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Vitamin D and Multiple Health Outcomes: An Umbrella Review of Observational Studies, Randomized Controlled Trials, and Mendelian Randomization Studies.

ABSTRACT: Observational studies, randomized controlled trials (RCTs), and Mendelian randomization (MR) studies have yielded inconsistent results on the associations of vitamin D concentrations with multiple health outcomes. In the present umbrella review we aimed to evaluate the effects of low vitamin D concentrations and vitamin D supplementation on multiple health outcomes. We summarized current evidence obtained from meta-analyses of observational studies that examined associations between vitamin D concentrations and multiple health outcomes, meta-analyses of RCTs that investigated the effect of vitamin D supplementation on multiple health outcomes, and MR studies that explored the causal associations of vitamin D concentrations with various diseases (international prospective register of systematic reviews PROSPERO registration number CRD42018091434). A total of 296 meta-analyses of observational studies comprising 111 unique outcomes, 139 meta-analyses of RCTs comprising 46 unique outcomes, and 73 MR studies comprising 43 unique outcomes were included in the present umbrella review. Twenty-eight disease outcomes were identified by both meta-analyses of observational studies and MR studies. Seventeen of these reported disease outcomes had consistent results, demonstrating that lower concentrations of vitamin D were associated with a higher risk for all-cause mortality, Alzheimer's disease, hypertension, schizophrenia, and type 2 diabetes. The combinations of consistent evidence obtained by meta-analyses of observational studies and MR studies together with meta-analyses of RCTs showed that vitamin D supplementation was associated with a decreased risk for all-cause mortality but not associated with the risk for Alzheimer's disease, hypertension, schizophrenia, or type 2 diabetes. The results indicated that vitamin D supplementation is a promising strategy with long-term preventive effects on multiple chronic diseases and thus has the potential to decrease all-cause mortality. However, the current vitamin D supplementation strategy might not be an efficient intervention approach for these diseases, suggesting that new strategies are highly needed to improve the intervention outcomes.

SUBMITTER: Liu D

PROVIDER: S-EPMC9340982 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Vitamin D and Multiple Health Outcomes: An Umbrella Review of Observational Studies, Randomized Controlled Trials, and Mendelian Randomization Studies.

Liu Di D Meng Xiaoni X Tian Qiuyue Q Cao Weijie W Fan Xin X Wu Lijuan L Song Manshu M Meng Qun Q Wang Wei W Wang Youxin Y

Advances in nutrition (Bethesda, Md.) 20220801 4

Observational studies, randomized controlled trials (RCTs), and Mendelian randomization (MR) studies have yielded inconsistent results on the associations of vitamin D concentrations with multiple health outcomes. In the present umbrella review we aimed to evaluate the effects of low vitamin D concentrations and vitamin D supplementation on multiple health outcomes. We summarized current evidence obtained from meta-analyses of observational studies that examined associations between vitamin D co ...[more]

PMID: 34999745

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Project description:Objective To map the diverse health outcomes associated with serum uric acid (SUA) levels.Design Umbrella review.Data sources Medline, Embase, Cochrane Database of Systematic Reviews, and screening of citations and references.Eligibility criteria Systematic reviews and meta-analyses of observational studies that examined associations between SUA level and health outcomes, meta-analyses of randomised controlled trials that investigated health outcomes related to SUA lowering treatment, and Mendelian randomisation studies that explored the causal associations of SUA level with health outcomes.Results 57 articles reporting 15 systematic reviews and144 meta-analyses of observational studies (76 unique outcomes), 8 articles reporting 31 meta-analyses of randomised controlled trials (20 unique outcomes), and 36 articles reporting 107 Mendelian randomisation studies (56 unique outcomes) met the eligibility criteria. Across all three study types, 136 unique health outcomes were reported. 16 unique outcomes in meta-analyses of observational studies had P<10-6, 8 unique outcomes in meta-analyses of randomised controlled trials had P<0.001, and 4 unique outcomes in Mendelian randomisation studies had P<0.01. Large between study heterogeneity was common (80% and 45% in meta-analyses of observational studies and of randomised controlled trials, respectively). 42 (55%) meta-analyses of observational studies and 7 (35%) meta-analyses of randomised controlled trials showed evidence of small study effects or excess significance bias. No associations from meta-analyses of observational studies were classified as convincing; five associations were classified as highly suggestive (increased risk of heart failure, hypertension, impaired fasting glucose or diabetes, chronic kidney disease, coronary heart disease mortality with high SUA levels). Only one outcome from randomised controlled trials (decreased risk of nephrolithiasis recurrence with SUA lowering treatment) had P<0.001, a 95% prediction interval excluding the null, and no large heterogeneity or bias. Only one outcome from Mendelian randomisation studies (increased risk of gout with high SUA levels) presented convincing evidence. Hypertension and chronic kidney disease showed concordant evidence in meta-analyses of observational studies, and in some (but not all) meta-analyses of randomised controlled trials with respective intermediate or surrogate outcomes, but they were not statistically significant in Mendelian randomisation studies.Conclusion Despite a few hundred systematic reviews, meta-analyses, and Mendelian randomisation studies exploring 136 unique health outcomes, convincing evidence of a clear role of SUA level only exists for gout and nephrolithiasis.

