Abstract
Thousands of observational studies have linked vitamin D deficiency with numerous diseases, but randomised controlled trials (RCTs) often fail to show benefit of supplementation. Population ...characteristics and trial design have long been suspected to undermine power but were not systematically investigated. We propose a flexible generative model to characterise benefit of vitamin D supplementation at the individual level, and use this to quantify power in RCTs. The model can account for seasonality and population heterogeneity. In a simulated 1-year trial with 1000 participants per arm and assuming a 25-hydroxyvitamin D (25OHD) increase of 20 nmol/L due to the intervention, with baseline 25OHD in the population of 15, 35, 50, 60 and 75 nmol/L, the power to detect intervention effect was 77%, 99%, 95%, 68% and 19%, respectively. The number of participants required per arm to achieve 80% power according to baseline 25OHD of 15–60 nmol/L was 1200, 400, 600 and 1400, respectively. As expected, larger increases in 25OHD due to supplementation improved power in certain scenarios. For a population baseline of 50 nmol/L, with 1500 participants in each arm, there was 100% power to detect a 20 nmol/L 25OHD increase while it was 76% for a 10 nmol/L increase. Population characteristics and trial design, including temporal considerations, have a dramatic impact on power and required sample size in vitamin D RCTs.
We report on the incidence of cutaneous eyelid tumours in Ireland over the 11-year-period from 2005 to 2015, we identify associations between demographic factors and cutaneous eyelid tumour risk.
...Skin cancers, including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), melanoma, and other cancers, located on the eyelid or canthus according to ICD-10 coding, as registered by the National Cancer Registry of Ireland (NCRI), were captured from the period 2005 to 2015. Age standardised rates (ASR) were calculated according to the European Standard Population (2013). Longitudinal data analysis using linear regression, and associations with age and sex were evaluated with the statistics program R.
There were 4824 patients diagnosed with eyelid BCC during the study period, the ASR in men and women was mean 15.87 and 13.49 per 100,00, respectively. The relative risk for eyelid BCC in men compared with women was 1.18, age was associated with incidence. There were 528 patients diagnosed with SCC; the ASR of eyelid SCC in men and women was 2.10 and 1.39 per 100,000, respectively, and increased in women annually (β = 0.07, p = 0.0005). The relative risk for eyelid SCC in men compared with women was 1.51, and age was exponentially associated with SCC. Melanoma and other eyelid tumours were uncommon-50 and 55 cases, respectively.
Incidence of both BCC and SCC increases with age and male sex. The incidence of eyelid SCC is increasing in women, and under age 50, eyelid BCC is more common in women than men.
We describe the recent incidence of eyelid cancers in Ireland, from National Cancer Registry Data. We find eyelid BCC, and also SCC, are associated with increased age. Rate of eyelid SCC is increasing in women.
Low circulating vitamin D levels are associated with poor colorectal cancer (CRC) survival. We assess whether vitamin D supplementation improves CRC survival outcomes.
PubMed and Web of Science were ...searched. Randomised controlled trial (RCTs) of vitamin D supplementation reporting CRC mortality were included. RCTs with high risk of bias were excluded from analysis. Random-effects meta-analysis models calculated estimates of survival benefit with supplementation. The review is registered on PROSPERO, registration number: CRD42020173397.
Seven RCTs (n = 957 CRC cases) were identified: three trials included patients with CRC at outset, and four population trials reported survival in incident cases. Two RCTs were excluded from meta-analysis (high risk of bias; no hazard ratio (HR)). While trials varied in inclusion criteria, intervention dose and outcomes, meta-analysis found a 30% reduction in adverse CRC outcomes with supplementation (n = 815, HR = 0.70; 95% confidence interval (CI): 0.48-0.93). A beneficial effect was seen in trials of CRC patients (progression-free survival, HR = 0.65; 95% CI: 0.36-0.94), with suggestive effect in incident CRC cases from population trials (CRC-specific survival, HR = 0.76; 95% CI: 0.39-1.13). No heterogeneity or publication bias was noted.
