deviation (SD) (3.8 kg/m2) higher BMI at 18 y was associated with 0.36 SD (95% confidence interval [CI] = 0.20, 0.52) higher concentrations of extremely large very-low-density lipoprotein (VLDL) particles at 25 y in males compared with 0.15 SD (95% CI = 0.09, 0.21) in females, P value for sex difference = 0.02. By contrast, at 50 y, a 1 SD (4.8 kg/m2) higher BMI was associated with 0.33 SD (95% CI = 0.25, 0.42) and 0.30 SD (95% CI = 0.26, 0.33) higher concentrations of extremely large VLDL particles in males and females, respectively, P value for sex difference = 0.42. Sex-specific associations of DXA-measured fat mass and waist circumference with cardiometabolic traits were similar to findings for BMI and cardiometabolic traits at each age. The main limitation of this work is its observational nature, and replication in independent cohorts using methods that can infer causality is required. CONCLUSIONS: The results of this study suggest that associations of adiposity with adverse cardiometabolic risk begin earlier in the life course among males compared with females and are stronger until midlife, particularly for key atherogenic lipids. Adolescent and young adult males may therefore be high priority targets for obesity prevention efforts.

Common variation at 16p11.2 is associated with glycosuria in pregnancy: findings from a genome-wide association study in European women.

Glycosuria is a condition where glucose is detected in urine at higher concentrations than normal (i.e. not detectable). Glycosuria at some point during pregnancy has an estimated prevalence of 50% and is associated with adverse outcomes in both mothers and offspring. Little is currently known about the genetic contribution to this trait or the extent to which it overlaps with other seemingly related traits, e.g. diabetes. We performed a genome-wide association study (GWAS) for self-reported glycosuria in pregnant mothers from the Avon Longitudinal Study of Parents and Children (cases/controls = 1249/5140). We identified two loci, one of which (lead SNP = rs13337037; chromosome 16; odds ratio of glycosuria per effect allele: 1.42; 95% CI: 1.30, 1.56; P = 1.97 × 10-13) was then validated using an obstetric measure of glycosuria measured in the same cohort (227/6639). We performed a secondary GWAS in the 1986 Northern Finland Birth Cohort (NFBC1986; 747/2991) using midwife-reported glycosuria and offspring genotype as a proxy for maternal genotype. The combined results revealed evidence for a consistent effect on glycosuria at the chromosome 16 locus. In follow-up analyses, we saw little evidence of shared genetic underpinnings with the exception of urinary albumin-to-creatinine ratio (Rg = 0.64; SE = 0.22; P = 0.0042), a biomarker of kidney disease. In conclusion, we identified a genetic association with self-reported glycosuria during pregnancy, with the lead SNP located 15kB upstream of SLC5A2, a target of antidiabetic drugs. The lack of strong genetic correlation with seemingly related traits such as type 2 diabetes suggests different genetic risk factors exist for glycosuria during pregnancy.

Investigating the relationships between unfavourable habitual sleep and metabolomic traits: evidence from multi-cohort multivariable regression and Mendelian randomization analyses.

BACKGROUND: Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery disease risk. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease. METHODS: We used AMV (N = 17,368) combined with two-sample MR (N = 38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex, and body mass index. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions. RESULTS: We found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (- 0.08 standard deviation (SD)[95% confidence interval (CI) - 0.12, - 0.03] in AMV and - 0.03SD [- 0.07, - 0.003] in MR), higher glycoprotein acetyls (0.08SD [95% CI 0.03, 0.12] in AMV and 0.06SD [0.03, 0.10) in MR]), lower total very large HDL particles (- 0.04SD [- 0.08, 0.00] in AMV and - 0.05SD [- 0.09, - 0.02] in MR), and lower phospholipids in very large HDL particles (- 0.04SD [- 0.08, 0.002] in AMV and - 0.05SD [- 0.08, - 0.02] in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1 h [0.01, 0.03] in AMV and 0.15SD [0.02, 0.29] in MR) and with isoleucine in MR analyses (0.22SD [0.08, 0.35]). No consistent evidence was observed for effects of chronotype on metabolomic measures. CONCLUSIONS: Whilst our results suggested that unfavourable sleep traits may not cause widespread metabolic disruption, some notable effects were observed. The evidence for possible effects of insomnia symptoms on glycoprotein acetyls and citrate and longer total sleep duration on creatinine and isoleucine might explain some of the effects, found in MR analyses of these sleep traits on coronary heart disease, which warrant further investigation.

Sex-specific trajectories of molecular cardiometabolic traits from childhood to young adulthood.

BACKGROUND: The changes which typically occur in molecular causal risk factors and predictive biomarkers for cardiometabolic diseases across early life are not well characterised. METHODS: We quantified sex-specific trajectories of 148 metabolic trait concentrations including various lipoprotein subclasses from age 7 years to 25 years. Data were from 7065 to 7626 offspring (11 702 to14 797 repeated measures) of the Avon Longitudinal Study of Parents and Children birth cohort study. Outcomes were quantified using nuclear magnetic resonance spectroscopy at 7, 15, 18 and 25 years. Sex-specific trajectories of each trait were modelled using linear spline multilevel models. RESULTS: Females had higher very-low-density lipoprotein (VLDL) particle concentrations at 7 years. VLDL particle concentrations decreased from 7 years to 25 years with larger decreases in females, leading to lower VLDL particle concentrations at 25 years in females. For example, females had a 0.25 SD (95% CI 0.20 to 0.31) higher small VLDL particle concentration at 7 years; mean levels decreased by 0.06 SDs (95% CI -0.01 to 0.13) in males and 0.85 SDs (95% CI 0.79 to 0.90) in females from 7 years to 25 years, leading to 0.42 SDs (95% CI 0.35 to 0.48) lower small VLDL particle concentrations in females at 25 years. Females had lower high-density lipoprotein (HDL) particle concentrations at 7 years. HDL particle concentrations increased from 7 years to 25 years with larger increases among females leading to higher HDL particle concentrations in females at 25 years. CONCLUSION: Childhood and adolescence are important periods for the emergence of sex differences in atherogenic lipids and predictive biomarkers for cardiometabolic disease, mostly to the detriment of males.

