Evaluation of genetic markers as instruments for Mendelian randomization studies on vitamin D.

Mendelian randomization (MR) studies use genetic variants mimicking the influence of a modifiable exposure to assess and quantify a causal association with an outcome, with an aim to avoid problems with confounding and reverse causality affecting other types of observational studies

Association of Lifestyle and Genetic Risk With Incidence of Dementia

This is the final version. Available from the American Medical Association via the DOI in this recordImportance: Genetic factors increase risk of dementia, but the extent to which this can be offset by lifestyle factors is unknown. Objective: To investigate whether a healthy lifestyle is associated with lower risk of dementia regardless of genetic risk. Design, Setting, and Participants: A retrospective cohort study that included adults of European ancestry aged at least 60 years without cognitive impairment or dementia at baseline. Participants joined the UK Biobank study from 2006 to 2010 and were followed up until 2016 or 2017. Exposures: A polygenic risk score for dementia with low (lowest quintile), intermediate (quintiles 2 to 4), and high (highest quintile) risk categories and a weighted healthy lifestyle score, including no current smoking, regular physical activity, healthy diet, and moderate alcohol consumption, categorized into favorable, intermediate, and unfavorable lifestyles. Main Outcomes and Measures: Incident all-cause dementia, ascertained through hospital inpatient and death records. Results: A total of 196 383 individuals (mean [SD] age, 64.1 [2.9] years; 52.7% were women) were followed up for 1 545 433 person-years (median [interquartile range] follow-up, 8.0 [7.4-8.6] years). Overall, 68.1% of participants followed a favorable lifestyle, 23.6% followed an intermediate lifestyle, and 8.2% followed an unfavorable lifestyle. Twenty percent had high polygenic risk scores, 60% had intermediate risk scores, and 20% had low risk scores. Of the participants with high genetic risk, 1.23% (95% CI, 1.13%-1.35%) developed dementia compared with 0.63% (95% CI, 0.56%-0.71%) of the participants with low genetic risk (adjusted hazard ratio, 1.91 [95% CI, 1.64-2.23]). Of the participants with a high genetic risk and unfavorable lifestyle, 1.78% (95% CI, 1.38%-2.28%) developed dementia compared with 0.56% (95% CI, 0.48%-0.66%) of participants with low genetic risk and favorable lifestyle (hazard ratio, 2.83 [95% CI, 2.09-3.83]). There was no significant interaction between genetic risk and lifestyle factors (P = .99). Among participants with high genetic risk, 1.13% (95% CI, 1.01%-1.26%) of those with a favorable lifestyle developed dementia compared with 1.78% (95% CI, 1.38%-2.28%) with an unfavorable lifestyle (hazard ratio, 0.68 [95% CI, 0.51-0.90]). Conclusions and Relevance: Among older adults without cognitive impairment or dementia, both an unfavorable lifestyle and high genetic risk were significantly associated with higher dementia risk. A favorable lifestyle was associated with a lower dementia risk among participants with high genetic risk.James Tudor FoundationMary Kinross Charitable TrustHalpin TrustNational Institute for Health Research (NIHR)National Health and Medical Research Council, AustraliaNational Institute on Aging/National Institutes of HealthEngineering and Physical Sciences Research Council (EPSRC

Mendelian randomization case-control PheWAS in UK Biobank shows evidence of causality for smoking intensity in 28 distinct clinical conditions.

Background: Smoking is one of the greatest threats to public health worldwide. We integrated phenome-wide association study (PheWAS) and Mendelian randomization (MR) approaches to explore causal effects of genetically predicted smoking intensity across the human disease spectrum. Methods: We conducted PheWAS case-control analyses in 152,483 ever smokers of White-British ancestry, aged 39-73 years. Disease diagnoses were based on hospital inpatient and mortality registrations. Smoking intensity was instrumented by four genetic variants, and disease risks estimated for one cigarette per day heavier intakes. Associations passing the FDR threshold (p<0•0025) were assessed for causality using several complementary MR approaches. Findings: Genetically instrumented smoking intensity was associated with 48 conditions, with MR supporting a possible causal effect for 28 distinct outcomes. Each cigarette smoked per day elevated the odds of respiratory diseases by 5% to 33% (nine distinct diseases, including pneumonia, emphysema, obstructive chronic bronchitis, pleurisy, pulmonary collapse, respiratory failure) and the odds of circulatory disease by 5% to 23% (seven diseases, including atherosclerosis, myocardial infarction, congestive heart failure, arterial embolisms). Further effects were seen for cancer within the respiratory system and other neoplasms, renal failure, septicaemia, and retinal disorders. No associations were observed in sensitivity analyses on 185,002 never smokers. Interpretation: These genetic data demonstrate the substantial adverse health impacts by smoking intensity and suggest notable increases in the risks of several diseases. Public health initiatives should highlight the damage caused by smoking intensity and the potential benefits of reducing or ideally quitting smoking

