metaGWASmanager: a toolbox for an automated workflow from phenotypes to meta-analysis in GWAS consortia.

SUMMARY: This article introduces the metaGWASmanager, which streamlines genome-wide association studies within large-scale meta-analysis consortia. It is a toolbox for both the central consortium analysis group and participating studies to generate homogeneous phenotypes, minimize unwanted variability from inconsistent methodologies, ensure high-quality association results, and implement time-efficient quality control workflows. The toolbox features a plug-in-based approach for customization of association testing. RESULTS: The metaGWASmanager toolbox has been successfully deployed in both the CKDGen and MetalGWAS Initiative consortia across hundreds of participating studies, demonstrating its effectiveness in GWAS analysis optimization by automating routine tasks and ensuring the value and reliability of association results, thus, ultimately promoting scientific discovery. We provide a simulated data set with examples for script customization so that readers can reproduce the pipeline at their convenience. AVAILABILITY AND IMPLEMENTATION: GitHub: https://github.com/genepi-freiburg/metaGWASmanager.

Omics feature selection with the extended SIS R package: identification of a body mass index epigenetic multimarker in the Strong Heart Study.

The statistical analysis of omics data poses a great computational challenge given their ultra-high-dimensional nature and frequent between-features correlation. In this work, we extended the iterative sure independence screening (ISIS) algorithm by pairing ISIS with elastic-net (Enet) and 2 versions of adaptive elastic-net (adaptive elastic-net (AEnet) and multistep adaptive elastic-net (MSAEnet)) to efficiently improve feature selection and effect estimation in omics research. We subsequently used genome-wide human blood DNA methylation data from American Indian participants in the Strong Heart Study (n = 2235 participants; measured in 1989-1991) to compare the performance (predictive accuracy, coefficient estimation, and computational efficiency) of ISIS-paired regularization methods with that of a bayesian shrinkage and traditional linear regression to identify an epigenomic multimarker of body mass index (BMI). ISIS-AEnet outperformed the other methods in prediction. In biological pathway enrichment analysis of genes annotated to BMI-related differentially methylated positions, ISIS-AEnet captured most of the enriched pathways in common for at least 2 of all the evaluated methods. ISIS-AEnet can favor biological discovery because it identifies the most robust biological pathways while achieving an optimal balance between bias and efficient feature selection. In the extended SIS R package, we also implemented ISIS paired with Cox and logistic regression for time-to-event and binary endpoints, respectively, and a bootstrap approach for the estimation of regression coefficients.

Alcohol consumption patterns and adherence to the Mediterranean diet in the adult population of Spain.

PURPOSE: The objective is to evaluate the association between various indicators of alcohol consumption and the degree of adherence to the Mediterranean diet among the Spanish adult population. METHODS: A cross-sectional study including 44,834 participants ≥ 15 years of age from the 2017 National Health Survey and the 2020 European Health Survey in Spain. Alcohol patterns were defined based on (1) average intake: individuals were classified as low risk (1-20 g/day in men and 1-10 g/day in women) and high risk (> 20 g/day in men or > 10 g/day in women), (2) binge drinking, and (3) alcoholic beverage preference. Non-adherence to the Mediterranean diet was defined as scoring < 7 points on an adapted Mediterranean Diet Adherence Screener index (range 0-10). Odds ratios (OR) were estimated using logistic regression models adjusted for relevant covariates. RESULTS: Compared to non-drinkers, low and high-risk drinkers were more likely to report non-adherence to the Mediterranean diet: ORs 1.35 (95% CI 1.23; 1.49) and 1.54 (95% CI 1.34; 1.76), respectively. Similarly, reports of binge drinking less than once a month was associated with higher likelihood of non-adherence (OR 1.17; 95% CI 1.04; 1.31). Individuals reporting no preference for a specific beverage and those with a preference for beer or for spirits had lower adherence: ORs 1.18 (95% CI 1.05; 1.33), 1.31 (95% CI 1.17; 1.46), and 1.72 (95% CI 1.17; 2.54), respectively, while a preference for wine showed no association (OR 1.01; 95% CI 0.90; 1.13). CONCLUSION: Alcohol consumption, even in low amounts, is associated with lower adherence to the Mediterranean diet. Therefore, alcoholic beverages should not be included in measures that define the Mediterranean diet.

