“CAM” Education in Medical Schools—A Critical Opportunity Missed

Mea culpa to the max. I completely forgot that today is my day to post on SBM, so I’m going to have to cheat a little. Here is a link to a recent article by yours truly that appeared on Virtual Mentor, an online ethics journal published by the AMA with major input from medical students. Note that I didn’t write the initial scenario; that was provided to me for my comments. The contents for the entire issue, titled “Complementary and Alternative Therapies—Medicine’s Response,” are here. Check out some of the other contributors (I was unaware of who they would be when I agreed to write my piece).

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Et tu, Biomarkers?

Everything you know may be wrong. Well, not really, but reading the research of John Ioannidis does make you wonder. His work, concentrated on research about research, is a popular topic here at SBM.  And that’s because he’s focused on improving the way evidence is brought to bear on decision-making. His most famous papers get to the core of questioning how we know what we know (or what we assume) to be evidence.

His most recent paper takes a look at the literature on biomarkers. Written with colleague Orestis Panagiotou, Comparison of effect sizes associated with biomarkers reported in highly cited individual articles and in subsequent meta-analyses is sadly behind a paywall -  so I’ll try to summarize the highlights. Biomarkers are chemical markers or indicators that can be measured to verify normal biology, detect abnormal pathology, or measure the effect of some sort of treatment. Ever had blood drawn for lab tests? Then you’ve had biomarkers tested. Had your blood pressure checked? Another biomarker. The AACR-FDA-NCI cancer biomarkers consensus report provides a nice categorization of the different biomarkers currently in use:

  • Diagnostic biomarkers
    • Early detection biomarkers
    • Disease classification
  • Predictive biomarkers
    • Predict the response to a specific agent
    • Predict a particular adverse reaction
  • Metabolism biomarkers
    • Biomarkers that guide drug doses
  • Outcome biomarkers
    • Those that predict response
    • Those that predict progression
    • Those that forecast recurrence

Biomarkers are developed and implemented in medical practice in a process that parallels drug development. It starts with a hypothesis, then progressive research to validate the relationship between the measurement of a feature, characteristic, or parameter, and the specific outcome of interest. The assay process, for measuring the biomarker itself must also undergo its own validation, ensuring that measurements are accurate, precise, and consistent. Biomarkers are generally considered clinically valid and useful when there is an established testing system that gives meaningful, actionable results that can make a clinically meaningful difference the way we prevent or treat disease.

Some of the most common medical tests are biomarkers. Serum creatinine to estimate kidney function, levels of liver enzymes to evaluate liver function, and blood pressure to predict the risk of stroke.  The search for new biomarkers has exploded in the past several years with the growing understanding of the molecular nature of many diseases. Cancer therapies are among the most promising areas for biomarkers, with tests like HER2 (to predict response to trastuzumab), or the KRAS test (to predict response to EGFR inhibitors like cetuximab and panitumumab) guiding drug selection. It’s a very attractive target: Rationally devising drugs based on specific disease characteristics, and then using biomarkers to a priori to identify patients most likely to respond to treatment.

Despite their promise, the resources invested, and isolate winners, biomarker research has largely failed to live up to expectations for some time. Most recently, David Gorski discussed how the hype of personalized medicine hasn’t yet materialized into truly individualized treatments: not because we’re not trying, but because it’s really, really, hard work. I’ve also pointed out that the the direct-to-consumer genetic tests, some of which rely on biomarkers, is a field still not ready for prime time, where the marketing outpaces the science. The reality is that few new biomarker tests have been implemented in clinical practice in the past decades. For many medical conditions, we continue to rely on traditional methods for diagnosis. Yes the promise of biomarkers is tantalizing. Every major conference heralds some new biomarker that sounds predictive and promising.  So we have a hot scientific fields, lots of preliminary research, multiple targets and approaches, and significant financial interests at play. Sound familiar? It’s exactly the setting describe by Ioannidis on therapeutic studies, in his well-known paper, Why Most Published Research Findings Are False. And based on this latest paper, the biomarker literature seems to share characteristics with the literature on medical interventions, which Ioannidis studied in another well-known paper, Contradicted and Initially Stronger Effects in Highly Cited Clinical Research.

This newest paper, which was published earlier this month, sought to evaluate if highly cited studies of biomarkers were accurate, when compared to subsequent  meta-analyses of the same data. To qualify, each study had to have been cited over 400 times, and each study had to have a matching subsequent meta-analysis of the same biomarker relationship conducted as follow-up. To reduce the field from over 100,000 studies down to something manageable, results were restricted to 24 high impact journals with the most biomarker research.  Thirty-five base papers, published between 1991 and 2006 were ultimately identified. These were well-known papers – some have been cited over 1000 times. For each paired comparison, the largest individual study in each meta-analysis was also identified, and compared to the original highly cited trial. Biomarkers identified included genetic risk factors, blood biomarkers, and infectious agents. Outcomes were mainly cancer or cardiovascular-disease related.  Most of the original relationships identified were statistically significant, though four were not.

So did the original association hold up? Usually, no.  Of that sample of 35, subsequent analysis failed to substantiate as strong a link 83% of the time. And 30 of the 35 reported a stronger association than observed in the largest single study of the same biomarker. When the largest studies of these biomarkers were examined, just 15 of the 35 original relationships were still significantly significant, and only half of these 15 seemed to remain clinically meaningful. For example, homocysteine use to be kind of a big deal, after it was observed that a strong correlation existed between levels of this biomarker and cardiovascular disease, in a small study. The most well-know study has been cited in the literature 1451  times,  and reported an whopping odds ratio of 23.9.  Subsequent analyses of homocysteine failed to show such a strong association. Nine years after the initial trial, a meta-analysis of 33 trials with more than 16,000 patients calculated an odds ratio of 1.58. Yet this finding has been infrequently cited in the literature: only 37 citations to date.

The authors identify a number of reasons why these findings may be observed. Many of the widely cited  studies were preliminary and had small sample sizes. Publication interest could have led to selective reporting from looking for significant findings. The preliminary studies preceded the meta-analysis often by several years, giving ample time for citations to accrue (though this was not always the case, and in some cases, the highly cited studies followed larger studies.) Limitations identified included the biomarker selection process which included several arbitrary selection steps, including the citation threshold, and the requirement for a paired meta-analysis. The authors warn readers to be cautions when authors cite single studies and not meta-analyses, and conclude with the following warning:

While we acknowledge these caveats, our study documents that results in highly cited biomarker studies often significantly overestimate the findings seen from meta-analyses. Evidence from multiple studies, in particular large investigations, is necessary to appreciate the discriminating ability of these emerging risk factors. Rapid clinical adoption in the absence of such evidence may lead to wasted resources.

The editorial that accompanied the article (also paywalled) echos the cautions and concerns in the paper:

It would be premature to doubt all scientific efforts at marker discovery and unwise to discount all future biomarker evaluation studies. However, the analysis presented by Ioannidis and Panagiotou should convince clinicians and researchers to be careful to match personal to hope with professional skepticism, to apply critical appraisal of study design and close scrutiny of findings where indicated, and to be aware of the findings of well-conducted systematic reviews and meta-analyses when evaluating the evidence on biomarkers.

More of the (Fake) Decline Effect? No.

The so-called “Decline Effect” has been discussed at length here at SBM. The popular press seems to be quick to reach for unconventional explanations of the weakening of scientific findings under continued scrutiny. Steven Novella discussed a related case earlier this month, pointing out there’s no reason to appeal to quantum woo, when the decline effect is really just the scientific process at work: adding precision and reducing uncertainty through continued analysis.

Biomarker research parallels therapeutic research, with all the same potential biases. The earliest and often most highly cited results may ultimately turn out to be inaccurate and quite possibly significantly overstated.  Trial registration and full disclosure of all clinical trials will help us understand the true effect more quickly. But that alone won’t solve the problem if we continue to attach significant merit to preliminary data, particularly where there is only a single study. Waiting for confirmatory research is hard to do, given our propensity to act. But a conservative approach is probably the smartest one, given the pattern we’re seeing in the literature on biomarkers.

References
ResearchBlogging.org
Ioannidis JP, & Panagiotou OA (2011). Comparison of effect sizes associated with biomarkers reported in highly cited individual articles and in subsequent meta-analyses. JAMA : the journal of the American Medical Association, 305 (21), 2200-10 PMID: 21632484

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We get mail

There are a few “laws” of the blogosphere, one of them being that a response to a post that comes more than a few weeks later is generally useless or crazy.  But once in a while, someone takes the time to look at an old post and formulate a thoughtful response.

This is not one of those times.

Or maybe it is.  I’ll report (and editorialize), you decide.

Regarding a piece I first published in September of 2010, a reader writes:

Dear Dr. Gorski:[our managing editor]

I am writing regarding your comments on the following blog

Your disease, your fault

I am not a doctor but am pursuing an MA and hopefully a PhD in nutrition and public health. I am very familiar with Dr. Fuhrman and his work. I have heard many of Dr. Fuhrman’s lectures and if anything they are all based on concrete scientific research. I must express my disappointment about both the tone and factual content of the article written. I read extensively about nutrition, exercise and their health benefits. Much of the research done in this field has been conducted in small clinical trials or in the laboratory. There is a good reason for this. Only the government has the financial ability to pay the tens of millions of dollars needed to conduct large scale clinical trials in this area since a drug company would in all probability not have any financial gain from a clinical trial showing that individuals eating 10 servings of vegetables each day have a significant reduction in chronic disease. I do feel that all epidemiological as well as clinical work done points to the very clear fact that people die years before they need to due to the poor diets they have. It is also very clear that most physicians have very little knowledge about nutrition since it is generally a very minor part of their education. I agree with doctor Fuhrman that any debate should be both science based and held to the highest ethical standards. From what I see the article written as well as your comments do not meet these standards. I find that most disconcerting due to the fact that individuals put their lives in their hands when they consult with you as a physician.

In closing I would like your comment on the follwing statement that was made by Dr. William Castelli, who ran the Framingham Study for about 20 years. An interviewer asked him what percent of heart disease could be avoided through proper nutrition and exercise. His response was very brief. 100%!! Do you agree with one of foremost reaearcers of the 20th century or do you consider him to be a quack too.

I await your response.

Sincerely,

[Name redacted]

What is instructive here is the usual thoughtful but incorrect “reasoning” used by someone with just enough knowledge to think he understands the topic at hand well enough to rebut.  The rebuttal, however, makes use of the usual fallacies that are the fallback position for the ignorant and the mendacious (and I must point out that I think our Dear Correspondent is the former).

Since I wrote the piece, not Dr. Gorski, I take full responsibility for its content and defend my writing personally.  A bit of a fisking is in order to help us all better understand how to think about these questions properly.

I am not a doctor but am pursuing an MA and hopefully a PhD in nutrition and public health. I am very familiar with Dr. Fuhrman and his work. I have heard many of Dr. Fuhrman’s lectures and if anything they are all based on concrete scientific research. I must express my disappointment about both the tone and factual content of the article written.

The writer first tries to establish himself as an authority on nutrition, public health, and one Dr. Fuhrman (the putative antagonist of my piece) as a reliable source of that authority.  Even if we were to be convinced by his level of authority, it is irrelevant to his arguments.   Our Dear Correspondent could be a Nobel laureate in physics, but this is no guarantee of relevant expertise.

Then he begs the question: he asserts that Dr. Fuhrman’s works are “all based on concrete scientific research”.  This may or may not be true, but it does not refute the points made in my post, such as Furhman’s stated idea that all disease is preventable with just the right lifestyle and avoidance of medication.

He finishes his point with a non sequitur (although one that loyal reader Peter Moran might agree with), that somehow my tone renders my argument less valid.  If I were to point at the sky and shout, “It’s &%$# blue, you ass!” the statement would be no less true for its crudeness.

I read extensively about nutrition, exercise and their health benefits. Much of the research done in this field has been conducted in small clinical trials or in the laboratory. There is a good reason for this. Only the government has the financial ability to pay the tens of millions of dollars needed to conduct large scale clinical trials in this area since a drug company would in all probability not have any financial gain from a clinical trial showing that individuals eating 10 servings of vegetables each day have a significant reduction in chronic disease.

This is simply untrue.  There is an enormous body of research on nutrition and exercise physiology.  Just glancing at today’s issue of the American Journal of Cardiology, we see Impact of Body Mass Index, Physical Activity, and Other Clinical Factors on Cardiorespiratory Fitness (from the Cooper Center Longitudinal Study); from The Lancet, a summary of Salt and cardiovascular disease mortality. These fields (nutrition, exercise) are and have been active areas of high quality research, just not to the exclusion of all else.  It would be rather foolish to focus on only one set of tools to prevent a heart attack.  When lifestyle modification is inadequate, it is not a failure of the patient, the doctor, or science-based medicine, but a simple case of “stuff happens” and it’s time to crack open another tool box.

These facts render irrelevant his subsequent suspicion-filled assumptions about the economics of medicine.  The government funds a great deal of this research, but so do pharmaceutical and related industries.  There is always a profit to be made, whether by developing a new drug, or opening a Whole Foods with aisles full of magic (some of which is quite healthy and quite tasty).

I do feel that all epidemiological as well as clinical work done points to the very clear fact that people die years before they need to due to the poor diets they have. It is also very clear that most physicians have very little knowledge about nutrition since it is generally a very minor part of their education.

Not to wax Crislipian, but Duh! Our country is suffering from an epidemic of obesity, leading to early, preventable deaths.  That’s not particularly controversial.  It’s also not a mystery that many physicians receive an inadequate education in nutrition.  The fallacy here is that it is better to worship a false god than to seek true knowledge.  The cure to our ignorance is not to listen to some pseudo-expert who is completely wrong about disease prevention and treatment, but to improve our education of the public and our professionals.

I agree with doctor Fuhrman that any debate should be both science based and held to the highest ethical standards. From what I see the article written as well as your comments do not meet these standards. I find that most disconcerting due to the fact that individuals put their lives in their hands when they consult with you as a physician.

Well, that’s just ad hominem nonsense.  What counts is facts, not one writer’s opinion about tone and ethics.  This statement betrays a complete misunderstanding of medical ethics.  Our duty, as physicians, is first to our patients, then to the wider public.  We must treat the patient in front of us with the best science-based medicine has to offer, delivered with compassion.  We must educate the public to teach the difference between real doctors and carnival barkers (h/t POTUS).

In closing I would like your comment on the follwing statement that was made by Dr. William Castelli, who ran the Framingham Study for about 20 years. An interviewer asked him what percent of heart disease could be avoided through proper nutrition and exercise. His response was very brief. 100%!! Do you agree with one of foremost reaearcers of the 20th century or do you consider him to be a quack too.

I’m not so sure about that Castelli quote.  He has a history of some pretty bold pronouncements that don’t quite follow the evidence, but if you dig into his efforts a bit deeper, you can see that he clearly doesn’t believe the statement above:

Castelli concedes diet and exercise won’t help the 5 to 10 percent of people who’s heart disease is genetic. The genetic predisposition to heart disease is responsible for 85% of heart attacks suffered by people under 65. These people often have cholesterol levels of a whopping 300 or higher. Medication can save their lives, but the health care system, Castelli charges, doesn’t do a good enough job of finding these patients in time.

If our Dear Correspondent would like to learn more about how to think more clearly about medicine and science, this blog has been live for a few years now and offers a treasure trove for those interested in banishing ignorance, or at least learning to tell fact from its opposite.

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Kudos to Steven Novella

It has just been announced, in the July/August issue of Skeptical Inquirer magazine, that our own Steven Novella has been awarded the 2010 Robert P. Balles Annual Prize in Critical Thinking. It will be formally presented at the CSIcon conference in New Orleans on October 28, 2011. The Prize is a $1500 award given to the author of the published work or body of work that best exemplifies healthy skepticism, logical analysis, or empirical science. The Committee for Skeptical Inquiry (CSI) selects the publication that, in its judgment, has the greatest potential to create positive reader awareness of currently important scientific concerns. Previous awards starting in 2005 were for individual publications. In Dr. Novella’s case, the award was for his entire body of work. In the letter informing him of his selection, CSI Executive Director Barry Karr said,

…you are being honored for your tremendous body of work including The Skeptic’s Guide to the Universe, Science-Based Medicine, Neurologica, your SKEPTICAL INQUIRER column “The Science of Medicine,” as well as your tireless travel and lecture schedule on behalf of skepticism. You may well be the hardest worker in all of skepticism today. And to me, the truly amazing thing is you do all of this on a volunteer basis.

He is also the president and co-founder of the New England Skeptical Society, a fellow of CSI, a founding fellow of the Institute for Science in Medicine, a medical advisor to Quackwatch, a contributor to other blogs, has produced a course for The Teaching Company on “Medical Myths, Lies, and Half-Truths,” and is Senior Fellow and Director of the James Randi Educational Foundation’s (JREF) new Science-Based Medicine project. And I have undoubtedly omitted several of his other accomplishments.

It is hard to believe he hasn’t cloned himself, since all of these achievements are in addition to his demanding day job as a clinical neurologist, assistant professor, and director of general neurology at Yale University School of Medicine.

Congratulations, Steve! The award couldn’t have gone to a better candidate. I want to add my personal thanks for all you do and say how proud I am to be associated with you. You da man!

 

 

 

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Acupuncturist’s Unconvincing Attempt at Damage Control

Acupuncture has been in the news recently. A former President of South Korea had to undergo major surgery to remove an acupuncture needle that had somehow lodged in his lung.  A recent study in Pain compiled a list of 95 published reports of serious complications of acupuncture including 5 deaths. Meanwhile, acupuncturists continue to insist that their procedures are “safe.”

Edzard Ernst et al.’s article Acupuncture: Does it alleviate pain and are there serious risks? A review of reviews was published in the journal Pain in April 2011. It had two parts: (1) it was a systematic review of 57 systematic reviews showing that there was “little truly convincing evidence that acupuncture is effective in reducing pain,” and (2) it tabulated published reports of 5 deaths and 90 other serious complications of acupuncture treatments. I wrote an accompanying commentary, “Acupuncture’s claims punctured: Not proven effective for pain, not harmless.”

William Morris chastised me for not declaring a conflict of interest (!?) in my commentary. Now, in Acupuncture Today, he has criticized the Ernst et al. study itself.

Morris’ first criticism is that the study

did not examine iatrogenic deaths due to conventional drugs, chemotherapy, radiotherapy and surgery. It was more focused on the safety and efficacy of acupuncture.

I laughed out loud when I read this. It was focused on the safety and efficacy of acupuncture because it was a study about the safety and efficacy of acupuncture. Duh!  A study of acupuncture for pain is not the appropriate place to examine iatrogenic deaths from four conventional treatment methods that are used for every disease from pneumonia to cancer. We need to know about acupuncture’s efficacy and safety (for pain) before we can even consider making any meaningful comparisons with other treatments (for pain). He says “it would be interesting to see results an [sic] in-depth ‘review of reviews’ on the safety and efficacy of conventional medicine and surgery.” Sure it would, but this is hardly the place.  He tries to forestall protests by insisting this is not a tu quoque argument; but it sure sounds like it, or like something worse.

Comparing iatrogenic deaths from different treatments would be a valid subject for a different article. But why does he single out conventional medicine instead of including deaths from all forms of alternative medicine? What about the risk of stroke from neck manipulation? Neck manipulation would be a particularly pertinent comparison to acupuncture because it is used by many chiropractors to treat pain as an alternative to both conventional medicine and acupuncture. And why single out deaths instead of looking at all serious adverse events? Most importantly, why not look at risks in the context of proven benefits?

Curiously, Morris does not address the results of the systematic review of acupuncture’s efficacy or attempt to counter its conclusions in any way. He only briefly criticizes its methodology, and then he focuses on the reports of adverse effects.

The Systematic Review of Systematic Reviews

He criticizes Ernst et al. for lack of detail in describing how they quantified the quality of the studies they included in their analysis. But they supplied a footnote to an article describing their method, indicating that they followed Oxman and Guyatt’s validated checklist. Does Morris think they should have reproduced the entire checklist and evidence for its validation in the text of their article? I can’t fault them for using a footnote to save space.

