Power determination in vitamin D randomised control trials and characterising factors affecting it through a novel simulation-based tool

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.

Association of changes in lipid levels with changes in vitamin D levels in a real-world setting

“…By comparison, the 41 randomized clinical trials included in the meta-analysis comprised a total of only 3434 participants. A recent simulation study highlights the importance of power of the study in vitamin D randomised control trials 21 . Second, we investigated the associations with both increased vitamin D levels and decreased vitamin D levels, an investigation that is not feasible for prospective clinical studies or not done in observations studies before.…”

Circulating 25-hydroxyvitamin D and survival outcomes of colorectal cancer: evidence from population-based prospective cohorts and Mendelian randomisation

“…Our MR analysis added evidence that vitamin D supplementation may lead to limited benefits in terms of survival outcomes for CRC patients. It could also be possible that the lack of evidence from RCTs was due to insufficient study sample size, study duration, and dose of supplementation [ 42 , 43 ]; the lack of evidence from MR studies could be due to the variance of vitamin D leveraged by genetic instruments was generally low [ 44 ]. Our previous MR analyses targeting CRC risk have challenged the protective effect of 25-OHD against carcinogenesis, which implied the effect on cancer progression could also be small [ 2 , 45 ].…”

Comprehensive Analysis of Seasonal and Geographical Variation in UVB Radiation Relevant for Vitamin D Production in Europe

“…On a separate but very important note, understanding seasonal changes in UVB and vitamin D is also important for interpreting findings from vitamin D randomized controlled trials [ 45 ], because seasonal fluctuation can undermine the trial power and drive null-findings [ 46 , 47 ].…”