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FDA warns maker of OSR #1, dietary supplement for autistic children is a “toxic” “drug”

24 Jun

“OSR#1 is not a dietary supplement but a toxic, unapproved drug with serious potential side effects, FDA warns”. So starts a recent article in the Chicago Tribune, FDA warns maker of product used as alternative autism treatment.

The article is by Trine Tsuderos who has previously reported on the the industrial chelator turned dietary supplement in Industrial chemical OSR#1 used as autism treatment.

According to the website for the product, “OSR#1® is a toxicity free, lipid soluble antioxidant dietary supplement that helps maintain a healthy glutathione level”. According to the story in the Tribune, the claim of “toxicity free” may not be accurate. According to the Tribune story:

The FDA letter lists side effects recorded during Haley’s animal studies: “soiling of the anogenital area, alopecia (hair loss) on the lower trunk, back and legs, a dark substance on lower trunk and anogenital area, abnormalities of the pancreas” and a rapid increase in normal cells contained in the lymph nodes.

Here is that section of the letter in full:

However, animal studies that you conducted found various side effects to be associated with OSR#1 use, including, but not limited to, soiling of the anogenital area, alopecia on the lower trunk, back and legs, a dark substance on lower trunk and anogenital area, abnormalities of the pancreas, and lymphoid hyperplasia. Based on these animal studies and side effects known to be associated with chelating products that have a similar mechanism of action to OSR#1, we believe the use of your product has the potential to cause side effects, and the before-mentioned website statements falsely assert that the product does not have the potential to cause side effects.

Mr. Haley is not unused to criticism of his so-called supplement. After the previous story by the Tribune, Boyd Haley tweeted multiple times “Contrary to the Chicago Tribune implication, OSR1 has undergone extensive safety testing. The truth is at http://www.OSR1.com. Please retweet!” When I checked the OSR website, I could find no mention of these test results–the results Boyd Haley himself submitted to the FDA. Is that the “truth”?

The Tribune quotes Ellen Silbergeld, a John’s Hopkins researcher:

“It would be hard to imagine anything worse,” said Ellen Silbergeld, an expert in environmental health who is studying mercury and autism at Johns Hopkins University’s Bloomberg School of Public Health. “An industrial chemical known to be toxic — his own incomplete testing indicates it is toxic. It has no record of any therapeutic aspect of it, and it is being marketed for use in children.”

and

Silbergeld said the product represents a clear example of endangerment of public health and that the FDA should stop CTI Science from selling it immediately. She drew a comparison to a city’s drinking water system: If contamination is found, she said, “they turn off the pumps.”

“They don’t have to engage in a long discussion with you,” Silbergeld said. “It would be hard to imagine a more clear example of immediate endangerment of public health. Turn off the pump.”

Kim Stagliano, Managing Editor of the Age of Autism blog, has touted OSR #1 in the past. She was quoted in the Tribune article:

In an e-mail, Stagliano wrote that she continues to support Haley, a regular speaker at autism recovery conferences. “Having met Dr. Haley at conferences, including Autism One in Chicago last month, I continue to trust his science,” she wrote on Wednesday. “I’m sure CTI Science will address the letter appropriately.”

There doesn’t seem to be any mention of the fact that Prof. Haley appears to have withheld safety information from the autism community. She “trusts his science”, yet makes no mention of the fact that it is precisely “his science” that indicates that this chemical is toxic.

The warning letter from the FDA is quoted below:

WARNING LETTER CIN-10-107927-14

Boyd E. Haley, President
CTI Science, Inc.
2430 Palumbo Drive, Suite 140
Lexington, Kentucky 40509

Dear Mr. Haley:

This letter concerns your firm’s marketing of the product OSR#1 on your website, http://www.ctiscience.com.This product is marketed in violation of provisions of the Federal Food, Drug, and Cosmetic Act (the Act) as described below.