On the hygroscopic growth of ammoniated sulfate particles of non-stoichiometric composition

International audienceThe hygroscopic growth of ammoniated sulfate particles was studied by measurements and model calculations for particles with varying ammonium-to-sulfate ratio. In the measurements, the ammonium-to-sulfate ratio was adjusted by using mixtures of ammonium sulfate and ammonium bisulfate in generating the solid particles. The hygroscopic growth was measured using a tandem differential mobility analyzer. The measurements were simulated using a thermodynamical equilibrium model. The calculations indicated that the solid phases in particle with ammonium-to-sulfate ratio between 1.5?2, were ammonium sulfate and letovicite. Both in the calculations and in the experiments the hygroscopic growth was initiated at relative humidities less than the theoretical deliquescence relative humidity of these particles. This indicates that the particles were multi-phase particles including solids and liquids. The equilibrium model yielded a satisfactory prediction of the hygroscopic growth of particles generated from a solution with 1:1 mass ratio between dissolved ammonium sulfate and ammonium bisulfate. However, for particles with 3:1 and 10:1 mass ratios, the model predictions overestimated the growth at relative humidities between about 60% and the point of complete deliquescence (close to 80% RH). In contrast, a model, in which letovicite was allowed to dissolve only after complete dissolution of ammonium sulfate, reproduced the observations well. This indicates that the dry particles had a letovicite core surrounded by an ammonium sulfate shell

Which Risk Factors Causally Influence Dementia? A Systematic Review of Mendelian Randomization Studies

This is the final version. Available from IOS Press via the DOI in this record.BACKGROUND: Numerous risk factors for dementia are well established, though the causal nature of these associations remains unclear. OBJECTIVE: To systematically review Mendelian randomization (MR) studies investigating causal relationships between risk factors and global cognitive function or dementia. METHODS: We searched five databases from inception to February 2017 and conducted citation searches including MR studies investigating the association between any risk factor and global cognitive function, all-cause dementia or dementia subtypes. Two reviewers independently assessed titles and abstracts, full-texts, and study quality. RESULTS: We included 18 MR studies investigating education, lifestyle factors, cardiovascular factors and related biomarkers, diabetes related and other endocrine factors, and telomere length. Studies were of predominantly good quality, however eight received low ratings for sample size and statistical power. The most convincing causal evidence was found for an association of shorter telomeres with increased risk of Alzheimer's disease (AD). Causal evidence was weaker for smoking quantity, vitamin D, homocysteine, systolic blood pressure, fasting glucose, insulin sensitivity, and high-density lipoprotein cholesterol. Well-replicated associations were not present for most exposures and we cannot fully discount survival and diagnostic bias, or the potential for pleiotropic effects. CONCLUSIONS: Genetic evidence supported a causal association between telomere length and AD, whereas limited evidence for other risk factors was largely inconclusive with tentative evidence for smoking quantity, vitamin D, homocysteine, and selected metabolic markers. The lack of stronger evidence for other risk factors may reflect insufficient statistical power. Larger well-designed MR studies would therefore help establish the causal status of these dementia risk factors.This work was supported by the Mary Kinross Charitable Trust (DJL and EK), Halpin Trust (DJL, EK and IL), the James Tudor Foundation (DJL and EK), National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsula (IL, JTC, AB and DJL) and the National Institute on Aging of the National Institutes of Health under Award Number RF1AG055654 (DJL)

Obesity and depressive symptoms in mid-life: a population-based cohort study

BACKGROUND: Obesity and depression are both highly prevalent public health disorders and evidence on their relationship is inconsistent. This study examined whether depressive symptoms are associated with current obesity, and further, whether obesity in turn is associated with an increased odds of depressive symptoms five years later after accounting for potential lifestyle confounders and depressive symptoms at baseline. METHODS: Data were obtained from the 1958 British birth cohort (N = 9217 for cross-sectional and 7340 for prospective analysis). Clinical Interview Schedule-Revised and Mental Health Inventory-5 were used for screening depressive symptoms at ages 45 and 50 years, respectively. General and central obesity were defined using measurements of body mass index (BMI) and waist circumference (WC) at 45 years, respectively. RESULTS: There was a cross-sectional association between depressive symptoms and obesity: participants with ≥2 depressive symptoms had 31% (95%CI 11% to 55%) higher odds of general and 26% higher odds of central obesity (95%CI 8% to 47%). In prospective analyses, both general and central obesity were associated with higher odds of depressive symptoms five years later among women but not in men (Pinteraction < 0.01). After adjustment for depressive symptoms at baseline, sociodemographic and lifestyle factors, women with general obesity had 38% (95% CI 7% to 77%) and women with central obesity 34% (95%CI 9% to 65%) higher odds of depression compared to others. CONCLUSIONS: Depressive symptoms are associated with concurrent obesity and related lifestyle factors among women and men in mid-life. Our study suggests that obesity in turn affects long-term risk of depressive symptoms in women but not in men, independently of concurrent associations, providing an important target group for the implementation of preventative strategies