“For data on efficacy, it doesn’t provide information about how the studies were controlled.” He wants to know whether it was “acupuncture alone, skin penetrating, non-penetrating or adjacent to the point location.” This only highlights the imprecision of acupuncturists’ own definitions of what qualifies as acupuncture and what constitutes appropriate controls. In my commentary I pointed out:

there are various schools of acupuncture with different acupoints, and studies of acupuncture have included “electroacupuncture” (with or without needles), ear acupuncture, cupping, moxibustion, and other loosely related procedures.

If he had any evidence that his preferred version of acupuncture was more effective or safer than other versions, or that one type of control is more appropriate than another, he could have presented it. He expresses doubts rather than offering data.

Safety

Morris criticizes Ernst et al. for including case reports where causality was uncertain, but each case report was listed individually and its causality categorized as certain or probable. The deaths were categorized as “certain” causality. Even if you eliminate the uncertain ones, the data show that acupuncture cannot be characterized as risk-free.

Bizarrely, he criticizes Ernst et al. for not including other complications such as fainting, vomiting, or bruising that are more common adverse effects. These are not “serious” risks, which is why they were not included in a study of “serious risks.” In essence, Morris seems to be arguing that acupuncture is even less safe than Ernst et al. depicted.

He says “Ernst and his colleagues do not reference previous studies showing acupuncture as safe,” citing a 2003 article by Lao and Berman published in an alternative medicine journal. That article’s conclusion included the authors’ opinion (a value judgment) that acupuncture is “a generally safe procedure”; but its text identified 202 adverse events, over twice as many as the Ernst et al. article. It included minor events like fainting and nausea, while the Ernst study was limited to serious events. I don’t have access to the full study. I wonder if it is exempt from the same criticisms: did its authors describe how they quantified the quality of the reports they included, did they assess the certainty of causation, and did they follow a validated checklist like Ernst et al. did?

Morris quotes a researcher who says “acupuncture is seen as an extremely safe therapeutic system whose complications are very rare and are easily avoided or rectified.”  This is not at all in conflict with the findings of the Pain study. Ernst et al. found a number of complications that was quite small in relation to the large number of acupuncture treatments, and they called for better training of acupuncturists to minimize the chance of complications. The real point is that there is no reason to accept any degree of risk, no matter how little, if there is no benefit to the treatment. Safety by itself is no recommendation: homeopathy is probably the safest treatment going.

Conflict of Interest

Morris criticized me for not declaring a conflict of interest in my commentary.  I have no conflict of interest: it makes no difference to me whether acupuncture works or not; I would follow the evidence wherever it led and write about it.  He, on the other hand, has a clear interest in defending his occupation, and I don’t see any declaration of his conflict of interest in his Acupuncture Today article. The Ernst et al. study is solid: it shows that there is little evidence that acupuncture is truly effective in reducing pain. Taken as a whole, a rigorous evaluation of the published evidence leads to the conclusion that acupuncture is no more effective than placebo, and it is not risk free.  Morris doesn’t want to accept this. He is biased in favor of acupuncture and is doing whatever he can to limit the damage from the Pain study. He can’t do much: his efforts are unconvincing and rather sad.


 

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Blatant pro-alternative medicine propaganda in The Atlantic

Some of my fellow Science-Based Medicine (SBM) bloggers and I have been wondering lately what’s up with The Atlantic. It used to be one of my favorite magazines, so much so that I subscribed to it for roughly 25 years (and before that I used to read my mother’s copy). In general I enjoyed its mix of politics, culture, science, and other topics. Unfortunately, my opinion changed back in the fall of 2009, when, on the rising crest of the H1N1 pandemic, The Atlantic published what can only be described as an terrible bit of journalism lionizing the “brave maverick doctor” Tom Jefferson of the Cochrane Collaboration. The article, written by Shannon Brownlee and Jeanne Lenzer, argued, in essence, that vaccinating against H1N1 at the time was a horrendous waste of time and effort because the vaccine didn’t work. So bad was the cherry picking of data and framing of the issue as a narrative that consisted primarily of the classic lazy journalistic device of a “lone maverick” against the entire medical establishment that it earned the lovely sarcasm of our very own Mark Crislip, who wrote a complete annotated rebuttal, while I referred to the methodology presented in the article as “methodolatry.” Even public health epidemiologist Revere (who is, alas, no longer blogging but in his day provided a very balanced, science-based perspective on vaccination for influenza, complete with its shortcomings) was most definitely not pleased.

I let my subscription to The Atlantic lapse and have not to this day renewed it.

Be that as it may, last year The Atlantic published an article that wasn’t nearly as bad as the H1N1 piece but was nonetheless pretty darned annoying to us at SBM. Entitled Lies, Damned Lies, and Medical Science, by David Freedman, it was an article lionizing John Ioannidis (whom I, too, greatly admire) while largely missing the point of his work, turning it into an argument for why we shouldn’t believe most medical science. Now, Freedman’s back again, this time with a much, much, much worse story in The Atlantic in the July/August 2011 issue under the heading “Ideas” and entitled The Triumph of New Age Medicine, complete with a picture of a doctor in a lab coat in the lotus position. It appears to be the logical follow up to Freedman’s article about Ioannidis in that Freedman apparently seems to think that, if we can’t trust medical science, then there’s no reason why we shouldn’t embrace medical pseudoscience.

Basically, the whole idea behind the article appears to be that, even if most of alternative medicine is quackery (which it is, by the way, as we’ve documented ad nauseam on this very blog), it’s making patients better because of placebo effects and because its practitioners take the time to talk to patients and doctors do not. In other words, Freedman’s thesis appears to be a massive “What’s the harm?” argument coupled with a false dichotomy; that is, if real doctors don’t have the time to listen to patients and provide the human touch, then let’s let the quacks do it. Tacked on to that bad idea is a massive argumentum ad populum portraying alternative medicine as the wave of the future, in contrast to what Freedman calls the “failure” of conventional medicine.

Let’s dig in, shall we? I’ll start with the article itself, after which I’ll examine a few of the responses. I’ll also note that our very own Steve Novella, who was interviewed for Freedman’s article, has written a response to Freedman’s article that is very much worth reading as well.

CHOOSE: HARRIED UNCARING DOCTORS OR QUACKS

You know an article about medicine going to be bad, at least on the science, when it starts out with a sympathetic profile of Brian Berman after an introduction that reads:

Medicine has long decried acupuncture, homeopathy, and the like as dangerous nonsense that preys on the gullible. Again and again, carefully controlled studies have shown alternative medicine to work no better than a placebo. But now many doctors admit that alternative medicine often seems to do a better job of making patients well, and at a much lower cost, than mainstream care—and they’re trying to learn from it.

One of these “many doctors” is, apparently, Dr. Brian Berman. One also notes that nowhere in Freedman’s article is a shred of compelling evidence is presented to support the assertion that alternative medicine can do a better job of making patients well at a much lower cost. It’s all assertions and speculations by “experts” in the field. In any case, regular readers might remember Dr. Berman, who has been featured on this very blog for his advocacy of quackademic medicine, most recently after he managed to get a credulous article about acupuncture into the New England Journal of Medicine (discussed by Mark Crislip and myself). Then, not unlike the vast majority of the evidence that CAM practitioners prefer over basic science and clinical trials, Freedman segues right into an anecdote about a man named Frank Corasaniti, a 60-year-old retired firefighter who had injured his back falling down a steel staircase at a firehouse some 20 years earlier and had subsequently injured both shoulders and his neck in the line of duty. Corasaniti was suffering from chronic pain due to his old injuries and at the urging of his wife tried acupuncture at Dr. Berman’s clinic under the direction of an acupuncturist named Lixing Lao. The consultation is described thusly:

Their first visit had lasted well over an hour, Corasaniti says, time mostly spent discussing every aspect of his injuries and what seemed to ease or exacerbate them, and also other aspects of his health–he had been gaining weight, he was constipated, he was developing urinary problems. They talked at length about his diet, his physical activity, his responsibilities and how they weighed on him. Lao focused in on stress–what was causing it in Corasaniti’s life, and how did it aggravate the pain?–and they discussed the importance of finding ways to relax in everyday life.

All of which is nothing that a real doctor couldn’t or wouldn’t do and completely unobjectionable. It’s what comes next that is the problem, as Lao tells Mr. Corasiniti about how acupuncture “works”:

Then Lao had explained how acupuncture would open blocked “energy pathways” in his body, allowing a more normal flow of energy that would lessen his pain and help restore general health. While soothing music played, Lao placed needles in and around the areas where Corasaniti felt pain, and also in his hands and legs, explaining that the energy pathways affecting him ran throughout his body.

Mr. Corasaniti feels better now; therefore acupuncture works.

I wonder how closely Lao is supervised by Dr. Berman or what the formal arrangement is, because, quite frankly, from the description I see here it sure sounds as though Lao is practicing medicine without a license. What are his qualifications in nutrition? Is he a dietician? What are his qualifications as a counselor or psychologist? In the article, Lao is described as a physiologist with Dr. Berman’s center, which to me sounds as though he has no legitimate qualifications whatsoever to be discussing diet and counseling Corasaniti how to deal with his chronic injuries. Yet there he is, practicing what sound to me like dietetics, counseling, and even medicine without a license at a major academic medical center. That’s leaving aside how, by Freedman’s own report, “practitioners” like Lao, with the approval of doctors like Berman, telling patients that there is a magical life force whose flow acupuncturists can rearrange to therapeutic effect by sticking little sharp objects into their bodies. Indeed, if there’s one thing I’ve found about alt-med, it’s that the supposedly “sensible,” science-based advice about diet and exercise that it’s co-opted as somehow “alternative” and pointed to as being better than what physicians offer often turns out not to be so sensible or science-based when you look at it more closely. Fad diets, supplements, various “detox” diets are all par for the course. We’ve pointed out numerous examples right here on this very blog of pure pseudoscience in medical schools and academic medical centers—even, I hate to admit it, at my medical alma mater.

Freedman then delves into what he apparently views as the failure of scientific medicine, beginning by proclaiming that “on balance, the medical community seems to be growing more open to alternative medicine’s possibilities, not less.” Unfortunately, I can’t actually argue with this assessment; thanks to the infiltration of unscientific CAM into former bastions of SBM like the University of Maryland, quackademic medicine is indeed coming to the fore, but Freedman seems to be arguing that this is a good thing rather than a bad thing because to him scientific medicine has “failed.” This leaves Freedman making this argument as to why quackademic medicine is so popular:

That’s in large part because mainstream medicine itself is failing. “Modern medicine was formed around successes in fighting infectious disease,” says Elizabeth Blackburn, a biologist at the University of California at San Francisco and a Nobel laureate. “Infectious agents were the big sources of disease and mortality, up until the last century. We could find out what the agent was in a sick patient and attack the agent medically.” To a large degree, the medical infrastructure we have today was designed with infectious agents in mind. Physician training and practices, hospitals, the pharmaceutical industry, and health insurance all were built around the model of running tests on sick patients to determine which drug or surgical procedure would best deal with some discrete offending agent. The system works very well for that original purpose, against even the most challenging of these agents–as the taming of the AIDS virus attests.

But medicine’s triumph over infectious disease brought to the fore the so-called chronic, complex diseases–heart disease, cancer, diabetes, Alzheimer’s, and other illnesses without a clear causal agent. Now that we live longer, these typically late-developing diseases have become by far our biggest killers. Heart disease, prostate cancer, breast cancer, diabetes, obesity, and other chronic diseases now account for three-quarters of our health-care spending. “We face an entirely different set of big medical challenges today,” says Blackburn. “But we haven’t rethought the way we fight illness.” That is, the medical establishment still waits for us to develop some sign of one of these illnesses, then seeks to treat us with drugs and surgery.

This is pure piffle. Preventative medicine is part and parcel of primary care, and by definition screening programs for disease (such as mammography) are anything but “waiting for us to develop some sign of one of these illnesses). Similarly, primary prevention (treating hypertension, for instance) is all about preventing serious diseases, such as heart disease or stroke. Moreover, because of our success against infectious diseases, people are now living long enough that chronic degenerative diseases, such as heart disease and cancer, have come to the fore, and these diseases are much more difficult to deal with than infectious diseases that can be cured with the right antibiotic. Basically, when you boil it all down, Blackburn’s assessment is nothing more than the same old complaint against “reductionistic Western medicine” that CAM supporters trot out again and again. The only difference is that it’s tarted up with a “just so” story about how modern medicine supposedly evolved that bears little resemblance to reality and is not questioned. It’s also presented as though physicians haven’t advocated healthy lifestyle interventions for many decades now. In Freedman’s narrative, cribbed from Blackburn, and then placed on steroids by Freedman, in come CAM and “integrative medicine” to deal with chronic disease.

Next comes a favorite CAM trope about how the U.S. spends more on health care than any other nation and has worse outcomes:

All of these shortcomings add up to a grim reality: as a prominent 2000 study showed, America spends vastly more on health as a percentage of gross domestic product than every other country–40 percent more than France, the fourth-biggest payer. Yet while France was ranked No. 1 in health-care effectiveness and other major measures, the United States ranked 37th, near the bottom of all industrialized countries.

This observation, even though true, is utterly irrelevant to the central thesis of Freedman’s article, namely that CAM can somehow improve health care in the U.S. The reason is that France, just as much as the U.S., uses SBM, not CAM. Nor does France, as far as I have been able to tell, “integrate” quackery with its “conventional” medicine any more than the U.S. does. Yet Freedman conflates two unrelated issues in order to suggest that CAM can show us the way out of the perceived “failure” of SBM because of its emphasis on “prevention” and “wellness” and the allegedly closer, more caring relationship between provider and patient, without providing anything other than anecdotes and argumentum ad populum to demonstrate that this might be so.

The one part of the article that comes closest to making sense is when Steven Novella is quoted as saying, “Alternative practitioners have a big advantage. They can lie to patients. I can’t.” This ethical problem appears not to bother Freedman at all. So enamored is he of placebo effects due to CAM that he proceeds to use and abuse them in the same way that Mike Adams did when he was seemingly amazed enough to discover that there are placebo effects in medicine that he tried to argue in a massive tu quoque argument that “Western medicine” is every bit as much a placebo as alt-med. Freedman’s argument, stripped to its essence, is no different than Mike Adams’. Freedman even pulls out an argument that I like to call, “Your Western science can’t study my woo because it’s ‘individualized,’” an argument much favored by woo-meisters:

Randomized controlled trials, the medical world’s gold standard for assessing the efficacy of treatments, cannot really test for this effect. Such studies are perfect for testing pills and other physically administered treatments that either have a direct physical benefit or don’t. (In its simplest form, a controlled study randomly assigns patients to receive either a drug or the equivalent of a sugar pill. If the real thing doesn’t bring on more improvement than the placebo does, the drug is a washout.) But what is it that ought to be tested in a study of alternative medicine? To date, the focus has mostly been on testing the physical remedies by themselves–divorced from any other portion of a typical alternative-care visit–with studies clearly showing that the exact emplacement of needles or the undetectable presence of special ingredients in homeopathic water isn’t really having any significant physical effect on the patient.

But what’s the sham treatment for being a caring practitioner, focused on getting a patient to adopt healthier attitudes and behaviors? You can get every practitioner in each of the study groups to try to interact in exactly the same way with every patient and to say the exact same things–but that wouldn’t come close to replicating what actually goes on in alternative medicine, where one of the main points is to customize the experience to each patient and create unique bonds.

This particular argument is, of course, utter nonsense, as has been pointed out time and time again. If Freedman couldn’t find at least a few studies examining the question of how much of a treatment is due to nonspecific or placebo effects and how much is due to actual interventions themselves, he just wasn’t looking very hard. The bottom line is that Freedman’s article is built on a false dichotomy. Basically, he seems to be arguing that, because conventional doctors are constrained by our current visit-based system of reimbursement from spending a lot of time with patients to get to know them better, empathize with them more, and deal with psychosocial issues, we should cede that aspect of patient care to quacks, letting them step into the breach, so to speak. No, that’s not a straw man position; that’s really what one can reasonably conclude to be Freedman’s argument. He just wouldn’t call it “quackery.” I would in many (but not all) cases. The reason I would is because what comes in with all the caring attention to patients is often pure pseudoscience based on prescientific vitalism. That’s what homeopathy, acupuncture, reiki, and various forms of “energy healing” popular today are. There has to be another way to bring back the “personal touch” and more attentiveness to patients besides telling them that if they want that personal attentiveness they have to go to a quack, which is what Freedman, for all his denials, does, whether he realizes it or not, whether he’ll admit it or not.

THE ATLANTIC SHOWS ITS HAND

As it sometimes does for controversial issues, The Atlantic is hosting an online “debate” about Mr. Freedman’s article and alternative medicine in general, in this case entitled Fix or Fraud? You can tell from the very beginning exactly which side of the issue The Atlantic comes down on by its choice of debaters. (Hint: It’s not “fraud.”) The lineup is stacked with “heavy hitters” in the alt-med movement, all arrayed against Steve Salzberg, who appears to have agreed to take on the role of the token skeptic as he correctly entitled his rebuttal A “triumph” of hype over reality. Besides the author of The Atlantic‘s paean to alt-med, arrayed against Salzberg are:

The rest of the “panelists,” who have not yet contributed responses as of this writing, include Dean Ornish, MD, “pioneering researcher of preventative medicine”; Mimi Guarneri, MD, Founder of the Scripps Center for Integrative Medicine (who also appeared as the pro-CAM physician paired with Dr. Novella on The Dr. Oz Show nearly two months ago); Vasant Lad, director of the Ayurvedic Institute; and Reid Blackwelder, MD, Board Member of the American Academy of Family Physicians who has written credulously about CAM. A more blatantly stacked panel it’s hard to imagine, short of adding Deepak Chopra and Dr. Oz himself! It must have been a painful decision for Steve Salzberg to agree to be the token skeptic; I don’t know what I would have done in his place. Or maybe he didn’t know when he agreed to do it.

Given the wealth and length of the text produced by this team of CAM apologists, I clearly have to do something that doesn’t come natural to me and point out only a few of the most blatantly wrong and misguided arguments, nearly all of which, it should be noted, Mr. Freedman supports when he pipes in. I can also point out that Steve Novella took the time to rebut some of Mr. Freedman’s responses to complaints made by Steve and others, so that I don’t have to. It is interesting, however, to note that in these comments, Mr. Freedman “takes the gloves off,” so to speak and lets his true pique at being criticized show, even as he tries to paint his critics’ responses as emotional, “hot and bothered” knee jerk insults rather than considered responses to his plethora of logical fallacies. On his own blog, he goes on and on about how our responses are so “angry” and elsewhere even goes so far as to accuse his critics of “scienceology,” which he defines as a “quasi-religious faith in a set of closely held beliefs that are dressed up in the trappings of science and kept immune to any counter-evidence or -opinion.” As Steve pointed out, Freedman got the word wrong and didn’t need to make one up. A word already exists to describe the concept Freedman is driving at, and that word is “scientism.” Scientism, by the way, is a favorite charge of advocates of pseudoscience, be it alternative medicine, evolution denialism (i.e., creationism), or whatever. In any case, if you want a taste of how Freedman responds to criticism, here’s an excerpt from his own blog:

Those two basic arguments underlie Gorski’s particularly rabid rant, too. But if you read it, you’ll quickly find yourself buried in a detailed, apparently point-by-point refutation of virtually everything I say in my article. He goes through the article paragraph by paragraph, sentence by sentence, finding in each the logical flaw, the fallacy, the error of argument. Do I compare A and B? Then I’m a fool because A and B are different! Do I contrast C and D? Then I’m a fool, because it’s a false dichotomy! Do I assert a point about science? What do I know about science, I’m a journalist, and therefore a fool! Do I quote a Nobel Laureate? Then I’m a fool, because I’m arguing from authority! Do I point out a problem with mainstream medicine? Then, fool that I am, I’m setting up a straw man! Do I cite a study? Then I’m a fool, because that study was trash, or I’ve misinterpreted it, or it doesn’t apply here! Do I say that randomized studies, the gold standard of medical science, can’t really settle the question of whether alternative medicine might ultimately do a better job in some ways? Then I’m a fool, because any question can be settled with randomized trials, and in fact the studies have been done!

