You Spin Me Right Round, Blaxill Right Round

On 12 February of this year Neurotoxicology withdrew the article Delayed acquisition of neonatal reflexes in newborn primates receiving a thimerosal-containing Hepatitis B vaccine: Influence of gestational age and birth weight co-authored by none other than Andrew Wakefield. KWombles of Countering Age of Autism was the first to break this news and Just the Vax also blogged about it along with Respectful Insolence, A Photon in the Darkness and several others that day.

AoA's Mark Blaxill only just issued a predictably petulant diatribe regarding the withdrawn paper by Hewitson et al. It starts off with the bewildered meanderings of one that is clearly not familiar with scientific publications and editorial accountability.

How can a scientific study simply vanish? This paper had cleared every hurdle for entry into the public scientific record: it had passed peer review at a prestigious journal, received the editor’s approval for publication, been disseminated in electronic publication format (a common practice to ensure timely dissemination of new scientific information), and received the designation “in press” as it stood in line awaiting future publication in a print version of the journal. Now, and inexplicably, it has been erased from the official record. For practical scientific purposes it no longer exists.

The answer, of course, is that this is no ordinary scientific study. Age of Autism reported previously on its importance HERE , where we noted that “one likely tactic of critics of the study will include attempts to nullify the evidence based on the alleged bias of those involved.” The obvious risk, of course, was that a co-investigator on the paper, Dr. Andrew Wakefield, might make the study a target, especially in light of the hearings then underway at the U.K.’s General Medical Council (GMC).

First, let me point out that Neurotoxicology isn't a prestigious journal; it's an okay journal with an impact factor of 2.4. It may be nitpicking but it is disingenuous to attach exaggerated attributes such as 'prestigious' and 'world-renowned', especially when referring to cranks and their science. But Blaxill is right about two things; that was no ordinary scientific study and Wakefield's self-inflicted predicament was undoubtedly targeted, after the fact however. The monkey HepB study was not good, in fact, the study design, methods and results were quite poor. It never should have passed peer-review but somehow did; perhaps the editorial staff at Neurotoxicology were hedging their bets on a bombshell study and had enough reputable authors to withstand the blowback. That is evidenced by this response to Lynn Redwood's request for information by Elizabeth Perill:

Elizabeth Perill (Elsevier is a division of Reed Elsevier PLC, a large scientific publishing corporation and owner of Neurotoxicology). Perill wrote the following note to Ms. Redwood on February 4th.

Dear Dr. Redwood [sic],
Aside from any authorship concerns, on reflection the paper is not suitable for publication in this journal. The decision was based on the fact that the paper should not have been accepted in Neurotoxicology and the paper is not suitable for the audience of Neurotoxicology.
Kind regards,
Liz
Elizabeth Perill
Publisher, Toxicology,
Elsevier
360 Park Av. South, New York, NY 10010

So when more scrutiny was applied to the study itself, it didn't pass muster.

When Joan Cranmer accepted the primate paper in Neurotoxicology, her decision could not have been an easy one. The study subject and one of the study authors, Andrew Wakefield, were known to be highly controversial. All of the information about the GMC proceedings and the accusations against Wakefield were well known to the editors and peer reviewers. Despite that knowledge and the risks involved, Cranmer and her editorial team judged the science to be sound and decided to go ahead. We complimented them at the time, noting that “the journal editors at Neurotoxicology have taken a courageous stand in publishing what is sure to be unwelcome evidence in some circles.” It appears, however, that Cranmer’s superiors within Elsevier did not share those views.

Emphasis mine. That's bollocks Blaxill; let's review what the Conflict of interest statement in the study stated:

Prior to 2005, CS and AJW acted as paid experts in MMR-related litigation on behalf of the plaintiff. LH has a child who is a petitioner in the National Vaccine Injury Compensation Program. For this reason, LH was not involved in any data collection or statistical analyses to preclude the possibility of a perceived conflict of interest.

And let's review what the known conflicts of interest really are. Andrew Wakefield was well in the midst of GMC misconduct proceedings against him regarding the 1998 Lancet paper and the Neurotoxicology study was not submitted until 16 June 2009. Thoughtful House routinely treats autism as vaccine injury and promotes the use of chelation and Wakefield was firmly in place as the director then. Laura Hewitson is registered as a DAN! and also is employed at Thoughtful House as is her husband, Dan Hollenbeck. He is on the board of directors for SafeMinds, one of the funding sources for the monkey studies and a vitriolic supporter of the mercury-autism 'hypothesis'. Additionally, both openly support chelation. David Atwood from the University of Kentucky is the patent holder for N,N’-bis (2-mercaptoethyl)isophthalamide an industrial chelator designed for cleaning up mining sludge, or better known as OSR which is being marketed by Boyd Haley, also of the University of Kentucky as an autism cure for children.

