Tuesday, December 29, 2015

Less glucose in the glucose intolerant is a good thing? Who'ulda thunk it.

In 2003, the JAMA released a paper from Chiasson, JL, et al, called: Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial.

(A little infographic-like sheet containing the major points can be found here, for a quick overview of the trial.)

Including some 1,400 people, the STOP-NIDDM trial is an international, randomized, double-blind, placebo-controlled clinical trial that, including follow-up, spanned a mean of 3.3 years. I have only briefly perused the methods and statistical analyses sections of the paper, so I have, what I would consider, only a superficial understanding of the methodology, thus far. So, take this with a grain of salt. That said, I am impressed with what I have seen, at least from the standpoint of the reporting of the data. (Any time study authors decide to include absolute risk reductions versus relative risk alone, for instance, I have to give props; and props are certainly due, on that front, here. Not to mention, all pertinent information, from what I can tell, was either offered up front, or links to such information were provided for us. Respect.)

Study question:

~ Is taking Acarbose associated with a meaningful decreased risk of cardiovascular events in persons with impaired glucose tolerance?*

*It should be noted that the original STOP-NIDDM trial, from which these data were taken, was, as the authors admit here, "not powered to answer that question." This is a secondary, retrospective analysis of the data, modified to tease out this potentially important confounding variable in order to see whether it had a significant part to play in the reduction of disease risk in the study population.

Inclusion criteria:

~ Age: 40-70 y/o,
~ BMI of 25-40,
~ Impaired glucose tolerance (IGT) (according to WHO criteria),
~ Fasting plasma glucose: 100-140 mg/dL (5.5-7.8 mmol/L)

Ultimately (after all reported dropouts), 1,368 people completed the trial and follow-up, which is pretty good. The outcome measures were kind of all over the place though, from my perspective. They claimed major cardiovascular events, including new angina, AMI, revascularization procedures, cardiovascular death, CHF, CVA, and peripheral vascular disease as primary outcomes. (Secondary outcomes were incident HTN and "rates of each type of cardiovascular event.") This does not constitute a "primary outcome." Albeit of course related, these are eight separate potential primary outcomes. For the love of God, just pick one primary outcome and study that to see if there is a legitimate association. (It is times like this that I can't help but think to myself, as cynical as it may seem, that this was intentional, as it might have been a means of using the problem of multiple comparisons to generate significant figures (to assure publication, particularly in a prestigious journal like the JAMA), where there are none. I will put that consideration on the back burner for now, I suppose...)

*Acarbose is an alpha-glucosidase inhibitor that prevents the cleavage of oligo- and polysaccharides into their single, monosaccharide sugars, during digestion.

The point of taking acarbose, clearly, is to prevent the absorption of glucose in those that do not tolerate glucose well. I follow the logic. However, it appears to beg the question: If someone does not tolerate dietary glucose, why feed them dietary glucose? Why feed someone carbohydrate just to turn around and try like hell to prevent its absorption into the extracellular fluid, because it might pose a problem in the carbohydrate intolerant individual? Does it not make sense simply to avoid ingesting said carbohydrate in the first place, and not bother taking the acarbose, at all?

I realize, I could be falling prey to a cognitive bias, here. "If a little of something is good, a lot more must be even better." However, there are other data that corroborate these findings in various ways. From a scientific perspective -- assuming these data are accurate, and I do not yet know whether or not I think they are -- I do find this intriguing, and, as I say, I think it jives rather well with much of the controlled nutritional literature I have seen on the topic. Personally, however, it strikes me as a touch illogical and futile. A little like trying to dig a massive hole using only the stick-end of your shovel.

The relative risk reduction in the acarbose group, versus those 600 some odd persons on placebo, was 49%. Note that this translated to a 2.5% absolute risk reduction. (At first glance, a 2.5% absolute risk reduction seems quite small, but, considering that many medications for cardiovascular disease translate to a much larger NNT and a much smaller absolute risk ratio, oftentimes <1%, I am actually somewhat pleased with that figure.) But, again, I just feel it would be more efficient and intelligent simply to say, "Okay, persons with IGT do not appear to tolerate glucose well, ergo, we shall see what restricting dietary glucose does," since, in the latter, they wouldn't have to play with inhibiting absorption, at all. It takes out the unnecessary middle-man.

One thing I think is important, and, in my opinion, is a huge confounder, is this:



a.) Almost invariably, dietary modification leads to a reduction in carbohydrates consumed, since a vast majority of the Calories eaten by the so-called "civilized" nations of the world come from this macronutrient category. Could these results have arisen out of a slight reduction in carbohydrate Calories?

b.) We know, without a doubt, that consistent exercise can improve both OGTT and insulin sensitivity. Why? Intense exercise turns the skeletal muscles into a glucose sink. (If you truly wanted to test the effectiveness of acarbose, alone, on glucose tolerance and disease risk, you would have to maintain the subjects' baseline lifestyle characteristics.)

A and B may just be study ruiners, for me. (Not necessarily for the STOP-NIDDM trial, as a whole, per se; but perhaps for these secondary, modified intention-to-treat analyses that followed.) At least, I cannot overlook the possibility that these confounders within the larger confounder couldn't have accounted for nearly all the 2.5% absolute reduction in disease outcomes.

All in all, I recommend that you check out the trial and read at least the methods and results sections, for yourself. Despite my personal annoyances, it really is an intriguing study, and you may be able to find some points of interest I have not alluded to. Enjoy!



REFERENCES

1. Chiasson, J. L., Josse, R. G., Gomis, R., Hanefeld, M., Karasik, A., Laakso, M., & STOP-NIDDM Trial Research Group. (2003). Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. Jama290(4), 486-494.

Thursday, December 17, 2015

Sex. Critical thinking skills need not apply?

Recently, I was half-listening to a 29 year old, gay, male friend of mine -- whose name shall remain anonymous -- discuss his latest conquest, while I flipped through some notecards on cardiovascular physiology. I offered little more than a few "uh huh"s and "Oh, really?"s, until I heard him say, "And then I convinced him to top me bareback, because I'm on PrEP, so I can't get the virus."

"Excuse me?" I stopped him. "You what?"
"I'm on PrEP," he said, "So I'm protected from getting HIV, or passing it to any of my partners."
Shocked, I replied, "Where exactly did you hear that?"
"They've studied it, and it's been shown to be 100% effective at protecting against transmission of the virus."
"100%?! Who's 'they'?"
"Lots of us are doing it. Considering you are in the medical field, I'm surprised this is the first time you're hearing about it..."
I took a few breaths to steady my nerves and then said, "Okay, well, what about side effects; are you concerned about any possible side effects of taking the drug?"
"There are no side effects," he said.

That's what did me in...

There is no such thing as a drug that does not have side effects. Ibuprofen has side effects! Either he is bullshitting, or someone has actually convinced him that there are only upsides to taking this medication, and he really believes there are zero adverse events associated with its ingestion.

After a long, exasperated conversation, which ended with me sifting through an immense amount of data on pre-exposure HIV transmission prophylaxis, and finding out that this is not the first time he has done this, I hung up the phone, horrified by what I had just learned.

This isn't the first time I had learned about PrEP, or "pre-exposure prophylaxis." It is, however, the first time I've learned of anyone using it as an excuse to fool around unsafely, and the first time I've ever heard someone tell me a medication has a "proven, 100% effectiveness" record -- which, for any of you scientists and medical professionals out there, you will recognize as being totally bogus. My friend, who I truly respect and care about, honestly thinks that because he is on PrEP he cannot get HIV, and, therefore, can fool around ("raw") with his sexual partners, without protecting them or himself by wearing a condom.* And, from what he tells me, there are multiple partners across the state.

*For the time being, let's forget that HIV is not the only sexually transmitted infection that is of concern, here. My friend is a smart guy, but, clearly, he has forgotten that (even if PrEP did work as he thinks it does -- and it doesn't) there's still syphilis, genital herpes, HPV, gonococcal infections, and a myriad other STIs he could be exposing himself and others to, by engaging in this sort of practice. This really is a potential public health crisis, on many levels. For now, however, I will focus exclusively on the HIV concern. (But, if you are reading this, and this sounds like something you do, yourself, or are aware of friends, colleagues or acquaintances doing, please understand that by engaging in this behavior, you are in fact putting yourself at risk of getting and transmitting disease, including but not limited to HIV, despite whatever official or unofficial PrEP marketing has led you to believe.)

I could be false dichotomizing here, but I can think of only two reasons someone in my friend's shoes might want to take PrEP; either:

a.) They truly believe they will be 100% protected from HIV transmission. Or,
b.) They want to misuse this purported inability to transmit the virus by manipulating other, unsuspecting men (or women, in some cases) into believing they will be protected, too, so they can screw around without having to wear a condom.

Truly disgusted with both possibilities -- as A implies a total lack of critical thinking on our part, as consumers, and B implies an intention to mislead another for ones own sexual gratification (which feels a lot like a sick form of rape, to me) -- I wanted to conduct a small poll with a few of my other gay friends, to see if they have heard of PrEP, take it, or know someone else who takes it, and their reasons for doing so.

Three of five people (none of whom knew I had spoken with anyone else regarding this topic, as far as I am aware) explicitly told me that they know of many people who are On PrEP because it "protects them from getting the virus," and at least two gay men who use the medication as an excuse to "fuck around bareback" -- which just means to have intercourse (anal, or otherwise) without a condom.

The CDC website, to which I've linked above, provides links to the four main clinical trials on pre-exposure prophylaxis. I would like to take a quick look at them, now. (In no particular order.)


I would like to make something clear: although I am currently at arms with the popular conception of PrEP, I'm not entirely against it -- HIV and, therefore, AIDS is a debilitating, life-changing (and eventually ending) disease process, and the scientific and medical communities at large are working very hard, and spending many billions of dollars per annum, to find ways to protect against and possibly rid people of the disease. I commend that! What I have an issue with is marketing it to people disingenuously, or convincing gay men that it will reduce their risk of transmission by "over 90%." (Is it really that hard to believe that men, regardless of sexual orientation, who are told they are nearly 100% protected won't round that number up to 100% and tell their partner(s), "Hey, it's cool if we mess around raw, now, because I'm on this new medication!"*)

*Obviously, if this is happening (and I know that it is), there's not just a critical thinking pandemic on the side of these drug-takers, but also with respect to those who are allowing themselves to be convinced of this nonsense. Wake up, people. Don't blindly trust everything you see or hear. Just because he bats his beautiful lashes at you while he says it does not make it true.

Getting back to the point, this study included roughly 1,200 participants, and followed them for a median of 1.1 years, which is pretty good. I have a few issues with it, however.

First, as the title implies, these people were reportedly all heterosexual. As the route of transmission, vaginally, is not the same, as rectally, because the nature of the epithelium of the rectum allows for a much greater absorption of seminal proteins from the ejaculate, and because the pH of the fluids in the vaginal canal are more acidic and, therefore, protein denaturing, we should not expect rates of HIV transmission in heterosexual persons to be representative of similar gay populations. As the outcome measures in this study looked at heterosexual men and women, we cannot extrapolate the results of this trial to homosexual men, who are engaging in unprotected anal intercourse.

