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EDITORIAL |
1 From Creighton University, Omaha, NE
2 Address reprint requests to RP Heaney, Creighton University, 601 North 30th Street, Suite 4841, Omaha, NE 68131. E-mail: rheaney{at}creighton.edu.
See corresponding article on page 616.
For the most part, the disorders that have shaped nutrition as a science have had 2 characteristics: each nutrient was the major factor in its cognate disease, and disease expression had short latency, which facilitated recognition of the connection between cause and effect. More recently, an extensive body of epidemiologic associations between nutrient intake and various outcomes has raised the possibility that insufficient nutrition may contribute to the burden of chronic disease. But true causal connections between specific nutrients and these other disorders have been hard to establish, partly because most chronic diseases are highly multifactorial and partly because they have long latency periods. Both factors make the evaluation of causality inherently difficult.
Vitamin D presents a good case in point. There has been an explosion of reports relating vitamin D status to various disorders in the past 10 y (1). Many of these disorders specifically afflict the aging population. This issue of the Journal contains another of these reports. Visser et al (2), from the Amsterdam Longitudinal Aging Study, report that the likelihood of nursing home admission was inversely related to baseline vitamin D status. The trend in risk was approximately linear up to the highest values measured (ie, >75 nmol/L). After various adjustments, persons with values <25 nmol/L had nearly 4 times the risk of being admitted to a nursing home as did persons with values >75 nmol/L. The true risk may be even higher, because some of the statistical adjustments involved factors through which vitamin D may be operating.
This finding has biological plausibility, inasmuch as low vitamin D status impairs lower-extremity function and contributes significantly to the risk of falling (3, 4). In these studies, as in the study by Visser et al, function improves in association with concentrations of 25-hydroxyvitamin D [25(OH)D] up to 80 nmol/L and perhaps even higher. More than 80% of the Amsterdam cohort had serum concentrations of 25(OH)D < 80 nmol/L; this finding is also supported by a still-growing body of studies showing that low vitamin D status is common.
In addition to the personal disaster for the persons concerned, institutionalization of the dependent elderly imposes staggering costs on society, which are destined only to increase as the population ages and family units become smaller. The high prevalence of vitamin D deficiency mandates that physicians assess and correct vitamin D status in their elderly patients (5).
However, the same high prevalence must cause us to ask why a global intervention should not be given serious consideration. Persons are, of course, always free to act on available information, but individual initiative is rarely an efficient way of changing public health status. Food fortification is an obvious alternative (7), but any such proposal bumps up squarely against the problem of proof. Most of the studies concerned (including the study by Visser et al) are observational in character. Do such studies constitute sufficient evidence for a population-level intervention?
The randomized controlled trial (RCT), which has become the gold standard for establishing the efficacy of pharmacologic agents, is poorly suited to the evaluation of nutritional effects, a fact that I believe many have been reluctant to acknowledge. Several important differences between nutrients and drugs lead to this conclusion. In addition to long latency and multifactorial causation for the diseases concerned, nutrients and drugs differ in 3 crucial respects. First, whereas a drug-free state exists that can be contrasted with a drug-added state, with respect to nutrients, the only contrast can be between different intakes, both usually well above zero. Second, most nutrients have what is known as threshold behavior, ie, some physiologic measure improves as intake rises up to a level of sufficiency, above which higher intakes produce no additional benefit. Third, most nutrients have beneficial effects on multiple tissues and organ systems, and thus a focus on a single or "primary" outcome measure, which is favored by RCTs, is often procrustean. As a consequence of the second point, investigators using the RCT design must contrast 2 groups of subjects, at least one of which has a distinctly inadequate intake of the nutrient concerned. Failure to do that, as occurred in the calcium arm of the Women's Health Initiative (WHI) (7, 8), constitutes an invalid test of the corresponding hypothesis. However, the assignment of subjects to an intake that is inadequate by current standards, for the span of time required to produce the necessary difference in serious outcomes, raises significant and probably insurmountable ethical problems (9).
