Saturday, June 18, 2016

Confused and afraid in the wake of terror.

As most of you reading this will already know, last week, on June 12, 2016, a man who I shall not bother to recognize by name, went into a gay dance club in Orlando, FL and used an apparently legally-acquired firearm to brutally murder 50 LGBTQIA persons, wounding roughly 53 others.

This will not be a rant on gun control. Other than the insinuation I have made above, I will not mention it again. Nor will I comment on the many talking points currently circulating in regard to this man's religious affiliation, or whether or not he may have had any ties to a particular terrorist organization.

Initially, I was extremely hesitant to write anything about this. I have felt, in the succeeding days since this senseless attack that has taken the lives of so many innocent people, and forever devastating hundreds of others, that, although a certain light should be shed on it, so we may learn from and hopefully prevent it from happening again, there may be a disdainful temptation by some on social media to profit from this tragedy in the form of dramatically increased views or readership. The thought of it disgusts me. It turns my stomach to think of it now, and I want nothing to do with that kind of pseudo-altruism. And, of course, this blog has been a means to disseminate potential insights into human metabolism and physiology. I am a budding scientist, not a source of pop-culture news. I didn't want to put anyone off by appearing political, and changing the course and tone of the dialogue so dramatically. But the longer I sit in silence and contemplate the nature of this unspeakable act, solemn and alone in the recesses of my mind, the more I realize how wrong it would be to say nothing, to let the events of the previous week fall away without acknowledging the simultaneous seriousness and senselessness of it all, and reconciling how lonely and petrified it has since made me feel. As distasteful as it may be for some of us who would like instead to forget that this happened and move forward with their lives, without having to relive the idea of it, we mustn't rush to dismiss all that lies in the wake of this terrifying ordeal. And some of us do not have the luxury of putting it on a shelf, out of sight, and forgetting that it happened.

Though I might otherwise have a lot more to say about this, from a variety of intellectual vantage points, I will spare you the vast majority of it, as I would rather sit beside you in a grassy field on a clear day and iron out the finer details of our thought processes, together, as fellow human beings. As a couple of short-lived creatures with an equal platform. Since that's clearly an impossibility, I should like instead to touch briefly on a few key things that have plagued my mind, and how this horrific tragedy, which will go down as one of the worst mass shootings in our country's history, has made me feel, as a member of the LGBT+ community.

I want to preface the remainder of this post by saying that I have not been directly affected by this event, in the sense that I did not lose any friends or loved ones at the hands of the killer, and I would never in my wildest dreams pretend to equivocate the pain this is causing me with the agony the victims in Orlando must be going through. I honestly cannot even begin to comprehend this from that standpoint, and I hope to God to never be forced to. That said, although I live over a thousand miles away from the Pulse nightclub, I have been powerfully affected by this tragedy (as have millions of others), albeit indirectly, as an openly out and proud gay man. It may be difficult to imagine why this should be the case, but I think it is true for many people in my community, at this time. For some, you may already have an all-too-intimate familiarity with the feeling of the desperate isolation and misunderstanding that comes with being "different" from the people around you. Friends, family and colleagues may conform to a certain normative standard, but you... well, you've always been different in some not insignificant way. To those of you that have been fortunate enough to have escaped the agony and social pressure to conform - even when conforming is not in the cards for you - which others of us have been forced to endure from a young age, please allow me to paint you a picture of how terrifying that life can be.

As an impressionable young child, vulnerable to the vicious mental attacks made by so many people around you, sometimes unwittingly, you are often made to feel as though the traits that make you different are not things that make you special, but chinks in your armor, the bits and pieces of your soul that are rotten and should be changed wherever possible. This has a tendency to make you wish you were someone else, someone "normal," whatever that means. Cut to adulthood, where you have spent the last few decades of your life trying to emulate the status quo, misappropriating masculinity where there was little before, or femininity where it feels unclean and un-You, adopting an idealized sense of self that has been forced upon you, because what you are inside has been conceptualized as wrong, or even bad. As a gay person, it is not uncommon for one to feel as though everyone walking past us on the street believes us to be perverted pedophiles, just itching at the opportunity to get our grimy hands on some poor unsuspecting children - whether or not this is in fact what they happen to think. Thankfully, times appear to be changing, what with the recent Supreme Court ruling to federally legalize gay marriage, etc., but the unfortunate fact is that the mental image you are cultivating was and often still is the reality for those of us a few standard deviations away from the mean.

As a gay man who has grown up in a relatively conservative, rural part of the northeastern United States, I have been hit, harangued, bullied, kicked, spit on, and called names I don't particularly care to repeat on more occasions than you might imagine. I have been physically and emotionally abused and taken advantage of, robbing me too soon of my innocence in a manner that took me ten years of therapy to process through and recover from. I have spent many of the precious days and nights of my teens imaging what, if anything, it might be like on the other side of Life. There are still states in this country where it is legal for the employer of a gay person to fire them for their sexual orientation, as if their proclivities in the bedroom have anything at all to do with their successful performance on the job, and there are no laws in place in those states to protect them. There are still states that refuse to allow LGBT people to adopt children who need stable, loving homes, because of their gender identity or sexual orientation. Some of you might feel inclined to cry out, "This is the 21st Century, for God's sake, what's going on!" I understand it's difficult to wrap your head around, if you are on the progressive side, and of course I agree with you, but as these words leave your lips, gay men and women are being slaughtered and stoned to death in real time in other parts of the world. It is a crime to be who they are in some countries. Just take a moment to imagine that, would you? To walk this earth knowing that the very essence of who you are is punishable by imprisonment or death. But don't be fooled. In no way is this strictly a third-world affair. Violent crimes and various other physically and socially aggressive acts are committed against members of this community, on a daily basis in the purportedly "civilized" western parts of the world, as well. And, from the standpoint of policy, We the United States are regressing as a nation, with bills passing to limit the rights of transgender individuals to use the bathroom they feel safest and most comfortable using, and the ability of gay consumers to take advantage of certain business establishments in the same way that their straight peers would be allowed to do. (Imagine refusing service to an Asian person because she was Asian, or going back to the dark days of black and white segregation. Would you turn away a black person because he was black? I thought not. So why is it okay for us to accept policies that would do the same to a gay person, because they happen to be a member of the LGBT+ community? It is not a choice. If it were, I can attest from personal experience, only a Munchausen's patient would seek it out!)

I'm not even legally allowed to donate blood to help save lives, unless I have been celibate for 12 months or more. Despite the daunting and undeniable fact that we are now entering a blood crisis, particularly in the wake of tragedies like the Orlando shooting, and the lab techs and pathologists test the blood extensively, anyway, I am still seen as too much of a risk to donate, even though I am a safe, exceptionally healthy, non-promiscuous and exclusively monogamous individual, and none of the victims who have survived can give blood at the hospitals in order to help save their friends. This is an utter travesty! As a gay man in particular, I am viewed by our healthcare policy-makers and politicians as significantly less than former prostitutes and IV drug users. But people don't hate or discriminate against gay people anymore, right? Where is the outrage!

When I eventually came to terms with who I am, and finally understood that I was not alone and I could actually build a life worth living, predicated not on who I was told I should be, but who I felt I needed to be on the inside, I felt an unburdening of proportions there will never be sufficient words to describe. I'm sure this resonates with many people in my community. I do not pretend to speak for anyone other than myself, but this seems to be a common theme with the "It Gets Better" movement; self-acceptance, other-acceptance and life-acceptance has led to an unimaginable improvement in the quality of my life (and probably the quantity, if I'm being honest with myself). Still, a great many of us are not as lucky as I have been to grow from these experiences, both positive and negative, and make it out the other side alive, where the birds of life can be found singing once again. So, you might imagine how horrifying it is for us to know that the one place which is ours, the one place for those of us who have been so lucky, to be able to seek refuge from the pressure of societal conformity, and the perpetual angst we feel to reign in who we really are on behalf of a shell of ourselves we don't really believe in - our sanctuaries, so to speak - no longer feels like the haven of safety and protection it ought to. It's not about dancing and loud music, it's not the thumpa-thumpa of the subwoofers and the glittering lights sparkling about the room. It's not about the muscles and the madness, or the party. It's about the fact that being in a room full of people like yourself, where you should get to feel perfectly safe and happy, elicits a cascade of warm emotions truly difficult to explain adequately, which set our souls on fire, and make us feel as though we have finally come home.

As the days after this terrible shooting trudge by, as if swimming through thickened mud, I am left imagining a scene where my friends and I go out for a Friday night and dance to the beat of the music, under the incessant flashing green lights, barely illuminating the room for but a second, feeling the heat of a hundred sweaty, smiling men and women all jumping up and down within a 600 square foot space, when those obnoxious hip-hop gunshot sounds go off in the song, because the DJ happened to have missed a set of them when (s)he was wiping them from their records. Everyone ducks and screams, terrified we are going to die. Heartbeats pounding in our ears, lungs on fire, we all look down and around at each other, checking for blood. Tears immediately streak from our eyes, as the DJ shuts off the music and apologizes profusely for the mishap. Was it a mistake to come back so soon? 