Project description:OBJECTIVE:To evaluate the breadth, validity, and presence of biases of the associations of vitamin D with diverse outcomes. DESIGN:Umbrella review of the evidence across systematic reviews and meta-analyses of observational studies of plasma 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D concentrations and randomised controlled trials of vitamin D supplementation. DATA SOURCES:Medline, Embase, and screening of citations and references. ELIGIBILITY CRITERIA:Three types of studies were eligible for the umbrella review: systematic reviews and meta-analyses that examined observational associations between circulating vitamin D concentrations and any clinical outcome; and meta-analyses of randomised controlled trials assessing supplementation with vitamin D or active compounds (both established and newer compounds of vitamin D). RESULTS:107 systematic literature reviews and 74 meta-analyses of observational studies of plasma vitamin D concentrations and 87 meta-analyses of randomised controlled trials of vitamin D supplementation were identified. The relation between vitamin D and 137 outcomes has been explored, covering a wide range of skeletal, malignant, cardiovascular, autoimmune, infectious, metabolic, and other diseases. Ten outcomes were examined by both meta-analyses of observational studies and meta-analyses of randomised controlled trials, but the direction of the effect and level of statistical significance was concordant only for birth weight (maternal vitamin D status or supplementation). On the basis of the available evidence, an association between vitamin D concentrations and birth weight, dental caries in children, maternal vitamin D concentrations at term, and parathyroid hormone concentrations in patients with chronic kidney disease requiring dialysis is probable, but further studies and better designed trials are needed to draw firmer conclusions. In contrast to previous reports, evidence does not support the argument that vitamin D only supplementation increases bone mineral density or reduces the risk of fractures or falls in older people. CONCLUSIONS:Despite a few hundred systematic reviews and meta-analyses, highly convincing evidence of a clear role of vitamin D does not exist for any outcome, but associations with a selection of outcomes are probable.

Project description:AimsThe aim of this study was to investigate the causal relationship and evidence of an association between increased adiposity and the risk of incident cardiovascular disease (CVD) events or mortality.Methods and resultsObservational (informing association) and Mendelian randomization (MR) (informing causality) studies were assessed to gather mutually complementary insights and elucidate perplexing epidemiological relationships. Systematic reviews and meta-analyses of observational and MR studies that were published until January 2021 and evaluated the association between obesity-related indices and CVD risk were searched. Twelve systematic reviews with 53 meta-analyses results (including over 501 cohort studies) and 12 MR studies were included in the analysis. A body mass index (BMI) increase was associated with higher risks of coronary heart disease, heart failure, atrial fibrillation, all-cause stroke, haemorrhagic stroke, ischaemic stroke, hypertension, aortic valve stenosis, pulmonary embolism, and venous thrombo-embolism. The MR study results demonstrated a causal effect of obesity on all indices but stroke. The CVD risk increase for every 5 kg/m2 increase in BMI varied from 10% [relative risk (RR) 1.10; 95% confidence interval (CI) 1.01-1.21; certainty of evidence, low] for haemorrhagic stroke to 49% (RR 1.49; 95% CI 1.40-1.60; certainty of evidence, high) for hypertension. The all-cause and CVD-specific mortality risks increased with adiposity in cohorts, but the MR studies demonstrated no causal effect of adiposity on all-cause mortality.ConclusionHigh adiposity is associated with increased CVD risk despite divergent evidence gradients. Adiposity was a causal risk factor for CVD except all-cause mortality and stroke. Half (49%; 26/53) of the associations were supported by high-level evidence. The associations were consistent between sexes and across global regions. This study provides guidance on how to integrate evidence from observational (association) and genetics-driven (causation) studies accumulated to date, to enable a more reliable interpretation of epidemiological relationships.