Except that I’ve never called Freedman a fool in any of my posts, either here or on my other blog, leaving me to marvel at his thin skin. Seriously. Go back and read if you don’t believe me. I’ve simply argued that he drew the wrong conclusions from his research and that he, as every writer must do, framed his presentation to support those conclusions. Apparently he can’t distinguish between criticism of his sloppy arguments and criticism of himself, although I do agree that Mr. Freedman did commit every sin of argumentation that he lists in the paragraph above, even as he frames my earlier criticism of his arguments as now a “rabid rant.” Personally, I’m more than happy for readers to compare Mr. Freedman’s own rant with my actually rather mild “rant” and decide whose is the more “rabid.” I also note that Freedman’s argument boils down to assuring us that, yes, he has done the research and that there is “no tearing apart Gorski could produce that I couldn’t in turn rip to shreds.” Trust him on that one, except that, for the umpteenth time, Mr. Freedman fails to produce any scientific evidence or examples to refute a single thing I’ve written and falls back on arguing from authority and straw men, such as claiming that I routinely assert that “alternative medicine is a purely evil and harmful thing that must be crushed.”

But enough of Freedman’s pique at having his work criticized. From now on, I’ll focus primarily on the framing of the pro-alternative medicine responses in The Atlantic “debate.” Freedman’s central thesis was that, even though he openly admits that alt-med is, by and large, placebo medicine and that many of the concepts behind its major modalities (for instance, acupuncture, homeopathy, and reiki) are pseudoscientific nonsense, alt-med still does a “better job of making patients well, and at a much lower cost.” Let’s start with Dr. Briggs and Dr. Killen, the heart of whose argument appears to be similar to Freedman’s. After pointing out that the most common problem for which people turn to CAM is chronic pain and that pharmacotherapy of chronic pain has problems, she argues:

Evidence is growing, based on carefully controlled studies, that certain non-pharmacological complementary interventions may be useful adjuncts to conventional care. For example, the pain of osteoarthritis can be lessened by acupuncture; tai chi may be helpful in reducing the pain of fibromyalgia; and massage and manipulative therapies may contribute to the relief of chronic back pain and related functional impairments. Furthermore, evidence from basic research points to ways in which such interventions use the body’s own pathways known to be involved in response to pain.

Let’s look at the latter two first. I discussed the tai chi/fibromyalgia paper when it came out. It’s nothing more than more of the classic “bait and switch,” because there is nothing unique to tai chi that can be invoked as the cause of better subjective outcomes. Basically, the study should have concluded that gentle exercise is better than, in essence, doing nothing other than talking and a bit of stretching for fibromyalgia. As I put it at the time, the “alternative” frame succeeded. The best you can say about this paper is that it showed that tai chi-style exercise for a longer period of time is better than stretching exercise and talking for a shorter period of time every day using an unblinded study. Similarly, no one argues that massage doesn’t make patients feel better or that manipulative therapies can’t help back pain. Indeed, physical therapists do manipulative therapy all the time. The difference is that they use more science-based interventions. There’s a reason I sometimes refer to chiropractors as “physical therapists with delusions of grandeur.” Physical therapists rely on the physical and don’t claim to be able to help anything not related to the musculoskeletal system. In contrast, many chiropractors infuse their craft with all sorts of woo-ful references to the “vital force” and flow of nerve impulses that have far more to do with a vitalistic, prescientific understanding of disease than with science. As for the acupuncture study, it’s certainly possible to find “positive” acupuncture studies; random noise in clinical trial results, bias, and publication bias will guarantee that. When you look at the totality of evidence for acupuncture, it is resoundingly negative for anything other than placebo or nonspecific effects.

Here’s the NCCAM leadership falls for the CAM frame and false dichotomy promoted by Freedman:

As Freedman also notes, research suggests that non-specific effects often make important contributions to the benefits patients may experience. For example, acupuncture involves a complicated interaction – including the stimulus of needles and their placement, expectancy, touch, a soothing environment, and a reassuring, supportive practitioner – that science has yet to disentangle.

Should we dismiss any benefits as mere placebo effects? Or should we explore the possibility, increasingly suggested by the science, that some complementary interventions provide powerful tools for studying the contributions of attention, touch, time, and reassurance, which are now in short supply in our health care system?

How many times does it need to be repeated that just because science doesn’t know everything doesn’t mean that you can fill in the gaps with “whatever fairy tale most appeals to you” or that it’s not necessary to study pseudoscientific, vitalistic, nonsensical health care systems based on a prescientific understanding of disease in order to determine the relative contributions of provider-patient interactions, nonspecific effects, and placebo effects versus actual benefit from medical treatments themselves? Apparently ad nauseam, because this canard keeps popping up again and again and again, Whac-A-Mole-style.

Moving on to Dr. Weil’s response, I can see from it just why he is the master of obfuscatory language in the service of CAM, as I discussed last month when I looked at his attack on evidence- and science-based medicine. Just look at the title which I’ll paraphrase: The times, they are a-changin’ and we need “smarter” doctors. Note the not-so-subtle implication that, by contrast, CAM opponents must be stupid Luddites who refuse to change with the times, a favorite framing device of CAM promoters. Then, to emphasize his mastery of language, Weil states:

Using synthetic drugs and surgery to treat health conditions was known just a few decades ago simply as “medicine.” Today, this system is increasingly being termed “conventional medicine,” and is the kind of medicine most Americans still encounter in hospitals and clinics. While often expensive and invasive, it is also extremely good for many things, such as medical and surgical emergencies. Some conventional medical approaches are scientifically validated, while others are not.

Any therapy typically excluded by conventional medicine, and that patients use instead of conventional medicine, is known by the catch-all term “alternative medicine.” Alternative therapies are generally perceived as being closer to nature, less expensive and less invasive than conventional therapies, although there are exceptions. Some alternative therapies are scientifically validated, some are not.

Note the dismissiveness towards “conventional” medicine, in particular the framing of its using only “synthetic” drugs and surgery. Never mind that many of the most commonly used drugs are every bit as much derived from natural products as anything touted by an herbalist. Sure, Dr. Weil says, SBM’s good for emergencies (I picture Dr. Weil looking down his nose as he says this, like a desert Santa Claus chastising a naughty child who won’t be getting anything for Christmas), but it’s “expensive and invasive.” Contrast this to the happy, “natural” CAM therapies that are “inexpensive” and “less invasive” than conventional therapies (except, apparently, when they’re not). And just like CAM, some of its approaches are scientifically validated and some are not! Got it? The two are equivalent! Except that Weil has constructed a false equivalency, given that the only alternative therapies that are “scientifically validated” are the ones that CAM has appropriated from SBM, such as diet and exercise, and Dr. Weil, not surprisingly, tries to use them as the proverbial Trojan Horse that I frequently reference:

Use of alternative medicine is but one component of integrative medicine. It attracts the most attention and the harshest criticism. But is nutrition counseling alternative? How about exercise recommendations? What about prescribing botanicals such as saw palmetto for benign prostatic hyperplasia or red rice yeast to lower cholesterol? There is as much or more hard science establishing the efficacy and safety of these therapies as there is behind drug interventions.

See what I mean? Notice how Dr. Weil blatantly co-opts science-based modalities, such as diet and exercise, as being somehow “alternative” when they are not and assiduously avoids any mention of the more hard core CAM modalities, such as “energy healing,” reiki, or homeopathy. Also, saw palmetto doesn’t work for prostatic hypertrophy, and the reason that red rice yeast appears to work to lower cholesterol is because it contains lovastatin, as the Mayo Clinic points out. Basically, as our very own Harriet Hall pointed out, using red rice yeast to lower cholesterol levels involves taking an uncontrolled and unregulated amount of an adulterated pharmaceutical drug. That makes it the height of chutzpah for Weil to claim that there is “as much or more hard science establishing the efficacy and safety of these therapies as there is behind drug interventions.” He can’t resist engaging in a bit of typical pharma-bashing, too.

In the end, Weil “frames” his version of “integrative medicine” not, as he should, as “integrating” quackery with science but rather as aiming to:

  1. Restore the focus of medical teaching, research, and practice on health and healing;
  2. Develop “whole person” medicine, in which the mental, emotional and spiritual dimensions of human beings are included in diagnosis and treatment, along with the physical body;
  3. Take all aspects of diet and lifestyle into account in assessing health and the root causes of disease;
  4. Protect and emphasize the practitioner/patient relationship as central to the healing process;
  5. Emphasize disease prevention and health promotion.

These are all noble ideas, but none of them requires integrating pseudoscience- and belief-based medicine with SBM; yet that is the false dichotomy that Freedman and Weil promote in their articles.

WINNING THE FUTURE OF MEDICINE

Finishing his article, Freedman looks to the future, proclaiming that the next generation of physicians will determine whether alternative medicine takes hold. Not surprisingly, Dr. Weil finishes his article the same way, proclaiming integrative medicine to be “the future of medicine and healthcare.” Meanwhile, in his responses, Freedman simply doubles down on his original article, repeating how he’s making his arguments “with the explicit support of many prominent researchers and physicians” and blithely dismissing both Steve Salzberg’s devastating retort to him, as well as inconvenient criticisms that he considers too harsh as doing away “with all pretenses of objectivity, civility, or respect for evidence and reason.” One can’t help but note that nowhere has Freedman actually been able to refute a single one of the criticisms thus far leveled against him with anything resembling sound arguments or scientific data.

Unfortunately, Weil and Freedman are probably correct about pseudoscience being the future of a disturbingly large swath of medicine. There’s a reason why promoters of unscientific medicine such as the Bravewell Collaborative are focusing so heavily on medical education and setting up “integrative medicine” programs at academic medical centers and bolstering its consortium of CAM-friendly academic medical centers. They’re playing for the long term; there’s no doubt about that. Right now, they’re succeeding, too. The infrastructure is rapidly being built to subvert science in the bastions of academia and replace it with quackademic medicine. Freedman views this as a good (or at least neutral) thing.

We at SBM do not.

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The Dow of Accutane

At home the kids current TV show of choice is How I Met Your Mother, supplanting Scrubs as the veg out show in the evening. Both shows are always on a cable channel somewhere and are often broadcast late at night. Late night commercials can be curious, and as I work on projects, I watch the shows and commercials out of the corner of my eye.

Law firms trolling for business seem common. If you or a family member has had a serious stroke, heart attack or death from Avandia, call now. The non-serious deaths? I suppose do not bother. One ad in particular caught my eye: anyone who developed ulcerative colitis or Crohn’s disease (collectively referred to inflammatory bowel disease, or IBD) after using Accutane, call now. Millions have been awarded.

My eye may have been caught because of my new progressive lenses, but I will admit to an interest in inflammatory bowel disease, having had ulcerative colitis for years until I took the steel cure. It also piqued my interest as these were three conditions among which I could not seen any connections. Accutane, ulcerative colitis, and Crohn’s. One of these is not like the other.

Accutane (its generic name is isotretinoin) is an anti-acne medication, released long after my puberty. The drug is chemically related to retinoic acid, a natural vitamin A derivative, and works in part by decreasing the production of sebum, not an issue with IBD.

Ulcerative colitis (UC) and Crohn’s have the same clinical presentation: lots of bloody diarrhea. Any resemblance stops there. Pathologically they are completely different diseases. Crohn’s can affect the entire GI tract, from the mouth to the rectum, and its hallmark is noncaseating granulomas. While considered an autoimmune disease, I have, for uncertain reasons, been drawn to the data that suggests the disease may be due to atypical mycobacteria. Wherever there are granulomas, some sort of infectious disease is often not far behind.

UC is limited to the colon, has a high risk of leading to colonic cancer, and its etiology is even more uncertain, perhaps also an autoimmune disease. The two illnesses have different rates of extraintestinal manifestations as well.  Besides the bloody diarrhea and abdominal pain, the two diseases have little in common except they can wax and wane for no damn good reason and when active are a compelling reason to know where every public toilet in the city is.

The Wikipedia pages for both diseases have nice ‘compare and contrast’ tables, and it is obvious the illnesses have little in common. UC and Crohn’s are as different as pulmonary tuberculosis and bronchiolitis obliterans with organizing pneumonia, so it would be most curious if an anti-acne medication could be cause either one, much less both.

Ulcerative colitis occurs in 35–100 people for every 100,000 in the United States, and Crohn’s in 6 to 7.1 per 100,000, and there have been over 13 million prescriptions given for Accutane, more if you add in the other brands of isotretinoin. So there are bound to be, by coincidence, some people who will get IBD around the time they get their Accutane. Like Guillain Barré and flu vaccine, the question is whether or not the risk is increased.

As one review pointed out:

Assuming 1) a background incidence of IBD in the US of approximately 45,000 cases per year, 2) the number of persons taking isotretinoin is approximately 400,000 per year, and 3) the total US population is approximately 306 million, the expected number of cases of IBD among isotretinoin users would be 59 cases per year (if there were no association between isotretinoin and IBD), or 0.01% of Accutane users. If more than 59 cases per year were observed in isotretinoin users, this would suggest a positive relationship between isotretinoin use and IBD. However FDA MedWatch reports include an average of only 14 cases per year.

There are a smattering of case reports on the pubmeds of people developing IBD around the time they started isotretinoin. A few cases of IBD waxed on the medication and waned when isotretinoin was stopped. Interesting, but given the variability of the disease, causality is suspect.

Is there a basic mechanism whereby isotretinoin would lead to IBD?

The mechanism by which (endogenous and exogenous) retinoids cause or exacerbate intestinal inflammation is not understood. Retinoic acid affects intestinal epithelial growth and is involved in cell repair and apoptosis. Retinoids also impair neutrophil chemotaxis, a mechanism involved in Crohn’s disease. The production of induced regulatory T cells (iTreg) and T helper 17 (Th17) cells is also controlled by retinoic acid — these also being involved in gut epithelial homeostasis.

But there is also basic science to suggest that retinoic acid has the potential to be protective for IBD.

Retinoic acid, a form of vitamin A, has been shown to enhance barrier function by increasing expression of numerous tight junction proteins such as occludin, claudin-1, claudin-4, and zonula occludens-1. Furthermore, from the standpoint of immune function, retinoic acid has been shown to be capable of inhibiting pro-inflammatory interleukin-17-producing T helper cell (Th17) responses, while augmenting anti-inflammatory regulatory T cell induction. Such responses would be more likely to prevent the development of IBD, as opposed to trigger it.

So maybe there is a supporting mechanism, and maybe there isn’t. The putative mechanisms can go either way, although since there is perhaps less IBD than expected in patients on isotretinoin, the sparse data suggests a protective effect. Whether any of the basic science is clinically applicable is unknown and doesn’t really explain why it could be associated with two such widely divergent illnesses. Still, there may be unknown mechanisms that would be hinted at by epidemiology.

There really is a paucity of data with a grand total of about 49 references on Pubmed. One study found a relationship with UC, but not Crohn’s (which, given the etiology and pathology, perhaps makes more sense):

Isotretinoin use and the risk of inflammatory bowel disease: a case-control study.
OBJECTIVES:
Isotretinoin is commonly prescribed for the treatment of severe acne. Although cases of inflammatory bowel disease (IBD) have been reported in isotretinoin users, a causal association remains unproven.
METHODS:
We performed a case-control study using a large insurance claims database. Incident cases of IBD were identified and matched to three controls on the basis of age, gender, geographical region, health plan, and length of enrollment. Isotretinoin exposure was assessed in a 12-month period before case ascertainment. Conditional logistic regression was used to adjust for matching variables.
RESULTS:
The study population comprised 8,189 cases (3,664 Crohn’s disease (CD), 4,428 ulcerative colitis (UC), and 97 IBD unspecified) and 21,832 controls. A total of 60 subjects (24 cases and 36 controls) were exposed to isotretinoin. UC was strongly associated with previous isotretinoin exposure (odds ratio (OR) 4.36, 95% confidence interval (CI): 1.97, 9.66). However, there was no apparent association between isotretinoin and CD (OR 0.68, 95% CI: 0.28, 1.68). Increasing dose of isotretinoin was associated with elevated risk of UC (OR per 20 mg increase in dose: 1.50, 95% CI: 1.08, 2.09). Compared with non-users, the risk of UC was highest in those exposed to isotretinoin for more than 2 months (OR 5.63, 95% CI: 2.10, 15.03).
CONCLUSIONS:
UC but not CD is associated with previous isotretinoin exposure. Higher dose of isotretinoin seems to augment this risk. Although the absolute risk of developing UC after taking isotretinoin is likely quite small, clinicians prescribing isotretinoin as well as prospective patients should be aware of this possible association.

and another study found no relationship:

Isotretinoin is not associated with inflammatory bowel disease: a population-based case-control study.
OBJECTIVES:
There is anecdotal evidence that isotretinoin use is associated with development of colitis. We aimed at determining whether there is an association between isotretinoin use and development of inflammatory bowel disease (IBD).
METHODS:
The population-based University of Manitoba IBD Epidemiology Database and a control group matched by age, sex, and geographical residence were linked to the provincial prescription drug registry, a registry that was initiated in 1995. The number of users and duration of isotretinoin use were identified in both IBD cases and controls.
RESULTS:
We found that 1.2% of IBD cases used isotretinoin before IBD diagnosis, which was statistically similar to controls (1.1% users). This was also similar to the number of IBD patients who used isotretinoin after a diagnosis of IBD (1.1%). There was no difference between isotretinoin use before Crohn’s disease compared with its use before ulcerative colitis.
CONCLUSIONS:
Patients with IBD were no more likely to have used isotretinoin before diagnosis than were sex-, age-, and geography-matched controls. Although there may be anecdotes of isotretinoin causing acute colitis, our data suggest that isotretinoin is not likely to cause chronic IBD.

One for, one against. Crockett et. al. reviewed all the data, such as it is, and applied the nine Bradford Hill criteria to the data. The conclusions were underwhelming for causality

In conclusion, the only evidence to support a causal association between Accutane and IBD consists of isolated case reports. These reports support a possible temporal association between isotretinoin and the development of IBD, though such observations may have resulted from chance, confounding, bias, and misrepresentation of the natural history of IBD. A causal relationship remains biologically plausible, but beneficial effects of vitamin A derivatives on intestinal injury have been reported as well. None of the other commonly accepted causal criteria are met. The lack of evidence does not necessarily indicate lack of a causal connection.

Doesn’t seem to be the kind of data that warrants millions to plaintiffs. To double check, I asked some drug company shills, er, I mean gastroenterologists, what they thought of the data. They were equally underwhelmed.

Dow Corning was in bankruptcy protection for years stemming from multibillion dollar lawsuits in the 1980’s and 90’s over the assertion that silicone breast implants lead to breast cancer and autoimmune diseases. Subsequently, after billions were spent and the company was bankrupt, it was then determined that silicone breast implants are associated with neither cancer nor autoimmune diseases. Oh. That’s different. Never mind.

Does isotretinoin lead to inflammatory bowel disease? Maybe. Maybe not. The facts to prove or disprove the association lean against, the odds are “Five to one against and rising…Anything you still can’t cope with is therefore your own problem.” It is hard to prove a negative, and money is being spent and awarded, independent of a reasonable set of confirming facts. Hopefully this will not be like the Dow cases, where “a tort system that allowed a few lawyers to extort billions of dollars using a dollop of junk science.” Although as is often the case with corporations, Dow Corning apparently did not act as the model of integrity. No one acts their best when there is money to be made.

As one reference on the topic noted

In most policy matters, scientific evidence is only one among a complex assortment of factors that interact to produce particular decisions.” A careful reading of the events, stakeholders, and outcomes in the silicone breast implant controversy reveals the social, economic, legal, political, and scientific factors involved “the practice of Federal regulation, the relationship between science and courts, the lack of consistently enforced professional standards in law, medicine and journalism.” A major lesson from this case also involves the role of the plaintiffs. The Houston lawyers’ relentless pressure with inconclusive medical facts on Dow Corning, along with their courtroom successes, demonstrates that “facts” alone are insufficient factors in determining truth.