Or perhaps our previously steadfast belief that everyone in that bar is just like us will go soaring out the window, and we won't be able to dance freely with other men and women, meeting new friends, new lovers, new brothers and sisters with the same ease, because we may not be able to shake that intense feeling of fear that we don't really know them. What if they are not actually like us? Can we ever really know anyone? What if they want to see me dead? Are they going to be the next mass murderer? How could I know one way or the other? Are there signs I should be able to pick up on? Are they putting on an act, to get me to let down my guard? Can I... let my guard down? Where's my sister, is she still here? I can't see her anymore....

Other than the streets of Key West, West Hollywood or Provincetown, LGBT-specific establishments such as Pulse are some of the only places in the world where we have been able to feel safe, truly ourselves, and now all of us will be left with a hole in our hearts that may never again be filled in quite the same way.

Late on the 12th of this month, a young mother received a text from her son, from a bathroom stall, where he is hiding from the shooter, who is just outside the door. The text reads: "I love you mommy." After asking whether or not he was okay, he responds that "he's coming," and "I'm going to die." The assailant entered the restroom and killed him and the others seeking refuge in the stalls beside him.

One of the young female patrons was a mere 18 years old. She had dreams of earning a college degree, and was said to be one of the happiest and kindest girls her family and friends had ever had the pleasure of knowing. She is now dead, because of one hateful individual with an agenda.

A boy recently came out to his mother, and, afraid that she would not accept him, was relieved when she expressed acceptance after all. To demonstrate this to him, to prove her love and affection, she was actually in attendance, dancing with him at the Pulse nightclub. Fortunately, the young boy survived the attack. His mother, on the other hand, was killed in the crossfire. Can you imagine having only recently come to accept that you are a gay man, and then because of a demonstration of support for your new identity, your loving mother is murdered over it? How is that poor young man supposed to go on from this, and not harbor the resentful feeling that who he is got his mother killed? Of course, we all know implicitly that this is clearly not the case. But do you really suppose that he will be able to think that rationally about it? (If so, you should consider spending some time observing the irrational fears and resentments that worm their way into peoples' psyches, which rear their ugly heads during psychotherapy.)

Some of the victims of the shooting had presumably not come out to their loved ones, because many of those in our community still keep knowledge of this limited or exclusive to a few select confidantes. Members of their family did not know they were involved in the incident, but also couldn't have fathomed learning that not only was their child keeping a life-changing secret from them out of fear that they would not be accepted, they were murdered and now were never coming home again. The thought that this child's mother will never be able to hold him or her in her arms and tell them that they will always be loved, and that they could never be a disappointment to them, is heartbreaking. 

One man was said to have held his partner's hand while he died. His partner of three years bled out and died before him, and he could do nothing to stop it, but lie beside him and simultaneously pray that he wasn't next, and then presumably feel terrible pangs of guilt that he felt that way, while his partner's life quickly drained from his body as he waited for the shrieks of horror and the pop, pop, pop of the rapid gunfire to subside.

I will agree that, first and foremost, this tragic mass shooting is an attack against humanity, for we are all human beings. In some ways, it may also be an attack on America, or at least all that She hypothetically stands for. This kind of extremist perspective (whether religiously-fixated or not) isn't exclusively anti-gay, it is anti-everything unlike itself. So, yes. Naturally, anyone who shares these so-called "American ideals" - whether American or not - was the intended target. But setting these important acknowledgements aside, please do not downplay the powerful impact this massacre has had and will continue to have on LGBT+ people all around the world, for all the reasons I've alluded to, and many more I have not, and the fact that it was directed explicitly at us. As well as being a crime against humanity, this was indeed a hate crime, and it has sent devastating shockwaves throughout the LGBT+ community that, at least in this moment, is hard to envision fully recovering from. This is the fear that currently pulsates through my veins, as I write this.

The ultimate point of my writing this, however, is to rise up and say that we cannot let this defeat us. I do not mean for this to be aimed exclusively at my fellow LGBT+ community members alone; I say this as a reminder to us all. The principle objective of terrorists is exactly that, to terrorize. We must not allow ourselves to fall victim to the fear mongering that is essential to their cause, or we are actually supporting their ability to cause more death, mayhem and civil destruction!

It would be remiss of me not to acknowledge that I am afraid. It would be a lie to suggest otherwise. I am terrified, right now. I've also been confused as to what to do, next; where do we go from here? After this attack, I walk the streets of my city differently. I think many of us are doing so, regardless of whether or not we happen to be a gay person. But, when an act like this is directed at your brothers and sisters, your kin, in this way, when who you are on the inside has three inch bullet holes in it, it's difficult to raise your stare from the ground as you pass people by and not wonder if they might be one of those who thinks the world would be a better place without you in it.

Side Note: To the ultra-conservative, regressive, right-wing politicians - and, of course, the mentally handicapped within the group; looking right at you, Mr. Trump - who, instead of doing anything helpful, have turned to parading around like buffoons on television, pretending to offer up their pathetic, insincere "condolences," while having spent the rest of the year working their tails off to prevent us from being able to use whichever bathroom we feel most comfortable and tirelessly trying to revoke the laws that allow us to marry the ones we love, I would like to offer up a big 'ol fuck you. You can keep your condolences. I, for one, don't give a rats ass about your favorability ratings, and I doubt anyone in Orlando does either. You don't see us as equals, and never have, so don't pretend to now. It doesn't become you. This senseless massacre doesn't change that. It's just a ploy for you to reign in some sympathy votes, and no one is buying it. You come across a little like an opportunistic infection in that way. If you truly meant these otherwise seemingly kind words, it would be a meaningful gesture of standing beside Orlando and the LGBT+ community in solidarity, but that's not what this is, and you do a shitty job of hiding it. It's a means to an end. We are not your means, but ends in ourselves. These are our lives. Just do your damn job and shut the fuck up. (As for those select few of you that may have had an awakening after this tragic event, I applaud your new insights; welcome to the reality where we are human beings, too. It's good to have you.)

It is with a heavy heart that I have spent the last few days thinking about what has happened to the victims involved in this tragedy. The resultant casualties have been immense, the pain our fellow man must be feeling is gut-wrenching and unimaginable.

I grieve for those people of Orlando who were killed in the shooting, ripped from life long before their time. I grieve for their families and loved ones, who must now arrange funerals for those people they never in a million years would have imagined they'd be burying early. I grieve for the people in my community, both here in the United States and abroad. I grieve for my family, especially my mother; no mother should ever have to beg her son not to go out dancing, because there's a chance he might never come home again. I grieve for myself, because I have, at least transiently, wondered whether my city might be next; whether I might be caught in the next shower of bullets. I have spent too many hours, as of late, contemplating how lucky I am that it didn't happen in my city, and subsequently feeling pangs of guilt for thinking it. It could have been me and my friends. It wasn't, but it could just as easily have been us.... And I grieve knowing that there are still many thousands of people out there who cheer this callous and inhumane behavior on, and wish it to continue. I feel very sad for them. To me, they are pitiable. I know that if they had their way, they wouldn't hesitate to do the same to me, and to my friends, all because we're supportive of the "gay agenda." Which agenda is that, pray tell? The fight for individual liberty and a life of happiness? Well, if that's the cause, I would choose to stand up and fight every single day for the rest of my days to secure that. I would die for it, should it ever come to that, because I could never accept living in a world where my basic human rights are denied, on the grounds that I refused to pretend to be somebody I am not. I will live free, or I will die free, but I will remain free. No one will ever again take from me what took a lifetime of struggle to realize.

There is room enough in this world for all of us, irrespective of our religious, sexual, cultural, and socioeconomic differences in belief and backgrounds. But, whoever we are, the fundamental platform from which we base our lives should not be predicated on hate and remorse, but on compassion, helpfulness and understanding. As do all human beings, we each deserve to be happy, to be loved, and to live a life of freedom, unafraid to be who we really are.

From my vantage point, I feel we mustn't stoop to the level of those who should seek to destroy us, for we are better than that. We are and should continue to be better. I understand the weapons are not identical, but perhaps the best way to combat their message of hate is with one of love. After all, we will get nowhere fighting hate with hate, we'll only propagate a further propagandized message into future generations of brainwashed individuals who have bought into the lies that have been sold to them about our nature.