Your firm markets OSR#l as a dietary supplement; however, this product does not meet the definition of a dietary supplement in section 201(ff) of the Act, 21 U.S.C. § 321(ff). To be a dietary supplement, a product must, among other things, “bear[ ] or contain[ ] one or more … dietary ingredients” as defined in section 201(ff)(1) of the Act, 21 U.S.C.§ 321(ff)(1). Section 201 (ff)(1) of the Act defines “dietary ingredient” as a vitamin, mineral, amino acid, herb or other botanical, or dietary substance for use by man to supplement the diet by increasing the total dietary intake, or a concentrate, metabolite, constituent, extract or combination of any dietary ingredient from the preceding categories. The only substance listed as a dietary ingredient on the labeling of OSR#1 is N1,N3-bis(2-mercaptoethyl)isophthalamide. N1,N3-bis(2mercaptoethyl) isophthalamide is not a vitamin, mineral, amino acid, herb or other botanical, or dietary substance for use by man to supplement the diet by increasing the total dietary intake. Further, N1,N3-bis(2-mercaptoethyl)isophthalamide is not a concentrate, metabolite, constituent, extract or combination of any such dietary ingredient. Thus, because OSR#1 does not bear or contain a dietary ingredient as defined in section 201(ff)(1) of the Act, this product does not qualify as a dietary supplement under section 201(ff) of the Act.
Your website includes claims such as the following:

• “OSR#1® … helps maintain a healthy glutathione level.”

• “Both OSR#1® and glutathione scavenge free radicals, allowing the body to maintain its own natural detoxifying capacity.”

The claims listed above make clear that OSR#1 is intended to affect the structure or any function of the body of man or other animals. Accordingly, OSR#l is a drug under section 201(g)(1) of the Act, 21 U.S.C. § 321(g)(1). Disclaimers on your website, such as “OSR#l® is not a drug and no claim is made by CTI Science that OSR#1® can diagnose, treat or cure any illness or disease,” do not alter the fact that the above claims cause your product to be a drug.

Moreover, this product is a new drug, as defined by section 201(p) of the Act, 21 U.S.C. § 321(p), because it is not generally recognized as safe and effective for use under the conditions prescribed, recommended, or suggested in its labeling. Under sections 301(d) and 505(a) of the Act, 21 U.S.C. §§ 331(d) and 355(a), a new drug may not be introduced or delivered for introduction into interstate commerce unless an FDA-approved application is in effect for it. Your sale of OSR#1 without an approved application violates these provisions of the Act.

Your website includes the following statements: “Thyroid conditions, hypertension, and diabetes: Because thyroid conditions, hypertension, and diabetes have been associated with low glutathione levels …” and “OSR#1® … helps maintain a healthy glutathione level.” These statements suggest that OSR#1 is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease. Because thyroid conditions, hypertension, and diabetes are not amenable to self-diagnosis and treatment by individuals who are not medical practitioners, adequate directions cannot be written so that a layman can use it safely for its intended uses. Thus, OSR#1’s labeling fails to bear adequate directions for its intended uses, causing it to be misbranded under section 502(f)(1) of the Act, 21 U.S.C. § 352(f)(1). OSR#1 is not exempt under 21 C.F.R. §§ 201.100(c)(2) and 201.115 from the requirement that its labeling bear adequate directions for use because OSR#1 lacks an approved application.

Additionally, under section 502(a) of the Act, 21 U.S.C. § 352(a), a drug is misbranded if its labeling is false or misleading in any particular. Section 201(n) of the Act, 21 U.S.C. § 321(n), provides that, “in determining whether a drug’s labeling or advertising is misleading, there shall be taken into account (among other things) not only representations made or suggested … but also the extent to which the labeling or advertising fails to reveal facts material in light of such representations ….” Your website states that” [s]ome reports of temporary diarrhea, constipation, minor headaches have been reported but these are rare and the actual causes are unknown,” as well as “OSR#1 is without detectable toxicity” and “OSR#1® … has not exhibited any detectable toxic effects even at exceptionally high exposure levels.” However, animal studies that you conducted found various side effects to be associated with OSR#1 use, including, but not limited to, soiling of the anogenital area, alopecia on the lower trunk, back and legs, a dark substance on lower trunk and anogenital area, abnormalities of the pancreas, and lymphoid hyperplasia. Based on these animal studies and side effects known to be associated with chelating products that have a similar mechanism of action to OSR#1, we believe the use of your product has the potential to cause side effects, and the before-mentioned website statements falsely assert that the product does not have the potential to cause side effects. Therefore, these statements render your product’s labeling false or misleading. As such, OSR#1 is misbranded under section 502(a) of the Act, 21 U.S.C. § 352(a).

Because the labeling does not warn consumers of the above-mentioned potential for side effects, the product OSR#1 is also misbranded under section 502(f)(2) of the Act, 21 U.S.C. § 352(f)(2), in that the labeling lacks adequate warnings for the protection of users. The introduction or delivery for introduction into interstate commerce of this misbranded drug violates section 301(a) of the Act, 21 U.S.C. §§ 331(a).