He could have been writing about SCAMs in general: the facts, in quotes, are insufficient factors in determining truth indeed.

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Exorcism and Sorcery as Health Benefits?!

Luis Fernando Verissimo, a Brazilian writer, once proposed “voodoopuncture”. Instead of going to the acupuncturist, you would be treated without leaving home. The voodoopuncturist would stick acupuncture needles in the voodoo dolls of you! I add that voodoopuncture could be outsourced to Haiti and/or China. It is a win-win-win situation!

– Leonardo Monasteri, Brazilian economist

As unbelievable as this might sound, “voodoopuncture” is no fiction at all.

The practice is called “Tong Ren healing,” and involves needling or hammering an acupuncture mannequin, as if it were a voodoo doll. The main Tong Ren “Master” in the US is an acupuncturist in the Boston area by the name of Tom Tam. He treats groups of terminally ill and debilitated patients in a deliverance ceremony that is noting but a revamped Taoist exorcism — only the clay or straw doll is replaced by a plastic mannequin:

Unfortunately, Tom Tam is not the only licensed healthcare provider who is treating patients with hocus pocus and crackpottery. There are over 30,000 other adepts of Traditional Chinese Medicine (TCM) in the US who practice medicine based on notions of health and disease that are rooted in paranormal and magical beliefs. Some of these practitioners take their delusions to the outer limits of absurdity: consider, for instance, “acutonics” and “colorpuncture” as described in these videos:

In anthropology of religion, the principles that underline the above practices are called “imitation” (e.g. using a doll to affect a person), and “correspondence” (e.g. using a sound to affect an object). They are the hallmarks of what is called “sympathetic magic,” meaning the belief that a person, or a thing, can be affected through something that represents it, or that has similar attributes.1 The principle of magical correspondence in TCM is called wu xing (??) in Chinese, and is known as the Five Phases/Elements Theory in English. It can be summarized as follows:

1. Everything (including our organs) is ruled by one of 5 entities: Water (?), Wood (?), Fire (?), Earth (?), and Metal (?) — which are also the Chinese names for the planets Mercury, Jupiter, Mars, Saturn, and Venus.2 For instance, the heart is ruled by Fire (Mars), the liver by Wood (Jupiter), etc.

2. There is a sympathetic connection (or resonance) between things that are ruled by the same entity (or planet). For example, the heart is connected with the color red, the direction south, the summer season, a bitter taste, and the feeling of joy — because all of these are ruled by Fire (Mars).

3. All 5 entities are interconnected and act on each other. Disease is understood as a result of either the over-, or under-influence of one entity on another. For example, digestive disruptions can be attributed to “Wood overacting on Earth.”3

The concept map (pictogram) of wu xing is often drawn by placing the 5 entities in a circle, and then connecting them according to the lines of influence. The connecting lines create a “pentacle,” or a pentagram within a circle (Image 1).

Image 1. The pictogram of wu xing. Image Source: acupuncture.com

This pictogram, unbeknownst to most TCM practitioners, is nearly identical to a sigil (magical or religious symbol) found in the Old Religion of Northern Europe, also known as “Wicca” (from the Old English word wicca, meaning a male sorcerer). The only difference between the Chinese and the Wiccan pictograms is that Wicca uses Air instead of Wood, and Spirit instead of Metal. The assignment of attributes (color, sound, taste, etc.) to each entity also varies slightly (Image 2).

Image 2. The Five Elements of Wicca.

According to the historian Cornelia J. de Vogel, this sigil was commonly used by the druids in the context of spell casting, and protection against evil and malevolence.4 It was likewise used in ancient Greece among Pythagoreans in the context of the cult of Hygieia (?????, Salus in Latin), the Greek patron of well-being, sanitation, and the prevention of disease (Image 3). Notably, their brotherhood (an esoteric cult based on numerology) also believed in resonance between numbers, tastes, colors, sounds, and the classical elements.5

Pythagoras

Image 3. Pythagorean pentagram in Three Books of Occult Philosophy (Libri Tres de Occulta Philosophia) by Heinrich Cornelius Agrippa (1486 – 1535). The word ????? (Hygieia) is inscribed on the outer circle.

In Christian Europe, some of these pagan beliefs and symbols were culturally assimilated. For instance, the pentacle became the symbol of the five wounds of Jesus Christ.6 But with the advent of science and modernity, magical thinking, its symbolism, and all the rituals that accompanied it were discredited as superstition and ignorance.

Paganism and magic, however, weren’t so easily done away with — and they experienced a renaissance with the American Counterculture of the 1960s. Vietnam-era demonstrations with large hippie contingents famously mixed politics with occultism, magic, and witchcraft. For example, at the mammoth antiwar protest near Washington DC, in October 1967, demonstrators performed a mock-exorcism to levitate the Pentagon and cast out its demons.7

The magical notions of occult resonance and interconnectedness now find their zealots in the growing Neo-pagan and New Age movements. These revamped notions provide the conceptual basis for energy or vibrational medicine, which includes not only colorpuncture and acutonics, but also herbalism, reiki, reflexology, crystal therapy, magnet therapy, aromatherapy, acupuncture, and many other methods to channel putative “energy fields.”

A 2006 publication reported that in 2004, the annual spending on various channeling methods and alternative healthcare in the US was about $10 to $14 billion. It also estimated the number of Americans involved with New Age activities to be around 12 million.8

The popularity of these unscientific ideas and practices in the last decades has had a terrible impact on the public health policy in the US. One consequence is the licensing of non-physician acupuncturists in over 40 states. As George Ulett wrote in 2003, “is a travesty that in this time of scientific evidence-based medicine, acupuncture treatments are given to unsuspecting US patients by some 20,000 acupuncturists, posing as primary care doctors.”9 Be noted that their number has now increased to over 30,000.

Another consequence is the attempt to mainstream TCM and energy medicine by means of lobbying and political pressure. This leads to national and regional healthcare policies that are not based on science and evidence, but on consumerism and financial interest. As Steven Novella writes in Politics and Science at the HHS, this tends to “contaminate” science, and change the rules so that a popular modality can get a free pass. Novella adds that “modalities that require political pressure to force them into our health care system are those that are not backed by good science.”

An example of politically-motivated healthcare policy is the Federal Acupuncture Coverage Act of 2011 (H.R.1328), which is sponsored by House Representatives Maurice Hinchey (D-NY), Judy Chu (D-CA). It intends to “… provide for coverage of qualified acupuncturist services under part B of the Medicare Program, and to amend title 5, United States Code, to provide for coverage of such services under the Federal Employees Health Benefits Program.”

Yet another example is the current pressure put on the US Department of Health and Human Services by Judy Chu (a Representative for a district with a heavy concentration of acupuncturists and apothecaries) to make TCM and acupuncture part of the “Essential Health Benefits.” These benefits are a set of federally-mandated services under the Patient Protection and Affordable Care Act (PPACA).

This comes at a time when California State Senator Leeland Yee is trying to expand the scope of acupuncturists’ practice in his state to include the performance of “Chinese traumatology” — whatever that means.

If Maurice Hinchey, Judy Chu, Leeland Yee, and the TCM syndicate get their way, then revamped exorcism and sorcery will further infest the American healthcare system.

And if they don’t, I can already imagine voodoopuncturists in their cubicals in China, just like Leonardo Monasteri predicted: “…tap, tap, tap, can you feel me now?”

REFERENCES:

1. Frazer JG (Author), Fraser R (Editor). The Golden Bough: A Study in Magic and Religion: A New Abridgement from the Second and Third Editions. Oxford University Press, USA; Abridged edition. 1998.
2. Walters D. Chinese Astrology. Aquarian Press. 1987.
3. Maciocia G. The Foundations of Chinese Medicine: A Comprehensive Text for Acupuncturists and Herbalists. Churchill Livingstone. 1989.
4. de Vogel CJ. Pythagoras and Early Pythagoreanism. Assen: Van Gorcum; 1966.
5. Burkert W. Lore and Science in Ancient Pythagoreanism. Cambridge, MA: Harvard University Press; 1972.
6. Ferguson G. Signs and Symbols in Christian Art. New York: Oxford University Press, 1959.
7. Paglia C. Cults and Cosmic Consciousness: Religious Vision in the American 1960s, Arion, Winter 2003.
8. Pike SM. New Age and Neopagan Religions in America. Columbia University Press. 2006.
9. Ulett GA. Acupuncture: archaic or biologic? Am J Public Health. 2003;93(7):1037; author reply 1037-1038.

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The Value of Replication

Daryl Bem is a respected psychology researcher who decided to try his hand at parapsychology. Last year he published a series of studies in which he claimed evidence for precognition — for test subjects being influenced in their choices by future events. The studies were published in a peer-reviewed psychology journal, the Journal of Personality and Social Psychology. This created somewhat of a controversy, and was deemed by some to be a failure of peer-review.

While the study designs were clever (he simply reversed the direction of some standard psychology experiments, putting the influencing factor after the effect it was supposed to have), and the studies looked fine on paper, the research raised many red flags — particularly in Bem’s conclusions.

The episode has created the opportunity to debate some important aspects of the scientific literature. Eric-Jan Wagenmakers and others questioned the p-value approach to statistical analysis, arguing that it tends to over-call a positive result. They argue for a Bayesian analysis, and in their re-analysis of the Bem data they found the evidence for psi to be “weak to non-existent.” This is essentially the same approach to the data that we support as science-based medicine, and the Bem study is a good example of why. If the standard techniques are finding evidence for the impossible, then it is more likely that the techniques are flawed rather than the entire body of physical science is wrong.

Now another debate has been spawned by the same Bem research — that involving the role and value of exact replication. There have already been several attempts to replicate Bem’s research, with negative results: Galak and Nelson, Hadlaczky, and Circee, for example. Others, such as psychologist Richard Wiseman, have also replicated Bem’s research with negative results, but are running into trouble getting their studies published — and this is the crux of the new debate.

According to Wiseman, (as reported by The Psychologist, and discussed by Ben Goldacre) the Journal of Personality and Social Psychology turned down Wiseman’s submission on the grounds that they don’t publish replications, only “theory-advancing research.” In other words — strict replications are not of sufficient scientific value and interest to warrant space in their journal. Meanwhile other journals are reluctant to publish the replication because they feel the study should go in the journal that published the original research, which makes sense.

This episode illustrates potential problems with the  scientific literature. We often advocate at SBM that individual studies can never be that reliable — rather, we need to look at the pattern of research in the entire literature. That means, however, understanding how the scientific literature operates and how that may create spurious artifactual patterns.

For example, I recently wrote about the so-called “decline effect” — a tendency for effect sizes to shrink or “decline” as research on a phenomenon progresses. In fact, this was first observed in the psi research, as the effect is very dramatic there — so far, all psi effects have declined to non-existence. The decline effect is likely a result of artifacts in the literature. Journals are more inclined to publish dramatic positive studies (“theory-advancing research”), and are less interested in boring replications, or in initially negative research. A journal is unlikely to put out a press release that says, “We had this idea, and it turned out to be wrong, so never-mind.” Also, as research techniques and questions are honed, research results are likely to become closer to actual effect sizes, which means the effect of researcher bias will be diminished.

If the literature itself is biased toward positive studies, and dramatic studies, then this would further tend to exaggerate apparent phenomena — whether it is the effectiveness of a new drug or the existence of anomalous cognition. If journals are reluctant to publish replications, that might “hide the decline” (to borrow an inflammatory phrase) — meaning that perhaps there is even more of a decline effect if we consider unpublished negative replications. In medicine this would be critical to know — are we basing some treatments on a spurious signal in the noise of research.

There have already been proposals to create a registry of studies, before they are even conducted (specifically for human research), so that the totality of evidence will be transparent and known — not just the headline-grabbing positive studies, or the ones that meet the desires of the researchers or those funding the research. This proposal is primarily to deal with the issue of publication bias — the tendency not to publish negative studies.

Wiseman now makes the same call for a registry of trials before they even begin to avoid the bias of not publishing replications. In fact, he has taken it upon himself to create a registry of attempted replications of Bem’s research.

While this may be a specific fix for replications for Bem’s psi research — the bigger issues remain. Goldacre argues that there are systemic problems with how information filters down to professionals and the public. Reporting is highly biased toward dramatic positive studies, while retractions, corrections, and failed replications are quiet voices lost in the wilderness of information.

Most readers will already understand the critical value of replication to the process of science. Individual studies are plagued by flaws and biases. Most preliminary studies turn out to be wrong in the long run. We can really only arrive at a confident conclusion when a research paradigm produces reliable results in different labs with different researchers. Replication allows for biases and systematic errors to average out. Only if a phenomenon is real should it reliably replicate.

Further — the excuse by journals that they don’t have the space now seems quaint and obsolete, in the age of digital publishing. The scientific publishing industry needs a bit of an overhaul, to fully adapt to the possibilities of the digital age and to use this as an opportunity to fix some endemic problems. For example, journals can publish just abstracts of certain papers with the full articles available only online. Journals can use the extra space made available by online publishing (whether online only or partially in print) to make dedicated room for negative studies and for exact replications (replications that also expand the research are easier to publish). Databases and reviews of such studies can also make it as easy to find and access negative studies and replications as it is the more dramatic studies that tend to grab headlines.

Conclusion

The scientific endeavor is now a victim of its own success, in that research is producing a tsunami of information. The modern challenge is to sort through this information in a systematic way so that we can find the real patterns in the evidence and reach reliable conclusions on specific questions. The present system has not fully adapted to this volume of information, and there remain obsolete practices that produce spurious apparent patterns in the research. These fake patterns of evidence tend to be biased toward the false positive — falsely concluding that there is an effect when there really isn’t — or at least in exaggerating effects.

These artifactual problems with the literature as a whole combine with the statistical flaws in relying on the p-value, which tends to over-call positive results as well. This problem can be fixed by moving to a more Bayesian approach (considering prior probability).

All of this is happening at a time when prior probability (scientific plausibility) is being given less attention than it should, in that highly implausible notions are being seriously entertained in the peer-reviewed literature. Bem’s psi research is an excellent example, but we deal with many other examples frequently at SBM, such as homeopathy and acupuncture. Current statistical methods and publication biases are not equipped to deal with the results of research into highly implausible claims. The result is an excess of false-positive studies in the literature — a residue that is then used to justify still more research into highly implausible ideas. These ideas can never quite reach the critical mass of evidence to be generally accepted as real, but they do generate enough noise to confuse the public and regulators, and to create an endless treadmill of still more research.

The bright spot is that highly implausible research has helped to highlight some of these flaws in the literature. Now all we have to do is fix them.

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Autism and Prenatal Vitamins

Science has found no evidence that vaccines cause autism; but the true cause(s) of autism have not yet been determined. So far the available evidence has pointed towards a largely genetic cause with possible interaction with environmental factors. A new study supports that interpretation. It also supports previous evidence that autism is triggered prior to birth, rather than at the time of vaccinations.

Schmidt et al. published a study in Epidemiology on May 23, 2011, entitled “Prenatal Vitamins, One-carbon Metabolism Gene Variants, and Risk for Autism.” It was a population-based case control study of 566 subjects comparing a group of autistic children to a matched control group of children with normal development. They looked at maternal intake of prenatal vitamins in the 3 months before conception and the first month of pregnancy, and they looked for genotypes associated with autism. They found that mothers who didn’t take prenatal vitamins were at greater risk of having an autistic child, and certain genetic markers markedly increased the risk. There was a dose/response relationship: the more prenatal vitamins a woman took, the less likely she would have an autistic child. There was no association with other types of multivitamins, and no association with prenatal vitamin intake during months 2-9 of pregnancy.

They had a large sample size, and they tried to eliminate confounders. They looked for these potential confounders of the association between prenatal vitamin intake and autism: child’s sex, birth year, parent-reported race/ethnicity, family history of mental health conditions, paternal age at child’s birth, maternal age at child’s birth, education, prepregnancy body mass index (BMI) category, cereal intake from 3 months before through the first month of pregnancy, cigarette smoking, alcohol consumption, and residence with a smoker during the period 3 months before pregnancy to delivery. Only maternal education and the child’s year of birth proved to be confounders. They adjusted for these two factors in their analyses. A weakness of their study is that it depends on patient recall long after the fact. Also, it did not attempt to gather any diet information.

Mothers of children with autism were less likely to report taking prenatal vitamins (odds ratio 0.62). Having certain genotypes increased the odds that a vitamin-omitting woman would have an autistic child. Children with the COMT 472 AA gene were at increased risk of autism. If their mothers took prenatal vitamins, the odds ratio for the risk of autism was 1.8; if their mothers didn’t, the odds ratio jumped to 7.2.  This suggests that the maternal-fetal environment can magnify the effects of a child susceptibility gene. There was an association with certain maternal genes as well: those odds ratios went as high as 4.5.

The association was robust. The authors think there are plausible biological explanations. Folate and other B vitamins are critical to neurodevelopment. Iron could be involved.  The gene variants were within one-carbon metabolism pathways; methylation mechanisms may be responsible.

The authors speculate as to why multivitamins did not have the same effect. Prenatal vitamins typically contain more iron, vitamins B6 and B12, and twice as much folic acid (800 mcg) as multivitamins (400 mcg).

In their summary, the authors say:

Our data suggest that supplementation with prenatal vitamins before pregnancy and during the first month of pregnancy might protect against autism, particularly in genetically susceptible individuals. Additionally, COMT genotype may contribute to an elevated risk for autism, especially in offspring of unsupplemented mothers. This evidence for gene-by- environment interaction effects in autism etiology could help explain variations in previous findings across genetic studies. Whether similar interactions exist for susceptibility genes in other pathways, particularly those epigenetically regulated through methylation, remains to be explored. More research is warranted to replicate the findings, explicate potential mechanisms, and explore interactions with other autism candidate genes.

This is fascinating stuff. It confirms that certain genotypes are associated with autism and that environmental factors can interact with genetics to increase risk. We still need to pin down what it is about prenatal vitamins that prevents autism better than other multivitamins. Is it the folic acid? Is it a subset of the ingredients, or the whole mixture?

We should never blindly accept the results of a first study. These findings will have to be confirmed by other studies. Meanwhile, should we take action? We already recommend folic acid supplements for women who might become pregnant, and we recommend prenatal vitamins during pregnancy. I can’t see any downside to recommending prenatal vitamins in the pre-conception period for any woman who is likely to become pregnant. Some advisors (for instance the Mayo Clinic) were already recommending this practice even before the new study came out.

How will the anti-vaccine contingent react to this new study? It was convenient and satisfying for parents to be able to blame vaccines and accuse the evil medical establishment of causing their children’s autism. Now will those parents accept that at least part of the responsibility lies with their own genetic contributions and the mother’s actions prior to pregnancy? That’s not as palatable a thought, but it’s more realistic.

 

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Science-based medicine, skepticism, and the scientific consensus

Editor’s note: This weekend was a big grant writing weekend for me. I’m resubmitting my R01, which means that between now and July 1 or so, my life is insanity, as I try to rewrite it into a form that has a fighting chance of being in the top 7%, which is about the level the NCI is funding at right now. This weekend, I buried myself in my Sanctum Sanctorum and tried like heck to try to pound the revision into a really good draft that I can distribute to my colleagues for feedback. Fortunately, I have some old posts that I can pull out, tart up (i.e., update a bit, as in correcting the parts that led me to groan as I reread them, thereby hopefully making them better). I think they’re quite good, if I do say so myself; so hopefully you will too.