Now is the time for grief. So, let us grieve. Let us mourn the loss of our fellow men and women, whether they be gay, straight or any of the myriad forms we humans take. But then, whenever that time should come - and it may be different for each of us - let us (each and every one of us), stand together and abolish the victim mentality that people like this shallow-minded, mentally disturbed murderer and his sympathizers should like to force upon us. We will not be victimized. But neither can we resort similarly to hate, lest we become precisely like these contemptible terrorists, and, again, they will have won. We must keep our dignity intact. We must strengthen our resolve. We must unify and come together. We must prioritize love above all else, and protect and help one another through this trying time, and the many yet to come.

I don't know that any of the victims of this attack will ever find themselves reading this, and, frankly, I would almost rather they didn't, so they might begin to move on and find some kind of solace and inner peace following this tragic horror story they have been living. However, should any of them be reading these words, I say only this directly to them: Although there are no words that could ever satiate the ache left in the wake of this horrible tragedy, I want to express my deepest sympathies for what has happened, my undying and unconditional love for you and your family, and apologize from the depths of my soul for all the hurt you must be feeling. I wish there was something, anything, I could do to right this wrong, to take away your pain, and to bring your loved ones back.

Let us all remember the love we feel for those we have lost, but not memorialize the fear and panic that is meant to scare us all into conforming back into what we have fought so desperately to break free of in the past.

If you are a straight person reading this, please understand that no matter where you happen to be from, or who you are, there may be multiple LGBT+ people in your life who are silently afflicted with an unspoken fear, anger and terrifying loneliness they may not be able to put into words, and it will not pay to brush this act of domestic terror off as though the hate crime part of it is of little concern, because, let me assure you, it means everything to them right now.

Our trust is broken, our faith obliterated. But, in the face of terror, we must unite and stand stronger than ever.

Let us find the capacity to forgive, but never forget.
Rest in peace, my friends.

With love to you all, whoever and wherever you should be.
- Ian Lane

Friday, April 22, 2016

The Importance of Statistics in the Biomedical Sciences: Some Initial Thoughts.

This may or may not turn into a series of random entries, over some yet undetermined length of time, because I actually have a great deal to say on it. I'm not sure, yet. But this particular post is more a less just a meandering of some of my initial thoughts on the matter.

Quite often, especially as of late, I wish I could go back in time and teach my 22 year old self about nuance, and what it means in the context of biomedical research. One of the pivotal things about said nuance, which is always present in the data, should you bother to look for it, is that this bit about context is supremely important. In what circumstances does your finding(s) apply? Under what conditions was your experiment conducted (assuming yours is an experimental finding)? Was the study performed on tissue culture in vitro, or was it done in vivo? On experimental animals or in human subjects? Children, males or females? Athletes or non-athletes? Et cetera, ad nauseam.

All too often, people -- laypeople and scientists alike; the development, or lack thereof, of logic and reasoning skills do not discriminate based on advanced degrees** -- take the results of some study or other at face value, and do not tend to look much more deeply into the nuances of the data set they have settled their faith in.

**To my knowledge, the vast majority of biomedical science and graduate biology programs in the United States do not require any advanced data science courses beyond introductory inferential statistics. At the very least, the addition of quantitative and qualitative research methodology and maybe one intermediate or advanced biostatistics class would seem like a good idea to start implementing, given the issues that have surfaced and run amuck over the last few years in the scientific community. 

Now, I do not intend to come across as unwilling or unable to understand that most of these people may not necessarily have the time, the desire or the education necessary to sufficiently decipher and deconstruct the methodology and results of some hypothetical paper. Nor do I wish to convey the incorrect idea that I take myself to be an expert in this area, without flaw. I am not a data scientist, by trade; though, the more I study the intricacies of the application and interpretation of statistical methods in medical research, the more knowledge I try to soak up in this area. With these acknowledgments squarely in mind, let us come to an understanding:

Science would mean very little if it could not be understood properly, in the appropriate context(s), and subsequently communicated in as an effective manner as possible to whatever audience for which it is intended. If it cannot be comprehended properly, we don't have science, what we have is a singular, irreproducible, jumbled observation. The biomedical sciences are no exception. In fact, due to the unimaginably expansive nature of... well, Nature, biology and medicine may have actually prompted this dictum.

I bring up my 22 year old self to reflect on my prior immaturity, as a student of these sciences, which I have only recently come to terms with. (I will do my best to succinctly and coherently circle this back to my main point in a moment.)

At that time, I had just become enamored with the biochemistry and physiology of nutrition, particularly fat and carbohydrate metabolism, and had just started to learn what Google Scholar and PubMed were. You may already see where this is headed.... After months and months of hyper-fixated, some might call obsessive, personal research and reading up on diet in the primary nutrition literature, I had reached a similar conclusion as many other people seemed to have come to, circa 2011 and beyond; that carbohydrate and linoleic acid restricted diets seem to be a more favorable option for the majority of people (although, I was far less subtle about it, then -- hence ye old nuance problem).

I was on Facebook, then, with my own "fan page" (puke), because I was trying to promote a business I had taken a few years off of college to start, out in Los Angeles. I was a fitness and nutritional consultant, with a boutique operation in North Hollywood, and am still a strength and conditioning coach, fascinated by physique science and athletic performance, today. (Of course, I have since left Los Angeles, and my priority is to finish my graduate and medical education.) Anyway, if I recall correctly, I remember posting something to my "followers" (gag) about how Nutrition is applied biochemistry, not statistics. Without going down a separate rabbit hole, altogether, which I could easily write another 10,000 words about, I would like to say that, although I was, yet again, completely oblivious to the (really very important) nuances with respect to what I was saying, I will agree with "old Ian" that nutrition is applied biochemistry. That said, he was at least partially an idiot, because we can come to zero conclusions about nutritional biochemistry and the physiological implications of our data, whether experimental or otherwise, if we do not conduct rigorous, systematic statistical analyses to understand the probability that our effect is indeed applicable to some representative population, or, indeed, whether or not we have simply generated a type I or type II error, or some other statistical fluke. But did I even know what the null hypothesis was? Pfft. Who has time for that, when I and a host of other people -- many of them professionals in the field -- had already convinced ourselves we had the right answers. (Whether or not we did, or still do, is beside the point I'm currently trying to make.)

An important part of the whole objective of the scientific endeavor, whatever the field in question, is to study a tightly controlled, highly specific natural phenomenon and extrapolate it (or "generalize") to other things, people, contexts, or situations. Science is a form of inductive reasoning. Hell, it is the form of inductive reasoning. As such, we try to make sweeping generalizations from impeccably specific observations, or datasets. It is imperative, therefore, that not only our data, but our interpretations thereof are on point, else our conclusions may have absolutely no bearing on reality. (Yet, we will all still strut around like we are clutching the truth in the palm of our hands.) Let's not forget how incredibly convoluted and complex the single eukaryotic cell is, let alone an entire organism, like a human being. One small slight of statistical haphazardness and your entire hypothesis or theory could be thrown out, plain wrong. Scarier still, of course -- as it should be, since proving ourselves wrong (e.g. falsifiability) is the name of the game -- is something that happens constantly, which is to say, statistical slights of hand or flukes that give rise to newly accepted theories, taken as the gospel truth, but which have no solid ground upon which to stand, because the data were misinterpreted, or worse, misrepresented, from the get go.

So, with all that aside, what's the point? My first point is that we cannot be truly good scientists or generate genuinely high-quality science, unless we, at the very least, take into account the statistical implications of our data. Without that, we have no generalizability, no applicability, even if we think we have observed a significant result. This is not to suggest that all biomedical scientists must also be data scientists, or biostatisticians. But should they not at least consult one, if they are not willing or otherwise able to figure out to how properly design, conduct and analyze their trials? Secondly, we must pay attention to the methods and results sections of the studies we read, and not ignore the methodological foundations of conducting research.** And we must read and pay attention to any opposing data, to fight against our own confirmation bias, lest we fall prey to the innumerable pitfalls of fallacious reasoning. Don't pretend it doesn't affect you, it hits us all from time to time, if we are honest. Reading just the abstract and conclusion of any given paper means you are taking the authors' own interpretations of their data as being "the truth" at face value, without any further investigation for yourself. Most scientists are good, honest people (at least the ones I know), and I am not insinuating that they are out to fool you, simply that they are biased. It's their data. But, as many are in the business nowadays of procuring a result, because they have no alternative, unfortunately, given the state of Academia these days, I would rather crosscheck their results and look into the methodology myself, if not to replicate their findings, to be sure they didn't fool themselves in an attempt to publish before their careers perished. Now, of course, if you happen to be reading an article on the intricacies of quantum electrodynamics as applied to chemical physics, that may be an implausible feat to ask of you, and I certainly understand and sympathize with that. But if you cannot comprehend the data, or cannot figure out how best to interpret the meat of the study you are reading, if indeed you are reading it at all, I would advise that you don't cite it in the first place.