The issues and violations cited in this letter are not intended to be an all-inclusive statement of violations that exist in connection with your product. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence or the occurrence of other violations. It is your responsibility to ensure that your firm complies with all requirements of federal law and FDA regulations. In this regard, please note that products are misbranded under section 502(j) of the Act, 21 U.S.C. § 352(j) if they are dangerous to health when used in the dosage or manner; or with the frequency or duration prescribed, recommended, or suggested in the products’ labeling.

You should take prompt action to correct the violations cited in this letter. Failure to promptly correct these violations may result in legal action, without further notice, including, without limitation, seizure and injunction. Other federal agencies may take this Warning Letter into account when considering the award of contracts.

Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct violations. Include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the time within which you will complete the correction. Furthermore, please advise this office what actions you will take to address product that you have already distributed. Additionally, if another firm manufactures the product identified above, your reply should include the name and address of the manufacturer. If the firm from which you receive the product is not the manufacturer, please include the name of your supplier in addition to the manufacturer. Address your reply to the Food and Drug Administration, 6751 Steger Drive, Cincinnati, Ohio 45237, Attention: Stephen J. Rabe, Compliance Officer.

A description of the new drug approval process can be found on FDA’s internet website at
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/NewDrugApplicationNDA/default.htm. Any questions you may have regarding this process should be directed to the Food and Drug Administration, Division of Drug Information, Center for Drug Evaluation and Research, 10903 New Hampshire Avenue, Silver Spring, Maryland 20993.

Sincerely,

/s/

Teresa C. Thompson
Cincinnati District

This story is being discussed at Countering Age of Autism as FDA Steps Up to the Plate on OSR#1.

Addenda:

CTI solicited charitable donations to help get started through the CTI Science Foundation, which includes “Katie Wright, Julie Obradovic, Dr. Jerry Kartzinel, Dr. Julie Buckley, Scott Barli and Kathryn Wachsman”

Kim Stagliano discussed previous Tribune stories and the question of toxicity of OSR in another piece

I was contacted by Ms. Tsouderos for an interview about her forthcoming article on a supplement called OSR from CTI Science. CTI’s Science’s FAQ page says OSR is less toxic than aspirin and Vitamin E. If the Tribune has its own toxicity testing, I’m sure readers will be interested in seeing the data. In light of the skewing of parental interviews in the past, I chose not to respond to her requests for an interview. Others, like the founder of CTI Science, Dr. Boyd Haley, graciously allowed the interview process to continue until such time as it became clear that the writer’s goal precluded gaining meaningful insight.

It appears to this reader that perhaps it was CTI Science and Boyd Haley who may have kept the readers from obtaining “meaningful insight”. If a reporter asks about toxicity and you have data showing hair loss, discolorations, and “abnormalities of the pancreas, and lymphoid hyperplasia” shouldn’t you produce that data?

In support of David Gorski

22 Jun

To whomever it may concern,

You have probably recently had to deal with a handful of vitriolic comments regarding the online activities of David Gorski. You will probably have been pointed to an online essay by a young man called Jake Crosby in which he makes a series of claims regarding David Gorski and his ‘ties’ to vaccines/vaccine manufacturers and other entities.

I urge you to read these comments and this essay very, very carefully. Once you do I am in no doubt that you will see what the rest of us clearly can – that this work is the work of a highly impassioned young man who believes that he is right. He believes that vaccines cause autism to state it clearly and he believes that by having some kind of – any kind of – tie to a pharma organisation means that David Gorski is ‘tainted’. But what really annoys master Crosby is the fact that David Gorski regularly blogs in support of the science that clearly shows vaccines do not cause autism and blogs against the pseudo science that attempts – and continually fails- to draw any kind of a link between vaccines and autism.

So this, in master Crosby’s eyes, is David Gorski’s crime – supporting the science and decrying the bad science.

In order to cast some kind of suspicion over David Gorski’s support of science, Crosby has ‘discovered’ that Gorski is conducting research into ways to reuse some types of drugs – drugs developed by Sanofi-Aventis who of course also manufacture some vaccines. And that, despite another few hundred words from master Crosby is that. That is the sum total of his ‘investigation’ and the sum total of David Gorski’s crime.

The only real eye-opener on this issue is that Jake Crosby managed to wring out as many words as he did on this total non-issue.

I have known David Gorski online for a number of years. We often quote one another and link to one anothers posts. We regularly email each other and I was disappointed to be unable to meet him for drinks on a visit to the UK he took a few years ago. In my experience of the man he is rigorous, almost fanatical with regards to accuracy and brings these traits to many areas of blogging and online writing including the investigation of bad science.

Why does it matter to me? It matters because I have an autistic child and an autistic step child. When my autistic child was first diagnosed I firmly believed that her autism was caused by vaccines. It was only through being exposed to writings of David Gorski and his peers on the science of autism and the bad science of the autism/vaccine connection that I eventually saw for myself what was obvious: vaccines don’t cause autism and never did.

Scientists such as David Gorski often blog and write online anonymously. They do this because to be exposed to the sort of people Jake Crosby colludes with often means being exposed to harassment and threats. David Gorski is now finding that out for himself. I hope that you as his peers, colleagues and employers will see how vital it is that David Gorski continues blogging and that you will support him in both his work and his blogging.

Functional impact of global rare copy number variation in autism spectrum disorders

14 Jun

A recent study by the autism genome project has been gathering a lot of publicity. Kev interviewed one of the principle investigators. But, we haven’t really presented a discussion of the science here. With that introduction, you might be surprised to read: and that isn’t going to change. A few good presentations have been written on this paper. Far better presentations than I can do. So I will refer you to:

The Simons Foundation SFARI blog has Autism marked by copy number changes in coding regions. (note: I added this link after the initial publication of this blog post)

P.Z. Myers in Autism and the search for simple, direct answers and Respectful Insolence with, More evidence for a genetic basis for autism.

The paper itself is Functional impact of global rare copy number variation in autism spectrum disorders, appears in the journal Nature.

Here is the abstract:

The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours1. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability2. Although ASDs are known to be highly heritable (~90%)3, the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4?×?10-4). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53–PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.

Interview with Stephen Scherer

11 Jun

Stephen Scherer is co-author on the recent paper ‘Functional impact of global rare copy number variation in autism spectrum disorders‘. I caught up with him via email to ask a few questions:

1) What is the ‘bottom line’ message readers can take away from your work?

I am always frustrated when I hear at the end of most news stories…’and we don’t know what can cause autism’. Data from the past few years including our new study show alterations in genes can cause autism. We have not found all of the genes yet, and not all autism cases can be accounted for (the genetics can be complex) but genes can cause autism. For the specialists, through our new study we show either de novo or rare inherited copy number variations as one form of genetic alteration involved in autism. The genes affected are often linked together in a connected functional pathway and may of these molecules dictate how brain cells (neurons) develop and communicate. Some of the autism genes we found have already been found to cause intellectual disabilities, which is not entirely surprising since many individuals with autism also have these challenges.

2) How does your paper tie in with other gene/autism studies?

We validate many previous findings, but also find dozens and dozens of new autism risk genes. Our data furthers the hypothesis that rare genetic alterations contribute much more relative risk to developing autism than common genetic variations.

3) What should future researchers use your study for in terms of direction to take their own work?

I think one of the most important impacts of the study is the design itself. Nature really wanted us to include the Figure 1, which outlines the design and analysis. CNV studies are still quite tricky to do and the data has to be of the highest quality to make sense of it. I think our study on autism will set the standard for all other studies going forward, so they should follow it. Moreover, many of the functional pathway studies published before may have been either underpowered, flawed by low resolution arrays or high false discovery rates, or incomplete study designs. We spent alot of time thinking of how to best do this properly so if others are interested they should read the Supplementary Information carefully. Use it as a guide. Finally, for the functional biologists look at the long list of genes we present in the Supplementary Information since they may find their favorite gene to be an autism candidate gene!

4) How difficult was it managing the input from such a very large amount of co-authors?

The Autism Genome Project has some 120 scientists from 11 countries involved (see the authorship list). We selected a ‘writing team’ comprised of genome scientists, statisticians, medical geneticists, psychiatrists and developmental pediatricians. Interesting, everyone saw their own story in the data. I pretty much new in advance what I wanted to see in the final manuscript so much of my job was bring focus to the many other good ideas (note that there are five other papers spinning out of this larger study presenting some of these other data and interpretations). In took about 12 solid months of analysis of the data, three months of writing and editing, alot of cursing, and then submission to Nature (with even more cursing). The review time from submission to publication took ~six months. This was the hardest for me (except other than constantly changing the author list….and affiliations). The reviewers were very very thorough and Nature can (rightfully) be very demanding. In the end we are very proud of the manuscript. Dalila Pinto who is the first author and a post-doc in the lab was the driving force behind the analysis and deserved a lions-share of the credit. Would I do it again? I’ve had two Senior Author papers in Nature this year, which have been very draining. But I would do it again!