Glyphosate exposure, muscular health and functional limitations in middle-aged and older adults.

BACKGROUND: Glyphosate is the most widely used herbicide worldwide, both in domestic and industrial settings. Experimental research in animal models has demonstrated changes in muscle physiology and reduced contractile strength associated with glyphosate exposure, while epidemiological studies have shown associations between glyphosate exposure and adverse health outcomes in critical biological systems affecting muscle function. METHODS: This study used data from a nationally representative survey of the non-institutionalized U.S. general population (NHANES, n = 2132). Urine glyphosate concentrations were determined by ion chromatography with tandem mass spectrometry. Hand grip strength (HGS) was measured using a Takei Dynamometer, and relative strength estimated as the ratio between HGS in the dominant hand and the appendicular lean mass (ALM) to body mass index (ALMBMI) ratio. Low HGS and low relative HGS were defined as 1 sex-, age- and race-specific SD below the mean. Physical function limitations were identified as significant difficulty or incapacity in various activities. RESULTS: In fully-adjusted models, the Mean Differences (MD) and 95% confidence intervals [95%CI] per doubling increase in glyphosate concentrations were -0.55 [-1.09, -0.01] kg for HGS in the dominant hand, and -0.90 [-1.58. -0.21] kg for HGS/ALMBMI. The Odds Ratios (OR) [95% CI] for low HGS, low relative HGS and functional limitations by glyphosate concentrations were 1.27 [1.03, 1.57] for low HGS; 1.43 [1.05; 1.94] for low relative HGS; 1.33 [1.08, 1.63] for stooping, crouching or kneeling difficulty; 1.17 [0.91, 1.50] for lifting or carrying items weighting up to 10 pounds difficulty; 1.21 [1.01, 1.40] for standing up from armless chair difficulty; and 1.47 [1.05, 2.29] for ascending ten steps without pause difficulty. CONCLUSIONS: Glyphosate exposure may be a risk factor for decreased grip strength and increased physical functional limitations. More studies investigating the influence of this and other environmental pollutants on functional aging are needed.

Methods for the Analysis of Multiple Epigenomic Mediators in Environmental Epidemiology.

PURPOSE OF REVIEW: Epigenetic changes can be highly influenced by environmental factors and have in turn been proposed to influence chronic disease. Being able to quantify to which extent epigenomic processes are mediators of the association between environmental exposures and diseases is of interest for epidemiologic research. In this review, we summarize the proposed mediation analysis methods with applications to epigenomic data. RECENT FINDINGS: The ultra-high dimensionality and high correlations that characterize omics data have hindered the precise quantification of mediated effects. Several methods have been proposed to deal with mediation in high-dimensional settings, including methods that incorporate dimensionality reduction techniques to the mediation algorithm. Although important methodological advances have been conducted in the previous years, key challenges such as the development of sensitivity analyses, dealing with mediator-mediator interactions, including environmental mixtures as exposures, or the integration of different omic data should be the focus of future methodological developments for epigenomic mediation analysis.

Causal mediation for uncausally related mediators in the context of survival analysis.

Objective: The study of the potential intermediate effect of several variables on the association between an exposure and a time-to-event outcome is a question of interest in epidemiologic research. However, to our knowledge, no tools have been developed for the evaluation of multiple correlated mediators in a survival setting. Methods: In this work, we extended the multimediate algorithm, which conducts mediation analysis in the context of multiple uncausally correlated mediators, to a time-to-event setting using the semiparametric additive hazards model. We theoretically demonstrated that, under certain assumptions, indirect, direct and total effects can be calculated using the counterfactual framework with collapsible survival models. We also adapted the algorithm to accommodate exposure-mediator interactions. Results and conclusions: Using simulations, we demonstrated that our algorithm performs better than the product of coefficients method, even for uncorrelated mediators. The additive hazards model quantifies the effects as rate differences, which constitute a measure of impact, with applications that can be highly informative for public health. Our algorithm can be found in the R package multimediate, which is available in Github.

Volume of alcohol intake, heavy episodic drinking, and all-cause mortality in Spain: A longitudinal population-based study.

