Archive for the ‘The Nutrition Story’ Category

The whacko suggestion by Hope Warshaw on DiabetesHealth that people with diabetes should increase their carbohydrate intake — I don’t know whether she was serious or just trying to infuriate — obviously generated a rather large response, especially on the DiabetesHealth website itself.  I was writing my own post on the issue when the editor Nadia Al-Samarrie published a piece which seems to have added to the discord. I decided to bypass the argument and I posted the following letter to her suggesting a way to introduce more information and fewer bad vibes.

==============================================================

Dear Nadia,

I understand that publishing a popular site requires one to be provocative and I think you can see that many people had a strong response to Hope Warshaw’s article and your response.  I think you will agree however that this is a serious matter and I want to suggest a mechanism for bringing the science out for the general public.  I am suggesting a discussion between opposing points of view, less a debate that than a presentation of facts although one implementation might be to have a kind of jury of impartial scientists to present summaries.  I would suggest that you and I be organizers and if DiabetesHealth would be one of the sponsors, I feel sure that I would be able to provide other sponsors. It would, of course, be imperative for the American Diabetes Association and the USDA Advisory committee to participate (send or endorse discussants) to establish that recommendations for people with diabetes conform to some kind of “sunshine law.”

The details of such a meeting could be worked out but as a starting point, I would suggest something along the lines of the following.

There would be two panels, one who maintains that a low-carbohydrate diet (definitions to be agreed upon in advance) is the default diet, that is, the one to try first, for both type 1 and type 2 diabetes and metabolic syndrome.  The other would conform to the very restricted view on such diets (only for weight loss, concerns about heart disease or kidney disease or whatever).

There would be, say, four representatives on each panel endorsed, again, by the ADA and USDA, DiabetesHealth and by the Nutrition and Metabolism Society.

Because of the voluminous literature, each side would specify ten papers in the literature, popular writings or book sections (max 30 pages each).  Discussion would be restricted to these sources.

Participants would meet before hand to set up preliminary procedures to avoid a free-for-all or any “defenestration.”

Variations might include a second day in which both panels took questions from the public or press.

I feel sure that such a meeting would go a long way towards reducing the palpable bad feelings and I am sure you agree that the enemy is diabetes and related diseases and not people with other opinions.  I would be glad to discuss, on the phone, how we can get started.

Best Regards,

Richard David Feinman

“These results suggest that there is no superior long-term metabolic benefit of a high-protein diet over a high-carbohydrate in the management of type 2 diabetes.”  The conclusion is from a paper by Larsen, et al. [1] which, based on that statement in the Abstract, I would not normally bother to read; it is good that you have to register trials and report failures but from a broader perspective, finding nothing is not great news and just because Larsen couldn’t do it, doesn’t mean it can’t be done.  However, in this case, I received an email from International Diabetes published bilingually in Beijing: “Each month we run a monthly column where choose a hot-topic article… and invite expert commentary opinion about that article” so I agreed to write an opinion. The following is my commentary:

“…no superior long-term metabolic benefit of a high-protein diet over a high-carbohydrate ….” A slightly more positive conclusion might have been that “a high-protein diet is as good as a high carbohydrate diet.”  After all, equal is equal. The article is, according to the authors, about “high-protein, low-carbohydrate” so rather than describing a comparison of apples and pears, the conclusion should emphasize low carbohydrate vs high carbohydrate.   It is carbohydrate, not protein, that is the key question in diabetes but clarity was probably not the idea. The paper by Larsen, et al. [1] represents a kind of classic example of the numerous studies in the literature whose goal is to discourage people with diabetes from trying a diet based on carbohydrate restriction, despite its intuitive sense (diabetes is a disease of carbohydrate intolerance) and despite its established efficacy and foundations in basic biochemistry.  The paper is characterized by blatant bias, poor experimental design and mind-numbing statistics rather than clear graphic presentation of the data. I usually try to take a collegial approach in these things but this article does have a unique and surprising feature, a “smoking gun” that suggests that the authors were actually aware of the correct way to perform the experiment or at least to report the data.

Right off, the title tells you that we are in trouble. “The effect of high-protein, low-carbohydrate diets in the treatment…” implying that all such diets are the same even though  there are several different versions, some of which (by virtue of better design) will turn out to have had much better performance than the diet studied here and, almost all of which are not “high protein.” Protein is one of the more stable features of most diets — the controls in this experiment, for example, did not substantially lower their protein even though advised to do so –and most low-carbohydrate diets advise only carbohydrate restriction.  While low-carbohydrate diets do not counsel against increased protein, they do not necessarily recommend it.  In practice, most carbohydrate-restricted diets are hypocaloric and the actual behavior of dieters shows that they generally do not add back either protein or fat, an observation first made by LaRosa in 1980.

Atkins-bashing is not as easy as it used to be when there was less data and one could run on “concerns.” As low-fat diets continue to fail at both long-term and short-term trials — think Women’s Health Initiative [2] — and carbohydrate restriction continues to show success and continues to bear out the predictions from the basic biochemistry of the insulin-glucose axis  [3], it becomes harder to find fault.  One strategy is to take advantage of the lack of formal definitions of low-carbohydrate diets to set up a straw man.  The trick is to test a moderately high carbohydrate diet and show that, on average, as here, there is no difference in hemoglobin A1c, triglycerides and total cholesterol, etc. when compared to a higher carbohydrate diet as control —  the implication is that in a draw, the higher carbohydrate diet wins.  So, Larsen’s low carbohydrate diet contains 40 % of energy as carbohydrate.  Now, none of the researchers who have demonstrated the potential of carbohydrate restriction would consider 40 % carbohydrate, as used in this study, to be a low-carbohydrate diet. In fact, 40 % is close to what the American population consumed before the epidemic of obesity and diabetes. Were we all on a low carbohydrate diet before Ancel Keys?