NIH funded research includes search for possible vaccine-autism link

11 Jun

Much time is spent discussing whether a study of autism and vaccination status could or should be undertaken. Generation Rescue has been trying to get funding for such a study, but their proposal is weak and vague. The question arises, why doesn’t any group with real strong credentials consider this project?

Would you be surprised to find out that it is already ongoing? And that the principle researcher is someone with mainstream credibility?

It turns out that potential environmental causation of autism, including vaccines, are a part of a study which (if all went according to schedule) just finished the data collection phase. The NIH funded project, GENE-ENVIRONMENT INTERACTIONS IN AN AUTISM BIRTH COHORT, was headed by Prof. Ian Lipkin of Columbia University. The project started in 2003 and was prospectively monitoring a cohort of children diagnosed with ASD’s and another cohort of controls.

The project is discussed below:

Reports of increasing prevalence of autism spectrum disorders (ASDs), a set of highly genetic conditions, are intensifying interest in the role of environmental exposures, including infectious, immune, and toxic factors. Retrospective studies exploring associations between environmental factors and ASDs are compromised by selection bias, small sample sizes, possibly invalid diagnosis, and absence of biologic measures. This prospective study will employ an unselected birth cohort of 75,500 in which cases are ascertained through screening of the entire population, diagnoses established using uniform procedures, extensive histories and clinical data obtained, and biologic samples collected serially throughout pregnancy and early childhood. The application of high throughput laboratory assays to derive maximal information from developmentally-influenced, finite, and nonrenewable biologic samples, and inclusion of early screening and diagnostic assessments, will permit an unprecedented, rich view of the longitudinal trajectory and nascent signs and symptoms of ASDs, facilitate discovery of biomarkers, and afford unique insights into the role of gene:environment interactions in ASD pathogenesis. Specific aims are to: (1) establish the autism Birth Cohort (ABC) through ascertainment of cases of autism spectrum disorder (ASD, N=150-233) and selection of controls (N-1000) from the Norway Mothers and Child (MoBa) cohort; (2) examine biologic pathways that may predispose to ASD, through evaluation of immune, endocrine, and neuroregulatory factors in mothers during early gestation or at birth and in children, at birth or 30 months postnatal; (3) identify environmental factors that may be directly or indirectly associated with ASD, including pre- or postnatal infection, vaccination, very low birth weight or other obstetric risk factors in which infections are implicated, dietary and/or environmental exposure to methylmercury; (4) describe the natural history of clinical, anthropometric, and neurobehavioral features of ASD; and (5) explore genotypic influences that may be directly or indirectly associated with ASD by testing associations of ASD and/or its endophenotypes with family history of autoimmune disease or selected candidate genes, and investigating conditional gene-environment effects using antecedent factors found to influence ASD risk.

Emphasis added.

Prof. Lipkin was a member of the team which looked at children with gastrointestinal disorders, Lack of Association between Measles Virus Vaccine and Autism with Enteropathy: A Case-Control Study. Amongst other findings, they found that (a) regression was not correlated with MMR vaccination and (b) persistent measles infections are not present in the guts of autistic kids more than in non-autistic kids. Basically it was the study that most closely replicated some of Mr. Wakefield’s team’s efforts and showed that Mr. Wakefield’s results were not reproducible.

Another study, THE CHARGE STUDY: CHILDHOOD AUTISM RISKS FROM GENETICS AND THE ENVIRONMENT, includes “vaccines” in the project terms. This study has been funded to the tune of about US$5,000,000 and is headed by Prof. Irva Hertz-Picciotto, who has stated that vaccines should be considered for research into autism causes.

If you are wondering if mercury is being investigated, AUTISM IN A FISH EATING POPULATION continues study on methyl mercury exposures in the Seychelles. Also, the University of Washington has a study ongoing, NEUROIMMUNOTOXICOLOGY OF MERCURY. Johns Hopkins has a study now going on 4 years, GENETIC SUSCEPTIBILITY TO MERCURY-INDUCED IMMUNE DYSFUNCTION IN AUTISM & ASD. Also, the University of Texas has a study, EPIDEMIOLOGICAL RESEARCH ON AUTISM IN JAMAICA, which also is monitoring heavy metal exposures.