INTRODUCTION: The impact of alcohol consumption on health, particularly in low quantities, remains controversial. Our objective was to assess the association between alcohol volume and heavy episodic drinking (HED) with all-cause mortality, while minimizing many of the known methodological issues. METHODOLOGY: This longitudinal study used data from the 2011-2012 National Health Survey and the 2014 European Health Survey in Spain. Data from 43,071 participants aged ≥ 15 years were linked to mortality records as of December 2021. Alcohol consumption categories were defined based on intake volume and frequency: never-drinkers, former drinkers, infrequent occasional drinkers (≤once/month), frequent occasional drinkers ( once /month). Regular drinkers (≥once/week) were further classified by volume: >0-10 g/day, >10-20 g/day, >20-40 g/day, and > 40 g/day. Heavy Episodic Drinking (HED) was defined as ≥ 6 and ≥ 5 standard drinks (10 g) within 4-6 h for men and women, respectively. Hazard ratios (HR) were calculated using Cox regression, adjusting for sociodemographic variables, lifestyle factors, health status, and alcohol volume or HED. RESULTS: Compared to infrequent occasional drinkers, HRs for never-drinkers and former drinkers were 1.30 (95 %CI:1.14-1.47) and 1.32 (95 %CI:1.15-1.50), respectively. No differences in mortality risk were observed for intakes up to 20 g/day, but it increased for consumptions > 20-40 g/day and > 40 g/day (HR = 1.29; 95 %CI:1.05-1.58 and HR = 1.57; 95 %CI:1.14-2.17, respectively). The HR of weekly HED vs. never was 1.31 (95 %CI:0.98-1.75). CONCLUSIONS: Compared to infrequent occasional drinking, consuming low amounts of alcohol had no impact on mortality risk. However, never-drinkers, former drinkers, individuals with regular consumption > 20 g/day, and those engaging in weekly HED, experienced higher mortality risk.

An epigenome-wide study of selenium status and DNA methylation in the Strong Heart Study.

BACKGROUND: Selenium (Se) is an essential nutrient linked to adverse health endpoints at low and high levels. The mechanisms behind these relationships remain unclear and there is a need to further understand the epigenetic impacts of Se and their relationship to disease. We investigated the association between urinary Se levels and DNA methylation (DNAm) in the Strong Heart Study (SHS), a prospective study of cardiovascular disease (CVD) among American Indians adults. METHODS: Selenium concentrations were measured in urine (collected in 1989-1991) using inductively coupled plasma mass spectrometry among 1,357 participants free of CVD and diabetes. DNAm in whole blood was measured cross-sectionally using the Illumina MethylationEPIC BeadChip (850 K) Array. We used epigenome-wide robust linear regressions and elastic net to identify differentially methylated cytosine-guanine dinucleotide (CpG) sites associated with urinary Se levels. RESULTS: The mean (standard deviation) urinary Se concentration was 51.8 (25.1) µg/g creatinine. Across 788,368 CpG sites, five differentially methylated positions (DMP) (hypermethylated: cg00163554, cg18212762, cg11270656, and hypomethylated: cg25194720, cg00886293) were significantly associated with Se in linear regressions after accounting for multiple comparisons (false discovery rate p-value: 0.10). The top hypermethylated DMP (cg00163554) was annotated to the Disco Interacting Protein 2 Homolog C (DIP2C) gene, which relates to transcription factor binding. Elastic net models selected 425 hypo- and hyper-methylated DMPs associated with urinary Se, including three sites (cg00163554 [DIP2C], cg18212762 [MAP4K2], cg11270656 [GPIHBP1]) identified in linear regressions. CONCLUSIONS: Urinary Se was associated with minimal changes in DNAm in adults from American Indian communities across the Southwest and the Great Plains in the United States, suggesting that other mechanisms may be driving health impacts. Future analyses should explore other mechanistic biomarkers in human populations, determine these relationships prospectively, and investigate the potential role of differentially methylated sites with disease endpoints.

Arsenic Exposure and Epigenetic Aging: The Association with Cardiovascular Disease and All-Cause Mortality in the Strong Heart Study.