**Please note that observational studies are not the only research studies that necessitate the application of statistical methods. Experimental, randomized controlled clinical trials do, as well. (Whether your flavor is Bayesian or Frequentist is another story.)

In all applied science, we face the notoriously difficult problem of determining the probability that our results are not-yet-wrong and, simultaneously, are roughly anticipated to occur again at such-and-such a probability in similar instances, in future observations. This challenge is substantially compounded in biology, due to the issue of complexity I mentioned previously. Fortunately, there are ways we can mitigate this, through precisely those statistical tools and theories of probability I have alluded to, above. However, should you operate under the naive and, in my estimation, false assumption that everything in the data analysis of a given research article was performed and documented exactly as planned from the outset, I firmly believe you will end up being sorely mistaken.

Dr. John P. A. Ioannidis wrote one of my all-time favorite articles, back in 2005, entitled "Why Most Published Research Findings are False," where he critically examined a massive amount of data previously published in major medical journals -- and we aren't talking random and obscure journals from east Papua New Guinea, we're talking the New England Journal, JAMA, the Lancet.... At the very least, he convincingly showed that we have an unequivocal problem of publication bias, non-replication, and false discoveries based on arbitrary and practically insignificant p-values. Another group, in 2011, published a correspondence paper in Nature Reviews suggesting that we cannot and should not trust the results of some individual drug trials, despite the fact that our medical standards of care are largely predicated on some of them.

There are a multitude of other articles like these, shedding light on the issues surrounding the interpretation of biomedical research, and how to better go about not only conducting research but deconstructing it, as a consumer of scientific literature (such as a clinician, practicing evidence-based medicine ought to be). The thing that shakes me to my core about this is that these reviews are discussing the false results of published clinical trials in major biomedical science journals, funded by millions and millions of NIH dollars, with substantive contributions left and right from Big Pharma, including thousands upon thousands of randomized participants. Not to mention, these trials generally have the luxury of being quite rigorous, from a research structuring perspective! Now let's bring this back to nutrition, which is oftentimes... not. small, often insignificant sample sizes, underpowered to detect an effect. Very short durations, due in part to considerable lack of funding for preventive health research. You get the picture. You can imagine why I might be a little hesitant to take it at face value that the study abstract you've linked to me on Twitter about such-and-such a dietary intervention "proved that X happens" without rechecking the statistics for myself, and trying to get a sense of the inherent limitations of the study. Besides, "proving" the truth of a thing is not something we do in nutrition science, or indeed any science; we can only temporarily demonstrate, after rigorously trying to falsify it, that our hypothesis or theory is not-yet-wrong.**

**Assuming you adhere to Popper's conception of falsifiability in the philosophy of science, that is, which most practicing scientists do.

Ultimately, mathematics is the only real precision we have with respect to data analysis and interpretation. Let's use it, and not cast it aside with the same immaturity I have only recently noticed in myself. Particularly because it is so often abused in the literature. In the end, my primary objective in writing this brief little rant is to suggest that you take it upon yourself to become the front-line blockade against shitty statistics, and in order to do that, you have to first understand that they are an essential aspect of any good research.

Once more, I should like to reiterate that I am by no means trying to paint myself as an expert in data science, per se. I am continually learning, the same as everyone else, and am, as of yet, still a student, crunching figures and assisting with small projects. I am just opinionated and passionate on this topic.

SIDEBAR: P < 0.05 =/= FACT.**
But that's a post for another day, I suppose.

**Statistical maladies abound! When one considers the significant Problem of Multiplicity, P-hacking, false discoveries, and the ever astounding type I and type II error rate, most p < 0.05 just = b-u-l-l-s-h-i-t.

There will likely be a part II (perhaps more) at some future date not yet determined. We'll see how I feel.

Thursday, April 14, 2016

The benefits of exercise exist on a U-curve

Few would dispute the idea that intense exercise, as a hormetic stressor, is beneficial for improving human health. From reducing blood pressure and cardiovascular disease mortality rates, to aiding in the prevention of body fat accumulation after or during diet-induced weight loss, and more, exercise has innumerable, virtually unquestionable benefits. However, the type, volume and intensity of said exercise matters a great deal.

Many people begin with the supposition that there are "cardio" based exercises, like running and swimming, and "strength" based exercises, such as resistance training, as in a gym, lifting weights, or partaking in Crossfit, which is all-the-rage now. Sticking with this concept, endurance exercises, such as running, biking and swimming, can be classified neatly in the "cardio" category, and have been quite popular since about the 1970s. In the last few decades, one of the most common themes I have seen in individuals who proactively decide to go from living a traditional American lifestyle, to engaging in healthy lifestyle behavior changes, has been that of deciding to "run the marathon."

As I have not yet spent much time overseas, I do not know whether this is strictly a Western phenomenon, but it seems to me that if someone in our neck of the woods learns that something is beneficial, well, by golly, a whole lot more of it must be that much better. Implicit in this notion is that if running is good for my heart, then participating in an ultra-endurance activity like the Boston marathon should make me IronGirl.

Sorry, no cigar. The benefits of [endurance] exercise exist on a U-curve.*

*This is not to suggest that the benefits of resistance exercise do not also exist on their own U-curve. They very well might. I have just not seen any corroborating data, with respect to that question.

Just because something is healthy at one level of intensity, or by a certain volume, does not mean that if you ramp it up a few notches, it will confer the same benefit, let alone even more. Now, we could sift through an endless array of decently well-controlled studies that exist in the peer-reviewed literature touting the benefits of exercise, many of which have looked exclusively or predominantly at endurance training. But I should like, instead, to take a gander at some of the fascinating data demonstrating what might happen if we intentionally ramp up the intensity and volume of endurance exercise in both humans and experimental animals, and look at a few n=1 case reports of people who have voluntarily done the same thing, under the presupposition that because running is healthy, running a lot must be even healthier.

A few years ago, I randomly stumbled across this experiment, by Benito, et al, conducted in Barcelona, and published in Circulation,[1] where they took male Wistar rats and exposed a group of them to intensive 4, 8 or 16 week exercise regimes, while a Sedentary group got to essentially kick back and relax, and then compared the effects of the intervention on the rats' hearts.

Significant functional and morphologic changes occurred in the hearts of those rats in the Exercise group, after 8 weeks of intense training, such that, upon close postmortem inspection, they had marked increases in interventricular septum and left ventricular wall thickness. Statistically significant increases in overall cardiac hypertrophy was noted in the Ex group. Evidence of both left ventricular systolic and diastolic dysfunction occurred by week 8 and 16, respectively, based on echocardiographic results. (RV diastolic dysfunction was claimed evident, but was apparently not statistically significant, and so did not make much of an appearance in the paper, from what I could tell.) In contrast, of course, the Sed group of rats did not show any signs of these significant pathological changes, throughout the duration of the 16 week experiment.

Perhaps the most interesting thing, to me, since hypertrophy of the myocardium as a result of intense and chronic over-exertion is an anticipated, or at least relatively expected, outcome, was when the researchers then looked at the effects of this exercise regimen on "chamber-specific ultrastructural remodeling." A.k.a. The development of myocardial fibrosis.

Here is what they found:

"There is widespread interstitial collagen deposition with disarray of myocardial architecture." Aside from being a clever way to say, "These rat hearts are fucked, and this kind of training is probably not a good idea," (at least for Wistar rats) these results suggest that the formation of these fibrotic lesions may present a substantially increased risk of potentially fatal dysrhythmia -- this could be one possible explanation for the all-too-common ultra-endurance athlete who drops dead at 35 from sudden cardiac related death. So, naturally, that's precisely what their team looked for next.

According to figure 6, researchers were able to induce polymorphic ventricular tachyarrhythmias via ventricular stimulation in the Ex rats:

Luckily -- again, if you are an unreasonably trained Wistar rat -- there is an upside to all this. A period of "de-training" post-intervention could reduce the cardiac remodeling seen in this experiment, which may indeed mitigate the detrimental effects of the overtraining seen, here. There are some pretty big questions implicit in this, however. Such as, will this detraining benefit continue to exist, if the intervention period is stretched further? At what point will the negative effects of the intervention persist? What are the mechanisms involved in producing these effects? As the authors state in their discussion: 

The biggest question of all, as many of you reading this will have already been screaming at me for the last ten minutes, assuming you've made it this far, is... Will it translate to humans?

Here is where things get really interesting.

In 2011, Wilson and colleagues published a paper in the Journal of Applied Physiology[2] examining 12 veteran endurance athletes, many of whom had either completed 100 marathons or spent over ten years continuously training at an olympic level. This is about as close as I can imagine coming to an ecological replication of the Benito experiment, if ever I've seen one.

