Archive for Basic Science

The Plausibility Problem

From the very outset, the founders of Science Based Medicine have have emphasized the importance of plausibility in the critical evaluation of scientific claims in medicine. What exactly does “plausibility” mean, and how should we apply it in science? My simple definition of plausibility would be “the likelihood that a premise is true.” The application in science is a little more complicated.

Consciously or unconsciously, we all consider plausibility in interpreting events in our lives. For example, if one of your coworkers showed up late for work and grumbled about a traffic jam, you would likely accept his story without question. If, instead, the same coworker attributed his tardiness to an alien abduction, you would not be so charitable. In each case, he has provided the same level of evidence: his anecdotal account. You are likely to accept one story and reject the other because of a perceived difference in the plausibility. The skeptic’s mantra “Extraordinary Claims Require Extraordinary Evidence” expresses this concept in a qualitative way.

Evidence-based medicine has traditionally ignored plausibility when interpreting the evidence for a medical intervention. Science-based medicine, as envisioned by the creators of this blog, includes plausibility when making these judgements.

Since experiment research employs rigorous controls, and statistical criteria, you might assume that plausibility is not an issue, however, this is not entirely true. An article written by John Ioannidis entitled “Why Most Published Research Findings Are False” is cited frequently as a reference for the impact of plausibility on the interpretation of research results. This article enumerates numerous factor leading to erroneous research conclusions. Most of them have been dealt with on this blog at one time or another. To me, the most eye-opening aspect of the paper was a quantitive approach to the influence of plausibility in interpreting positive research findings. I was never taught this approach in medical school, or in any other venue. When it comes to implausible hypotheses, the traditional P-value can be very misleading.

As good as Ioannidis’ article is, it is not easy reading for the statistically or mathematically challenged. What I attempt to do in this post is to demonstrate the importance of plausibility in graphic format, without a lot of complex math. If you can grasp the concepts in this post, you will have an understanding that many researchers, and consumers of research, lack.

Posted in: Basic Science, Clinical Trials

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Foolishness or Fraud? Bogus Science at NCCAM

Voodoo science is a sort of background noise, annoying but rarely rising to a level that seriously interferes with genuine scientific discourse… The more serious threat is to the public, which is not often in a position to judge which claims are real and which are voodoo. Those who are fortunate enough to have chosen science as a career have an obligation to inform the public about voodoo science.

– Robert L. Park, PhD, 20001

Imagine you are an ordinary person with limited knowledge of science and medicine, and you see this 2010 video on tai chi and qi gong by the National Center for Complementary and Alternative Medicine (NCCAM) — one of the agencies that make up the National Institutes of Health (NIH). I am certain that the solemn voice of the Director of NCCAM, Dr. Josephine Briggs, talking about “rigorous scientific research” and “accurate, authoritative information on complementary and alternative medicine,” will leave you with a strong sense of confidence in her message.

In addition, despite the fine-print and the disclaimer, the appearance of Dr. Briggs in the video could be broadly viewed as a sign of tacit endorsement. Often, the very fact that a treatment is associated with the government is already a de facto stamp of approval and a warranty of efficacy. For instance, the publication below by the California Department of Consumer Affairs states that the NIH formally “endorses” acupuncture, simply because in 1997, a panel of scientists assessed its use and effectiveness for a variety of conditions. Since 1997 the scientific review of acupuncture by NIH has become synonymous with its endorsement, despite the fact that as a federal research agency, the NIH does not endorse any product, service, or treatment.

In October 26, 2011, a few weeks after Steve Jobs’ death, Josephine Briggs decided to do something she has never done before: she put an explicit disclaimer on her blog:

When making treatment decisions, unproven “alternative medicine” approaches should not replace conventional medical care approaches known to be useful or helpful. Simply put, the evidence is not there (emphasis added).2

Three paragraphs down the page, she goes on — with a candor rarely seen from her — that given the recent news about Steve Jobs’ choices for cancer treatment, all health decisions “should be guided by the best available evidence.”

Posted in: Acupuncture, Basic Science, Health Fraud, Politics and Regulation, Public Health, Science and Medicine

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More “bait and switch” acupuncture studies

Acupuncture has been a frequent topic on this blog because, of all the “complementary and alternative medicine” (CAM) modalities out there, it’s arguably the one that most people accept as potentially having some validity. The rationale behind acupuncture is, as we have explained many times before, little different than the rationale behind any “energy healing” method (like reiki, for example) in that it claims to redirect the flow of “life energy” (the ever-invoked qi). The only difference is that acupuncturists claim to bring this therapeutic qi rearrangement about by sticking thin needles into the pathways in the body through which this qi is fantasized to flow. These pathways, called meridians, are just as much a fantasy as qi itself or the “universal source” that reiki masters claim to be able to channel through themselves and into believers. Contributing to the popularity of acupuncture is its mythology as having been routinely practiced for over two thousand years, a myth that was the creation of Chairman Mao, who elevated what was a marginal practice at the time to a modality that the state supported and promoted (1,2,3,4).

In addition, because acupuncture involves sticking actual metal objects into the skin rather than simply laying on hands or making magical gestures over the patient, it retains some credibility, even among doctors. It doesn’t matter that, reviewing the totality of the research, one finds that it doesn’t matter where you stick the needles or even if you stick the needles in the skin. The results are the same and indistinguishable from placebo. The inescapable conclusion is that acupuncture is placebo medicine with needles. Personally, I’d prefer my placebo medicine without needles, but that’s just me.

Yet, the studies keep rolling in, trying desperately to demonstrate that acupuncture works or assuming that acupuncture works . Two more popped up within the last couple of weeks, and one of them, if you read the press releases, sounds really convincing. As is frequently the case, for this latter study, there is less to it than meets the eye. I’ll start, however, with a study that is a followup to a study I blogged about a couple of years ago that I characterized as another overhyped acupuncture study misinterpreted. This one, thankfully, is not nearly as hyped as the study from two years ago—or as the second study I will discussed, but it is very instructive how the original misinterpreted story is leading to a classic CAM “bait and switch” applied to acupuncture.

Posted in: Acupuncture, Basic Science, Energy Medicine, Science and the Media

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The drug expiry date: A necessary safety measure, or yet another Big Pharma conspiracy?

Consider this scenario: You’re in good health and take no prescription drugs. You use the following remedies occasionally:

  • Excedrin for the rare migraine
  • Arnica 30CH for bumps and bruises
  • Echinacea capsules, when you feel a cold coming on

Today you look in your cupboard, and notice all three products expired last year. Would you still consider taking any of them? Why or why not?

Your answer is probably influenced by a number of factors, including perceptions of risk and benefit. I’ve encountered patients who believe that drugs are less active as they near the expiration date, and others who see expiry dates solely as marketing ploy from Big Pharma. Few understand how they’re calculated.

Over the past few months I’ve written several posts on different aspects of drug development and testing, including drug interactions, fillers and excipients in drug products, the equivalence testing of generic drugs, and the management of drug allergies. I’ve done this for two reasons. The first is to develop a SBM-oriented resource for common questions and misconceptions about the mechanics of modern medicines. The second, less obvious reason for these posts has been to illustrate the serious credibility gaps with CAM therapies. Largely because of a lax regulatory framework, the CAM industry has ballooned into a multi-billion dollar market without answering basic questions that should be asked of any supplement or drug, “alternative” or otherwise. What’s not well known to consumers, but is glaringly obvious to SBM advocates, is that CAM largely ignores issues of  pharmacology: understanding how a chemical substance, once consumed, behaves in the body. It’s critical to scientific medicine, but an unnecessary step for CAM, where there’s no need to determine if a product has a beneficial biological effect before selling it. Fundamental tests in medicine, like the identification and isolation of an active ingredient, or understanding dose-effect relationships, are simply ignored. As David Gorski and Mark Crislip have pointed out over the past week, we have a reality bias at SBM.  And this bias is equally jarring when it comes to considering expiry dates for products: real drugs, and also CAM.


Posted in: Basic Science, Herbs & Supplements, Pharmaceuticals

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Plausibility bias? You say that as though that were a bad thing!

On Friday, you might have noticed that Mark Crislip hinted at a foreshadowing of a blog post to come. This is that blog post. He knew it was coming because when I saw the article that inspired it, I sent an e-mail to my fellow bloggers marking out my territory like a dog peeing on every tree or protecting my newfound topic like a mother bear protecting her cubs. In other words, I was telling them all to back off. This article is mine.

Mine! Mine! Mine! I tell you!

