Comparing the Evidence from Observational Studies and Randomized Controlled Trials for Nonskeletal Health Effects of Vitamin D
Abstract
:1. Introduction
- Basal nutrient status must be measured, used as an inclusion criterion for entry into study, and recorded in the report of the trial.
- The intervention (change in nutrient exposure or intake) must be large enough to change nutrient status and must be quantified.
- The change in nutrient status produced in trial participants must be measured by validated laboratory analyses and recorded in the report of the trial.
- The hypothesis to be tested must be that a change in nutrient status (not just a change in diet) produces the sought effect.
- Conutrient status must be optimized to ensure that the test nutrient is the only nutrition-related, limiting factor in the response.
2. Results
2.1. Diseases and Outcomes
2.1.1. Autoimmune Diseases
2.1.2. Cancers
Cancers—RCTs
- With findings based on vitamin D dose rather than achieved 25(OH)D concentration, enrolled participants would include those with relatively high 25(OH)D concentrations, lowering the chances of detecting reduced cancer incidence.
- Higher 25(OH)D concentration lower cancer mortality risks more strongly than it reduces cancer incidence rates [24].
- Vitamin D simply has no significant effect on cancer incidence.
Cancers—Geographical Ecological Studies
- They are easy to conduct because they can be based on publicly available data.
- They include many participants.
- No participants are omitted.
- The analysis can include many other cancer risk–modifying factors averaged at the population level.
- They can be used to locate cancer hot spots globally.
- Analyses can be performed for different ethnicities and races and can be repeated for different periods.
Cancer—Mendelian Randomization Study
2.1.3. Cardiovascular Disease
Cardiovascular Disease—RCTs
Cardiovascular Disease—Mendelian Randomization
2.1.4. COVID-19
2.1.5. Diabetes Mellitus Type 2
Diabetes Mellitus Type 2—RCTs
Diabetes Mellitus Type 2—Mendelian Randomization
2.1.6. Hypertension
Hypertension—RCTs
Hypertension—Mendelian Randomization
2.1.7. Mortality, All-Cause
2.1.8. Respiratory Tract Infections
2.1.9. Alzheimer’s Disease and Other Dementias
2.1.10. Major Depressive Disorder
2.1.11. Pregnancy Disorders and Neonatal Outcomes
Pregnancy Outcomes in Interventional Studies
3. Discussion
- Strength of association
- Consistency in findings
- Temporality, that is, the risk factor must be experienced before the event
- Biological gradient, that is, dose–response relationship.
- Plausibility, for example, mechanisms that can explain the relationship
- Coherence with known biological facts
- Experiment, for example, RCT
- Analogy with related associations
- 9.
- Accounting for confounding factors
- 10.
- Accounting for bias such as publication bias
- 11.
- Quality of study design
4. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Study | Change in 25(OH)D | Incidence, RR or HR (95% CI) | Mortality, RR or HR (95% CI) | Author |
---|---|---|---|---|
Observational Studies | ||||