I have two questions. First, why do groups like Generation Rescue, SafeMinds, the National Autism Association and TACA claim that vaccine-autism and mercury-autism research isn’t being done? They are represented on government committees. Second, what do they hope to learn from doing their own study that isn’t going to be done better and sooner by other groups?

Urine test for autism? Hmmm

4 Jun

Following on from Lisa Jo’s well placed concerns about this study,I also have a few. Namely the references. Not being scientifically qualified to tackle the meat of the paper I look straight at what the researcher uses to support his ideas. So far I’ve found these references the authors base their paper on:

1) Kidd, P. M. Autism, an extreme challenge to integrative medicine. Part: 1: The knowledge base. Altern. Med. Rev. 2002, 7 (4), 292–316.

2) Ashwood, P.; Anthony, A.; Pellicer, A. A.; Torrente, F.; Walker-Smith, J. A.; Wakefield, A. J. Intestinal lymphocyte populations in children with regressive autism: evidence for extensive mucosal immunopathology. J. Clin. Immunol. 2003, 23 (6), 504–17.

3) Bolte, E. R. Autism and Clostridium tetani. Med. Hypotheses 1998, 51 (2), 133–44

4) James, S. J.; Cutler, P.; Melnyk, S.; Jernigan, S.; Janak, L.; Gaylor, D. W.; Neubrander, J. A. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am. J. Clin. Nutr. 2004, 80 (6), 1611–7

At the very least, relying on studies from Alternative Medical Review, studies co-authored by Andrew Wakefield, studies from Medical Hypothesis and studies co-authored by Jim Neubrander should give rise to questions over the credibility of this paper. Is it enough to scupper it? Of course not. But when we take Lisa Jo’s questions into the bargain – that autism does not always, if ever, have a distinct GI component, I have to wonder about this paper.

Addressing the ‘too many too soon’ hypothesis

3 Jun

Regular readers may be aware that I blogged about a study recently that demonstrated the early stages of tackling the ‘too many too soon’ hypothesis. It came in for some fierce criticism in the comment section so I wrote to the lead author to get his thoughts. What follows is his answer to me via email:

Reviewing your blog, there are two related criticisms of our study.

First, I must clarify the conflict of interest comment. Though less relevant in my mind, it addresses the other limitations noted by your readers. This study was completely unfunded – not by any pharmaceutical company, not by the CDC. We did this all in our free time because of a simple non-financial “conflict” – as infectious disease physicians we take care of children who suffer needlessly from vaccine preventable diseases. This clarification of funding leads to point 2 – because we
did not have millions of dollars at our disposal we chose to use pre-existing data to address a common parental concern for which we could not find any evidence-based talking points.

This strategy had significant benefits – once we had the idea for this study we got right to work and did not have to wait 7-10 years to see what the outcomes might be. However, as we acknowledge in the discussion (and your readers point out), the use of pre-existing data also introduces limitations. We did not have control over which outcomes were tested, nor which children were included or excluded from the original study.

Nevertheless, I believe this study was accepted for publication in an academic medical journal because it offers a unique methodology that may be used to study the effects of delayed vaccination on any outcome of choice, whether it be the incidence of vaccine-preventable diseases or the proposed vaccine side effect du jour. Unfortunately, I do not have the resources to perform these studies myself.

A separate question – which is really a critique of the original NEJM study (with which I was not involved) and not ours per se – is why the authors chose to exclude the children they did. In the time since you e-mailed be I believe “Luna_the_cat” has explained this fairly clearly. Basically, the original study excluded children with brain injuries that would not have been related to vaccination (except for a few – pneumococcal and haemophilus influenza meningitis which vaccines PREVENT) and this seemed reasonable in the initial study. Furthermore, the majority of these exclusion criteria are prenatal or congenital diagnoses that would have predated vaccination anyway.

Finally, regarding lack of “controls”. This was not a “vaccinated versus unvaccinated” study, nor was it intended to be. It was designed to address the “too many too soon” hypothesis. Our “controls” were those children in the cohort who received fewer vaccines later during the first year of life. In this case the “exposure” was timely vaccine receipt – which was never associated with any adverse neurodevelopmental outcomes.