My extreme territorial tendencies (even towards my friends and colleagues) notwithstanding on this issue aside, if you read Mark’s post (and if you didn’t go back and read it now—seriously, go now), you might also remember that he was discussing a “reality bias” in science-based medicine (SBM), a bias that we like to call prior plausibility. In brief, positive randomized clinical trials (RCTs) testing highly implausible treatments are far more likely to be false positives than RCTs testing more plausible treatments. That is the lesson that John Ioannidis has taught us and that I’ve written about multiple times before, as have other SBM bloggers, most prominently Kimball Atwood, although nearly all of us have chimed in at one time or another about this issue.

Apparently a homeopath disagrees and expressed his disagreement in an article published last week online in Medicine, Health Care, and Philosophy entitled Plausibility and evidence: the case of homeopathy. You’ll get an idea of what it is that affected us at SBM like the proverbial matador waving his cape in front of a bull by reading this brief passage from the abstract:

Prior disbelief in homeopathy is rooted in the perceived implausibility of any conceivable mechanism of action. Using the ‘crossword analogy’, we demonstrate that plausibility bias impedes assessment of the clinical evidence. Sweeping statements about the scientific impossibility of homeopathy are themselves unscientific: scientific statements must be precise and testable.

Scientific. You keep using that word. I do not think it means what you think it means. Of course, his being a homeopath is about as close to a guarantee as I can think of that a person doesn’t have the first clue what is and is not scientific. If he did, he wouldn’t be a homeopath. Still, this particular line of attack is often effective, whether yielded by a homeopath or other CAM apologist. After all, why not test these therapies in human beings and see if they work? What’s wrong with that? Isn’t it “close-minded” to claim that scientific considerations of prior plausibility consign homeopathy to the eternal dustbin of pseudoscience?

Not at all. There’s a difference between being open-minded and being so “open-minded” that your brains threaten to fall out. Guess which category homeopaths like Rutten fall into. But to hear them tell it, homeopathy is rejected because because we scientists have a “negative plausibility bias” towards it. At least, that’s what Rutten and some other homeopaths have been trying to convince us. This article seems to be an attempt to put some meat on the bones of their initial trial balloon of this argument published last summer, which Steve Novella duly deconstructed.

Before I dig in, however, I think it’s necessary for me to “confess” my bias and why I think it should be your bias too.

Posted in: Basic Science, Clinical Trials, Homeopathy, Science and Medicine

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G-Spot Discovered? Not So Fast!

Is this the G-Spot?

The press release proclaims “Study Confirms Anatomic Existence of G-Spot.” The study itself is titled “G-Spot Anatomy: A New Discovery.”  It was just published in The Journal of Sexual Medicine.  The author, Adam Ostrzenski, is an “internationally renowned gynecologic surgeon” with multiple degrees (MD, PhD, Dr Hab) and many peer-reviewed articles listed in PubMed.

The G-spot, or Gräfenberg Spot, is an area on the anterior wall of the vagina that can be stimulated to produce sexual excitement, stronger orgasms, and maybe even female ejaculation. Its existence is questionable. Wikpedia has an extensive article explaining the controversy and the published evidence, pro and con, with links to the original sources. You can read more than you ever wanted to know about it there, so I won’t bother trying to repeat it here. A 2012 review of the G-spot literature concluded:  

Objective measures have failed to provide strong and consistent evidence for the existence of an anatomical site that could be related to the famed G-spot. However, reliable reports and anecdotal testimonials of the existence of a highly sensitive area in the distal anterior vaginal wall raise the question of whether enough investigative modalities have been implemented in the search of the G-spot.

Dr. Ostrzenski claims to have found the G-spot and taken its picture (above). Believers in Bigfoot and the Loch Ness monster have pictures too. They even had “Bigfoot hair” that later turned out to be synthetic wig fibers. Ostrzenski’s “proof” is no more credible than theirs.


