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Archive for Clinical Trials

Healing Touch and Coronary Bypass

A study published in Alternative Therapies in Health and Medicine is being cited as evidence for the efficacy of healing touch (HT). It enrolled 237 subjects who were scheduled for coronary bypass, randomized them to receive HT, a visitor, or no treatment; and found that HT was associated with a greater decrease in anxiety and shorter hospital stays.

This study is a good example of what I have called “Tooth Fairy Science.” You can study how much money the Tooth Fairy leaves in different situations (first vs. last tooth, age of child, tooth in baggie vs. tooth wrapped in Kleenex, etc.), and your results can be replicable and statistically significant, and you can think you have learned something about the Tooth Fairy; but your results don’t mean what you think they do because you didn’t stop to find out whether the Tooth Fairy was real or whether some more mundane explanation (parents) might account for the phenomenon. (more…)

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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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Screening Tests – Cumulative Incidence of False Positives

It’s easy to think of medical tests as black and white. If the test is positive, you have the disease; if it’s negative, you don’t. Even good clinicians sometimes fall into that trap. Based on the pre-test probability of the disease, a positive test result only increases the probability by a variable amount. An example: if the probability that a patient has a pulmonary embolus (based on symptoms and physical findings) is 10% and you do a D-dimer test, a positive result raises the probability of PE to 17% and a negative result lowers it to 0.2%.

Even something as simple as a throat culture for strep throat can be misleading. It’s possible to have a positive culture because you happen to be an asymptomatic strep carrier, while your current symptoms of fever and sore throat are actually due to a virus. Not to mention all the things that might have gone wrong in the lab: a mix-up of specimens, contamination, inaccurate recording…

Mammography is widely used to screen for breast cancer. Most patients and even some doctors think that if you have a positive mammogram you almost certainly have breast cancer. Not true. A positive result actually means the patient has about a 10% chance of cancer. 9 out of 10 positives are false positives.

But women don’t just get one mammogram. They get them every year or two. After 3 mammograms, 18% of women will have had a false positive. After ten exams, the rate rises to 49.1%. In a study of 2400 women who had an average of 4 mammograms over a 10 year period, the false positive tests led to 870 outpatient appointments, 539 diagnostic mammograms, 186 ultrasound examinations, 188 biopsies, and 1 hospitalization. There are also concerns about changes in behavior and psychological wellbeing following false positives.

Until recently, no one had looked at the cumulative incidence of false positives from other cancer screening tests. A new study in the Annals of Family Medicine has done just that. (more…)

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Tactless About TACT: Critiques Without Substance Should Be Abandoned

In May 2008, the article “Why the NIH Trial to Assess Chelation Therapy (TACT) Should Be Abandoned” was published online in the Medscape Journal of Medicine. The authors included two of our own SBM bloggers, Kimball Atwood and Wallace Sampson, along with Elizabeth Woeckner and Robert Baratz. It showed that the existing evidence on treating heart disease with IV chelation did not justify further study, and that the TACT trial was questionable on several ethical points. Their ethical concerns were taken seriously enough that enrollment in the trial was put on hold pending an investigation. It has now been re-opened after a few band-aids were applied to the ethical concerns. The scientific concerns were never addressed.

I have seen many critiques of the Atwood study, and not a single one has offered any cogent criticism of its factual content or reasoning. Most of them could have been written by someone who had not bothered to read beyond the title. Their arguments can be boiled down to a few puerile points that can be further simplified to:

(1) I believe the testimonial evidence that chelation works.
(2) Atwood and his co-authors are bad guys.

Now Beth Clay has chimed in with an article entitled “Study of Chelation Therapy Should Not Be Abandoned.” I found it truly painful to read, but even the worst has some value as a bad example. Clay’s article could be used for a game of “Count the Errors.” I will point out some of them below. (more…)

Posted in: Clinical Trials, Politics and Regulation, Science and Medicine

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How do scientists become cranks and doctors quacks?

As a physician and scientists who’s dedicated his life to the application of science to the development of better medical treatments, I’ve often wondered how formerly admired scientists and physicians fall into pseudoscience or even generate into out-and-out cranks. Examples are numerous and depressing to contemplate. For example, there’s Linus Pauling, a highly respected chemist and Nobel Laureate, who in his later years became convinced that high dose vitamin C could cure cancer. Indeed, Pauling’s belief that high dose vitamin C could cure the common cold and cancer fueled the development of a whole new form of quackery known as “orthomolecular medicine,” whose entire philosophy seems to be based on the concept that if some vitamins are good more must be better. In essence, “orthomolecular medicine” is a parody of nutritional science; indeed, its advocates take credit for how some strains of “complementary and alternative medicine” (CAM) so frequently advocate the ingestion of huge amounts of dietary “supplements.” I could even go farther and say that orthomolecular medicine is clearly a major part of the “intellectual” (and I do use that term loosely) underpinning of the various biomedical treatments for autism that Jenny McCarthy and Generation Rescue advcoate.