Combining machine learning and conventional statistical approaches for risk factor discovery in a large cohort study

We present a simple and efficient hypothesis-free machine learning pipeline for risk factor discovery that accounts for non-linearity and interaction in large biomedical databases with minimal variable pre-processing. In this study, mortality models were built using gradient boosting decision trees (GBDT) and important predictors were identified using a Shapley values-based feature attribution method, SHAP values. Cox models controlled for false discovery rate were used for confounder adjustment, interpretability, and further validation. The pipeline was tested using information from 502,506 UK Biobank participants, aged 37–73 years at recruitment and followed over seven years for mortality registrations. From the 11,639 predictors included in GBDT, 193 potential risk factors had SHAP values ≥ 0.05, passed the correlation test, and were selected for further modelling. Of the total variable importance summed up, 60% was directly health related, and baseline characteristics, socio-demographics, and lifestyle factors each contributed about 10%. Cox models adjusted for baseline characteristics, showed evidence for an association with mortality for 166 out of the 193 predictors. These included mostly well-known risk factors (e.g., age, sex, ethnicity, education, material deprivation, smoking, physical activity, self-rated health, BMI, and many disease outcomes). For 19 predictors we saw evidence for an association in the unadjusted but not adjusted analyses, suggesting bias by confounding. Our GBDT-SHAP pipeline was able to identify relevant predictors ‘hidden’ within thousands of variables, providing an efficient and pragmatic solution for the first stage of hypothesis free risk factor identification.Iqbal Madakkatel, Ang Zhou, Mark D. McDonnell, and Elina Hyppöne

Critical Micronutrients in Pregnancy, Lactation, and Infancy: Considerations on Vitamin D, Folic Acid, and Iron, and Priorities for Future Research

The Early Nutrition Academy and the European Commission-funded EURRECA Network of Excellence jointly sponsored a scientific workshop on critical micronutrients in pregnancy, lactation, and infancy. Current knowledge and unresolved questions on the supply of vitamin D, folic acid, and iron for pregnant women, lactating women, and infants, and their health effects were discussed. The question was addressed of whether, and under which circumstances, supplementation with these micronutrients in addition to usual dietary intakes is advisable. The workshop participants concluded that public health strategies for improving supplementation with these micronutrients in pregnancy, lactation, and infancy are required. Further research priorities should focus on adequately powered human intervention trials to obtain a stronger evidence base for the amounts of vitamin D, folic acid, and iron that have optimal effects on health. The conclusions of the workshop should help to inform the scientific community as well as public health policy strategies. Copyright (C) 2011 S. Karger AG, Base

25-Hydroxyvitamin D and pre-clinical alterations in inflammatory and hemostatic markers: a cross sectional analysis in the 1958 British Birth Cohort

BACKGROUND: Vitamin D deficiency has been suggested as a cardiovascular risk factor, but little is known about underlying mechanisms or associations with inflammatory or hemostatic markers. Our aim was to investigate the association between 25-hydroxyvitamin D [25(OH)D, a measure for vitamin D status] concentrations with pre-clinical variations in markers of inflammation and hemostasis. METHODOLOGY/PRINCIPAL FINDINGS: Serum concentrations of 25(OH)D, C-reactive protein (CRP), fibrinogen, D-dimer, tissue plasminogen activator (tPA) antigen, and von Willebrand factor (vWF) were measured in a large population based study of British whites (aged 45 y). Participants for the current investigation were restricted to individuals free of drug treated cardiovascular disease (n = 6538). Adjusted for sex and month, 25(OH)D was inversely associated with all outcomes (p or =75 nmol/l compared to < 25 nmol/l. D-dimer concentrations were lower for participants with 25(OH)D 50-90 nmol/l compared to others (quadratic term p = 0.01). We also examined seasonal variation in hemostatic and inflammatory markers, and evaluated 25(OH)D contribution to the observed patterns using mediation models. TPA concentrations varied by season (p = 0.02), and much of this pattern was related to fluctuations in 25(OH)D concentrations (p < or =0.001). Some evidence of a seasonal variation was observed also for fibrinogen, D-dimer and vWF (p < 0.05 for all), with 25(OH)D mediating some of the pattern for fibrinogen and D-dimer, but not vWF. CONCLUSIONS: Current vitamin D status was associated with tPA concentrations, and to a lesser degree with fibrinogen and D-dimer, suggesting that vitamin D status/intake may be important for maintaining antithrombotic homeostasi

Hospital admissions for vitamin D related conditions and subsequent immune-mediated disease: record-linkage studies

PMCID: PMC3729414The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1741-7015/11/171. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited