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Persistence of Memory

I have steadily endeavored to keep my mind free so as to give up any hypothesis, however much beloved (and I cannot resist forming one on every subject), as soon as the facts are shown to be opposed to it.
— Charles R. Darwin

I’m getting old: 50, almost 51, and that’s over 350 in dog years. As a result of my advancing age there are things I do not get: tattoo’s, hip hop, visible undergarments, and those rectangular, square plastic glasses that seem so popular and look hideous on everyone. It gets harder to change.

I have been able to stick MD after my name for almost a quarter century now (175 dog years for those keeping track), and it does give a sense of perspective to the ebb and flow of medical therapies. Medicine for the last hundred years has been all about change. Dogma from last century is nonsense this century, all due to that damn science. It gets so tiresome having to learn something new.

Last month’s New England Journal of Medicine was another in a seemingly endless series of plus ça change, plus c’est la même chose moments.4 They published the results of the CORTICUS study, a trial that looked at Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration, was conducted by Irving Kirsch and colleagues, who reviewed clinical trials of six antidepressants (fluoxetine, venlafaxine, nefazodone, paroxetine, sertraline, and citalopram). They looked at all studies submitted to the FDA prior to approval, whether published or unpublished. They found:

Drug–placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients. The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication.

The press has largely reported this study as showing that “antidepressants don’t work” but the full story is more complex. This analysis certainly has important implications for how we should view the body of evidence for these antidepressants. It also illuminates the possible role of publication bias in the body of scientific literature – something that has far ranging implications for science-based medicine.

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Posted in: Clinical Trials, Neuroscience/Mental Health, Pharmaceuticals, Science and Medicine

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The Hannah Poling case and the rebranding of autism by antivaccinationists as a mitochondrial disorder

Regular readers of this blog may have noticed that I seem to have taken on the role of the primary vaccine blogger of this little group of bloggers trying desperately to hold the forces of pseudoscience and magical thinking at bay in the face of powerful forces trying to “integrate” prescientific belief systems with science- and evidence-based medicine, a process that would be unthinkable in just about any other field of applied science, such as aeronautics or the physics used in engineering, just as creationists try to “integrate” religion with biology. Although I do have a strong interest in the antivaccination movement in general and the claim that vaccines, or the mercury in the thimerosal preservatives that was in many childhood vaccines in the U.S. until late 2001 or early 2002 (when they were taken out) are a major cause or contributor to autism, such had not been my intention. When I started here on SBM, I had intended to be a lot more diverse. Indeed, I had even had another topic entirely in mind for this week’s post, but, as happens far too often, news events have overtaken me in the form of a story that was widely reported at the end of last week. It was all over the media on Thursday evening and Friday, showing up on CNN, Larry King Live, the New York Times, and NPR. It happens to be the story of a girl from Georgia named Hannah Poling whose case before the Vaccine Injury Compensation Program (VICP), which had originally part of a much larger proceeding known as the Autism Omnibus in which nearly 5,000 parents are petitioning the VICP for compensation based on the claim that their children’s autism were caused by vaccines, was settled by the government. This settlement was based on the observation that Poling had a rare genetic mitochondrial disease that may have been exacerbated by a series of vaccines that she had, after which, among many other problems, Hannah regressed and developed some autism-like symptoms and then months later a seizure disorder. Instantly, it was being trumpeted all over the Internet, blogosphere, and media that the government had “admitted” that vaccines cause autism. One particularly excitable antivaccinationist named Kent Heckenlively (whom we’ve met before), even went so far as to foreshadow the propaganda blitz that was to come as he wrote on the antivaccine blog Age of Autism a full week before this news blitz began:

It’s official.  The sky has fallen.  The fat lady has sung.  Pigs are flying.

[...]

In a settlement, the settling party tries to admit as little as possible.  It’s like what I imagine the settlement claim against Bill Clinton in the Paula Jones case must look like.  Nowhere in the document does he admit to dropping his pants in a hotel room and asking her to kiss it.  It likely says something along the lines of he concedes they were in a hotel room together, they were alone, and something happened which formed the basis of her law suit.

