Medicine: The art of applied science

I read this NPR article this morning and had to do a post in response. The gist is that the military is turning to what we might call the less conventional (for us in the West) medical modalities to deal with the injuries sustained by the current crop of vets. Instead of getting them hooked on pain meds for life (we saw plenty of this in the VAs in the '80s and '90s among Vietnam vets), they are turning to stuff like massage and acupuncture. And, predictably, it is stirring up controversy.

The story that is told is of a Sgt. Rick Remalia who fractured his back and pelvis in Afghanistan:

Remalia broke his back, hip and pelvis during a rollover caused by a pair of rocket-propelled grenades in Afghanistan. He still walks with a cane and suffers from mild traumatic brain injury. Pain is an everyday occurrence, which is where the needles come in.

And lately he has been receiving acupuncture treatments, with this result:

"I've had a lot of treatment, and this is the first treatment that I've had where I've been like, OK, wow, I've actually seen a really big difference," he says.

And incidentally, her gets these treatments from a military physician, who, herself a skeptic, admits to perceiving a personal benefit from her own exposure to it:

"I actually had a demonstration of acupuncture on me, and I'm not a spring chicken," she says, "and it didn't make me 16 again, but it certainly did make me feel better than I had, so I figured, hey ... let's give it a shot with our soldiers here."

So, all good so far, right? Well, Harriet Hall is quoted in the same article, and to her this falls right into what she likes to call "quack-ademic" medicine. She says,

"The military has led the way on trauma care and things like that, but the idea that putting needles in somebody's ear is going to substitute for things like morphine is just ridiculous," Hall says.

Now, as you know, I have had some debates with the SBM crowd in the past, and as it turns out, we agree on the science more than we disagree. However, I am thinking that this argument is not about science, but about politics.

I am well aware that a group of anecdotes does not amount to science. And I am also well aware that what we are hearing here are anecdotes. But here is the thing: when your kid tells you that she likes chocolate ice cream better than vanilla, do you ask for evidence that chocolate is better than vanilla at the population level? No, that's absurd! OK, you say, but this is a strawman: nobody is going for a claim of superiority of chocolate ice cream over vanilla. That is true, but is this about the science or about being able to make a claim? If my kid likes chocolate, why not let her have that when ice cream is on the menu? If acupuncture seems to provide some relief to Sgt. Remalia, why not let him have that relief? After all, whose opinion about what works counts in this individual example, ours or the patient's? And if the ethics of using placebo are the concern, there is nothing wrong with letting him know that in large clinical trials the evidence is equivocal, which means that it may work for some and not for others. In fact, this might be a good disclaimer to make before commencing any treatment, one with the right to claims and one without.

Another argument is that there is no way that insurance (or our taxes) should pay for this unproven treatment. Still about science? Do any of you want to stand up and tell Sgt. Remalia, who fought for our freedom, that we will not pay for the only thing that seems to help him, that is pretty cheap and safe and that has very few, if any, long-term adverse effects, in stark contrast to pain killers? Yes, I understand that this is not science, but is there no room for humanism in the practice of medicine? After all we have throaty debates as to whether or not it is ethical to deny a $100,000 payment for a treatment that, on average, prolongs life by 2 weeks. Surely, denying Sgt. Remalia access to this relief would diminish our humanity. And what about the costs of treating addiction to pain killers?

So, here are my points:
1. I completely agree that that acupuncture "works" for Sgt. Remalia, does not mean that "acupuncture works" in the scientific sense. It may or may not work; furthermore, our current models of the universe do not allow us to have an adequate mechanistic explanation. But that is not the point -- it works for this young man whose life will never be the same because he signed up to defend his country. To this extent his "claim" has all kinds of internal validity.
2. Making claims is subject to legal and regulatory frameworks that have very little to do with science. I have done much blogging on clinical vs. statistical considerations in clinical research that feeds regulatory approvals and hence claims, and I remain of the opinion that a lot of the acceptable claims are specious. I know, I know, this is a "tu quoque" argument, but if we are talking about the goose and the gander, well...
3. Whether or not a treatment should be paid for is more prone to political than evidence-based decisions. Given that most medicines work in a minority of patients, and none comes without adverse events, the extent of which remains largely unknown because of our negligence to build real regulatory systems to quantify them, we are spending a lot of dollars on stuff that does not work at the individual level.

Medicine has to be part science and part art; in fact the art is in how and when to apply the science. That latter portion must be about humanism.