Although there are a few inherent limitations in its use, such as it "relies on the signal intensity difference between fibrotic and normal myocardial tissue, and hence a region of 'normal' nulled myocardium is needed as a reference to detect abnormalities,"[3] Wilson, et al, used late gadolinium enhancement imaging (LGE) to detect patterns of myocardial fibrosis in the study participants. 50% of them had diffuse patterns of myocardial fibrosis. These are people who are supposed to be healthier than all of us, especially due in large part to their exceptional athleticism. In spite of it, they actually appear to be worse off, at least with respect to the health of their heart muscle! (Age is a factor for some of the athletes studied in this trial, but age-matched controls were examined, and the age-confounder was set aside as an important contributor.)

The study was of course a small one, and so generalizability may be a factor of consideration. But think about it, though. This is not supposed to be representative of the population at large, but of a small subset of elite athletes. Therefore, the sample may in fact be sufficient to generalize, at least to other extreme endurance athletes. And remember, all 12 of these individuals were "otherwise healthy" at the outset of the study. None of them were smokers, as far as they were willing to admit to on the inclusion data. (Though, being that they were all males, translating these data to females may prove challenging. Gosh, we could really use some more data on female athletes...)

Although I found this study fascinating because it was almost like a real-life corroboration of Benito and colleagues animal study, this is not the end of the line for similar research in human beings. Oh, no. There's actually quite a bit more, following this same line of logic:

In 2012, Dr. James O'Keefe, et al, published a review in Mayo Clinic Proceedings[4] suggesting that, although the hypothesis warrants further research for substantiation, there is good human and animal data to suggest, at least on a preliminary basis, that excessive endurance exercise (EEE) may predispose susceptible individuals to adverse cardiovascular events, including arrhythmia and extensive myocardial fibrosis.

In a 2011 issue of the European Heart Journal[5], La Gerche, et al, describe their study of 40 endurance athletes, after the completion of a marathon, and suggest that "although short-term recovery appears complete, chronic structural changes and reduced right ventricular function are evident in some of the most practiced athletes..."

In 2010, Wilson, et al, published a study in the European Journal of Applied Physiology[6] demonstrating that long-term, high intensity endurance activity is strongly associated with maladaptive changes in cardiac morphology and electrical conductivity, among other physiologic and pathophysiologic alterations, even connecting it to implications with respect to brain function.

In 2013, Doutreleau, et al[7] showed that such chronic and excessive endurance training could have negative consequences on the conduction pathways in the heart, presumably through this remodeling and fibrotic changes in the myocardium. In their study, they report two cases of type II second-degree atrioventricular block in well-trained, otherwise healthy, middle-aged adult athletes.

Although merely a case report, and not a study, per se, in 2012, in the Journal of Athletic Training[8], Poussem, et al, describe a highly-trained, 30 year old cyclist with "nonsustained ventricular tachycardia originating from the left ventricle on a stress test associated with myocardial fibrosis of the left ventricle as shown with magnetic resonance imaging." The unique thing about this case report was that most often these findings are seen after sudden cardiac death (SCD), on autopsy. Presumably, the diagnosis in this instance is being relegated to an effect of intense, unrelenting endurance exercise, but, there are probably too many confounding variables in this particular instance to be able to say one way or another. It is particularly interesting, however, that it happens to line up quite nicely with the rest of the data, thus far. (Was the cyclist in this case a recreational drug user? Could that have caused or contributed to the pathology seen, here?) Still...

In 2008, published in the British Journal of Sports Medicine,[9] professor Whyte and colleagues ask the question whether exercise may or may not have been the cause of the idiopathic left ventricular hypertrophy and idiopathic interstitial myocardial fibrosis found during the autopsy of an "experienced, highly trained" marathon runner, who died suddenly while running.

Published in the British Journal of Sports Medicine back in 2007[10], Mitchell M. Lindsay and Francis G. Dunn conducted the first experiment, to my knowledge, demonstrating that, in veteran endurance athletes with left ventricular hypertrophy, there is "biochemical evidence of disruption of the collagen equilibrium favoring fibrosis... suggest[ing] that fibrosis occurs as part of the hypertrophic process in veteran athletes."

In 2011, La Gerche published another trial[11], this time with 39 endurance athletes and 14 controls, looking for evidence that intense exercise might be putting an exorbitant load on the right ventricle of the heart. Despite some inherent limitations, which they carefully outline in the paper, the following is what they found after careful analysis of the data:

On top of all the myocardial fibrosis business, there are other potential risks that have been outlined in the literature, since Benito and others' work. For instance, just this year, M Sanz de la Garza, et al, published a study in the Scandinavian Journal of Medicine and Science in Sports[12] looking to examine the potential impact of intense endurance training on multiple thrombotic risk factors, and claim that excessive endurance exercise may actually increase the chances of pulmonary embolism, through the development of deep vein thromboses (DVT), or clots in the legs. Unlike the mechanisms that may be involved in the development of cardiac morphologic changes via collagen recruitment in cardiomyocytes, etc., these are likely to be due to extraneous complications from overexercising; including dehydration, inflammation and, as they put it in the abstract of the paper, "hemoconcentration."

So, ultimately, what does this mean? Does this mean that I think cardio is uniformly "bad" and that you should stop partaking entirely? Do I think any and all forms of endurance training are unhealthy?

Uh... No. Wait, that wasn't good enough. Can I get a hell no, instead?

Look at the one consistency in all these data. Everyone studied (including the rodents!) were pushed -- or, rather, pushed themselves, in the vast majority of cases -- to the breaking point. There is an unimaginable difference between running a weak 2 miles per day and running 11 miles per day, at 80% of your purported maximum heart rate.

Will some regular, light endurance training destroy your heart? No! Will training at intensities similar to ultra-endurance triathletes destroy your heart? It's a little too soon to tell, but, it appears quite possible... so, again, what's "the answer?"

My recommendation would be to avoid participating in multiple marathons. Otherwise, I would be equally as concerned about the health of your heart muscle, if you remain seated on your love seat like a lazy slob eating Sun Chips all day, delicious though they are.

As I have said twice now, there is an undoubted U-curve associated with the benefits of [endurance] exercise. Too little is not good; way too much is also bad. My final recommendation? Adopt the Goldilocks principle of "just right" and you'll be good to go. But, whatever you do, please choose to move, rather than be a slug. "Eat less, move more" doesn't have to be "right" for me to know that exercise in appropriate amounts is incredibly beneficial and health promoting. The lesson in this post is more about what happens if you push it to an extreme on the spectrum -- and to suggest that, as with most things, there may be a sweet spot, somewhere in the middle, where a balanced approach confers the best results.

(Me? I'll stick with picking up heavy things and putting them back down, and the occasional sprint or HIIT session, here and there... but my rationale for that will have to wait. I've already kept you plenty long enough.)


1. Benito, B., Gay-Jordi, G., Serrano-Mollar, A., Guasch, E., Shi, Y., Tardif, J. C., ... & Mont, L. (2011). Cardiac arrhythmogenic remodeling in a rat model of long-term intensive exercise training. Circulation, 123(1), 13-22.
2.Wilson, M., O'Hanlon, R., Prasad, S., Deighan, A., MacMillan, P., Oxborough, D., ... & George, K. (2011). Diverse patterns of myocardial fibrosis in lifelong, veteran endurance athletes. Journal of Applied Physiology, 110(6), 1622-1626.
3. Karamitsos, T. D., & Neubauer, S. (2013). Detecting diffuse myocardial fibrosis with CMR: the future has only just begun. JACC: Cardiovascular Imaging, 6(6), 684-686.
4. O'Keefe, J. H., Patil, H. R., Lavie, C. J., Magalski, A., Vogel, R. A., & McCullough, P. A. (2012, June). Potential adverse cardiovascular effects from excessive endurance exercise. In Mayo Clinic Proceedings (Vol. 87, No. 6, pp. 587-595). Elsevier.
5. La Gerche, A., Burns, A. T., Mooney, D. J., Inder, W. J., Taylor, A. J., Bogaert, J., ... & Prior, D. L. (2011). Exercise-induced right ventricular dysfunction and structural remodelling in endurance athletes. European heart journal, ehr397.
6. Wilson, M., O’hanlon, R., Basavarajaiah, S., George, K., Green, D., Ainslie, P., ... & Nevill, A. (2010). Cardiovascular function and the veteran athlete. European journal of applied physiology, 110(3), 459-478.
7. Doutreleau, S., Pistea, C., Lonsdorfer, E., & Charloux, A. (2013). Exercise-induced second-degree atrioventricular block in endurance athletes. Medicine and science in sports and exercise, 45(3), 411-414.
8. Poussel, M., Djaballah, K., Laroppe, J., Brembilla-Perrot, B., Marie, P. Y., & Chenuel, B. (2012). Left ventricle fibrosis associated with nonsustained ventricular tachycardia in an elite athlete: is exercise responsible? a case report. Journal of athletic training, 47(2), 224.
9. Whyte, G., Sheppard, M., George, K., Shave, R., Wilson, M., Prasad, S., ... & Sharma, S. (2008). Post-mortem evidence of idiopathic left ventricular hypertrophy and idiopathic interstitial myocardial fibrosis: is exercise the cause?. British journal of sports medicine, 42(4), 304-305.
10. Lindsay, M. M., & Dunn, F. G. (2007). Biochemical evidence of myocardial fibrosis in veteran endurance athletes. British journal of sports medicine, 41(7), 447-452.
11. La Gerche, A., Heidbuchel, H., Burns, A. T., Mooney, D. J., Taylor, A. J., Pfluger, H. B., ... & Prior, D. L. (2011). Disproportionate exercise load and remodeling of the athlete’s right ventricle. Med Sci Sports Exerc, 43(6), 974-981.
12. Sanz de la Garza, M., Lopez, A., & Sitges, M. (2016). Multiple pulmonary embolisms in a male marathon athlete: Is intense endurance exercise a real thrombogenic risk?. Scandinavian Journal of Medicine & Science in Sports.