It is important to consider that, even though these 1,200 study subjects were free of HIV at the start of the trial, 36 of them tested positive for HIV before the end of the trial. 10 of these subjects were in the intervention group, receiving the antiretroviral therapy. That means that ~28% of the newly HIV infected persons were on the drug. The authors go on to state:

"With the exclusion of 3 participants who were HIV-infected at the time of enrollment, the overall protective efficacy of TDF–FTC [the antiretroviral drug] in the modified intention-to-treat analysis (comprising 1216 participants) was 62.2%."

I wonder, if my friend had heard that the drug was reportedly 62.2% effective in a trial on heterosexual men and women, whether he would still have jumped as quickly onto it as he seemed to. After all, 62.2% isn't bad, but it's certainly not 90%, let alone 100%.

Lastly, the trial boasts a randomized, double-blind, placebo-controlled design, at the start, but, for whatever reason -- and I have my suspicions -- the trial did not proceed as designed until the very end. Retention and adherence issues abound, this study converted to an observational trial, by default, which is, unfortunately, insufficient to tease out imperative causes and effects. There were also some significant adverse events in both groups, with far more nausea and vomiting in the group receiving medication. The CDC makes it clear on their website that this is a possibility of taking PrEP, but states (as did the trial authors) that these symptoms appeared to subside after a few months of consistent treatment. Whether that's true or not, they did not mention that bone mineral densities were substantially decreased in the group receiving the medication versus those receiving placebo. So much for "no side effects."


Already, we are faced with the same concern as the last trial. The outcomes of a trial on heterosexual intercourse (presumably vaginal) -- and, in this case, on HIV-1-serodiscordant couples, who are presumably committed to one another and not having sexual relationships with other persons -- cannot be extrapolated to homosexual men or anal intercourse. Individual study designs attempting to answer these specific questions must be conducted, before we can have any reliable answers pertinent to them. Otherwise, we are just guessing, which would not only be a disservice to homosexual men (cis- or trans), and other persons who engage in anal sex, it would be scientifically disingenuous.

From a variety of large epidemiological studies, HIV appears to be the most difficult sexually transmitted infection to transmit sexually, among non-promiscuous, heterosexual men and women.[3] That, of course, does not mean it doesn't happen; it certainly does. But, when compared to the incidence of syphilis and chlamydia, for example, it is significantly less. However, this is just another reason to question whether these results would translate to homosexual men. The incidence of HIV infection in homosexual persons is notably higher than in heterosexual persons -- I read somewhere that it is something in the ball park of 2% as compared with 0.4%, respectively; but, please don't quote me on that. Let's say that these results are ~67% effective, as the authors suggest; would anyone want to wager that the same exact number would result in a study of serodiscordant homosexual male couples?*

*Yet again, this study reports the efficacy of PrEP to be roughly 67%. Not bad. In fact, it's pretty damn impressive! But certainly not 90-100% protection.

In this trial, statistically significant adverse effects associated with once daily ingestion of the antiretroviral drug (TDF-FTC), as compared to placebo, were neutropenia, gastrointestinal upset and general fatigue.

Interestingly, and importantly, in my opinion, there were accounts of antiretroviral resistance in the intervention group. This means that the HIV virus, in infected individuals, had mutated in such a way, as a result of receiving PrEP therapy, that it may have effectively rendered any future antiviral therapy useless.

Lastly, of those individuals who began the trial free of HIV infection, who subsequently became seropositive, by the end of the trial, 31% of them had detectable levels of the drug in their plasma samples. This means that at least these people had been consistently taking the medication, enough to have built up a meaningful amount in their system, and still became infected, regardless. (Thus continuing to serve as evidence that a proposed 90% efficacy rating is utter horse shit.)


Consistently and habitually sticking "dirty" needle in ones arm, and thus injecting HIV directly into ones bloodstream is, once again, a very different route of transmission than having unprotected anal intercourse... And, in this trial, the reduction in HIV transmission was only 49%.* (At this point, I have absolutely no idea where anyone is getting this >90% reduction in transmission rates nonsense?)

*Now, I do not wish to demean this figure, per se. 49% reduction is pretty good, all things considered. There is an enormous difference, however, between 50% and 90%. Also, let me reiterate: the outcome measure in question matters. Habitual intravenous drug users =/= habitual recipients of anal sex.


Finally, we get to the one and only study that matters, for our purposes. The only one that actually examined the results of homosexual men, partaking in consistent anal intercourse, taking this prophylactic chemotherapeutic antiviral therapy.

The enrolled cohort was roughly 2,500 persons, from 11 different countries, and they were followed for a median of 1.2 years. Those numbers are highly promising, considering the quality of data we are looking for. Then again, it is very important to remember that this is only one trial.

Out of the 2,500 persons enrolled in the trial who continued evaluation until the end, 110, or approximately 4%, of the initially seronegative men tested positive for emergent HIV infection. 36 were in the intervention arm. The authors conducted a modified intention-to-treat analysis and here is what they concluded:


"...representing a relative reduction of 44% in incidence in the modified intention-to-treat population."

44%. Now, of course, that's just a modified analysis of a specific subgroup, post hoc. But, isn't this the population we should be concerned with? Brand new, emergent cases of HIV, despite being on the drug and having adequate blood levels of it in their system. This concerns me.

Also important to consider is that every individual who participated in this trial was also hit, fresh from the start, with biobehavioral counseling, which included risk reduction techniques and condoms. The authors go on to state, in the results, that the "total numbers of sexual partners with whom the respondent had receptive anal intercourse decreased, and the percentage of those partners who used a condom increased after subjects enrolled in the study." (Emphasis, mine.)

Don't we now have to ask ourselves whether the positive outcomes we are so eagerly attributing to the use of PrEP might not also have had something to do with the increased condom use? Would it not be inappropriate to realize this confounding variable and then brush it off as a triviality?

We know that HIV transmission doesn't come about as easily as we are often led to believe -- it was "just" 4% in this particular trial -- otherwise the international HIV epidemic would be unfathomable, right now, instead of remaining at the decade-long lull we have gotten accustomed to. We also know that the false positive and false negative rates of rapid and even western blot tests are quite common in the infectious disease literature. So, there are certainly a great deal of possible confounding factors to consider, here; certainly far more than I could possibly conceive of right now. But, one thing we know for sure is that condom use is already a well-established, powerfully effective preventive measure to protect against the emergent acquisition of HIV infection in previously seronegative individuals.

Naturally, it would be completely unethical to divide people up into two groups, as one would need to do to find "the answer" to this outcome question, where one group got the drug, and no condoms, while the other group got condoms, but no drug.... Clearly, this trial couldn't even be done. But, to make the sorts of claims made about PrEP, now, this is precisely what we would need to see conducted, and it just serves to remind us that there may be innumerable factors at play, here, that we are unaware of. From my perspective, it would be unwise to jump to any premature conclusions, considering the evidence of the efficacy of this treatment is still in its infancy, and the answers we need have not yet been fully elucidated.

Lastly, statistically significant alterations in serum creatinine and phosphorous levels changed, as a result of taking PrEP in many of the studies conducted, thus far. Among other concerns, including, but not limited to, significant negative changes to glomerular filtration rates -- even in previously healthy persons -- should, if not serve as cause for concern, at least be considered among the list of potential downsides of taking this new medication.

I should like to say, I am not "anti-PrEP," per se. I am anti-manipulative marketing tactics. I am anti-non-scientific statements like:

Take this wonderful drug. There are no side effects, and you'll never have to worry about getting sick again!

which are not only unsupported by the data, but are also wholly intellectually absurd. Will I also get to ride into work on Monday morning on a rainbow? C'mon...


KEEP IN MIND, THERE MAY OR MAY NOT BE OTHER STATISTICAL PROBLEMS OR METHODOLOGICAL LIMITATIONS WITH THESE DATA THAT I HAVE NOT TOUCHED ON, AND MY PSEUDO-ANALYSIS MAY NOT BE TOTALLY COMPLETE -- THE AFOREMENTIONED OPINIONS ARE MERELY MY PERSONAL THOUGHTS ON THE LIMITED DATA THAT CURRENTLY EXISTS ON PrEP AND ITS EFFICACY AND SAFETY. (THERE ARE ALSO STUDIES ON PrEP WHICH HAVE NOT BEEN PUBLISHED, AS OF YET, BUT ARE COMING OUT SOON. I AM SAYING NOTHING OF THOSE STUDIES, HERE, AS I HAVE NOT YET HAD THE OPPORTUNITY TO REVIEW THEM.)


TL;DR

1. Do not manipulate others into having bareback sex with you by telling them you "can't" get HIV. You absolutely can. PrEP is not a cure or a pill with magical properties. (If you are not morally concerned about hurting another person, at least understand that you're not necessarily getting a "free ride" either.)

2. Do not let others manipulate you into having bareback sex with them, by believing that just because they're on PrEP that they "can't give you HIV." Viral transmission rates may be lower, but they are not zero, and you can still become infected.

3. Think critically, before putting any drug into your body. There's no such thing as a medication with 100% efficacy and 0 side effects. (Indeed, there aren't any that have either 100% efficacy or 0 side effects. Even Tylenol can cause severe hepatotoxicity at doses on the high end of normal, and PrEP drugs are chemotherapeutic, just like those given to persons already seropositive for HIV. Ergo, It is reasonable to at least anticipate the possibility of similar long-term adverse events from chronic PrEP treatment.)

4. Wear a condom. (Even if you choose to take PrEP; which is your right as a healthcare consumer.) Even the CDC, which, in my opinion, inappropriately and prematurely provides young homosexual men with the hope that if they "just take this little pill" they'll save themselves years of heartache and eventually-fatal autoimmune disease, state that the only way to virtually ensure protection from HIV infection is to couple PrEP with the regular use of a condom, during any and all sexual penetration.

5. Wear a condom, regardless. Even if PrEP worked the way people seem to think -- and it doesn't -- it will not protect you from contracting other STIs, like HPV, genital herpes, chlamydia, gonorrhea and more. If you don't want your junk to fall off, or go insane from neurosyphilis, never let anyone put any of their body parts inside of yours (or vice versa), unless it is protected.

6. Get tested, make your partner get tested, too, and don't be afraid to ask about previous sexual relationships. (This is an incredibly serious public health concern, and ought to be treated as such.)


NOTE: I am not trying to dissuade the use of PrEP, per se. I am trying to help the men and women in my community and elsewhere understand that not all of the wonderful things they have been told about this medication are quite so wonderful, and to suggest they simply open their minds and think critically before embracing something as "the truth." In other words, I am not against PrEP; I am against people using it to manipulate other, innocent and ignorant people into potentially giving up their lives for 12 minutes of pleasure.