Posted in: Basic Science, Obstetrics & gynecology

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The problem with preclinical research? Or: A former pharma exec discovers the nature of science

If there’s one thing about quacks, it’s that they are profoundly hostile to science. Actually, they have a seriously mixed up view of science in that they hate it because it doesn’t support what they believe. Yet at the same time they very much crave the imprimatur that science provides. When science tells them they are wrong, they therefore often try to attack the scientific method itself or claim that they are the true scientists. We see this behavior not just in quackery but any time scientific findings collide with entrenched belief systems, for example, medicine, evolution, anthropogenic global warming, and many others. So it was not surprising that a rant I saw a few weeks ago by a well-known supporter of pseudoscience who blogs under the pseudonym of Vox Day caught my interest. Basically, he saw a news report about an article in Nature condemning the quality of current preclinical research. From it, he draws exactly the wrong conclusions about what this article means for medical science:

Fascinating. That’s an 88.6 percent unreliability rate for landmark, gold-standard science. Imagine how bad it is in the stuff that is only peer-reviewed and isn’t even theoretically replicable, like evolutionary biology. Keep that figure in mind the next time some secularist is claiming that we should structure society around scientific technocracy; they are arguing for the foundation of society upon something that has a reliability rate of 11 percent.

Now, I’ve noted previously that atheists often attempt to compare ideal science with real theology and noted that in a fair comparison, ideal theology trumps ideal science. But as we gather more evidence about the true reliability of science, it is becoming increasingly obvious that real theology also trumps real science. The selling point of science is supposed to be its replicability… so what is the value of science that cannot be repeated?

No, a problem with science as it is carried out by scientists in the real world doesn’t mean that religion is true or that a crank like Vox is somehow the “real” intellectual defender of science. Later, Vox doubles down on his misunderstanding by trying to argue that the problem in this article means that science is not, in fact, “self-correcting.” This is, of course, nonsense in that the very article Vox is touting is an example of science trying to correct itself. Be that at it may, none of this is surprising, given that Vox has demonstrated considerable crank magnetism, being antivaccine, anti-evolution, an anthropogenic global warming denialist, and just in general anti-science, but he’s not alone. Quackery supporters of all stripes are jumping on the bandwagon to imply that this study somehow “proves” that the scientific basis of medicine is invalid. A writer at Mike Adams’ wretched hive of scum and quackery,, crows:

Begley says he cannot publish the names of the studies whose findings are false. But since it is now apparent that the vast majority of them are invalid, it only follows that the vast majority of modern approaches to cancer treatment are also invalid.

But does this study show this? I must admit that it was a topic of conversation at the recent AACR meeting, given that the article was published shortly before the meeting. It’s also been a topic of e-mail conversations and debates at my very own institution. But do the findings reported in this article mean that the scientific basis of cancer treatment is so off-base that quackery of the sort championed by Mike Adams is a viable alternative or that science-based medicine is irrevocably broken?

Not so fast there, pardner…

Posted in: Basic Science, Cancer, Clinical Trials

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Why haven’t we cured cancer yet? (Revisited): Personalized medicine versus evolution

About a year ago, I addressed what might seem to the average reader to be a very simple question: Why haven’t we cured cancer yet? As I pointed out at the time, it’s a question that I sometimes even ask myself, particularly given that cancer has touched my life. Three years ago, my mother-in-law died of a particularly nasty form of breast cancer. Even though I am a breast cancer surgeon, I still wonder why there was nothing that could save her (and there still is nothing that could have saved her, if it existed then) from a decline over several months followed by an unpleasant death. Yet, as a cancer researcher, I do understand somewhat. A couple of years ago, I wrote in depth about the complexity of cancer from a science-based viewpoint, as compared, of course, to the incredibly simplistic view that many purveyors of alternative medicine quackery promote as being The One True Cause of Cancer. As I put it at the time, shamelessly stealing from Douglas Adams: Cancer is complicated. You just won’t believe how vastly, hugely, mind-bogglingly complicated it is. I mean, you may think algebra is complicated, but that’s just peanuts to cancer.

I saw more evidence of that at the American Association for Cancer Research meeting last week. In fact, if there’s anything I’ve learned, it’s that developing personalized therapy for cancer is going to be a hell of a lot more difficult than we had ever suspected. Actually, it wasn’t just the AACR meeting that taught me this, but it’s as good a pretext as any to discuss some cool new science. I only wish it was science that pointed an obvious path forward to the development of personalized therapy. On the other hand, if it were easy then anyone could do the “personalized therapy for dummies” approach that, for example, Stanislaw Burzynski takes. Then there’s the even more ridiculously simplistic approach that certain practitioners of “complementary and alternative medicine” (CAM) take.

