The following post appeared earlier this week at my Chemical & Engineering News CENtral Science blog, Terra Sigillata. For some odd reason – perhaps this week’s frantic academic schedule of commencement activities – it was not highly read there. I thought that our Science-Based Medicine readers would appreciate it because this new prescription drug is derived from a family of fungi that have been used in traditional Chinese medicine. A few editorial changes have been made later in the post to increase the relevance to our readership here.

A very well-written review of an orally-active drug for multiple sclerosis has just appeared in the April 25th issue of the Journal of Natural Products, a joint publication of the American Chemical Society and the American Society of Pharmacognosy.

The review, Fingolimod (FTY720): A Recently Approved Multiple Sclerosis Drug Based on a Fungal Secondary Metabolite, is co-authored by Cherilyn R. Strader, Cedric J. Pearce, and Nicholas H. Oberlies. In the interest of full disclosure, the latter two gentlemen are research collaborators of mine from Mycosynthetix, Inc. (Hillsborough, NC) and the University of North Carolina at Greensboro. My esteemed colleague and senior author, Dr. Oberlies, modestly deflected my request to blog about the publication of this review.

So, I am instead writing this post to promote the excellent work of his student and first author, Cherilyn Strader. As of [Wednesday] morning, this review article is first on the list of most-read articles in the Journal. This status is noteworthy because the review has moved ahead of even the famed David Newman and Gordon Cragg review of natural product-sourced drugs of the last 25 years, the JNP equivalent of Pink Floyd’s The Dark Side of the Moon (the album known for its record 14-year stay on the Billboard music charts.).

Reproduced from Strader et al., J. Nat. Prod. 2011, 74, 900–907.

The story of fingolimod is a fascinating journey from early 1970s work on fungal-derived immunosuppressants in Japan to synthetic organic synthesis by Tetsuro Fujita at Kyoto University in 1992 that has led to a non-injectable option for patients with multiple sclerosis. Some of these fungi are ones that infect insects and their fruiting bodies have been used in traditional Chinese medicine as elixirs.

From the review:

Isaria sinclairii is native to Asia, mainly China, Korea, and Japan, and is classified as an entomopathogenic fungus. It is the imperfect stage of Cordyceps sinclairii (Clavicipitaceae) and is closely related to Cordyceps sinensis Sacc., whose Chinese name, Dong Chong Xia Cao, means “winter worm, summer grass”; this species was reclassified recently to Ophiocordyceps sinensis. Fungal spores infect the larvae of suitable insect hosts, including members of the order Hymenoptera and Lepidoptera; the fungus is parasitic, growing within the host and resulting in death of the insect. The fungus completely colonizes the insect cadaver, and in the spring and summer white fruiting bodies appear as stalks up to 6 cm in height. Fungi at this stage of development are regarded as mysterious and mystical in some Asian cultures and have been used for thousands of years in traditional Chinese medicine, as they are believed to impart eternal youth.

From a biology standpoint, Ms. Strader very nicely describes the in vitro and in vivo assays used to identify the natural product progenitor from Isaria sinclairii, myriocin (ISP-1), as an immunosuppressant agent. A clever mixed lymphocyte assay was used by Fujita and colleagues to detect inhibition of T-cell proliferation when splenocytes from two strains of mice were co-cultured in the presence of alloantigen. To confirm activity in vivo, the investigators then used rat skin transplant model where tissue would normally be rejected when transplanted from one rat strain to another. Active compounds were scored based on their ability to prolong the viability of the transplant. This work from the Journal of Antibiotics is available here as free full text.

In both the in vitro and in vivo assays, ISP-1 exhibited activity superior to that of the immunosuppressant, cyclosporin A. But as with many natural products, the compound has some toxicity and solubility issues. Several groups went on to synthesize over 50 analogs of the ISP compounds and Ms. Strader details the reaction schemes and strategies, again pointing out that the two biological assays were crucial to evaluating the structure-activity relationships.

Strader discusses how the molecular mechanism of action of the lead, fingolimod, was then picked up by the group at Novartis, the company that licensed the compound. In this currently-free paywalled article in the “Case Histories” section of Nature Reviews Drug Discovery, Brinkmann et al. detail how fingolimod is actually a prodrug, requiring phosphorylation by sphingosine 2-kinase (SPHK2) to inhibit a series of G-protein-coupled receptors in the sphingosine 1-phosphate (S1P) family. These receptors that bind sphingosine lipids mediate actions of T-cells and endothelial cells that lead to the neuroinflammation of multiple sclerosis.

Most relevant from a drug discovery standpoint is that this mechanism of action is distinct from other immunosuppressants such as FK506 and cyclosporin A which act upstream in this pathway to inhibit serine palmitoyltransferase. This observation is a central theme in natural products pharmacology: naturally-occurring compounds often revealed novel mechanisms of therapeutic action. A far more detailed description of these investigations can be found in this cited review.

Strader then continues in her JNP review to discuss the clinical pharmacology and pharmacokinetics of fingolimod and the other potential uses of the compound, specifically in organ transplantation and cancer therapy. Her review is a lovely example of a comprehensive story that spans from traditional Chinese medicine – where fungi have been used for centuries – to modern drug development.

Why do I single out this review?
As a biologist and pharmacology instructor, I appreciated learning about the chemistry of the drug and the painstaking dissection of its mechanism of action, all directed by a clever battery of bioassays to probe some excellent synthetic work.

Moreover, Strader’s review demonstrates that fungal natural products, while part of our history, remain today a robust source of leads for drug discovery. When studied using solid, science-based techniques, even something as bizarre as an insect fungus can give rise to useful therapeutic agents. In particular, this work demonstrates that drug companies are indeed interested in natural products and can generate new intellectual property and patents: the chemical modifications to ISP-1 created the new composition of matter claim for fingolimod.

Finally, I believe that this published review originated as a graduate class assignment by Cherilyn’s instructor. Ms. Strader seized upon the encouragement of her professor to further develop this story, expanding and refining it to the quality and breadth required to be considered for publication. Cherilyn could have just stopped and gotten an A for the original assignment. Instead, she took on this additional effort under the guidance of my colleagues. She is deserving of congratulations on achieving this milestone. It certainly doesn’t hurt one’s career development prospects to have a review paper among the most highly-read articles in an official journal of the ACS and American Society of Pharmacognosy.

Regular readers know that I am driven to use this blog as a mechanism to recognize the efforts of the next generation of chemists and pharmacologists – students, postdocs, and early-career scientists. As such, please feel free to recommend to me other cases of such publications and interesting backstories that are deserving of this less traditional mode of dissemination.

While this review is currently behind the ACS paywall, many of you should be able to access it via institutional or personal subscriptions.

Reference: Strader, C., Pearce, C., & Oberlies, N. (2011). Fingolimod (FTY720): A Recently Approved Multiple Sclerosis Drug Based on a Fungal Secondary Metabolite Journal of Natural Products, 74 (4), 900-907 DOI: 10.1021/np2000528

<!--<!--

Whether it’s acupuncture, homeopathy or the latest supplement, placebo effects can be difficult to distinguish from real effects. Today’s post sets aside the challenge of identifying placebo effects and look at how placebos are used in routine medical practice.  I’ve been a pharmacist for almost 20 years, and have never seen a placebo in practice, where the patient was actively deceived by the physician and the pharmacist. So I was quite surprised to see some placebo usage figures cited by Tom Blackwell, writing in the National Post last week:

The practice is discouraged by major medical groups, considered unethical by many doctors and with uncertain benefit, but one in five Canadian physicians prescribes or hands out some kind of placebo to their often-unknowing patients, a new study suggests.

The article references a paper in the Canadian Journal of Psychiatry which, sadly, does not have much of a web presence. The article continues:

McGill’s Prof. Raz and his team conducted a survey of specialists throughout Canada, receiving responses from 606 doctors, 257 of them psychiatrists. About 20% of both psychiatrists and non-psychiatrists said they had used placebos in treating patients. The specific treatments they confirmed using included actual placebo tablets, sugar pills and saline injections. Some — including 35% of psychiatrists — said they also used “sub-therapeutic” doses of real drugs, amounts too small to have any chemical effect on the patient.

One in five physicians actively using placebos? Even if they’re being used sporadically, that’s a lot more use than I would have expected, and what my own practice would suggest. Is my experience typical? I put a short post on my own blog and on Twitter, and I was surprised by the responses. While use seems to be uncommon, it’s definitely  still happening, and some pharmacists participate in the charade. I was surprised to see that there are even some impressive-looking commercially-manufactured placebo capsules out there, too. (I wonder if they’re covered by insurance plans?)

I was able to obtain a full copy of the article, and it provided some context to the prevalence numbers. The web-based survey (still online) was sent to 7600 academic physicians, plus an undisclosed number of psychiatrists. Given the response rate was so low (though perhaps not unexpected for a survey), there is no information to suggest that the sample that responded is representative of the broader physician population. Given the subject matter, I’d expect that supporters of placebo use might be more inclined to respond. All of this leads me to conclude that, yes, it is happening, but no, it’s probably not one in five physicians.

The usage of placebos in active practice is one that David Gorski has discussed before, and he had some serious ethical problems with their use. Gorski reviewed a paper by Tiburt et al, which was a survey of 1,200 internists and rheumatologists, and noted that among the 57% that responded, about half reported prescribing placebo treatments on a regular basis. Big numbers, and a much better response rate. But  it also could have been skewed towards placebo prescribers.

I turned to the biomedical literature for some prevalence information. PubMed looked kindly upon my request: A 2010 paper entitled Frequency and circumstances of placebo use in clinical practice – a systematic review of empirical studies. In their study, Fässler and colleagues searched the literature with a wide net, looking for articles on the frequency of placebo use and attitudes among health professionals, students or patients.

Before we dive into the results, it must be noted that not all placebos are the same. And this might explain the disconnect between the surveys, and my pharmacy observations.  “Pure” placebos are truly inert: they contain no active ingredients. These are the sugar/lactose pills, saline injections, and most homeopathy (products diluted beyond 12C, at least).  “Impure” placebos, on the other hand, actually contain active ingredients, but are ineffective for the condition being treated. This could be because of a sub-therapeutic dose, or the active ingredient has no effectiveness against the condition being treated (e.g., antibiotics for viral infections, or the less-dilute homeopathic products). So perhaps those prevalence numbers may not be so wrong – subtherapeutic doses or antibiotics are less obviously detectable as being prescribed with placebo effect intent.

The review identified 22 studies of relevance, some dating back as far as 1973. (The Tiburt paper referenced above was among them.) Most were quantitative studies, based on interviews or questionnaires. Studies were conducted in a range of countries, with North America being reasonably well represented. The data quality was not impressive. Most of the sampling was non-random, none of these surveys used consistent questions, and response rates were all over the map. Even the definition of placebo varied between studies.

All of the studies that looked at frequency of placebo prescribing reported some use: 17-80% for pure placebos, and 41-99% for impure placebos. Pure placebos seemed to be more commonly used in hospital settings, and impure placebos were reported more in the primary care setting. The frequency of use of both pure and impure placebos was low: less than once per month in most studies. So overall, it seems consistent with the Canadian data reported last week.

Under what circumstances would deceiving a patient be felt to be acceptable? Without a systematic survey, it’s impossible to quantify the conditions and reasons for use. But some of the themes identified include:

Pure Placebos

• pain, insomnia, anxiety, risk of substance abuse
• difficult/demanding patients

Impure Placebos

• desire of patients to receive a prescription
• take advantage of placebo effects
• avoid conflicts with patients
• as a supplemental treatment for non-specific symptoms

Respondents in the different studies generally believed that placebo could be effective in a subset of patients, ranging from 5% to 42%. Among physicians and medical students, up to a third believed that placebos can induce objective, physiological changes. The overall appropriateness of placebo use led to some divergent opinions. From an ethical perspective, very few thought the use of placebos should be prohibited, though many considered the use problematic. A surprising number considered the use of placebos acceptable if used for patient benefit.

Another interesting paper, not included in the Fässler review, was published in 2010 in the journal Family Medicine. Kerman et al reported on a survey of 412 physicians in the paper Family physicians believe the placebo effect is therapeutic but often use real drugs as placebos [PDF]. Again, the response rate (43%) was poor, but among responders, 56% reported using a placebo in active practice, with 19% doing so more than 10 times per year. The most common placebo cited was the use of antibiotics (43%) followed by vitamins (23%) and herbal supplements (12%). Pure placebos were infrequently used.

Survey responders had very positive opinions of placebo use, with 85% believing that placebos have psychological and physical benefits. Remarkably, 92% supported placebo use in clinical practice. Only 8% felt placebo use should be prohibited. The most common reasons for placebo use were “unjustified” demand for medication (32%) followed by the desire to calm the patient (20%) and after therapeutic options were exhausted (20%).

It’s the impure placebos that concern me the most. The popularity of antibiotics as placebo treatments is alarming. While generally well tolerated, they’ve got a long list of side effects, which can be serious in rare cases. And antibiotic resistance, driven by misuse, has public health consequences. The use of vitamins and herbal supplements is also troubling: it’s increasingly clear that these products can cause harms, too. And it leaves me wondering what proportion of physician-recommended use of vitamins and supplements that I see is just a deliberate attempt to harness placebo effects.

The literature can tell us much about the placebo, but much less about how these products are actively used in the practice of medicine. The data are poor, but there’s enough to suggest that deliberate placebo prescribing is taking place, albeit with some ethical discomfort for many prescribers. Outside of perhaps a hospital setting where a “pure” placebo could be evaluated somewhat more objectively, I can’t imagine any situation where their provision would be ethically acceptable. As a pharmacist, my responsibility is to the patient, not the physician, and in a community pharmacy setting, I’d refuse to provide any treatment that would require me to deceive the patient about true nature of  prescription. The idea of placebo effects may be tantalizing, but not at the cost of patient autonomy, or inappropriate prescribing.

References

Fässler, M., Meissner, K., Schneider, A., & Linde, K. (2010). Frequency and circumstances of placebo use in clinical practice – a systematic review of empirical studies BMC Medicine, 8 (1) DOI: 10.1186/1741-7015-8-15

Kermen R, Hickner J, Brody H, & Hasham I (2010). Family physicians believe the placebo effect is therapeutic but often use real drugs as placebos. Family medicine, 42 (9), 636-42 PMID: 20927672

<!--<!--

Late last week, the anti-vaccine underground was all atwitter. The reason was the announcement of an impending press conference, scheduled for yesterday at noon in Washington, DC that proclaimed:

Investigators and Families of Vaccine-Injured Children to Unveil Report Detailing Clear Vaccine-Autism Link Based on Government’s Own Data

Report Demands Immediate Congressional Action

Directors of the Elizabeth Birt Center for Autism Law and Advocacy (EBCALA), parents and vaccine-injured children will hold a press conference on the steps of the U.S. Court of Federal Claims (717 Madison Place, NW in Washington, DC) on Tuesday, May 10 at 12:00 PM to unveil an investigation linking vaccine injury to autism. For over 20 years, the federal government has publicly denied a vaccine-autism link, while at the same time its Vaccine Injury Compensation Program (VICP) has been awarding damages for vaccine injury to children with brain damage, seizures and autism. This investigation, based on public, verifiable government data, breaks new ground in the controversial vaccine-autism debate.

The investigation found that a substantial number of children compensated for vaccine injury also have autism. The government has asserted that it “does not track” autism among the vaccine-injured. Based on this preliminary investigation, the evidence suggests that autism is at least three times more prevalent among vaccine-injured children than among children in the general population.

I could hardly wait.

After all, the anti-vaccine flacks at Age of Autism started flogging this press conference announcing this report relentlessly immediately upon its announcement. So did other anti-vaccine groups, including SafeMinds, the Autism Action Network, and others. I knew this because I’m on the mailing list for a number of anti-vaccine groups. I do it for you, to keep my finger on the pulse of the anti-vaccine movement and as an early warning system to let me know when they’re up to various forms of chicanery. Being thus plugged in to anti-vaccine blogs and various mailing lists, I can report that the entire anti-vaccine crankosphere was abuzz with excitement and anticipation over the release of this report, so much so that I was starting to wonder if there would be anything there that might be be worth paying attention to. Even FOX News took the bait:

As is usually the case when the anti-vaccine movement announces the impending announcement of some “blockbuster” study or report that will demonstrate—or so they say—beyond a shadow of a doubt that, even against the mountains of epidemiological evidence indicating no correlation between vaccines and autism, there really, truly is a good scientific reason to suspect that all that evidence is wrong and that vaccines are the cause of an “autism epidemic,” when the press conference rolled around yesterday and the report was published, I was disappointed. I thought it would be a challenge. It wasn’t. Still, I view it as my duty to explain why this report is a whole lot of nothing that in fact is entirely consistent with the current scientific consensus that vaccines don’t cause autism, not so much because I have any hope of changing any minds among those who released the report, but for the good of the fence sitters who might come across this report and find it convincing.

Not surprisingly, the report was written by anti-vaccine stalwarts, namely Mary Holland, Louis Conte, anti-vaccine lawyer Robert Krakow, and Lisa Colin and is entitled Unanswered Questions from the Vaccine Injury Compensation Program: A Review of Compensated Cases of Vaccine-Induced Brain Injury. Apparently the buildup was too great. Now that I’ve actually read this report I can’t believe it. It’s just that bad.

If there’s one thing that cranks routinely do when they can’t win their case on science is to shift to other venues to convince people that they are not, in fact, cranks. After all, if they stuck to arguing facts, science, and evidence, they wouldn’t be cranks. They also wouldn’t have a prayer of obtaining influence because the science is so much against them. So, failing at science yet again, what the anti-vaccine movement has done yet again is to move over to law. In essence, they are implying that legal decisions can mean that there is a scientific case to be made in favor of the hypothesis that vaccines cause autism. This is an utterly fallacious argument at its core, because findings of law all too often have very little to do with findings of science. Examples abound, but my favorite one is the scare over silicone breast implants during the 1980s and 1990s. The science supporting the claims that silicone from these implants was causing systemic diseases, such as cancer, autoimmune diseases, and a panoply of other conditions, was never good. In fact, it was weak to nonexistent. None of that stopped an avalanche of lawsuits from bankrupting Dow-Corning in 1995 Later, as more studies were carried out, it was found that there was no correlation between silicone implants and the conditions attributed to them. Even so, it wasn’t until 2006 that the FDA approved these implants again for cosmetic use.

Basicaly, law is not science, and, as much as lawyers would like you to think that the law can deal with science easily, the two cultures, law and science, are very, very different. In law, for example, the object is to win your case, not to find out how nature works and develop models (i.e., theories) that accurately describe it and predict its behavior. In law, there are no truly objective right or wrong answers about issues of science. There is only the law and how it has been interpreted by courts. Advocacy for one’s position, using every tool at one’s disposal and denigrating or ignoring evidence that conflicts with that position, is not just acceptable, but mandatory. And that’s what Holland et al do, with little exception. In fact, they go so far as to use the common legal tactic of making like Humpty Dumpty in this passage from Lewis Carroll’s Through the Looking Glass:

‘When I use a word,’ Humpty Dumpty said, in rather a scornful tone, ‘it means just what I choose it to mean — neither more nor less.’

‘The question is,’ said Alice, ‘whether you can make words mean so many different things.’

‘The question is,’ said Humpty Dumpty, ‘which is to be master — that’s all.’

Alice was too much puzzled to say anything; so after a minute Humpty Dumpty began again. ‘They’ve a temper, some of them — particularly verbs: they’re the proudest — adjectives you can do anything with, but not verbs — however, I can manage the whole lot of them! Impenetrability! That’s what I say!’

And that’s what Holland et al also appear to say, as well. Impenetrability based on legal jargon is their shield and their sword. They also fall back on the famous “just asking questions” ploy, so beloved of cranks, which is colloquially known among critical thinkers as JAQing off, which they do blatantly here:

This assessment of compensated cases showing an association between vaccines and autism is not, and does not purport to be, science. In no way does it explain scientific causation or even necessarily undermine the reasoning of the decisions in the Omnibus Autism Proceeding based on the scientific theories and medical evidence before the VICP. Nor does this article have anything to say about state childhood immunization mandates in general.

What this article does point to are unanswered questions about vaccines and autism, a thorny issue that affects approximately one in one hundred and ten children.10 On this point, this study strongly suggests the need for further Congressional and scientific investigation to explore the association between vaccine-­induced brain injury and autism and the integrity of this federally-­administered compensation program.

If you admit that what you are peddling is not science (and it most definitely is not), and you can’t show convincing evidence of an association between vaccines and autism (which can only be shown by science anyway), then why even bother? The answer is easy if you understand the authors’ purpose. It is not to demonstrate whether there is a true correlation between vaccination and autism or whether vaccines do cause or increase the risk of autism. Rather, it is advocacy. It is persuasion. It is a tool to use to try to get legislators to change the law, science be damned.

It is propaganda.

The core of the argument in Holland et al appears to boil down to three claims. First, they claim to have found 83 cases of autism associated with vaccine-induced brain injury, which, they claim, makes autism three times more prevalent in children compensated by the Vaccine Injury Compensation Program (VICP). Second, because they base this estimate primarily on children for whom there are reports of “autistic-like” symptoms or who ultimately developed autism, they argue that there is no difference between autism and having been noted to exhibit “autism-like” behaviors or symptoms. Finally, they claim that this means that autism is three times more prevalent in VICP-compensated children than in the general population. Let’s look at these one at a time.

Looking at the second claim first, only a non-physician could make such a risibly silly argument as this and not be expected to be subjected to ridicule:

Because autistic disorder is defined only by an aggregation of symptoms, there is no meaningful distinction between the terms “autism” and “autism-­like symptoms.” This article makes the distinction only to accurately reflect the terms that the Court of Federal Claims, caregivers, and others use. It is not a distinction to which the authors attach significance.

It is not as uncommon as we would like in medicine for conditions and diseases to be defined primarily (or even only) by aggregations of symptoms. Irritable bowel syndrome is an example. Ditto tension headache. Moreover, it is often the context within which those symptoms arise that distinguish one diagnosis from another. In any case, the DSM-IV provides fairly clear diagnostic criteria for autism. If the child doesn’t have enough of these criteria to be diagnosed as autistic, that child could have “autism symptoms” but not autism. In other words, if a child shows a number of odd behaviours but not the classic triad of impairments, then they might have ASD or Asperger’s Syndrome or HFA, but they don’t have autism because the diagnosis of autism depends upon a specific set of diagnostic criteria, and the child doesn’t meet those criteria. If he did, he’d have a diagnosis of autism. It’s just that simple, but Holland et al try to obfuscate by trying to make terms like “autism-like symptoms and similar terms mean what they want them to mean.

Humpty Dumpty indeed.

Nor are diagnostic criteria for a condition like autism spectrum disorders a difficult concept for most people; certainly they aren’t for doctors. Apparently, however, they represent a very difficult concept indeed for Holland et al, who seem to be arguing that any child with autism-like symptoms must have autism. This is akin to arguing that anyone who has a belly ache or diarrhea must have irritable bowel syndrome or that someone who experiences a headache must have migraines. In addition, such an argument assumes that all symptoms are equal when it comes to making the diagnosis of autism.

Regarding the first claim, if we take at face value the claim that there are 83 children compensated by the VICP, it is first essential to compare this number to the number of children compensated by the VICP. This the authors try to do but utterly miss the point in doing it:

This discussion must start with the caveat that we are able only to interpret the subgroup of eighty-­three compensated cases that we have located. Out of a total number of approximately two thousand five hundred compensated vaccine injury claims,137 we recognize that this is a small subset. It is our hope that this preliminary study will lead to more complete study of all cases of compensated vaccine injury. Such a study might provide a far more comprehensive understanding of vaccine injury.

83/2,500 results in an estimated prevalence rate of approximately 3.3%. On the surface, this seems to support the claim that the prevalence of autism/ASD is three-fold higher in VICP-compensated children than it is estimated to be in the general population (around 1%). Of course, there’s at least one problem. The authors are even forced to admit it. Specifically, of these 83 children, Holland et al could only find documentation of autistic symptoms for only 39. The rest of those 83 were “diagnosed” solely on the basis of a parental questionnaire. This lower number results in an estimated prevalence of autism of around 1.6% in the VICP-compensated population, an estimate that is falling into the range of what we would expect in the general population. Given that the VICP population is a skewed sample, most of whom have developmental disabilities, I’d be shocked if the prevalence of autism/ASD symptoms in this group weren’t significantly higher than they are in the general population, given how much overlap there is between symptoms exhibited by children with developmental delay and children with autism. Of course, this “study” is not good evidence that the prevalence of autism/ASD even is higher in the VICP-compensated population. Taking into account the skewed population and the noise inherent in looking at a small population over 20 years, the prevalence of autism in VICP-compensated children does not appear to be detectably different than it is in the general population. That’s even accounting for very loose criteria used by the authors to define who might be autistic. As Prometheus put it:

If the prevalance is higher among people compensated by the VICP, there is a basis for further investigation. It still wouldn’t “prove” that vaccines cause autism – it would simply be an indication for further study.

If, on the other hand, the prevalence of autism among people compensated by the VICP is the same as the general population (or less – see below), the argument that “vaccines cause autism” receives yet another (totally redundant) nail in its coffin.

The problem is that the autism prevalence numbers for the general population – even the educational numbers – use much tighter criteria than used by the authors of this study.

According to a Generation Rescue telephone survey (in other words, a “study” by the anti-vaccine movement iteself), the prevalence of autism is even higher than what Holland et al found in the VICP-compensated group of children. It’s even worse than that, though. In fact, the timing of this study’s release is very, very bad indeed. In an ironic twist of fate that leads me to think that there might justice in the universe after all, shortly before the anti-vaccine movement tried to make hay out of this poorly argued, scientifically nonsensical report, a real scientific study, was released out of South Korea that found the prevalence of autism to be considerably higher than previously believed. Steve Novella even discussed this study earlier today. Basically, in this study, researchers administered a screening test for autism spectrum disorders in a population and then did more detailed tests on children who screened positive. Their results were stunning. The study estimated that the prevalence of autism spectrum disorders was 2.64% in the population studied and that 2/3 of those cases were undiagnosed. True, this study will need to be replicated, but it adds more support for the hypothesis that autism spectrum disorders are more common than previously thought and that a significant proportion of them are subclinical and thus undiagnosed. The timing of this study, of course, couldn’t be worse for Holland et al, because it simply reemphasizes that the prevalence of autism that they think they measured in the VICP population is almost certainly not higher than the prevalence in the general population.

In other words, Holland et al did all that work and wrote all those words in order to add yet more evidence to support what we already know from copious evidence from a large and robust existing body of studies: That vaccines do not cause autism.

They just refuse to realize or admit that that’s what they’ve done.

<!--<!--

Crossposted from NeuroLogica Blog

Over the last 20 years the prevalence of autism (now part of autism spectrum disorder, ASD) has been increasing. The medical community is largely agreed that this increase is mostly due to expanding the diagnostic category and greater efforts at surveillance. There remains some controversy over whether or not these factors explain all of the measured increase, or if there is a small real increase hidden in there as well. But largely – we are finding more children with ASD because we are casting a wider net with smaller holes.

If this is true, then we do not yet know what the true prevalence of ASD is. There must be a pool of undiagnosed children out there. Eventually the measured prevalence will hit the ceiling of the true prevalence (unless, of course, we expand the definition further) – but where is the ceiling?

That is the question researchers recently set out to answer, and they did so with a comprehensive 5 year study conducted in South Korea. The results surprised even them:

Results: The prevalence of ASDs was estimated to be 2.64% (95% CI=1.91–3.37), with 1.89% (95% CI=1.43–2.36) in the general-population sample and 0.75% (95% CI=0.58–0.93) in the high-probability group. ASD characteristics differed between the two groups: the male-to-female ratios were 2.5:1 and 5.1:1 in the general population sample and high-probability group, respectively, and the ratios of autistic disorders to other ASD subtypes were 1:2.6 and 2.6:1, respectively; 12% in the general-population sample had superior IQs, compared with 7% in the high-probability group; and 16% in the general-population sample had intellectual disability, compared with 59% in the high-probability group.

The previous estimate of autism prevalence was 1% of the population, or about one child in 100. This study found a prevalence of 2.64%, or about one child in 38 – more than twice the previous estimate. They came upon their higher measurement by taking a thorough survey of the general population. Previous studies have looked at high probability groups – children receiving special services or who have already been diagnosed. This study went into the general population and did a thorough survey for undiagnosed cases. Therefore there is a vast untapped pool of potential ASD diagnoses out there.

The results above also indicate that children with undiagnosed ASD in the general population had less intellectual disability than those in the recognized high probability group. They were also less likely to be male and less likely to have classic autism rather than a more subtle variant than the high probability group – which is not surprising. In other words, the undiagnosed children in the general population met the diagnostic features to be considered on the spectrum, but were largely functioning well in mainstream classrooms. In some cases parents were in denial about their child’s condition, in other cases the parents simply had no idea. In South Korea there is apparently still some stigma attached to the diagnosis.

While the authors conclude that their results indicate the need for still better detection of ASD, many of the undiagnosed children would likely not require or even benefit from special services. Although some would, and of course it would be desirable to capture all of those children.

While 2.6% is a high number for any such disorder, it is not out of line with other common mental disorders such as anxiety, depression, or ADHD. Of course these questions always bring up the very relevant issue of where to draw the line between “normal” and “disordered.” As I discussed recently, categorizing brain function is tricky business. Any identifiable psychological or neurological trait seems to vary at least along the classic bell-curve. You can therefore take any trait and declare two standard deviations to either side as the cut-off for “normal” (a standard practice in much of medicine) and declare those at the fringes to have one or another disorder. That would result in 5% of the population being abnormal.

But it takes more than being at the tails of the bell curve to be considered as having a disorder. The definition also requires that the identified traits are associated with (and plausibly cause) some dysfunction or negative outcome. In the case of ASD the disorder is a lack of social ability (not just learned skills, but the raw neurological hardwiring that underlies our ability to socialize). Interestingly, the current measured rate of 2.64% is almost exactly two standard deviations to the left of the curve (the other 2.5%, making a total of 5%, is the cutoff to the right of the curve – those with high social ability, which is generally not considered a disorder).

Since many of the children captured in the current study seemed to be doing fine, it is possible that the current definition of ASD is simply capturing the left two standard deviations of human variability along the bell curve of social ability. Perhaps the definition is therefore too broad, and needs to be tied more closely with some measure of disability. That is a subject for future research.

The bell curve hypothesis also can be used to support those in the “neurodiversity” community. They argue that ASD is just what I described – normal human neurological variation. I agree with this view to some degree, and I think the data above support that. However – when you get out far enough to the left side of the bell curve you do get to the point where dysfunction is undeniable. At some point it is useful to consider a neurological phenomenon to be a disorder. Children with low social ability (even if they make up for it in other ways) tend to have difficulty in school, with making friends, and later in life functioning in the work environment. No matter what you choose to call it, it is useful to identify children who can benefit from programs to help them compensate for their lack of social ability.

Also – we cannot assume that ASD is simply everyone more than two standard deviations to the left of the bell curve. It is possible that the actual curve is not a pristine bell-shape but is bi-modal, representing one hump of normal human variation, and then another hump at the low end of social ability that represents a theoretically definable separate population. This second hump might represent those with one of a group of genetic variants that leads to what we recognize as autism. This is almost certainly true, as children with autism have a higher incidence of intellectual impairment and seizures, suggesting a neurological disorder and not just normal variation. There is also increasing evidence of genetics links to autism.

Further – the low end of the bell curve of normal variation would blend imperceptibly into the second hump of autism disorder. At present the diagnosis of ASD is based entirely on clinical features, making it difficult to separate out different underlying causes. (As I stated above, we can make subtype distinctions based upon associated neurological conditions, but this is still a clinical inference rather than a distinction based upon known cause.)

As neuroscience advances, h0wever, it may become possible to tease out the current mixed bag of clinical ASD by identifying specific underlying genetic or neurological conditions. We may undo the lumping of all these children into one ASD spectrum by identifying subtypes by either their genetic profile, or perhaps their neurological function as examined by functional MRI scanning or a similar functional scan. We are already making significant progress in this area, but this is still an area ripe for further research.

Conclusion

This study adds an interesting data point to the whole picture of ASD. If correct, then the theoretically upper limit of ASD prevalence is about 2.6% of the population, more than twice the previous estimate. It also indicates that when you undergo a program of thorough searching, you will find more diagnoses. No one can reasonably think that the true prevalence of ASD suddenly doubled.

While it doesn’t prove that the steady increase in ASD diagnoses over the last 20 years was due to increased surveillance, it does support that hypothesis by showing the potential of just looking harder. Those children with ASD were always there, they were simply not identified.

<!--<!--

In my recent review of Peter Palmieri’s book Suffer the Children I said I would later try to cover some of the many other important issues he brings up. One of the themes in the book is the process of critical thinking and the various cognitive traps doctors fall into. I will address some of them here. This is not meant to be systematic or comprehensive, but rather a miscellany of things to think about. Some of these overlap.

Diagnostic fetishes

Everything is attributed to a pet diagnosis. Palmieri gives the example of a colleague of his who thinks everything from septic shock to behavior disorders are due to low levels of HDL, which he treats with high doses of niacin. There is a tendency to widen the criteria so that any collection of symptoms can be seen as evidence of the condition. If the hole is big enough, pegs of any shape will fit through. Some doctors attribute everything to food allergies,  depression, environmental sensitivities,  hormone imbalances, and other favorite diagnoses.  CAM is notorious for claiming to have found the one true cause of all disease (subluxations, an imbalance of qi, etc.).

Favorite treatment.

One of his partners put dozens of infants on Cisapride to treat the spitting up that most normal babies do.  Even after the manufacturer sent out a warning letter about babies who had died from irregular heart rhythms, she continued using it. Eventually the drug was recalled.

Another colleague prescribed cholestyramine for every patient with diarrhea: not only ineffective but highly illogical.

When I was an intern on the Internal Medicine rotation, the attending physician noticed one day that every single patient on our service was getting guaifenesin.  We thought we had ordered it for valid reasons, but I doubt whether everyone benefited from it.

Recognizing warblers.

Like birdwatchers, hospitalists like Palmieri learn to identify which doctor admitted a patient. Child doesn’t appear sick; admitting diagnosis is “occult bacteremia”; patient was given an intramuscular injection of Cephotaxime in the office — oh, that must be Dr. X.

Rapid identification vs pareidolia

Humans are good at pattern recognition. This allows experienced clinicians to make rapid diagnoses, but it also allows us to see the Virgin Mary on a grilled cheese sandwich.

Rooster syndrome

Rooster crows, sun comes up; therefore rooster made sun come up. Baby had colic, was given treatment X, colic resolved; therefore X cures colic. In reality, colic resolves spontaneously by 3-4 months of age and X was useless.

Copycats

Mimicking what other physicians in the community are doing.

Availability

Choosing a drug because you have samples handy that the drug rep left.

Ulysses syndrome

Ulysses went from one adventure to another in the odyssey of returning home from the Trojan War. A false positive test can lead to a fruitless odyssey of further investigation: tests lead to more tests, maybe even invasive procedures and harm to the patient. Eventually it is realized that the patient has been healthy all along.

Unnecessary lab tests

Sometimes tests are done in a scattershot attempt to find something, anything. Palmieri’s pathologist wife directs a laboratory and frequently gets calls from doctors who have ordered an unfamiliar test and have no idea what to do when they get an abnormal result. Instead of getting an individual chemistry test, we get SMAC panels because the machine is there and it’s so convenient and cheap. With 20 tests on these panels, there is a 66% probability that at least one test will be outside normal limits on a perfectly healthy normal person.

Defensive medicine

With the present legal climate, doctors sometimes do tests or treatments with an eye to how things would look in court, rather than for the direct benefit of the patient.

Showmanship

Ordering tests to impress the patient that the doctor is being thorough and is actually doing something.

Hardwired fallibility

Our brains do not function in a rational, objective, logical way. We have built-in psychological mechanisms and defects in information processing; our brains have evolved a repertoire of tricks and shortcuts that serve us well in everyday life but that must be overcome for critical thinking and science.

Confirmation bias

Once we form a belief, we seek out evidence that confirms it and reject evidence that contradicts it. We are all biased, but by being aware of our biases we can activate a self-correcting mechanism.

Over-generalization

We form opinions about the many based on our experience of a few. We may base our idea of a disease on a patient who had an atypical presentation, or tend to avoid using a drug because of a patient who had an uncommon side effect. Radiologists who have missed a diagnosis are tempted to over-interpret x-ray findings for a time afterwards.

Anchoring

We tend to reach an early diagnosis and cling to it even when subsequent evidence doesn’t fit. We tend to accept the diagnosis of the referring physician rather than going back to square one to make up our own mind.

Diagnosis momentum

An early possibility becomes a presumptive diagnosis and gains legitimacy as it is repeated by more and more health care providers.

