Evidence-based nutrition: is proof of efficacy

for nutrients too high?

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evidence-based nutrition (EBN), has seemingly swallowed EBM [evidence-based medicine]
whole without either asking how well it might fit, or adapting it to the unique features of the
nutrition context evidence-based nutrition (EBN), has seemingly swallowed EBM whole without
either asking how well it might fit, or adapting it to the unique features of the nutrition context.

This passage is from a new paper by Robert Heaney, Connie Weaver, and Jeffrey
Blumbergtitled EBN (Evidence-Based Nutrition) Ver. 2.0 (1).
This shorter paper more concisely summarizes a paper published late last year titled Evidencebased criteria in the nutritional context (2) from a workshop gathering in 2008 in which
Blumberg, Heaney, Weaver attended along with Michael Huncharek, Theresa Scholl,Meir
Stampfer, Reinhold Vieth, and Steven Zeisel who also contributed.
EBN, influencing nutrient recommendation policies generally at the population level, affects all of
us in some way or another. Below I summarize these important papers that raise this question:
Is the same high level of certainty required regarding the nutrient intake recommendations to
prevent disease as is needed for drugs used to treat disease? (2)

What are EBM and EBN?

EBM is a hierarchy of evidence levels developed to standardize the interpretations of medical
treatments. The RCT (Randomized, placebo-Controlled Trials) are rightly considered the
highest quality design as they infer strong causal relationships. Studies that do not randomize,
observational research, case studies, and expert opinions follow in evidence rank. EBM draws
conclusions on treatments based on the level and amount of research.
As Blumberg et al. describe (2), these rules were adopted by the nutritional science field in the
1990s with the 1997 Dietary Reference Intakes and the 2005 Dietary Guidelines for Americans.
The FDA published EBN criteria for nutrient claims here, and the American Dietetic Association
has criteria here. So how does EBM differ from EBN?
(i) medical interventions are designed to cure a disease not produced by their absence, while
nutrients prevent dysfunction that would result from their inadequate intake; (ii) it is usually not
plausible to summon clinical equipoise for basic nutrient eects, thus creating ethical
impediments to many trials;(iii) drug eects are generally intended to be large and with limited
scope of action, while nutrient eects are typically polyvalent in scope and, in eect size, are

typically within the noise range of biological variability; (iv)drug eects tend to be monotonic,
with response varying in proportion to dose, while nutrient eects are often of a sigmoid
character, with useful response occurring only across a portion of the intake range; (v) drug
eects canbe tested against a nonexposed (placebo) contrast group, whereas it is impossible
and/or unethical to attempt a zero intake group for nutrients; and (vi) therapeutic drugs are
intended to be ecacious within a relatively short term while the impact of nutrients on the
reduction of risk of chronic disease may require decades to demonstrate a dierence with
significant implications for the feasibility of conducting pertinent RCTs.
In contrast to drug interventions where the null hypothesis is that there is no health benefit,
essential nutrients must have some health benefit, otherwise they would not be defined as such.
Thus the questions instead must be:
(i) What is the full spectrum of dysfunctions or diseases produced by low intake of a nutrient?
and (ii) How high an intake is required to ensure optimal physiological function or reduced risk
for disease across all body systems and endpoints?
The effects of nutrients on diseases can take decades to manifest as measurable outcomes,
which vary by individual and organ system, etc. The Recommended Dietary Allowances (RDAs)
generally focus on single organ system endpoints; often defining amounts for disease
prevention of the disease in which the consensus is strongest on (they term this the index
disease). Vieth and Heaney are prominent vitamin D researchers, so it fits that they provide the
example that the amount of D needed to reduce risk of falls and fractures (nonindex) is greater
than that needed to prevent rickets or osteomalacia (index diseases).
A very recent example was the Institute of Medicines review of calcium and vitamin D, which
concluded that nobody needs to be taking more than 600 IU of vitamin D unless you are over 70
years old. The report dismissed the research links between vitamin D and calcium and disease
as not conclusive enough except for bone health. Vieth, William Grant and John Cannell have
publicly responded so far in protest, the middle writing that over 100 diseases have some link to
vitamin D in research, and the latter writing that Heaneys (and 13 other vitamin D researchers)
input was not considered. Just today (March 29) a debate occurred at the Harvard School of
Public Health between Walter Willett, Bess Dawson-Hughes, JoAnn Manson, and Patsy
Brannon (the latter 2 were on the IOM committee that analyzed the vitamin D research). A
video is posted here. Dr. Manson brought up the point a couple times that randomized
controlled trials are simply not available yet for many of the vitamin D/disease links that
observational studies show. Dr. Willett questioned whether these ultra-conservative
recommendations should be made, or if we should go with the best evidence that we have now
instead of demanding the RCTs (and in fact Willett and Dr. Dawson-Hughes essentially both
questioned how the IOM arrived to some of their efficacy and risk conclusions). The IOM
recommendations for D is a prime example of taking EBN too far. Of course many of the vitamin

