In the following sections, the ethical and statistical concerns are discussed with respect to each of the important aspects of the study design.
Exclusion of participants with skin type I (eligibility criterion: skin type II to IV).
Fitzpatrick skin types are widely used in photobiology as a measure of sun sensitivity. Skin type is assessed using a brief questionnaire (for example ) and categorised as I (very fair) to VI (very dark). There is considerable variability in the minimum erythemal dose (MED, the dose of UV radiation that causes a barely perceptible reddening of the skin) within each skin type category and overlap between the categories . The enhanced sun exposure advice given within the SEDS Study is for a change in the pattern rather than the overall amount of sun exposure. The sun exposure monitor provided to participants in the ESEA arm is set to the individual’s skin type. To allow for the variation in sensitivity to UV radiation within each Fitzpatrick skin type, each monitor is set conservatively to alarm well before the average MED for that skin type. Participants are requested to report any instance where they developed erythema after being outdoors and the sun exposure monitor did not alarm. In this situation, the participant would be instructed to enter one skin type lower into the monitor. Thus, skin type I is excluded from the study, to minimise the risk that participants will be sunburnt while following the ESEA guidelines.
Exclusion of participants with a 25(OH)D level less than 40 nmol/L (eligibility criterion: recent vitamin D result of 40–60 nmol/L)
To the best of our current knowledge, there is no harm in delaying treatment of people with a 25(OH)D level of 40–60 nmol/L for one year . If there is a causal association between vitamin D deficiency and disease risks, the increased risk appears to be primarily in those with very low 25(OH)D levels (e.g. <30 nmol/L) . Each participant in the SEDS Study has a one in four chance of being in the placebo vitamin D and SSEA group and will not receive any active treatment. Hence we have chosen a conservative cut-off of 40 nmol/L, below which there is stronger evidence that active treatment for vitamin D deficiency may be required.
Exclusion of participants at high risk of skin cancer
Participants with low 25(OH)D levels are likely to have had low recent sun exposure. If they follow the sun exposure advice for their intervention arm, they may receive a higher dose of UV radiation than would have otherwise occurred. Potential participants who report that they are being monitored due to a high risk for skin cancer, have had a previous diagnosis of melanoma or squamous cell carcinoma, or more than five basal cell carcinomas (BCCs) removed in the past five years, are thus excluded from participation. BCC is extremely common in adults in Australia  so that it is not practicable to exclude anyone who has had a single previous BCC diagnosed. The ESEA includes advice to always wear a hat and protect the face, neck and ears with sunscreen when outdoors, as most skin cancers arise in these areas .
Exclusion of medical conditions where sun exposure or vitamin D supplementation may have adverse effects
Although the doses of vitamin D supplementation used in the SEDS Study are relatively low, potential participants with a history of the following medical conditions are excluded from participation, since the intervention could adversely affect their health (or that of their offspring): sarcoidosis, history of renal calculi, uncontrolled endocrine disease, hepatic or renal disease, photosensitivity diseases such as systemic lupus erythematosus with cutaneous manifestations, pregnancy or lactation.
Doses of vitamin D supplementation
The United States Institute of Medicine (IOM) Recommended Dietary Allowance of vitamin D for adults aged up to 70 years with limited sun exposure is 600 IU/day . The current recommendation in Australia is 200–400 IU/day (depending on age), with a maximum dose of 3200 IU/day . In the SEDS Study, we have chosen to use the dose recommended by the IOM (i.e., 600 IU/day) as our lower reference point against which to assess the effectiveness of sun exposure in raising 25(OH)D levels, and an upper dose of 2000 IU/day as this has been previously shown to effectively raise 25(OH)D levels without evidence of toxicity over a prolonged period of administration .
Enhanced sun exposure advice (ESEA) as an intervention
Previous work has shown that the amount of the body surface area that is exposed to the sun strongly influences vitamin D production [29,30]. Prolonged sun exposure can result in degradation of vitamin D in the skin to non-biologically active photo-products . Thus, the ESEA focuses on short, frequent sun exposure, with as much skin exposed as is feasible for the circumstances. If longer periods in the sun are planned, participants are advised to use sun protection if the UV Index is 3 or more. The UV Index is available on daily weather forecasts on television, radio, internet, in most daily newspapers in Australia, and on the Cancer Council Australia website. This information is provided to participants in their sun exposure guidelines.
Enhancing the statistical power of the SEDS study
The study aims to recruit 228 participants in each group, spread evenly across the four study regions (west, east, north, and south, as described above). Assuming 20% attrition over the one year of the study, this sample size will have 90% power to show equivalence in the post-intervention mean serum levels of 25(OH)D, assuming that equivalence is plus or minus 1/3 of the standard deviation (that is, ± 5 nmol/L) .