Framing

We seek a diagnosis within the context of how the information is presented to us. Palmieri tells about a boy who presented with “frequent throat infections.” He was referred to ENT and even had a tonsillectomy before it was discovered that he had never even had a sore throat, only unexplained fevers that had been falsely attributed to throat infections but that eventually turned out to be due to juvenile rheumatoid arthritis.

Miscommunication and assumptions

Palmieri describes a case where an ENT consultant was called in directly by the worried parents of a child hospitalized with an ear infection. He assumed that they and the pediatrician must have wanted him to put in PE tubes; otherwise there would have been no earthly reason for a consult. He had booked an OR and scheduled the patient for surgery before it became clear that the child had a first ear infection that was responding to treatment, that ENT input was unnecessary, and that PE tubes were clearly not indicated.

Algorithms

We simplify our approach to complex problems by following algorithms like “if the white count is over 15,000, give antibiotics.” This is not always appropriate. Algorithms provide a convenient framework, not an unalterable directive.

Tunnel vision

We are cautioned against thinking of zebras every time we hear hoofbeats, but we often fall into the opposite trap: we tend to fixate on the diagnoses we commonly see in our practice and not consider rare possibilities. On a recent episode of the television show “Untold Stories from the ER” there was a toddler who was refusing to walk because of leg pain. They took x-rays looking for fractures to confirm their initial diagnosis of child abuse. It turned out he had scurvy, a vitamin C deficiency that simply doesn’t occur in the 21^st century US — but it did, because he was refusing all foods but oatmeal and his uneducated parents didn’t know there was anything wrong with catering to his wishes.

Conclusion

In medical school, doctors learn science but they may not learn to think like a scientist. Once out in practice, they become vulnerable to unproven claims, myths, and pseudoscience; and they are encouraged to give advice based on common sense and intuition rather than on evidence. Not just doctors but everyone needs to better understand the cognitive traps we all fall into. Since our human brains are inherently fallible, only critical thinking and good science can keep us on track. A major theme of this blog is that good science is essential for correcting our errors.

<!--<!--

One of the most persistent myths is one that’s been particularly and doggedly resistant to evidence, science, clinical trials, epidemiology, and reason. It’s also a myth that I’ve been writing about a long time. Specifically, I’m referring to the now scientifically discredited myth that the mercury-containing thimerosal preservative that used to be in quite a few childhood vaccines causes autism. The myth began in the late 1990s and was later fed by the publication of David Kirby’s book Evidence of Harm, which was basically a paean to various brave maverick doctors who promoted the claim that mercury in vaccines cause autism. Among the “scientists” promoted by David Kirby were the father-son team of Mark and David Geier. Mark Geier is a physician who also has a PhD and represents himself as a medical geneticist; his son David has no medical degree, leading to my wondering from the very beginning how it was that he got away with helping his father evaluate and treat autistic children, in essence practicing medicine without a license.

The Geiers are most infamous for their “Lupron protocol,” which I first learned about back in 2006. As I wrote about it in 2009, when the mainstream media finally noticed the Geiers’ dubious medicine and how they were franchising it to different states, it was chemical castration for autism. The short version is that, somehow some way, Mark Geier got the idea in his head that testosterone contributes to autism. That in and of itself isn’t woo, given that scientists have from time to time hypothesized that very thing. What made the Geiers’ conclusions pseudoscience is their explanation. Basically, Geier claimed that testosterone binds mercury from vaccines, making it more “toxic” to the brain and also making it harder to get rid of the mercury using chelation therapy. Never mind that the only paper showing testosterone binding to mercury did it in benzene (hint: your blood is not benzene) under extreme conditions. What was worse, however, was the Geiers’ “solution” to this problem, which was to add to the autism quackery known as chelation therapy another potentially harmful form of quackery, namely chemical castration using Lupron, a drug that shuts down the production of sex hormones, including testosterone. It’s a drug that’s used to treat metastatic prostate cancer, a treatment that replaced the old treatment for metastatic prostate cancer, namely surgical castration. (Not coincidentally, it’s also used to chemically castrate sex offenders.) Even worse still, the Geiers somehow got away with a highly unethical clinical trial in which they packed the Institutional Review Board overseeing it with their cronies, going merrily on their way offering an unethical “clinical trial” untouched and seemingly untouchable.

Finally, the law acts

For over five years now, I’ve been wondering just how in the world the Geiers got away with such unethical pseudoscience and how they got away with it for so long. I couldn’t figure it out. Not only did they ply their dubious medicine on autistic children, but David Geier appeared to be functioning as a “diagnostician,” somehow fooling the State of Maryland’s Autism Commission into appointing him as a member, even though he completely lacks expertise to be practicing medicine and does not have a medical or clinical degree of any kind. Meanwhile, evidence suggested that the Geiers appeared to be playing fast and loose with insurance companies by making lots of diagnoses of “precocious puberty,” a very uncommon diagnosis. Truly, I wondered what was wrong with the State of Maryland…until last week, when online acquaintances, not to mention some of you started sending me the news that Mark Geier has had his medical license suspended by the State of Maryland, as outlined in this 48-page court order. Kathleen Seidel, as usual, is already on the case as well.

Yes, the Maryland State Board of Physicians has finally acted. All I can say is: It’s about time. Let’s take a look at some of the relevant sections of the order. First, here’s the money section, namely the summary statement, which I cite nearly in its entirety:

The Respondent misdiagnosed autistic children with precocious puberty and other genetic abnormalities and treated them with potent hormonal therapy (“Lupron Therapy” or “Lupron Protocol”), and in some instances, chelation therapy, both of which have a substantial riskof both short-term and long-term adverse side effects. The Respondent’s treatment exposed the children to needless risk of harm.

The Respondent, in addition to being a physician, is certified as a genetic counselor. His assessment and treatment of autistic children, as described herein, however, far exceeds his qualifications and expertise. The extensive and extensive batteries of laboratory studies the Respondent initially orders, many of which he orders to be repeated on a monthly basis, are outside the standard quality of care for a work-up for an autistic patient or to determine the underlying cause of autism. The Respondent failed to conduct adequate physical examinations of any of the patients and in several instances, began his Lupron Protocol based merely on a telephone consultation with the child’s parent and the results of selected laboratory tests he ordered. The Respondent’s omission of a comprehensive physical examination constitutes a danger because his treatment is based on a diagnosis that requires documentation of sexual development beyond that expected for the age of the child. Moreover, his treatment may constitute more of a risk to a child with an underlyingl medical condition.

The Respondent failed to provide adequate informed consent to the parents of the autistic children he treated. In one (1) instance, he misrepresented that his treatment protocol had been approved by a federally approved IRB.

[...]

The Respondent endangers autistic children and exploits their parents by administering to the children a treatment protocol that has a known substantial risk of serious harm and which is neither consistent with evidence-based medicine nor generally accepted in the relevant scientific community.

In the order, Mark Geiers’ numerous other offenses are listed, including his corrupt, crony-packed IRB overseeing his clinical trial, possible insurance fraud (billing insurance companies for services never rendered), failing to obtain informed consent, misdiagnosing children with “precocious puberty” in most egregious ways (such as diagnosing children who did not meet the age criteria for precocious puberty) and writing medical necessity letters based on this mistaken diagnosis, and misrepresenting himself as a geneticist. Basically, regarding this latter charge, Mark Geier claimed to be a geneticist, which is a “physician who evaluates a patient for genetic conditions, which may include performing a physical examination and ordering tests,” even though he is not a medical geneticist; rather, he is a genetic counselor, which is “an individual with a master’s degree who helps to educate the patient and provides an assessment of the risk of the condition recur in the family.” I know genetic counselors. I work with genetic counselors. They don’t diagnose genetic conditions; rather, they counsel patients after either a genetic diagnosis has been rendered or the patient has developed a condition (such as breast cancer at a young age) that might indicated a genetic predisposition to a disease. It turns out that Geier also misrepresented himself as a board-certified epidemiologist when he is not.

Particularly disturbing are the treatments to which Mark Geier submitted children in his care. Case studies described in the report include include a battery of over 40 tests, spironolactone for misdiagnosed hyperaldosteronism, chelation therapy for “heavy metal toxicity,” Lupron, and methyl B12 drops for unclear and undocumented indications. One patient, patient F, a female, was given Femara, an aromatase inhibitor, which is used to treat estrogen receptor-positive breast cancer. It’s used mainly in post-menopausal women to shut down hormone production in the peripheral tissues. (It doesn’t work in premenopausal women because their ovaries make lots of estrogen, far more than the small amount made in peripheral tissues.) The presumed rationale, I have to guess, would be the same as in younger woman with breast cancer, where sometimes it is necessary to shut down ovarian hormone production and then to top it off by shutting down peripheral hormone production. My guess is that Geier somehow thought he needed to shut down not just ovarian sex hormone production in this girl but peripheral production as well. Why, I have no idea, but its profoundly idiotic and potentially harmful, particularly when combined with chelation therapy. Meanwhile, in other patients, Mark Geier proposed adding another anti-androgen drug, Androcur.

The abuse of autistic children was staggering. As a result, the Board made a finding of law:

Based on the foregoing facts, the Board concludes that the public health, safety or welfare imperatively require emergency action in this case, pursuant to Md. State Gov’t Code Ann. § 10-226 (c) (2) (i) (2009 Repl. Vol.).