As Orac pointed out, those of us involved in the topic of vaccines and the claims of 'damage' are an oddball bunch; it's a niche interest and it is audacious to assume that journal editors would have all of this information at their fingertips about any authors that makes submissions to their publications. That is what COI statements are for and probably a substantial reason why this study was withdrawn. Think about it; a group of authors don't declare their full COIs and then one is later shown in a formal proceeding to have acted with callous disregard for children that he was supposed to care for, unethically and dishonestly, not to mention the other glaring omissions. That cannot be simply ignored, at least in the real world. As Dr. Perill stipulated, "Aside from any authorship concerns, on reflection the paper is not suitable for publication in this journal.", can certainly be taken as the science was more closely scrutinised after the appalling COIs came to light. An update to AoA's post on this confirms this:

UPDATE: After publishing the article, Age of Autism received this statement from Joan Cranmer.

“Scientific integrity and good science are fundamental principles for publication of research articles in Neurotoxicology. Although rare, the journal withdraws papers whenever these essential principles are cast into doubt. The January 28, 2010 UK General Medical Council ruling of research dishonesty by Dr. Andrew Wakefield cast into doubt the scientific integrity of a new related paper co-authored by Wakefield*. However, it would be inappropriate for either me or the other editors to discuss the specific factors publicly.

Professor Joan M. Cranmer, Editor, Neurotoxicology

This shouldn't be so difficult for Blaxill and Co. to parse, but somehow it is. Scientific integrity and good science; principles that seem to allude the vaccine-autism pseudo-scientists. Blaxill also predictably pulls out the Galileo gambit and compares Wakefield to Herbert Needleman a physician who made the discovery that lead poisoning is responsible for developmental disorders and took on a powerful industry that tried to railroad him.

One of the reasons that Needleman is revered in the neurotoxicology community is because he had to surmount formidable obstacles and fight powerful opponents in order to protect children from dangerous exposures to heavy metals. Like Wakefield, Needleman once served as an expert witness in a legal proceeding, in this case on behalf of a child from Utah who had been injured by lead pollution. Also like Wakefield, Needleman found himself facing off against powerful industry forces, in this case the oil and gas industry and their suppliers of lead, companies such as Ethyl Corp and E.I. DuPont de Nemours. Most notably, in order to defend their profits, the lead industry mounted an aggressive effort to discredit Needleman. In 1991, he was called before the Office of Scientific Integrity at the National Institutes of Health (NIH) on charges of scientific misconduct.

The chasmic differences between Dr. Needleman and Wakefield are scientific integrity and unassailable science that prevailed even under intense scrutiny. It really is a grotesque affront to someone of Dr. Needleman's credentials and righteousness. Wakefield is no Galileo, no Needleman and no Marshall and Warren. Just because Wakefield is viewed by his supporters as David taking on the big bad Goliath of Pharma, that doesn't make him right. If he had the science to support his assertions, it would have been replicated and it would have withstood scrutiny.

Seen from this perspective, what if the next-generation incarnation of Herbert Needleman is Andrew Wakefield, but in today’s version of the story, the balance of power has shifted in critical ways? In Wakefield’s case the product is neither gasoline nor paint, but vaccines, one of the most privileged product categories ever invented, products that are produced and promoted by the medical industry with missionary zeal. In contrast to the limited scientific influence of the oil and gas industry, the medical industry Wakefield faces is far more powerful, pursues its interests with greater skill, controls the flow of scientific information and effectively dictates media coverage. It appears now that the medical industry is so powerful that it can rewrite scientific history when it wants and even erase important scientific publications in a reputable journal.

The oil and gas industry have limited influence? Are you kidding me? Sadly, that was a rhetorical question that I well know the answer to. If Pharma is so competent and omnipotent, how did they allow Wakefield to not only publish the 1998 Lancet case series, but leave it published for almost 12 years, not to mention all of his subsequent publications and the most recent Neurotoxicology study? And only just got around to getting the GMC to instigate proceedings against him? Scientific publications get retracted all the time, it's part of the process when scientific fraud is discovered, and Wakefield fits that bill.