What happened?  As you might guess, there weren’t notable differences on most outcomes but like other such studies in the literature, the authors report only group statistics so you don’t really know who ate what and they use an intention-to-treat (ITT) analysis. According to ITT, a research report should include data from those subjects that dropped out of the study (here, about 19 % of each group). You read that correctly.  The idea is based on the assumption (insofar as it has any justification at all) that compliance is an inherent feature of the diet (“without carbs, I get very dizzy”) rather than a consequence of bias transmitted from the experimenter, or distance from the hospital, or any of a thousand other things.  While ITT has been defended vehemently, the practice is totally counter-intuitive, and has been strongly attacked on any number of grounds, the most important of which is that, in diet experiments, it makes the better diet look worse.  Whatever the case that can be made, however, there is no justification for reporting only intention-to-treat data, especially since, in this paper, the authors consider as one of the “strengths of the study … the measurement of dietary compliance.”

The reason that this is all more than technical statistical detail, is that the actual reported data show great variability (technically, the 95 % confidence intervals are large).  To most people, a diet experiment is supposed to give a prospective dieter information about outcome.  Most patients would like to know: if I stay on this diet, how will I do.  It is not hard to understand that if you don’t stay on the diet, you can’t expect good results.  Nobody knows what 81 % staying on the diet could mean.  In the same way, nobody loses an average amount of weight. If you look at  the spread in performance and in what was consumed by individuals on this diet, you can see that there is big individual variation Also, being “on a diet”, or being “assigned to a diet” is very different than actually carrying out dieting behavior, that is, eating a particular collection of food.  When there is wide variation, a person in the low-carb group may be eating more carbs than some person in the high-carb group.  It may be worth testing the effect of having the doctor tell you to eat fewer carbs, but if you are trying to lose weight, you want them to test the effect of actually eating fewer carbs.

When I review papers like this for a journal I insist that the authors present individual data in graphic form.  The question in low-carbohydrate diets is the effect of amount of carbohydrate consumed on the outcomes.  Making a good case to the reader involves showing individual data.  As a reviewer, I would have had the authors plot each individual’s consumption of carbohydrate vs for example, individual changes in triglyceride and especially HbA1c.  Both of these are expected to be dependent on carbohydrate consumption.  In fact, this is the single most common criticism I make as reviewer or that I made when I was co-editor-in chief at Nutrition and Metabolism.

So what is the big deal?  This is not the best presentation of the data and it is really hard to tell what the real effect of carbohydrate restriction is. Everybody makes mistakes and few of my own papers are without some fault or other. But there’s something else here.  In reading a paper like this, unless you suspect that something wasn’t done correctly, you don’t tend to read the Statistical analysis section of the Methods very carefully (computers have usually done most of the work).  In this paper, however, the following remarkable paragraph jumps out at you.  A real smoking gun:

  • “As this study involved changes to a number of dietary variables (i.e. intakes of calories, protein and carbohydrate), subsidiary correlation analyses were performed to identify whether study endpoints were a function of the change in specific dietary variables. The regression analysis was performed for the per protocol population after pooling data from both groups. “

What?  This is exactly what I would have told them to do.  (I’m trying to think back. I don’t think I reviewed this paper).  The authors actually must have plotted the true independent variable, dietary intake — carbohydrate, calories, etc. — against the outcomes, leaving out the people who dropped out of the study.  So what’s the answer?

  • “These tests were interpreted marginally as there was no formal adjustment of the overall type 1 error rate and the p values serve principally to generate hypotheses for validation in future studies.”

Huh?  They’re not going to tell us?  “Interpreted marginally?”  What the hell does that mean?  A type 1 error refers to a false positive, that is, they must have found a correlation between diet and outcome in distinction to what the conclusion of the paper is.  They “did not formally adjust for” the main conclusion?  And “p values serve principally to generate hypotheses?”  This is the catch-phrase that physicians are taught to dismiss experimental results that they don’t like.  Whether it means anything or not, in this case there was a hypothesis, stated right at the beginning of the paper in the Abstract: “…to determine whether high-protein diets are superior to high-carbohydrate diets for improving glycaemic control in individuals with type 2 diabetes.”

So somebody — presumably a reviewer — told them what to do but they buried the results.  My experience as an editor was, in fact, that there are people in nutrition who think that they are beyond peer review and I had had many fights with authors.  In this case, it looks like the actual outcome of the experiment may have actually been the opposite of what they say in the paper.  How can we find out?  Like most countries, Australia has what are called “sunshine laws,” that require government agencies to explain their actions.  There is a Australian Federal Freedom of Information Act (1992) and one for the the state of Victoria (1982). One of the authors is supported by NHMRC (National Health and Medical Research Council)  Fellowship so it may be they are obligated to share this marginal information with us.  Somebody should drop the government a line.

Bibliography

1. Larsen RN, Mann NJ, Maclean E, Shaw JE: The effect of high-protein, low-carbohydrate diets in the treatment of type 2 diabetes: a 12 month randomised controlled trial. Diabetologia 2011, 54(4):731-740.

2. Tinker LF, Bonds DE, Margolis KL, Manson JE, Howard BV, Larson J, Perri MG, Beresford SA, Robinson JG, Rodriguez B et al: Low-fat dietary pattern and risk of treated diabetes mellitus in postmenopausal women: the Women’s Health Initiative randomized controlled dietary modification trial. Arch Intern Med 2008, 168(14):1500-1511.

3. Volek JS, Phinney SD, Forsythe CE, Quann EE, Wood RJ, Puglisi MJ, Kraemer WJ, Bibus DM, Fernandez ML, Feinman RD: Carbohydrate Restriction has a More Favorable Impact on the Metabolic Syndrome than a Low Fat Diet. Lipids 2009, 44(4):297-309.