   

Some implications of biologic plausibility

Ever since my... ahem... skirmish... with the folks over at the SBM, I have been contemplating the issue of biologic plausibility. They contend that our tax dollars are wasted by being allocated to the NCCAM to pursue research into CAM. Their reasoning is that there is no biological plausibility to any of it having any therapeutic effect. Now, this is a big bite to swallow. As I have said before there is CAM and then there is CAM. CAM seems to be a convenient wastebasket of modalities that we feel justified in bashing as "woo" since there is limited scientific evidence behind them. But really, I am more willing to give acupuncture and massage the benefit of the doubt than, say, healing crystals (even though I confess I really like rocks!).

So, what of this biologic plausibility, and who came up with it anyway? And is it truly fiscally irresponsible, and possibly even unethical, to test interventions that do not fit our biological plausibility criteria? As a corollary, is there a level of our understanding of biology that makes testing equally wasteful or even unethical? And finally, should plausibility of benefit and harm be required to reach the same evidentiary bar?

For the definition of biological plausibility we apparently thank the milestone 1964 Surgeon General's report linking smoking to cancer. This report was the first official US government document to state that there was enough evidence to implicate cigarette smoking in the rise in lung cancer and cancer deaths. Since the limitations of observational research were used by the critics for decades to derail this definitive statement, the report itself does a nice job laying out the methodologic considerations and the need to rely on the Bradford-Hill criteria. It was in the "coherence" criterion that biologic plausibility entered the picture.

A quick check of my favorite crowd-sourced information site, the Wikipedia, uncovers this treasure from Sir Bradford Hill himself:

It will be helpful if the causation we suspect is biologically plausible. But this is a feature I am convinced we cannot demand. What is biologically plausible depends upon the biological knowledge of the day. To quote again from my Alfred Watson Memorial Lecture [1962], there was

"…no biological knowledge to support (or to refute) Pott’s observation in the 18th century of the excess of cancer in chimney sweeps. It was lack of biological knowledge in the 19th that led to a prize essayist writing on the value and the fallacy of statistics to conclude, amongst other “absurd” associations, that 'it could be no more ridiculous for the strange who passed the night in the steerage of an emigrant ship to ascribe the typhus, which he there contracted, to the vermin with which bodies of the sick might be infected.' And coming to nearer times, in the 20th century there was no biological knowledge to support the evidence against rubella."

In short, the association we observe may be one new to science or medicine and we must not dismiss it too light-heartedly as just too odd. As Sherlock Holmes advised Dr. Watson, "when you have eliminated the impossible, whatever remains, however improbable, must be the truth."^[1]

Aha, so biologic plausibility is a function of the state of our current knowledge, today. By this litmus test, Marshall and Warren should have been laughed out of all funding agencies. Instead, they rewrote our understanding of what can live in the stomach, and how a microorganism can cause peptic ulcer disease and stomach cancer. And got themselves a cool Nobel to boot. So much for the ethics and finances of biologic plausibility informing meaningful research.

Now, on to the question of whether there exist relationships with such high biologic plausibility that they do not require irrefutable proof. Well, how about tobacco and its health effects? How about radiation exposure? Now, how about what we know today about the evolution of microbial resistance to antibiotics? Is it enough that the biologic plausibility for ill-effects of antibiotics in our food chain is strong? Can we now stop the madness? If my colleagues over at SBM are given to the same logic, they would say yes to this. However, extrapolating from this post about organic food production, I somehow think that they would not. So, I am guessing that, although they believe that lack of biologic plausibility should preclude attempts at study, they will nevertheless be reluctant to set a threshold for biologic plausibility that might obviate the need for further research. I am just guessing, and would love to hear what they really think.

And finally, what of the plausibility of benefit vs. that of harm? Should our bar for biologic plausibility for harm be lower than that for benefit? Well, the question really boils down to this: How many bodies do we need to see lying in the streets before we concede that there is a problem? My point is that we Americans have a hard time subscribing to the precautionary principle, applied generously in other parts of the world. If we were a tad less reckless with our need for irrefutable evidence, how many decades of equivocation about tobacco and cancer would we have avoided? How many lives might have been saved? Biologic plausibility for the connection was known even in the 1930s, yet it took another three decades for us to act. What are we obfuscating today that will come back to bite us (and our children) tomorrow? Could it be the cynical injection of doubt that our food production system is causing irreversible damage to us and life around us?

So, what I am saying is that biologic plausibility has several facets. We have to admit humbly that its assumption relies on our necessarily incomplete knowledge, and denying this may prevent us from awe-inspiring discoveries that will advance science in leaps. However, if we feel strongly about the need for it in order to justify our research allocation, some careful soul searching is in order for those thresholds of probability, especially of harm, where we may admit that science makes us sure enough, and, instead of awaiting perfect evidence, we must act promptly.      

    

Addressing the comments

A very lively discussion indeed! Thanks to everyone who contributed, and thanks for keeping it civil, mostly.

