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Functional Medicine (FM) What Is It?

Functional Medicine – What is it?

After extensive searching and examination, my answer is still – only the originators of “FM” know. Or, at least one must assume they know, because so far as I can see, I certainly see nothing that distinguishes “FM” from other descriptions of sectarian and “Complementary/Alternative Medicine” practices. A difference may lie in the advocates’ assumptions to have found some “imbalance” of body chemistry or physiology before applying one or more unproved methods or substances. From what I could determine, the “imbalance” or dysfunction is usually either imaginary or at least presumptive. And the general principles are so poorly defined as to allow practioners vast leeway to apply a host of unproven methods.

I figured there would be several ways to find out. One would be to read FM’s material – mainly what “they” placed on the Internet. Another would be to enter the system and find out as a patient or as a prospective practitioner what it is that “FM” claims to be. The third would be to listen to a practitioner or advocate on tape, disk, radio, etc.
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Posted in: Basic Science, Herbs & Supplements, Nutrition, Science and Medicine

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Does popularity lead to unreliability in scientific research?

One of the major themes here on the Science-Based Medicine (SBM) blog has been about one major shortcoming of the more commonly used evidence-based medicine paradigm (EBM) that has been in ascendance as the preferred method of evaluating clinical evidence. Specifically, as Kim Atwood (1, 2, 3, 4, 5, 6, 7, 8) has pointed out before, EBM values clinical studies above all else and devalues plausibility based on well-established basic science as one of the “lower” forms of evidence. While this sounds quite reasonable on the surface (after all, what we as physicians really want to know is whether a treatment works better than a placebo or not), it ignores one very important problem with clinical trials, namely that prior scientific probability matters. Indeed, four years ago, John Ioannidis made a bit of a splash with a paper published in JAMA entitled Contradicted and Initially Stronger Effects in Highly Cited Clinical Research and, more provocatively in PLoS Medicine, Why Most Published Research Findings Are Wrong. In his study, he examined a panel of highly cited clinical trials and determined that the results of many of them were not replicated and validated in subsequent studies. His conclusion was that a significant proportion, perhaps most, of the results of clinical trials turn out not to be true after further replication and that the likelihood of such incorrect results increases with increasing improbability of the hypothesis being tested.

Not surprisingly, CAM advocates piled onto these studies as “evidence” that clinical research is hopelessly flawed and biased, but that is not the correct interpretation. Basically, as Steve Novella and, especially, Alex Tabarrok pointed out, prior probability is critical. What Ioannidis’ research shows is that clinical trials examining highly improbable hypotheses are far more likely to produce false positive results than clinical trials examining hypotheses with a stronger basis in science. Of course, estimating prior probability can be tricky based on science. After all, if we could tell beforehand which modalities would work and which didn’t we wouldn’t need to do clinical trials, but there are modalities for which we can estimate the prior probability as being very close to zero. Not surprisingly (at least to readers of this blog), these modalities tend to be “alternative medicine” modalities. Indeed, the purest test of this phenomenon is homeopathy, which is nothing more than pure placebo, mainly because it is water. Of course, another principle that applies to clinical trials is that smaller, more preliminary studies often yield seemingly positive results that fail to hold up with repetition in larger, more rigorously designed randomized, double-blind clinical trials.

Last week, a paper was published in PLoS ONE Thomas by Thomas Pfeiffer at Harvard University and Robert Hoffmann at MIT that brings up another factor that may affect the reliability of research. Oddly enough, it is somewhat counterintuitive. Specifically, Pfeiffer and Hoffmann’s study was entitled Large-Scale Assessment of the Effect of Popularity on the Reliability of Research. In other words, the hypothesis being tested is whether the reliability of findings published in the scientific literature decreases with the popularity of a research field. Although this phenomenon is hypothesized based on theoretical reasoning, Pfeiffer and Hoffmann claim to present the first empirical evidence to support this hypothesis.
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Posted in: Basic Science, Clinical Trials, Science and Medicine

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Could Francis Collins’ Faith Create Conflicts For His Potential Directorship of NIH?