REFERENCES:

1. Thigpen, Michael C., et al. "Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana." New England Journal of Medicine 367.5 (2012): 423-434.
2. Baeten, Jared M., et al. "Antiretroviral prophylaxis for HIV prevention in heterosexual men and women." New England Journal of Medicine 367.5 (2012): 399-410.
3. Padian, Nancy S., et al. "Heterosexual transmission of human immunodeficiency virus (HIV) in northern California: results from a ten-year study." American journal of epidemiology 146.4 (1997): 350-357.
4. Choopanya, Kachit, et al. "Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3 trial." The Lancet381.9883 (2013): 2083-2090.
5. Grant, Robert M., et al. "Preexposure chemoprophylaxis for HIV prevention in men who have sex with men." New England Journal of Medicine 363.27 (2010): 2587-2599.

Sunday, October 11, 2015

Shut Up and Calculate

Over the last few days, I have completely submerged myself in an intellectual world with which I'm familiar, but am by no means any kind of expert in. Namely, Quantum Mechanics.

Physics has always been a particularly interesting subject for me, in that, as a scientist, I have naturally developed a causal-mechanical thinking-style, if you will, and take great pleasure in knowing that if I compute things a certain way, I will almost certainly get one, very specific answer. That A causes, or reacts with B to produce C, and that this can be predicted to occur with regularity, given a set of environmental circumstances, is nice and clean, and gives me a warm gooey sense of knowledge about the nature of reality.

Then came my first introduction to quantum mechanics.**

**I'd like to take this moment to restate that I am a quantum physics enthusiast out of sheer philosophical and scientific curiosity; I do not claim to be an authority on the subject.

If any of you are at all versed in rudimentary quantum mechanics -- and it doesn't matter much if you are or not, in order to follow along with the gist of this post, so don't worry -- I'm sure you'll understand why this threw me off. (Nothing about quantum mechanics is ever totally predictable, in the traditional, strict deterministic sense. Quantum mechanics relies on probability distributions, described by the Schrodinger equation. In other words, just like Schrodinger's famous cat: the universe is probabilistic, not deterministic.)

This tends not to jive with most physicalists/determinists in science and philosophy, who claim "we're all just physical machines," because their picture of reality tends to revolve around the concept that life at the "classical level" somehow reverts to traditional, Newtonian mechanics (the world of billiard balls bouncing off of one another in predictable patterns), and that the realm of quantum mechanics is virtually meaningless to us, at least in our being able to utilize it to determine anything meaningful about actions and reactions at the order of magnitude at which we live. And, to some extent, I can sympathize with this view, from the perspective of the mathematics of quantum mechanics. For instance, have you ever been shown how to solve the Schrodinger equation for the hydrogen atom? Can you fathom doing it for a pancreas? Me either. That said, however, recently conducted experiments clearly demonstrate that large 60-C molecules called "buckeyballs" display wave-like interference patterns, similar to photons and electrons. This phenomenon has been replicated over and over, in various ways, and, in each case, seems to hold true. To me, this begs a pivotal question: where do we draw the line? At what point does the nuisance that is quantum mechanics fade away and give rise to the nice, clean, mathematically-precise world Newton described so well? It should be clear, at this point, that we can no longer suggest that "quantum mechanics only describes ultra-microscopic particles." Do we simply keep moving the line up and up? Or, perhaps the line is a figment of our imagination, and there really is only one reality; and it's quantum mechanical. Just a thought.

Without delving too deeply into the specifics of any aspect of fundamental quantum mechanics, or the dynamics of subatomic particles (as much as I find myself wanting to), let me just say this:

Quantum mechanics has never failed experimental replication. Ever. Along with Einstein's theories of general and special relativity -- although both are still technically falsifiable; and, interestingly, neither should be able to exist in the same universe as the other, yet very clearly do; hence the search for 'quantum gravity' -- quantum mechanics is quite possibly the most successful scientific theory that has ever been proposed, to date.

Although it is true, I daresay, that there is no more a successful theory in science than quantum mechanics, there are several competing interpretations of its so-called "spooky" nature, which has been observed since the time of Bohr and Heisenberg, and card-carrying theoretical physicists to this day have not come to any consensus as to which of these purported interpretations makes the most sense. Although there is universal agreement among physicists that quantum mechanics is an amazingly accurate and successful theory that describes reality in a seemingly infinite number of ways**, and that the so-called "wave-particle duality" is a fundamental aspect of the theory, there is no such universal agreement on how best to interpret the meaning and the implications of this theory and its application to reality.

**e.x. If quantum mechanics did not work as detailed, cell phones would not exist. Neither would personal computers, and a host of other things. Life as you know it couldn't be. (I say this to make sure you understand that this isn't just idle theorizing on the part of a number of incredibly smart men and women, there are vitally important practical implications of quantum mechanics.)

They know that quantum mechanics describes reality, but not necessarily the intricate hows and whys of the theory and its auspices. (Which, it seems to me, tends to be true of much of our scientific understanding in biology, as well.)

So, anyway, I was amid a discussion with two friends of mine, this week, wherein each of us held a distinct and opposing position on how we view the strangest aspects of quantum mechanics

I am of the opinion that the Copenhagen interpretation of quantum mechanics seems to be the most accurate way of describing the nature of reality. Specifically, I think there's an implicit role for consciousness (or, rather, the conscious observer) in the collapse of the wave-function. Therefore, I fall into what's called the Von Neumman interpretation camp.

One of my friends falls into the camp that believes in the Many Worlds (or Many Minds) interpretation of quantum mechanics. He doesn't believe the wave-function collapse occurs, at all; but, instead, that all possible realities exist and are retained in infinite states of probabilistic superposition. (Basically, that any and all possible realities that can occur do occur, simultaneously.)

My other friend believes in something called the Pilot-wave theory or the de Broglie-Bohm interpretation of quantum mechanics. (Or, at least denounces that, if the wave-function collapse indeed takes place, it needn't require a conscious observer to collapse it; thus, introducing the question: "What constitutes an observer?")

Although both of my friends disagree with me, and I with them -- which is totally fine, and all in good fun -- I cannot escape the idea that the wave-function collapse occurs, effectively condensing all the potentialities that exist into a single, unified, so-called "objective" reality. (e.g. Schrodinger's cat is no longer both dead and alive, simultaneously, after observation [re: measurement] takes place. Once observed, the wave-function collapses, quantum superposition fades -- rather, the state vector is reduced -- and the cat turns out to be either alive or dead, but not both.) I'm not a fan of the concept of "eternal superposition," which seems, to me, to be the natural philosophical progression of the Many Worlds view. And, despite the recent popularity of the many worlds interpretation of quantum mechanics, proponents tend to evade questions I would want answered, like: "What about the quantum Zeno effect?

There are, of course, a variety of different interpretations of the quantum mechanical phenomena that have been observed over the past decades, and every one of them (including the Copenhagen interpretation, to which I have sided, here) has issues in need of resolution. As well, there are many pop-culture references to things like quantum entanglement, some of which are quite accurate, although perhaps not well explained, while others are flagrant misrepresentations of these concepts. The point is, of the scientifically accurate and mathematically sound theories surrounding quantum mechanics, none seems to be able to delineate precisely which of these interpretations is most correct. And, as I say, physicists today still cannot agree.** Hence, my friends and I are free to speculate, and debate within our group discussions, about which concept seems to have a more solid basis in nature and why.

**This graph on Sean Carroll's website clearly shows what I'm trying to tell you; those polled, here, are card-carrying physicists, per se.


The point is that there's no consensus. And consensus, in science, is one of the predominant things that takes a bold, counterintuitive conjecture, or educated hypothesis and solidifies it into an accepted theory. There may not be universal agreement in the lay public about whether or not evolution, as a theory that describes biological adaptation over time, is true, but if you were to poll professional biological scientists, there would be an overwhelming majority vote that yes, in fact, evolutionary theory is true.

Could Einstein's relativity theory have made history, if no one came to realize and accept he was correct, after which followed the almost universal consensus that his ideas could be doubted no longer? I would think not. Then again, some would make the argument -- and, I find myself in agreement, here -- that it might have inevitably become the truth, at some point, because, mathematically, it is the only theory that appears to make sense and accurately describe the cosmological reality.

This focus on mathematical proofs, the quantifiable measurements we make which point us in one direction or another, is what drove the evolution of classical, non-relativistic physics toward relativistic physics and, then again, toward quantum physics. We go where the math takes us. Which brings me to the bottom 12% of the votes in Carroll's graph.

The bottom 12% that voted "I have no preferred interpretation," are often called the "Shut up and calculate" group. They are frequently cited as being the kind of hard nosed physicists that care only about the measurements and how the data adds up, and harbor a certain kind of cynicism about philosophical introspection. More importantly, they're not interested in speculating past what we can know beyond a reasonable doubt, from the data before them, and if they don't yet have sufficient data to come up with a reliable answer, then by God, they have yet to generate enough information; ergo, "your question will have to wait, we simply don't know yet; we need more data."

I would argue that the late, great Dr. Richard Feynman was in this Shut Up and Calculate camp. He cared very little for the philosophical implications of his (or others') work. I happen to think there's something immensely important about considering all the implications of our data and our scientific theories, past and present. But, in a world where there seems to be a lot more up-in-the-air speculation than nose-to-the-grindstone computation happening, I can certainly sympathize with his view.

Here's the message I'm trying to convey: In a world where physics is so often viewed as the golden ticket of truth and knowledge, and yet the fundamental basis on which the entire structure of physics is built is riddled with confusion, and not even the greatest minds in the field to date can agree on what hypotheses are more or less correct, how can we expect to have any hope, whatsoever, in determining what diet is best for human beings, when the system in question is unimaginably more complicated than those the greatest minds in the world are stuck on?

In a community where everyone has a divergent opinion on what's healthy and what's not, what's obesogenic and what's not, which diet is best for which people, under which circumstances, etc., I can't help but wonder if the nutrition and metabolism community might be better suited to follow the path of the aforementioned 12% minority [of physicists], and just shut up and calculate. Forget about what we think we know, and just focus our attention, instead of on ideals, on generating better, more generalizable data, utilizing solid statistical methods, carefully avoiding common missteps (like overemphasizing p-values, running too many significance tests, and using relative risk ratios rather than absolute risk and NNT, among other things), making all the data available for objective re-computation, analyzing quantifiable changes in biochemical assays, and more.

"But Ian," you might retort, "If we don't stand up for our ideas in this way, the raw food vegans will win!"