Just such a dilemma may have been part of the explanation for the high calcium intake in the placebo group in the calcium arm of WHI. The median intake from the third National Health and Nutrition Examination Survey of women in the age range concerned was 
600 mg Ca/d, and the logical hypothesis would have been that the currently recommended calcium intake (1200 mg/d) would produce certain benefits not realizable at 600 mg/d. But both the state of the science at the time when WHI was designed and a multiplicity of National Institutes of Health Consensus Development Conference Reports made it effectively impossible for the WHI designers to impose a 600-mg limit on the control group's intake when National Institutes of Health policy statements had said that 600 mg/d was inadequate. Whatever the explanation, there was no low-calcium contrast group in WHI.
Unfortunately, the reports from WHI primarily stressed the outcome of the controlled intervention, as if calcium and vitamin D had been drugs, and tended to deemphasize the observational data that the study had also generated. Examples are the fact that, in addition to a baseline calcium intake in the participants nearly twice that predicted from the third National Health and Nutrition Examination Survey, the hip fracture rate was approximately half of that predicted from Medicare. No connection seems to have been made between these 2 departures from expectation. There was a similar lapse with respect to the connection between vitamin D intake and colon cancer. Whereas the designed low dose of vitamin D in WHI did not significantly alter colon cancer incidence, baseline vitamin D status was, in fact, significantly inversely related to cancer risk. The lowest 25(OH)D quartile had a risk 2.5 times that of the highest quartile. No actual contradiction exists between these findings, because the vitamin D input required to move subjects from the first quartile to the fourth quartile in WHI is now known to be 10 times the achieved dose (10).
Such circumstances raise 2 related questions: 1) to what extent should current standards of proof be relaxed for nutrient benefits? and 2) what alternative investigational design might be used to produce results that could be used as a basis for nutritional policy?
Public policy has long been comfortable in using a more relaxed standard of proof for potentially harmful effects. The studies leading to a food label for trans fats would not likely have been considered adequate to support the promotion of the use of trans fats (had the relation been the other way around). Nor do we require RCTs to set the cutoffs for various environmental toxins, from lead to polychlorinated biphenyl. Should the standard of proof be relaxed for benefit, as in the instance of a fortification program that elevates nutrient status (in this case vitamin D) to demonstrably safe intakes? If the balance of the potential for harm tilts in favor of fortification, then the answer should be "yes," irrespective of the level of evidence.
With respect to study design, there is one approach that offers a reasonably practicable alternative to the RCT, ie, the nonconcurrent cohort study. As are all cohort studies, it is prospective. It is "nonconcurrent" in the sense that the exposure to the various amounts of nutrient precedes the investigation; ie, the entering of subjects into study is done after the exposure but before any analysis. As does an RCT, it equalizes the placebo effect between the contrast groups (ie, there is essentially none in either group), but, as are other observational studies, it is subject to the effects of extraneous factors that cannot be randomized. To minimize the distortions introduced by such factors, all plausible confounders must be identified in advance of the investigation and then factored into the criteria (inclusion and exclusion) for assignment of participants to the groups in which the desired outcomes may be counted or measured. If done carefully, this approach can minimize the admission rate bias inherent in most observational study designs. However, because assignment to the contrast groups is not random, it is not possible to define exact probability limits to the differences that may emerge.
The foregoing approach could be readily evaluated in existing databases, but, whatever the study design, the problem of proof remains, and, as a consequence, a substantial potential for reduction in the burden of chronic disease hangs in the balance.
ACKNOWLEDGMENTS
The author had no personal or financial conflict of interest with the study by Visser et al.
REFERENCES
60 y. Am J Clin Nutr 2004; 80: 752–8.This article has been cited by other articles:
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  B. N Ames, J. C McCann, M. J Stampfer, and W. C Willett Evidence-based decision making on micronutrients and chronic disease: long-term randomized controlled trials are not enough Am. J. Clinical Nutrition, August 1, 2007; 86(2): 522 - 523. [Full Text] [PDF]
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 B. N. Ames Low micronutrient intake may accelerate the degenerative diseases of aging through allocation of scarce micronutrients by triage PNAS, November 21, 2006; 103(47): 17589 - 17594. [Abstract] [Full Text] [PDF]
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