The big news in the low carb world is that Consumer Reports has published, for the first time, faint praise for the Atkins diet. However, the vision one might have of CR employees testing running shoes on treadmills doesn’t really apply here. They did not put anybody on a diet, even for a day. They didn’t have to. They have the standards from the government. Conform to the USDA Guidelines and CR will give you thumbs up. It probably doesn’t matter since, these days, most people buy a food processor by checking out the reviews on the internet — there are now many reviews online of what it’s like to actually be on a low-carbohydrate diet, so rather than follow CR’s imaginings of what it’s like, you can check out what users say — Jimmy Moore, Tom Naughton and Laura Dolson together get about 1.5 million posts per month with many tests and best buy recommendations. What caught my eye, though, is the ubiquitous Dean Ornish; the ratio of words written about the Ornish diet to the number of people who actually use it is probably closing in on a googol (as it was originally spelled). The article says: “to lose weight, you have to burn up more calories than you take in, no matter what kind of diet you’re on. ‘The first law of thermodynamics still applies,’ says Dean Ornish, M.D.

That’s how I got into this field. My colleague Gene Fine, and I published our first papers in nutrition on the subject of metabolic advantage and thermodynamics and we gave ourselves credit for reducing the number of people invoking laws of thermodynamics. “Metabolic advantage” refers to the idea that you can lose more weight, calorie-for-calorie on a particular diet, usually a low-carbohydrate diet. (The term was used in a paper by Browning to mean the benefits in lipid metabolism of a low-carbohydrate diet, but in nutrition you can re-define anything you want and you don’t have to cite anybody else’s work if you don’t want to). The idea of metabolic advantage stands in opposition to the idea that “a calorie is a calorie” which is, of course, the backbone of establishment nutrition and all our woe. As in the CR article, whenever the data show that a low-carbohydrate diet is more effective for weight loss, somebody always jumps in to say that it would violate the laws of thermodynamics. Those of us who have studied or use thermodynamics recognize that it is a rather difficult subject — somebody called it the physics of partial differential equations — and we’re amazed at how many experts have popped up in the nutrition field.

Finding the right diet doesn’t require knowing much thermodynamics but it is an interesting subject and so I’ll try to explain what it is about and how it’s used in biochemistry. The physics of heat, work and energy, thermodynamics was developed in the nineteenth century in the context of the industrial revolution — how efficiently you could make a steam engine operate was a big deal.  Described by Prigogine as the first revolutionary science, it has some interesting twists and intellectual connections. The key revolutionary concept is embodied tin the second law which describes the efficiency of physical processes.  It has broad philosophical meaning.  The primary concept, the entropy, is also used in communication and  the content of messages in information theory.  The entropy of a message is, in one context, how much a message has been garbled in transmission.  The history of thermodynamics also has some very strange characters, besides me and Gene, so I will try to describe them too.

First, we can settle the question of metabolic advantage, or more precisely, energy inefficiency. The question is whether all of the calories in food are available for weight gain or loss (or exercise) regardless of the composition of the diet. Right off, metabolic advantage is an inherent property of higher protein diets and low carbohydrate diets. In the first case, the thermic effect of feeding (TEF) is a measure of how many of the calories in food are wasted in the process of digestion, absorption, low-level chemical transformation, etc. TEF (old name: specific dynamic action) is well known and well studied. Nobody disputes that the TEF can be substantial for protein, typically 20 % of calories. It is much less for carbohydrate and still less for fat. So, substituting any protein for either of the other macronutrients will lead to energy inefficiency (the calories will be wasted as heat). A second unambiguous point is that in the case of low-carbohydrate diets, in order to maintain blood glucose, the process of gluconeogenesis is required. You learn in biochemistry courses that it requires a good deal of energy to convert protein (the major source for gluconeogenesis) into glucose.

So, right off, metabolic advantage or energy inefficiency is known and measurable. Critics of carb restriction as a strategy admit that it occurs but say that it is too small in a practical sense to be worth considering when you are trying to lose weight. These are usually the same people who tell you that the best way to lose weight is through accumulation of small changes in daily weight loss by reducing 100 kcal a day or something like that. In any case, there is a big difference between things that are not practical or have only small effects and things that are theoretically impossible. If metabolic advantage were really impossible theoretically, that would be it. We could stop looking for the best diet and only calories would count. Since we know energy inefficiency is possible and measurable, shouldn’t we be trying to maximize it.  But what is the story on thermodynamics? What is it? Why do people think that metabolic advantage violates thermodynamics? What is their mistake? More specifically, doesn’t the first law of thermodynamics say that calories are conserved? Well, there is more than one law of thermodynamics and even the first law has to be applied correctly. Let me explain. (Note in passing that the dietary calorie is a physical kilocalorie (kcal; 1000 calories).

There are four laws of thermodynamics. Two are technical. The zeroth law says, in essence, that if two bodies have the same temperature as a third, they have the same temperature as each other. This sounds obvious but, in fact, it is an observational law — it always turns out that way. The law is necessary to make sure everything else is for real. If anybody ever finds an experimental case where it is not true, the whole business will come crashing down. The third law describes what happens at the special condition known as the absolute zero of temperature. In essence, the zeroth and third laws, allow everything else to be calculated and practical thermodynamics like bioenergetics pretty much assumes it in the background.

The second law is what thermodynamics is really about — it was actually formulated before the first law — but since the first law is usually invoked in nutrition, let’s consider this first. The first law is the conservation of energy law. Here’s how it works: thermodynamics considers systems and surroundings. The thing that you are interested in — living system, a single cell, a machine, whatever, is called the system — everything outside is the surroundings or environment. The first law says that any energy lost by the system must be gained by the environment and any energy taken up by the system must have come from the environment. Its application to chemical systems, which is what applies to nutrition, is that we can attribute to chemical systems, a so-called internal energy, usually written with symbol U (so as not to confuse it with the electrical potential, E). In thermodynamics, you usually look at changes, and the first law says that you can calculate ΔU, the change in U of a system, by adding up the changes in heat added to the system and work done by the system (you can see the roots of thermo in heat machines: we add heat and get work). In chemical systems, the energy can also change due to chemical reactions. Still, if you add up all the changes in the system plus the environment, all the heat, work and chemical changes, the energy is neither created nor destroyed. It is conserved.