A couple of thoughts on some of the comments:

1. Craigmont: "Between the testable and the untestable; between science and woo; there can be no middle ground. You're going to have to pick a side."

Really? There is no middle ground? I have to choose a side? Really? I am pretty sure that this is how we advance a discussion or knowledge. Seems to me that this is a good way to get elected to office these days, as well as sell news. But does it really get us to a better, more advanced place? I think not.

2. Timm: "You may not have meant the term "allopathic medicine as derogatory, but that is indeed, what it is. It is a slight, a slur, a marginalization.Many people these days recognize what it refers to and do not (as you) intend it as a slur, but it remains a belittling term."

OK, Timm, the point is clear, even though there is nothing that seems to suggest its derogatory nature other than who coined it. This notwithstanding, I am perfectly happy to respect your experience of the word and not use it in any way. But here is what I need from you: 1). Please, tell me what term you would like me to apply to Western medicine that differentiates it from other? and 2). Do you think that "woo" is a respectful way to refer to the other side? Or perhaps you think that "those people" do not deserve your respect, so it is OK to use derogatory shorthand. Either way, if we are interested in advancing the issue in some direction, there has to be a civil conversation between the opposing sides. So, I would suggest that we aim for that, and the way to start is to stop calling each other names, knowingly or not, as you pointed out.

3. Liz Ditz: "To me, high uptake rates for all vaccine-preventable illnesses, including those you characterize as minor (varicella or chicken pox) are a social justice issue. The social and economic costs burden of vaccine-preventable diseases falls disproportionately on those least able to pay for them: the poor and the working poor."

Liz, can you please say more about what you mean? I think that I understand, but want to be sure that we are talking about the same thing. Thanks.

4. Ian Monroe: "They are constantly talking about what a complicated process science is. And it is a process, not an answer. Of course the media is pretty much a four-letter word on their blog."

Yes, Ian, and I am constantly talking about it on my blog as well. And to me, even though I share similar understanding of evidence as the SBM group, my conclusions are different. And they are not only my conclusions. And this is why it is important to have this conversation: in science, as in anything else, you can look at the same data, and walk away with very different lessons. This is why I advocate an open-minded conversation between the opposing sides, rather than just throwing grenades at each other across an imaginary separating line.

5. Calli Arcale: "Homeopathy, in the traditional sense, should be harmless except insofar as it causes people to delay effective treatment. However, what is sold today is not strictly homeopathy in the traditional sense."

Dear Calli, can you show me a study or a body of evidence that indicates the presence of a delay, the magnitude of that delay and the real consequences of it (i.e., morbidity and mortality)? Something that can be specifically attributed to it, rather than the patient's own reluctance to present to a physician for a work-up? In other words, I am interested in the attributable outcomes of what you are referring to. As for your second point (and this was brought up by several commenters), can someone tell me how the mechanism of recalling the harmful stuff from the market is different from these preparations than it is for conventional pharmaceuticals? Thanks.

6. Opit: "Sorry. You've lost."

 Really? Somehow I do not feel like I've lost. Somehow I feel like I've won. The discussion is enriched, the tone is more constructive, and we are actually getting to the issues. Contrary to our political discourse, this is not a zero sum game. My aim is not to walk away with the same opinions that I started out with or making the chasm between us more prominent. My desire is to understand the issues better and to have a respectful conversation about stuff that we feel is important. So, while I thank you for your strategic advice, I will not be following it.

7. moderation: "As to the varicella vaccine, I think you have fallen victim to 'I have not seen it, so it must not exist' syndrome."

Dear moderation, while it seems to be the habit to draw inferences about people in the conversations that I have seen in other blogs, I would prefer it if you did not do so here. Most of the time, as I try to teach to my students, these inferences will be incorrect. I think we should stick to the arguments that have been made, and if you want to extend it to inquiring as to whether or not I have fallen victim to denying the invisible (in this case a bad thing), please, inquire away first. Now you have to go back and come up with a different hypothesis, alas. And if you sense a little bit of snideness in my remark, please, forgive me this transgression, as I am so wary of people assigning labels to others based on what they want to see only and not in what is really there. 

8. Orac: "Ah, yes, the 'just asking questions' gambit."

Really? Come on! You don't mean that asking questions is anti-science, do you?

I am grateful to see that Dr. Novella has posted a response to my response. His response seems measured and inviting to a respectful discussion, and I particularly appreciate that. I will take the time later to address some of his points further in a different post. In the meantime, let the discussion continue. I would love the answers to my questions above, so that I can get educated further on these issues.

As ever, thanks!  

 

  

  

   

Furthering the discussion

My original intent was to go through Dr. Novella's and Orac's criticisms individually and take it from there. On second thought I decided not to take that approach. Instead, here is my response.

Firstly, I am grateful that there has been so much discussion about our views. Amid many valid points in their posts made with a skillful turn of the phrase, I saw quite a lot of sarcasm as well. I am sure that the tone of my original post is what incited it, and for that I am sorry: I really do want to have a civil discussion about these ideas, as I realize that we are all learning all the time, and the only way to gain a better understanding of a topic is through discourse. So, again, I apologize for setting the confrontational tone, and will try to avoid it in the future.

I do believe our views are more same than different. We both (SBM group and I) understand that science evolves, that evidence is not stagnant and the sense of certainty frequently conveyed to the lay public by the media is oftentimes misplaced. We simply disagree on the extent to which there is uncertainty in evidence. While it is true that the oft-cited 5-20% number representing the proportion of medical treatments having solid evidence behind them is very likely outdated, the kind of evidence we are talking about is a different matter.

In the hierarchy of evidence, depending on where you look, it is either meta-analyses or the randomized controlled trial that is the gold standard. The latter is a great proof of concept tool, but it is necessarily limited in its external validity, or generalizability. The reason for this is that these trials, frequently done for regulatory purposes, very limited types of patients, exert extremely stringent controls on the total care of the patient (or else are criticized for not doing so if they fail to do so), focus on short-term and surrogate outcomes (hence, the use of cholesterol lowering as a marker for cardiac mortality, for example), and do a fairly abysmal job as a rule considering the sources of heterogeneity of response. The interventions come to market and are typically used in a much broader population based on the evidence of the RCT. This paper, one of many in the same vein, is a nice illustration of a perennial problem with trial evidence, where real-world use of a therapy goes far beyond the available evidence. And although this paper addresses issues with evidence used for reimbursement, these are the same studies that feed guideline recommendations. Certainly meta-analyses, which are a way to combine the data from multiple RCTs in a systematic way, when done well can give us greater confidence of the direction and the magnitude of the treatment effect, but they in no way overcome the generalizability issues of their component RCTs.

The next rung of the evidence ladder is observational data, specifically cohort studies first prospective, then retrospective. I am actually a great fan of observational data, as I have mentioned in the past. Cohort studies give us the opportunity to examine what happens in the real world without imposing artificial conditions necessary in a clinical trial. Observational data can be great when describing epidemiology of a particular disease, the frequency of a given exposure, how different characteristics can modify the relationship between the exposure and the outcome. One of the most attractive features of cohort studies is that the population can be observed over long period of time -- just look at the Nurses' Study, the Framingham Cohort, and others. But these types of studies also have important limitations, and these are readily acknowledged as a heightened susceptibility to bias (especially in the retrospective studies), the possibility of misclassifying important events, and, despite our best efforts to adjust for it, residual confounding. I will come clean and admit my affection for observational data, even despite the fact that it is lower on the totem pole of evidence than an RCT. I really love this paper by Rothman and Greenland that takes a bird's eye view of our research debates. The whole paper really tickles the brain, but I will quote from a section of it briefly here:

Impossibility of Proof

Vigorous debate is a characteristic of modern scientific philosophy, no less in epidemiology than in other areas. Perhaps the most important common thread that emerges from the debated philosophies stems from 18th-century empiricist David Hume’s observation that proof is impossible in empirical science. This simple fact is especially important to epidemiologists, who often face the criticism that proof is impossible in epidemiology, with the implication that it is possible in other scientific disciplines. Such criticism may stem from a view that experiments are the definitive source of scientific knowledge. Such a view is mistaken on at least two counts. First, the nonexperimental nature of a science does not preclude impressive scientific discoveries; the myriad examples include plate tectonics, the evolution of species, planets orbiting other stars, and the effects of cigarette smoking on human health. Even when they are possible, experiments (including randomized trials) do not provide anything approaching proof, and in fact may be controversial, contradictory, or irreproducible. The cold-fusion debacle demonstrates well that neither physical nor experimental science is immune to such problems.

Some experimental scientists hold that epidemiologic relations are only suggestive, and believe that detailed laboratory study of mechanisms within single individuals can reveal cause–effect relations with certainty. This view overlooks the fact that all relations are suggestive in exactly the manner discussed by Hume: even the most careful and detailed mechanistic dissection of individual events cannot provide more than associations, albeit at a finer level. Laboratory studies often involve a degree of observer control that cannot be approached in epidemiology; it is only this control, not the level of observation, that can strengthen the inferences from laboratory studies. Furthermore, such control is no guarantee against error. All of the fruits of scientific work, in epidemiology or other disciplines, are at best only tentative formulations of a description of nature, even when the work itself is carried out without mistakes.