There are some arguments made in blogs, articles, or books that strike me so hard that I remember them, even three and a half years later. Sometimes I even file them away for later use or response if the issue raised by them is interesting, relevant or compelling enough to me. Although this topic is a bit broader than many of the topics I write about for this blog, I think it also goes to the heart of science-based medicine and communicating scientific skepticism about medicine to the masses. A few years back, a Swedish blogger named Martin Rundkvist made a rather provocative observation about skepticism. Specifically, he argued that a “real skeptic always sides with scientific consensus.” Among his reasons was this one:

Science presupposes that all participants have a skeptical frame of mind and arrive at conclusions through rational deliberation. If a large group of knowledgeable people working in this way arrive at a consensus opinion, then there is really no good reason for anybody with less knowledge of the subject to question it. Informed consensus is how scientific truth is established. It’s always provisional and open to reevaluation, but as long as there’s informed consensus, then that’s our best knowledge. Humanity’s best knowledge.

Although at the time I saw where Martin was coming from, I found this viewpoint somewhat disturbing, leading me to echo Martin’s own words in response to his own rhetorical question asking whether accepting a scientific consensus is nothing more than “kowtowing to white-coated authority”: Well, yes and no.

For a skeptic and supporter of science-based medicine, in matters of science it is undoubtedly true that the scientific consensus is always the best place to start when evaluating unfamiliar issues. While it is certainly possible that a given scientific consensus regarding an issue can be wrong in almost any area, it nonetheless almost always represents the best current scientific understanding. It is also correct, as Martin argues, that legitimate authority matters. I emphasize the word “legitimate” because in pseudoscience arguments from authority are common, but rarely is the authority relevant to the point being argued. Often it’s not even legitimate, as in when anti-vaccine activists point to Andrew Wakefield’s work as justification for their claims that vaccines cause autism and other conditions. Like Martin, I’m more inclined to accept the pronouncements of someone who has actually dedicated his or her life to studying the issue systematically; i.e., an expert. If the topic is evolution, then that expert would be an evolutionary biologist. If the topic is the Holocaust, then a historian specializing in World War II and/or the Holocaust would represent an appropriate expert. For cancer, an appropriate expert would be an oncologist (or an surgical oncologist, such as myself). The list goes on.

Where I start to have a bit of a problem with Martin’s viewpoint is when I start to contemplate the nature of scientific consensus itself in many areas of science. Not all scientific consensuses are created equal because, in different fields the strength of scientific consensus can vary quite markedly depending upon the topic or even the subtopic within the topic. For example, the scientific consensus supporting the theory of evolution, particularly common descent, is exceedingly strong. It’s one of the strongest of all scientific consensuses, arguably the strongest. Similarly, the consensus that natural selection is a major driving force behind evolution is very nearly as strong. However, as the discussion devolves into more detailed areas, inevitably the consensus weakens. Eventually, subsidiary areas of a discipline are reached where the consensus is weak or where there is no consensus, such as what the function of “junk DNA” is, whether it is subject to natural selection, and if so how much. (Real evolutionary biologists could probably come up with a better example.) These sorts of questions are often at the cutting edge of scientific knowledge, and it is not always easy to recognize what they are. It is also these issues at the edge of our knowledge that are attacked as proxies for the much more strongly supported core theory. Creationists are notorious for this sort of tactic, often using new findings of molecular biology that appear peculiar or out of sync with specifics of evolution as wrecking balls to try to demolish the edifice of “Darwinism.” I can’t count the number of times I’ve seen supporters of “intelligent design” creationism point to either “junk DNA” or the findings of new genomic techniques as “evidence” that “Darwinism” is doomed. Never mind that some of the very strongest support for the theory of evolution, in particular common descent, comes from genetics and that new genomic techniques only keep confirming that.

The same is true of scientific consensuses in many other disciplines, including my own disciplines of medicine and surgery. However, scientific consensuses in medicine are almost never as strong as the theory of evolution. Germ theory of infectious disease probably comes close, but otherwise I’m hard-pressed to think of one. Usually, the strength of a consensus in medicine is proportional to the ratio of data supporting it that comes from randomized clinical trials to data from epidemiological studies, the latter of which are more prone to confounding factors. That does not, however, mean that there doesn’t exist strong consensus about many medical issues. For example, there is, for all intents and purposes, no doubt that HIV is the causative agent for AIDS, the claims of HIV/AIDS denialists notwithstanding. Similarly, there is in essence no doubt that smoking cigarettes vastly increases a person’s risk of lung cancer and heart disease, along with a host of other medical problems. Not even the tobacco companies try to argue against that anymore. When we come to subsidiary questions, however, the consensus is generally not as strong. For example, it has become increasingly appreciated that secondhand tobacco smoke increases the risk of heart disease and lung cancer in people chronically exposed to it. However, because the effect is considerably smaller than it is for people who actually smoke cigarettes, there is a lot more “noise” in the studies, giving more wiggle room for people who dislike the idea of the government banning smoking to claim that such bans are not scientifically supported, and it’s taken a long time for scientific and clinical studies to firm up the conclusion enough to the point that it is now a strong consensus.

Not surprisingly, given the difficulty doing controlled experiments and the nature of the material, which makes it more easily politicized or influenced by biases, a truly strong consensus is harder to come by in the humanities and social sciences. However, even so, it is not impossible. For example, one of my areas of interest is the Holocaust. There is overwhelming and incontrovertible evidence that the Nazi regime embarked on a systematic program to round up and exterminate the Jews in territories they controlled. Methods used included shooting, hanging, gas chambers, and a system of camps designed to literally work their inmates to death through a combination of grueling labor, insufficient food, and unsanitary and crowded conditions. However, this consensus becomes less clear when various issues surrounding the Holocaust are discussed. For example, there is the whole “intentionalism” versus “functionalism” debate. In a nutshell, this debate is over the question of whether the intent was there from the very beginning of the Nazi regime or even before the Nazis rose to power to exterminate the Jews or whether the Holocaust evolved “organically” or “functionally” from the persecution of Jews that began early in the Nazi regime and became increasingly radical and violent in the pre-war era, the radicalization of Nazis carrying out the program, and the question of what to do with the millions of Jews that suddenly fell under Nazi control after Hitler had invaded the Soviet Union. Holocaust deniers love to misrepresent and misuse this debate to claim that Hitler didn’t know about and didn’t order the Holocaust or to claim that there was never a plan to systematically exterminate European Jewry.

One thing that I’ve come to realize is that it’s not always obvious when skepticism devolves into denialism. In some cases it’s pretty easy, for example creationism, Holocaust denial, HIV/AIDS denialism, anti-vaccine activism and the germ theory denialism that often fuels it, and many sectarian belief systems that lead to the use of unscientific “alternative” medicine, such as homeopathy. Sometimes, appropriate skepticism about most scientific issues can exist side-by-side in a single person with credulity and pseudoskepticism about other scientific issues. For example, among skeptics who count themselves science-based, there is a disturbingly large contingent who do not accept the science behind anthropogenic global climate change, as Penn Jillette, for example, does not. Only recently does he appear to be grudgingly dragged towards accepting the scientific consensus in this area. His resistance to the idea appears to be due to his Libertarian beliefs.

One example that I used to use routinely before she shut down her blog was Sandy Szwarc at Junkfood Science. Most of her non-obesity-related posts were often actually not too bad. However, whenever she blogged about diet and obesity, there was usually a problem, sometimes a big problem like the one Steve Novella blogged about a couple of years ago. And it’s not the sort of thing that necessarily jumps right at you off of her blog, as it does from an obvious crank blog like Age of Autism. Certainly it didn’t for me. Rather, it’s the sort of thing you have to read her blog closely for a while (which I did) to start to realize. As I read her blog, more and more it bothered me that all of her “skepticism” was inevitably in the direction that being obese is not only not unhealthy but is actually at least as healthy as not being obese, that eating fatty foods is perfectly fine, and that virtually any study she looks at that says that eating fatty foods or too many calories predisposes to health problems is a pile of crap while any pile of crap study claiming otherwise is the latest and greatest. All of this led her to conclude that virtually every warning made by scientists and physicians about diet is fearmongering. Worse, she had a distressing tendency to use unscientific tactics, such as cherry picking data, attacking consensus, and alleging conspiracies. I also found it telling that, unlike most bloggers, myself included, Szwarc does not permit comments. If there’s one thing that skeptics usually encourage (as we do here on SBM), it’s spirited debate. That’s impossible in a blog that doesn’t permit comments.

In the end, I remain a bit uncomfortable with Martin’s blanket statement that “a real skeptic always sides with scientific consensus.” The reason is that what the scientific consensus actually says is not always that clear for many issues, even among those who work in the field. Indeed, there are comparatively few issues in science (evolution, for example) for which a strong consensus exists, and even fewer in the social sciences and history (the Holocaust, for example) for which an equally strong consensus exists. These are very strong consensuses, and to overturn them would require extraordinary evidence, evidence at least equal to the evidence supporting them. Consequently, when someone says that evolution is false or that the Holocaust didn’t happen (or the lessor form of Holocaust denial, that nowhere near 6 million Jews died), it’s fairly easy to recognize such person as a crank and denialist, and I usually do not hesitate to label them as such when appropriate.

But what about consensuses that are strong but not as bullet-proof, usually because, although there is a consensus, there are fairly wide error bars around the predictions or uncertainty regarding the importance of various factors? The prototypical example of this is anthropogenic global warming, for which there is a strong consensus among climate scientists but still a fair amount of uncertainty about the outcome. Another example, of course, is the scientific consensus about the link between obesity and adverse health outcomes. How do we differentiate legitimate skepticism about the consensus from denialism?

This is where I tend to agree with Mark Hoofnagle. It’s more about tactics and how evidence is used to support an argument. Scientific skepticism looks at the totality of evidence and evaluates each piece of it for its quality. Cranks are very selective about the data they choose to present, often vastly overselling its quality and vastly exaggerating flaws in current theory, in turn vastly overestimating their own knowledge of a subject and underestimating that of experts. In medicine in particular, denialists frequently emphasize anecdotes over epidemiology, clinical trials, and science. They also tend to leap to confuse correlation with causation. A great example that I just saw a week or two ago comes from our “friends” at the anti-vaccine group the International Council on Vaccination, a group that Mark Crislip and I had such fun deconstructing. There, Sherri Tenpenny posted an article entitled Vaccines and Blue Foot Syndrome (crossposted on her own blog). In the post, after citing anecdotes about “vaccine injury,” Tenpenny then segues into a story of a child who dropped a large frozen turkey on his foot, which became painful and blue within hours. The parents are then confronted with doctors who tell her that this is “Blue Foot Syndrome” and that they have shown by epidemiology that it is not linked to being struck by a frozen turkey. It’s an analogy obviously designed to mock scientists who quite correctly refer to the studies that have failed to find a link between vaccines and autism that ignores the fact that correlation does not necessarily equal causation and that the correlations reported by parents are not nearly as obvious as a blue foot after having a frozen turkey land on it. Anti-vaccine activists think they are, though.

In addition, because the mainstream rejects their ideas, there is often a strong sense of being underappreciated—persecuted, even—among cranks, leading them to view their failure to persuade the mainstream of the correctness of their views as being due to conspiracies or money. Global warming denialists, for example, tend to see the currently existing scientific consensus as being politically motivated by the desire of “liberals” to tell them how to live. Evolution deniers view evolution as the result of atheistic scientists wanting to deny God. People like Sandy Szwarc view the consensus that obesity leads to health problems as being due more to moralizing and bigotry against the obese, which, whether it is true or not, is an easy claim to make because there has been and is a lot of bigotry against the obese. Antivaccinationists view the rejection of their belief that mercury in vaccines or even vaccines themselves cause autism by mainstream medicine as evidence that we’re all in the pocket of big pharma. Practitioners of “complementary and alternative medicine” view the rejection of their beliefs in homeopathy, “energy healing,” and vitalism similarly: Science-based doctors must be in the pocket of big pharma! Or they’re close-minded! Or they’re threatened by the “success” of alternative medicine!

What a lot of this distinction boils down to is that crankery, denialism, pseudoskepticism, or whatever you want to call it tends, either intentionally through ideology or unintentionally through an ignorance of the scientific method, to conflate and/or confuse emotiona, nonscientific, and/or ideological arguments with scientific arguments. This is not to say that scientists and skeptics and supporters of SBM are free from their own biases, whether ideological or simply a desired result that they hope to find. Far from it. However, skepticism means applying the scientific method to claims, whatever its faults, scientific method is the best method thus far devised to minimize these biases. As scientists, the reason we use the scientific method is not because we consider ourselves superior to the cranks, but rather because we recognize that we are human too and thus just as prone to falling into the same traps as they. As Richard Feynman once famously said, “The first principle is that you must not fool yourself—and you are the easiest person to fool. So you have to be very careful about that. After you’ve not fooled yourself, it’s easy not to fool other scientists. You just have to be honest in a conventional way after that.” The scientific method is, above all, a methodology by which scientists try to avoid fooling themselves. Skeptics cross the line dividing skepticism and denialism and quacks the line between science and quackery when they forget that.

Moreover, skeptics and supporters of SBM know that science is a work in progress. What is considered correct today may well be modified tomorrow. This change, however, is not brought about by cranks cherry-picking data but by rather skeptical scientists probing for weak spots in our current understanding, making hypotheses, and then testing whether current theory or the new hypotheses make the better prediction. Thus, being skeptical of the consensus is not the mark of the crank. It’s how and why that skepticism exists that distinguishes crankery from genuine scientific skepticism.

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The impact of antivaccination lobbying

Here’s an excellent news report from Australia on the human costs of the anti-vaccine movement:

The video features Viera Scheibner, who has nothing good to say about vaccines and thinks that vaccines are dangerous and infectious diseases in childhood are good. It also features the stories of children who caught vaccine-preventable diseases. This is how it’s done.

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Failed Flaxseed and Bad News Brownies

Well, it’s been a tough month for herbs since my last monthly soiree here at SBM.

Just last week at the American Society for Clinical Oncology (ASCO) meeting, a group out of the Mayo Clinic presented data from a study showing that a well-characterized flaxseed extract was ineffective against hot flashes in postmenopausal women. But as Steve Novella noted here earlier this week, negative clinical trials data on supplements rarely influence the behavior of those who continue to advocate for their herbal use.

Flaxseed, known to contain phytoestrogen compounds such as secoisolariciresinol diglucoside (SDG) and enterolactone, has been purported to relieve hot flashes.

But I think the hypothesis was flawed in the first place: while these compounds bind the estrogen receptor, they have largely been shown to be estrogen receptor modulators that act in a negative manner. Work from the group of Dr. Lillian Thompson at the University of Toronto has repeatedly shown in an estrogen-dependent animal model of human breast cancer that flaxseed components act in a predominantly anti-estrogenic manner. One might suspect that hot flashes would be made worse by flaxseed, although this was not the case in the study presented as ASCO.

However, flaxseed is definitely a great source of fiber and may have preventive effects in prostate cancer, but not through an estrogenic mechanism. Instead, another flaxseed component, the omega-3 fatty acid alpha-linoleic acid (ALA), reduces the conversion of testosterone to its more active form, dihydrotestosterone. This work comes from a former colleague at Duke University, Wendy Demark-Wahnefried, now at the University of Texas-M.D. Anderson Cancer Center.

Bottom line: A good understanding of the basic science of herbal medicines is absolutely essential to good clinical trial design.

Don’t Bogart My Brownies

A story that’s more likely to have been seen by SBM readers is Lazy Cakes, a dietary supplement-laden brownie intended as a sleep-aid (here’s an example from NPR). The implied undercurrent of this product, of course, is the longstanding tradition of baking marijuana into brownies to – uh – get baked. The packaging itself evokes memories of the Grateful Dead, Phish, and Widespread Panic – musical groups closely associated with marijuana use who the reader will identify with depending on their age. Their tagline, “Relaxation Baked In,” isn’t even a veiled association with this traditional herbal practice.

Lazy Cakes have created an uproar in part because they contain a dietary supplement with potential of central nervous system activity, melatonin. This naturally-occurring hormone is synthesized in the pineal gland and appears to regulate our circadian rhythms. The reader may best recognize melatonin for prevention of jet lag. It is, in simple terms, a sedative and appears to be more potent in younger people. National poison control centers report several thousand calls regarding melatonin each year, with the majority of reports of sedation in children who’ve gotten hold of a parents supplement. Here’s one example from the Texas Department of State Health Services.

Lazy Cakes might also be riding on the well-known Philadelphia-area delicacy, Tastykake. The fact that I have included Tastykake in a post about Lazy Cakes is most certainly not pleasing to this East Coast institution but I have yet to find anything in the Philadelphia press about this issue. By the way, these wonders of the food world fueled my childhood and my scientific training at the school known previously as the Philadelphia College of Pharmacy and Science.)

The concern with Lazy Cakes seems to be that each brownie contains 7.8 mg of melatonin, well above the generally recommended sleeptime dose of 1 to 3 mg. While there have been no controlled trials of Lazy Cakes, anecdotal reports suggest that the brownies do indeed have physiological action. From the NPR story:

“There is an effect with Lazy Cakes, but I wouldn’t say it’s comparable to marijuana at all,” says Niki D’Andrea, who bought one while at a shop that sells drug paraphernalia.

D’Andrea’s not shy about having tried both; it’s part of her job writing about subculture for the Phoenix New Times. She didn’t get high from the Lazy Cake, but she was shocked at how sleepy it made her.

“I really did go to bed for about, I think 10 to 12 hours after I ate that first Lazy Cake, so well, maybe I should have started with half,” D’Andrea says.

Actually, half is the recommended serving size. As if anyone ever just eats half a brownie.

Less attention has been given to the other herbal components: valerian and passionflower extracts.

Valerian (Valeriana officinalis L.) has been investigated for sleep-inducing and anti-anxiety effects. In fact, some of the same researchers who presented the ASCO work above on flaxseed conducted a Phase III trial of valerian extract in cancer patients. Published earlier this year in the Journal of Supportive Oncology, the study revealed that this valerian root extract had no effect on overall measures of sleep efficacy, although some beneficial effects were observed on secondary measures such as fatigue.

However, we have no idea what valerian might do together with this rather high dose of melatonin. Come to think of it, I have no idea how the manufacturer made a valerian-containing brownie even remotely palatable. I have a 16-year-old bottle of valerian root that I use for classroom demonstrations and it still smells of rancid gym socks. But, then again, baking valerian extract is likely to release some of these volatiles.

Less is known about passionflower (Passiflora incarnata). Even a Cochrane review of passionflower for anxiety was unable to come to a solid conclusion due to the low number of studies.

Another issue not addressed in most MSM reports is that the actual content of components can vary wildly from amounts listed on dietary supplement labels. In most cases, the products contain less but this inconsistency is concerning with a product that contains a human hormone well-known to induce sleep.

The bottom line: don’t mess with Lazy Cakes. As with any sedative drug – whether a supplement, prescription or over-the-counter – there’s always a concern for additive or synergistic effects with alcohol.

But rest assured that the uproar over Lazy Cakes will further fuel sales. And given dietary supplement regulations in the United States, I really don’t see this product being banned – although the manufacturer has added additional warnings about sedation and intended use by adults.

That’s right – a product featuring a sleepy brownie that resembles Spongebob Squarepants is intended solely for adults.

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Placebos as Medicine: The Ethics of Homeopathy

Is it ever ethical to provide a placebo treatment? What about when that placebo is homeopathy? Last month I blogged about the frequency of placebo prescribing by physicians.  I admitted my personal discomfort, stating I’d refuse to dispense any prescription that would require me to deceive the patient. The discussion continued in the comments, where opinions seemed to range from (I’m paraphrasing)  “autonomy, shmatonomy, placebos works” to the more critical who likened placebo use to “treating adults like children.”  Harriet Hall noted,  “We should have rules but we should be willing to break them when it would be kinder to the patient, and would do no harm.” And on reflection, Harriet’s perspective was one that I could see myself accepting should I be in a situation like the one  she described. It’s far easier to be dogmatic when you don’t have a patient standing in front of you. But the comments led me to consider possible situations where a placebo might actually be the most desirable treatment option. If I find some, should I be as dogmatic about homeopathy as I am about other placebos?