Now, why doesn’t the first law apply to nutrition the way Ornish thinks it does? To understand this, you have to know what is done in chemical thermodynamics and bioenergetics, (thermo applied to living systems). If you want to. In nutrition, you can make up your own stuff. But, if you want to do what is done in chemical thermodynamics, you focus on the system itself, not the system plus the environment. So, from the standpoint of chemical thermodynamics, the calories in food represent the heat generated by complete oxidation of food in a calorimeter.

In a calorimeter, the food is placed in a small container with oxygen under pressure and ignited. The heat generated is determined from the increase in temperature of the water bath. (Before the food measurement, we determine the heat capacity of the water bath, that is, how much heat it takes to raise the temperature). The heat is how we define the calories in the food. The box around the sample in the figure shows that we are measuring the heat produced by the system, not the system plus the environment, that is, not applying the first law. If you applied the first law, the calories associated with the food would be zero, because any heat lost in combustion of the food would show up in the water bath of the calorimeter. The calories per gram of carbohydrate would be 0 instead of 4, the calories per gram of fat would be 0 not 9, etc. So, in studying reactions in chemical thermodynamics, energy is not conserved, it is dissipated. When systems dissipate energy, the change is indicated with a minus sign, so for oxidation of food, generally: ΔU < 0. So, no, the first law does not apply. That’s one of the reasons that “a calorie is not a calorie.”
There is an additional point that we assumed in passing. In chemical thermodynamics, the energy goes with the reaction, not with the food. It is not like particle physics where we give the mass of a particle in electron-volts, a measure of energy, because of E=mc2. What this means, practically, is that the 4 kcal per gram of carbohydrate is for the reaction of complete oxidation. Do anything else, make DNA, make protein and all bets are off.
The bottom line is that, contrary to what is usually said, thermodynamics does not predict energy balance and we should not be surprised when one diet is more or less efficient than another. In fact, the question to be answered is why energy balance is ever found. “A calories is a calorie” is frequently what is observed (although there is always a question as to how we make the measurement). The answer is that insofar as there is energy balance, it is a question of the unique behavior of living systems, not physical laws. Two similar subjects of similar age and genetic make-up may, under the right conditions, respond to different diets so that most of what they do is oxidize food and the contributions of DNA or protein synthesis, growth, etc. may be similar and may cancel out so that the major contribution to energy exchange is the heat of combustion.
But thermodynamics is really not about the first law which, while its history is a little odd, it is not revolutionary. Intellectually, the first law is related to conservation of matter. Thermodynamics is about the second law. The second law says that there is a physical parameter, called the entropy, almost always written S, and the change in entropy, ΔS, in any real process, always increases. In ideal, theoretical processes, ΔS may be zero, but it never goes down. In other words, looking at the universe, (any system and its surroundings), energy is conserved but entropy increases. The first law is a conservation law but the second law is a dissipation law. We identify the entropy with the organization, order or information in a system. Systems proceed naturally to the most probable state. In one of the best popular introductions to the subjects, von Baeyer’s Warmth Disperses and Time Passes, entropy is described in terms of the evolution of the organization of his teenage daughter’s room.  To finish up on calorimeters, though, there is Lavoisier’s whole animal calorimeter.

One of Lavoisier’s great contributions was to show that combustion was due to a combination with oxygen rather than the release of a substance, then known as the phlogiston. Lavoisier had the insight that in an animal, the combination of oxygen with food to produce carbon dioxide was the same kind of process. The whole animal calorimeter was a clever way to show this. The animal is placed in the basket compartment f. The inner jacket, b, is packed with ice. The outer jacket, a, is also packed with ice to keep the inner jacket, cold. The heat generated by the animal melts the ice in the inner jacket which is collected in container, Fig 8. Lavoisier showed that the amount of carbon dioxide formed was proportional to the heat generated as it would be if an animal were carrying out the same chemical reactions that occur, for example, in burning of charcoal. “La vie est donc une combustion.” His collaborator in this experiment was the famous mathematician Laplace and people sometimes wonder how he got a serious mathematician like Laplace to work on what is, well, nutrition. It seems likely that it was because Laplace owed him a lot of money.

“In the Viking era, they were already using skis…and over the centuries, the Norwegians have proved themselves good at little else.”

–John Cleese, Norway, Home of Giants.

With the 3-foot bookshelf of popular attacks on the low-fat-diet-heart idea it is pretty remarkable that there is only one defense.  Daniel Steinberg’s Cholesterol Wars. The Skeptics vs. The Preponderance of Evidence is probably more accurately called a witness for the prosecution since low-fat, in some way or other is still the law of the land.

The Skeptics vs. the Preponderance of Evidence

The Skeptics vs. the Preponderance of Evidence

The book is very informative, if biased, and it provides an historical perspective describing the difficulty of establishing the cholesterol hypothesis. Oddly, though,  it still appears to be very defensive for a witness for the prosecution.  In any case, Steinberg introduces into evidence the Oslo Diet-Heart Study [2] with a serious complaint:

“Here was a carefully conducted study reported in 1966 with a statistically significant reduction in reinfarction [recurrence of heart attack] rate.  Why did it not receive the attention it deserved?”

“The key element,” he says, “was a sharp reduction in saturated fat and cholesterol intake and an increase in polyunsaturated fat intake. In fact. each experimental subject had to consume a pint of soybean oil every week, adding it to salad dressing or using it in cooking or, if necessary, just gulping it down!”

Whatever it deserved, the Oslo Diet-Heart Study did receive a good deal of attention.  The Women’s Health Initiative (WHI), liked it.  The WHI was the most expensive failure to date. It found that “over a mean of 8.1 years, a dietary intervention that reduced total fat intake and increased intakes of vegetables, fruits, and grains did not significantly reduce the risk of CHD, stroke, or CVD in postmenopausal women.” [3]

The WHI, adopted a “win a few, lose a few” attitude, comparing its results to the literature, where some studies showed an effect of reducing dietary fat and some did not — this made me wonder: if the case is so clear, whey are there any failures.  Anyway, it cited the Oslo Diet-Heart Study as one of the winners and attributed the outcome to the substantial lowering of plasma cholesterol.