Monday, January 11, 2016

Are dietary carbohydrates required for building muscle?

The question I am concerned with asking is not so much "Is it possible to build muscle while eating very low carb," but more like, "Can I build an appreciable amount of muscle, without adding extra carbohydrates into my ketogenic diet?"

The important question is not necessarily "Is it optimal?" or "Is it the easiest way?" or "Is it the best way?" It is definitely possible, at the very least; I know this from first-hand experience, anecdotal though that is. It may or may not be optimal, I don't know. Nor, for the time being, does it matter much. Let us concern ourselves with one question at a time.

We want to know whether it is reasonable to expect, coupled with resistance exercise, a ketogenic diet to be appreciably anabolic, without additional carbohydrates. Can one accrue significant muscle mass with this approach, or do we require supplemental carbohydrates to make this happen?

If you are not immersed in today's exercise science dogma, you might find yourself wondering why supplemental carbs should be necessary for muscle building, at all. The hypothesis essentially goes as follows:

Carbohydrates stimulate the secretion of insulin; insulin is a highly anabolic hormone (one of its essential functions is to regulate tissue hypertrophy); therefore, driving insulin by eating carbohydrates around your workouts will accelerate muscle protein synthesis (MPS) and accretion on a greater scale than would have been possible without them.

Or, stated a different way:

Because carbohydrates stimulate insulin, and insulin is one of the body's most anabolic hormones, it is reasonable to think that, without the additional insulin secretion caused by the consumption and absorption of these carbs, muscle protein accretion on a very low carbohydrate diet will be minimal, blunted, or otherwise unlikely.

(AKA: Without supplemental carbs, and, therefore, bursts of hyperinsulinemia, building muscle mass while on a very low carbohydrate diet is unlikely to occur. That's the presumption, anyway.)

This latter proposition is, in a roundabout sort of way, how I've seen the argument formed, more times than not. In my opinion, there are a few important caveats to consider, with regard to this particular argument, before moving on.

a.) We are not just considering the potential effects of consuming a ketogenic diet, alone, on muscle protein synthetic rates, but as coupled with weight training (or some other form of resistance exercise), designed for skeletal muscle hypertrophy. Assuming dietary protein, and, therefore, the plasma free amino acid pool, is appropriately topped off, and exercise intensity sufficient to promote tissue growth and remodeling is present, is it reasonable to think that the amount of dietary carbohydrate matters all that much?*

*Remember, we are thinking specifically of intracellular (myofibrillar) hypertrophy, at the moment, not of myocyte bioenergetics and energy utilization to fuel specific workouts, per se. Let's not confuse fuels that may or may not be required to sustain certain types of contractions with fuels that may or may not maximize hypertrophy. As far as we can tell, right now, the exercise science literature seems to show, rather consistently, that carbohydrates are quite useful for sports performance purposes, and have their place, depending on the context and the activities in question. However, this may not be reflective of what metabolic fuels best suit muscular hypertrophy. (e.x. Elite long-distance runners and other high-volume endurance athletes typically consume large quantities of carbohydrates, yet remain quite... frail, for lack of a better term.* No offense intended, of course.)

*Just a random consideration, but, something to ponder: These ultra-endurance athletes are quite emaciated, despite large quantities of dietary carbohydrate and, thus, big bursts of hyperinsulinemia.... Hence my perspective that this popular conception of "more insulin = bigger anabolic response" is too simplistic.

b.) Oftentimes, for the sake of simplicity, we like to talk about "The" Ketogenic Diet, as though it is a single, uniform approach to nutrition. For the most part, this seems to be sufficient for the purposes of discussing very low carbohydrate diets versus diets higher in carbohydrate, in general. Naturally, however, distinctions must be made, when certain points of discussion or contention are brought up. In this situation, to say The ketogenic diet is not necessarily appropriate, because there is not just one approach to ketogenic dieting. There is the traditional, pediatric, anti-epileptic approach to ketogenic dieting that was low in protein, virtually zero carbohydrate, and even restricted water intake (for whatever reason). We are not talking about that. Nor are we talking about the kind of ketogenic diet that is used as a neuropsychiatric therapy, today, to keep glucose and glutamate low and insulin at bay, for neuronal health. Because I tend to occam's razor most things, where possible, I think we could simplify this into ketogenic diets that restrict protein as well as carbohydrates, and ketogenic diets that contain ample dietary protein.

In most circumstances, for healthy persons, it is my personal and professional opinion that it is unreasonable to suggest one should be asked to restrict dietary protein -- even for the purposes of keeping glucose and insulin at its absolute floor. (It is highly unlikely that you will experience souring plasma glucose excursions by eating 10 oz of chicken, instead of 3.5 oz of 80:20 ground beef.) Therefore, "the ketogenic diet" I am considering, here, with special regard to the aforementioned question(s) regarding muscular hypertrophy, include not only concomitant and consistent resistance exercise, but also an appropriate amount of protein to maximize hyperaminoacidemia.

c.) Lastly, I used the word "significant," earlier in the post, re: building muscle on keto. How much muscle are we talking about, here? Massive, Lee Priest-like, bodybuilding muscles are never built by anyone without (1) a genetic propensity, and a vast, inborn number of myocytes for it, or are (2) taking exogenous anabolic steroid hormones. Will the ketogenic diet help me in my unlikely pursuit to look like Ronnie Coleman? Not a chance. Then again, neither will a high carbohydrate, high protein, traditional bodybuilding-style diet, so...

I don't intend for that to come across as snarky so much as to say that it is imperative that for this discussion to have any meaning, we must first define our terms. What level of bulk are we considering "built," here? (I may have my own view on what constitutes built, and your view may differ significantly from that, maybe by a few orders of magnitude. For the sake of this argument, I'd like to use a pictorial example of what, in competitive bodybuilding circles, is considered a "physique" build. Below is a picture of a friend of mine. Although he is not a bodybuilder in the traditional sense, in that he isn't ridiculously massive, he is quite muscular and symmetrical, even after cutting down to a low body fat percentage. This is what I would consider sufficiently muscular to make this discussion worth having:

This is probably how I would distinguish muscular, in this context, because anything less can be construed as simply "lean" or "toned," and anything more might be taken to be "unachievable muscularity" for most normal people. You might disagree, and that's fine, but I'm simply putting this here as a point from which to argue from, for the sake of logic. It can't just be some up-in-the-air, random target post, on which none of us agree, or have even attempted to nail down. At least not if we can hope to achieve anything meaningful in having this discussion. Perhaps important to note is that Ari was not using a low carbohydrate diet to bulk, as far as I know. That is beside the point, however. The picture is meant to serve as a reference point, not evidence on behalf of my position.

From my perspective, most significant muscle building seems to occur, predominantly, as a result of two things: Amino acid availability, and consistent strength training, intense enough to maximally stimulate the muscle fibers and fatigue the motor units. Bing, bang, boom. Little to no evidence, from what I have seen, demonstrates a further need for carbohydrate to augment the process of muscle protein accretion.*

*I am not denying the anabolic effect of insulin. That would be silly. In fact, I am suggesting that perhaps the post-prandial insulinemia achieved by obtaining a nice big bolus of protein, post-workout, should be sufficient to induce this process.[1] (For the record, that wasn't really meant to be a sly reference to the "anabolic window," which is sort of a bunk concept.) Unless you are a type I diabetic producing so little insulin that if you don't inject it you will wither away and die, it is unlikely, in my opinion, that hyperinsulinemia to the degree that is presumed to be necessary from the aforementioned pro-high-carb camp is, in any way, a requirement for substantial skeletal muscle hypertrophy.