So why haven’t we cured cancer yet? Again? One reason that I discussed last time I covered this topic concerns a study that used the latest next generation sequencing (NGS) techniques to sequence seven aggressive and advanced prostate cancers. I described the results as these genomes looking like someone threw a miniature grenade into the nucleus of a prostate epithelial cell. In other words, these are some really messed up genomes. (I wanted to use another word to describe it, but this is a family blog—sort of, anyway.) I used this example to explain once again that cancer is not a single disease. It’s hundreds of diseases. Although there are common themes in how cells become cancerous, such as loss of responsiveness to growth signals with a resultant ability to grow unchecked, evasion of programmed cell death (apoptosis), inducing the surrounding tissue to provide a blood supply (angiogenesis), evading the immune system, and invading the blood or lymphatic systems to travel elsewhere in the body and take up shop in other organs, such as liver, lung, or bone, individual cancers acquire these necessary (to the cancer) abilities through many different mechanisms. For this reason, it’s completely ridiculous to speak of a “cure for cancer.”

It’s also the reason I expressed skepticism when Steve Novella discussed a potential universal anti-cancer drug. Ditto when the press breathlessly reports studies suggesting a “universal cancer vaccine.” While these sorts of research findings are promising, they need to be put into perspective. We’ve seen their like many times before, and various cancers are still deadly diseases. In fact, my career intersected with this sort of hype back in the 1990s, when I studied combining angiogenesis inhibitors with radiation therapy in experimental models of cancer in mice. For a period of time in the late 1990s, I lived the hype. Then reality, as it always does, brought us all down to earth. Now, 15 years later, we know that angiogenesis inhibitors, although useful, are not any sort of “magic bullet” cure for all solid tumors. Like many advances before, they have now taken their place in the armamentarium of anticancer drugs, more important than some but not as important as others.

It’s even more complicated than that.


Posted in: Basic Science, Cancer, Evolution

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Drinking from the Fire Hose: Odds and Ends on the Gasping Oppression

I spend most of my time taking care of hospitalized patients with acute infections and issues of public health are, outside of infection control, not a high priority. Vaccinations in training were always like clean water and fresh food: their benefit was a given and I never needed to consider the benefits and subtleties of  vaccination. There is just so much time in a day and I was more concerned with AIDS, endocarditis and meningitis to worry about the ins and outs of vaccination.

One of the many benefits of writing for SBM, and being the Chair of Infection Control, is it is a stimulus to keep up on aspects of medicine that I might not otherwise pay close attention to, like vaccines. I have been far more interested in vaccines, especially influenza vaccines, since starting practice in 1990 than I ever was in the decade I spend in training.

Vaccination and the efficacy of vaccines is not as straightforward as I would have thought 30 years ago. It was give a vaccine, generate an antibody, and, viola, the patient is protected. The vagaries of the flu vaccine are even more pronounced, since response to the vaccine is variable and the population has never been vaccinated at levels, more than 90%, where herd immunity would likely kick in.

My ideal flu vaccine study, which would be both impossible and unethical, would be to vaccinate everyone West of the Mississippi and no one to the East (no coincidence that me and mine live in the West) and study the short and long term effects. Until that day, I am stuck with the hodgepodge of medical studies that look at the results of influenza vaccination and add insights into the disease.

I thought this week it would be fun to mention some interesting studies about influenza, the vaccine and flu immunity that have come out in the last 2 years. This is not meant to be anything more than a compilation of articles I thought were interesting, and the only purpose is to give a hint as to the complexities of influenza and  vaccination. (more…)

Posted in: Basic Science, Science and Medicine, Vaccines

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The Species in the Feces

I do not understand the interest many appear to have in their bowels and the movement there of.  But then, I pay little attention to most of my body functions as long they are functioning within  reasonable parameters, and as I get  older the definition of reasonable is increasingly flexible.

The elderly especially seem to obsess about their bowels.  My theory is that since they have often lost taste, smell, hearing and are alone with little direct human touch,  a good BM is the only remaining physical joy left, and when it is compromised they are understandably upset.

Still, the concept of colonics for ‘detoxification’  strikes me as more humorous than repellent, despite the lack of efficacy and documented complications of the procedure.  Under normal circumstances, when it comes to the colon it is probably better to be removing substances than to be introducing them.  (more…)

Posted in: Basic Science, Naturopathy, Science and Medicine

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