There are other examples as well, all just as depressing to contemplate. For example, consider Peter Duesberg, a brilliant virologist who in the 1980s was widely believed to be on track for a Nobel Prize; that is, until he became fixated on the idea that HIV does not cause AIDS. True, lately he’s been trying to resurrect his scientific reputation with his interesting and possibly even promising chromosomal aneuploidy hypothesis of cancer, but, alas, true to form he’s been doing it by acting like a crank. Specifically, he sees his hypothesis as The One True Cause of Cancer and disparages conventional thinking as having been so very, very wrong all these years (with his being, of course, so very, very brilliant that he saw what no one else could see). Then there are people like Dr. Lorraine Day, who was a respected academic orthopedic surgeon in the 1980s. In the late 1980s, she started to flirt with AIDS pseudoscience through a scare campaign about catching AIDS from aerosolized blood. Of course, given the mystery and fear over HIV in the early years of the epidemic, such a fear, although overblown, was not so far out of the mainstream as to be worthy of the appellation crank. However, after being diagnosed with breast cancer, unfortunately Dr. Day rapidly degenerated into a purveyor of rank pseudoscience, as well as a New World Order conspiracy theorist, religious loon, and Holocaust denier. And let’s not forget Mark Geier, who, although not a distinguished scientist, did, before his conversion to antivaccinationism, apparently do a real fellowship at the NIH and appeared to be on track to a respectable, maybe even impressive, career as an academic physician. Now he’s doing “research” in his basement, injecting autistic children with a powerful anti-sex hormone drug and abusing epidemiology. There are innumerable other examples.
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Posted in: Clinical Trials, Health Fraud, Science and Medicine

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Homeocracy IV

In the three prior posts of this series I tried to analyze some of the defects in the randomized clinical rials (RCTs) of homeopathic remedies for childhood diarrhea. The first entry showed that the first two RCTs’ (done in Nicaragua) methods could not produce a meaningful result because of the way the RCTs were set up (methods.) The second entry showed that the results obtained in the first two trials were meaningless clinically even if assumed to have resulted from more legitimate methods. The same applied to the third trial in Nepal, analyzed in the third entry.

This entry  will suggest that the authors’ fourth paper (Jacobs J, Jonas WB, Jimenez-Perez M, Crothers D. Homeopathy for childhood diarrhea: combined results and metaanalysis from three randomized, controlled clinical trials.  Pediat Inf Dis J, 2005;22:229-234.)- a meta-analysis (MA) of the data from the three RCTs resulted in conclusions equally as meaningless as those of the three trials.

The MA authors – several of the same workers from the three RCTs – begin by agreeing that the data from the RCTs, taken individually, were of borderline significance:

In our previous three studies, we evaluated the use of individualized homeopathic treatment of childhood diarrhea … The results of the two larger studies (n = 81, n = 116) were just at or near level of statistical significance. Because all three studies followed the same basic study design , […] we analyzed the combined data from these three studies to obtain greater statistical power.  In addition we conducted a meta-analysis of effect-size difference […] to look for consistency of effects.

MAs and systematic reviews (SRs) are the two consensus methods for summarizing data from multiple individual studies. The inclusion and search methods of RCTs for SRs and MAs are similar, but the objectives of the two are a bit different, as are the forms of the reports.  In SRs, the results are summarized  in more in narrative form, whereas in MAs the data are treated mathematically and the results are defined in statistical terms.  Thus authors of SRs are freer to speculate on the degree of confidence that a method is effective based on what is shown by the numbers of positive and negative RCTs collected.  Authors of MAs usually limit their comments to what the mathematical formulation of the summarized data show.
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Posted in: Clinical Trials, Energy Medicine, General, Homeopathy, Science and Medicine

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Chemical castration for autism: After three years, the mainstream media finally notices

We’ve written a lot about anti-vaccine zealotry on this blog, as Steve and I take a particular interest in this particular form of dangerous pseudoscience for a number of reasons. One reason, of course, is that the activities of antivaccine groups like Generation Rescue and its spokesmodel since 2007 (Jenny McCarthy, a frequent topic on this blog) have started to frighten parents about vaccines enough that vaccination rates are falling well below that required for herd immunity in some parts of the country. Indeed, McCarthy, at the behest of her handlers in Generation Rescue, serves up a regular “toxic” brew of misinformation and nonsense about vaccines, most recently in a video that was the subject of a post by Val Jones about her unbelievably pseudoscience-laden blather. Truly, it has to be seen to be believed. Meanwhile, Generation Rescue has sent McCarthy on a media propaganda tour for her latest antivaccine pro-quackery book and set up a misinformation-laden propaganda site called Fourteen Studies (blogged about by Steve Novella, Mark Crislip, and, of course, yours truly) in which they attack well-designed studies that have failed to confirm their pet idea that somehow, some way, vaccines must be the cause of autism. And, when their pseudoscience is criticized, the antivaccine movement has a tendency to launch vicious ad hominem attacks, as they recently did against Steve Novella and have done multiple times in the past against me.