Exclusion of individuals under 18 or over 64 years old (eligibility criterion: aged 18–64 years)
Restricting participation in the SEDS Study to a specific age group limits the generalisability of the findings, and thus requires careful consideration. Elderly people tend to have lower vitamin D status than younger people, possibly due to lower cutaneous stores of the precursor, 7-dehydrocholesterol . In addition, skin cancer incidence increases exponentially with increasing age . We considered that the risks for skin cancer may outweigh the benefits of vitamin D synthesis, for the doses of UV radiation required to achieve and maintain vitamin D sufficiency in older adults. Although there is no clearly defined age cut-off, we excluded people over the age of 64 years from participation in the SEDS Study. Participation in the study is limited to adults due to the greater difficulties involved in relation to consent, recruitment and taking blood from children (<18 years).
Exclusion of individuals with 25(OH)D level over 60 nmol/L (eligibility criterion: recent 25(OH)D result of between 40–60 nmol/L)
The change in 25(OH)D level following both exposure to UV radiation and vitamin D supplementation depends on the baseline 25(OH)D concentration [34,35]. Additionally, the increase in 25(OH)D level is not linear, and plateaus at approximately 70–80 nmol/L [36,37]. Participants with a recent 25(OH)D level of >60 nmol/L are excluded from participation, so as to maximise the evidence of the response to sun exposure or vitamin D supplementation.
Exclusion of individuals with skin type V or VI (eligibility criterion: skin type II–IV)
Although there is debate about whether more deeply pigmented skin produces less vitamin D following UV irradiation than paler skin, the weight of current evidence suggests that this does occur and is particularly evident for lower doses of UV radiation [34,38]. We have thus chosen to exclude individuals with skin types V and VI from the SEDS Study, although additional work is required to specifically study the needs of people with these darker skin types.
Exclusion of individuals currently taking vitamin D supplementation
The doses of vitamin D supplementation chosen are relatively low compared to those used in other supplementation trials. Individuals who are currently taking a daily multivitamin (containing more than 200 IU vitamin D3), are asked to switch to one containing no, or low dose, vitamin D in order to be eligible to participate in the Study. The aim is to avoid contamination across the groups, maintaining minimal supplemental vitamin D in the placebo arms and ensuring that the low-dose arm remains as a low-dose, intermediate group.
Multicentre trial–participants recruited from across Australia
The SEDS Study is recruiting Australia-wide in order to provide wide variation in levels of ambient solar UV radiation, as well as the amplitude of the seasonal variability, and temperature, which affects patterns of clothing and time outdoors. Australia spans a wide range of latitudinal zones, from Darwin at 12° South to Hobart at 43° South. This results in considerable variation in the typical sun exposure and doses of UV radiation. For example, at the end of June (Southern Hemisphere winter), the maximum UV Index in Darwin in the Northern Territory is around 8, compared to Kingston (15 km from Hobart) in Tasmania, which has a maximum UV Index of around 1. The SEDS Study aims to contribute to the evidence base for messages of optimal sun exposure (amount and pattern) under different climatic conditions, including temperature, humidity and ambient UV radiation. Australia provides a good location to assess this broad range of climatic conditions, within a homogeneous healthcare system and a population that is relatively homogeneous in terms of composition across different regions.
Challenges in study methodology
Recruiting nearly 1000 people across Australia with a recently measured 25(OH)D level within a specific range is challenging. Random selection from a population register is not feasible, unless the study then carries out screening for the 25(OH)D level. The main route of recruitment is through GPs who identify potential participants following vitamin D testing undertaken as part of routine clinical care. Research in general practice is known to be difficult due to the time pressures faced in this environment. We have therefore worked hard to initially elicit support and then to maintain engagement using the following methods.
To recruit GPs to assist with the SEDS Study, we use face-to-face meetings with GPs, their practice managers and practice nurses, our personal networks, academic units of general practice attached to universities and medical schools, faxes to regional GP mailing lists, advertisements in GP newsletters, conference flyers, and unannounced visits to general practices. The latter is the least productive, and face-to-face contact the most productive in terms of generating referral of potential participants.
The GPs and their medical practices are provided with information about the study aims, methods and how patients can be referred to the study. In some cases, and only with the permission of the GP, pathology providers have agreed to add a comment to the pathology report for patients with a serum 25(OH)D of 40–60 nmol/L stating that the patient may be eligible for the SEDS Study. GPs receiving the 25(OH)D result seek the patient’s consent to release his/her contact details to the SEDS Study team via fax, email or the SEDS website, including confirmation that the patient has agreed to the release of his/her contact details. To maximise participant recruitment and maintain GP interest and commitment to the Study, researchers visit practices in person throughout all study regions and provide regular study updates via email or post, including relevant publications.
Participants can also self-refer in response to media coverage, the study website (http://www.sedsstudy.org/), or the clinical trials register. However, many of these potential participants are not eligible because they have either not had a recent vitamin D test or are already being treated for vitamin D deficiency. Vitamin D testing is common in Australia, (there were 4 million tests in 2013–4) and has been subsidised by the government medical insurance agency, Medicare. We have used a mail out to a random sample of people who have recently claimed the rebate for a vitamin D test, inviting claimants to contact study personnel to discuss possible participation. We are thus using a multi-pronged approach to maximise recruitment to the SEDS Study.