So, “cross-examination” would tell us why, if  “a statistically significant reduction in reinfarction  rate”  it did “not receive the attention it deserved?”

First, the effect of diet on cholesterol over five years:

The results look good although, since all the numbers are considered fairly high, and since the range of values is not shown, it is hard to tell just how impressive the results really are. But we will stipulate that you can lower cholesterol on a low-fat diet. But what about the payoff? What about the outcomes?

The results are shown in Table 5 of the original paper:   Steinberg described how in the first 5 years: “58 patients of the 206 in the control group (28%) had a second heart attack” (first 3 lines under first line of blue-highlighting) but only

“…  32 of the 206 in the diet (16%)…”  which does sound pretty good.

In the end, though, it’s really the total deaths from cardiac disease.  The second blue-highlighted line in Table 5 shows the two final outcome.  How should we compare these.

1. The odds ratio or relative risk is just the ratio of the two outcomes (since there are the same number of subjects) = CHD mortality (diet)/ CHD mortality control) = 94/79 =  1.19.  This seems strikingly close to 1.0, that is, flip of a coin.  These days the media, or the report itself, would report that there was a 19 % reduction in total CHD mortality.

2, If you look at the absolute values, however, the  mortality in the controls is 94/206 = 45.6 % but the diet group had reduced this  to 79/206 = 38.3 % so the change in absolute risk is  45.6 % – 38.3 % or only 7.3 % which is less impressive but still not too bad.

3. So for every 206 people, we save 94-79 = 15 lives, or dividing 206/15 = 14 people needed to treat to save one life. (Usually abbreviated NNT). That doesn’t sound too bad.  Not penicillin but could be beneficial. I think…

Smoke and mirrors.

It’s what comes next that is so distressing.  Table 10 pools the two groups, the diet and the control group and now compares  the effect of smoking: on the whole population,  the ratio of CHD deaths in smokers vs non-smokers is 119/54 = 2.2 (magenta highlight) which is somewhat more impressive than the 1.19 effect we just saw.  Now,

1. The absolute difference in risk is (119-54)/206 = 31.6 % which sounds like a meaningful number.

2. The number needed to treat is 206/64 = 3.17  or only about 3 people need to quit smoking to see one less death

In fact, in some sense, the Oslo Diet-Heart Study provides smoking-CHD risk as an example of a meaningful association that one can take seriously. If only such a significant change had actually been found for the diet effect.

So what do the authors make of this? Their conclusion is that “When combining data from both groups, a three-fold greater CHD mortality rate is demonstrable among the hypercholesterolemic, hypertensive smokers than among those in whom these factors were low or absent.”  Clever but sneaky. The “hypercholesterolemic, hypertensive” part is irrelevant since you combined the groups. In other words, what started out as a diet study has become a “lifestyle study.”  They might has well have said “When combining data from fish and birds a significant number of wings were evident.” Members of the jury are shaking their heads.

Logistic regression. What is it? Can it help?

So they have mixed up smoking and diet. Isn’t there a way to tell which was more important?  Well, of course, there are several ways.  By coincidence, while I was writing this post, April Smith posted on facebook, the following challenge “The first person to explain logistic regression to me wins admission to SUNY Downstate Medical School!” I won although I am already at Downstate.  Logistic regression is, in fact, a statistical method that asks what the relative contribution of different inputs would have to be to fit the outcome and this could have been done but in this case, I would use my favorite statistical method, the Eyeball Test.  Looking at the data in Tables 5 and 10 for CHD deaths, you can see immediately what’s going on. Smoking is a bigger risk than diet.

If you really want a number, we calculated relative risk above. Again, we found for mortality, CHD (diet)/ CHD (control) = 94/79 =  1.19. But what happens if you took up smoking: Figure 10 shows that your chance of dying of heart disease would be increased by 119/54 = 2.2  or more than twice the risk.  Bottom line: you decided to add saturated fat to your diet, your risk would be 1.19 what it was before which might be a chance you could take faced with authentic Foie Gras.

Daniel Steinberg’s question:

“Here was a carefully conducted study reported in 1966 with a statistically significant reduction in reinfarction  rate.  Why did it not receive the attention it deserved?”

Well, it did. This is not the first critique.  Uffe Ravnskov described how the confusion of smoking and diet led to a new Oslo Trial which reductions in both were specifically recommended and, again, outcomes made diet look bad [4].  Ravnskov gave it the attention it deserved. But what about researchers writing in the scientific literature. Why do they not give the study the attention it deserves. Why do they not point out its status as a classic case of a saturated fat risk study with no null hypothesis.  It certainly deserves attention for its devious style. Of course, putting that in print would guarantee that your grant is never funded and your papers will be hard to publish.  So, why do researchers not give the Oslo-Diet-Heart study the attention it deserves?  Good question, Dan.

Bibliography

1. Steinberg D: The cholesterol wars : the skeptics vs. the preponderance of evidence, 1st edn. San Diego, Calif.: Academic Press; 2007.

2. Leren P: The Oslo diet-heart study. Eleven-year report. Circulation 1970, 42(5):935-942.

3. Howard BV, Van Horn L, Hsia J, Manson JE, Stefanick ML, Wassertheil-Smoller S, Kuller LH, LaCroix AZ, Langer RD, Lasser NL et al: Low-fat dietary pattern and risk of cardiovascular disease: the Women’s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA 2006, 295(6):655-666.

4. Ravnskov U: The Cholesterol Myths: Exposing the Fallacy that Cholesterol and Saturated Fat Cause Heart Disease. Washington, DC: NewTrends Publishing, Inc.; 2000.

In 1985 an NIH Consensus Conference was able to “establish beyond any reasonable doubt the close relationship between elevated blood cholesterol levels (as measured in serum or plasma) and coronary heart disease” (JAMA 1985, 253:2080-2086).