Um, no. No they will not. Because their data (i.e. their math) will not prove their bias. It never does. Either, they want to think it does, but vital information is missing or intentionally excluded, or they purport something to be true, but their own calculations prove them wrong!**

**e.x. Willet, et al. have continuously tried to vilify red meat as etiologic in the pathogenesis of cardiovascular disease. Yet, each time they present an epidemiological data set that "seems to suggest" a "trend toward significance" that "red meat consumption is linked to [heart disease, diabetes, etc.]" they fail miserably and are forced to write things like: "After adjusting for [BMI, smoking, drug use, added sugar, etc.] the significance of this finding was attenuated." (i.e. We found shit, but we want you to come away thinking meat is bad, so... let's skew the conclusion. But, guess what, they can't skew the mathematics! They can only try to cover things up in sneaky ways, for whatever reason, by omitting relevant data points. But, assuming all the mathematical methods are made available to you, you can re-compute their findings and confirm or deny their association for yourself.)

Perhaps if we spent less time analyzing the introductions and conclusions of new papers, from the perspective of our biases, and, instead, spent our time diligently comparing, calculating and re-calculating the tables, the results and the statistical methods, we might actually be able to realize some new insights. Or at least postulate more accurate assertions into the "reality" of human metabolism, based on more than our conceptions of "common sense."

Perfect example: Hall, et al. (2015) purported to "prove the insulin hypothesis of obesity wrong." Everyone freaked out over the potential for methodological bias, blah, blah, and yes, I agree those things are important to consider, on some level -- even though I mostly disagree that they really played a part in that particular trial -- but, for those who really wanted to "win the argument" on this one, all they had to do was look at the figures. Stop seething over your hurt feelings and do the math: No statistically significant difference between intervention groups, with respect to serum insulin concentrations, by the end of the trial. But, there was a significant drop in both groups, from baseline. Both groups lost [the same amount of] weight. Insulin decreased [the same] in both groups. Oh look, there's still a correlation between insulin concentrations and fat mass.

Shut up and calculate.

There's a special kind of power in mathematics and scientific computation. Use it.

And if, in time, the math proves you (or I) wrong, we must all suck it up and roll with the punches, because 2+2 will always = 4. Science readily adapts as its hypotheses are falsified, and this is almost always due to better calculations! Quantifiable data sits at the heart of "what is Science."

Wednesday, September 30, 2015

Questioning the Nutritional Competency of Physicians

Considering the current lack of nutrition education in medical school curricula throughout the United States, it has become common in the lay public to question the dietary advice offered by physicians - assuming it's offered, at all. Can we trust what our doctors tell us about what we should eat?

In response to this question, I would be inclined to ask is you can really trust anyone's dietary advice, regardless of their education and credentials?

* * * * *

For many people, their doctor is the all-knowing encyclopedia of human form and function, an omniscient being, elevated to throne-like proportions; particularly in America, where status means everything. Physicians, through unparalleled grit and arduous training, sit at the pinnacle of the ladder of what we consider "success."

Don't know what's wrong with you? Go see the doctor. Inexplicable symptom your WebMD searches fail to diagnose? Time to see the doctor. Yet, on some level, we all know doctors are human like the rest of us. Their training, time- and labor-intensive as it is, doesn't enable some kind of super-human, photographic memory. One human being cannot be expected to remember everything they were ever taught.* (This is why, when they leave the room after the H&P, they often spend time consulting with other specialists or referencing their Merck Manual - or Dr. Google - about your case; if it happens to be an uncommon presentation.)

*Of course, no one prefers to think of doctors this way. In a sense, they are a little like commercial airplane pilots. Infallible is an unspoken requirement for the job. We disassociate humanity from these professionals, because our lives are literally in their hands. Who in their right mind is content to imagine their airplane pilot as an anxious drunk?

When it comes to prevention and wellness, from the standpoint of nutrition and exercise doctors have tended not to fare so well. From my experience, the task of discussing these options was generally delegated to other professionals, whether they be registered dietitians (RD), exercise physiologists (RCEP) or others. There's nothing wrong with sending patients out to have someone with more specialty training discuss their case with them, in greater detail. In fact, in some cases it's not only warranted, but you'd be doing your patients' a serious disservice not to. (It's important that all of us have an intimate understanding of our own limitations.) Depending on their level of expertise and the quality of their evidence-based practice, this might even be the best option. But, from what I've seen, it can take a lot just to get someone in for a check-up with their primary care provider. They're busy enough with school, work and families of their own. The point is, patients are people, and people are busy and frustrated, or generally stressed out with life. Getting them to go see a specialist practitioner, unless it's a life or death situation, may pose a challenge.

But most medical practices do not employ RDs, for example, or preventive health coaches of any kind; they're stuck in hospitals, rounding on intensive care patients with TPN - for good reason, of course. Not to mention, in today's healthcare economy, it can be a troubling extra expense for the primary care provider, who's already experiencing difficulty maintaining their overhead and getting by, with changes to the system that directly impact their ability to provide high-quality care.

Ideally, I would like for someone with extensive knowledge and expertise in nutrition (or exercise, depending on what we're considering), and the time to truly sit with someone and discuss their individual needs, to spend some quality time with patients, and create a personalized plan they can implement immediately and with sufficient ease; particularly considering medical providers don't usually have the time to get into the nitty gritty of what's involved, here, to be effective. Or, at least, one wouldn't think so. Unfortunately, ignoring the challenges that come with trying to implement something like this, and the compliance and patient adherence issues that would likely tag along with it, I am wrought with a bigger concern:

How can I trust the competency of the [average] nutrition professional, in a world where over 50% of our research findings are false,[1] in areas of biomedical science that are considered to comply with high-quality experimental science (e.g. Genetics and drug targets) -- compared to fields like nutrition, which, from my perspective, have not had such compliance, historically. Why should I put my faith, and, more importantly, my patients' health, in the hands of someone whose evidence base is predicated largely on nutritional epidemiology; precisely the kind of observational data that has done little more than confuse the world for the last 50 years, with sensationalism like the following (albeit slightly exaggerated):

Eggs are bad.
No, eggs are good!
Wait, wait, no... they're bad again.

Red meat gives you cancer.
"Red meat gives you heart disease... through TMAO! We've found a mechanism."
"Oops, never mind. TMAO production is actually greater with fish consumption. We like fish."
"Systematic reviews reveal no connection of SFA to heart disease."

"Fiber is beneficial, ergo, we must eat all the fiber."
"Diverticulosis is a 'fiber deficiency disease'..."
"No, wait, no. There's no causal connection between fiber intake and diverticular disease."

Et cetera, ad infinitum.

Epidemiology, although imperative for detecting mass effects on a large-scale, with respect to infectious disease epidemics, is virtually worthless for giving us useful data with regard to what to eat, and which nutritional practices cause what physiological responses, apart from giving nutrition scientists more questions to attempt to find answers to. Then, of course, there's the additional concern I would have that the few controlled experiments in nutrition that are out there are under-powered to detect significant effects, riddled with statistical peculiarities, like the (massive) problem of multiplicity, and more. I don't mean to suggest this isn't also a problem within many or even most other areas of biomedical research. It certainly is. The point, however, is that I can't help but wonder how much I can actually trust the views of the typical nutritionist, when I can't trust their data. It has nothing to do with them, or their degree, but where their information is trickling down from.

With all that said, however, if the licensed nutrition professional (the RD, in this case) exists specifically to help educate and treat folks with nutritional deficiencies of some kind or another, or to help optimize someone's diet and individualize it for their personal needs, and the information that predicates their practice isn't very strong, what makes the physician think he or she is qualified or capable of providing expert nutritional advice to patients, when they have, at most, 20 hours of nutrition education throughout the entirety of their medical training[2] -- much of which probably told them that vitamins and minerals are useless, dieting doesn't work and medical nutrition therapy for prevention should join the ranks of complimentary and alternative "medicine" (CAM).**

**For the record, I think this is utter crap. It is my opinion that nutrition is perhaps the single most important and influential factor in maintaining ones health and preventing any undue lifestyle disease. I just also happen to hold the simultaneous belief that most of the data used to determine treatment paradigms in this field are currently poor, or analyzed and interpreted horrendously. I do believe, however, that there are more intelligent and practical determinations that can be made from the available data, depending on where one chooses to focus their attention. (Easier said than done, sometimes, I realize.)

On the one hand, I believe there are still medical schools that do not include nutrition in their curricula, at all. Not one single hour of lecture on the topic. That's abysmal, and pretty depressing, if you ask me. Then again, medical students amass an inordinate number of hours studying gastroenterology and the digestive system, medical physiology and biochemistry, the pathology and pathophysiology of every body system, and then some - which is an understatement, actually, if you ask me.

On the other hand, I suspect that all it would reasonably take for someone with this sort of unparalleled training in human physiology to teach themselves the requisite facts re: nutritional biology would be a bit of extrapolation from their organic and bio-chemistry and physiology training, and some intelligent re-affiliation with their biostatistics texts. (Considering most of the books used to teach physiology and pathology to dietetics students are watered down versions of medical physiology and classic tomes like Robbin's Pathologic Basis of Disease, which medical students learn from directly for years, I don't think it's too wild to suggest that these people are equally as capable of distilling the important points from the field of nutrition, if given sufficient attention and applying some critical thinking to the task.)**

**I do think it's an important consideration, however, to acknowledge that physicians are trained to think algorithmically. Knowing this, many physicians are bound to accept that the established paradigms and guidelines for nutrition (like the DGAC) are correct, until proven otherwise, and so, I suspect many of them just push the standard nutrition information: 6-11 servings of grains, 3-4 servings fresh fruits and vegetables, no processed junk, etc., a little like a robot, because "that's the [currently acceptable] answer," plugged into the [currently accepted] algorithms.

Frankly, almost no one questions whether physicians are capable or qualified to treat individuals with hypertension, for example, but how many total hours do you suspect medical schools actually spend lecturing on this specific subject? Consider the amount of material thrown at medical students over the course of the four years they spend in school; there's simply far too much of it for any one particular topic to take much more of their time than that. Not to mention, the majority of a physicians training actually occurs in their chosen specialty, during residency. So, attacking medical schools for their so-called "poor design," may not be the most efficient tactic to rectify this problem. Perhaps, if anything, the question ought to be: how can we incorporate more nutrition and preventive health education in primary care residencies?

A friend on twitter, who happens to be a registered dietitian, studying for a Ph.D. in nutritional sciences, and who I have a great deal of respect for, recently posed this question, which I thought was interesting (and relevant):


Having already partially addressed the second question, I'd like to spend a moment reflecting on the first. "How are MDs expected to give diet advice in a 15 minute visit?"

As with most things in medicine and patient care, this question has a multifaceted answer, much of which I don't intend to get into. For instance, not every PCP only spends 15 minutes with a patient. But, let's say they did... I personally know many physicians (not all of whom are primary care docs) who successfully do this kind of thing, on a daily basis, which often seems to culminate in astonishingly positive results for their patients. These individuals include, but are not limited to:

               Dr. Rakesh Patel (family physician)
               Dr. Ted Naiman (family physician)
               Dr. Emily Deans (psychiatrist)
               Dr. Dea Roberts (preventive medicine physician)
               Dr. Jeff Stanley (internist)
               Dr. James Crownover (sports medicine physician)
               Dr. Jason Fung (nephrologist)
               Dr. Nicole Anderson (general practitioner)
               Dr. Victoria Prince (family physician)
               Dr. Anastasia Boulais (general practitioner)
               Dr. Colin Champ (radiation oncologist)

Then again, I also know a number of RDs and nutritionists who have succeeded in helping innumerable clients achieve equally positive results, yet, I imagine, spend substantially more time with each individual, coaching and educating them on nutrition. [Adele Hite, RD, MPH, Franziska Spritzler, RD, CDE, Amy Berger, MS, NTP, and many, many others...]