Enhancing accurate data collection
Where possible, the SEDS Study uses validated questionnaires for data collection that can be completed online or in hard-copy. Tools to facilitate the accuracy and standardisation of data collection include online videos and a set of Frequently Asked Questions (FAQs). The online videos describe how to take an accurate measurement of waist circumference, how to use the two types of dosimeter, and also how to complete one of the more complex questionnaires. The FAQs provide guidance for each of the more complicated questionnaires, and are modified as new questions arise.
Participant compliance is known to be a challenge in clinical trials . To optimise compliance we contact participants weekly by SMS text message, email or telephone, to remind them to take their study medication and follow their sun exposure advice every day for the entire year. Each week the SMS focuses on one of the elements of the sun exposure guidelines specific to the participant’s intervention group. For the participants in the SSEA groups, these guidelines are the standard “Slip, Slap, Slop, Seek and Slide” messages used by Cancer Council Australia. Participants receiving the ESEA receive specially developed guidelines made to look and sound familiar: Skin (expose as much skin as possible), Short time (brief sun exposures), Slap (wear a hat), Slide (wear sunglasses), Safe (use the sun exposure monitor) and Stride (be physically active). In order to enhance compliance with the sun exposure guidelines, participants are provided with a postcard-sized magnet for the refrigerator that has the specific sun exposure guidelines in a simple, colourful and easy-to-read image so that participants will see the guidelines many times each day.
Participant retention over a 12-month period
Each participant is involved in the SEDS Study for one year. In addition to the weekly reminders, study personnel make regular contact by telephone or email. Packages are posted to the participants every three months for data collection, and blood collection forms are sent four times a year; these provide additional opportunities to engage with participants. The SEDS Study website has information about, and photographs of, the study team – since the researchers do not meet the participants, this is an opportunity to make the team as “real” as possible. In addition, a study Facebook page allows participants to communicate with the study team.
Participants who complete the entire 12 months of participation are entered into a draw for one of several shopping vouchers. Since the study will be ongoing over nearly two years, a draw is held for every 200 participants completing the SEDS Study.
Sun exposure for the management of mild vitamin D insufficiency
Using this intervention study design, the SEDS Study will test whether advice to change the pattern of sun exposure can effectively achieve and maintain vitamin D adequacy (serum 25(OH)D levels of 50 nmol/L or higher) over 12 months. We will also calibrate the effectiveness of ESEA against different doses of vitamin D supplementation. In secondary analyses we will examine actual sun exposure over one year (from questionnaire, diary and dosimeter data) in relation to vitamin D sufficiency, and according to a range of parameters including age, sex, body mass index and levels of physical activity. These findings will have direct clinical applicability for primary care physicians seeing community-dwelling patients with mild vitamin D insufficiency and needing to choose management options.
Separate effects of sun exposure and vitamin D on immune and cardio-metabolic function
At the completion of the SEDS Study we will measure, on the stored blood, levels of specific immune and cardio-metabolic markers for which there is past evidence from experimental studies that a vitamin D or a sun exposure effect is likely to be apparent. For immune function, these markers include DNA methylation of the FoxP3 gene as a measure of T regulatory cell number and function [40,41]; total and house dust mite-specific IgE levels [42-44]; varicella zoster IgG (King, unpublished data). Previous work on sun exposure, vitamin D and cardio-metabolic health suggests that the following markers are likely to show an effect of changes in vitamin D or exposure to the sun: fasting lipid profile [45-47]; fasting serum glucose [48-50]; fasting serum leptin and adiponectin [51-53]. The intervention study design has been deliberately chosen to allow us to examine whether ESEA (and higher sun exposure) and vitamin D supplementation (and measured 25(OH)D and vitamin D metabolites) have independent effects on these markers of immune function and cardio-metabolic health.
What is the potential value of the SEDS Study?
Research in Australia and New Zealand has shown that both health professionals [7,54] and the public  are confused about the health benefits and risks of vitamin D supplementation and sun exposure. The SEDS Study has been specifically designed to recruit a population sample to provide an evidence base to clarify some of the issues of concern.
Firstly the study aims to assess and quantify the effect of advice to change the pattern of sun exposure in achieving and maintaining vitamin D adequacy, compared to different doses of vitamin D supplementation. This is an outcome of direct value to clinicians managing vitamin D deficiency.
Secondly, the study builds on recent evidence to suggest that sun exposure and vitamin D may have independent effects on disease risks [10,11,55,56]. In these observational studies, although there is evidence of statistical independence, vitamin D status and sun exposure are closely inter-related, and measurement of both is subject to considerable error. It is difficult therefore to be confident of the existence or relative magnitude of any independent effects. The intervention study design is specifically being used in the SEDS Study to test these factors and to unravel some of the confusion surrounding vitamin D and sun exposure.