Nicely, Kevin Smith, writing in the journal Bioethics, examines the ethics of placebos, based on an analysis of homeopathy. Homeopathy is the ultimate placebo in routine use — most remedies contain only sugar and water, lacking a single molecule of any potentially medicinal ingredient. Smith’s paper, Against Homeopathy — A Utilitarian Perspective, is sadly behind a paywall.  So I’ll try to summarize his analysis, and add my perspective as a health care worker who regularly encounters homeopathy.

The first third of the paper is a concise summary of the scientific absurdity of homeopathy.  Hahnemann’s “Law of Similars”, based on a single observation of the effects of  quinine on malaria, is the basis for the non-scientific process of “provings” to match symptoms to substances. The results of provings are compiled in the Homeopathic Materia Medica, which homeopaths select their remedies from. (So now we have remedies based on products including  “sleep”, Stonehenge, shipwrecks, ascending colons, light bulbs, and vacuum cleaner dirt.) Smith summarizes this law as:

More fundamentally, there is simply no plausible or rational basis for supposing that substances that produce particular symptoms can cure the same symptoms. The assumption that ‘like cures like’ places the onus on  proponents of homeopathy to elucidate the special logic involved: to the knowledge of the present author, a satisfactory account of this logic has not been made.

Hahnemann’s second law, the “Law of Infinitesimals” is as absurd as the law of similars. That a product can gain potency and effect with dilution, and that effect persists (and even grows stronger) even after being diluted completely away defies physical laws. Smith points out the contradiction between the idea that water is touted to have a memory of the “proved” substance, yet has forgotten everything else that has every been dissolved in it:

The fact that physiological chaos does not ensure whenever we drink a glass of water provides a simple but powerful refutation of the ‘memory’ concept in homeopathy.

Smith then covers the research on homeopathy. Given its premise is implausible (or impossible), it is not surprising that the highest quality clinical trials have demonstrated no efficacy beyond placebo effects.  Yet positive trials are to be expected from statistical effects alone. And when combined with bad design, weak blinding and other potential biases, it should not be surprising that a supportive clinical trials appear in the literature — and some even show up in Cochrane reviews. His conclusion is very much along the lines of the position taken by SBMers:

From Hume onward, it has been accepted that extraordinary claims require extraordinary evidence. Considering the extent to which the fundamental tenets of homeopath run counter to established rules of science and reason, empirical evidence in support of homeopathy would have to be particularly robust, in view of the fact that acceptance of homeopathy would entail a major epistemic scientific revolution.

So it’s implausible, the remedies contain no medicinal ingredients, and, not surprisingly, it works no better than a placebo. Yet it is popular, even among some physicians and scientists. But is it ethical? And here’s where we get to the meat of the ethical analysis.

Non-Invasiveness/Cost-effectiveness

Placebos, as commenters to my past post noted, do have one merit. If the alternative to antibiotics for a cold is homeopathy for a cold, then homeopathy is probably a better therapeutic choice, because “no treatment” is the preferred treatment. There are many medical conditions for which we have few effective medical therapies, and in some cases the impetus to prescribe a placebo may be simply to obtain the psychological (placebo) effects associated with their use.  And given the habit (as I described last month) for some physicians to select impure placebos (those containing subtherapeutic or non-toxic ingredients), then isn’t a pure placebo like homeopathy sometimes preferable? Here’s where Smith gives homeopathy credit:

In cases where ineffective medication is considered to be in the best interests of the patient, which form of such medicine should be prescribed?

The answer to this question seems clear: the ineffective medicine that is the least invasive and least expensive should be used. On these criteria, homeopathy scores highly.

So in situations where a placebo is felt to be in the patient’s best interest, homeopathy might be felt to be favorable, particularly if an “impure” placebo has a greater potential for unwanted effects.   But Smith makes a small error here: Homeopathy isn’t always the least expensive option – a point I’ll return to.

Holism

Holistic is a popular term among alternative medicine proponents and is usually used to deride science-based medicine, with the fallacious claim that various alternative treatments treat the “whole patient” while medicine does not. And as has been described elsewhere on this blog, the extended consultation offered by alternative medicine providers is probably the source of most if not all of the benefits of treatments. However the non-specific benefits of talk therapy, dialogue, empathy and reassurance are not limited to homeopathy, and can be incorporated into science-based practices.  And importantly, since homeopathic “remedies” can be purchased in pharmacies and other stores without consultation, the “holistic” approach, and its benefits, are by no means certain when consultation is omitted. For these reasons, Smith rejects holism as providing any unique support for homeopathy.

Placebo effects

In the research setting, placebo effects are any measured response in patients that receive the inert (placebo) treatment. But as has been noted on this blog, there are actually multiple elements and observations that sum into what’s described as “placebo effects.” Some of what can contribute to the apparent efficacy of a placebo may not be due to patient-reported outcomes: Researcher bias, poor blinding, and weak overall study design and conduct can all add to the measurement of, and subsequent conclusion that a placebo has effects. Even a disease’s natural history, or regression to the mean can lead one to conclude a correctly-timed placebo treatment is effective.

Smith does not dive deeply into placebo effects, but makes two arguments against homeopathy’s value as a placebo. First, he notes that placebo effects are generally restricted to subjective symptoms like pain and fatigue, with no evidence supporting any meaningful disease-modifying effects. This limits the usefulness of homeopathy to those conditions for which there is some evidence to show that there may be placebo effects. Smith then raises the ethical appropriateness of a key component of successful placebo use: in order for placebos to work, patients must believe something that is untrue. From a utilitarian perspective, Smith notes that lying may be acceptable when it (on balance) is an overall positive — that is, it generates a positive utility.  However, patient autonomy must also be considered — the right for patients to make an informed decision about their treatments. Smith suggests that if you personally rank autonomy above the potential placebo benefits, then the use of homeopathy is untenable from an ethical perspective.

But are homeopaths deliberately deceiving their clients? Smith argues (and I agree) that most homeopaths genuinely believe “remedies” to be effective — so they are not acting in bad faith when they advocate their use. However, the fact remains that patients that are told that homeopathy is effective are being given information that is contrary to the scientific evidence. Consequently Smith describes their actions as “ethically unacceptable” regardless of their sincere (but wrong) beliefs.

But what about placebo use by health professionals? While routine use of placebos wouldn’t be considered ethically acceptable, Smith notes that reinforcing the efficacy of a conventional medication, in a way that could enhance potential placebo effects, is acceptable. This is a routine part of the pharmacist’s dialogue with patients – understanding and addressing concerns, summarizing therapeutic effects, and managing overall treatment expectations. It can be done in a non-deceptive way that should maximize the non-specific effects.  But what about pure placebos?  Smith gives the example of  battlefield use of saline injections for pain as a circumstance where pure placebo use would be ethically acceptable. So in situations where no other options exist, perhaps. But as a matter of course, providing pure placebos would not be considered ethically appropriate.

Autonomy

What if patients elect to choose homeopathy, despite counsel that the product is inert? I’ve encountered this situation in the pharmacy: when asked for advice, I inform the patient that the product has no active ingredients and has no medicinal effects. They’re usually grateful for that, but sometimes my advice will be challenged or ignored, and they’ll purchase it anyway. In situations where it’s clear that the patient may be avoiding appropriate consultation or treatment, I may press my argument further. But once I’ve described the scientific evidence, and given my advice, I’m comfortable letting the patient make their own purchasing decision. And that’s consistent with Smith’s analysis:

If utility is generally maximized by allowing patient autonomy, then patients should be free to choose homeopathy. Secondly, exercise of autonomy provides psychological benefits for the agent: it is well accepted that denial of free choice, or coercion, results in reduced happiness in the subjects concerned.

Smith describes the challenge of drawing lines between paternalism and autonomy, concluding that restriction of autonomy is probably reasonable when the risk of self-harm is greater — which is consistent with the case for restricting drugs to “prescription-only” status. While risks of contamination and unwanted medicinal effects do exist, the more common and real risk is probably the avoidance of proper medical treatment — which is one of the major disutilities of homeopathy.

Failing to Seek Medical Care

While some might be willing to accept the use of homeopathy in cases where placebo effects are possible and probably adequate, most draw the line when homeopathy is positioned as a substitute for effective medical treatment. Yet that’s the case when homeopathy is promoted as malaria prophylaxis, a substitute for vaccination, or even as a treatment for HIV or tuberculosis. Probably the best approach to mitigating this risk, while promoting individual patient autonomy, is to ensure that adequate information is provided to patients so that they are well informed of the lack of medicinal ingredients and the demonstrated lack of efficacy, beyond placebo, for any condition. Smith questions the ability of CAM practitioners to provide reliable advice on efficacy, and describes the promotion of a therapeutic doctrine, rather than reliable advice, as “ethically unacceptable.” He further characterizes any harms resulting in those unable to give fully informed consent (e.g., children or non-competent adults) as “ethically indefensible.”

Waste of Resources

If you’ve never bought it before, homeopathy is not cheap: its prices are comparable to conventional products with active ingredients.  Given the lack of efficacy, every dollar spent on homeopathy is a waste of resources, in that it could otherwise be put to more effective use — for plausible treatments, or anything else, for that matter.  So from a utilitarian perspective, Smith argues that this expenditure is unethical. Smith notes that homeopathy may not just act as a substitute for other care due to its lack of effect: When the homeopathy fails to work, conventional care may subsequently be sought.

Smith makes the same ethical evaluation of research into homeopathy, where because of  a lack of “logico-scientific validity”, human trials of homeopathy are ethically contentious and an inappropriate use of resources.

Credibility Issues

One of the issues that concerns me as a pharmacist is the veneer of credibility that homeopathy gains when it’s packaged and positioned alongside conventional medicine in pharmacies.  I suspect that most consumers expect the products on pharmacy shelves to contain medicinal ingredients, and to have some sort of evidence to support their sale. If I substituted placebos for prescription drugs, I’d quickly lose my license to practice. And if I sold boxes of toothpaste or tissue that were empty inside, I’d probably be out of business pretty quickly.  So I’m dismayed when I see pharmacies selling cough syrups without active ingredients, sending an unwarranted message of homeopathy’s effectiveness.

Another credibility issue arises from an educational perspective, when homeopathy is “integrated” into science and and medical education as well, increasing the perception that homeopathy has medical credibility.  Smith sums it up:

“…inappropriate ‘approval’ for homeopathy serves as a disutility, as it will tend to magnify several negative outcomes, namely resource wastage, risk of patients failing to seek effective healthcare, and reduced patient autonomy through the promulgation of erroneous medical knowledge”

Smith goes on to note a number of other concerns documented repeatedly at SBM, including a weakening of a societal commitment to scientifically-established treatments, as well as the confusion of ineffective treatments such as homeopathy with treatments that he describes as genuinely complementary, such as mediation, relaxation, music and exercise — something that has been described here as the CAM Trojan horse.

Conclusion

So where does that leave us? Unfortunately we cannot simply sum up the arguments in a formula to give us the ethical answer. It seems clear that the ethical downsides to homeopathy outweigh its benefits under most circumstance I can envision.  Smith uses the example of an ineffective defibrillator to point out that the use of such a device device in the context of medical care would be “morally unjustifiable.”  He notes,

Because it is inherently ineffective, homeopathy cannot be ethically neutral. It follows that the purchase, deployment or promotion of homeopathy is morally unacceptable.

Perhaps there may yet emerge a framework where placebos can be ethically (and judiciously) justified. Homeopathy isn’t it. So what should health professionals do? For one, we should stop promoting homeopathy, and the sale of homeopathic remedies.  We should advocate against the allocation of limited health resources to researching, facilitating or providing homeopathy. We should avoid giving homeopathy undeserved credibility by selling it alongside actual medicine, or allowing it to be sold without clear labelling that describes its lack of ingredients and effectiveness. And when we’re asked, we have an ethical responsibility to explain why we believe homeopathy is no ‘alternative” at all.

Reference

ResearchBlogging.orgSmith K (2011). Against Homeopathy – A Utilitarian Perspective. Bioethics PMID: 21320146

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Black Cohosh and Hot Flashes

Black Cohosh, an herbal “supplement” (i.e. unregulated drug) remains popular for the treatment of hot flashes and other autonomic symptoms resulting from menopause. This product is yet another good example of the double standard that the supplement industry and ideological promoters are allowed to employ.

The NCCAM website gives this summary:

Black cohosh, a member of the buttercup family, is a plant native to North America. It has a history of use for rheumatism (arthritis and muscle pain) but has been used more recently to treat hot flashes, night sweats, vaginal dryness, and other symptoms that can occur during menopause.

While the information is available if you look through the links below, their summary makes no mention of the fact that their own studies show black cohosh is ineffective. In their “at a glance” summary they characterize the scientific evidence as “mixed.”


The Natural Standard website is far worse. Although touted as a reliable source of scientific information on herbal supplements, they reveal a very biased editorial agenda. Here is their “bottom line” summary of Black Cohosh:

Black cohosh is one of the highest selling herbs in the United States and is popular as an alternative to hormonal therapy in the treatment of menopausal (climacteric) symptoms such as hot flashes, mood disturbances, diaphoresis, palpitations, and vaginal dryness (1;?2). Several controlled trials and case series have reported black cohosh to improve menopausal symptoms for up to six months. Although these initial studies are suggestive, they have been few in number and have universally suffered from methodological weaknesses.

They also state:

Since the Women’s Health Initiative Trial was halted early due to an excess risk of stroke and other adverse outcomes, millions fewer women are using prescription hormone replacement therapy. However, a 2005 survey has shown there has been no appreciable increase in alternative therapies, including black cohosh (13).

Why are they so concerned that women are not using black cohosh or other “alternative” therapies when the evidence does not support their efficacy?

Let’s take a look at the actual evidence. The best study to date is the 2006 double-blind placebo-controlled trial funded by the NCCAM. They compared Black Cohosh alone, plus with other herbs, plus with other herbs and soy, to standard hormone replacement therapy and placebo. The three herbal groups showed no significant difference from placebo, while the hormone replacement group did show significant improvement. The only exception was the soy group, which showed greater symptom intensity at 12 months. This is the best evidence to date and it was dead negative.

The authors of the study listed as a limitation:

The trial did not simulate the whole-person approach used by naturopathic physicians.

How is this a limitation? Where is the evidence that the “whole-person” approach of naturopaths has any basis in reality or provides any improvement in outcome? This is nothing but special pleading, an attempt to water down the significance of these negative results.

A 2008 systematic review of black cohosh and hot flashes concluded:

The evidence from these RCTs does not consistently demonstrate an effect of black cohosh on menopausal symptoms; a beneficial effect of black cohosh on peri-menopausal women cannot be excluded. The efficacy of black cohosh as a treatment for menopausal symptoms is uncertain and further rigorous trials seem warranted.

In other words — the evidence is negative, but we don’t want to give up yet because black cohosh is still popular. Of course, its popularity was manufactured by unfounded claims for efficacy, which have not held up under rigorous study.

It must also be noted that in the controlled trial all groups, placebo included, did show a decrease in the number of hot flashes over the year of the study. This likely reflects the natural course of symptoms (hot flashes do tend to resolve over time) and also the placebo effect in terms of noticing and reporting symptoms. The lesson from this is that any unblinded study of any treatment for menopausal hot flashes is likely to show a significant decrease in symptoms over time. This study emphasizes the virtual uselessness of unblinded studies in evaluating subjective symptoms, like hot flashes.

And yet, it is precisely these unblinded studies that proponents are using to argue that the evidence is “mixed” and that black cohosh deserves further study.

However, a more rational science-based evaluation would take into consideration the relationship between the rigor of the studies and the effect size. The most rigorous studies are negative — that is consistent with the null hypothesis — with the conclusion that black cohosh simply does not work for hot flashes.

Conclusion

If black cohosh were a pharmaceutical and not a supplement, I don’t think there would be much debate about its effectiveness. The data is essentially negative, which means that the only reasonable science-based recommendation is not to recommend black cohosh for hot flashes. Further study is not unreasonable, but neither it is needed.

However, the NCCAM and Natural Standard shy away from this recommendation. Natural Standard doesn’t even mention the negative evidence in their bottom line summary, but rather decry the fact that more women are not using black cohosh or other supplements. NCCAM resorts to their typical weasel statement that black cohosh “has a history of use” or “has been used for.”

For proponents, when it comes to supplements (or any so-called “alternative” modality), no evidence for lack of efficacy ever seems to be adequate.

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Another Anti-Vaccine Book

I was asked to review the book Make an Informed Vaccine Decision for the Health of Your Child by Mayer Eisenstein with Neil Z. Miller. Fortunately my public library had it so I didn’t have to buy a copy. Reading it was a painful déjà vu experience. I can honestly say it met all my expectations: I expected that its concept of “informed decision” would equate to deciding not to vaccinate, and that it would rely on the same tired old fallacious arguments that have been heard before and rejected by knowledgeable scientists. The only thing that surprised me was a warning/disclaimer statement that admitted

this book tends to find fault with vaccines, therefore readers are advised to balance the data presented here with data presented by “official” sources of vaccine information, including vaccine manufacturers, the FDA, CDC and World Health Organization.

The fact that the book omitted all that balancing data undermines its pretense that it is intended to help readers make a truly informed decision.

It regurgitates every argument of the anti-vaccine faction without fairly presenting the arguments for vaccines and without acknowledging that every anti-vaccine argument has been thoroughly rebutted. For instance, it repeats reporter Dan Olmsted’s myth that the Amish do not vaccinate and do not get autism.

It deceptively argues that deaths from vaccine-targeted illnesses were decreasing before the development of vaccines. Deaths were decreasing due to improving medical treatment and other factors, but the diseases were not going away: the incidence of the diseases had not decreased significantly. Graphs of the yearly incidence of diseases like measles, mumps, polio, diphtheria, pertussis, etc. all show a striking reduction after vaccines were introduced. The book does not present those graphs. The real proof of the pudding is that in various countries around the world, when vaccination rates dropped, the diseases returned; and when vaccination rates rose again, the diseases subsided. The book does not acknowledge those inconvenient facts.

It does rely heavily on horror stories, mainly drawn from VAERS (Vaccination Adverse Event Reporting System) data. For every vaccine it provides a list of cases reported to VAERS. It says these are “just a small sample of the potential side effects associated with vaccines.” This is deliberately deceptive. The fact that a case is reported to VAERS only means that an adverse event occurred after vaccination; it does not even establish a correlation with the vaccine (because we don’t know whether the event occurs with equal frequency in a control group), and it certainly doesn’t establish that the vaccine caused the event.

It claims that VAERS data show that Rotateq vaccine causes intussusception in children. It doesn’t mention that the CDC investigated those VAERS reports and found that the rate of intussusception after the vaccine did not exceed the expected background rate of intussusception in the population.

It cites cases of adverse reactions to diphtheria antitoxin; but antitoxin is never needed unless you get the disease, which is prevented by the vaccine. And then it recommends avoiding tetanus vaccine since a tetanus antitoxin is available. It fails to mention the adverse reactions to tetanus antitoxin and the fact that it will not be needed if the vaccine has prevented the disease in the first place. How could anyone think it is preferable to get tetanus and then treat it with antitoxin?

It cites Andrew Wakefield’s studies allegedly linking the MMR vaccine to autism and his unsupported speculations that single vaccines are preferable. It mentions that his Lancet study was retracted, supposedly only because a British medical panel had concluded that he had violated ethical rules. It quotes Wakefield’s disingenuous protestation that the allegations against him were unfounded. It fails to mention that he had falsified data in his study and that he was stripped of his medical license. It also favorably cites the Geiers’ discredited research; the book was published before one Geier was stripped of his license and the other Geier was prosecuted for practicing medicine without a license.

It admits that removing thimerosal from vaccines did not decrease the rate of autism, but it claims that autism was increased by thimerosal added to flu vaccines and by the amount of aluminum in vaccines.

It bewails all those antigens injected into “pure, innocent” babies.

I won’t belabor all the other misconceptions in the book: we’ve heard them all before.