BACKGROUND: Inorganic arsenic (As) may increase the risk of cardiovascular disease (CVD) and all-cause mortality through accelerated aging, which can be estimated using epigenetic-based measures. OBJECTIVES: We evaluated three DNA methylation-based aging measures (PhenoAge, GrimAge, DunedinPACE) (epigenetic aging measures) as potential mediators of the previously reported association of As exposure with CVD incidence, CVD mortality, and all-cause mortality in the Strong Heart Study (SHS), an epidemiological cohort of American Indian adults. METHODS: Blood DNA methylation and urinary As levels were measured in 2,323 SHS participants (41.5% men, mean age of 55 years old). PhenoAge and GrimAge values were calculated using a residual-based method. We tested the association of urinary As with epigenetic aging measures using linear regression, the association of epigenetic aging measures with the three health outcomes using additive hazards models, and the mediation of As-related CVD incidence, CVD mortality, and all-cause mortality by epigenetic aging measures using the product of coefficients method. RESULTS: SHS participants with higher vs. lower urinary As levels had similar PhenoAge age, older GrimAge age, and faster DunedinPACE. An interquartile range increase in urinary As was associated with higher of PhenoAge age acceleration [mean difference (95% confidence interval)=0.48 (0.17, 0.80) years], GrimAge age acceleration [0.80 (0.60, 1.00) years], and DunedinPACE [0.011 (0.005, 0.018)], after adjusting for age, sex, center location, genetic components, smoking status, and body mass index. Of the 347 incident CVD events per 100,000 person-years associated with a doubling in As exposure, 21.3% (9.1, 57.1) and 22.6% (9.5, 56.9), were attributable to differences in GrimAge and DunedinPACE, respectively. DISCUSSION: Arsenic exposure was associated with older GrimAge and faster DunedinPACE measures of biological age. Furthermore, accelerated biological aging measured from DNA methylation accounted for a relevant fraction of As-associated risk for CVD, CVD mortality, and all-cause mortality in the SHS, supporting the role of As in accelerated aging. Research of the biological underpinnings can contribute to a better understanding of the role of aging in arsenic-related disease. https://doi.org/10.1289/EHP11981.

Traffic Density Exposure, Oxidative Stress Biomarkers and Plasma Metabolomics in a Population-Based Sample: The Hortega Study.

Exposure to traffic-related air pollution (TRAP) generates oxidative stress, with downstream effects at the metabolic level. Human studies of traffic density and metabolomic markers, however, are rare. The main objective of this study was to evaluate the cross-sectional association between traffic density in the street of residence with oxidative stress and metabolomic profiles measured in a population-based sample from Spain. We also explored in silico the potential biological implications of the findings. Secondarily, we assessed the contribution of oxidative stress to the association between exposure to traffic density and variation in plasma metabolite levels. Traffic density was defined as the average daily traffic volume over an entire year within a buffer of 50 m around the participants' residence. Plasma metabolomic profiles and urine oxidative stress biomarkers were measured in samples from 1181 Hortega Study participants by nuclear magnetic resonance spectroscopy and high-performance liquid chromatography, respectively. Traffic density was associated with 7 (out of 49) plasma metabolites, including amino acids, fatty acids, products of bacterial and energy metabolism and fluid balance metabolites. Regarding urine oxidative stress biomarkers, traffic associations were positive for GSSG/GSH% and negative for MDA. A total of 12 KEGG pathways were linked to traffic-related metabolites. In a protein network from genes included in over-represented pathways and 63 redox-related candidate genes, we observed relevant proteins from the glutathione cycle. GSSG/GSH% and MDA accounted for 14.6% and 12.2% of changes in isobutyrate and the CH2CH2CO fatty acid moiety, respectively, which is attributable to traffic exposure. At the population level, exposure to traffic density was associated with specific urine oxidative stress and plasma metabolites. Although our results support a role of oxidative stress as a biological intermediary of traffic-related metabolic alterations, with potential implications for the co-bacterial and lipid metabolism, additional mechanistic and prospective studies are needed to confirm our findings.