What follows in the hierarchy of evidence are case-control studies, done for some very specific reasons, then case reports and finally expert opinion. When evidence-based guidelines are developed, a comprehensive systematic literature review is undertaken, and all the evidence is examined and ranked. Based on these papers, a recommendation is made and a strength of this recommendation is reported based on the quality of the underlying evidence. This is an arduous and costly process, and it is commendable that it is undertaken. At the same time, given the limitations of the components of the guideline, the final product can be quite inconclusive or even misleading (I hate to bring it up, but look at the screening mammography debate, as well as the recent HRT recommendation reversal). I think it is obvious that I believe in the scientific method, I am simply not convinced that we have done such a great job generating trustworthy evidence in many instances. At the same time, I am not totally nihilistic about what we know, but am somewhere between thinking we have good evidence for a lot of stuff vs. not having any for anything at all.

Allow me one more piece of evidence, if you will, though this is merely anecdotal coming from my dual experience as an author and peer reviewer. I am occasionally floored by the quality of peer review. I have had reviews say on the one hand that of course the paper should be accepted, since it comes from such a reputable group, and on the other reject out of hand papers based on the reviewers' profound lack of understanding of the methods employed. And lest I sound like a crybaby, let me say that I welcome a well-reasoned rejection. What I am talking about is not that. And this is not a surprise, since pretty much anyone can sign up to be a peer reviewer, since, to the best of my knowledge, there is no set of qualifications that journals ask for in their reviewers. And this, so far as I know, applies even to such high caliber publications as JAMA.

So, these are my thoughts on evidence-based medicine. I welcome responses to this, as my understanding of this science is constantly evolving, and differing well-reasoned opinions really help me get a better handle on this stuff.

I will try to tackle my CAM argument next. If I in any way implied in my remarks that I encourage allopathic physicians (by the way, I am not using it in a derogatory way, but merely as it is defined here; in fact, until today I was blissfully unaware of its negative connotation) to be purveyors of CAM, I sincerely apologize. I am pretty sure, however, that I have never made such a statement, as this is not what I believe. My belief is that all modalities that may impact what happens to public's health need to be evaluated for safety, not question. I think we both agree, since there is really no reason to think that something like homeopathy has anything that can help, by the same token we do not believe that it have anything that can hurt. Same with healing crystals, reiki and prayer. So, if a person wants to engage in these activities, and they are perfectly safe physically, be my guest. Other modalities, such as chiropractic, acupuncture, herbalism and the like, definitely need to be evaluated more stringently, as there is reason to think that they may cause harm. And the decisions about their use must be made based on the probability of harm vs. the perceived probability of benefit. Why do I think that these should not be regulated the same way as allopathic treatments? Well, herbs grow naturally and I dare say we have little to say about what our patients grow in their back yards, unless of course the thought is to regulate them the way we do marijuana. As for chiropractic, it is already regulated, though to what extent I am not sure, and would love to hear from someone who knows. Since its techniques most resemble surgical interventions, the level of evidence for them should perhaps be the same as that which we demand in the surgical literature. This is just a thought, and I am not sure that I am correct in this, so other views are, as always, welcomed. What is coming through for me is that perhaps my call to equipoise was a little over the top, as I do not seem to be approaching the above CAM issues in a frequentist, but more in a Bayesian way (though I remain committed to equanimity). Yet, there is something to be said about the frequentist approach, even though it is not my way generally. The frequentist approach, which is what underlies the bulk of our traditional clinical research, does not rely on differential prior probabilities for different possible associations, but treats them all equally. Despite many disadvantages, one obvious advantage is that we do not discount potential associations that do not have biologic plausibility, given our current understanding of biology, and sometimes help us stumble on brand new hypotheses. So, clearly, there is a tension here, and I am still working on what is the better way, if any.

My final words will be about vaccination. It is disheartening to be lumped with "anti-vaxers", as has been done in the comments to Dr. Novella's and Orac's posts. While my bruised ego will survive this insult, I would like to question this assertion. Nowhere have I said that vaccinations are a bad idea or present a real danger to our children. The hype surrounding the vaccination-autism "debate" is abhorrent to me. What I have stated, however, is that I am of the opinion that we have gone a bit overboard with some of them, one being the chicken pox vaccine. Now, this does not make me an "anti-vaxer"; this just makes me a bit skeptical. The way I view the data is that the advantages for this vaccine are mostly economic, in that they prevent parents from missing days at work. Now, I am certainly not opposed to making such a vaccine available to parents who desire it, but I am not convinced that it should be a prerequisite for my kid to go to school. Given that there is always a possibility of an adverse reaction, no matter how small that possibility is, if the risk of it may outweigh the benefit (and here I do not mean the benefit of having mom show up at work), it has to be weighed very carefully. And even though the question asked by one of the comments raises the issue of an immunocompromised child worrying about potentially being exposed to chicken pox, given the known issues with breakthrough disease, I am not sure that immunizing all of his/her contacts would produce anything other than a false sense of security. My sentiment about the HPV vaccine is similar, to respond to another comment. For reasons laid out here and elsewhere on my blog, I am pretty convinced that it would be a compete subversion of the intent of vaccinations to make it into another mandated shot. To date HPV is merely a recommendation, whose validity I am free to question, though last I heard there was movement afoot to make it mandatory. If in your informed opinion your daughter should get vaccinated against HPV, well then I have very little to say about it. But if I were to counsel an individual patient in the context of my understanding of the data, I would be very upfront with my view.