Francis Collins, M.D., Ph.D., is probably best known for his leadership of the Human Genome Project, though his discoveries of the Cystic Fibrosis, Huntington’s, and Neurofibromatosis genes are also extraordinary accomplishments. Dr. Collins is a world-renowned scientist and geneticist, and also a committed Christian. In his recent best-selling book, The Language Of God, Dr. Collins attempts to harmonize his commitment to both science and religion.

Some critics (such as Richard Dawkins) have expressed reservations about Dr. Collins’ faith, wondering if it might cloud his scientific judgment. Since Collins is rumored to be the most likely candidate for directorship of the NIH, and because I wanted to know if Dawkins et al. had any reason for concern, I decided to read The Language Of God.

First of all, Christians are a rather heterogeneous group – with a range of viewpoints on evolution, science, and the interpretation of Biblical texts. On one extreme there are Christians (often referred to as “young earth creationists” or simply “creationists”) who believe in an absolutely literal interpretation of the Genesis story, and see evolution as antithetical to true faith. Dr. Collins suggests that as many as 45% of Christians may actually be in this camp.
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Posted in: Basic Science, Book & movie reviews, Evolution

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Cancer research: Going for the bunt versus swinging for the fences

A couple of weeks ago, our resident skeptical medical student Tim Kreider wrote an excellent article about an op-ed in NEWSWEEK by science correspondent Sharon Begley, in which he pointed out many misconceptions she had regarding basic science versus translational research, journal impact factors, and how journals actually determine what they will publish. Basically, her thesis rested on little more than a few anecdotes by scientists who didn’t get funded or published in journals with as high an impact factor as they thought they deserved, with no data, science, or statistics to tell us whether the scientists featured in her article were in fact representative of the general situation. Begley’s article caught flak from others, including Mike the Mad Biologist and our very own Steve Novella. Naturally, as the resident cancer surgeon and researcher, I had thought of weighing in, but other issues interested me more at the time.

In retrospect, I rather regret it, given that this issue crops up time and time again. In essence, it’s a variant of the lament that pops up in the press periodically, when science journalists look at survival rates for various cancers and ask why, after nearly 40 years, we haven’t yet won the war on cancer. Because of his youth, Tim probably hasn’t seen this issue crop up before, but, trust me, every couple of years or so it does. Begley’s article and the NYT article strike me as simply “Why are we losing the war on cancer?” 2009 edition.

Now the New York Times has given me an excuse both to revisit Begley’s article and discuss yesterday’s front page article in the NYT Grant System Leads Cancer Researchers to Play It Safe. Basically, they are variants of the same complaints I’ve heard time and time again. Now, don’t get me wrong. By no means am I saying that the current system that the NIH uses to determine which scientists get funded. Those who complain that the system is often too conservative have a point. The problem, all too often, however, is that the proposals for how to fix the problem are usually either never spelled out or rest on dubious assumptions about the nature of cancer research themselves.
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Posted in: Basic Science, Cancer, Medical Academia, Politics and Regulation

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Applying evolutionary principles to cancer treatment

ResearchBlogging.orgEDITOR’S NOTE: Unfortunately, this weekend, I was forced to get my slides together for the upcoming SBM Conference, plus editing a manuscript for resubmission, plus working on a manuscript that I should have submitted six months ago, plus reading over some grants, plus…well, you get the idea. What this means is that, alas, I didn’t have any time to prepare one of the new, long posts that you’ve come to love (or hate). Fortunately, there are a lot of other things I’ve written out there that can be rapidly adapted to SBM. For instance, what I am about to present now. Since I wrote this, I’ve thought of a couple of things that I should have said the first time (and was kicking myself for not having done so); so publishing an updated version here allows me to rectify those omissions.

A couple of weeks ago, there was a lot of hype about a study that hadn’t been released yet. Indeed, there was a story in Wired entitled To Survive Cancer, Live With It and an editorial by the study’s lead author in Nature entitled A change in strategy in the war on cancer. Not bad for a study that hadn’t been released yet. Intrepid medical and science blogger that I am, I waited until the actual study was published a week ago the June 1 episode of Cancer Research. It’s a clever study, but the hype over it was a bit overblown. For example:

For all the weapons deployed in the war on cancer, from chemicals to radiation to nanotechnology, the underlying strategy has remained the same: Detect and destroy, with no compromise given to the killer. But Robert Gatenby wants to strike a peace.