I have been making an analogy between scientific behavior and the activities of the legal system and following that idea, the wording of the conference conclusion suggests a criminal indictment. Since the time of the NIH conference, however, data on the role of cholesterol fractions, the so-called “good (HDL)” and “bad (LDL)” cholesterols and, most recently, the apparent differences in the atherogenicity of different LDL sub-fractions would seem to have provided some reasonable doubt. What has actually happened is that the nutrition establishment, the lipophobes as Michael Pollan calls them, has extended the indictment to include dietary fat, especially saturated fat at least as accessories on the grounds that, as the Illinois Criminal Code put it “before or during the commission of an offense, and with the intent to promote or facilitate such commission, … solicits, aids, abets, agrees or attempts to aid… in the planning or commission of the offense. . . ..”

A major strategy in the indictment of saturated fat has been guilt by association.  The American Heart Association (AHA), which had long recommended margarine (the major source of trans-fats), has gone all out in condemning saturated fatty acids by linking them with trans-fats.  The AHA website has a truly deranged cartoon film of the evil brothers: “They’re a charming pair, Sat and Trans.  But that doesn’t mean they make good friends.  Read on to learn how they clog arteries and break hearts — and how to limit your time with them by avoiding the foods they’re in.”. While the risk of trans-fats is probably exaggerated — they are a small part of the diet — they have no benefit and nobody wants to defend them; dietary saturated fat, however, is a normal part of the diet, is made in your body and is less important in providing saturated fatty acids in the blood, than dietary carbohydrate.  Guilt by association is a tricky business in courts of law — just having a roommate who sells marijuana can get you into a good deal of trouble — but it takes more than somebody saying that you and the perpetrator make a charming pair.

The failure of the diet-cholesterol-heart hypothesis in clinical trials as been documented by numerous scientific articles and especially in popular books that document the original scientific sources. It is unknown what the reaction of the public is to these books.  However, amazingly, there is only one book I know of that takes the side of the lipophobes and that is Daniel Steinberg’s Cholesterol Wars. The Skeptics vs. the Preponderance of Evidence. A serious book with careful if slightly biased documentation and an uncommon willingness to answer the critics,  it is worth reading.  I will try to discuss it in detail in this and future posts.  First, the title indicates a step down from criminal prosecution.  “Preponderance of the evidence” is the standard for conviction in a civil court and is obviously a far weaker criterion.  One has to wonder why it is that the skeptics have the preponderance of the popular publications — if the scientific evidence is there and health agencies are so determined that the public know about this, why are there so few —  maybe only this one — rebutting the critics.

The Skeptics vs. the Preponderance of Evidence

In any case, what is Steinberg’s case?  The indictment on page 1 is somewhat different than one would have thought.

“….the [lipid] hypothesis relates to blood lipids not dietary lipids as the putative directly causative factor. Although diet, especially dietary lipid is an important determinant of blood lipid levels, many other factors play important roles. Moreover, there is a great deal of variability in response of individuals to dietary manipulations. Thus, it is essential to distinguish between the indirect “diet-heart” connection and the direct “blood lipid — hard” connection failure to make this distinction has been a frequent source of confusion. (his italics)”

What?  Are we really supposed to believe that diet is an incidental part of the lipid hypothesis?  Are we supposed to believe that our cholesterol is just a question of the variability of our response to diet.  Has the message really been that diet is not critical and that heart-disease is just the luck of the draw (until we start taking statins)?  This is certainly the source of confusion in my mind.  Of course by page 5, we are confronted with this:

“In 1966, Paul Leren published his classic five-year study of 412 patients who had had a prior myocardial infarction. He showed that substitution of polyunsaturated fat and saturated fat-rich butter-cream-venison diet favored by the Norwegians reduced their blood cholesterol by about 17 per cent and kept it down.  The number of secondary current events in the treated group was reduced by about one-third and the result was significant at the p < 0.03 level.”

In a future post, I will describe Paul Leren’s classic five-year study which, by 1970, had a follow-up to eleven years and the results will turn out not to be as compelling as described by Steinberg.  For the moment, it is worth considering that, given the strong message, from the AHA, from the American Diabetes Association, from the NIH Guidelines for Americans, the criterion really should be beyond a reasonable doubt. There shouldn’t be even a single failure like the Framingham Study or the Women’s Health Initiative. In fact, the preponderance of the evidence when you add them all up, isn’t there.

The phrase “Evidence-based Medicine” (EBM) guarantees its proponents a certain degree of protection. After all, who would be against medicine that is based on the data, on hard facts rather than opinion. On the other hand, a study that needs to cloak itself in such a self-aggrandizing phrase must raise a few eyebrows; as usual, the Dietary Guidelines, moves to the top of the list in that category but there are many examples.  Martin Tobin, professor of Medicine at Loyola College provided an excellent deconstruction of evidence based medicine [1]. Some of his points were that the grading system has divorced itself from basic science.  For example, he points out that:

  • “ homeopathy uses drugs in which less than one molecule of active agent is present. … A meta-analysis of 89 placebo-controlled trials revealed a combined odds of 2.45 in favor of homeopathy. EBM grades meta-analysis as level 1 evidence but completely ignores scientific theory. There is nothing necessarily wrong with this particular meta-analysis, but the example illustrates how a system that grades findings of all meta-analyses as level 1 evidence is inherently flawed.  A grading system that ranks homeopathy as sounder evidence than centuries of pharmacologic science commits the reductio ad absurdum fallacy in logic.” [1]

Among the things that we found in our critique of the USDA dietary guidelines Report [2] was that the cited evidence did not meet their own standards. They were critical of low-carbohydrate diets on the basis of studies that their own analysis gave a “neutral” quality rating, even those that took dietary assessment at baseline and then assessed  cardiovascular mortality up to 12 years later.