To me the fact that there are such heated debates about this stuff is a testament exactly to how NOT straightforward our science is. I do understand that as a researcher I can afford a certain amount of analysis paralysis that is unacceptable at the bedside. However, I think we (and the press) do a disservice to the patients, to ourselves and the science if we are not upfront about just how uncertain much of what we think we know is. I could not have said it better than this story about Dr. Devereaux's presentation at the recent ASA meeting did here:

It would be nice if we could all agree that science is not static, but rather progresses and regresses. We learn, and then find out that some of what we thought we had learned was wrong, and set about using that information to seek the next level of truth. Repeat, ad infinitum. Personally, I’d love it if my doctors couched every bit of advice with, “Here’s what we think we know today.”

But I suspect that wouldn’t sit well with many patients, who want certainty (as if there is such a thing). And it especially seems like a difficult proposition in our contentious society, where anti-science nay-sayers like to jump on contradictory findings to challenge the basic value of science overall.

That is exactly NOT what I am trying to do. I am merely reflecting on many of the issues that threaten the validity of what we think we know. I am confident that disclosure and transparency not only lead to better science, but they also lead to science that can withstand the test of nay-sayers.

I have come to the end. I am not sure that I have addressed each and every one of the criticisms, though I hope that I have addressed the majority; I am sure you will point out what I missed. A couple of things about comments: Tomorrow I will be in the air most of the day and may not have the opportunity to sign on to approve comments. So, please, if your comment does not go up until Wednesday, do not think that it has been rejected. Also, I really would like to keep it civil and, though I did not apply this rule today, I will not accept any overt insults or name calling from either side of the debate.

I am sincerely looking forward to continuing this discussion!                

          

The reality of "science-based medicine"

Dr. Novella continues with his egregious oversimplification of the concept of science-based medicine here. I again felt compelled to respond. And given my previous difficulties with getting my responses accepted by the web site, I thought I'd post it here too. Tell me what you think.

Dear Dr. Novella,

Once again I have to agree with some of your premises, but disagree with your misguided leaps of illogic. I agree that if a modality has not been proven effective, the only way it should be left alone to be used by the public is if it has been shown to be safe. Alas, the risk-benefit equation is an individual choice, and we cannot impose our quantitative bottom line on it. Your assertion that scientific medicine is being eschewed because of acceptance of alternative modalities is as flawed as maintaining that a rain dance brings on rain. I know you said the relationship was complicated, but let's be honest: you think that CAM acceptance is killing allopathic medicine.

Now, let's get on to "proof" in science-based medicine. As you well know, while we do have evidence for efficacy and safety of some modalities, many are grandfathered without any science. Even those that are shown to have acceptable efficacy and safety profiles as mandated by the FDA, are arguably (and many do argue) not all that. There is an important concept in clinical science of heterogeneous response to treatment, HTE, which I have addressed extensively on my blog. I did not make it up, it is very real, and it is this phenomenon that makes it difficult to predict how an individual will respond to a particular intervention. This confounds much of what we think is God's own word on what is supposed to work in allopathic medicine.

Finally, do you really think that agents that are approved based on a 2-week prolongation of median survival in a desperately ill population of patients are used because of their supposed scientific merit? I would have to argue that there is a lot of subcortical emotional thinking that goes into these decisions. Can you really prove to me that a 2-week increase in median survival is not tantamount to placebo effect, aka type I error? Yet this is science-based. I think if I had a horrible disease, I might opt for acupuncture to make me feel better in the weeks I have left rather than rely on this kind of "science" to prolong my misery by 2 weeks.

Bottom line, we need to appreciate that none of the science is all that straightforward. Let us not dumb down the arguments and create false dichotomies. If we do, no one wins.

Allopathic medicine and CAM: Nonoverlapping magisteria revisited?