However, there is one other consequence of the antivaccine movement, however, and it is at least as important as the public health implications of the potential dimunition of herd immunity caused by the fear mongering of groups like Generation Rescue. That consequence is the cottage industry of “biomedical” treatments to which desperate parents subject their children. Gluten-free diets, chelation therapy (which has caused deaths), hyperbaric oxygen chambers (a recent story described a child getting severely burned when one of these caught fire), autistic children have been subjected to it all. But of all the biomedical woo to which autistic children have been subjected, one form of woo stands out as being particularly heinous. Indeed, I agree with our fearless leader Steve in characterizing it as an “atrocity.”

I’m referring to Mark and David Geier’s favored “treatment” for autistic children, namely a drug called Lupron.
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Posted in: Clinical Trials, Health Fraud, Medical Ethics, Neuroscience/Mental Health, Politics and Regulation, Public Health, Science and the Media, Vaccines

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Homeopathy and Sepsis

ResearchBlogging.orgIt had once been suggested in the comments section of the blog that homeopathy is useful in the treatment of diseases that are not self limited. Homeopathy is effective therapy for diseases that do not get better on their own, that homeopathy has a real effect on real diseases.

One example given was for the treatment of sepsis.

“Frass M, Linkesch, M, Banjya, S, et al. Adjunctive homeopathic treatment in patients with severe sepsis: a randomized, double-blind, placebo-controlled trial in an intensive care unit. Homeopathy 2005:94;75–80. At a University of Vienna hospital, 70 patients with severe sepsis were enrolled in a randomized double-blind, placebo-controlled clinical trial, measuring survival rates at 30 days and at 180 days. Those patients given a homeopathic medicine were prescribed it in the 200C potency only (in 12 hour intervals during their hospital stay). The survival rate at day 30 was 81.8% for homeopathic patients and 67.7% for those given a placebo. At day 180, 75.8% of homeopathic patients survived and only 50.0% of the placebo patients survived (p=0.043). One patient was saved for every four who were treated.”

I am, as I have mentioned before, but I mention again for those who might be new to the blog, an Infectious Disease physician. My job is to diagnosis and treat infectious diseases and sepsis is up there at the top of the list of diseases I take of. Sepsis butters my bread, and I consider myself knowledgeable about sepsis.

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Posted in: Clinical Trials, Homeopathy

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Homeocracy 3

The previous post of this series analyzed the results of the 1994 Pediatrics paper purporting to show a statistically significant effect of homeopathic preparations on acute childhood diarrhea in a population in Nicaragua. That clinical trial followed a pilot study that also had shown a small but statistically significant effect of homeopathic remedies.

A moment here for explanation as to why I am going through these old studies. Reports like the four or five in this series made headlines. They are also so well cloaked in manipulated data and overdrawn conclusions that press and even academicians accept their conclusions – and even overdraw more. This is still going on.

Over the past thirty years some of us informally and gradually developed semi-systematic ways of analyzing these increasingly scientific-appearing claims of sectarians (sCAMmers.) Errors, inconsistencies and falsifications we recognize now were not so obvious decades ago. SCAMmers developed imaginatively new methods as their fields progressed. We in the science-based or knowledge based medicine field have been trailing along, detecting their tricks and twists as they developed, and like street sweepers behind horses, picking up their excrement (metaphor to force attention.)  Yesterday’s lucid post on the latest acupuncture study by Steve Novella exemplifies this expertise (no offense intended.)
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Posted in: Clinical Trials, Homeopathy, Medical Academia, Science and Medicine

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Re-evaluating Home Monitoring for Diabetes: Science-Based Medicine at Work

There is no question that patients on insulin benefit from home monitoring. They need to adjust their insulin dose based on their blood glucose readings to avoid ketoacidosis or insulin shock. But what about patients with non-insulin dependent diabetes, those who are being treated with diet and lifestyle changes or oral medication? Do they benefit from home monitoring? Does it improve their blood glucose levels? Does it make them feel more in control of their disease?

This has been an area of considerable controversy. Various studies have given conflicting results. Those studies have been criticized for various flaws: some were retrospective, non-randomized, not designed to rule out confounding factors, high drop-out rate, subjects already had well-controlled diabetes, etc. A systematic review showed no benefit from monitoring. So a new prospective, randomized, controlled, community based study was designed to help resolve the conflict. (more…)

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