Project description:BackgroundHomelessness has been associated with multiple detrimental health outcomes across observational studies. However, relatively few randomized controlled trials (RCTs) have been conducted on people who experience homelessness (PEH). Thus, this umbrella review ranked the credibility of evidence derived from systematic reviews (SRs) and meta-analyses (MAs) of observational studies investigating the associations between homelessness and any health outcome as well as RCTs targeting health needs in this population.MethodsSeveral databases were systematically searched from inception through April 28, 2021. Any SR and/or MA reporting quantitative data and providing a control group were eligible for inclusion. The credibility of the evidence derived from observational studies was appraised by considering the significance level of the association and the largest study, the degree of heterogeneity, the presence of small-study effects as well as excess significance bias. The credibility of evidence was then ranked in five classes. For SRs and/or MAs of RCTs, we considered the level of significance and whether the prediction interval crossed the null. The AMSTAR-2 and AMSTAR-plus instruments were adopted to further assess the methodological quality of SRs and/or MAs. The Newcastle-Ottawa Scale (NOS) was employed to further appraise the methodological quality of prospective cohort studies only; a sensitivity analysis limited to higher quality studies was conducted.ResultsOut of 1549 references, 8 MAs and 2 SRs were included. Among those considering observational studies, 23 unique associations were appraised. Twelve of them were statistically significant at the p≤0.005 level. Included cases had worst health-related outcomes than controls, but only two associations reached a priori-defined criteria for convincing (class I) evidence namely hospitalization due to any cause among PEH diagnosed with HIV infection, and the occurrence of falls within the past year among PEH. According to the AMSTAR-2 instrument, the methodological quality of all included SRs and/or MAs was "critically low." Interventional studies were scant.ConclusionWhile homelessness has been repeatedly associated with detrimental health outcomes, only two associations met the criteria for convincing evidence. Furthermore, few RCTs were appraised by SRs and/or MAs. Our umbrella review also highlights the need to standardize definitions of homelessness to be incorporated by forthcoming studies to improve the external validity of the findings in this vulnerable population.