Medioambiente y salud cardiovascular: causas, consecuencias y oportunidades en prevención y tratamiento / Environment and cardiovascular health: causes, consequences and opportunities in prevention and treatment

El medioambiente es un gran determinante de la salud cardiovascular. La cardiología ambiental estudia la contribución de las exposiciones ambientales con el objetivo de minimizar las influencias nocivas de la contaminación y promover la salud cardiovascular mediante estrategias preventivas o terapéuticas específicas. La presente revisión se centra en el material particulado y los metales, contaminantes con la evidencia científica más sólida, e incluye las posibles intervenciones. La legislación, la mitigación y el control de los contaminantes en el aire, el agua y los alimentos y las políticas ambientales de espacios cardiosaludables son medidas clave para la salud cardiovascular. Entre las estrategias individuales, cabe reseñar la quelación de metales divalentes como el plomo y el cadmio, que solamente pueden eliminarse del cuerpo vía quelación. El ensayo clínico TACT (NCT00044213) demostró el beneficio cardiovascular en pacientes con un infarto de miocardio previo, especialmente en los diabéticos. Actualmente, el ensayo TACT2 (NCT02733185) está reproduciendo los resultados del TACT en personas con diabetes. Datos de Estados Unidos y Argentina también han mostrado la posible utilidad de la quelación en la enfermedad arterial periférica grave. Más investigación y acción en cardiología ambiental podría contribuir sustancialmente a mejorar la prevención y el tratamiento de las enfermedades cardiovasculares.(AU)

The environment is a strong determinant of cardiovascular health. Environmental cardiology studies the contribution of environmental exposures with the aim of minimizing the harmful influences of pollution and promoting cardiovascular health through specific preventive or therapeutic strategies. The present review focuses on particulate matter and metals, which are the pollutants with the strongest level of scientific evidence, and includes possible interventions. Legislation, mitigation and control of pollutants in air, water and food, as well as environmental policies for heart-healthy spaces, are key measures for cardiovascular health. Individual strategies include the chelation of divalent metals such as lead and cadmium, metals that can only be removed from the body via chelation. The TACT (Trial to Assess Chelation Therapy, NCT00044213) clinical trial demonstrated cardiovascular benefit in patients with a previous myocardial infarction, especially in those with diabetes. Currently, the TACT2 trial (NCT02733185) is replicating the TACT results in people with diabetes. Data from the United States and Argentina have also shown the potential usefulness of chelation in severe peripheral arterial disease. More research and action in environmental cardiology could substantially help to improve the prevention and treatment of cardiovascular disease.(AU)

Desigualdades sociales en la mortalidad cardiovascular en España desde una perspectiva interseccional / Social inequalities in cardiovascular mortality in Spain from an intersectional perspective

INTRODUCCIÓN Y OBJETIVOS: El sexo, la edad y el nivel de estudios, entre otros factores, interaccionan e influyen sobre la mortalidad. En España aún no se ha analizado de manera comprehensiva las desigualdades sociales en la mortalidad cardiovascular considerando la influencia conjunta del sexo, la edad y el nivel de estudios (perspectiva interseccional). MÉTODOS: Estudio de todos los fallecidos en España ≥ 30 años durante 2015 (datos del Instituto Nacional de Estadística) por enfermedad cardiovascular total, cardiopatía isquémica, insuficiencia cardiaca y enfermedad cerebrovascular. El índice relativo de desigualdad (IRD) y el índice de desigualdad de la pendiente (IDP) se estimaron mediante modelos de regresión de Poisson utilizando mortalidad ajustada por edad; el IRD se interpreta como el riesgo relativo de mortalidad entre el nivel de estudios más bajo y el más alto, y el IDP como la diferencia absoluta de mortalidad. RESULTADOS: El IRD en mortalidad por enfermedad cardiovascular total fue 1,88 (IC95%, 1,80-1,96) en mujeres y 1,44 (IC95%, 1,39-1,49) en varones. Los IDP fueron 178,46 y 149,43 muertes/100.000 respectivamente. Las mayores desigualdades se observaron en cardiopatía isquémica e insuficiencia cardiaca en mujeres más jóvenes, con IRD> 4. No hubo diferencias entre sexos en desigualdades por enfermedad cerebrovascular. CONCLUSIONES: La mortalidad cardiovascular está inversamente asociada con el nivel educativo. Esta desigualdad afecta más a la mortalidad prematura por causas cardiacas, especialmente entre mujeres. Su monitorización podría orientar la Estrategia de Salud Cardiovascular del Sistema Nacional de Salud, para reducir la desigualdad en la primera causa de muerte