Meta-analysis demonstrates a clinically meaningful benefit of vitamin D supplementation on CRC survival outcomes. Further well-designed, adequately powered RCTs are needed to fully evaluate benefit of supplementation in augmenting 'real-life' follow-up and adjuvant chemotherapy regimens, as well as determining optimal dosing.
A growing body of evidence suggests that vitamin D deficiency has been associated with an increased susceptibility to viral and bacterial respiratory infections. In this study, we aimed to examine ...the association between vitamin D and COVID-19 risk and outcomes. We used logistic regression to identify associations between vitamin D variables and COVID-19 (risk of infection, hospitalisation and death) in 417,342 participants from UK Biobank. We subsequently performed a Mendelian Randomisation (MR) study to look for evidence of a causal effect. In total, 1746 COVID-19 cases (399 deaths) were registered between March and June 2020. We found no significant associations between COVID-19 infection risk and measured 25-OHD levels after adjusted for covariates, but this finding is limited by the fact that the vitamin D levels were measured on average 11 years before the pandemic. Ambient UVB was strongly and inversely associated with COVID-19 hospitalization and death overall and consistently after stratification by BMI and ethnicity. We also observed an interaction that suggested greater protective effect of genetically-predicted vitamin D levels when ambient UVB radiation is stronger. The main MR analysis did not show that genetically-predicted vitamin D levels are causally associated with COVID-19 risk (OR = 0.77, 95% CI 0.55-1.11, P = 0.160), but MR sensitivity analyses indicated a potential causal effect (weighted mode MR: OR = 0.72, 95% CI 0.55-0.95, P = 0.021; weighted median MR: OR = 0.61, 95% CI 0.42-0.92, P = 0.016). Analysis of MR-PRESSO did not find outliers for any instrumental variables and suggested a potential causal effect (OR = 0.80, 95% CI 0.66-0.98, p-val = 0.030). In conclusion, the effect of vitamin D levels on the risk or severity of COVID-19 remains controversial, further studies are needed to validate vitamin D supplementation as a means of protecting against worsened COVID-19.
We investigated whether the plasma level of 25-hydroxyvitamin D (25-OHD) after a diagnosis of colorectal cancer (CRC) influences survival outcome.
We prospectively studied 1,598 patients with stage I ...to III CRC. We sought association between plasma 25-OHD and stage-specific survival and tested for interaction between 25-OHD level and variation at the vitamin D receptor (VDR) gene locus. Blood was sampled postoperatively, and plasma was assayed for 25-OHD by liquid chromatography-tandem mass spectrometry. VDR polymorphisms (rs1544410, rs10735810, rs7975232, rs11568820) were genotyped, and haplotypes were inferred by using BEAGLE software. We tested for association between survival and 25-OHD, VDR genotype/haplotype, and after applying a VDR genotype-25-OHD interaction term. We conducted Kaplan-Meier survival analysis and used Cox proportional hazards models to estimate adjusted hazard ratios (HRs).
We found strong associations between plasma 25-OHD concentration and CRC-specific (P = .008) and all-cause mortality (P = .003). Adjusted HRs were 0.68 (95% CI, 0.50 to 0.90) and 0.70 (95% CI, 0.55 to 0.89), respectively (highest v lowest 25-OHD tertile), particularly in stage II disease (HR, 0.44; P = .004 for CRC-specific mortality). We detected gene-environment interactions between 25-OHD concentration and rs11568820 genotype for CRC-specific (P = .008) and all-cause (P = .022) mortality, number of protective alleles (P = .004 and P = .018, respectively), and GAGC haplotype at the VDR locus for all-cause mortality (P = .008).
In patients with stage I to III CRC, postoperative plasma vitamin D is associated with clinically important differences in survival outcome, higher levels being associated with better outcome. We observed interactions between 25-OHD level and VDR genotype, suggesting a causal relationship between vitamin D and survival. The influence of vitamin D supplementation on CRC outcome will require further investigation.