Eisenstein has not only an MD but a JD and an MPH. He has not let his scientific training interfere with his prejudices. He directs Homefirst Health Services, an organization that promotes home births, discourages immunization, provides vaccination waivers to everyone on the general principle that vaccines are harmful, sells natural supplements (profits from recommending them), offers HCG treatment (proven to be useless) for obesity, and claims there are virtually no autistics among its patients. Dr. Eisenstein is also billed as Assistant Medical Director of Alternative Medicine Integration and he has appeared on the Oprah Winfrey show; regular readers of this blog will recognize that “integration” and Oprah are both red flags for non-scientific medicine. He doesn’t think much of conventional medicine. He dismisses mammograms as never having saved even one minute of life, and another of his statements is calculated to really make Dr. Gorski’s blood boil:

Scientists also looked at breast cancer treatments: mastectomy, simple mastectomy, radial [sic] mastectomy. There was no benefit on outcome of survival.

This is a terrible book. It is dishonest, misrepresents the facts, and is likely to persuade the average reader not to vaccinate, thereby putting the rest of us at risk from decreased herd immunity. The average reader has no way of knowing what is wrong with its claims or what has been omitted. Unfortunately, its flaws will only be apparent to those of us who are able to recognize the book as merely another polemical restatement of discredited anti-vaccine propaganda.

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The ultimate in “integrative medicine,” continued

It’s been a recurring theme on this blog to discuss and dissect the infiltration of quackademic medicine into our medical schools. Whether it be called “complementary and alternative medicine” (CAM) or “integrative medicine” (IM), its infiltration into various academic medical centers has been one of the more alarming developments I’ve noted over the last several years. The reason is that “integrative” medicine is all too often in reality nothing more than “integrating” pseudoscience with science, quackery with medicine. The most popular modalities that medical schools and academic medicine centers can’t seem to resist are acupuncture and various forms of “energy” healing, such as reiki and therapeutic touch. Unfortunately, when you “integrate” something like reiki or therapeutic touch (TT), which basically assert that there is mystical, magical energy source (called the “universal source” by reiki practitioners, for example) that practitioners can tap into and channel into patients for healing effect, you are in essence integrating a prescientific understanding of the world with science, religious faith healing (which, let’s face it, is all that reiki is), and magic with reality.

Why would medical institutions ostensibly based on science do that?

I don’t know, but I know it’s happening. There are many forces that conspire to insert sectarian versions of medicine into bastions of scientific medicine. These include cultural relativism leading to a reluctance to call quackery quackery; financial forces such as the Bravewell Collaborative, which funds a number of IM programs at academic centers; the National Center for Complementary and Alternative Medicine (NCCAM); and a variety of other factors. It’s been a depressing slide, and periodically I wonder just how much more pseudoscience can be “integrated” into medical schools and academic medical centers or how much further medical schools can go in pandering to nonsense. I’m not wondering anymore, at least for now, not after learning about a cooperative agreement between Georgetown University and the National University of Health Sciences:

National University of Health Sciences (NUHS) has announced a new cooperative arrangement with the Graduate Program in Complementary and Alternative Medicine at Georgetown University Medical Center in Washington D.C., which will benefit students preparing for careers in health care and integrative medicine.

Faculty at the two schools will now work together to help students seeking advanced degrees in health care, by advising students of the benefits of each other’s programs and providing preferential seating and advanced standing in each other’s programs when appropriate.

Take a look at the NUHS website. Look at its offerings: chiropractic, naturopathy, traditional Chinese medicine, acupuncture, massage therapy, and “biomedical science,” which, given all the other woo being taught at NUHS, I have to wonder about. Just take a look, too, at the curriculum for obtaining a doctor of naturopathy degree. It’s full of homeopathy, traditional Chinese medicine, hydrotherapy and, of course, naturopathy. I must admit, however, to some amusement when I saw that there is a course entitled, “Evidence Based Practice: Critical Appraisal of the Biomedical Literature.” Quite frankly, if this course truly taught evidence-based practice, then it would teach that all that homeopathy taught in other courses is nonsense, along with naturopathy itself.

Fat chance of that happening, not with “integration” like this:

Program directors at Georgetown selected NUHS as a top-tier institution providing educational excellence in its professional degree programs, thus meriting Georgetown’s recommendation for its graduates seeking professional degrees. According to Aviad “Adi” Haramati, who co-directs the program with Hakima Amri, PhD, the academic affiliation is intended to “…break down the silos that hold the disciplines apart and create relationships between the disciplines and the educational institutions that prepare the nation’s future healthcare providers.”

Great. Just what we need: “breaking down silos” separating pseudoscience from science-based medicine. That’s exactly what’s happening here, and Georgetown is leading the way, so much so, in fact, that this is not the first time it has forged a partnership with an institute dedicated to teaching pseudoscience and quackery. If you want to see another example of this sort of “integration,” behold this academic “integration” model championed by Georgetown University, this time with the infamous school of naturopathy, Bastyr University:

A model inter-institutional relationship may help bridge the chasm that separates health professions education in conventional academic health centers from institutions educating students for the distinctly licensed integrative practice (“CAM”) professions. Says one leader: “I believe we are poised to make an important advance in how the future training of health professionals may evolve.” The speaker is Adi Haramati, PhD, integrative medicine leader at Georgetown University, describing a new relationship between Georgetown and Bastyr University relative to Bastyr’s naturopathic medical program and Georgetown’s MS CAM program. Haramati and his co-director Hakima Amri, PhD are exploring similar relationships with chiropractic schools and other health professions institutions. The developers “would like nothing more” than to see this bridge-building relationship be used as a model for other academic health centers and CAM institutions.

That’s right. Georgetown is partnering with schools of pseudoscience in order to train the next generation of CAM practitioners. It’s not enough to team up with the naturopaths. Even several months ago, when Georgetown first teamed up with a naturopathic school, Dr. Haramati had been envisioning teaming up with chiropractic schools. That’s what the NUHS is, mostly, and the agreement between Georgetown and NUHS seems to be the first step towards realizing the vision he presented at the time he teamed up with Bastyr.

But it’s more than that. More than five years ago, Georgetown decided that CAM should be “integrated” into its curriculum to the point where it was made part of its medical school curriculum. However, Georgetown went way beyond simply having a lecture or two on CAM here and there and offering clinical electives to fourth year medical students in CAM. That wasn’t enough. The vision was far more bold and—dare I say, given what’s happened in the last five years?—forward-looking. What Georgetown offered was what it referred to in its own brochures as:

The “seamless” weaving of CAM into existing classes includes, for instance, a presentation by an acupuncturist on the “anatomy of acupuncture” in the gross anatomy course for first-year students. The same lecturer explores acupuncture’s application in pain relief in the neuroscience course.

I wish this were a joke, but it’s not. The “anatomy” of acupuncture? Which “anatomy,” given that the magical, mystical meridians along which a life energy that science can’t detect allegedly flows? Teaching such material in anatomy class is indeed the ultimate seamless “integration” of pseudoscience with science, quackery with science-based medicine. Breaking down silos, indeed. Fast forward five years, and here is the vision for true “integration” in medical education towards which Georgetown is working with Bastyr (and now, NUHS), in which it isn’t just Georgetown but Georgetown teaming up with institutions of quackery:

Student A completes an academic Masters of Science program at a highly esteemed academic health center. He or she is wondering her/his future. The program focused on the science of complementary and integrative medicine. But what does the individual’s future hold? Go on to medical school? Personnel with the program lay out options. Among them, without prejudice: Have you considered this naturopathic medical school?

Meantime, Student B is considering naturopathic medical college. The field of complementary and alternative medicine intrigues. But is he or she ready to make the jump for that 4-year, residential commitment? Is naturopathic medicine or regular medical school or chiropractic medical education what they want? Personnel with the naturopathic medical program say: You might consider this year-long Masters of Science in complementary and alternative medicine at this academic health center.

The basis of this relationship between Bastyr and Georgetown, we hear, is a new “respect” being shown towards CAM modalities, and this is the way that the joint program will be structured:

The fundamental aim of this program is to provide students with competencies in three areas: grounding in science (especially systems and cell physiology), introductory exposure and understanding of CAM disciplines and philosophies, and the ability to rigorously assess the state of evidence regarding safety and efficacy of various CAM therapies.

Let’s see. Science…good. We like to see medical students exposed to science. Exposure to CAM disciplines…not so good. Don’t get me wrong. I very much believe that medical students should be taught about CAM modalities, but they should be taught about them from a the perspective of the state of the science, the evidence, and clinical trials. They should be taught about skepticism and critical thinking. They should be taught about how various CAM remedies, such as herbal medicines, interact with pharmaceuticals. That is not what this program sounds like, as a science-based perspective leads to the conclusion that the vast majority of CAM either hasn’t been shown to work or has been shown to work. If such weren’t the case, CAM wouldn’t have the word “alternative” in it.

Let me just put it this way. When this program claims to teach students how to “rigorously” assess the state of evidence regarding the safety and efficacy of various CAM therapies, the word “rigorously” applied to such teaching doesn’t mean the same thing that “rigorously” means when scientists actually do rigorously assess the evidence. What it usually means is buying into the aforementioned philosophy of various CAM disciplines and then proceeding from there. Either that, or it means what Harriet Hall likes to call Tooth Fairy science, which refers to doing research on a phenomenon without first establishing that the phenomenon exists first. In essence, it’s like studying the Tooth Fairy. You can measure how much money she leaves under the pillow. You can study whether she leaves more or less money for the first or last tooth. You can get a whole lot of data that appear reproducible. You might even get data that is statistically significant. But at the end of the day you haven’t actually established that the Tooth Fairy actually exists.

A better metaphor for research into CAM modalities like reiki, TT, or homeopathy is hard for me to imagine. After all, reiki is nothing more than faith healing that substitutes Eastern mysticism for Christian beliefs. TT is basically reiki lite, where even the Eastern mysticism is stripped down to vague New Agey-sounding ideas like channeling “energy” into patients through their hands. (You know, whenever I picture reiki or TT, I visualize one of my favorite comic book characters of all time, Dr. Strange, casting a spell. In fact, as has been suggested before, that’s the only real way I can see of making homeopathy work: a fictional Sorcerer Supreme and Master of the Mystic Arts casting a spell.

But, wait, I hear: What about something that’s less highly improbable? Homeopathy is obviously utter nonsense. So are reiki and other “energy” therapies. What about herbal medicine? What about manipulative therapies (leaving aside the dubious philosophical underpinnings of some such therapies, like homeopathy, which similarly appeal to “energy flow” through various locations)? Well, there’s already a branch of pharmacology that can study herbal remedies. It’s called pharmacognosy, and it isolates the active fractions of natural products and studies them, just as pharmacologists have done for decades, if not centuries. There’s nothing “alternative” in that that needs to be “integrated” into science-based medicine. Similarly, manipulative therapies are not beyond the reach of science to study rigorously, either. However, to do such studies it is necessary first to verify that a phenomenon exists, which can be done using the scientific method. What I fear will happen in this new Bastyr-Georgetown integration will be Tooth Fairy science. There’ll be a lot of data, but it won’t mean anything.

The other purpose of this integrated program is explicitly promotional of CAM. It explicitly seeks the “integration” of quackery with science-based medicine. Don’t believe me? Check out this vision:

The Georgetown agreement with Bastyr, and those Haramati and Amri are seeking with other schools, are terrific steps, laying scaffolding toward the vision, articulated at NED and embraced by ACCAHC, of “a healthcare system that is multidisciplinary and enhances competence, mutual respect and collaboration across all CAM and conventional healthcare disciplines.”

Georgetown is the trailblazer in “integrating” quackery into science-based medicine, but, although it’s first, it won’t be the last. This is a well-coordinated, longstanding effort on the part of CAM advocates, in which they actively lobby for such partnerships and such “integration” with science-based practitioners. Indeed, the Academic Consortium for Complementary and Alternative Health Care supports what it calls the Center for Optimal Integration, which explicitly works towards the sorts of partnerships that Georgetown has undertaken with Bastyr and NUHS.

Personally, I don’t see how “integrating” CAM into science-based health care would enhance competence, but then that’s just the nasty reductionist in me who rejects the false dichotomy of “alternative” medicine. After all, “alternative” medicine is nothing more than medicine that either hasn’t been shown to work or has been shown not to work. “Alternative medicine” that works is no longer “alternative.” It’s just medicine. Naturopathy is a hodge-podge, a grab bag of all sorts of unscientific and pseudoscientific medical treatments, most of which fall squarely into the “alternative” camp in every definition, particularly the ones about either not working or not having been demonstrated to work.

Unfortunately, when it comes to quackademic medicine, the false dichotomy lives, and institutions like Georgetown are betraying science-based medicine by being so open to the point of its brains falling out—and partnering with Bastyr to integrate nonsense with sense, pseudoscience with science, and quackery with medicine.

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Ambiguity

Some people have made the mistake of seeing Shunt’s work as a load of rubbish about railway timetables, but clever people like me, who talk loudly in restaurants, see this as a deliberate ambiguity, a plea for understanding in a mechanized world. The points are frozen, the beast is dead. What is the difference? What indeed is the point? The point is frozen, the beast is late out of Paddington. The point is taken. If La Fontaine’s elk would spurn Tom Jones the engine must be our head, the dining car our esophagus, the guard’s van our left lung, the cattle truck our shins, the first-class compartment the piece of skin at the nape of the neck and the level crossing an electric elk called Simon. The clarity is devastating. But where is the ambiguity? It’s over there in a box. Shunt is saying the 8:15 from Gillingham when in reality he means the 8:13 from Gillingham. The train is the same only the time is altered. Ecce homo, ergo elk. La Fontaine knew his sister and knew her bloody well. The point is taken, the beast is moulting, the fluff gets up your nose. The illusion is complete; it is reality, the reality is illusion and the ambiguity is the only truth. But is the truth, as Hitchcock observes, in the box? No there isn’t room, the ambiguity has put on weight. The point is taken, the elk is dead, the beast stops at Swindon, Chabrol stops at nothing, I’m having treatment and La Fontaine can get knotted.

— Art Critic

Ambiguity. Medicine, like art, is filled with ambiguity, at least the way I practice it. Most of my practice is in the hospital. I am sometimes called to see patients that other physicians cannot figure out. And that puts me at a disadvantage, because the doctors who were referring patients to me are all bright, excellent doctors. Often the question is ‘Why does the patient have a fever?’ or ‘Why is the patient ill?’ Sometimes I have an answer. Most of the time I do not.

I am happy, however, to be able to tell the patient what they don’t have. I can often inform the patient and their family that whatever they have is probably not life-threatening or life-damaging, just life-inconveniencing, and most acute illnesses go away with no diagnosis. I always put the ‘just’ in air quotes, because illnesses that require hospitalization are rarely ‘just.’ Just without quotes is reserved for the antivaccine crowd and applied to the small number of deaths from vaccine preventable diseases in unvaccinated children. John Donne they ain’t.

We are excellent, I tell them, at diagnosing life-threatening problems that we can treat, and terrible at diagnosing processes that are self-limited. Of course diagnostic testing is always variable. No test is 100% in making a diagnosis, and often with infections I cannot grow the organism that I suspect is causing the patient’s disease. So for hospitalized patients, ambiguity and uncertainty are the rule of the day.

However, the situation is much better than they used to be. I am now one of the oldest physicians practicing in my hospital. After 21 years most of the prior old guard has retired or died, leaving me. I have gone from being the young whippersnapper to the old geezer in what to me seems to be a blink of an eye.

However, the advantage to being old is you get to bore people with the stories of your gloried past. I remember a time, I tell the residents, before CAT scans, before third-generation cephalosporins, before PCR diagnostics. I remember the beginning of the AIDS epidemic, when we saw young men dying of an unknown illness. I still vividly remember my first AIDS patient, dying from disseminated MAI, who offered me a chocolate from his box of candy. I declined. I told him I wasn’t hungry. He told me “I would have to spit in your mouth to give you AIDS.” I did not know that at the time. No one did. Today I would eat the candy.

Times have changed, mostly for the better. AIDS has gone from an unknown disease with a short life expectancy to a mostly chronic manageable illness whose pathophysiology is understood in remarkable detail. Medicine advances. It is often an uncomfortably slow and aggravating process, because diagnostics and therapeutics that look promising at the beginning often turn out to not live up to their promise. Kind of like many people I have known.

Some therapeutic interventions have remained in limbo my entire practice. Steroids, as an example, have been tried for every illness except for Cushing’s disease. In almost every instance they have been found wanting. When I was an intern, every patient with a neurologic event was put on aspirin and Persantine. I don’t think Persantine is used much anymore. Common admission diagnoses were an aminophylline toxicity and digoxin toxicity; both drugs are rarely used today since we have less toxic and superior alternatives.

Certainly my practices changed dramatically over the last 21 years. I used to make a living from diseases that are rapidly becoming of historical interest. Ventilator-associated pneumonia, line-related sepsis, AIDS opportunistic infections, neutropenic fever’s, diabetic foot infections in smokers, all used to be common admitting diagnoses that resulted in infectious disease consultation. No longer.

Despite the wackaloon opinion that doctors are in it for the money, combined with big pharma greed, the last 21 years has seen a concerted effort on the part of the medical industrial complex to decrease the diseases we treat for living. This is not only true in infectious diseases, but cardiologists have been at the forefront of stop smoking and lipid control. The same is true of pulmonary doctors. Every physician fights the battles of obesity in the outpatient clinic. Much of the time physicians try to put themselves out of work. And in infectious diseases it seems to be successful. That is why at TAM 9 this year I plan on letting everyone buy me a beer. I’m sure the rest of the SBM crew would feel the same way. But no lite beers, puh-leaze.

Medicine does advance.

There is an infectious disease therapy that superficially resembles acupuncture and homeopathy: ribavirin. A drug with few proven benefits. Like most SCAMs, case reports, uncontrolled series and wishful thinking has kept ribavirin alive and around for my entire practice. I say superficially as most SCAMs now have a proven lack of benefit. Ribavirin is an antiviral medication that has probably been tried on virtually every virus, but has never been shown to have efficacy by itself in almost any infection. It is of benefit in RSV, and combined with interferon for the treatment of hepatitis C.

Ribavirin is a broadly active antiviral has rarely been tested in randomized controlled trials. Many of the infections that are allegedly treated with ribavirin are not common in the United States. So when a question of West Nile virus, dengue virus, Tick-borne Encephalitis Virus, Yellow Fever Virus, Lassa fever, Crimean-Congo hemorrhagic fever, or Hantavirus appears, the answer is ribavirin. But is the answer the correct?

This leads to an interesting editorial from several years ago in the journal Clinical Infectious Diseases entitled How Medicine Advances. How?

The editorial concerned an article on a study that looked at the efficacy of ribavirin in the treatment of Japanese encephalitis virus. Significant time, money and effort has been expended using ribavirin for diseases like Japanese encephalitis. But there have never been randomized clinical trials to demonstrate or deny the efficacy of ribavirin in the treatment of Japanese encephalitis. Until 2009 that is.

In CID that year they published a randomized placebo-controlled double-blind study that evaluated the effectiveness of ribavirin in the treatment of children who had Japanese encephalitis. And ribavirin was found to do nothing.

What was striking about this trial, as pointed out in the editorial, was that the study was done in the poorest part of India, it was done in children, and it was done with a definitive rigor that allowed the issue of ribavirin (always with the caveats of orally and at the dose given) to be put to rest for the treatment of this one infectious disease. A little more ambiguity in medicine has been removed.

I think the final paragraphs of the editorial sum up nicely why we do science-based medicine and the importance of doing clinical trials to determine what does and does not wor:

Kumar et al., whose study is published in this issue of Clinical Infectious Diseases, are to be commended for refusing to bow to any of the complexities reputed to make clinical trials impossible. In Uttar Pradesh, India’s most populous and poorest state, Kumar and colleagues sustained over 3 years the first randomized, placebo-controlled, doubled-blind trial of ribavirin for the treatment of the most vulnerable patients—children (age, 6 months to 15 years)—to be hospitalized with acute febrile encephalopathy, and they per- formed seroreactive testing for IgM anti-bodies to Japanese encephalitis virus. By so doing, they established that oral ribavirin, at the dosage used in their study, did not improve either early or late outcomes. By demanding scientific justification for investment in this mode of therapy, they have both encouraged searches for more-effective interventions and prevented the expenditure of scarce resources ineffectively.
Both faith and science are important components of the art of medicine. We ought not to mistake one for the other.

