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Archive for Clinical Trials

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…)

Posted in: Clinical Trials, Diagnostic tests & procedures

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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, 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…)

Posted in: Clinical Trials, 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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Homeocracy II

ResearchBlogging.orgThis is the second installment analysis of a three (and now 4) part series of articles on effects of homeopathy on childhood diarrhea. This second installment elaborates on our findings on data from the second clinical trial in Nicaragua. (1)

I should first explain the title. In order for homeopathy to operate as a base or operating system for medicine “for the 21st century,” the entire system of measurement and of course all physical laws would have to be changed. In analogous political terms, it would be similar to – but more massive a change than – changing a nation from a democracy to a completely different system such as a theocracy with completely different laws and behavior expectations. So…well, it was the best I could think up at the time.

Last time I recounted how the Jacobs ll trial setup was incoherent and unable to produce  results that could prove efficacy – unless the differences between treatment and controls were quite large,  greater than just barely significant. Most patients were treated differently from others, with multiple preparations (that were in reality the same: pill filler) at differing times during the illness, with each preparation selected according to symptoms that likely varied by the hour, and influenced by memory, well known to be faulty in medical studies.

In fact, given the lack of homogeneity in the trial diagnoses and treatments, outcomes should not have made sense at all.  Now I must admit that the thought did not occur to us at the time we undertook the review, nor during the review. If it had, our job would have been easier and the paper shorter.
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Posted in: Clinical Trials, Health Fraud, Homeopathy, Science and Medicine

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