As you may have already noticed, this experiment looked at a 50 g bolus of protein, from chicken, as compared to a 50 gram bolus of glucose, and then a 50 g bolus of each, coupled together. As you can see, 50 grams of protein rather substantially increases serum insulin concentrations; quite similarly to dietary glucose alone. Recall, however, that, under the circumstances of most therapeutic ketogenic diets, people do not tend to consume 50 g boluses of protein in single meals. Hence, insulin levels may not go nearly that high. But, again, we are considering a very low-carb diet with more protein than is typical.

We know from metabolic ward overfeeding experiments -- even in sedentary people (or, more specifically "untrained individuals") -- that lean body mass (LBM) can increase concomitantly (though not necessarily proportionally) with adipose tissue growth, even in spite of lower protein intakes sometimes. Therefore, I contend that perhaps we are putting far too much stake on "what should I eat for growth?" Importantly, muscle building is about more than just diet. Arguably, more than anything else, it is about lifting; or otherwise maximally fatiguing the muscle tissue with resistance training. Are you sleeping like shit, always stressed out and constantly over-trained? Prepare for more muscle protein degradation, due to chronically elevated cortisol levels and a dysregulated circadian rhythm, even if your diet is considered well-formulated by some standard or other. A well-formulated diet is imperative for success in this area, of course, but, it is not the only component involved.

It has been hypothesized that poor sleep quality and sleep deprivation could both decrease the muscle protein synthetic response to exercise and protein ingestion and increase muscle protein degradation.[7] Speaking of lifestyle factors other than nutrition that impact muscle mass, cigarette smoking can impair muscle protein synthesis and may increase the expression of myostatin, a powerful muscle growth-inhibitor.[8]

Up until this point, much of the discussion has centered around anecdotes. In fairness, that's probably because there is little to no substantive and controlled data on muscular hypertrophy in the context of ketogenic dieting. In fact, I only know of one research group actively studying this specific area, right now. Whatever answer one chooses to accept must, if we are being honest, inevitably come from a piecing together of various data points from random, and sometimes seemingly arbitrary, trials, and then a commonsense summation of all the data.

Now, let's take a look at some relevant data.

Throughout my career in the fitness industry, nothing else has been claimed or cited as the gospel truth with more vehemency than the notion that there is an anabolic window that ends about 45-60 minutes post-exercise. That if you don't get all the protein and sugar in the world into your system within that period of time, the fucking moon will explode and Jupiter will shit molten meteorites that will fall into your grandmother's living room and kill her and your favorite childhood cat in one fell swoop. Basically, 30 minutes post-workout, you had better pound that protein shake, or else all your hard work will have gone to Hell in a handbag.

In reality, there is very little reason to believe this concept. At least nothing that has really been substantiated by the scientific literature. In fact, if there is an anabolic window, per se, it likely spans the course of several hours after an intense workout, not one. An interesting bit of evidence in favor of this idea is the fact that GLUT4 translocation occurs in skeletal muscle cells after a workout, irrespective and totally independent of insulin secretion,[2-3] which allows for amino acids to be taken up into the myocytes and initiates the physiological process of exercise-induced muscle protein synthesis -- and also for glucose to be oxidized, which is one of the reasons exercise is prescribed for hyperglycemic diabetic patients. This GLUT4 transmembrane receptor translocation alone is maintained for a few hours after the workout is over, meaning a good percentage of the subsequent glucose and amino acids you absorb will likely be shuttled preferentially to fuel the muscle tissue.

Also, intense muscular contractions (acute resistance exercise) cause a complicated intracellular biomolecular cascade called mammalian target of rapamycin complex 1 (mTORC1), which is a powerful regulator of protein synthesis. Although you can augment this process with supplemental leucine, as would be found in a BCAA drink or whey protein shake, or by consuming more protein in general, intense exercise, by itself, is sufficient to initiate the mTOR redox signal and lead to an impressive increase in rates of muscle protein synthesis.[4-6] Albeit an extremely complicated process, as you can see from the chart below, this signaling cascade does not appear to be reliant on post-workout carbohydrate consumption for activation. (That's not to suggest insulin does not play its own interesting role in regulating mTORC1. Merely that it is more complicated than this, and does not rely exclusively or necessarily upon either carbohydrates or insulin for activation.)

From Hulmi, et al. (2009). [ref 6]...

So why were people so adamant that this refueling immediately post-workout was a downright necessity for optimal recovery and hypertrophic muscular adaptations to exercise? I think, to a large extent, it had something to do with the hypothesis that tapping off muscle glycogen levels as quickly as possible is an essential component to post-workout recuperation.

I'm not sure I believe there is any good published literature that substantiates the claim that we must replenish intramuscular glycogen stores immediately after an intense bout of exercise for recovery or performance -- unless one is an elite athlete, or overreaching. Or, indeed, that these energy storage sites would not appropriately refill themselves, as the day goes on and you eat your normal diet. Frankly, with rare exceptions for elite ultra-endurance athletes and the like, virtually no one is totally wiping out their glycogen stores in a single workout.

That said, Camera, et al, in 2012, showed that low intramuscular glycogen levels do not appear to have any suppressive effect with respect to the anabolic impact of resistance exercise on muscle growth.[9] When I first read the conclusions of that paper, I thought to myself, Well, even if the hypertrophic response to low intramuscular glycogen isn't impaired, perhaps athletic performance is a different beast.... It turns out that Symons, et al, studied this back in 1989 and found that there is no such performance declination as a result of training with low intramuscular glycogen, either.[10]

Over the last few years, there have been some rather fascinating studies in the exercise physiology literature that have set out to examine whether or not increasing carbohydrates along with an athletes post-workout protein might aid in building more muscle than with the protein, alone. If the answer to these questions clearly favors the hypothetically anabolic role of supplemental carbohydrate, in this context, it would mean, of course, that more carbohydrate would be better for building muscle, while a diet lower in carbohydrate, like the ketogenic diet, might be decidedly less effective in promoting the same level of muscle growth. If, on the other hand, the answer is negative, we cannot necessarily suggest, then, that a very low carbohydrate diet is better or even equal to a high-carbohydrate diet for muscle protein accretion; just that supplemental carbohydrates, post-workout, are not a necessary requirement for additional hypertrophy beyond consuming protein alone. A standard training diet, already high in carbohydrates, without extra post-workout carbs =/= a ketogenic diet without post-workout carbs.

There are three specific studies I would like to touch on, quickly, each of which I believe did a fantastic job at covering this particular topic:

~ [11] Figueiredo, et al (2013).
~ [12] Koopman, et al. (2007).
~ [13] Staples, et al. (2011).

Overall, I think the JISSN review is a good one. The authors asked some very interesting questions, not the least of which was Does leucine require insulin to stimulate protein synthesis? The answer they arrived at, by the way, was no. Not necessarily.

In the end, as anticipated, Figueiredo and Cameron-Smith concluded, after a well thought out and provocative article, that there is currently (circa 2013) insufficient evidence to suggest that supplemental carbohydrates should be expected to provide any muscle building effects beyond protein alone; but that, as always, further investigations are warranted.

The Koopman study was a randomized-controlled crossover trial of 10 healthy, physically fit men, designed to answer the same basic question: Do supplemental carbohydrates contribute to further muscle protein synthesis, above and beyond the consumption of protein, alone?

Even though the sample population seems small, it was statistically powered to detect an effect, and this population is sufficiently representative of that which we are interested in extrapolating to. Their answer was another resounding No, seen clearly in their title: "Co-ingestion of carbohydrate with protein does not further augment post-exercise muscle protein synthesis."

Figure 1 shows the between group insulin levels, which were significantly greater in the PRO + HCHO group, yet, despite this difference, as the results demonstrate, there was no difference in muscle protein synthesis. This seems to lend further credence to my hypothesis that adequate protein and exercise intensity are the two most important factors for muscular hypertrophy.

Lastly, we have the Staples study. This is easily one of my all-time favorite papers. I thought the authors did a fantastic job writing up this experiment and connecting all the dots. Here are some important highlights, relevant to the same study question as before:

"Muscle protein synthesis increased by approximately 54% after exercise, compared with the values in the non-exercised leg, but there were no differences between the protein and protein + carbohydrate trials in the non-exercised or the exercised legs."

"Muscle protein breakdown was increased by approximately 37% after exercise compared with values from the non-exercised leg, but there were no differences between the protein and protein + carbohydrate trials in the non-exercised leg or after exercise."

There was a statistically significant difference between the PRO vs PRO + CHO, in favor of the latter, with respect to Akt phosphorylation, as shown above. However, it clearly wasn't important enough to cause any discernible changes in muscle protein accretion between groups which would be necessary to show that the CHO supplemented group reaped additional benefit. (This alteration in Akt, favoring the PRO + CHO group is likely due, from what I understand of the mechanisms of this molecular signaling pathway, from the significantly higher insulin levels in the PRO + CHO group, as compared with PRO alone. As is clear, though, this was insufficient to contribute to an appreciable difference in MPS in favor of PRO + CHO over PRO alone.)

