Vitamin D-disease associations vary with the type of study – RCT, Observational, MR - July 2022

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

Advances in Nutrition, Vol 13, #4, July 2022, Pages 1044–1062, https://doi.org/10.1093/advances/nmab142
Di Liu, Xiaoni Meng, Qiuyue Tian, Weijie Cao, Xin Fan, Lijuan Wu, Manshu Song, Qun Meng, Wei Wang, Youxin Wang

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.
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Discussion (from PDF)

The present umbrella review integrated the results of MR studies and RCTs to avoid the inevitable bias or reverse causality of observational studies. The results indicated that low vitamin D concentrations were a causal risk factor for all-cause mortality, Alzheimer’s disease, hypertension, schizophrenia, and type 2 diabetes. These findings were combined with the results of meta-analyses of RCTs, and the data indicated that vitamin D supplementation decreased the risk for all-cause mortality. The present study is the first attempt to evaluate associations of low vitamin D concentration and vitamin D supplementation with health outcomes by combining the findings of meta-analyses of observational studies, meta-analyses of RCTs, and MR studies. Unlike a previous umbrella review of systematic reviews and meta-analyses of observational studies and RCTs that assessed associations ofvitamin D with multiple health outcomes (25), the present study also combined and compared the findings reported by MR studies.
Comparison of the findings of both MR studies and meta-analyses of observational studies with the data reported by meta-analyses of RCTs indicated significant associations of low vitamin D concentration and vitamin D supplementation with all-cause mortality (136, 214, 278). Associations of low vitamin D concentration with Alzheimer’s disease, hypertension, schizophrenia, and type 2 diabetes were significant only in meta-analyses of observational studies and in MR studies, and meta-analyses of RCTs reported little or no effect of vitamin D supplementation onthe prevention or treatment of these diseases. Overall, assessments of associations of vitamin D deficiency and vitamin D supplementation with the same diseases yielded conflicting results, and the effects of vitamin D deficiency and vitamin D supplementation on all-cause mortality were consistent. These findings suggested that vitamin D supplementation has a long-term effect on the prevention of overall mortality. In addition, future studies should focus on the impact of low vitamin D concentration and vitamin D supplementation on the incidence of the diseases and on healthy life expectancy. Importantly, genetic variants related to vitamin D deficiency, especially variants of the vitamin D receptor, binding protein, and metabolizing enzyme 1-a-hydroxylase, may contribute to these divergent results. Additionally, increasing evidence suggests that genetic variation may impact variable results reported in the case of vitamin D supplementation in various trials (308,309), indicating that additional studies are required to assess the roles of genetic variations as potential determinants of beneficial and negative effects of over-the- counter supplements used for health promotion. Future studies need to focus on the combined effects of genetic variations and vitamin D supplementation on Alzheimer’s disease, hypertension, schizophrenia, and type 2 diabetes. Notably, some subjects without vitamin D deficiency but with genetic variations suffered from these diseases, and in some subjects with genetic variations, vitamin D intervention had no effect. Future RCTs should consider interindividual differences and identify whether certain subgroups of individuals may benefit from vitamin D supplementation in the context of disease outcomes. The purpose of MR studies should not be limited to simple exploration of whether low vitamin D concentration is a causative factor or a biomarker of a disease and should also aim to suggest effective interventions that consider both genetic variations and low vitamin D concentration.