D links require more study, but we shouldnt ignore them and establish recommendations far too
low to the public until the evidence builds up to a semi-arbitrary level of confidence.
Just because RCTs on nonindex diseases do not find significant differences with regard to
disease outcomes between groups does not mean they dont exist. RCTs for example may be
more likely to contain control groups with intakes too close to the typical intake (as true
placebo/no-intake groups arent possible), transforming studies into testing is more better.
Graphically (1):
It is not ethical to use the RCT design to test if a low amount of a nutrient causes disease,
because it would be inevitable that some of the subjects in the study would develop the disease.
This is where observational studies greatly aid, as they can test (without intervening and
causing harm) in a spectrum of subjects who are consuming low to high amounts of a nutrient
and assess disease endpoints. They link to Hills seminal 1965 paperthat give general
guidelines to assess causation from observational research.
To go back to their questioning if we need the amount of certainty for nutrient intake
recommendations to prevent disease as that for drugs to treat disease, Blumberg et al.suggest
that confidence in nutrient recommendations can be made at a lesser certainty than what is
established for drugs (and nutrients with a high benefit:risk ratio may require less certainty of
efficacy). Unlike for drugs where irrefutable proof of efficacy should be demanded, decisions for
nutrient recommendations should be instead based on if the evidence shows an inadequate (or
excessive) intake shows probable harm. Apart from benefit:risk ratio, they also list some other
factors that influence confidence include consequences of type II error (relationships that are
real but not yet conclusively proven), deployment cost, opportunity cost, and multiplicity of lines
supporting the evidence.
Within RCTs, the interactions of nutrients must be considered with regard to certainty. The
authors give several examples in the Supporting Information, like calcium and vitamin D on
bone, or interactions between B vitamins and the endogenous antioxidant network. If RCTs are
designed without taking existing knowledge into account, they may produce a false result.
I have to interject my own slight skepticism here, focusing on one nutrient that Heaney, Weaver,
and Blumberg bring up in their newest paper (1). They note a 24 year delay in mandatory folate
fortification because of a level of confidence that is too high, which may have saved at least
6,000 infants from neural tube defects. But they do not mention the growing concern that with
the reduction of this index disease secondary consequences are arising: the form used for
fortification increases blood concentrations of unmetabolized folic acid and natural folates
and some research links this with certain cancers and cognitive impairment. What may have
been a scientific triumph in the reduction of NTDs may have unintentionally led to an increased
in nonindex diseases with a lack of foresight. What if many times more people now will develop