Vitamin D is essential for good health. Dermal vitamin D production is dependent on environmental factors such as season and latitude, and personal factors such as time spent outdoors and genetics. ...Varying heritability of vitamin D status by season has been reported, suggesting that gene-environment interactions (GxE) may play a key role. Thus, understanding GxE might significantly improve our understanding of determinants of vitamin D status. The objective of this review was to survey the existing methods in GxE on vitamin D studies and report on GxE effect estimates. We searched the Embase, Medline (Ovid), and Web of Science (Core Collection) databases. We included only primary research that reported on GxE effects on vitamin D status using 25-hydroxyvitamin D as a biomarker. Sun exposure was the only environmental exposure identified in these studies. The quality assessment followed the Newcastle–Ottawa Scale for cohort studies. Seven studies were included in the final narrative synthesis. We evaluate the limitations and findings of the available GxE in vitamin D research and provide recommendations for future GxE research. The systematic review was registered on PROSPERO (CRD42021238081).
Vitamin D deficiency has been implicated in numerous human diseases leading to an increased interest in assessing vitamin D status. Consequentially, the number of requests for vitamin D measurement ...keeps dramatically increasing year-on-year. Currently, the recognised best marker of vitamin D status is the concentration of the 25-hydroxyvitamin D (25(OH)D₃) in the blood circulation. While providing an accurate estimate of vitamin D status at the point in time of sampling, it cannot account for the high variability of 25(OH)D₃ concentration. In this proof of concept study we set out to provide evidence that 25(OH)D₃ can be extracted from hair samples in a similar fashion to steroid hormones. Two of the authors (L.Z. and M.H.) provided hair samples harvested from the crown area of the scalp and the third author (E.L.) provided beard samples. These samples, cut into 1 cm lengths, were weighed, washed and dried. 25(OH)D was extracted using a previously published steroid hormones extraction procedure. Blood samples were taken from the subjects at the same time all tissue samples were analysed using liquid-chromatography mass spectrometry. Hair samples showed presence of quantifiable 25(OH)D₃ with concentrations ranging from 11.9⁻911 pg/mg. The beard sample had a concentration of 231 pg/mg. Serum levels of 25(OH)D₃ ranged from 72⁻78 nmol/L. The results presented here confirm the feasibility of measuring 25(OH)D₃ in hair samples. The findings warrant further validation and development and have the potential to yield valuable information relating to temporal trends in vitamin D physiology.
Abstract
Background
Vitamin D deficiency is highly prevalent across the globe. Existing studies suggest that a low vitamin D level is associated with more than 130 outcomes. Exploring the causal role ...of vitamin D in health outcomes could support or question vitamin D supplementation.
Methods
We carried out a systematic literature review of previous Mendelian-randomization studies on vitamin D. We then implemented a Mendelian Randomization–Phenome Wide Association Study (MR-PheWAS) analysis on data from 339 256 individuals of White British origin from UK Biobank. We first ran a PheWAS analysis to test the associations between a 25(OH)D polygenic risk score and 920 disease outcomes, and then nine phenotypes (i.e. systolic blood pressure, diastolic blood pressure, risk of hypertension, T2D, ischaemic heart disease, body mass index, depression, non-vertebral fracture and all-cause mortality) that met the pre-defined inclusion criteria for further analysis were examined by multiple MR analytical approaches to explore causality.
Results
The PheWAS analysis did not identify any health outcome associated with the 25(OH)D polygenic risk score. Although a selection of nine outcomes were reported in previous Mendelian-randomization studies or umbrella reviews to be associated with vitamin D, our MR analysis, with substantial study power (>80% power to detect an association with an odds ratio >1.2 for per standard deviation increase of log-transformed 25OHD), was unable to support an interpretation of causal association.
Conclusions
We investigated the putative causal effects of vitamin D on multiple health outcomes in a White population. We did not support a causal effect on any of the disease outcomes tested. However, we cannot exclude small causal effects or effects on outcomes that we did not have enough power to explore due to the small number of cases.
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