Stephen J. Gould is known to most of us as the evolutionary biologist who brought much scientific thought on evolutionary science to the public. A self-acknowledged Jewish agnostic, he also struggled with how to help the world hold two seemingly conflicting philosophies: that of science and that of religion. He discusses some of his views in this essay and at more length in his book Rocks of Ages. In the essay he says the following:

The lack of conflict between science and religion arises from a lack of overlap between their respective domains of professional expertise—science in the empirical constitution of the universe, and religion in the search for proper ethical values and the spiritual meaning of our lives. The attainment of wisdom in a full life requires extensive attention to both domains—for a great book tells us that the truth can make us free and that we will live in optimal harmony with our fellows when we learn to do justly, love mercy, and walk humbly.

Gould coined the idea of "nonoverlapping magisteria" to describe the complementarity of rather than a conflicted relationship between these two domains of human condition. In this view he echoes another iconic scientist of the last century, Albert Einstein, who concluded that "Science without religion is lame. Religion without science is blind". Both scientists seem to boil the complementary nature of the two fields down to the idea that science asks the question "how?" and religion asks the question "why?", both so necessary for our understanding of life in this Universe. Thus, forcing oneself or others to choose between the two creates a false dichotomy so prevalent in our discourse today.

Along the same lines, I am struck by the nearly always contentious and occasionally hostile conversation about the role of complementary and alternative medical (CAM) modalities alongside of our traditional Western style allopathic medicine. Both sides seem to imply that there is no room for both in our healthcare. And while the allopathic side holds up scientific method and evidence as the oracle of their field, the CAM practitioners, with equal zeal, cite tradition, spirituality and mystery of the human body as the central dogma in theirs. And when each is subjected to a critical appraisal by the other's methods, failure is the most frequent, if not unexpected, result.

So what is the answer? Should allopathic medicine, the side that right now holds much greater power and sway over our healthcare system, let in these pseudo-scientific usurpers even without any scientific evidence that they do any good? Should the two just coexist side by side, much like suggested by Einstein and Gould for science and religion? Well, it's complicated.

It is hard to argue with a straight face that the earth is flat or that it is indeed only six thousand years old, given the plentiful fossil record to the contrary. Believing an ancient text verbatim and denying the reality of the evidence to the contrary is not only a logical fallacy, it betrays stupidity and petulance. Similarly, denying that uncontrolled hypertension is the cause of coronary disease is ridiculous. However, given the complexity of the organism, we know that it is not the only cause of coronary disease. Furthermore, there may be causes that we have not discovered yet because we have either not thought to look or are unable to discern because we do not yet have the necessary scientific tools. This is to say that we know a lot, but probably not everything.

Now, let's move on to treatment of hypertension. The way we establish whether a modality works is through randomized controlled trials, where we look for differences in outcome based on the differences in the main exposure, in our particular case, the treatment for hypertension. Randomization is meant to ensure that the two groups being compared are not different from one another in any systematic way, and we reassure ourselves that randomization worked by looking at aggregate physiologic measures of the two groups, such as average blood pressure, average age, etc, and seeing if they are the same in both groups. If they are roughly equivalent, we say that the randomization worked, and all the differences in the outcome we see must be due to the experimental intervention, in our case the blood pressure treatment.

But what are we unable to measure? Oh so much! The burgeoning science of neurobiology, for example, has raised so many interesting questions about not only what the mind can do to the body, but what the body can do to the mind (please forgive this dualistic language). Why is this important? Because, due to our lack of adequate tools until recently, and because of the overwhelming complexity of the subject, we have traditionally neglected to include any measures of our patients' and trial subjects' neurobiological milieu into the consideration of differences between groups. But if randomization takes care of other systematic differences, should it not take care of the neurobiological ones? Perhaps, but without understanding the magnitude of variability of these characteristics in a population, one cannot begin to know how large a swathe of the population has to be enrolled in a study in order to smooth out these potential differences. And this goes for other so far unknown or unidentifiable characteristics. So what we think we learn from these trials is, much like in any other branch of science, subject to interpretation within the context of our knowledge today, and is, therefore, far from the universal and immutable truth. And the more we learn, the less absurd certain heretical ideas of the past seem. It's OK, we are all in good company. Even Einstein was not infallible: when he said that "God does not play dice with the Universe", he was alluding to his skepticism with regard to randomness of quantum motion, which has since been confirmed.  

But I stray from my main question, which is "Is the dichotomy between allopathic medicine and CAM a false one?" Well, what if we broaden the argument. We know that a human being is a fairly complex animal. As I alluded to above, we are only now beginning to put the data from neurobiology behind the phenomena of the human condition that have been observed for millennia. Such human impulses as the need to be surrounded by nature, compassion and need for retribution are all gaining scientific underpinnings in neurobiological research. So, what we already knew and understood about ourselves is now being explained (the "how") by science. This is comforting, and it should make my evidence-based allopathic colleagues pleased. It should also please the CAM practitioners, as the traditional views of what it means to be human are being validated.