Wakefield is in a league with the likes of Victor Ninov, Jan Hendrik Schön, Robert P. Liburdy and Hwang Woo-Suk, the latter also feigning ignorance of bioethics in his defence. But Wakefield is a rank amateur compared to the Piltdown Man hoax. Whoever that was, kept that going for more than 4 decades and the true identity of the perpetrator(s) remains unknown. Wakefield's fraud was discovered a mere 5 years after the 1998 (now retracted) Lancet paper by a journalist, no less. Even if one wishes to (erroneously) argue that Mr. Deer was aimed at Wakefield, if there was nothing there, then Wakefield wouldn't have been so thoroughly discredited and looking for his next gig right now.

AoA's call for Neurotoxicology's editor Joan Cranmer to resign in the name of 'think of the children' is preposterous and just isn't going to be considered, let alone done. It is a vapid attempt to rally the troops in the face of yet another failed attempt to get their pseudo-scientific tripe into a real peer-reviewed journal and game over for Wakefield. I think that even they can see the disgrace of having to publish in bottom-dwelling vanity press journals such as JAPandS, Medical Veritas (ooo, they say it's a 'pre-eminent' journal) and of course, Medical Hypotheses and even though that is an Elsevier journal, I think they would give the monkey study a go, given their standards.

If you are interested in reading more on this topic, please visit Countering Age of Autism and of course, Respectful Insolence.

And So the Spin Begins

Age of Autism has finally broken it's silence regarding the departure of Andrew Wakefield from Thoughtful House. Since Mark Blaxill and Carol Stott, the latter also quietly removed from Thoughtful House's research staff, couldn't procure the services of PR powerhouse Max Clifford, he had to settle for the bumbling, albeit puppy-dog loyal, Dan Olmstead. Here is Wakefield's 'exclusive' statement to AoA:

“There has been an extraordinary outpouring of support from the autism community in response to the events of the last two weeks”, Wakefield told Age of Autism in an exclusive interview. “The most exciting part of it has been the opening up of an entirely new sort of opportunity that will allow me to continue my work on behalf of autism families.” Wakefield said he would provide more specifics on the nature of that opportunity soon. “In addition, I will now speak publicly to refute the findings that have been made against me. I know my necessary silence on these issues has troubled many parents in both the U.K. and the U.S. But I’m ready now to get back on the front foot and publicly contest the false accusations that have been made against me, my colleagues, and indirectly The Lancet children. It’s been long overdue.”

I can only take that to mean that Wakefield will adopt the nom de plume of 'Dr. Andy' as notable celebretricians and all chiropractors do. And "The most exciting part of it has been the opening up of an entirely new sort of opportunity that will allow me to continue my work on behalf of autism families.” sounds like a segue to the announcement of, 'Dr. Andy is available for children's birthday parties; his specialities are magic tricks, balloon animals and venipuncture.'

Dan, you're a little late to the party as the news of Dr. Wakefield's departure from Thoughtful House was announced 18, February. You also forgot to mention the departure of Arthur Krigsman from Thoughtful House as well. I'm sure the spin which has been fed to you by Wakefield and, in turn passed on, serves as temporary morale boost for your readers. But make no mistake, Thoughtful House is cleaning house and Wakefield, Krigsman and Stott are liabilities. If they can't support them, notably Wakefield in light of the recent UK General Medical Council Ruling, the Lancet retraction of his 1998 paper and the subsequent withdrawn monkey study from Neurotoxicology, it certainly makes me wonder who could.

Wakefield is finished. There has been no conspiracy; his original publication was based upon atrocious ethics and conflicts of interest, highly-flawed science and fudged medical records. It doesn't get much worse than that. This man is no hero; he's nothing more than a predator.

Andrew Wakefield resigns from Thoughtful House!

Rumours had been going around since the early morning that Andrew Wakefield had resigned from his post as Director of Research at Thoughtful House. I have just had confirmation by email that he has indeed resigned. Note that this link www.thoughtfulhouse.org/staff/andrew-wakefield.php now leads to their home page and the statement of support recently posted after the GMC ruling has disappeared from their landing page. They issued the following statement today:

The needs of the children we serve must always come first. All of us at Thoughtful House are grateful to Dr. Wakefield for the valuable work he has done here. We fully support his decision to leave Thoughtful House in order to make sure that the controversy surrounding the recent findings of the General Medical Council does not interfere with the important work that our dedicated team of clinicians and researchers is doing on behalf of children with autism and their families. All of us at Thoughtful House continue to fight every day for the recovery of children with developmental disorders. We will continue to do our very best to accomplish our mission by combining the most up-to-date treatments and important clinical research that will help to shape the understanding of these conditions which are affecting an ever-increasing number of children worldwide.