That’s right, not just action but emergency action. I guess the State of Maryland has a different definition of “emergency,” given that the Geiers have been at this for at least six years, but I’ll take what I can get. At least when finally roused from its torpor, the Maryland State Board of Physicians recognized the Geiers for the threat to autistic children that they are and, as a result, ordered that Mark Geier’s license to practice medicine in the State of Maryland be summarily suspended. As a result, Mark Geier was required to surrender the following to the Board:

• his original Maryland License D24250
• his current renewal certificate
• his Maryland Controlled Dangerous Substance Registration
• all controlled dangerous substances in the Respondent’s possession and/or practice;
• all Medical Assistance prescription forms
• all prescription forms and pads in the Respondent’s possession and/or practice
• any and all prescription pads on which his name and DEA number are imprinted

Excellent.

I only have a couple of remaining questions. First, what will be the response of the anti-vaccine movement. One thing I’ve noticed over the last couple of years, since the mainstream media first noticed his Lupron protocol is that the anti-vaccine movement seems to have distanced itself from the Geiers. They’re almost never mentioned anymore on Age of Autism these days, even though they used to be regular features there a couple of years ago. They’re not the headliners at the yearly Autism One quackfest anymore; they are, however, still listed as speakers for this year’s quackfest. One has to wonder whether they’ll be quietly disinvited now that Geier has had his medical license yanked, or whether Lisa Sykes will remove the Geiers’ epilogue from her book. Probably not, I’d guess. Most likely the Autism One organizers will see the loss of Mark Geier’s medical license as evidence of his cred as a “brave maverick doctor,” much as Wakefield’s cred remains high in the anti-vaccine movement. Even so, in the several days since the suspension of Geiers’ license became widely known, I’ve seen almost nothing written about them by the anti-vaccine movement, which is in marked contrast to the wailing and gnashing of teeth observed after Andrew Wakefield lost his medical license in the U.K.

Be that as it may, I’m now left wondering how long it will be before the conspiracy theories come out. The most obvious one hasn’t hit the blogosphere yet, at least not as I write this. How long do you think it’ll be before an anti-vaccine loon claims that stripping Mark Geier of his medical license (just like another brave maverick doctor, Andrew Wakefield!) was a plot by the miltiary-industrial-pharma-CDC complex to distract attention from the case of Poul Thorsen. You know it’s coming sooner or later.

Finally, what of the metastatic deposits of Geier père et fils quackery in other states? After all, besides Maryland, the Geiers have spread their clinics to Kentucky, Missouri, Florida, Illinois, and Indiana. Will these states now act to shut down the Geier clinics there, known as ASD Centers, LLC? I know I’ve complained about how long it took the State of Maryland to do the right thing. Even so, I’m glad that the Board there finally acted. It’s time for the medical boards in these other states to do likewise.

Fallout

There was one truly odd aspect about this incident, as long overdue as it was and as happy as I was to learn about it. Basically I learned something else along the way that I hadn’t known. In fact, I was pretty shocked to find this out, and I wanted to know how something like this could possibly have happened. I’m referring to the fact that Mark Geier’s son David Geier had somehow slimed his way onto the State of Maryland Commission on Autism as a “diagnostician.” As I pointed out at the time, David Geier is not a physician and has no qualifications to diagnose or treat autism (or anything other medical condition, for that matter). Not that that’s stopped him thus far; he does it anyway.

By way of the Baltimore Sun, I now learn that part of the fallout in the aftermath of Mark Geier’s humiliation is that, not only is the state trying to get rid of David Geier but people are asking–shall we say?–inconvenient questions about how he was appointed to the Commission on Autism in the first place:

A day after Dr. Mark Geier’s medical license was suspended in Maryland over allegations of putting children with autism at risk, state officials were seeking to remove his son from a state commission that advises the governor on the disorder.

The officials were also struggling to explain why David Geier, who has an undergraduate degree in biology and does not have a medical license, was identified by the Commission on Autism as its “diagnostician.” The commission’s website had listed him as a doctor until Wednesday, which officials said was a clerical error. The commission’s listing also includes the Geiers’ company, ASD Centers LLC, whose website lists a corporate center in Silver Spring but is not registered in Maryland.

“Under the circumstances, we do not believe it’s appropriate for David Geier to serve on the autism commission,” said David Paulson, a spokesman for the state Department of Health and Mental Hygiene, which submitted 19 names to the governor, including David Geier’s, for approval to the panel. “Unfortunately, he declined to resign his commission. … As a result, we are considering the appropriate next steps.”

Leave it to a Geier not to take the hint when not wanted, leading the state to try to get rid of him. Like father, like son, I suppose. However it is a very interesting question. How could someone like David Geier, a man with no qualifications, associated with pseudoscience like the Geiers’ Lupron protocol get on such a panel? While it’s true that he has been caught in the past inflating his credentials, I doubt that explains it. The explanation coming from the Department of Health and Mental Hygiene doesn’t sound particularly convincing:

Paulson said the state was aware of “the controversial nature of David Geier’s views” when he was recommended for the position on the commission, which was formed by the legislature in 2009. But officials were looking for a “diverse” panel.

“Controversial.” You keep using that word. I do not think it means what you think it means. David Geier’s views are most definitely not “controversial,” at least not from a scientific standpoint. They’re demonstrably wrong. They’re pseudoscientific. They’re advocacy of abuse of autistic children. But controversial? Not so much. One potential explanation for David Geier’s presence on the panel has been suggested by Robert Goldberg, author of Tabloid Medicine: How the Internet is Being Used to Hijack Medical Science for Fear and Profit, who asks how an autism quack got on the Maryland autism panel and then tries to answer the question:

Here’s a clue: The Geiers did have their association with John L. Young, MD.

Who is Dr. Young and why might he be connected to David Geier’s appointment?
In 2009, Dr. Young “was the President of the Montgomery County Medical Society, the largest component medical society in Maryland. From 2007 to 2009, he was asked by Maryland Governor Martin O’Malley to serve as a Commissioner for the Maryland Community Health Resources Commission, and in 2009, was appointed by Governor O’Malley to serve on the Board of Regents for the University System of Maryland.”

That information is taken from the website of ASD Centers, which the Geiers set up to peddle Lupron and other dangerous and disproven autism treatments. That’s because John L. Young, MD — founded in 2008 — along with Mark Geier — ASD Centers.

http://www.autismtreatmentclinics.com/Staff.html

And there’s more: The Geiers set up an Institutional Review Board (IRBs are established to review the impact of clinical research on human subjects) to approve their own research, conducted by ASD Centers of course. The IRB called the Institute for Chronic Illnesses turned out to be Mark Geier’s home.
More problematic, John Young was a ‘co-investigator’ with Mark and David Geier in their Lupron research.

Even worse, Young was also a member of the IRB.

http://www.neurodiversity.com/weblog/article/98/

It certainly does look suspicious, doesn’t it?

Whether Dr. Young is the conduit through which David Geier managed to find a seat on Maryland’s autism panel or not, the Geiers have built a virtual “autism biomed” empire in Maryland, Illinois, Indiana, Texas, Florida, New Jersey, Missouri, Kentucky, and Washington based on, in essence, the chemical castration of children. We have to remember that Geier’s only been shut down in one state. True, it’s the state of his current residence, which is huge, but that doesn’t stop the Geiers from simply relocating to one of the other states in which Mark Geier holds a medical license. Heck, if Dr. Geier were to relocate to Virginia, he might not even have to move out of his very large, very expensive home; he could just deal with a longer commute. The problem, as I’ve discussed before, boils down to ineffective state medical boards, many of which are overburdened and hampered by laws that mistake giving doctors due process with viewing a medical license as a right. It’s not; it’s a privilege. In any case, the ineffectual regulation of physicians by many state medical boards have allowed “unconventional” doctors like Rashid Buttar to continue their dubious medicine with impunity, in essence thumbing their noses at the medical establishment.

Which is what the Geiers are still doing in Illinois, Indiana, Texas, Florida, New Jersey, Kentucky, and Washington.

So, how to stop them? In most states, for the medical board to act, there have to be complaints, either from patients or fellow health care professionals. Whether there have been complaints about the Geiers or not, I don’t know, but there should be. Also, a license suspension in one state can trigger an investigation in another state. At the very least, the Mark Geier will have to report it the next time he applies for renewal of his license in the several states in which he is licensed, a convenient list of which has been kindly provided here.

I have two hopes right now. The first, and lesser, of the two is that David Geier will be kicked off of the Maryland Commission on Autism. He should never have been on that panel in the first place, and it would be very, very interesting to find out exactly who pushed for his appointment, given that the competition for the spots on that committee was pretty fierce. I highly doubt that David Geier got a spot on the committee on his merits; almost certainly someone somewhere pulled some strings, possibly Dr. Young. The second, and more important, hope is that the State of Maryland’s action, as long overdue as it may have been, ultimately cascades, and Mark Geier finds himself losing his medical license in each and every state in which he holds one.

<!--<!--

The anti-vaccine movement is a frequent topic on the Science-Based Medicine blog. There are a number of reasons for this, not the least of which being that the anti-vaccine movement is one of the most dangerous forms of pseudoscience, a form of quackery that, unlike most forms of quackery, endangers those who do not partake of it by breaking down herd immunity and paving the way for the resurgence of previously vanquished diseases. However, anti-vaccine beliefs share many other aspects with other forms of quackery, including the reliance on testimonials rather than data. Even so, although the intelligentsia (and I do use the term loosely) of the anti-vaccine movement realizes and exploits the power of anecdotes and testimonials and how human beings tend to value such stories over dry scientific data, leaders of the anti-vaccine movement realize that science is overwhelmingly against them and that testimonials alone are not adequate to counter that science in the realm of public policy and relations.