Moreover, associations of low vitamin D concentration and vitamin D supplementation with 14 overlapping health outcomes were supported by evidence that was not fully consistent. These outcomes included all-cause mortality in prostate cancer patients, small for gestational age, and sustained virologic response to hepatitis C virus, which showed a significant association in both meta-analyses of observational studies and meta-analyses of RCTs. Inconsistent evidence was presented for other outcomes. Inconsistencies between observational and randomized evidence may be due to the low frequency of these outcomes, which can limit the conclusions of randomized trials, thus necessitating additional validation by MR studies.
MR is rapidly becoming a powerful method for inferring causality based on routinely conducted observational studies. The present study aimed to investigate the current status and limitations of MR studies for exploring the causal associations of vitamin D concentrations with disease outcomes. Most of the findings of the present umbrella review indicated that genetic risk factors related to vitamin D concentration did not predict disease risk. These null findings may be explained by 4 reasons. First, the findings could have been influenced by a bias of weak IVs because variability of vitamin D concentration explained by single nucleotide polymorphisms was 1.61-2.84%. Therefore, additional genome-wide association studies are needed to systematically explore genetic variants related to vitamin D concentration. Moreover, it is important to investigate network relationships between genetic variants and other molecular intermediates (e.g., DNA methylation, gene expression, metabolites, and metagenomic information) in vitamin D deficiency to understand the molecular mechanism related to vitamin D concentration, including the application of systems biology and pharmacogenomics. Second, these null findings suggested that associations between vitamin
D concentration and diseases can be attributed to a reverse causation bias. Additional bidirectional MR studies are needed to prove this hypothesis and are expected to identify interventions aiming to reduce the prevalence of low vitamin D concentrations. Third, MR studies consider lifelong effects of genetic variations on diseases; however, the association of vitamin D concentrations with disease outcomes may vary over time and are not constant. Thus, evaluations are limited due to the cross-sectional observational nature of current MR studies. Therefore, MR studies should incorporate some follow-up data to evaluate the effects of vitamin D concentrations on various diseases and to investigate the changes in the effects of genetic variants over time on these diseases. Finally, a previous study demonstrated that vitamin D supplementation was effective only in subjects with baseline 25(OH)D concentrations of no more than 30 nmol/L, suggesting that associations between the 25(OH)D concentration and disease outcomes may be nonlinear (310-312). The MR analysis included an assumption of linearity (313), suggesting that nonlinear relationships could not be tested and could have supported the null hypothesis of the lack of an effect of 25(OH)D concentration on the diseases. Therefore, the null findings indicated a possible lack of linear causal associations of 25(OH)D concentrations with the diseases. Nonlinear MR studies are needed to prove this hypothesis and are expected to explore the real effects of the vitamin D deficiency on disease risk. Thus, we hope to contribute to more reliable evaluations of MR findings.
The present study has several limitations. First, the risk of type I errors may be increased due to testing multiple outcomes; however, this risk is generally acceptable considering the exploratory nature of umbrella reviews. Second, selected studies could have been heterogeneous due to the variable methodological quality of meta-analyses. The diagnostic criteria used for low vitamin D concentration and outcomes could have influenced estimated effects and increased between-study heterogeneity. In addition, most included meta-analyses were at high risk of bias, which might decrease the robustness of statistical analyses. The studies did not control for confounding factors that could have mediated associations between vitamin D concentration and outcomes because this information was often unavailable in published meta-analyses. Additionally, some potential outcomes for vitamin D concentration and vitamin D supplementation have not been subjected to meta-analyses at present. Notably, comparisons of the results included evidence from MR studies that assessed the effects of vitamin D deficiency on outcomes, which was largely negative or inconclusive due to a bias ofweakIVs. Comparison of the results has to account for differences in the duration and timing of exposure to vitamin D. For example, vitamin D concentrations can be influenced by various factors, such as exposure, sunlight, altitude, and race, potentially leading to unidentified biases. Considering these caveats, the main strengths of this umbrella review include a topically comprehensive literature search, inclusion of a large body of evidence, and systematic quantitative and qualitative approaches used to assess the quality of available evidence.

Conclusions (from PDF)

Low vitamin D concentrations are a causal factor for multiple noncommunicable chronic diseases. Accordingly, vitamin D supplementation is a promising strategy with long-term preventive effects on these diseases and thus decreases all cause mortality. However, the current vitamin D supplementation strategy might not be an efficient intervention factor for these diseases, suggesting that new strategies are highly needed to improve the intervention outcomes. Considering the existence of high risk bias in original meta-analyses, the finding might not robust enough, and needs confirming in future studies. Future studies should focus on personalized interventions for diseases involving considerations of genetic variations in combination with low vitamin D concentrations.

Vitamin D Life – Some reasons why Meta-analyses might not find Vitamin D benefits

Unfortunately, a meta-analysis will frequently fail to consider one or more of the following

1. Dose size (Some gave the same importance to 40 IU as 10,000 IU)
2. Dose frequency (Some ignore differences between daily, weekly, monthly, and annual dosing)
3. Duration, (Some gave same importance to 4 weeks as 4 years)
      It takes 3 to 12 months for vitamin D levels to come to a new plateau
      and it often takes months for the body to then utilize it
4. Pre-existing Vitamin D blood level
      adding vitamin D does not provide much benefit if person alrady has a good level
5. Cofactors (Most meta-analyses ignore the importance of Magnesium, Omega-3, Vitamin K2, etc)
6. Type of Vitamin D - D3 far better than D2
7. Those with poor guts need a different type of vitamin D
8. Those who are Obese need 2.5 X more vitamin D
9. Many drugs, such as statins deplete vitamin D or the Magnesium needed by Vitamin D
10. For some health problems pulsed vitamin D, not daily, is far better (gets over possible Vitamin D receptor limitation)

Vitamin D Life has 641 Meta-analyses in 50+ health categories

6+ Vitamin D Life items have MENDELIAN in the title

This list is automatically updated

A few Vitamin D Life items that have OBSERVATIONAL in their title

Comparing Vitamin D Randomized controlled Trials and Observational studies – Sept 2022 Dr. Grant
Vitamin D and COVID-19 - observational studies found it helps, never hurts - Campbell Oct 31, 2020
Off topic: For proof: Random Controlled and Observational Trials should agree– May 2013
Can Observational Studies be as good as Random Controlled Trials for Vitamin D

Mendelian randomization - Feb 2022

https://doi.org/10.1038/s43586-021-00092-5   Download the PDF from Vitamin D Life

Absract: "Mendelian randomization (MR) is a term that applies to the use of genetic variation to address causal questions about how modifiable exposures influence different outcomes.
The principles of MR are based on Mendel’s laws of inheritance and instrumental variable estimation methods, which enable the inference of causal effects in the presence of unobserved confounding.
In this Primer, we outline the principles of MR, the instrumental variable conditions underlying MR estimation and some of the methods used for estimation.
We go on to discuss how the assumptions underlying an MR study can be assessed and describe methods of estimation that are robust to certain violations of these assumptions.
We give examples of a range of studies in which MR has been applied, the limitations of current methods of analysis and the outlook for MR in the future.
The differences between the assumptions required for MR analysis and other forms of epidemiological studies means that MR can be used as part of a triangulation across multiple sources of evidence for causal inference."