Perhaps the secret sauce is distilling the most important points into manageable chunks for people to implement, immediately, in consistent baby steps. Whatever it is, all of these professionals are making it happen, somehow. I don't think it is fair, at all, to suggest that physicians are incompetent in the area of nutrition and preventive health, it is merely that the vast majority of them either do not understand or appreciate this avenue of health science (generally, from my experience, because they've never bothered to look into it, or have other vested interests that occupy too much of their mental capacity -- once again, a single individual human being cannot know or do it all, and shouldn't be expected to.)

All things considered, I wouldn't be content to question the nutritional competency of the physician -- although most would still do well to examine the randomized-controlled clinical data that do exist, at present, and formulate their own educated opinions, as I believe I and many others have finally began to do. I would question the nutritional competency of anyone and everyone, irrespective of their purported expertise. In a world where one dietitian will tell you to eat the Blue Zone way, another will tell you to eat low-carb, high fat (LCHF), and a third will tell you to stop eating altogether; meanwhile, one doctor will tell you to go on a juice fast for three weeks, another will tell you to do a protein sparing modified fast, and yet a third will tell you that militant veganism is the road to optimal health, how can you afford not to question it all?

For what it's worth, I am not writing any of this with the intention of knocking my nutrition colleagues in any way, shape or form. I know a great deal of dietitians and nutritionists who are absolutely phenomenal, highly intelligent and very competent. Some of them are getting doctorates in nutrition and metabolism. Some are working in private practices of their own, changing lives every single day for the better. I commend them, and I have the utmost respect for each one of them. However, I find that the number of healthcare providers in the field of nutrition who have done the intellectual work necessary to truly weed out the important nuggets of information from the insanely convoluted world that is nutrition science and public health is absurdly low, and so my trust in the overall state of the profession has waned over the years.

We all know great physicians and awful physicians, fantastic nutritionists and horrible nutritionists. This goes for every career in health care; medicine, nursing, pharmacy, social work, physical therapy, etc.. Nobody is exempt. It's never about the degree, or the title one wears, but the individual who has earned it.


As always, "The greatest amount of scientific eminence is trumped by the smallest amount of scientific evidence."

Decrees, accolades, credentials... none of these things matter. Science is concerned with evidence.



REFERENCES

[1] Ioannidis, J. P. (2005). Why most published research findings are false. Chance, 18(4), 40-47.
[2] Devries, S., Dalen, J. E., Eisenberg, D. M., Maizes, V., Ornish, D., Prasad, A., ... & Willett, W. (2014). A deficiency of nutrition education in medical training. Am J Med, 127(9), 804-806.

Wednesday, September 23, 2015

Believe What You Will

Belief is a funny thing, in that one need not reflect on a fact for a long time, in a deliberate attempt to determine its truth, in order to take it as being the truth. In essence, there is always a little faith tied to every belief. (Including within science, I might add - For an in depth analysis as to why I say this, I implore you to read this article by Stanford Philosophy: The Problem of Induction.)

With respect to scientific thinking, it is common for a belief to be predicated on Plato's epistemic rule for what constitutes knowledge. (i.e. Justified True Belief.)

Is your belief true, and are you justified in believing that this thing is, in fact, true?

According to Plato's dialogues, one cannot have knowledge of something unless they believe in this something, and if this something can be proved to be the case.* It is the word proved, in this context, that typically matters most to scientists and critical thinkers.

*This presupposition ignores the Gettier problem, in epistemology, which purports to disprove Plato's JTB concept of knowledge. However, interesting as it might be to go down that rabbit hole, I must insist that we temporarily accept this presupposition, for the sake of argument.

Proof requires evidence.

Evidence is - or, should be - the only thing that matters in science. The premise of empirical knowledge is that, once all the data is collected, analyzed and interpreted, beliefs will tend to shift in accordance with what the agreed upon result of this scientific synthesis seems to be, at least transiently.

The reality, however, is that, with particular regard to biological research, there is so much noise in the system, so much data to collect in different ways, so many hypotheses to refute as it were, that just about anything could have some credence. All one has to do is spin the data a certain way, give it a certain flare and a plausible underlying mechanism, and BAM!, we have a potential belief-winner.

If biology were more like analytical chemistry or experimental physics, it might be a different story. More solid evidence would be required to confirm mechanistic principles that underlie various conjectures. Experimental conditions set to confirm or disprove a cause and effect relationship would hopefully elucidate "the answer." And if, in 20, 50 or 800 years, someone has falsified the previous result with a more refined experiment and observation, the beliefs change accordingly.

A great example of such an event is the shift that took us from Newtonian (classical) mechanics to relativistic mechanics to describe so-called large scale, cosmological occurrences. It is understood to be the case in the physics community that Isaac Newton had it right with his laws of motion, but, when Albert Einstein came along and ruined all that perfect mathematical deliciousness with his theories of special and general relativity, an amazing shift occurred (over time) where people began to realize that he was, in fact, indisputably correct - with the implicit understanding, of course, that his theories were also subject to falsification, as are all other theories -- and their beliefs about Nature changed to reflect this paradigm shift.

The trouble is, biology -- although it rests on the laurels of physics and chemistry, from a purely reductionist perspective -- functions quite differently from its sister sciences, wherein, due to the innumerable and often immeasurable variability in the systems, it can be nearly impossible to discover "the answer." And, in fact, it may be the case that there is no such thing as the answer, at all; there may indeed be more than one answer, more than one mechanism that causes the exact same outcome or set of results.

Because of the aforementioned complexity in studying the life sciences, and the nature of biological phenomena to be convoluted and elusive, it is easy to suspect that we have an answer to a particular question, when, in fact, we might well be dead wrong. Or perhaps we're not so wrong, but just a little wrong. Or maybe we're on the right track, yet still no cigar. Or maybe we are right, but our ideas behind the mechanism are too simplistic....

Ultimately, my point is simple: At the end of the day, everyone's hypotheses are valid - much more so, of course, if they are predicated on previously "proven" theories. More importantly, it is that science is an ever-changing, constantly adapting discipline, which requires supple minds to morph along with it. You cannot be a rigid thinker and call yourself a scientist. It is inappropriate for the discipline, and, if you are a biological researcher, it will (at least in my opinion) turn out to be the bane of your existence. You ought not conduct your life as a scientist by trying to angrily refute every conjecture thrown your way, regardless of your purported expertise or your credentials, even if you assume to "know" that they are incorrect. It is a fruitless endeavor.

The truth will out, in the end. As it did with Newton and Einstein, and then again with Bohr, Heisenberg and the advent of quantum mechanics, the data will eventually shine a light on the nature of reality, as we're meant to understand it, when the time comes. In the meantime, please do not assume I am suggesting you take the superficial view that these last few paragraphs appear to be saying, "every conjecture is okay, because it could be right, or it could be wrong, and you may just note know yet," or something like that. Rather, I'm saying, "Don't fret over every little thing, or take yourself (or others) too seriously."

"It is the mark of an educated mind to be able to entertain a thought without accepting it." - Aristotle

Thursday, September 17, 2015

A Life on Drugs: We've Lost Sight of What's Important

We are at a place in our healthcare economy where a vast majority of American adults are on more than one chronic medications, with what seems like no hope of ever coming off of any of them. Of the more common kinds, HMG-CoA reductase inhibitors (statins) are high on that list, as are anti-hypertensives, anti-depressants and anti-anxiolytics, and many others. Frankly, we are not really taught about taking people off of these drugs in health care, since, more often than not, this isn't something we imagine taking place. Rather, once someone is put on a medication, the likely course of action is that the disease process will continue to progressively worsen, not improve to a point where they no longer need the support of the drug.

Now, I would gladly be one of the first people to stand up and tout the benefits of a well-studied pharmaceutical drug that has a proven track-record of eradicating some disease or another, particularly with respect to things like infectious microorganisms. The fact is, we need medicine like this. If we didn't have access to certain kinds - e.g. vaccines, antibiotics, etc. - or, if they were never invented, droves of people would still be dying of smallpox.

That said, I can think of many examples of prescription drugs which have either not been proven sufficiently well, prior to their institution, or simply have so many adverse events that the purported benefits of taking the drug may not outweigh the side effects. The example I feel most comfortable giving here, with respect to the latter, is of statins. It is my fervent belief that lifestyle diseases cannot be cured or well-treated with pharmaceuticals, but that environmental and lifestyle changes must be implemented intelligently and consistently if one is to hope to truly overcome it. If poor diet, awful sleep habits and sedentary behavior is the cause of someone's disease, I find it doubtful that pharmacological inhibition of the mevalonate pathway, as is the case with HMG-CoA reductase inhibitors, for instance, will be of much help, rather than addressing the fundamental concerns mentioned previously. (Other scenarios, such as certain genetic conditions that predispose to severe hyperlipidemia, like heterozygous familial hypercholesterolemia, may be quite a different story - although, it's worth pointing out that the causes of death in persons suffering from heterozygous-FH are multifactorial and amount to more than just "they've got too much cholesterol in their blood."[1]

Millions of people in the United States are currently taking statin drugs. One of the more popular varieties is atorvastatin. It has been postulated many times that, should someone suffer from what's called hyperlipidemia, or coronary artery disease (CAD), taking a statin, such as Lipitor, may serve to prolong their lifespan. But, I have to wonder, if this is truly the case, by how much? In other words, would it be worth it? Do the pros of taking the medication outweigh whatever cons exist?

It turns out this was studied by Ferket, et al., in 2012, in asymptomatic individuals with established, non-fatal coronary artery disease.[2] Here's what the authors had to say on the matter:


Two important caveats come to mind, for me:

1.) Their model estimated... "x." That doesn't mean someone else's model, predicated on different criteria, couldn't be made to estimate "y."

2.) It's also important to note that the study population they are referring to are people with stable disease and non-fatal atherosclerosis. These numbers might look a little different, should they have examined folks with unstable atherosclerotic disease. Possibly. But, again, I would wonder by how much.

Having prefaced with those two statements, I think this was an incredibly interesting study. All the more fascinating, because they seemed to have found a maximum lifespan increase in primary CVD prevention patients of roughly 0.7 years.