But it is really the idea that there is some set of systematic definitions of science that everybody agrees on. My last post mentioned, by analogy with courts of law, the Frye standard which accepts as evidence, opinions supported by  “general acceptance’ in the scientific community.  While still accepted in some state courts, the federal courts have tried to go beyond trust in such narrow descriptions of science. In 1975, Congress established Federal Rules of Evidence.  The rules are quite general and the major impact is to broaden the range of evidence that could be considered.  Rule 401, defined relevance as  “evidence having any tendency to make the existence of any fact that is of consequence to the determination of the action more probable or less probable than it would be without the evidence,”  in other words, whatever works.  In a future post, I will discuss Daubert v. Merrell Dow, Inc. (pr. Dow-burt as in English), an outgrowth of the Rules of Evidence and generally considered the key judgment in the modern interaction of science and the law.  In the real world of jurisprudence, ideas on what constitutes scientific evidence have become problematical and Daubert may have had the paradoxical effect of restricting admissible data but, in the analogy with evidence in medicine, the Federal Rules of Evidence and Daubert have better captured the real quality of science in recognizing the need for flexibility. The kinds of absolute criteria — association does not imply causality, random controlled trials are a “gold standard,” etc. are at least different from the spirit of Daubert.

More important, nobody in any physical science would recognize the tables of levels of evidence.  A random controlled trial may be good for one kind of experiment but not for another and EBM is critical of “observational studies” but all of astronomy is observational.  In the end, most scientists would agree with the physicist Steven Weinberg, echoing Judge Potter Stewart’s famous take on pornography:

  •  “There is no logical formula that establishes a sharp dividing line between a beautiful explanatory theory and a mere list of data, but we know the difference when we see it — we demand a simplicity and rigidity in our principles before we are willing to take them seriously [3].”

So where do these arbitrary guidelines in EBM come from?  They were set up by the  medical community, a community that is stereotyped as being untrained in science. I hate stereotypes, especially medical stereotypes since I think of myself as coming from a medical family (my father and oldest daughter are physicians) but stereotypes come from someplace and, of course, it is well known that physicians never study nutrition.  In the end, it makes me think of the undoubtedly apocryphal story about Mozart.

  • A man comes to Mozart and wants to become a composer.  Mozart says that they have to study theory for  a couple of years, they should study orchestration and become proficient  at the piano, and goes on like this.  Finally, the man says “but you wrote your first symphony when you were 8 years old.”  Mozart says “Yes, but I didn’t ask anybody.”

Bibliography 

1. Tobin MJ: Counterpoint: evidence-based medicine lacks a sound scientific base. Chest 2008, 133(5):1071-1074; discussion 1074-1077.

2. Hite AH, Feinman RD, Guzman GE, Satin M, Schoenfeld PA, Wood RJ: In the face of contradictory evidence: report of the Dietary Guidelines for Americans Committee. Nutrition 2010, 26(10):915-924.

3. Weinberg S: Dreams of a final theory, 1st edn. New York: Pantheon Books; 1992.

According to the Journal of the American Medical Association (JAMA), the principle of “evidence-based medicine (EBM),” arose in the 1990s [1]. It is widely invoked in the medical literature as a kind of certification that the conclusions of the author are not mere opinions but are backed up by compelling information in biomedical science.  It sounds good. Or does it? It is certainly self-serving and a little bit suspicious, somewhat like Nixon assuring us that he was not a crook.  Evidence based medicine?  What were we doing before?  How was Pasteur able to function in the absence of such an idea?  One thing to think about is that evidence is what is introduced into courts of law.  But not all evidence is admissible. A judge decides what is admissible and there are many precedents, in particular, on what constitutes scientific evidence in a legal proceeding.

EBM relies on a hierarchy of levels of evidence (e.g. Table 1) with the random controlled trial (RCT) as the highest and expert opinion as the lowest.  Recommendations from health agencies and awarding of research grants are frequently justified on conformity to EBM or at least on their placing primary importance on RCTs.

Evidence from the USDA

Early in 2011, the USDA released its 2010 Dietary Guidelines for Americans [2].  With the dates suggesting the backward-looking nature of the Guidelines, they were nonetheless based on the Report of a prestigious committee (DGAC) [3] who, in turn, made much of their reliance on a new Nutrition Evidence Library (NEL). I and my colleagues were invited to submit a critique of the Report by the journal Nutrition. The editor, Michael Meguid indicated that the journal wanted a balanced report, pros and cons.  I called Dr. Meguid:

RDF: You know, the report is not particularly balanced. I’m not sure how you write a balanced review of an unbalanced report.

MM:  You can make the critique as strong as you like as long as you carefully document everything. But what’s your main problem with the Report?

RDF: Well, it makes very strong recommendations in the face of contradictory evidence.

MM: Make that the title of your article.

So we wrote an article called “In the face of contradictory evidence: Report of the Dietary Guidelines for Americans Committee” [4]. The journal was kind enough to make it an open access article and it’s available on this blog. In the end, on titles, we were one-upped by Steven Malanga, whose article in the New York Post was called “Fed’s Food Fog.”

For sure, both the Report and the final Guidelines were the proverbial camel-like production of a committee, tedious, repetitive and stylistic dreadful.  But what about the NEL?  What about the evidence?  Style aside, wasn’t this evidence based medicine?

Where do these guidelines come from? The assumption is that evidence follows its etymologic roots, stuff that is visible, stuff that comes from the sensible and true avouch of our own eyes. In fact, it is most often applied, as in the case of the DGAC, to the most controversial and contentious subjects. Calling something evidence is not enough. So what happens in courts of law? In a court of law, a judge decides on whether the jury can hear the evidence.  Who decides admissibility of the evidence in EBM?

Conflict resolution in science.

Science is a human activity. Conflict, controversy and a resistance to new ideas are well known even in the so-called hard, that is, more mathematical, sciences, and even where there are no outside forces as there was in the case of Galileo.  In the twentieth century, conflicts do not generally impede progress for long. Especially in the physical sciences, there is usually agreement on basic assumptions and on the rules of logic, allowing ultimate acceptance of strong evidence. Competing theories may coexist and supporters of both are likely to admit that they are awaiting reconciliation.