Update: please also check out this paper[18], by Glynn, et al., from 2013. This one in particular -- because of the way the experiment was designed -- coupled with the strength of the Staples paper, is, from my perspective, sufficient to conclude, once and for all, that supplemental carbohydrates are in no way required for building muscle.

As it stands, it seems that the answer to the question we have been asking is that supplemental post-workout carbohydrate ingestion is not needed to further augment the well-established benefits of protein alone. However, as was mentioned previously, this does not serve as sufficient evidence in favor of ketogenic diets for muscle building, in and of itself. Moving on...

What about some other biochemical changes that result from altering the macronutrient composition of the diet?

At the University of Connecticut, in 2002, Dr. Jeff Volek and his team conducted an experiment[14] where they examined various biochemical assays to assess the effects of a carbohydrate-restricted diet on different hormones, such as thyroid hormone, testosterone and others. Unfortunately, this particular trial did not look at the effects of the intervention on female hormonal status, so we cannot extrapolate from the 20 otherwise healthy men who were involved, here, to whether this would also apply equally to women. However, with respect to male physiology, the 12 men who were randomized to receive carbohydrate restriction as a therapy for 6 weeks saw some rather dramatic changes in their blood panels.

Even though the authors make no mention that I can see of having the participants of this trial exercise, the low carb arm lost a mean of 3.4 kg in body fat over the 6 weeks, while increasing their lean body mass by an average of over 1 kilogram. These changes were apparently the direct result of changing just the macronutrient composition of their diets, favoring fats and restricting carbohydrates.

Interesting changes occurred with many of the assays, it seems, but, of particular importance to the question we are interested in, here, both total and free testosterone increased significantly, while sex-hormone binding globulin decreased. Depending on how substantial this difference is, this should mean that the men who were lucky enough to be randomized to the intervention group would experience an increase in lean mass and a decrease in fat mass. And, as we have just learned, that is precisely what happened. (Some of the reduction in body fatness was probably also due to increases in total and free thyroxine, in the carbohydrate-restricted arm, as well, as compared with the controls, whose laboratory findings, as predicted, remained largely the same throughout the duration of the trial.)

Fascinating though I think Volek and colleagues findings are, the impact of higher fat, lower carbohydrate dietary modifications on sex and steroid hormones has been well-established for many years. In 1986, Reed, et al, conducted an experiment to see what would happen to sex-hormone binding globulin (SHBG), free testosterone and total cholesterol concentrations, should the macronutrient ratios be shifted in this manner.[15] They, too, came to conclusions similar to those Volek and his team eventually reached.*

*Many traditional bodybuilders are indoctrinated to believe they need to eat very low fat diets for fat loss during the cutting aspect of their training, and, while reducing total fat intake can, under the right circumstances, certainly aid in the loss of body fat, to reduce it too low is to risk reducing total and free testosterone, as demonstrated in the two studies mentioned above. For both fat mass reduction and the inhibition of muscle protein breakdown, it would seem this is a bad plan.

More recently, in 2014, Jeremy Silva put together a nice little study on the effects of a very low carb, high fat diet on lipid and anabolic hormone status.[16] Like Volek and Reed, Silva, et al, also found that increasing dietary fat and decreasing carbohydrate led to a significant increase in total testosterone, as compared with the control group on the standard western diet.

So far, it seems there are no apparent strikes against the ketogenic diet as it pertains to building muscle, yet, with specific regard to these last three trials, there may be some interesting strikes against high carbohydrate, low-fat diets for muscle building -- the implications of which, if there are any such implications worth noting, will have to be further elucidated elsewhere.

Lastly and perhaps most importantly of all, these bits and pieces of articles will mean nothing, if a good randomized-controlled trial comes along and proves that very low carbohydrate diets significantly impede muscle growth or drastically increase protein degradation and that carbohydrate supplementation is necessary to attenuate this process, or something like that. However, as it happens, there is only one published trial that has ever set out to research the effect of a ketogenic diet on skeletal muscle strength and hypertrophy in trained individuals. Dr. Jacob Wilson is another active voice in the online fitness community, and he is how I learned about this study, which he contributed to, along with esteemed Drs. Volek and D'Agostino.

Wilson's trial (Rauch, et al[17]) of 26 trained, college-aged men used ultrasonography of the quadriceps muscles to determine that the VLCKD group increased their lean body mass by an average of 4.3 kg, while the traditional western diet controls only increased their lean body mass by 2.2 kg, even though the two groups were matched equally with dietary protein and exercise.

To be honest, I am not so sure about the use of ultrasound to accurately and reliably determine subtle changes in muscle tissue with enough sensitivity to be reasonably precise. Then again, I don't know, because it's the first time I've seen it. They did, however, use DEXA to determine bone and fat mass, which we know is one of the most reliable tools we have for measuring body fatness in trials like these. Perhaps if the authors juxtaposed the results of both pieces of equipment...?

In any case, this particular trial -- first of its kind -- actually looked directly at the impact of a ketogenic diet on muscle protein synthesis and skeletal muscle hypertrophy and body composition, and the very low carbohydrate diet in this case was actually superior! Significantly so, it seems. (Then again, I think each group may have had these measurements taken after glycogen and water replenishment, at the end of the trial, so that figure might actually be a bit confounded. However, when considering the only experiment we have, so far, on this very particular outcome question, one cannot say that a ketogenic diet of the sort we mean, here, is less anabolic than one higher in carbohydrate. At the very least, when matched for dietary protein intake and exercise intensity, they are equivalent, and seem to lead to virtually identical outcomes.)

So, do we need carbs to build muscle?

Based on my experience, and all the #anecdata I am aware of, I would say absolutely not. Based on the state of the evidence, right now, I don't think we can appropriately answer that question, in the context we are inquiring about, without better and more exhaustive research. That said, I do think we have enough bits and pieces of data, as compiled above, to at least tentatively suggest that a ketogenic diet is not "less than" a carbohydrate-rich diet, for the purposes of building muscle. I am willing to stick my neck out a little and wager that the results of these future studies, if and when they hit the press, will probably conclude that it really doesn't matter much whether you eat high or low carb, if your primary outcome is to maximize hypertrophy. (Although, if I'm being honest, I have a sneaking suspicion that similar results to Volek, Wilson and D'Agostino paper might make a consistent appearance over time...)

What should we do in the meantime, if building a decent amount of muscle is the goal?

1. Don't be afraid to eat enough food.

2. Maximize the anabolic potential of your diet by consuming sufficient protein. (Right now, this seems to peak at ~2x the RDA.)

3. Exercise to muscular fatigue a few times per week.

* * * * * * * * * *


1. Given sufficient dietary protein to maximize plasma hyperaminoacidemia and the anabolic response to exercise, and consistent resistance training with the right level of intensity and appropriate recovery, supplemental carbohydrate does not seem to be a requirement for the average person to build an appreciable amount of muscle.

2. Exercise, itself, as a means of initiating the mTORC1 cascade and other cellular anabolic signaling pathways is likely the single most important stimulus for promoting skeletal muscle cell protein synthesis, independent of any other factor, including carbohydrate consumption and insulin secretion.

3. Genetics arguably plays the biggest role in determining whether or not your muscle tissue will grow substantially. If I have some significant number of myocytes less than you, from birth, and we train and eat and sleep and live in exactly the same way, for the same exact same length of time, no matter what I do, I will never be able to build more muscle than you; muscle cells do not divide. This is genetic. I'm sorry. We do our best with the hands we're dealt... (Someone could have taken Jay Cutler as a young man, pre-bodybuilding, fed him a strict, low protein vegan diet, and he would still be the biggest guy in the room as soon as he picked up something heavy and put it back down.) In other words, it is highly doubtful, in my opinion, that extra carbs will really be your edge. (Bear in mind: whether or not supplemental carbohydrates are healthy and/or useful for other things, in other contexts, is beyond the scope of this post.)

4. If there did happen to be some advantage of higher carbohydrate, hyperinsulinemic diets, over very low carbohydrate diets, with respect to building muscle mass, it is probably so small as to be negligible. (At least as predicated on the data I have available to me, at this time.)

5. Carbohydrate-restricted diets higher in fat may have other anabolic benefits, distinct from insulin, like increased total and free-testosterone, as shown in Volek's study. But again, whether this will turn out to hold true in further human clinical trials remains to be seen. (Who knows, someday there may be data suggesting that "training low" is ideal for building muscle mass. Only time, and good experiments, will tell.)


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2. Holloszy, J. O. (2005). Exercise-induced increase in muscle insulin sensitivity. Journal of Applied Physiology99(1), 338-343.
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