Autism and mental retardation – genetic overlap

30 May

Post taken from Medical News Today

Researchers working with Professor Gudrun Rappold, Director of the Department of Molecular Human Genetics at Heidelberg University Hospital, have discovered previously unknown mutations in autistic and mentally impaired patients in what is known as the SHANK2 gene, a gene that is partially responsible for linking nerve cells. However, a single gene mutation is not always enough to trigger the illness. In some cases, a certain threshold of mutation must be exceeded. The researchers conclude from their results that a correct inner structure of the nerve cell synapses is necessary to enable the normal development of language, social competence, and cognitive capacity. Essential for the success of the project were the studies by the Heidelberg research team with the doctoral student Simone Berkel and collaboration with a Canadian research team headed by Steve Scherer. The study has already been published online in the leading scientific journal Nature Genetics.

Autism is a congenital perception and information-processing disorder of the brain that is often associated with low intelligence, but also with above-average intelligence. The disease is characterized by limited social communication and stereotypical or ritualized behavior. Men are affected much more frequently than women. Autism and mental retardation can occur together but also independently of one another and are determined to a great extent by hereditary factors. Some of the responsible genes have already been identified but the precise genetic mechanisms have not yet been explained.

Genetic makeup of hundreds of patients analyzed

Professor Rappold and her team focused their studies on the SHANK2 gene, which encodes a structural protein at the nerve cell synapses. It is responsible for the mesh structure of the basic substance in the postsynapse. Only when the postsynapse is properly structured can nerve impulses be correctly transmitted. The researchers analyzed the genetic material of a total of 396 patients with autism and 184 patients with mental retardation. They found different mutations in their SHANK2 genes in the area of individual base pairs, but also variants in the number of gene copies. The mutations led to varying degrees of symptoms. None of the observed gene variants occurred in healthy control persons. “Apparently an intact postsynaptic structure is especially important for the development of cognitive functions, language, and social competence,” explained Professor Rappold.

Identical mutations as the cause of different diseases

Some of the genetic mutations identified were new occurrences of mutations that were not inherited from the parents, but some of the mutations were also found in one parent. Since there are also healthy carriers of gene variants, we must assume that a certain threshold of gene mutations must be exceeded for the disease to appear. “Moreover, the same mutation can be present in an autistic patient with normal intelligence and in a mentally impaired patient,” said Professor Rappold. There is some overlap in the clinical symptoms of mental retardation and autism, which can now be explained by a common genetic cause.

Social influence and the autism epidemic

28 May

Prof. Peter Bearman at the University of Columbia has spent considerable effort studying the autism data from the California Department of Developmental Services.

I wrote about Prof. Bearman’s paper Social influence and the autism epidemic before. It just popped up in pubmed.

When I checked the website for the center where Prof. Bearman’s team works, I found the press release from the paper:

Study: “Social influence” playing role in increased autism diagnoses

Social influence plays a substantial role in recent increases in autism diagnoses, according to a study in the March, 2010 issue of the American Journal of Sociology.

The study, by researchers from the Institute for Social and Economic Research at Columbia University, found that children living near a child who has been previously diagnosed with the disorder are far more likely to be diagnosed themselves in the following year. The proximity effect is not due to environmental factors or contagious agents, the study found. Rather, it is due mainly to parents learning about autism from other parents who have a child diagnosed with autism.

“We show that the likelihood of getting an autism diagnosis is clearly associated with person-to-person transmission of information,” said Peter Bearman, a sociologist who authored the study along with Ka-Yuet Liu and Marissa King. “Parents learn about autism and its symptoms; learn about doctors who are able to diagnose it; and learn how to navigate the process of obtaining a diagnosis and services from parents who have already been through the process with their own child.”

The researchers stress that the results do not mean that autism is not real or that it is overdiagnosed. “Our study doesn’t address the underlying cause of autism,” Dr. Bearman said. “We are describing the mechanism by which the number of diagnoses is increasing. It could be that the real incidence of the disorder is only now being uncovered. I think that is a reasonable message from this paper.”

In California, where this study was conducted, the number of autism cases handled by the California Department of Developmental Services increased 636 percent between 1987 and 2003.

The Columbia University team looked at data on over 300,000 children born between 1997 and 2003 throughout California. The team found that children who live within 250 meters of a child with autism have a 42 percent higher chance of being diagnosed with the disorder in the following year compared with children who do not live near a child with autism. Children who lived between 250 meters and 500 meters from a child with autism were 22 percent more likely to be diagnosed. The chance of being diagnosed decreases significantly the farther children live from another child with autism.