What happens when the spontaneous process of conflict resolution in science breaks down?  What happens in conditions where scientific disagreement is strong and a majority position becomes so dominant that it controls the funding and publication of scientific work and can ignore or repress contradictory evidence and repress exposition of alternative theories.  In essence, how do we deal with a recapitulation of the case of Galileo?

There is no system to decide on the admissibility in the cases considered by EBM.   I am not the first person to point out that EBM is largely the position of experts on one side of a scientific conflict [5], the lowest level of evidence on traditional EBM scales (e.g. “Level III: Opinions of respected authorities… of the US Preventive Services Task Force Systems,” Table 1).  EBM is sustained by those who want to use its particular criteria but these have never been subjected to outside affirmation.

In this situation, where science cannot police itself, we have to look for some outside guidance.  What do the courts do?  As one would expect there, is a long and extensive history of the legal system’s  attempt to deal with what constitutes scientific evidence.  On the chance that the legal perspective may help, I will discuss some of the issues.

Frye and the need for rules.

A key decision in the history of science in the courts is Frye v. United States.  In 1923, a Federal Appeals court ruled that the opinions of experts have to be supported by a scientific community. Frye had been convicted of second-degree murder but appealed on the grounds that he had successfully passed a lie-detector test.  At that time the device was a simple blood pressure machine and an expert witness testified as to the results. The court ruled that the lie-detector test “has not yet gained such standing and scientific recognition among physiological and psychological authorities as would justify the courts in admitting expert testimony‚” affirming the judgment of the lower court.

The ruling in Frye gave rise to the idea of “general acceptance,” and, by analogy, this appears to be the main principle in the admissibility of evidence in the nutrition world.  Sufficiently well established that it could be included in a biochemistry text is the idea that “consumption of saturated fats is positively associated with high levels of total plasma cholesterol and LDL cholesterol and an increased risk of CHD”[6] Known to students as “the Lippincott Book,” Harvey and Ferrier is the best selling biochemistry book in the world and it is correct when it states “Most experts strongly advise limiting intake of saturated fats.”

Most, but not all.  A small but not insignificant minority hold otherwise and whereas they agree that dietary saturated fat may raise blood cholesterol, they can provide overwhelming evidence that it is not associated with cardiovascular disease. This has been demonstrated in almost every large trial.

The problem is described in Marcia Angell’s Science on Trial [7].  Angell explains that Frye was not without its critics ([7], page 126).  Opponents, she wrote,

“claimed somewhat improbably, that it would tend to exclude novel, far-sighted testimony by modern-day Galileos. There is no record of this happening once, let alone often.  Furthermore, even if a modern-day Galileo did not make into court at first, that fact should not stop him from prevailing in the scientific community.  Courts do not determine scientific acceptance, as implied by the argument that we need to keep our courts open to the hidden Galileos in our midst.”

But isn’t this exactly what has happened in nutrition and maybe, in general, in the medical community?  The “experts” control editorial boards, granting agencies and academic departments and are as powerful as the Catholic Church in repressing dissent.  They have prestige and, in many cases, undisputed accomplishments, but does science run on general acceptance? Does majority (of experts) rule?

One of the problems with Frye that lawyers have addressed is a question of identifying the field of academic or scientific field in which the general acceptance is to be considered.  Different disciplines hold to different standards.  In the case at hand, many ideas in nutrition would be dismissed out of hand by biochemists. Many methodologies would be considered absurd by physical scientists: Intention-to-treat is perhaps the most absurd.  It has been pointed out that the question of who is an expert might have applied to the techniques in the original Frye case, at least as it might be implemented today: “If polygraph examiners are selected as the relevant field, polygraph results would be admissible.” (http://law.jrank.org/pages/2006/Scientific-Evidence-Frye-v-United-States.html).

The epidemic of obesity and diabetes stands as a testament to the failure of the experts.  A small library can be assembled of books attacking establishment medical nutrition. Uffe Ravnskov’s classic Cholesterol Myths is updated in Ignore the Awkward. Gary Taubes’s recent Good Calories, Bad Calories is the most compelling and James Le Fanu’s Rise and Fall of Modern Medicine, the most succinct but just sitting at my desk now I can see a dozen others on the book shelf.  Surprisingly, there has been only one rebuttal, Steinberg’s Cholesterol Wars, the subject of the next post .

Table 1.  Examples of Levels of Evidence from Various Sources. 

US Preventive Services Task Force Systems for ranking evidence about the effectiveness of treatments or screening:

Level I: Evidence obtained from at least one properly designed randomized controlled trial.

Level II-1: Evidence obtained from well-designed controlled trials without randomization.

Level II-2: Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group.

Level II-3: Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence.

Level III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.

Bibliography

1. Torpy JM, Lynm C, Glass RM: JAMA patient page. Evidence-based medicine. JAMA 2009, 301(8):900.

2. Dietary Guidelines for Americans, 2010 [http://www.dietaryguidelines.gov.]

3. US Department of Agriculture and US Department of Health and Human Services: Report of the Dietary Guidelines Advisory Committee on the dietary guidelines for Americans, 2010. June 15, 2010. In.; 2010.

4. Hite AH, Feinman RD, Guzman GE, Satin M, Schoenfeld PA, Wood RJ: In the face of contradictory evidence: report of the Dietary Guidelines for Americans Committee. Nutrition 2010, 26(10):915-924.

5. Marantz P, Bird E, Alderman M: A Call for Higher Standards of Evidence for Dietary Guidelines. Am J Prev Med 2008, 34(3):234-239.

6. Harvey R, Ferrier D: Biochemistry, 5th edn. Baltimore and Philadelphia: Lippincott Williams & Wilkins; 2011.

7. Angell M: Science on Trial. New York: W. W. Norton & Co.; 1996.