A mathematical oncologist at the Moffitt Cancer Center, Gatenby is part of a new generation of researchers who conceive of cancer as a dynamic, evolutionary system. According to his models, trying to wipe cancer out altogether actually makes it stronger by helping drug-resistant cells flourish. Rather than fighting cancer by trying to eradicate its every last cell, he suggests doctors might fare better by intentionally keeping tumors in a long-term stalemate.

Maybe I’m being a bit picky, but what annoys me about the news reports on this study is that the concept of turning cancer into a manageable chronic disease like diabetes or hypertension is not by any means a new idea. Remember, one of my major research interests is the inhibition of tumor angiogenesis. Consequently, I know that the late, great Judah Folkman first proposed the concept of using antiangiogenic therapy to turn cancer into a chronic disease at least as early as the mid-1990′s. The only difference is the strategy that he proposed. The idea had also been floating around for quite a while before that, although I honestly do not know who first came up with it.

But let’s see what Dr. Gatenby proposes. What makes it interesting is that his study actually looks at how scientists have applied evolutionary principles to cancer until recently, argues that we’ve been doing it wrong. He then proposes a way to use the evolutionary dynamics of applied ecology. He may well be on to something. First, here’s the problem:
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Posted in: Basic Science, Cancer, Science and Medicine

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Threats to science-based medicine: Big pharma pays a publisher to produce a fake journal

It’s times like these when I’m happy that I haven’t published in too many Elsevier Journals during the course of my career. Actually, I’m not sure if I’ve ever published in an Elsevier journal, although I have reviewed manuscripts for them. In any case, I say that because on Thursday, it was revealed that pharmaceutical company Merck, Sharp & Dohme paid Elsevier to produce a fake medical journal that, to any superficial examination, looked like a real medical journal but was in reality nothing more than advertising for Merck. As reported by The Scientist:

Merck paid an undisclosed sum to Elsevier to produce several volumes of a publication that had the look of a peer-reviewed medical journal, but contained only reprinted or summarized articles–most of which presented data favorable to Merck products–that appeared to act solely as marketing tools with no disclosure of company sponsorship.

“I’ve seen no shortage of creativity emanating from the marketing departments of drug companies,” Peter Lurie, deputy director of the public health research group at the consumer advocacy nonprofit Public Citizen, said, after reviewing two issues of the publication obtained by The Scientist. “But even for someone as jaded as me, this is a new wrinkle.”

The Australasian Journal of Bone and Joint Medicine, which was published by Exerpta Medica, a division of scientific publishing juggernaut Elsevier, is not indexed in the MEDLINE database, and has no website (not even a defunct one). The Scientist obtained two issues of the journal: Volume 2, Issues 1 and 2, both dated 2003. The issues contained little in the way of advertisements apart from ads for Fosamax, a Merck drug for osteoporosis, and Vioxx. (Click here and here to view PDFs of the two issues.)

This is wrong on so many levels that it’s hard to know where to begin.
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Posted in: Basic Science, Clinical Trials, Medical Ethics, Science and the Media

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Mathematically modeling why quackery persists

ResearchBlogging.orgIt’s often puzzled me (and, I daresay, many other skeptics and boosters of science- and evidence-based medicine) why various forms of quackery and woo that have either about as close to zero prior probability as you can get and/or have failed to show evidence greater than placebo in clinical trials manage to retain so much traction among the public. Think homeopathy. Think reiki. The former is nothing more than sympathetic magic prettied up with science-y sounding terms, while the latter is nothing more than faith healing given a slant based on Eastern mysticism and religion instead of Christianity. Indeed, reiki was even inspired by stories of Jesus’ healing powers, complete with a trip into the wilderness for fasting and prayer, resulting in revelation. Or consider acupuncture, a modality that is seemingly more popular than ever, even invading the very sanctum sanctorum of the ivory towers of academic medicine, yet every study of which that is done under rigorous conditions with proper placebo controls shows it to be no more efficacious than a placebo. It’s easy enough to shake one’s head and chalk it up to irrationality, ignorance of science, or even religious faith, but I’ve always been dissatisfied with such glib explanations, even though admittedly I have myself used them on occasion.