But we all know what happened there.  And we know what this settlement means.

The government just dropped its pants.

One thing this shows us is just how the blogosphere can be bubbling with information that lets one predict a public relations blitz like this. The mainstream press seemed to have been totally blindsided by this story, but if reporters had only been checking the right blogs, they would have known about it a full week before, if not longer. In any case, since Thursday, there has been a very well orchestrated public relations campaign to frame this settlement as the government “admitting” that vaccines cause autism. It’s not, as I will try to explain, but framing it that ways has thus far been a very effective PR strategy for antivaccinationists. In my nearly three years of following this topic, I thought that I had never seen anything like it before.

But I had.

This case is nothing more than a demonstration that everything old is new again and that, no matter what the science says, it’s always all about the vaccines, the claims of antivaccinationists otherwise notwithstanding, as I will now show. What we are seeing now, as we did a few years ago, is the rebranding of autism as a condition in order to serve the purposes of the antivaccination movement.
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Posted in: Public Health, Science and Medicine, Science and the Media, Vaccines

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RCT Plausibility Scale

RCT Plausibility Scale

After a few intro paragraphs, I want to present a scale of probability to estimate a value of a “prior” to plug into the formula for obtaining a Bayes Factor. The scale can help to estimate a value, but will still rely on an estimate, the non-quantitative element in Bayesian simulations. However, the checklist may at least provide some objective bases on which to hang a value, and that value would actually make a semi-quantitative statement of its own. Although that value would retain some subjective quality, it would at least be backed by known quantities and laws of nature.

Begging your patience again, I became aware of this problem in 1999 when asked to moderate an online (BioMednet.com) debate on “CAM” among 4 physicians. My role soon morphed into participant-debater when I could not get all to agree on what I thought was obvious common ground to proceed with the discussion – that 1) concepts that violate scientific laws do not have to be subjected to clinical trial (RCT) and that trial results had to be interpreted in light of previous knowledge; and 2) clinical trials could not constitute adequate evidence in the absence of plausibility because their results were too varied and inconsistent. The matter was p-recipitated by systematic reviews (SRs) showing efficacy of acupuncture in back pain. I was truly surprised when one of the participants (Dr. Edzard Ernst) assured me that indeed, RCTs were now the gold standard for efficacy. The debate went downhill from there.

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Posted in: Clinical Trials, Science and Medicine

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Science-Based Nutrition

One of the most successful propaganda campaigns within health care in the last few decades has been the re-branding of nutrition as “alternative” or out of the mainstream of scientific medicine. I have marveled at how successful this campaign has been, despite all the historical evidence to the contrary. I suppose this is partly a manifestation of the public’s short-term memory, but it also seems to reflect basic psychology.

Some History

There is evidence that most ancient cultures recognized the importance of diet in health. The Greeks recognized both the benefits of a varied diet and the negative health consequences of obesity, for example. But knowledge of nutrition was limited to these broad observations and was mixed with superstition and cultural beliefs.

The science of nutrition probably dates back to 1614 when scurvy (the disease that results from vitamin C deficiency) was first recognized as a dietary deficiency, one that could be cured by eating fresh fruits and vegetables. In 1747 Lind conducted what might be the first clinical trial – systematically comparing various diets for the treatment of scurvy and finding that citrus fruits were the key to treatment.

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Posted in: Herbs & Supplements, Nutrition, Public Health, Science and Medicine

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Bad scientific arguments in the service of animal rights activism

One of the greatest threats to the preclinical research necessary for science-based medicine today is animal rights activism. The magnitude of the problem came to the forefront again last week with the news that animal rights terrorists tried to enter the home of a researcher at the University of California Santa Cruz (UCSC) whose research uses mice to study breast cancer and neurologic disease while she and her husband were having a birthday party for one of their children and assaulted her husband, who had gone to the front of the house to confront them. Fortunately, the license plate number of the car fleeing the scene was reported to police, leading to a raid on a house by police and the confiscation of computers and other materials. This attack appeared to be the latest crescendo in an increasing campaign of harrassment and intimidation by animal rights “activists” that has also been observed in nearby Berkeley.