That’s why, over the years, various anti-vaccine “scientists” (and I use that term very loosely as well) have produced poor quality, sometimes even fraudulent studies, which are then touted as evidence that vaccines cause autism or at least as evidence that there is actually still a scientific controversy when in fact from a scientific standpoint the vaccine-autism hypothesis is pining for the fjords. Examples abound, including the work of Mark and David Geier, whose studies led the to use chemical castration to treat autistic children; Andrew Wakefield, whose small case series almost certainly included fraudulent data; a truly incompetent “phone survey” commissioned by Generation Rescue designed to compare “vaxed versus unvaxed” children; and an even more incompetent “study” in which Generation Rescue used a cherry picked group of nations to try to argue that nations that require more vaccines have higher rates of infant mortality. These efforts continue. For example, last year Generation Rescue requested $809,721 from the Airborne settlement to set up a “vaxed versus unvaxed” study, despite the known difficulties with such a study and the low likelihood of finding anything without huge numbers of children.

Last week, they were at it again.

The return of the revenge of the claim that more vaccines equal more infant mortality

Over the last week or so, anti-vaccine activists have been busy touting two “studies” or “reports,” one I can write about now, one that will have to wait. I’ll start with the one that has to wait first:

Investigators and Families of Vaccine-Injured Children to Unveil Report Detailing Clear Vaccine-Autism Link Based on Government’s Own Data

Report Demands Immediate Congressional Action

Directors of the Elizabeth Birt Center for Autism Law and Advocacy (EBCALA), parents and vaccine-injured children will hold a press conference on the steps of the U.S. Court of Federal Claims (717 Madison Place, NW in Washington, DC) on Tuesday, May 10 at 12:00 PM to unveil an investigation linking vaccine injury to autism. For over 20 years, the federal government has publicly denied a vaccine-autism link, while at the same time its Vaccine Injury Compensation Program (VICP) has been awarding damages for vaccine injury to children with brain damage, seizures and autism. This investigation, based on public, verifiable government data, breaks new ground in the controversial vaccine-autism debate.

The investigation found that a substantial number of children compensated for vaccine injury also have autism. The government has asserted that it “does not track” autism among the vaccine-injured. Based on this preliminary investigation, the evidence suggests that autism is at least three times more prevalent among vaccine-injured children than among children in the general population.

Stay tuned. This appears to be the same “study” that anti-vaccine activist Robert F. Kennedy, Jr. was originally going to announce in front of the White House back in April, but his press conference was ultimately canceled. Apparently, this publication was to appear in the Pace University Law School journal, which, of course, the sort of venue that is always preferable to the peer-reviewed scientific literature, at least to cranks.

Whatever the announcement turns out to be, the second example is indeed a study that somehow made it into the peer-reviewed literature. I found out about it from two sources, first, you our readers, several of whom have sent me links to the study, and, second, the ever-popular all-purpose quackery website, NaturalNews.com, which announced triumphantly last week that nations requiring the most vaccines tend to have the worst infant mortality rates:

A new study, published in Human and Experimental Toxicology (http://het.sagepub.com/content/earl&hellip;), a peer-reviewed journal indexed by the National Library of Medicine, found that nations with higher (worse) infant mortality rates tend to give their infants more vaccine doses. For example, the United States requires infants to receive 26 vaccines — the most in the world — yet more than six U.S. infants die per every 1000 live births. In contrast, Sweden and Japan administer 12 vaccines to infants, the least amount, and report less than three deaths per 1000 live births.

Before we get to the study itself—which, as you might imagine, has…flaws—let’s take a look at the authors. The first author, Neil Z. Miller, is described as an “independent researcher, and the second author, Gary S. Goldman, is described as an “independent computer scientist.” This is not a promising start, as neither of them appear to have any qualifications that would lead a reader to think that they have any special expertise in epidemiology, vaccines, or science. Still, I suppose one could look at the fact that these two somehow managed to get a paper published in a peer-reviewed journal as being pretty strong evidence for the democratic nature of science, where you don’t necessarily have to be affiliated with a university or a biotech or pharmaceutical company in order to publish in the scientific literature. On the other hand, even though it is stated that this was not funded by any grants or companies, I still see a conflict of interest. Specifically, the NaturalNews.com article points out that the “National Vaccine Information Center (NVIC) donated $2500 and Michael Belkin donated $500 (in memory of his daughter, Lyla) for open access to the journal article (making it freely available to all researchers).” The NVIC, as you recall, was founded by Barbara Loe Fisher and is one of the oldest and most influential anti-vaccine groups in the U.S., having recently teamed up with Joe Mercola to promote anti-vaccine views.

Not a promising start.

It’s also not surprising. I did a bit of Googling, as is my wont whenever I encounter someone whose name I don’t recognized, and I found abundant evidence in his Wikipedia entry that Miller has a long history of anti-vaccine activism, having written books with titles like Vaccine Roulette: Gambling With Your Child’s Life, Immunization Theory vs Reality: Expose on Vaccinations, and Vaccines: Are They Really Safe and Effective?, among others. But that’s not all; he’s also the director of the ThinkTwice Global Vaccine Institute and in fact is hosting a copy of this study on his website. Gary S. Goldman is even more interesting. It turns out that he is the President and Founder of Medical Veritas, a rabidly anti-vaccine “journal” that is into HIV/AIDS denialism, having published dubious “reanalyses” of autopsy results of victims of AIDS, such as Eliza Jane Scovill. He also notes at his website that he’s written books entitled The Chickenpox Vaccine: A New Epidemic of Disease and Corruption.

Even less promising.

Still, one might wonder why I pointed this out. Isn’t that an ad hominem attack? Not at all. I’m not arguing that this latest paper is wrong because its authors are clearly members of the anti-vaccine fringe. Who knows? They might be on to something. I’m merely pointing out that what’s good for the goose is good for the gander when it comes to pointing out conflicts of interest (COIs) and, as Harriet has recently discussed COIs do not necessarily have to be financial. As I’ve pointed out time and time again, COIs do not necessarily mean that a study is in error, poorly done, or out-and-out wrong. They merely demand a bit more skepticism, particularly when they are not disclosed, which they are not in the actual paper, which fails to list the connection to NVIC, Medical Veritas, and ThinkTwice. Why didn’t Miller list himself as editor or founder of ThinkTwice or Goldman as founder and editor of Medical Veritas? One wonders, one does. Knowing that these two hold those positions is every bit as relevant as knowing when a pharmaceutical company publishes a study about its latest blockbuster drug.

But who knows? Maybe I’m wrong. Well, actually, I don’t think I am, but it will take delving into the actual paper to show why.

Infant mortality as a function of number of vaccines

The first thing you need to know is that this is a really, really simple paper. In fact, I’d go so far as to say it is simple-minded more than just simple. Basically, Miller and Goldman went to The World Factbook maintained by, of all organizations, the Central Intelligence Agency. Noting that in 2009 the U.S. ranked 34th in infant mortality, they looked up the infant mortality rates from the U.S. and all the nations that have lower infant mortality rates than the U.S. and then compared them to the number of vaccine doses each nation require. They then graphed the infant mortality rate as a function of vaccine dose, and this resulted in Figure 1:

Whenever I see a paper like this, I ask myself: What would I say about it if it had been sent to me as a peer reviewer. This graph leads to a number of questions. First, why did the authors use 2009 data? The cited reference notes that the data were accessed back in April 2010. That’s over a year ago. Did it really take over a year between submission and publication. Be that as it may, whenever I see investigators trying to correlate two variables like infant mortality and the number of vaccines I ask: What is the rationale? I also note that the authors here seem to have pulled the same trick that J.B. Handley and crew like to pull when trying to convince people that U.S. infants are “overvaccinated” by artificially pumping up the apparent number of vaccine doses by counting multivalent vaccines as more than one. For instance, the MMR and DTaP are counted as three each because each vaccine is trivalent; i.e., containing vaccines against three different diseases.

After pointing out that the U.S. has a poor infant mortality rate (IMR) relative to its wealth and what it spends on health care, the authors state:

There are many factors that affect the IMR of any given country. For example, premature births in the United States have increased by more than 20% between 1990 and 2006. Preterm babies have a higher risk of complications that could lead to death within the first year of life.⁶ However, this does not fully explain why the United States has seen little improvement in its IMR since 2000.⁷

Nations differ in their immunization requirements for infants aged less than 1 year. In 2009, five of the 34 nations with the best IMRs required 12 vaccine doses, the least amount, while the United States required 26 vaccine doses, the most of any nation. To explore the correlation between vaccine doses that nations routinely give to their infants and their infant mortality rates, a linear regression analysis was performed.

This is known as starting with a reasonable observation and then switching to a hypothesis with little or no scientific justification, in essence pulling it out of thin air. The second question I would have is: Why a linear relationship? No justification is given for performing a linear regression analysis. My third question would be: Why this data set?