Systematic review and meta-analyses: What has the application of Mendelian randomization told us about the causal effect of adiposity on health outcomes?

Mendelian randomization (MR) is increasingly used for generating estimates of the causal impact of exposures on outcomes. Evidence suggests a causal role of excess adipose tissue (adiposity) on many health outcomes. However, this body of work has not been systematically appraised. We systematically reviewed and meta-analysed results from MR studies investigating the association between adiposity and health outcomes prior to the SARS-CoV-2/COVID-19 pandemic (PROSPERO: CRD42018096684). We searched Medline, EMBASE, and bioRxiv up to February 2019 and obtained data on 2,214 MR analyses from 173 included articles. 29 meta-analyses were conducted using data from 34 articles (including 66 MR analyses) and results not able to be meta-analysed were narratively synthesised. Body mass index (BMI) was the predominant exposure used and was primarily associated with an increase in investigated outcomes; the largest effect in the meta-analyses was observed for the association between BMI and polycystic ovary syndrome (estimates reflect odds ratios (OR) per standard deviation change in each adiposity measure): OR = 2.55; 95% confidence interval (CI) = 1.22-5.33. Only colorectal cancer was investigated with two exposures in the meta-analysis: BMI (OR = 1.18; 95% CI = 1.01-1.37) and waist-hip ratio (WHR; OR = 1.48; 95% CI = 1.08-2.03). Broadly, results were consistent across the meta-analyses and narrative synthesis. Consistent with many observational studies, this work highlights the impact of adiposity across a broad spectrum of health outcomes, enabling targeted follow-up analyses. However, missing and incomplete data mean results should be interpreted with caution.

The EWAS Catalog: a database of epigenome-wide association studies.

Epigenome-wide association studies (EWAS) seek to quantify associations between traits/exposures and DNA methylation measured at thousands or millions of CpG sites across the genome. In recent years, the increase in availability of DNA methylation measures in population-based cohorts and case-control studies has resulted in a dramatic expansion of the number of EWAS being performed and published. To make this rich source of results more accessible, we have manually curated a database of CpG-trait associations (with p<1x10 -4) from published EWAS, each assaying over 100,000 CpGs in at least 100 individuals. From January 7, 2022, The EWAS Catalog contained 1,737,746 associations from 2,686 EWAS. This includes 1,345,398 associations from 342 peer-reviewed publications. In addition, it also contains summary statistics for 392,348 associations from 427 EWAS, performed on data from the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Gene Expression Omnibus (GEO). The database is accompanied by a web-based tool and R package, giving researchers the opportunity to query EWAS associations quickly and easily, and gain insight into the molecular underpinnings of disease as well as the impact of traits and exposures on the DNA methylome. The EWAS Catalog data extraction team continue to update the database monthly and we encourage any EWAS authors to upload their summary statistics to our website. Details of how to upload data can be found here: http://www.ewascatalog.org/upload. The EWAS Catalog is available at http://www.ewascatalog.org.

Glyphosate-resistant and glyphosate-susceptible Palmer amaranth (Amaranthus palmeri S. Wats.): hyperspectral reflectance properties of plants and potential for classification.

BACKGROUND: Palmer amaranth (Amaranthus palmeri S. Wats.) is a troublesome agronomic weed in the southern United States, and several populations have evolved resistance to glyphosate. This paper reports on spectral signatures of glyphosate-resistant (GR) and glyphosate-sensitive (GS) plants, and explores the potential of using hyperspectral sensors to distinguish GR from GS plants. RESULTS: GS plants have higher light reflectance in the visible region and lower light reflectance in the infrared region of the spectrum compared with GR plants. The normalized reflectance spectrum of the GR and GS plants had best separability in the 400-500 nm, 650-690 nm, 730-740 nm and 800-900 nm spectral regions. Fourteen wavebands from within or near these four spectral regions provided a classification of unknown set of GR and GS plants, with a validation accuracy of 94% for greenhouse-grown plants and 96% for field-grown plants. CONCLUSIONS: GR and GS Palmer amaranth plants have unique hyperspectral reflectance properties, and there are four distinct regions of the spectrum that can separate the GR from GS plants. These results demonstrate that hyperspectral imaging has potential application to distinguish GR from GS Palmer amaranth plants (without a glyphosate treatment), with future implications for glyphosate resistance management. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

Nonpresciption medicines and the North American Pharmacist Licensure Examination.

The North American Pharmacist Licensure Examination (NAPLEX) is currently used by all 50 state boards of pharmacy to aid in determining whether a candidate for licensure possesses the minimal knowledge and skills required to safely and effectively practice pharmacy. The blueprint for this examination periodically undergoes revision so that it remains current with the demands and trends of modern-day pharmacy practice. During the most recent revision, which occurred between 2002 and 2004, several substantial content changes were incorporated. One of the most notable changes was the elimination of any distinction of importance between prescription and nonprescription medications. This change was in response to several factors, including the growing variety of conditions for which nonprescription medications are available and the recent switching of several pharmaceutical products from prescription-only to nonprescription status. The previous example is indicative of how the practice of pharmacy is continually evolving and the need for periodic changes to the examination used in the licensure process. As such, the NAPLEX blueprint is continually reviewed and revised to ensure it includes the most current knowledge and skills required of entry-level practitioners.