That’s why a study released last week in PLoS One by Mark M. Tanaka, Jeremy R. Kendal, Kevin N. Laland out of the Evolution & Ecology Research Centre, School of Biotechnology & Biomolecular Sciences, University of New South Wales, the Department of Anthropology, University of Durham, and the School of Biology, University of St Andrews, Fife, respectively, entitled From Traditional Medicine to Witchcraft: Why Medical Treatments Are Not Always Efficacious. Besides loving the title, I also like the methodology, which in essence adapts the tools of modeling evolution and the spread of traits throughout a population and asks the question: Why do ineffective or even harmful (or, as the authors characterize them, “maladaptive”) treatments for various illnesses persist in populations? The results are surprising and counterintuitive, yet ring true. In essence, the authors conclude that the most efficacious self-treatments are not always the ones that spread and that even harmful treatments can spread. Both of these observations are entirely plausible based on the prevalence of usage of common woo and quackery, and what the authors have done, in essence, is to model mathematically why quackery persists.

Indeed, the authors set the stage:
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Posted in: Basic Science, Clinical Trials, Science and Medicine

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Homeocracy

Recent comments on homeopathy again resulted in references to the 1994 Pediatrics paper by Jacobs et al on use of homeopathic remedies for childhood diarrhrea.  The authors of that paper concluded from their blinded study that homeopathic remedies, tailored to the individual infants and children, were effective in reducing the number of diarrhea stools and thus in shortening the illness.  The paper has been widely referenced and reported to have proved  homeopathy efficacy, and the critiques have been argued by homeopaths as irrelevant, as has been done by Mr. Ullman.

In this short series I want to recount my experience with the report, its predecessor, and its two major sequellae, as well as its effect on systematic reviews of homeopathy.  I will begin with a description of the first two studies, concentrating on their methods. Then I will discuss the results of the 1994 Pediatrics report and the authors’ interpretation of the results. Then (I hope last) I will discuss the third paper which the authors claimed supported findings of the first two and the meta-analysis which combined data from all three. If you are imagining why this  series interests me, and imagining the worst, you are probably right. The sequence will  help to reveal how some of the information in “holistic” and “alternative” systems become published, and despite critiques and disproofs through a sort of systematic deconstructions, still develop wheels of their own and enter the fund of general knowledge seemingly forever. Or, at least for several decades, until a social belief switch is finally turned off.
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Posted in: Basic Science, Clinical Trials, Homeopathy

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NCCAM is a victim of its own history

Let me begin with a story. An assistant professor submits a reasonable application to NCCAM to investigate the potential metabolic and pharmacodynamic interactions of St. Johns wort with conventional chemotherapy. This was the year or year-and-a-half before SJW was known to have significant CYP3A4 inductive activity due primarily to its component, hyperforin. Said investigator used this preliminary data, not explicitly required for theNIH funding mechanism (called an R21), to question whether St. John’s wort used by depressed cancer patients might interfere with chemotherapy. The original proposal earned a priority score of 228 (as with golf, the lower the better: the best is 100, the worst is 500.)

The major reviewer critique was that the assistant professor, Your Humble Pharmacologist, lacked, at the time, significant natural products chemistry expertise. YHP was then doing his sabbatical in the NC Research Triangle area and wisely sought the support and expertise of the now-late Dr. Monroe Wall and surviving Dr. Manuskh Wani. These gentlemen discovered and solved the structures of taxol from Taxus brevifolia and camptothecin from Camptotheca acuminata. Taxol itself became a blockbuster drug for Bristol-Myers Squibb while camptothecin required water-soluble modifications to foster topotecan (Hycamptin) and irinotecan (Camptosar) that collectively saved or prolonged the lives of thousands of men and women subjected to breast, ovarian, lung, and gastrointestinal tumors. In 2003, they received the designation of an American Chemical Society National Historic Chemical Landmark for their three decades of work in this area. (Sadly, they received none of the profits from these drugs as their discoveries pre-dated the Bayh-Dole Act that allowed NIH funded researchers to share in the revenues of intellectual property emerging from their work.).