diseases than what are prevented in number of NTD cases? Maybe thousands of cancer cases
were prevented with the extended delay prior to fortification. Although it seems logical that
nutrients not require the same level of confidence as drugs, this may be difficult to generalize to
each nutrient. Even though the above hypothetical graphics incorporate a benefit:risk ratio, will
we be able to accurately estimate this from current data? Perhaps the folate example can be
considered in the context of new recommendations, but wouldnt it then increase conservatism
among researchers and call for a higher evidence level?
In the Supporting Information, the authors argue that although nutrient toxicity of certainly a
concern (they use the example that mercury may now accompany omega-3 sources), it
generally isnt to the same degree of drugs, which are usually more targeted and potent in their
effects. By their model, this greater safety net would allow for more aggressive
recommendations based on a lesser certainty. So now what should be done about folate? If
lesser evidence is needed to give a nutrient recommendation that may benefit health, the same
logic should go the other way- it seems a reasonable body of research exists on the concerns of
folate fortification, so we should be more proactive about it. Weighing the systemic effects of
each nutrient and together in different contexts (diseases, genetic interactions, etc) is invariably
difficult, though I think with the constant improvement in research design, technology use, and
building on existing knowledge, fewer cases of concern will likely surprise us (like that of the
vitamin D deficiency epidemic or that of folic acid and NTDs, and Willett gives the example of
how long it took for us to discover the negative effects of partial hydrogenation on health- almost
100 years! But research moves much quicker now.). But those examples are not what future
research will bring us- it is the subtle effects from nutrients on our chronic health status that are
still largely ill understood, and the importance that nutrigenomics brings to the table in taking
mass micro-measurements. How should this data be gathered and interpreted if we demand
each subtlety be held to RCTs, which generally only measure the group averages? Individual
differences will require different design considerations as well. Keith Grimaldi gives a nice
example of this (and other examples of concerns these papers bring up) in his post: Is it the
vitamins or the trials? Also see So vitamins fail again, this time its folate and B12. Really?.
Of another concern, would a reduction in a necessary confidence level in nutrient
recommendations increase an already problematic health claims problem by food and
supplement companies? This is not something that was brought up in the articles, but it would
seem inevitable. Food companies already often piggy back recommendations by regulatory
bodies (like the low fat phase or advertising specific vitamins), so if they loosen the confidence
constraints they may be further abused; this seems to fall within the realm of public health.
Blumberg et al. have considered future research needs and suggest that beside measurements
like drug and alcohol use, physical activity level, etc that are commonly measured as covariates
in studies, DNA (especially for SNP analysis- which definitivelyinfluences many study variables),
fasting and postprandial serum/plasma (for metabolomicsand proteomics analysis), urine,

relevant tissue samples, and archiving primary data would be ideal so that re-analysis of study
results can be done once new biological relationships are discovered and newer technology is
available. Intake biomarkers should be gathered so assess compliance and inter-individual
bioavailability variation, and different forms of nutrients should be considered in reviews and
meta-analyses. They note that the inclusion of more than one endpoint (into a global index) in
studies would improve the ability of studies to see if a nutrient has subtle effects that may not be
statistically significant individually. With regard to meta-analyses, they suggest that metaanalyses that only use RCTs miss differing design features [that] can provide insight into
variability in the physiologic resasons for heterogeneity. Considering the covariates is crucial to
using meta-analyses to examine not only what the average effect of a nutrient is, but how much
the effect can vary in different studies. Such considerations lead Heaney et. al (1) to write:
It is likely that most reviews of nutrients will come to erroneous conclusions if they are not
performed by individuals who are content experts in the relevant biology.
These arguments make sense and are important problems that many scientists may not
currently consider. The risk of making nutrient recommendations based on less than conclusive
proof should be considered against not making recommendations when a relationship is real but
conclusive proof is still lacking (which seems to be the case for vitamin D right now). Their
concluding paragraph puts it perfectly:
To sum up, it is both appropriate and necessary to make recommendations in the absence of
definitive proof, particularly when it is recognized that not changing an existing recommendation
is itself a recommendation. That fact cannot be side stepped. With nutrients, the question is
always not whether buthow much?
If there is anything I hope readers take from this post it is that you not only have to carefully
consider research methodologies but how they are interpreted in the bigger picture based on
predefined levels of confidence. Regulatory bodies can set evidence-based criteria how they
choose, leading to differing results between them. Is it a wonder why there are so many
different recommendations on nutrients/foods, not even considering so many other influences?
Consensus are extremely difficult to reach (see the vitamin D debate video linked in this post
for a perfect current example).

References
1. Robert P. Heaney, Connie M. Weaver, & Jeffrey Blumberg (2011). EBN (Evidence-Based
Nutrition) Ver. 2.0 Nutrition Today : 10.1097/NT.0b013e3182076fdf

2. Blumberg J, Heaney RP, Huncharek M, Scholl T, Stampfer M, Vieth R, Weaver CM, & Zeisel
SH (2010). Evidence-based criteria in the nutritional context. Nutrition reviews, 68 (8), 478-84
PMID: 20646225