INTRODUCTION AND OBJECTIVES: There is an interaction between age, sex, and educational level, among other factors, that influences mortality. To date, no studies in Spain have comprehensively analyzed social inequalities in cardiovascular mortality by considering the joint influence of age, sex, and education (intersectional perspective). METHODS: Study of all deaths due to all-cause cardiovascular disease, ischemic heart disease, heart failure, and cerebrovascular disease among people aged ≥ 30 years in Spain in 2015. Data were obtained from the Spanish Office of Statistics. The relative index of inequality (RII) and the slope index of inequality (SII) were calculated by using Poisson regression models with age-adjusted mortality. The RII is interpreted as the relative risk of mortality between the lowest and the highest educational level, and the SII as the absolute difference in mortality. RESULTS: The RII for all-cause cardiovascular mortality was 1.88 (95%CI, 1.80-1.96) in women and 1.44 (95%CI, 1.39-1.49) in men. The SII was 178.46 and 149.43 deaths per 100 000, respectively. The greatest inequalities were observed in ischemic heart disease and heart failure in younger women, with a RII higher than 4. There were no differences between sexes in inequalities due to cerebrovascular disease. CONCLUSIONS: Cardiovascular mortality is inversely associated with educational level. This inequality mostly affects premature mortality due to cardiac causes, especially among women. Monitoring this problem could guide the future Cardiovascular Health Strategy in the National Health System, to reduce inequality in the first cause of death

Utilización del aislamiento infeccioso en pacientes no críticos de un hospital universitario / Utilization of patient isolation in non critical units from a university hospital

Fundamento y objetivo: La correcta utilización del aislamiento infeccioso (AI) en los hospitales es importante para el adecuado aprovechamiento de los recursos hospitalarios, así como para el bienestar del paciente aislado. El objetivo de este trabajo es evaluar la utilización del AI medido a través de la adecuación de estancias. Pacientes y método: Durante un período de 19 meses se realizó un estudio prospectivo observacional de los AI indicados a pacientes no críticos de un hospital universitario de la Comunidad Valenciana. La información se obtuvo a partir de los datos de la unidad de admisión, la visita diaria a las salas de hospitalización y la consulta de las historias clínicas. Resultados: Se indicó un total de 239 AI que sumaron 2.589 estancias en AI (mediana de 8 días; extremos: 1-56 días). La incidencia acumulada en el período de estudio fue de 6,74 AI por cada 1.000 ingresos y la densidad de incidencia, de 1,08 AI por paciente-día. El 36,8% de los AI indicados se consideraron incorrectos, lo que se tradujo en 703 estancias en AI inadecuadas, es decir, un 27,1% del total de estancias realizadas en AI. Las infecciones de herida quirúrgica motivaron la inadecuación de los AI con mayor frecuencia (45,2%), sobre todo tras intervenciones de inserción de prótesis de cadera y rodilla (el 42,9 y el 17,9%, respectivamente). Conclusiones: Es necesario elaborar criterios e indicadores de calidad para implementar acciones de mejora continua que permitan optimizar la gestión de las estancias realizadas en AI

Background and objective: Correct utilization of source isolation (SI) in hospitals is important to take advantage of hospital resources. The objective of this work was to evaluate the utilization of SI considering the appropriateness of isolation length-stay. Patients and method: During a period of 19 months a prospective observational study was carried out among non-critical inpatients who underwent SI in a university hospital. The information was obtained from Admission Unit data, daily ward rounds and review of case history records. Results: A total of 239 SIs were identified, summarizing 2,589 days in isolation (median: 8 days, range: 1-56 days). These data supposed a cumulative incidence of 6.74 isolations by 1,000 admissions, and an incidence density of 1.08 isolations by 1,000 inpatient-day. 36.8% of SIs were considered incorrectly used, meaning a total of 703 inappropriate stays in isolation (27.1% of all stays carried out in SI). Surgical wound infections prompted inappropriate isolations with a greater frequency (45.2%), mainly after hip and knee prosthesis implantation interventions (42.9% and 17.9%, respectively). Conclusions: It is necessary to develop quality criteria and indicators in order to implement quality improvement actions to optimize SI length-stay management