Project description:BackgroundThe incidence of prostate cancer is increasing in older males globally. Age, ethnicity, and family history are identified as the well-known risk factors for prostate cancer, but few modifiable factors have been firmly established. The objective of this study was to identify and evaluate various factors modifying the risk of prostate cancer reported in meta-analyses of prospective observational studies and mendelian randomization (MR) analyses.Methods and findingsWe searched PubMed, Embase, and Web of Science from the inception to January 10, 2022, updated on September 9, 2023, to identify meta-analyses and MR studies on prostate cancer. Eligibility criteria for meta-analyses were (1) meta-analyses including prospective observational studies or studies that declared outcome-free at baseline; (2) evaluating the factors of any category associated with prostate cancer incidence; and (3) providing effect estimates for further data synthesis. Similar criteria were applied to MR studies. Meta-analysis was repeated using the random-effects inverse-variance model with DerSimonian-Laird method. Quality assessment was then conducted for included meta-analyses using AMSTAR-2 tool and for MR studies using STROBE-MR and assumption evaluation. Subsequent evidence grading criteria for significant associations in meta-analyses contained sample size, P values and 95% confidence intervals, 95% prediction intervals, heterogeneity, and publication bias, assigning 4 evidence grades (convincing, highly suggestive, suggestive, or weak). Significant associations in MR studies were graded as robust, probable, suggestive, or insufficient considering P values and concordance of effect directions. Finally, 92 selected from 411 meta-analyses and 64 selected from 118 MR studies were included after excluding the overlapping and outdated studies which were published earlier and contained fewer participants or fewer instrument variables for the same exposure. In total, 123 observational associations (45 significant and 78 null) and 145 causal associations (55 significant and 90 null) were categorized into lifestyle; diet and nutrition; anthropometric indices; biomarkers; clinical variables, diseases, and treatments; and environmental factors. Concerning evidence grading on significant associations, there were 5 highly suggestive, 36 suggestive, and 4 weak associations in meta-analyses, and 10 robust, 24 probable, 4 suggestive, and 17 insufficient causal associations in MR studies. Twenty-six overlapping factors between meta-analyses and MR studies were identified, with consistent significant effects found for physical activity (PA) (occupational PA in meta: OR = 0.87, 95% CI: 0.80, 0.94; accelerator-measured PA in MR: OR = 0.49, 95% CI: 0.33, 0.72), height (meta: OR = 1.09, 95% CI: 1.06, 1.12; MR: OR = 1.07, 95% CI: 1.01, 1.15, for aggressive prostate cancer), and smoking (current smoking in meta: OR = 0.74, 95% CI: 0.68, 0.80; smoking initiation in MR: OR = 0.91, 95% CI: 0.86, 0.97). Methodological limitation is that the evidence grading criteria could be expanded by considering more indices.ConclusionsIn this large-scale study, we summarized the associations of various factors with prostate cancer risk and provided comparisons between observational associations by meta-analysis and genetically estimated causality by MR analyses. In the absence of convincing overlapping evidence based on the existing literature, no robust associations were identified, but some effects were observed for height, physical activity, and smoking.

Project description:BackgroundHigher vitamin D status has been suggested to have beneficial effects on the brain.ObjectivesTo investigate the association between 25-hydroxyvitamin D [25(OH)D], neuroimaging features, and the risk of dementia and stroke.MethodsWe used prospective data from the UK Biobank (37-73 y at baseline) to examine the association between 25(OH)D concentrations with neuroimaging outcomes (N = 33,523) and the risk of dementia and stroke (N = 427,690; 3414 and 5339 incident cases, respectively). Observational analyses were adjusted for age, sex, ethnicity, month, center, and socioeconomic, lifestyle, sun behavior, and illness-related factors. Nonlinear Mendelian randomization (MR) analyses were used to test for underlying causality for neuroimaging outcomes (N = 23,901) and dementia and stroke (N = 294,514; 2399 and 3760 cases, respectively).ResultsAssociations between 25(OH)D and total, gray matter, white matter, and hippocampal volumes were nonlinear, with lower volumes both for low and high concentrations (adjusted P-nonlinear ≤ 0.04). 25(OH)D had an inverse association with white matter hyperintensity volume [per 10 nmol/L 25(OH)D; adjusted β: -6.1; 95% CI: -11.5, -7.0]. Vitamin D deficiency was associated with an increased risk of dementia and stroke, with the strongest associations for those with 25(OH)D <25 nmol/L (compared with 50-75.9 nmol/L; adjusted HR: 1.79; 95% CI: 1.57, 2.04 and HR: 1.40; 95% CI: 1.26, 1.56, respectively). Nonlinear MR analyses confirmed the threshold effect of 25(OH)D on dementia, with the risk predicted to be 54% (95% CI: 1.21, 1.96) higher for participants at 25 nmol/L compared with 50 nmol/L. 25(OH)D was not associated with neuroimaging outcomes or the risk of stroke in MR analyses. Potential impact fraction suggests 17% (95% CI: 7.22, 30.58) of dementia could be prevented by increasing 25(OH)D to 50 nmol/L.ConclusionsLow vitamin D status was associated with neuroimaging outcomes and the risks of dementia and stroke even after extensive covariate adjustment. MR analyses support a causal effect of vitamin D deficiency on dementia but not on stroke risk.

Dataset Information

Vitamin D and Multiple Health Outcomes: An Umbrella Review of Observational Studies, Randomized Controlled Trials, and Mendelian Randomization Studies.

Publications

Vitamin D and Multiple Health Outcomes: An Umbrella Review of Observational Studies, Randomized Controlled Trials, and Mendelian Randomization Studies.

Similar Datasets

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