The study used several tests to determine whether these results could indeed be explained by a social influence effect, or if environmental toxicants or a virus are to blame. For example, the researchers looked at children who live close to each other, but on opposite sides of school district boundaries. These children are likely exposed to the same environmental conditions, but their parents likely belong to different social networks. The research shows that the proximity effect only exists when parents reside in the same school district. Children who live equally close to a child with autism but in another school district were no more likely to be diagnosed with the disorder than children who do not have a neighbor with autism.

The results also showed the proximity effect to be strongest among children on the milder side of the autism spectrum. That is also consistent with a social influence explanation, Dr. Bearman says. “Parents of severely disabled kids are more likely to recognize the disorder without needing input from social contacts, so we would expect to see a weaker social influence effect there, and that’s exactly what we found.”

The Strength of Social Influence

The data set used in the study allowed the researchers to judge just how strong the influence effect is compared to other factors that may be driving the epidemic. For example, previous studies have found a link between autism and parents’ ages. Parents today are having children later in life, and that could be causing autism cases to increase. Other studies have found that parents’ education plays a role as well. Better educated parents may be more likely to obtain a diagnosis for their children.

The Columbia team found that each of these factors plays a role in the epidemic, but the social influence phenomenon was the strongest. The researchers estimate that the proximity effect explains about 16 percent of the recent increases in autism diagnoses. Put another way, if no child lived within 500 meters of a child with autism, there would be a 16 percent reduction in autism diagnoses. That effect was stronger than the other factors tested. For example, the mother’s age explained about 11 percent of the increase. The mother’s education accounted for 9 percent.

The study was funded by the NIH Pioneer award for innovative health research.

What caught my eye was that last paragraph, where they note that 16% of the increase can be accounted for from this social influence phenomenon, but also that 11% was due to increased maternal age and maternal education accounts for another 9%.

This is in addition to diagnostic substitution, which accounts for about 25% of the increase in the CDDS client caseload.

One of the footnotes in the Social Influence paper also caught my eye:

The strong positive association of autism (during the period of increasing prevalence, 1992–2000) with socioeconomic status (King and Bearman 2009b), coupled with the increasingly negative socioeconomic status gradient for MR (arising from differential abortion rates for fetuses identified as chromosomally damaged through amniocentesis), has led to a relative stigma reversal and a consequent decline in the rate of MR diagnoses.

King and BEarman, 2009b is a “working paper” at Columbia University (“The Increased Prevalence of Autism.” Working paper. Columbia University, Paul F. Lazarsfeld Center for the Social Sciences.)

One feature that is very interesting in the paper is the how the level of “functioning” of the child relates to the social influence effect. The basic result of the paper is that when a family lives near another family with an autistic child, they are more likely to obtain CDDS services under the autism label. That effect is stronger for “high functioning” autism. To me, at least, this seemed counter intuitive. Here is a graph from the paper showing that the social influence effect means that a child with “high-functioning” autism is about 40% more likely to be registered with the CDDS if he/she lives close to a family with an autistic child.

The trend with proximity is very clear, as shown in the figure below. The probability of a child be registered with the CDDS with an autism label drops off very smoothly and clearly with distance to a family whose child was recently diagnosed. This is not seen for mental retardation.

As the authors point out:

Compared with children who are 501 meters–1 kilometer away from their nearest neighbor with autism, those in close proximity (1–250 meters) to a child with autism have a 42% higher chance of being diagnosed with autism in the subsequent year. Proximity of 201–500 meters increases the chance by 22%. In contrast, being farther away from a child with autism reduces the chance of a diagnosis.

I know this is a repeat in many respects. But I also have found this work to be very interesting and thought it worthwhile to bring up these points I didn’t discuss before.

Anne Dachel, Age of Autism Editor, makes remarkable claim

27 May

I was browsing the comments section of a seemingly innocuous story about autism – that early intervention might not be the universal panacea once thought – when I came across a comment from Anne Dachel, one of the leading ‘thinkers’ and editors behind the online anti-vaccine blog Age of Autism.

…I think a disorder that was unheard of 25 years ago…

I had to read it a couple of times to make sure I was seeing it right – I was – Anne Dachel believes autism was unheard of prior to 1985.

To say this is a remarkable claim is being overly fair to Dachel. Its one of those claims that is regularly made by the Age of Autism team that leaves one’s jaw on one’s chest with the sheer audacity of either its boldness or stupidity. It reminds one of John Best’s claim that autism was unheard of in China prior to 1999. Another rampant piece of stupidity.

As previously noted, Dachel writes for Age of Autism. I’ll leave you to form your own conclusions as to the accuracy of their blogging based on their Editors own bizarre beliefs about autism.

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