I wish, besides sarcasm punctuation marks, we had whiny little baby tags punctuation marks, since the lament of many a SCAM proponent is that their particular intervention can’t be tested because of “complexities reputed to make clinical trials impossible.” Riiiiggghhhhttttt, Mr. Powers. It is easier to curse the darkness than to light a candle.

There is then the more difficult application of applying the data. If someone has a long history of being committed to a treatment, it is surprisingly difficult to get individuals and groups to alter their behavior. I expect the urge to give ribavirin for Japanese encephalitis will rapidly fade. Not so the urge to balance qi, fix subluxations, or realign the energy flux. Wait. The last is either reiki or Galaxy Quest. The latter at least is recognized as fiction. Unfortunately, there are many other infections for which people will try ribavirin and for which there are no randomized placebo-controlled clinical trials. Ribavirin will continue to be a drug mostly searching for a disease.

But still medicine progresses. Studies get done, there is an incremental improvement in our understanding of the diagnosis or treatment of the disease. And slowly and painfully medicine changes. Emphasis on slowly. Change has to be balanced with the knowledge that much of the information we have in medicine is not final. When I talk about studies with residents, I try and be careful to mention the often endless caveats about the applicability of the results beyond the study population. Back in the day it seemed that all coronary artery disease studies were done in old, white male veterans. Probably widely applicable, but maybe not. But at least as an old white man, I can be taken care of.

There’s an old saying that goes something like ‘be neither the first to abandon the old nor be the first to use the new.’ I certainly feel that way about antibiotics. Over the years new drugs have been approved, released into widespread use, and then found to have serious side effects that resulted in their being withdrawn from the market. So I’m always a little leery about new medications and new treatments unless I do not have other options.

So I look back on 21 years of infectious diseases 25 years of being a physician and note the incredible changes that have occurred. Diagnostics that have improved, therapies that have improved, and more importantly diagnostics and therapies that have been abandoned. Abandoned because they were shown not to work. Medicine advances.

Contrast that with the bête noire of this blog: supplements, complementary and alternative medicine. Anybody who subscribes to reality-based medicine would say at this point that the preponderance of data strongly points to the conclusion that most SCAMs do not work. Acupuncture, homeopathy, energy medicines, etc. do not materially alter disease. Yet has any of these ever been abandoned? Nope.

It would seem that they are being embraced, at least in academic institutions. SCAMs are an archetype example of failing up. It has been noted that with SCAMs that better and better studies show less and less effect until well-designed studies show no effect. For the last decade it would seem the greater the failure, the greater the spread into academia and the more popular the SCAM. By the same standards we should be using internal mammary artery ligation for coronary artery disease, high dose chemotherapy with bone marrow transplant for breast cancer, and continue to suppress all abnormal cardiac rhythms in heart attack patients. All the interventions failed spectacularly, and so should be embraced, each with their endowed Chairs.

SCAMs probably are growing for the financial benefit. Since standard medicine has declining reimbursement and most alternative therapies are out-of-pocket, it’s a good cash cow for institutions that want a flow of money and are not picky about their intellectual standards. Not only are the standard SCAMs proliferating, they often combine in most peculiar ways to come up with new variations. Doctor Moreau would be impressed with the slow mutant reassortments: acupuncture (at least 6 kinds) morphing into acupressure, laser acupuncture, acupuncture with tuning forks and color, and soon there will be dark energy acupuncture. You heard it here first. Don’t get me wrong, I am jealous. I would love to combine ID with cardiac bypass surgery and make some real cash, but they just don’t mix. Sigh.

It is said that the majority of medical practice has no basis in science-based medicine. Certainly in the practice of infectious diseases in the hospital, that is often the case. I will see an organism in a odd place, for example a Gemella endocarditis, and there are no long-term randomized placebo-controlled clinical trials to determine what the best therapy is for the treatment of a Gemella endocarditis. There probably never will be. It is so rare that it is probably impossible to generate enough cases to do a clinical trial. I am stuck with the basic principles of biologic plausibility and in vitro antibiotic susceptibilities and that is often enough. I know that if I can kill the bug in the test tube, I can often kill it in the patient as well. In the absence of clinical trials, reality can reliably determine effective therapy.

It is quite a stark contrast between SCAMs and of medicine and how they are practiced. Medicine changes. Or perhaps it would be better to say medicine evolves. The old is be shown to be worthless. It is abandoned, and patient care overall improves. Even when there are no good clinical trials to guide therapies, often we have prior plausibility and biologic plausibility to help guide our therapies. Not always, as ribavirin demonstrates, but we have to fight the war with the armies we have. Advances have not been without their side effects and bad consequences, as no good deed ever goes unpunished, but medicine still adheres to the Victorian principle that human societies are perfectible. And while we always fall short of our goal, what has accomplished has been admirable.

SCAMs persist with no improvement, no evolution, and are increasingly discredited by reality. Nothing is ever abandoned, instead persisting, mutating and growing. With alternative memes, what determines replicative fitness is not, apparently, the real world. Oh well, it gives me something to write about.

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Anti-vaccine warriors vs. research ethics

Three weeks ago, the anti-vaccine movement took a swing for the fences and, as usual, made a mighty whiff that produced a breeze easily felt in the bleachers. In brief, a crew of anti-vaccine lawyers headed by Mary Holland, co-author of Vaccine Epidemic: How Corporate Greed, Biased Science, and Coercive Government Threaten Our Human Rights, Our Health, and Our Children, published a highly touted (by Generation Rescue and other anti-vaccine groups, that is) “study” claiming to “prove” that the Vaccine Injury Compensation Program (VICP) had actually compensated children for autism. As is typical with such “studies” generated by the anti-vaccine movement, it was bad science, bad law, and just plain bad all around. The authors intentionally conflated “autism-like” symptoms with autism, trying to claim that children with neurological injury with “autism-like” symptoms actually have autism. Never mind that there are specific diagnostic criteria for autism and that, if the children actually had autism, many of them would have been given a diagnosis of autism. Never mind that what they were doing was akin to claiming that all patients with “Parkinson’s-like symptoms” have Parkinson’s disease. (Hint: They don’t.) Never mind that all they did was to demonstrate a prevalence of autism spectrum disorders among the VICP-compensated children that was clearly within the range of what would be anticipated if there were no relationship between vaccines and autism. Never mind all that. This was Holland’s big chance, but it went over like the proverbial lead balloon. No one bit, other than FOX News.

The study rapidly faded into the obscurity it so richly deserves, in spite of mighty efforts by Generation Rescue, SafeMinds, and the likes of Ginger Taylor to keep it alive and use it as a rallying point to persuade legislators to pass anti-vaccine-friendly legislation. You could feel the frustration in its backers as Holland’s study, into which groups like Generation Rescue had apparently poured their hopes of being vindicated, crashed and burned.

However, there’s one aspect of this study that I didn’t discuss. In fact, I thought of it as I read it, but I wasn’t sure. What I (and others) have noticed is that there was no statement in the article that approval had been obtained from the relevant institutional review boards (IRBs) to do human subjects research. For those not familiar with what an IRB is, an IRB is a committee that oversees all human subject research for an institution. It is the IRB’s responsibility to make sure that all studies are ethical in design and that they conform to all federal regulations. Basically, IRBs are charged with weighing the risks and benefits of proposed human subject research and making sure that

  1. risks are minimized and that the risk:benefit ratio, at least as well as it can be estimated, is very favorable;
  2. to minimize any pain, suffering or distress that might come about because of the experimental therapy; and
  3. to make sure that researchers obtain truly informed consent.

During the course of a study, regular reports must be made to the IRB, which can shut down any study in its institution if it has concerns about patient welfare.

Of course, I know this all because I happen to be involved in human subjects research. It’s part of what I do while doing research in breast cancer. Clinical trials are obviously human subjects research. After all, their very purpose is to test a new drug or treatment on human subjects in order to determine if it works. However, human subjects research encompasses a lot more than just clinical trials; in fact, it encompasses almost any research study that involves either human subjects or human subjects’ protected health information (i.e., medical charts). Basically, any human subject experimentation requires approval by a properly constituted IRB. There is no documentation in Holland et al that IRB approval had been obtained, either from the for NYU (given that Mary Holland is a research scholar at the NYU School of Law) and/or Pace University, given that Pace Law School is cited as having “provided significant research support for this study” in the footnotes of the paper:

Mary Holland, Research Scholar and Director of the Graduate Legal Skills Program, NYU School of Law; Louis Conte, independent investigator; and Robert Krakow and Lisa Colin, attorneys in private practice. Pace Law School provided significant research support for this study.

Autism News Beat and Sullivan are already all over this issue, but I thought I’d throw in a bit from my perspective, given that I actually have to work with IRBs and, before my career is over, will probably be roped into serving on an IRB. In any case, as is true of any researcher who is involved in human subjects research, I had to undergo specific training regarding the “rules of the road,” so to speak, as a requirement of being an investigator on any study involving human subjects research.

How is human subjects research defined? According to 32 CFR 219.102(d), research means “a systematic investigation, including research development, testing, and evaluation, designed to develop or contribute to generalizable knowledge,” and according to 32 CFR 219.102(f) a human subject is defined as ” living individual about whom an investigator (whether professional or student) conducting research obtains data through intervention or interaction with the individual, or identifiable private information.”

Under these criteria, I believe that the Pace study clearly qualifies as human subjects research. First of all, as poorly designed as the study was, it was clearly intended as a systematic investigation designed to contribute to generalizable knowledge and testing a hypothesis, namely that autism is associated with vaccine-induced brain injury. The authors claim to have found data in the VICP-compensated cases indicating that there is a higher incidence of autism in these children. Never mind that they found nothing of the sort, they set out to test that hypothesis and their methods were designed to support it. Moreover, as Autism News Beat pointed out, members of the Elizabeth Birt Center for Autism and Legal Advocacy (EBCALA) administered the Social Communication Questionnaire (SCQ) to the parents or caregivers of 22 children. This clearly makes the parents who answered the questionnaire (and their children) human subjects, as identifiable protected health information about the children is being solicited and used to test their hypothesis.

To be fair, I have to point out that there are types of studies that are exempt from full IRB approval. In fact, there are six categories of so-called “exempt” studies. I frequently use category four, which involves the use of already existing clinical information that has been de-identified. I also note that this particular exemption involves research that does not involve interacting with living humans about their health information; rather, these sorts of studies tend to involve chart reviews or the examination of human tissue specimens that have already been collected. Be that as it may, there is one potential exemption that EBCALA might claim. First, number two:

Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures or observation of public behavior, unless:

  1. information obtained is recorded in such a manner that human subjects can be identified, directly or through identifiers linked to the subjects; and
  2. any disclosure of the human subjects responses outside the research could reasonably place the subjects at risk of criminal or civil liability or be damaging to the subjects financial standing, employability, or reputation.

Unfortunately for Holland et al, the first “unless” probably kills this exemption. The information they obtained was obtained in a manner such that the human subjects can be identified. The second “unless” might or might not kill the exemption; I note that both criteria are used to decide whether an exemption is not permissible. However, even if this research could potentially be considered exempt – and I highly doubt that a reputable IRB operating within the law and the Common Rule would find it exempt, particularly since IRBs are charged with taking special care to protect human subjects considered to be vulnerable, such as children, and that the survey is in fact a screening/diagnostic tool, making the results protected health information – it should also be noted it is not the investigators who get to decide whether a protocol is exempt or not and therefore whether a protocol requires IRB evaluation and approval. Period. Investigators do not have the power to determine whether their research falls under one of these exempt categories; only the IRB can make that determination, usually in an expedited review that determines whether a potentially exempt protocol meets the standards of one of the categories that are exempt from full IRB approval. It’s right there in the rules:

Only the IRB may determine which activities qualify for an exempt review. Investigators do not have the authority to make an independent determination that research involving human subjects is exempt and must contact the IRB concerning the status of proposed research or changes in ongoing research.

Also note that the research cannot begin until after IRB approval is obtained.

Personally, unlike the case with the Geiers, my guess is that as lawyers Holland et al were simply ignorant that what they were doing constituted human subjects research and that’s why they didn’t bother with a little thing (to them) like obtaining IRB approval before doing their study. Indeed, when Autism News Beat inquired at Pace Law School about whether the EBCALA study had IRB approval, this is what he was told:

When asked if the Pace study had IRB approval, Pace Law spokesperson Lauren Rubenstein referred the question to the study’s co-author, Louis Conte. In an email, Rubenstein wrote “Louis Conte has told me that there was no human subjects research in this study.”

Which reveals Conte’s utter cluelessness about human subjects research. Investigators interacted with the parents of these children, administering a questionnaire to them for purposes of looking for data to support their hypothesis. It’s human subjects research until judged otherwise–by an IRB, not by Conte, Holland, or any of the other of the merry band of anti-vaccine lawyers who put this travesty of a study together. Not surprisingly, attempts to get Conte to respond to e-mails regarding IRB approval of the study were not returned.

Of course, ignorance of the law is no excuse; as lawyers the authors of Holland et al should know. I also find it rather hard to believe, whether or not they were ignorant of federal law and regulations regarding human subjects research, that at some point either Holland and her coauthors weren’t made aware somehow by someone that what they were doing constituted human subjects research under federal law. Surely someone must have realized this, given that questionnaires about protected health information were being administered to living human beings. If they did not, then, quite frankly, I find the level of incompetence and lack of concern about basic ethical standards that every investigator in the U.S. who engages in human subjects research knows as basic information because they are required to know them and abide by them as part of ethics and the law.

This lack of concern about such niceties of the ethical treatment of human subjects is nothing new in anti-vaccine studies. Andrew Wakefield demonstrated it with his callous treatment of children at a party, whom he basically bribed for blood samples and whose fear he made light of. The Geiers père et fils demonstrated it when they created an IRB to oversee their own research, sat on that IRB themselves with Dr. Geier himself chairing the committee (a massive conflict of interest), and packed it with their anti-vaccine cronies.

There’s one more “out” that Holland et al might try for, and that’s to say that their research was not federally funded and is therefore not covered by the Common Rule. However, most universities that accept federal funding for research agree to be bound by the Common Rule for all research carried out by their faculty, students, and trainees. Even if Holland et al tried to justify their failure to obtain IRB approval this way and argue that they are not legally bound to follow the Common Rule, their failure to obtain IRB approval for their study and submit to IRB oversight is a massive ethical failing. I characterized Holland et al as evidence that that when the anti-vaccine movement can’t win on science, it will appeal to the law. It also appears that when it can’t win on ethics, it will appeal to the law as well.

While Holland et al tout “unanswered” questions about autism and the VICP, the only question I have is: Will Pace University and NYU will investigate how such a study could be performed without its investigators obtaining the requisite IRB approval? Or will they sweep this massive ethical (and possibly legal) breach under the rug and hope it goes away?

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Pragmatic Studies – More Bait and Switch

The course of research into so-called alternative medicine (CAM) over the last 20 years has largely followed the same pattern. There was little research into many of the popular CAM modalities, but proponents supported them anyway. We don’t need science, they argued, because we have anecdotes, history, and intuition.

When media attention, which drove public attention, was increasingly paid to CAM then serious scientific research increased. A specific manifestation of this was the National Center for Complementary and Alternative Medicine (NCCAM). CAM proponents then argued that their modalities were legitimate because they were being studied (as if that’s enough). Just you wait until all the positive evidence comes rolling in showing how right we were all along.

But then the evidence started coming in negative. A review of the research funded by NCCAM, for example, found that 10 years and 2.5 billion dollars of research had found no proof for any CAM modality. They must be doing something wrong, Senator Harkin (the NCCAM’s major backer) complained. They engaged in a bit of the kettle defense – they argue that the evidence is positive (by cherry picking, usually preliminary evidence), but when it is pointed out to them that evidence is actually negative they argue that the studies were not done fairly. But then when they are allowed to have studies done their way, but still well-controlled, and they are still negative, they argue that “Western science cannot test my CAM modalities.”

But at the same time, they cannot shake the need for scientific evidence to continue to push their modalities into the mainstream. The “your science can’t test my woo” defense only goes so far. So they have put themselves into a pickle – they demanded funding for CAM research, but now have to deal with the fact that the research is largely negative. CAM proponents are mostly not interested in finding what really works, and abandoning what does not work (I have an open challenge to anyone who can point to a CAM modality that was largely abandoned, rejected, or condemned by CAM proponents because of evidence of lack of efficacy). They are interested in using science to support and promote what they already believe works (a cardinal feature of pseudoscience).

And so they have entered the next phase of CAM research – the post-RCT (randomized controlled trial) phase. They have discovered the “pragmatic” study. You have to give it to them for their cleverness. A pragmatic study is meant to be a comparison of treatment options in real-world conditions. It studies treatments that already have proven efficacy from RCTs to see how they work, and how they compare, when applied in the less controlled environment of real-world practice. Pragmatic studies are useful for addressing the weaknesses of RCTs, mainly their somewhat contrived conditions (having strict inclusion criteria, for example).

But pragmatic studies are not efficacy trials themselves. They cannot be used to determine if a treatment works, because they do not control for variables and they are not blinded, so they are susceptible to placebo and non-specific effects. It is an abuse of the pragmatic study design to test a treatment that is not proven or to make efficacy claims based upon them. That has not stopped CAM proponents from doing just that.

In the news recently is just the latest example. Let me tell you the results of the study before I tell you what the study is of – just look at the data (I replaced the name of the treatment in the tables with just the word “treatment”):

This is what you need to know about the trial. There were two groups, treatment and control. Subjects were those with frequent doctor visits for symptoms that have not been diagnosed. While they were randomized, they were completely unblinded – everyone involved with the subjects knew who was getting treated and who wasn’t. At 26 weeks the control group was crossed over to receive treatment – so the difference up to 26 weeks is most important.

On two of the measures, quality of life and general practitioner consultation rates, there was no difference. In the other two measures there was a slight improvement in the treatment group, barely statistically significant. If this were an efficacy trial, this data would be unconvincing. What can fairly be concluded from this trial is that the treatment has no to minimal effect, and the tiny and inconsistent effect seen cannot be separated from placebo or non-specific effects. Further, it shows how anemic even placebo effects are for this treatment in this patient population. As a pragmatic trial, it’s essentially negative. As an efficacy trial, it’s worthless.

The study author’s, however, concluded that their treatment was effective and recommended it be incorporated into general practice.

The treatment in question is five-element acupuncture – acupuncture designed to balance the five elements of fire, water, metal, earth, and wood. This is the equivalent of balancing the four humors – in other words, it is pre-scientific superstitious nonsense. The study authors are all proponents. What is most amazing is how they got their paper, complete with unsupported conclusions, past peer-review.

The study authors are using the “part of this nutritious breakfast” con. Even as a child I understood that the sugary cereal, or whatever the commercial was trying to sell to me, was only “part of this nutritious breakfast” because the rest of the breakfast was nutritious all by itself. A doughnut would be “part of this nutritious breakfast.” So the authors of this study include five-point acupuncture with an hour of kind attention from a practitioner along with lifestyle advice and encouragement. They admit that they cannot separate out the variables here. Then they conclude that acupuncture is “part of this healthy regimen.” There is every reason to believe that it is an irrelevant part – as irrelevant as the doughnut is to the nutrition of a complete breakfast.

Conclusion

The pragmatic study bait and switch is here – it is now a firm part of the CAM strategy for promoting implausible therapies that don’t work. Editors and peer-reviewers need to be more aware of this scam so they don’t fall for it and inadvertently promote it, as they did in this case. Further, the results of this trial are not impressive even at face value – it’s basically negative, so it’s a double swindle.

All of this has not stopped the headlines from declaring that “acupuncture works” – which appears to be the only goal of such research.

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