Let's assume that this result holds for a moment. Listed below are just a few of the well-documented adverse events associated with statin therapy, in the primary biomedical literature:

               - Short-term memory loss and cognitive impairment[3]
               - Worsened insulin resistance, or newly developed type 2 diabetes mellitus[4-5]
               - Severe muscle disease, including myositis and rhabdomyolysis[6-7]
               - Mitochondrial dysfunction[8]
               - Significant vascular calcification and arteriosclerosis[9]
               - Atherosclerosis and heart failure[10]

So, you tell me (because it may just be a thing of personal preference or philosophy); would it be worth it for you, to have just one more year of life, but to potentially suffer any one of a number of significant side effects in the process, or even develop other serious and debilitating diseases?

Moving along....

Years ago, there was yet another cholesterol-related drug in the clinical trial phases of testing, but was, it turned out, a miserable failure, because it was killing people.[11] Torcetrapib, a cholesteryl-ester transfer protein (CETP) inhibitor, was actually completely halted during the testing process, the clinical trials stopped in their tracks, because the deaths were piling up with a frequency that the FDA was uncomfortable with.

This led Tall and colleagues, among other researchers throughout the world, to question whether or not the cause of these deaths was the molecule in the drug, or the mechanism, itself.

In my opinion, all one must do to reach a conclusion here is to look at the aforementioned adverse events, when we inhibit cholesterol synthesis or mess with the mevalonate pathway, and it should be clear to us all: the problem seems to be with the evolutionarily conserved mechanisms we are messing with, not necessarily the molecules.

Now, in 2015, Big Pharma has its eye on another "big win" for preventing cardiovascular disease - still regarding cholesterol, mind you. Another mechanistic inhibitor, pharmacological PCSK9-inhibition. Where statins target synthesis, CETP-inhibitors attempt to block the transfer of cholesterol and triacylglycerols from lipoproteins to cells, PCSK9-inhibitors work to prevent certain strains of the enzyme proprotein convertase subtilisin/kexin type 9 (PCSK9), from downregulating or destroying LDL-receptors in the liver, which is the primary disposal site of excess LDL-particles from the blood.

What will the results of these experiments be, I wonder? It could be that this turns out to be a miracle drug for someone with advanced hyperlipoproteinemia. But, what, for example, do you suppose might happen to an otherwise healthy person when their overly eager health care provider prescribes the PCSK9-inhibitor as a first line of defense, in the primary prevention setting, not realizing that very low cholesterol is also quite dangerous. Hypocholesterolemia is associated with cognitive deficits, increased risks of cancer, and, most notably, a three-fold higher risk of hemorrhagic stroke. There is a reason that every single eukaryotic cell in the entire body synthesizes and requires cholesterol to some degree to exist healthfully.

Just today, I saw on Twitter a post from Nature Medicine regarding the membrane protein Nogo-B, which has recently been shown to have inhibitory effects on sphingolipid biosynthesis in murine models. How long do you suspect it will be before they've concocted a pharmaceutical drug designed to inhibit human sphingolipid biosynthesis, because of this new information? Whether that may turn out to be beneficial or harmful, I couldn't say. But that's not the point.

My point is that we've lost sight of what is most important in health care: quality of life. (In favor of "quantity of life.") In an attempt to halt one aspect of the progression of one disease, we have forsaken functional, positive health, well-being and quality of life, in the hopes for longevity, in the form of "delaying death."

This is not health. This is not what health care should be about. We can and should do better.



REFERENCES

[1] Sijbrands, E. J., Westendorp, R. G., Lombardi, M. P., Havekes, L. M., Frants, R. R., Kastelein, J. J., & Smelt, A. H. (2000). Additional risk factors influence excess mortality in heterozygous familial hypercholesterolaemia. Atherosclerosis, 149(2), 421-425.
[2] Ferket, B. S., van Kempen, B. J., Heeringa, J., Spronk, S., Fleischmann, K. E., Nijhuis, R. L., ... & Hunink, M. M. (2012). Personalized prediction of lifetime benefits with statin therapy for asymptomatic individuals: a modeling study.
[3] Galatti, L., Polimeni, G., Salvo, F., Romani, M., Sessa, A., & Spina, E. (2006). Short‐Term Memory Loss Associated with Rosuvastatin. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 26(8), 1190-1192.
[4] OHMURA, C., WATADA, H., HIROSE, T., TANAKA, Y., & KAWAMORI, R. (2005). Acute onset and worsening of diabetes concurrent with administration of statins. Endocrine journal, 52(3), 369-372.
[5] Koh, K. K., Quon, M. J., Han, S. H., Lee, Y., Kim, S. J., & Shin, E. K. (2010). Atorvastatin causes insulin resistance and increases ambient glycemia in hypercholesterolemic patients. Journal of the American College of Cardiology, 55(12), 1209-1216.
[6] McClure, D. L., Valuck, R. J., Glanz, M., & Hokanson, J. E. (2007). Systematic review and meta‐analysis of clinically relevant adverse events from HMG CoA reductase inhibitor trials worldwide from 1982 to present. Pharmacoepidemiology and drug safety, 16(2), 132-143.
[7] Manoukian, A. A., Bhagavan, N. V., Hayashi, T., Nestor, T. A., Rios, C., & Scottolini, A. G. (1990). Rhabdomyolysis secondary to lovastatin therapy. Clinical chemistry, 36(12), 2145-2147.
[8] Statin adverse effects: a review of the literature and evidence for a mitochondrial mechanism. Am J Cardiovasc Drugs. 2008; 8(6): 373-418. doi: 10.2165/0129784-200808060-00004.
[9] Auscher, S., Heinsen, L., Nieman, K., Vinther, K. H., Løgstrup, B., Møller, J. E., ... & Egstrup, K. (2015). Effects of intensive lipid-lowering therapy on coronary plaques composition in patients with acute myocardial infarction: assessment with serial coronary CT angiography. Atherosclerosis, 241(2), 579-587.
[10] Okuyama, H., Langsjoen, P. H., Hamazaki, T., Ogushi, Y., Hama, R., Kobayashi, T., & Uchino, H. (2015). Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms. Expert review of clinical pharmacology, 8(2), 189-199.
[11] Tall, A. R., Yvan-Charvet, L., & Wang, N. (2007). The Failure of Torcetrapib Was it the Molecule or the Mechanism?. Arteriosclerosis, thrombosis, and vascular biology, 27(2), 257-260.

Wednesday, September 16, 2015

A Calorie is a Calorie... Right?

I will offer my best attempt at explaining this concept, while keeping the impending rant relatively brief.

How many times have you seen both of these phrases, at one time or another?:

1. "A Calorie is a Calorie." (Thus insinuating that the composition of our food doesn't matter.)
2. "A Calorie is not a Calorie." (Thus implying that the quality and composition of the food we eat is the only thing that matters.)

In order to satisfactorily answer the question whether a Calorie is a Calorie, we must first define our terms.

A calorie is a unit of thermochemical energy, equal to approximately 4.184 joules. Roughly speaking, it is the amount of heat released from a substance when that substance is oxidized, or burned. Classically: a calorie is the "amount of energy needed to raise the temperature of 1 g of water by 1 degree Celsius, at a pressure of 1 atm."

Important to note here is that a calorie and a Calorie are not mathematically equivalent. Calorie, with a capital C, is actually 1,000 gram calories, or 1 kilocalorie (kilogram calories; 4,184 J). It's confusing at first, I know, but you'll get it.

The thing that bothers me is this: by saying "a Calorie is not a Calorie," what you are effectively suggesting is that 4.184 J does not equal 4.184 J. Uh... Yes it is and yes it does. It's math, and the thing about mathematical proofs is: they can be proven. But let's ignore the philosophy and science of mathematics, for the time being. I understand what you are really trying to say. You're trying to say that "Counting calories is ineffective." So, why why not just say that? Let us all choose to be more precise in our thinking, and in the way we convey those thoughts to the world.

Make no mistake about it. A Calorie is a Calorie is a Calorie, because, 4.184 J is 4.184 J is 4.184 J.

That said, just because 1 Calorie = 1 Calorie, chemically and mathematically, that does not necessarily mean that oxaloacetate is phosphoenolpyruvate is acetyl-CoA is alpha-ketogluterate, or that protein is carbohydrate is fat. Or, for that matter, that glucose is fructose is cellulose is ribose. Or, really, any other combination of similar nutrition-related sets you can conceive of. Do you see where this is going? That's because these compounds are actually different "things" with different biochemical and physiological actions. Different molecules, different substrates, different structures, composed of different things, or even just different amounts of different "stuff." Point being, just as 8 of something is always the same as any other 8 of the same something, a Calorie is and will always be a calorie.

Duh.

But by conceding the truth of that cliched statement, I've told you nothing useful about metabolic processes. At least not with regard to their various causes and effects. Appealing to an energy flux, with respect to physiology and metabolism, speaks only to the large-scale (macro-level) results of thousands of chemical interactions happening within the system, yet it says nothing about those (micro-level) biochemical interactions.

What frustrates me about the opposing idea, that "a Calorie is a Calorie," at least as it is currently argued in the nutrition sphere, is that this notion implies that the 1st law of thermodynamics (the conservation of mass and energy) and "Calories in, Calories out" are exactly equivalent scientific hypotheses. In fact, they are not -- at least not from a pragmatic perspective, and I'll tell you why.

Calories in, calories out (CICO) could only be identical to Energy Conservation if all of the incoming energy and all of the outgoing energy (and every biochemical or biophysical transformation in the middle) could be measured and accounted for. As far as I am aware, this is currently impossible. Calories in, as measured by the average person, is often hundreds of Calories off the mark; and even our best methods of measurement in this area are not precise enough to account for all the physiological activity that takes place after said energy has been consumed. (After all, we don't just care about what's incoming, we care about what our cells are doing with this energy, and this is incredibly complex. To my knowledge, this is not something we are able to measure with any amount of precision.) On the other end of the spectrum, Calories out is equally, if not much more, challenging to measure.

You know that little monitor on your elliptical which tells you how many calories you're supposedly burning, during your workout? It's wrong; and not just some of the time, it's always wrong. So wrong, you'd be astonished. You might as well put a piece of black electrical tape over it and forget it's even there, that's how useless it is.

In most cases, energy expenditure is so multivariate, complicated, dynamic and difficult to measure with sufficient accuracy and precision, that it's a wonder anyone can conflate CICO with energy conservation - even if the underlying conception isn't entirely incorrect.

You shouldn't come away from this post going: this author thinks all Calories are equivalent, so eat whatever you'd like. Don't misinterpret. I'm saying all calories of the same amount are equivalent amounts of energy -- however, the substrates from which they came may not be. The latter is not only more important, but far more interesting, in my opinion, as this is where the intricate biology takes place, and is one of the things that separates us from physical machines.

Human beings are not bomb calorimeters.