This sort of threat to researchers is not a problem just in Santa Cruz and the Bay area, but in particular has been a problem in southern California as well. Just earlier this week, the University of California Los Angeles announced that it was suing several animal rights groups and individuals suspected of attacks on researchers who use animals, including UCLA Primate Freedom Project, the Animal Liberation Front (ALF), and the Animal Liberation Brigade (ALB), as well as several individuals believed to affiliate with these groups. The inciting event for this action was the second attack on the home of Edythe London, Professor of Psychiatry and Bio-behavioral Sciences and of Molecular and Medical Pharmacology at the David Geffen School of Medicine at UCLA, in early February. Her research involves the use of primate models to study nicotine addiction. In this most recent attack, an attempt was made to set her house on fire. This came on the heels of a previous attack in October, in which animal rights activists flooded her house. Prior to that, animal rights terrorists had indeed succeeded in their aim of intimidating a scientist sufficiently that he gave up animal research after a fellow researcher was targeted with a Molotov cocktail meant for her home that was mistakenly placed on the porch of an elderly neighbor. Also, we in the U.S. often forget how much more radical animal rights extremists are in the U.K., where the campaign of intimidation takes the form of death threats, intimidation of personnel of companies that supply researchers, and even in one case digging up the grave of Gladys Hammond, whose family ran a farm that raised Guinea pigs for use in medical research, and stealing her remains.

Readers may make the argument that my introduction to this discussion is unfairly inflammatory, but I have my reasons for starting this way, and I think they are good ones. First, make no mistake, the aim of the most radical of these activists is nothing short of the cessation of the use of all animals in biomedical research. Second, sooner or later, someone will be hurt or killed. As a researcher who on occasion uses mouse models of cancer myself, I state up front that I could be on the firing line just as much as the UCSC researcher or others and am justifiably disturbed when I hear spokesperson for the ALF Dr. Jerry Vlasak, for example, repeatedly advocate violence against researchers who use animals. In this article, I am not going to discuss the moral issues involved in animal research. What I am going to discuss is the seemingly scientific arguments that some opponents of animal research and animal rights activists like to invoke, arguments increasingly used in addition to the moral arguments that extremists use to justify their actions. If the arguments of opponents of animal rights research were indeed good science, then their appropriation by extremists would not allow me to do much other than bemoan the misuse of valid science as a justification for extremism. Unfortunately, such is not the case, and the bad scientific arguments used by opponents of animal research are often piled onto the extreme moral arguments that fuel actions such as those earlier this week at UCSC. Consequently, given the events of the last month or so, I thought I would take this opportunity to look at some of the common scientific indictments of animal research by its opponents.
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Posted in: Basic Science, Clinical Trials, Politics and Regulation, Science and Medicine

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Prior Probability: the Dirty Little Secret of “Evidence-Based Alternative Medicine”—Continued Again

After the previous posting on the Bayesian approach to clinical trial data, several new comments made it clear to me that more needed to be said. This posting addresses those comments and adds a few more observations regarding the unfortunate consequences of EBM’s neglect of prior probability as it applies to “complementary and alternative medicine” (“CAM”).†

The “Galileo Gambit” and the Statistics Gambit

Reader durvit wrote:

A very interesting example, for a number of people, might be estimating the prior probability for Marshall and Warren’s early work on Helicobacter pylori and its impact on gastroduodenal management. I frequently have Marshall quoted to me as a variation on the Galileo gambit, so establishing whether he and Warren would have been helped or hindered by Bayesian techniques would be useful.