Harvard Health Professionals Follow-Up Study, all cancer | 10 ng/mL | RR = 0.83 (0.74–0.92) | RR = 0.71 (0.60–0.83) | Giovannucci et al., [65] |
Adult patients living in Olmsted County, Minnesota, all less skin cancer | <12 ng/mL | HR = 1.56 (1.03–2.36) | HR = 2.35 (1.01–5.48) | Johnson et al., [66] |
Meta-analysis, breast cancer | High vs. low | RR = 0.92 (0.83–1.02) | RR = 0.58 (0.40–0.85) | Kim et al., [67] |
VITAL, exclude first 2 years | Vitamin D treatment vs. placebo | HR = 0.94 (0.83–1.06) | HR = 0.75 (0.59–0.96) | Manson et al., [8] |
RCTs | ||||
RCTs, meta-analysis | All participants | (12 RCTs) SRR = 0.99 (0.04–1.03) | (6 RCT) SRR = 0.92 (0.82–1.03) | Keum et al., [24] |
RCTs, meta-analysis | Normal-weight individuals | (1 RCT) SRR = 0.76 (0.60–0.94) | Keum et al., [24] |
Mean 25(OH)D Concentration (ng/mL) | aHR | aHR Adjusted | aHR Adjusted, 95% CI Low | aHR Adjusted, 95% CI High | Author |
---|---|---|---|---|---|
12.5 | 1.20 | 1.39 | 1.01 | 1.90 | Melamed et al., [79] |
21.0 | 0.88 | 1.02 | 0.80 | 1.32 | |
28.3 | 0.83 | 0.96 | 0.75 | 1.24 | |
36.0 | 1.00 | 1.16 | 1.16 | 1.16 | |
7.00 | 2.36 | 1.17 | 4.75 | Ginde et al. [78] | |
15.0 | 1.54 | 1.01 | 2.34 | ||
25.0 | 1.26 | 0.85 | 1.88 | ||
35.0 | 1.20 | 0.79 | 1.81 | ||
45.0 | 1.00 | 1.00 | 1.00 | ||
7.00 | 2.64 | 3.55 | 2.27 | 2.96 | Semba et al., [80] |
13.0 | 1.68 | 2.26 | 1.03 | 5.02 | |
21.0 | 2.19 | 2.95 | 1.42 | 6.20 | |
30.0 | 1.00 | 1.35 | 1.35 | 1.35 | |
15.0 | 1.52 | 1.79 | 1.52 | 2.11 | Liu et al., [81] |
25.0 | 1.09 | 1.29 | 1.11 | 1.51 | |
35.0 | 1.00 | 1.18 | 1.18 | 1.18 |
Country | Mean 25(OH)D (ng/mL) | Follow-Up (yrs) | Vascular Dementia, HR (95% CI) for 10 ng/mL Increase | Alzheimer’s, HR (95% CI) for 10 ng/mL Increase | Author |
---|---|---|---|---|---|
US | 12 | 5.6 | 0.57 (0.34–0.97) | 0.61 (0.41–0.93) | Littlejohns et al., [141] |
France | 14 | 11.4 | 0.60 (0.47–0.78) | 0.60 (0.47–0.78) | Feart et al., [142] |
Finland | 16 | 17.0 | 0.77 (0.62–0.92) | Knekt et al., [143] | |
Denmark | 16 | 21.0 | 0.91 (0.82–1.02) | Afzal et al., [130] | |
Netherlands | 20 | 13.3 | 0.77 (0.63–0.95) | 0.73 (0.59–0.93) | Licher et al., [144] |
US | 22 | 16.6 | 0.93 (0.79–1.07) | Schneider et al., [145] | |
US | 25 | 9.0 | 1.01 (0.88–1.14) | 1.09 (0.95–1.12) | Karakis et al., [146] |
Sweden | 28 | 12.0 | 1.04 (0.93–1.17) | 0.95 (0.81–1.12) | Olsson et al., [140] |
Outcome | Setting | Outcome | Finding | Author |
---|---|---|---|---|
Birth weight | ||||
Cesarean delivery, primary | Maternal 25(OH)D < 15 vs. >15 ng/mL | aOR = 3.8 (95% CI, 1.7–8.6) | Merewood et al., [162] | |
Cesarean delivery, primary | Maternal 25(OH)D < 15 vs. >15 ng/mL | aOR = 2.0 (95% CI, 1.2–3.3) | Scholl et al., [163] | |
Gestational diabetes | Meta-analysis, 29 studies | <20 vs. >20 ng/mL | OR = 1.39 (95% CI, 1.20–1.60) | Hu et al., [164] |
Gestational diabetes | Meta-analysis, 27 studies | >20 vs. >30 ng/mL | OR = 1.26 (95% CI, 1.13–1.41) | Milajerdi et al., [165] |
Preeclampsia | Hospital study | Early-onset severe preeclampsia, 10-ng/mL increase in 25(OH)D | aOR = 0.37 (95% CI, 0.22–0.62) | Robinson et al., [171] |