(As an aside: we do not "burn calories" -- our cells burn chemical substrates and release the thermochemical energy in their chemical bonds as heat. Which substrates are oxidized, at what rates, in which pathways, etc., all of this matters far more in describing the "whys" of metabolic interactions than any appeal to an energy flux ever could.)**

**To the many internet nutrition gurus who have come to believe that the human body - or, indeed Life (i.e. cells), in general - does not obey and cannot be described by the laws of thermodynamics, I suggest you do some reading in statistical mechanics and non-equilibrium thermodynamics, because the statement: "We are open systems, therefore, thermodynamics doesn't apply" is misleading and incorrect.

Saturday, August 15, 2015

Did low fat beat low carb for fat loss, after all?

A new paper, published in Cell Metabolism, by Dr. Kevin Hall and colleagues, entitled: "Calorie for Calorie, Dietary Fat Restriction Results in More Body Fat Loss than Carbohydrate Restriction in People with Obesity"[1] claims (as its self-evident title would imply) that this is precisely the case.

I feel compelled to clarify something for the many people who are already priming themselves to comment below, something to the tune of: "This study does not reflect real world dieting," etc.... The authors know this. In fact, they state it in the paper, and Dr. Hall said the same thing in his WebMD interview[2]:


That's not to suggest this isn't an important consideration. It certainly is. My point is simply that it isn't something the authors neglected to take into account. This study was designed primarily to answer a specific research question. (I do not think they succeeded in doing so - or, at least I suspect their confidence is substantially over-estimated, hence the reason I am writing this post.) Keep that in mind, but we will return to this idea, toward the end of my thought process.

Before getting into the meat of the paper, I would also like to comment that, although I do expect that if carbohydrates were restricted even further, the results of this study (carried out for a longer period of time and with a larger sample) may well have turned out differently, perhaps favoring the carbohydrate-restricted approach, this trial was never intended to be a ketogenic diet study. What would have happened, had they tried to reduce total carbohydrate (CHO) intake further, and "match" it to total fat intake? When the authors did the calculations, the only reasonable way they figured they could keep total Calories and protein intake constant across both study groups was to have the Reduced Carbohydrate (RC) arm eat 140 g of CHO (29% of total kcal) per day, which is exactly what they did. If not, something else would have had to give. It seemed like the only way the researchers could be certain that, if the RC arm reduced adiposity more than the Reduced Fat (RF) arm, it didn't come from an increase in protein, and, conversely, that if the RF arm came out on top, that it wasn't due to a decrease in calories; both of which would be important confounding variables that would have ruined the study and destroyed their chances of being able to discern the mechanistic understanding of weight loss diets they were seeking. In order for them to do what they set out to do, which was to measure potential metabolic changes and inefficiencies under isocaloric conditions - more specifically, to prove that insulin levels need not be low for a "metabolic advantage" to occur in fat mobilization and oxidation - they had no choice but to match Calories and protein, and reduce CHO as low as was possible; which, unfortunately, only turned out to be 29% of total kcal. In their own words:


Ignoring the fact that most people simply cannot resist jumping on the bandwagon and riding out a scandalous message, the main reason I think this trial has already seen so much popularity, in less than 24 hours, is because this was a metabolic ward study; an experiment where people are held in a hospital ward for the duration of the intervention, closely monitored and fed carefully controlled amounts of food, to enforce accurate observations and data point measurements, and avoid contaminating results. As well, this type of controlled experiment avoids the pitfalls of the "free-living" diet study, where participants supposedly eat some kind of diet, but no one can say for certain exactly what that diet might have been, because no one's following each of them around and keeping the would-be-necessary tabs. It is merely presumed that the prescribed diet is adhered to throughout the study. (It's true that metabolic ward studies of this kind may have little practical relevance to the reality of our day-to-day lives, in cases like this where one of the experimental diets is unsustainable outside of the laboratory setting, but that's actually beside the point - the research question (primary outcome) wasn't "Can people adhere to an 8% fat diet, in real life." It was, apparently, "Is Gary Taubes' carbohydrate-insulin hypothesis of obesity correct?")*

*Something that was brought to my attention after I originally published this blog post, and which I think is a fair point, is that, since this was clearly not a "diet trial," -- although, everyone and their grandmother will misinterpret this aspect of the methodology to exploit their personal bias, whether low fat or low carb -- but a human nutritional biochemistry experiment to test the effects of an acute-phase response of insulin on adipocyte metabolism, why not put one group on a 0% CHO diet (for RC) and the opposite (RF) on a 0% fat diet and then make both arms isocaloric, thus, taking the issue of changes in protein right off the table, and fixating exclusively on the question of "What about changes in insulin?" As I say, it is a fair point. After all, what would it really hurt? And if it wasn't a diet trial, but an experimental model of metabolic biochemistry...

Anyway, getting to the point, here...

19 obese, but otherwise seemingly-healthy, subjects (all free from diabetes), between the ages of 18 and 45 years, were selected to complete this trial. 9 women and 10 men were randomized to either a RC or RF arm for 6 days, after a 5 day observation, prior to the intervention, to maintain and document a strict caloric intake:


The inclusion criteria was one of the things about the study that I thought was quite good.

Although, overall, this seems to be a rather small sample, statistically-speaking, it's difficult to conduct a much larger metabolic ward experiment of this type, due to a variety of factors, not the least of which is the expense. However, per their Statistical Analyses, it appears to be adequately powered (at 80%) to detect the changes they're hoping to observe. (As I'm not a statistician by trade, please realize that I'm sort of taking them at their word for this.) As is common, their alpha-level (significance) was set at p < 0.05.

Of the things I enjoyed about this study, one was that the authors controlled for intentional physical activity, by requiring each study participant to partake in the exact same level and intensity of treadmill exercise, throughout the intervention. As someone who tends to pick apart research by the number of possible confounders I can conceive and apply to the data, this one made me smile. They even made sure the female subjects were in the follicular phases of their menstrual cycles, prior to initiating their interventions. Impressive. (And, unless I'm reading them incorrectly, it wasn't just intentional exercise; they also monitored daily walking, with a hip-worn, pager-like accelerometer. This is important, as changes in physical activity, non-exercise activity thermogenesis (NEAT), etc., can add up quickly and could have muddied the energy expenditure data.)

One of the things I was surprised about was that HOMA-IR scores, prior to the intervention periods of the experiment, averaged about 2.7; pretty clearly indicating insulin resistance in these obese persons. Yet, in all the other literature I've seen, thus far, RC diets tend to be more effective for fat loss in IR persons than RF diets do. Clearly, 8% fat is very different, metabolically, than the usual 30% fat (LF) diet. Then again, perhaps it's too premature to anything like this, since subjects spent just 6 days in a chamber, and insulin levels were not significantly different between groups....

The aspect of this study that bothers me - predominantly due to the many silly extrapolations into real world advice to "eat low-fat for fat loss" it has since generated - is that the intervention period was only 6 days. (Now, let's be clear. It was 6 days, per intervention. Let's not forget, this was a cross-over design. In between interventions, each participant underwent a 2- to 4-week "washout" period, before entering the next 6-day intervention.) Still, 6 days is incredibly short, particularly considering the primary outcome they were testing. As many low-carbers have vehemently (and perhaps rightly) argued, 6 days is an insufficient time for one to fully fat-adapt.[3] Keep in mind, once again, this was not a ketogenic diet trial; we aren't talking keto-adaptation, per se. But, it is still quite possible that there are enzymatic changes that may take place, even in the context of a moderately low-carbohydrate diet, such as this one was, which did not have sufficient time to develop and persist. (e.x. Even though fat oxidation did just begin to ramp up in the RC arm, it's likely that these people were still metabolizing glycogen for a few days, all while the RF subjects were starved of almost any incoming fat.)

Sharing the opinion that much more adaptation time may be needed to detect any of the meaningful metabolic changes Hall et al. were looking for - although perhaps related more to transgenerational epigenetic reasons than acute metabolic changes - is respected scientist and renowned islet cell and diabetes researcher, Dr. Jim Johnson (below), who has recently published a paper demonstrating that hyperinsulinemia is a prerequisite for the development of obesity in a genetically-humanized mouse model, and that suppressing it early on can determine the course of that animal's lifetime susceptibility to developing obesity:[4]*


*Don't misinterpret, here, please: I don't mean to suggest that we should extrapolate from rodent data before we do so from human experiments. I'm merely suggesting we ought to be careful extrapolating from a trial of exceptionally short-duration, whose tendentious and yet unreplicated results stand in opposition to mountains of literature regarding historic high-carbohydrate diets, hyperinsulinemia & insulin resistance syndrome and obesity in a variety of experimental, clinical and observational models.

For what it's worth, many of the metabolic ward diet studies I have read have been equally brief. 6-8 days is fairly common for controlled feeding studies. But I don't think it wise to extrapolate widely from those data, either. It's not as if Dr. Hall and his colleagues have committed some egregious misdeed by intentionally undercutting things. I don't think it would be fair to assume this was the case - although, I think it's understandable, to a degree, that some people are left wondering if this wasn't an easy and ill-intentioned way to make the RF arm look better in a shorter amount of time. The troubling thing is when one sees the preliminary results of a 6-day trial and proclaims to the world, "This style of eating works! Low-fat for the win!" This is where I take issue, and where I disagree. (Though, it should be noted that droves of low-carbers do the same thing with preliminary data favoring low carb, which is equally problematic.)

Even if the results of this study prove true, and end up being generalizable, over time - which seems like a long-shot, from my perspective - it doesn't address whether the dietary composition used to achieve 8% of Calories as fat would be healthy. Nor does it suggest whether this eating style is something one could adhere to for longer than 6 days, let alone long-term. It's one thing to force an individual to consume cardboard, while you watch them through a hole in their box to make sure they choke down the last bit, before shutting them back in. It's quite another to expect that they could do it, themselves, in free-living circumstances. (For the record, Dr. Hall and his team already realize this, as well):


Sounds appealing. Sign me up.

8% of Calories as fat (or roughly 17 grams of fat, per day) is equivalent to a little less than 140 grams of lean chicken breast. Are you prepared to count out your walnuts, one by one, and totally avoid otherwise conventionally-healthful fatty foods, like olive oil and avocado, maybe even become a vegan (because it seems the only plausible way to maintain such a low level of total fat intake, on a day-to-day basis)? Good luck with that. Please, report back with your quantified-self results.

This, of course, is only where we stand if we choose to accept these data at face value. I am not ready to do that. There appear to be a few important inconsistencies between the conclusions drawn in the discussion and the raw data.

Firstly, they make us aware that each subject underwent a DEXA scan, to assess fat mass and body fat percentage, but - disregarding that the title of the paper claims that fat loss was superior in the RF arm - no statistically significant differences in either fat mass or body fat percentage could be seen, comparing DEXA scans between the RF and the RC subjects. (p < 0.78 & p < 0.24, respectively; a la Table 3, pictured below.)