This suggestion raises a couple of issues. First, the “Galileo gambit” regarding Marshall and Warren’s discovery is a straw man (as durvit seems to have surmised). (more…)

Posted in: Homeopathy, Medical Academia, Medical Ethics, Politics and Regulation, Science and Medicine

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Antiscience-Based Medicine in South Africa

South Africa’s Health Minister, Manto Tshabalala-Msimang, is fighting to protect the traditional healers of her country from having their methods tested scientifically. She warns that, “We cannot use Western models of protocols for research and development,” and that she does not want the incorporation of traditional healing to get “bogged down in clinical trials.” Her arguments are anti-scientific and represent a health tragedy for South Africa. However, such attitudes are not uncommon within the community of sectarian medicine and represent some of the common rhetoric used to disguise anti-scientific positions.

This is also not the first controversial statement made by South Africa’s health minister. In 2006 she advocated using garlic and beetroot to treat HIV infection, prompting outrage from South Africa’s academic community. In response to criticism about delays and funding cuts in providing anti-retroviral drugs to HIV sufferers in South Africa, the Health Minister said, “Garlic is absolutely critical, we need to do research on it. We cannot just ridicule it.” South Africa’s president, Thabo Mbeki, resisted calls for Ms. Tshabalala-Msimang’s resignation.

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Posted in: Politics and Regulation, Science and Medicine

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When the popularity of new surgical procedures outpaces science

ResearchBlogging.orgIn science- and evidence-based medicine, the evaluation of surgical procedures represents a unique challenge that is truly qualitatively different from the challenges in medical specialties. Perhaps the most daunting of these challenges is that it is often either ethically unacceptable or logistically impossible to do the gold-standard clinical trial, a double-blind, randomized placebo trial for an operation. After all, the “placebo” in a surgical trial involves patients to anaesthesia, making an incision or incisions like the ones used for the operation under study, and then not doing the operation. Clearly, even leaving the ethics aside, it’s impossible to blind the surgeons and operative team involved to which treatment, real surgery or placebo, the patient is receiving without having a different surgeon do the surgery from the one overseeing the postoperative care of the patient, with the operative surgeon barred from communicating to the postoperative surgeon what happened in the operating room and from participating in the postoperative care of the patient upon whom he operated. This sort of restriction, besides being also highly dubious ethically speaking, goes against the grain of surgical culture, in which a surgeon is expected to provide the postoperative care for his patients almost as a matter of surgical honor. A final problem that complicates any surgical trial is that surgeons of differing technical operating skill will necessarily be involved, and surgical skill is indeed very important in determining outcome. Although there have been examples of double-blinded trials with sham surgery as placebo, for example, in injecting dopamine-producing cells into the brain to treat Parkinson’s disease, difficulties doing such studies tend to force us as surgeons in many cases either to rely on retrospective data, prospective non-randomized data, or, when we’re lucky, a prospective randomized (but not double-blinded) trial of one surgical procedure versus another.
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Posted in: Clinical Trials, Medical Ethics, Science and Medicine, Surgical Procedures

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Prior Probability: the Dirty Little Secret of “Evidence-Based Alternative Medicine”—Continued

This is an addendum to my previous entry on Bayesian statistics for clinical research.† After that posting, a few comments made it clear that I needed to add some words about estimating prior probabilities of therapeutic hypotheses. This is a huge topic that I will discuss briefly. In that, happily, I am abetted by my own ignorance. Thus I apologize in advance for simplistic or incomplete explanations. Also, when I mention misconceptions about either Bayesian or “frequentist” statistics, I am not doing so with particular readers in mind, even if certain comments may have triggered my thinking. I am quite willing to give readers credit for more insight into these issues than might be apparent from my own comments, which reflect common, initial difficulties in digesting the differences between the two inferential approaches. Those include my own difficulties, after years of assuming that the “frequentist” approach was both comprehensive and rational—while I had only a cursory understanding of it. That, I imagine, placed me well within two standard deviations of the mean level of statistical knowledge held by physicians in general.

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Posted in: Clinical Trials, Medical Academia, Science and Medicine

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