Final Research Plan

Vitamin D Deficiency in Adults: Screening

January 24, 2019

Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

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The final Research Plan is used to guide a systematic review of the evidence by researchers at an Evidence-based Practice Center. The resulting Evidence Review will form the basis of the USPSTF Recommendation Statement on this topic.

The draft Research Plan was available for comment from October 25 until November 21, 2018 at 8:00 p.m., ET.

This figure is the analytic framework depicting the four key questions and the research approach that will guide the evidence review outlined in this research plan. In general, the figure illustrates the overarching and first key question of whether screening for vitamin D deficiency leads to reduced all-cause mortality; reduced incidence of fractures and falls; reduced incidence of cancer, cardiovascular disease, diabetes, dementia, autoimmune disease, and infections; improved physical functioning; and improved quality of life. The framework starts on the left and follows the intervention pathway for the population of interest, namely asymptomatic adults without underlying disorders of bone metabolism who are not known to be vitamin D deficient. Moving from left to right, the second key question examines whether any harms result from such screening. The third key question examines whether treating vitamin D deficiency leads to reduced all-cause mortality; reduced incidence of cancer, cardiovascular disease, diabetes, dementia, autoimmune disease, and infections; improved physical functioning; and improved quality of life. The fourth key question examines whether any harms result from such treatment.

Abbreviation: KQ=Key Question.

1. a. Does screening for vitamin D deficiency improve health outcomes?
    b. Does screening efficacy vary among patient subpopulations at higher risk for vitamin D deficiency (e.g., persons residing in institutions, persons with obesity, persons with low levels of sun exposure, or older adults) or vary by race/ethnicity?
2. What are the harms of screening for vitamin D deficiency?
3. a. Does treatment of vitamin D deficiency with vitamin D improve health outcomes?
    b. Does treatment efficacy vary among patient subpopulations at higher risk for vitamin D deficiency (e.g., persons residing in institutions, persons with obesity, persons with low levels of sun exposure, or older adults) or vary by race/ethnicity?
4. a. What are the harms of treatment of vitamin D deficiency with vitamin D?
    b. Do harms vary among patient subpopulations at higher risk for vitamin D deficiency (e.g., persons residing in institutions, persons with obesity, persons with low levels of sun exposure, or older adults) or vary by race/ethnicity?

Contextual questions will not be systematically reviewed and are not shown in the Analytic Framework.

  1. What are the various assays for measuring serum vitamin D (including total and free 25-hydroxyvitamin D and 1,25-dihydroxycholecalciferol), and what is known about the intermethod and interlaboratory variability of these assays?
  2. In observational studies, what is the association between vitamin D use or serum vitamin D levels and the incidence of selected health outcomes (i.e., mortality, fractures, falls, cardiovascular disease, cancer, diabetes, dementia, autoimmune disease, and infections)?
  3. In randomized, controlled trials, what is the effect of vitamin D treatment on selected intermediate outcomes (i.e., bone mineral density, blood pressure, glucose levels, lipid levels, and measures of physical or muscle strength)?

The Research Approach identifies the study characteristics and criteria that the Evidence-based Practice Center will use to search for publications and to determine whether identified studies should be included or excluded from the Evidence Report. Criteria are overarching as well as specific to each of the KQs.

The EPC will synthesize findings separately, where possible, based on the vitamin D serum level used to define deficiency (i.e., 20 ng/mL vs. 30 ng/mL). The EPC will also synthesize findings separately for community-dwelling vs. institutionalized populations.