As you can see at the bottom of the table, however, "cumulative fat imbalance" differed between groups by 218 grams. (Which, for us Americans, equates to approximately 0.48 lb. of fat.) The alpha-level was far exceeded (<0.0001), in stark favor of the RF arm.*

*Considering that a relatively large number of significance tests were performed, and DEXA was apparently not sensitive enough to detect the ~0.5 lb. fat loss, is it possible that these findings might have been the result of a type I error? I ask only because of the discordance between the cumulative fat imbalance data and the DEXA results. DEXA should have been sensitive enough to pick up a 0.48 lb. change in fat mass, no?

Someone suggested to me that perhaps the DEXA scans were not sensitive enough to pick up the results of said fat imbalance, due, perhaps in part, to some potential concerns with respect to soft-tissue fluid status and the impact of hydration on the intra- and inter-individual variability of DEXA results. Although this sounds plausible, I gather that this hypothesis is predicated on the idea that RC dieters have likely lost some body water due to heightened fluid excretion and depletion of glycogen - as evidenced by the statistically significant changes that were seen in body weight and BMI, which are shown at the top of the table. And I think he's quite right; it's unlikely that participants lost 1.2 lb. of muscle mass in just 6 days; it's probably mostly losses in tissue hydration and glycogenolysis. Unfortunately, all the data I've seen on this topic suggests that fluid overload is more important than fluid excretion, with respect to DEXA screening, and that its impact has more to do with results of lean mass than fat mass[5]. Nevertheless, there is some data suggesting physical mechanisms for why this might be the case, but the concern is minimal, to the point that I'm not sure it makes any practical difference:[6]


Therefore, I am left to think that, since DEXA revealed no significant difference, and because DEXA tends to be the most accurate - albeit not necessarily always the most precise - anthropometric measure we have to assess changes in body fatness that doesn't cost an arm and a leg to implement, it might be the case that this aforementioned claim is false, and that the most any reputable thinker would reason that the conclusions should have read as follows:

Body fatness decreased slightly, concomitant with the total Caloric deficit from baseline, regardless of any changes in the macronutrient composition of the two diets. Between-group DEXA analyses revealed no statistically significant difference in body fatness, after the 6-day intervention periods.

One of the things that concerns me, simply because the data is omitted, and I really think it ought to at least be included in the supplemental materials, is that one of the female participants in the trial - and it was never explained from which arm she belonged - achieved a DEXA result that was a "clear outlier," and was excluded from the statistical analyses. In the supplemental materials, the authors briefly explain that including her results in the analysis would have skewed the distribution - and yet, Dr. Hall's e-mail correspondence with me conflicts with this, as he claimed to have run the computations both including and excluding this subject and that neither significantly changed the results in any meaningful way. But, in a study of 9 women, doesn't every one of their individual data points matter, on some level? Regardless, shouldn't that data be readily available for consumers? And, lastly, what exactly does it mean that her results were "not physiological?" Did she have unexpected lipoplasty before the scan?:

This may come across as accusatory, and I don't intend for it to, but, from what I understand, these data are represented as SEM (or standard error of the mean), as opposed to SD (standard deviation), and, while this may not be the case here, it is widely accepted in statistics that it is easier to emphasize small, but unimportant differences in the data with SEM than with SD, especially with small sample sizes. Since I don't have access to the data necessary to do the appropriate calculations to switch it to standard deviation (because it is not made readily available), I cannot see what the distribution would look like, afterward, but it definitely makes me curious....

Lastly, and the thing that rattles my chain the most, is this:


Someone please explain to me how it is responsible to extrapolate from a 6-day controlled feeding study of 17 subjects, two of which were eating the wrong diet altogether for one of those days? This trial appears seriously flawed on that count alone.

Overall, the experimental design looks good. I found myself impressed with many things about it. And I also think (assuming Dr. Hall and his team can provide some answers to these questions and wouldn't mind relinquishing the rest of the data to absolve the trial of these potential water-marks), it may, if not provide insights into the questionable effects of the immediate impact of insulin secretion on whole-body adipose tissue metabolism directly, serve to ask further questions regarding the nature of the application of this hypothesis to human beings. But, all things considered, it's a big "what if."

~ ~ ~ ~ ~ ~ ~ ~ ~ ~

There is one aspect of this study that I have intentionally omitted from this post. The mathematical models with which Hall, et al have extrapolated weight loss out 6 months from the end of the trial. (The model is described in detail in a separate PDF, in the supplemental materials section.) Although they are intriguing, in their own right, they mean little to me until they have been corroborated with real world data. At this point, they're just mathematical hypotheses, which doesn't interest me. I am only interested in real-time physiological data.

I must admit, I have not tried to go through those numbers to get a more complete understanding of his mathematical model of metabolic regulation, but, I will say this... even if we make the enormously presumptuous leap of faith that Dr. Hall's model is flawless, and he could find subjects who could adhere perfectly to this RF diet for a full 6 months, can you guess how much more weight they will lose, compared to their RC comparators, who get to eat virtually all the fat they want? 3 kg. (or 6.6 lb.). That's roughly 0.25 lb. per week; barely more than intense exercise seems to provide, over the same time interval, which we know is minuscule compared to the benefits carbohydrate restriction seems to provide in free-living experiments. Hardly worth the sacrifice, I think.*

*Some people are bound to jump to the erroneous conclusion that, because an 8% fat diet "worked," any generic fat reducing approach will do the same. Sorry, no cigar. I'd be interested to see what Hall's mathematical models would look like if he assumed even a 2% error in compliance. Let's assume someone complied almost perfectly, and ate, say, 10% dietary fat. How would this alter the extrapolated mathematical data?

Once again, although interesting, this is just a hypothesis, and is predicated on a the results of 17 people after a 6 day trial, which may have gone differently had more adaptation time been given and the trial time extended, or the sample size increased. If we ignore their mathematical extrapolations, which is what I chose to do here, the most a reasonable person might say regarding the actual - as opposed to reported - outcome is something like: "After 6 days of eating RF or RC, participants who ate RF seemed to have an average of 0.4 lb. less body fat than the RC group, but which DEXA was not sensitive enough to detect." And this was a massive and unrealistic reduction in dietary fat, and it was still either equivalent or barely better than the RC group, that ate a comparatively whopping 108 g fat per day. Already, there are hundreds of people saying, "See, fat does make us fat!" I suppose that's one rather silly way to look at it. Then again, both groups lost weight and body fat from baseline, due to the reduction in total Calories, and, even though the RF group ate substantially less fat, they barely had any discernible differences in outcome. Imagine that.

Perhaps the most important and, indeed, most relevant aspect of this study was the authors' attempt to determine whether a reduction in serum insulin could accelerate lipolysis, as predicted by so-called low-carb dogma (specifically Taubes, et al), and whether, leaving insulin elevated, as in the RF arm, would result in an "inability" to mobilize and subsequently burn fat. This was the ultimate research question, and the reduction in serum insulin levels between groups were comparable, and did not reach the statistical significance they were hoping to see (p < 0.48), despite the graphic they used to show a slight reduction in fasting insulin in the RC, as compared to RF arm.

(Table 4):


So, it seems the real answer to the original research question posited by Hall et al. is more like a resounding "We can't really know, based on these data alone," than a clear-cut yes or no, regardless of what some people would like to have you believe.

One 6-day intervention study of 17 participants proves nothing, nullifies nothing and is generalizable to no one. (But, it could possibly provide insights or generate new questions, if it is replicated and these results can be reproduced (a bit longer), and insulin levels actually differ more significantly between comparator arms.)

* * * * *

Important Takeaways (TL;DR):

(1) This experiment was not designed to test diet efficacy for real-world living, it was an attempt to prove the carbohydrate-insulin hypothesis of obesity wrong.

(2) Insulin levels fell only slightly more in the RC arm than in the LF arm, but not enough to be statistically significant or clinically important between groups, thus invalidating the conclusion, from my perspective. (And perhaps only suggesting: "Low carb isn't the only way to reduce circulating insulin or improve insulin sensitivity.")

(3) Controlled feeding studies of this sort may say nothing generalizable to everyday life, or to designing pragmatic nutritional strategies. (Regardless of what the LA Times seems to think.)

(4) The study design was interesting, and quite good. Aspects of the implementation, however, turned me off. (e.g. Feeding 1 RC-er RF on the first day, and 1 RF-er RC on the last day. Mistakes like these can turn out to be study-ruiners, especially when the totality of the time under observation is 6 days per intervention.)

(5) One of the not-so-exceptional aspects of this methodology was brought to my attention by a reader who commented over at Hyperlipid: "...the biggest flaw in this study is that it was not done in a steady state." This calls into question extrapolating from metabolic data collected in an state that has not yet reached an appropriate equilibrium, and speaks back to the lack of an essential adaptation period on the RC diet. This is critical.

(6) DEXA results do not corroborate the message that is being brought to the attention of every media outlet who will listen that the RF arm lost more body fat than RC. Therefore, I'm inclined to think this wasn't actually the case. (If you can't show it, it didn't happen. And, if you have to show it with a microscope, it's not clinically relevant.)

(7) For the sake of argument, let's assume that none of the issues I've brought up are of any real concern. The most accurate thing one can say about these results is not: "More body fat loss with low fat," but something like... "According to these preliminary data, after 6 days in a strictly and artificially controlled environment, a very low-fat diet, compared to an isocaloric, euproteinemic, reduced-carbohydrate diet, appears to have the potential to reduce adiposity in obese, adult human beings by roughly 218 grams (or ~0.22 kg) by day 6. It is unclear whether these results are generalizable to a wider sample of the population, whether they might persist in this manner, as time goes on, whether extrapolating them to free-living conditions is warranted, and whether either dietary model would serve to improve human health over time. More studies are needed to address these questions."* And the issues are concerning.



EDIT: The study protocol for this experiment was finally released, but are, in my opinion, woefully inadequate. Sampling method? Not provided. Intervention? Not provided. All outcome measures? Not provided




REFERENCES

[1] Hall, Kevin D., et al. Calorie for Calorie, Dietary Fat Restriction Results in More body Fat Loss than Carbohydrate Restriction in People with Obesity." Cell Metabolism, Available online, 13 August 2015.
[2] Goodman, Brenda. "Low-Carb Diets May Not Work the Way We Think They Do." WebMD, 13 Aug. 2015. Web. 14 Aug. 2015.
[3] Westman, Eric C., et al. "Low-carbohydrate nutrition and metabolism." The American journal of clinical nutrition 86.2 (2007): 276-284.
[4] Templeman, Nicole M., Susanne M. Clee, and James D. Johnson. "Suppression of hyperinsulinaemia in growing female mice provides long-term protection against obesity." Diabetologia (2015): 1-11.
[5] Horber, F. F., et al. "Impact of hydration status on body composition as measured by dual energy X-ray absorptiometry in normal volunteers and patients on haemodialysis*." The British journal of radiology 65.778 (1992): 895-900.
[6] Pietrobelli, Angelo, et al. "Dual-energy X-ray absorptiometry: fat estimation errors due to variation in soft tissue hydration." American Journal of Physiology-Endocrinology And Metabolism 274.5 (1998): E808-E816.