Preeclampsia | Meta-analysis, 13 studies | Comparison of 25(OH)D | OR = 0.57 (95% CI, 0.51–0.65) | Serrano-Diaz et al., [172] |
Preeclampsia | Meta-analysis, 11 studies | 25(OH)D < 30 vs. >30 ng/mL | OR = 1.44 (95% CI, 1.26–1.64) | Aguilar-Cordero et al., [160] |
Preterm delivery | Hospital study | 25(OH)D < 20 vs. >40 ng/mL, <16 wks | OR = 3.8 (95% CI, 1.4–10.7) | Wagner et al., [166] |
Preterm delivery | Meta-analysis, 16 studies | 25(OH)D < 20 vs. >20 ng/mL | OR = 1.25 (95% CI, 1.13–1.38) | Zhou et al., [167] |
Preterm delivery | Open-label vitamin D supplementation | 25(OH)D > 40 vs. >20 ng/mL | SES adjusted OR = 0.41 (95% CI, 0.24–0.72) | McDonnell et al., [14] |
Infant outcomes | ||||
Brain dysfunction | Language impairment in childhood vs. maternal 25(OH)D at 18 weeks pregnancy | 6-18 vs. 29-62 ng/mL | aOR = 1.97 (95% CI, 1.00–3.93, p < 0.05) | Whitehouse et al., [168] |
Brain dysfunction | Risk of ADHD, meta-analysis, 5 studies | High vs. low 25(OH)D | OR/RR = 0.72 (95% CI, 0.59–0.89) | Garcia-Serna et al., [169] |
Respiratory dysfunction | Risk of asthma vs. maternal 25(OH)D, 11 studies | High vs. low 25(OH)D | OR = 0.78 (95% CI, 0.69–0.89) | Shi et al., [170] |
Respiratory dysfunction | Risk of wheeze vs. maternal 25(OH)D, 14 studies | High vs. low 25(OH)D | OR = 0.65 (95% CI, 0.54–0.79) | Shi et al., [170] |
Outcome | Setting | Finding | Author |
---|---|---|---|
Birth weight, low | Review of 5 RCTs | RR = 0.55 (95% CI, 0.35–0.87) | Palacios et al., [174] |
Birth weight | Review of 11 RCTs | Increased weight, mean difference = 114 g (95% CI, 63–165 g) | Gallo et al., [173] |
Cesarean delivery, primary | Review of 6 RCTs | OR = 0.9 (95% CI, 0.7–1.2) | Gallo et al., [173] |
Cesarean delivery in Iran | Review of 5 RCTs | RR = 0.61 (95% CI, 0.44–0.83) | Saha and Saha, [175] |
Gestational diabetes | Review of 4 RCTs | RR = 0.51 (95% CI, 0.27–0.97) | Palacios et al., [174] |
Preeclampsia | Review of 27 RCTs | RR = 0.37 (95% CI, 0.26–0.52) | Fogacci et al., [176] |
Preterm delivery | Review of 17 RCTs | RR = 0.70 (95% CI, 0.49–1.00) | Kinshella et al., [177] |
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Grant, W.B.; Boucher, B.J.; Al Anouti, F.; Pilz, S. Comparing the Evidence from Observational Studies and Randomized Controlled Trials for Nonskeletal Health Effects of Vitamin D. Nutrients 2022, 14, 3811. https://doi.org/10.3390/nu14183811
Grant WB, Boucher BJ, Al Anouti F, Pilz S. Comparing the Evidence from Observational Studies and Randomized Controlled Trials for Nonskeletal Health Effects of Vitamin D. Nutrients. 2022; 14(18):3811. https://doi.org/10.3390/nu14183811
Chicago/Turabian StyleGrant, William B., Barbara J. Boucher, Fatme Al Anouti, and Stefan Pilz. 2022. "Comparing the Evidence from Observational Studies and Randomized Controlled Trials for Nonskeletal Health Effects of Vitamin D" Nutrients 14, no. 18: 3811. https://doi.org/10.3390/nu14183811
APA StyleGrant, W. B., Boucher, B. J., Al Anouti, F., & Pilz, S. (2022). Comparing the Evidence from Observational Studies and Randomized Controlled Trials for Nonskeletal Health Effects of Vitamin D. Nutrients, 14(18), 3811. https://doi.org/10.3390/nu14183811