Being a savvy young investigator, I sought and enlisted the assistance and support of Dr. Wall and colleagues to provide my team with world-class, natural products expertise. Stunningly, the subsequent application was awared a score of 345 (*much worse than the original) with the criticism from reviewers that all Dr. Wall did was to lend a drug development aspect to an otherwise “herbal” applicaton.

To this day, I cannot fathom who better I could have sought for natural products expertise on this grant application.

Since then, three of my colleagues and I have submitted 13 applications to NCCAM, including an application for a comprehensive Botanical Research Center grant. All 13 received unfundable scores. Among these was a 279-page application for a NCCAM Botanical Research Center – reviewed but not discussed by the evaluation panel.

Nonetheless, I have taken the approach that if NCCAM were to continue its existence, I would try to be part of the solution.  I have accepted several invitations to review research and training grants for NCCAM and I am pleased to say that one or two projects that I ranked highly ended up being very productive, specifically in the area of natural products and traditional herbal medicines.  I also have some friends and valued colleagues who contribute to the scientific integrity of NCCAM. However, my collective experiences lead me to believe that they are voices quenched by the vast wilderness of the promotion and advocacy of “integrative medicine” and CAM.
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Posted in: Basic Science, Herbs & Supplements, Politics and Regulation, Science and Medicine

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Fakin’ it

Last week the Times of London revealed inside information from the General Medical Council (UK, responsible for physician licensing) of an ongoing investigation of Dr. Andrew Wakefield and from its own investigation. This revelation recalled other instances of fakery from reports of sectarian medicine (“CAM”) successes. The Medical Council information contained evidence that the data from the now famous Wakefield cases used to claim an association of the MMR vaccine with childhood autism and inflammatory bowel disease were misinterpreted, altered, and to some extent, faked. The report and history were reviewed by David Gorski last week. In eight of twelve cases, the dates of autism onset were “rearranged” to fit the needed time association, and many small bowel biopsies were “reinterpreted” to show inflammation.

The Wakefield claims were long suspected by reputable medical scientists and skeptics  as being erroneous or fraudulent.  Note: the Council hearings are still in progress, and the Times report is subject to legal complaint.  The original details can also be seen in the Times articles.

This expose’ adds to a growing list of reports with erroneous and faked information in medical journals used either for economic reward, undeserved fame, or to promote ideological claims for medical sects and cults. Although history of erroneous or false claims goes back hundreds of years, the altering or synthesizing of data passing the recently conceived peer review system is new,  illuminating defects in the journal peer review and editing system.

If journals were invented in the 18th century, and operated like journals of today, Mesmer’s demonstrations might have been published, and the Ben Franklin and Antoine Lavoisier and French Academy’s disproof might have been rejected. (Laughter here.) But journals continue to make major goofs in publishing implausible results despite the popularity of a famous specialty journal for that purpose.

Examples vary from acceptance of language manipulation – “alternative,” “healing,” “integrative,” etc., to the fakery of recent papers showing effects of prayer. The two famous studies of prayer in the cardiac care unit ranged from the unadmitted breaking of the blind in the Bird study (So Med J 1988; 81:826-826) to unadmitted imbalances of subject and control groups (Harris, Arch Int Med 1999;159:2273-2278.) And from those to the likely fakery of the distant prayer study of in vitro fertilization (Cha, Wirth, Lobo; J Reprod Med 2001:46;781-786) in which three separate prayer groups on two continents improved pregnancy rates in a group of women on a third continent by an implausible 100 percent. In all of these cases, the papers passed peer or editorial review despite the methodological defects that were picked up by us skeptics (K. Atwood, K.Courcey [an RN] B. Flamm, and others.)

Adding insult to the above, Annals of Internal Medicine published a systematic review of intercessory prayer (Astin et al, Ann Int Med, 2000;132: 903-910) containing not only the Bird and Harris studies counted as positive, but also the Targ study on brain tumors, found by reporter Po Bronson to have had its end point altered by the authors when the primary one showed no effect.
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Posted in: Basic Science, Clinical Trials, Faith Healing & Spirituality, General, Health Fraud, Medical Academia, Science and Medicine, Vaccines

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