Actually, this third question is probably the most interesting of all. Miller and Goldman only looked at one year’s data. There are many years worth of data available; if such a relationship between IMR and vaccine doses is real, it will be robust, showing up in multiple analyses from multiple years’ data. Moreover, the authors took great pains to look at only the United States and the 33 nations with better infant mortality rates than the U.S. There is no statistical rationale for doing this, nor is there a scientific rationale. Again, if this is a true correlation, it will be robust enough to show up in comparisons of more nations than just the U.S. and nations with more favorable infant mortality rates. Basically, the choice of data analyzed leaves a strong suspicion of cherry picking. Were I reviewing this paper, I would insist on the use of one or two other data sets. For example, I would ask for different years and/or perhaps the use of the rankings by the United Nations Population Division, which can be found in the Wikipedia entry containing the list of countries by infant mortality rate. And I would insist on doing the analysis so that it includes several nations with worse IMRs than the U.S. Indeed, since the focal point of the analysis seems to be the U.S., which, according to Miller and Goldman, requires more vaccine doses than any other nation, then it would make sense to look at the 33 nations with worse IMRs than the U.S.

Be that as it may, I looked at the data myself and played around with it One thing I noticed immediately is that the authors removed four nations, Andorra, Liechenstein, Monaco, and San Marino, the justification being that because they are all so small, each nation only recorded less than five infant deaths. Coincidentally, or not, when all the data are used, the r²=.426, whereas when those four nations are excluded, r² increases to 0.494, meaning that the goodness of fit improved. Even so, it’s not that fantastic, certainly not enough to be particularly convincing as a linear relationship. More dubiously, for some reason the authors, not content with an weak and not particularly convincing linear relationship in the raw data, decided to do a little creative data manipulation and divide the nations into five groups based on number of vaccine doses, take the means of each of these groups, and then regraph the data. Not surprisingly, the data look a lot cleaner, which was no doubt why this was done, as it was a completely extraneous analysis. As a rule of thumb, this sort of analysis will almost always produce a much nicer-looking linear graph, as opposed to the “star chart” in Figure 1. Usually, this sort of data massaging is done when a raw scatterplot doesn’t produce the desired relationship.

Finally, it’s important to remember that IMRs are very difficult to compare across nations. In fact, the source I most like to cite to illustrate this is, believe it or not, an article by Bernadine Healy, the former director of the NIH who has over the last three or four years flirted with the anti-vaccine movement:

First, it’s shaky ground to compare U.S. infant mortality with reports from other countries. The United States counts all births as live if they show any sign of life, regardless of prematurity or size. This includes what many other countries report as stillbirths. In Austria and Germany, fetal weight must be at least 500 grams (1 pound) to count as a live birth; in other parts of Europe, such as Switzerland, the fetus must be at least 30 centimeters (12 inches) long. In Belgium and France, births at less than 26 weeks of pregnancy are registered as lifeless. And some countries don’t reliably register babies who die within the first 24 hours of birth. Thus, the United States is sure to report higher infant mortality rates. For this very reason, the Organization for Economic Cooperation and Development, which collects the European numbers, warns of head-to-head comparisons by country.

Infant mortality in developed countries is not about healthy babies dying of treatable conditions as in the past. Most of the infants we lose today are born critically ill, and 40 percent die within the first day of life. The major causes are low birth weight and prematurity, and congenital malformations. As Nicholas Eberstadt, a scholar at the American Enterprise Institute, points out, Norway, which has one of the lowest infant mortality rates, shows no better infant survival than the United States when you factor in weight at birth.

It’s ironic that Bernadine Healy, who’s associated herself so heavily with the anti-vaccine movement, to the point of having been named Age of Autism’s Person of the Year in 2008, provided such a nice, concise explanation about why it’s so problematic to compare infant mortality rates between nations. Miller and Goldman claim that they tried to correct for these differences in reporting for some of the nations who do not use reporting methods consistent with WHO guidelines, but they do not say how they did so or what data source they used to do so. Note that these children who die within the first day of life also tend to be the ones who have either received no vaccines yet or only the birth dose of the hepatitis B vaccine (here in the U.S.). Given that infant mortality is defined as the fraction of children who die before one year of age and many infants lost die very early, many of them have had few or no vaccines, given that the bulk of the U.S. vaccine schedule does not really start until two months of age. In other words, no effort was made to determine if there was actually any sort of correlation between vaccine dose number whether the infants who died actually died at an age where they would be expected to have received most of the vaccines required within the first year. Worse, no real attempt was made to correct for many potential confounding factors. Not that that stops the authors from asking:

Among the 34 nations analyzed, those that require the most vaccines tend to have the worst IMRs. Thus, we must ask important questions: is it possible that some nations are requiring too many vaccines for their infants and the additional vaccines are a toxic burden on their health? Are some deaths that are listed within the 130 infant mortality death categories really deaths that are associated with over-vaccination? Are some vaccine-related deaths hidden within the death tables?

Never mind that the authors present no real data to justify such a speculation. They do speculate, however. Oh, how they speculate! The spend two whole pages trying to link vaccines to sudden infant death syndrome and argue that SIDS deaths, hinting at some sort of conspiracy to cover up the number of SIDS deaths by reclassifying them and then cite old studies that suggested a correlation between vaccination and SIDS while neglecting the more recent data that show that the risk of SIDS is not increased after immunization and that, if anything, vaccination is probably protective against SIDS. Indeed, one of the studies the authors discuss is an abstract presented in 1982, not even a paper published in a peer-reviewed journal.

Finally, there is the issue of ecological fallacy. The ecological fallacy can occur when an epidemiological analysis is carried out on group level data rather than individual-level data. In other words, the group is the unit of analysis. Clearly, comparing vaccination schedules to nation-level infant mortality rates is the very definition of an ecological analysis. Such analyses have a tendency to magnify any differences observed, as Epiwonk once described while analyzing–surprise, surprise!–a paper by Mark and David Geier:

To make this jump from group-level to individual-level data is The Ecological Fallacy, which can be defined simply as thinking that relationships observed for groups necessarily hold for individuals.

The ecological fallacy was first described by the psychologist Edward Thorndike in 1938 in a paper entitled, “On the fallacy of imputing the correlations found for groups to the individuals or smaller groups composing them.” (Kind of says it all, doesn’t it.) The concept was introduced into sociology in 1950 by W.S. Robinson in 1950 in a paper entitled, “Ecological correlations and the behavior of individuals,” and the term Ecological Fallacy was coined by the sociologist H.C. Selvin in 1958. The concept of the ecological fallacy was formally introduced into epidemiology by Mervyn Susser in his 1973 text, Causal Thinking in the Health Sciences, although group-level analyses had been published in public health and epidemiology for decades.

To show you one example of the ecological fallacy, let’s take a brief look at H.C. Selvin’s 1958 paper. Selvin re-analyzed the 1897 study of Emile Durkheim (the “father of sociology”), Suicide, which investigated the association between religion and suicide. Although it’s difficult to find Selvin’s 1958 paper, the analyses are duplicated in a review by Professor Hal Morgenstern of the University of Michigan. Durkheim had data on four groups of Prussian provinces between 1883 and 1890. When the suicide rate is regressed on the percent of each group that was Protestant, an ecologic regression reveals a relative risk of 7.57, “i.e. it appears that Protestants were 7½ times as likely to commit suicide as were other residents (most of whom were Catholic)….ln fact, Durkheim actually compared suicide rates for Protestants and Catholics living in Prussia. From his data, we find that the rate was about twice as great among Protestants as among other religious groups, suggesting a substantial difference between the results obtained at the ecologic level (RR = 7.57) and those obtained at the individual level (RR = 2).” Thus, in Durkheim’s data, the effect estimate (the relative risk) is magnified by 4 by ecologic bias. In a recent methodological investigation of bias magnification in ecologic studies, Dr. Tom Webster of Boston University shows that effect measures can be biased upwards by as much as 25 times or more in ecologic analyses in which confounding is not controlled.

The bottom line is that Miller and Goldman’s ecological analysis virtually guaranteed overestimating any relationship found, the way some studies of radiation hormesis have done. Given that the difference between the highest and lowest IMR is only around two-fold, in essence, given this data set it is highly unlikely that there is any relationship there. This is particularly true given that the authors cannot possibly have controlled for the major confounders. Add to that the fact that they only used one data set and didn’t even include nations with higher IMRs than that of the U.S., and I declare this paper to be utterly worthless. It’s an embarrassment to Human and Experimental Toxicology that its peer reviewers didn’t catch all these problems and that an editor let this paper see print. The Editor-in-Chief Kai Savolainen and the Editor for the Americas A. Wallace Hayes ought to be ashamed of themselves.

Conclusion

The current study joins a long list of poorly planned, poorly executed, poorly analyzed studies that purport to show that vaccines cause autism, neurological diease, or even death. It is not the first, nor will it be the last. The question is: How do we respond to such studies? First off, we as skeptics have to be very careful not to become so jaded that knee-jerk hostility predominates. As unlikely as it is, there is always the possibility that there might be something worth taking seriously there. Next off, we have to be prepared to analyze these studies and explain to parents, when appropriate (which is the vast majority of the time) exactly why it is that they are bad science or why their conclusions are not supported by the data presented. Finally, we have to be prepared to provide these analyses fast. The Internet is speed. Already, if you Google the terms “infant mortality” and “vaccine,” anti-vaccine blogs gloating over Miller and Goldman’s study and the study itself appear on the very first page of search results.

Such is the power of a bad study coupled with the reach of the Internet and the naivete of peer reviewers and journal editors who don’t realize when they’re being played.

<!--<!--