So, what am I driving at? Krista Tippett in the Introduction to her latest book Einstein's God says that "opinion polls create false dichotomies". Since we live in a time when polarization seems to be the norm (just look at our political discourse), it is natural for allopathic medicine and CAM to retreat more deeply into their own corners and to become more entrenched in and convinced of their own singularity. This is the wrong approach. Humans are not all easily-understood physiology, but we are also not all spirit and mystery. We are in fact both. Some of the conditions we define as physiologic illnesses are nothing more that the products of our distorted expectations and philosophies. Some of our impulses to treat cancer with CAM alone are misinformed. If acupuncture seems to help my neighbor with her subjective symptoms of menopause, so be it, I am happy for her, even if I do not fully understand how it works. If yoga gives me a sense of well-being, yet there are no randomized controlled trials to validate this assertion, so what? Perhaps more "N of 1" trials are the way to go for CAM, I don't know. But I do think there is something to the subjective experience, even if we call it placebo effect, which incidentally implies that it is your own organism, with the help of an external stimulus, that has achieved the desired end. Why is this bad? Especially if there is no adverse consequence to counterbalance it? Granted, we have to be conscious of the attendant costs in this mammoth healthcare system of ours. Well, I for one am not averse to subsidizing my neighbors' well-being, even if the science tells me the effect is no different from a placebo. We already pay a premium dollar for interventions that only seem to work in a small minority of individuals who qualify for them based on well-accepted scientific evidence. And this is not even getting into the discussion of how much adverse reactions cost, even when there is no individual benefit of treatment.

It is true that science sets a high bar for gathering evidence. But one must acknowledge the inherent subjectivity in how we define endpoints of importance, and a complete antithesis to clinical sensibility of pursuing the p value. Medicine is and will remain inexact, part science, part art. To hold these two seemingly different philosophies together does not present an internal conflict for anyone, just as holding the methods, aims and philosophies of allopathic practice and CAM should not. Bridging these as nonoverlapping magisteria in healthcare can eliminate much of the conflict felt by the medical profession, and promote a more open-minded and humanistic approach to our public's health.                              

    

   

Voodoo Medicine

An excellent post the other day on the Science-Based Medicine blog addressed "Incorporating Placebos into Mainstream Medicine". In it the author, Harriet Hall, rails against complementary and alternative medicine as inherently leveraging the placebo effect. She goes on to ask "What if scientific medicine were to co-opt the CAM movement? We could take these treatments out of the hands of the less ethical practitioners and outright scam artists and place it in the hands of those who are more likely to be altruistic". This mouthful grabbed my attention.

Here is what bothered me. The traditional healthcare providers believe that they are practicing scientific medicine. And why wouldn't they? The clinical research establishment (of which I am a part, mind you) is constantly touting new breakthrough results, and the FDA after all only approves therapies that are proven to be effective! Well, not so fast; there are an awful lot of assumptions in this statement. First, how much of the research out there is of high quality and how much is bovine excrement? Next, even the best of studies that find statistical advantages to one course of action over another show minute, potentially inconsequential differences that a lot of the time translate into zero benefit outside the laboratory of clinical trials. And as for the FDA, they are paid by the manufacturers to review and approve drugs and devices. And even though I trust in their earnestness, most of the time they require only statistically significant differences (microscopic ones can still emerge given a large enough study size) in outcomes that are not all that meaningful to one's well-being (e.g., drop in cholesterol as a surrogate for a reduced risk of death from cardiovascular disease, a less straight-forward relationship than you might suspect).

So, there is the science bit. As for ethics, I will give Dr. Hall that for the most part MDs do try to practice what is commonly accepted as scientific medicine. The key here is "for the most part". Remember Gawande's story of McAllen, TX? And lo' and behold, just a few hours ago Reuters reported a bust of a large Medicare fraud scheme, where, believe it or not, docs were charging $3,000 to $4,000 for simple knee and shoulder braces and heating pads, calling them "arthritis kits". And while I do not question the ethics of the majority of my brethren, this incident sure underscores that, just as CAM practitioners, the house we live in is also made out of glass.

We have a long way to go to achieve good health in this country. Our culture has become over-reliant on experts in everything, including healthcare and evidence, to slap our wrists when we have been "bad" and to give us marginally useful advice on how to cure our ills. We must question our assumptions. I agree with Dr. Hall, nothing replaces a combination of evidence and experience. Or the placebo effect.