  Include Exclude
Population KQs 1, 2: Nonpregnant adults age ≥18 years without known vitamin D deficiency

KQs 3, 4: Nonpregnant adults enrolled in studies based on a vitamin D deficiency <30 ng/mL; studies in which at least 90% of the study population have serum vitamin D levels below this threshold will also be included
  • Pregnant women
  • Persons with clinical signs of vitamin D deficiency
  • Studies in which participants are selected for a condition (e.g., osteoporosis, malabsorption, chronic kidney disease) that is associated with altered vitamin D levels or bone metabolism
  • Studies in which participants are selected for a specific clinical condition (e.g., depression, diabetes, infertility, multiple sclerosis) to assess the benefit of adding vitamin D to existing treatment
Intervention KQs 1, 2: Screening with serum 25-hydroxyvitamin D assay

KQs 3, 4: Treatment with oral or injectable vitamin D2 or D3 with or without calcium

 KQs 1, 2: Vitamin D−binding protein; 1,25-dihydroxycholecalciferol assay

KQs 3, 4: Food-based interventions; vitamin D analogs, multivitamins with a vitamin D component, sun, or ultraviolet exposure
Comparison KQs 1, 2: No screening

KQs 3, 4: Placebo or no treatment, or usual care

 KQs 1, 2: Head-to-head comparisons of different serum vitamin D assays

KQs 3, 4: Head-to-head comparisons of vitamin D doses or formulations
Outcomes KQs 1, 3:
  • All-cause mortality
  • Incidence of falls
  • Incidence of fractures
  • Incidence of other health outcomes, such as diabetes, cardiovascular disease, cancer, dementia, autoimmune disease, and infections
  • Quality of life, as measured by a validated instrument
  • Self-reported physical functioning, as measured by a validated instrument

KQ 2: Anxiety and labeling

KQ 4: Toxicity, renal harms (e.g., nephrolithiasis), and other adverse events

 KQs 1, 3: Changes in serum vitamin D levels, intermediate physiologic outcomes (bone mineral density, osteoporosis, blood pressure, cholesterol, glucose, muscle mass), behavioral outcomes (changes in diet or physical activity), or physical fitness/muscle strength measures (e.g., grip strength, timed up and go test, distance walked test, step test, balance test)

KQs 2, 4: None
Timing KQ 1: Outcomes measured at 8 weeks or longer after screening

KQ 3: Treatment intervention lasting at least 8 weeks; outcomes measured at 8 weeks or longer after start of treatment

KQs 2, 4: Any duration and any timing of measurement

 KQ 1: Outcomes measured at less than 8 weeks after screening

KQ 3: Ttreatment intervention lasting less than 8 weeks or outcomes measured at less than 8 weeks after start of treatment

KQs 2, 4: None
Settings Countries categorized as “very high” on the 2016 Human Development Index (as defined by the United Nations Development Programme); primary care settings and settings generalizable to primary care institutional settings (e.g., nursing homes) Countries categorized as less than “very high” on the Human Development Index
Study design KQs 1, 3: CCTs, RCTs, and nested case-control studies within RCTs; systematic reviews of CCTs or RCTs with a similar scope to this review

KQs 2, 4: CCTs, RCTs, cohort studies, case-control studies, and systematic reviews with a similar scope to this review

 Editorials, narrative reviews, letters to the editor, and study designs not listed as specifically included (e.g., case reports, case series, studies without a comparison group)
Language English language Languages other than English
Study quality Good- and fair-quality studies (i.e., studies with low risk of bias or some concerns for bias) Poor-quality studies (i.e., studies with high risk of bias)

Abbreviations: CCT=controlled clinical trial; RCT=randomized, controlled trial.

The draft Research Plan was posted for public comment on the USPSTF Web site from October 25, 2018 to November 21, 2018. In response to comments, the USPSTF modified KQs 1b, 3b, and 4b to include race/ethnicity as a characteristic of interest. In addition, the USPSTF added dementia, autoimmune diseases, and infections to the list of eligible health outcomes. The EPC clarified its analytic approach for KQ 3 with respect to stratifying analyses by threshold used to define deficiency (20 ng/mL vs. 30 ng/mL) and by population (community-dwelling vs. institutionalized). Several comments requested that the USPSTF expand the population to include children and pregnant women and persons with symptoms of deficiency, and expand the scope of the interventions to include sun exposure, food-based interventions, and comparative effectiveness trials; these populations and interventions are considered to be outside the scope of this review. Other comments requested the inclusion of intermediate outcomes; the USPSTF will address them as a contextual question.