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In 2014, the United States Preventive Services Task Force (USPSTF) concluded that among community-dwelling asymptomatic adults aged 18 years and older, there was insufficient evidence (ie, I statement) to assess the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic adults.1 Over the past 7 years, many randomized clinical trials (RCTs) have evaluated vitamin D supplementation for improving primary or secondary outcomes of cardiovascular disease, cancer, diabetes, depression, bone health, and falls,2-8 necessitating a reevaluation of whether screening for vitamin D insufficiency might be worthwhile. The evidence is still not there to inform this decision.9,10 Screening is the routine evaluation of an asymptomatic population with the goal of detection of a disease, when the natural course of that disease can be altered by early intervention. The benefits of screening in a population need to outweigh any potential harms that might arise from false positive tests, inappropriate downstream testing, and overtreatment of so-called pseudodisease.11 Thus, the rationale for screening a broad population by measuring blood 25-hydroxyvitamin D (25[OH]D) levels would be to identify a deficiency state, with the expectation that eliminating the deficiency in individuals (through an intervention) will improve health. In epidemiological studies, low blood levels of 25(OH)D have consistently been a factor strongly associated with many health outcomes, such as depression, fractures, frailty, falls, diabetes, hypertension, cardiovascular diseases, cancer, and others.7 However associations do not equal causation, and low 25(OH)D status might reflect a poorer health status in general owing to reverse causation or confounding by other health or behavioral factors.7 For example, individuals with obesity, reduced outdoor physical activity, and less healthy diets are more likely to have lower 25(OH)D levels. Importantly, high quality RCTs have not found that supplementation with vitamin D meaningfully mitigates these outcomes.2-7 Even the benefit of vitamin D on bone health and musculoskeletal outcomes has been challenged,5,12 and its efficacy may depend on whether concomitant calcium supplementation is given.13 While many of these RCTs did not specifically enroll individuals with a documented deficiency state, post hoc subgroup analyses failed to find outcome benefit for vitamin D supplementation among those with low 25(OH)D levels (ie, <20 ng/mL [to convert to nanomoles per liter, multiply by 2.496]), with less data available for the subgroup of those below 12 ng/ml.2,3,7 Might the commonly used vitamin D measure be the wrong measure? In the blood, 25(OH)D is the major circulating form and reflects both endogenous and exogenous sources. It has a half-life of 2 to 3 weeks and has long been considered to be the best marker of vitamin D status,14 although 25(OH)D is largely biologically inert. The activated form, 1,25-dihydroxyvitamin D (also known as calcitriol), confers the biological activity through the binding of the vitamin D nuclear receptor in the small intestine, kidneys, and other tissues. However, given its short half-life and tightly controlled regulation, calcitriol levels do not adequately reflect vitamin D stores. Furthermore, it has been challenging to measure 25(OH)D accurately, with substantial overestimation or underestimation of 25(OH)D levels with the most commonly used immnoassays.15 This has improved with implementation of the Vitamin D Standardization Program and, currently, liquid chromatographymass spectrometry is the criterion standard, although it is unknown how broadly this is used across commercial laboratories. Additionally, 25(OH)D circulates predominately in the bound form, with + Related article at jama.com