Call me Cassandra - I had indeed foreseen that this would happen on this blog.

Further commentary on Respectful Insolence here and here, and on LeftBrainRightBrain - this was Strike 4 (after the GMC ruling, the retraction by The Lancet, and the retraction of the NeuroToxicology paper). Can I predict there is more to come (this may cause some fallout for Wakefield for example)?

Monkey Business Indeed

The infamous monkey-hep B vaccine study, co-authored by none other than Andrew Wakefield, that was clearly part of a larger body of work has been withdrawn by the editors of Neurotoxicology after being accepted. First though, hat-tip to KWombles at Countering Age of Autism for the find. Last October, when the study was announced and e-published ahead of print, Just the Vax, Respectful Insolence and A Photon in the Darkness thoroughly debunked the methods and results but also highlighted the blatant conflicts of interest that remained undeclared in the study proof and corrected proof.

Elsevier's Policy on Article Withdrawl states:

An outcome of this principle is the importance of the scholarly archive as a permanent, historic record of the transactions of scholarship. Articles that have been published shall remain extant, exact and unaltered as far as is possible. However, very occasionally circumstances may arise where an article is published that must later be retracted or even removed. Such actions must not be undertaken lightly and can only occur under exceptional circumstances, such as:

Article Withdrawal: Only used for Articles in Press which represent early versions of articles and sometimes contain errors, or may have been accidentally submitted twice. Occasionally, but less frequently, the articles may represent infringements of professional ethical codes, such as multiple submission, bogus claims of authorship, plagiarism, fraudulent use of data or the like.

Article Withdrawal
Articles in Press (articles that have been accepted for publication but which have not been formally published and will not yet have the complete volume/issue/page information) that include errors, or are discovered to be accidental duplicates of other published article(s), or are determined to violate our journal publishing ethics guidelines in the view of the editors, may be “Withdrawn” from ScienceDirect. Withdrawn means that the article content (HTML and PDF) is removed and replaced with a HTML page and PDF simply stating that the article has been withdrawn according to the Elsevier Policy on Article in Press Withdrawal with a link to the current policy document.

At this juncture, it is purely speculation as to what led to the withdrawl of this study, however, it stands to reason that Andrew Wakefield's recent woes with the GMC rulings and the Lancet retraction of his 1998 study that implicated the MMR triple jab with his, entirely made-up, autistic enterocolitis diagnosis. In any event, it is safe to say that the withdrawl of this recent study by Neurotoxicology editors indicates something untoward.

There is no doubt that anti-vax sites like Age of Autism and Generation Rescue will use this opportunity to screed about 'persecution', 'suppression', 'censorship' and 'conspiracy' and keeping the 'Brave Maverick Doctors' down. But that is simply not the case. There is no doubt that that editors of reputable journals don't take such actions lightly and will have to answer for them. So whether this is a case of the science or ethics being more closely-scrutinised and/or the massive, undeclared conflicts of interest coming to light, that is more than enough to justify the withdrawl of this study.

In any event, we hope that the anti-vaxxers can at least get it straight that there were 20 monkeys used for this study. Twenty monkeys that were sacrificed (sorry Orac) to further a warped personal agenda and not to advance our scientific knowledge.

"Independent" the Wakefield way (really something for the fail blog)

One of the claims that keeps reappearing in the comments sections under articles covering the GMC ruling on Andrew Wakefield and colleagues is that

The key finding (chronic colitis found in ASD children) of Dr. Wakefield's early case report published in The Lancet in 1998 HAS been independently confirmed by medical researchers in five different countries.

That is a very significant claim. After all, independent confirmation of a recent finding, would make the validity of a finding more likely, and if 6 independent laboratories found the same gut changes in autistic children, then then likelihood that this was a) a fluke or b) made up by Andrew Wakefield would be drastically reduced.

Finally, one of those commenters has posted those ‘independent confirmations’ – so I thought it might be worth having a look at them.

Krigsman, A. (Assistant Professor of Pediatrics, New York University School of Medicine Director of Gastroenterology Services), et al.,Ileocolonoscopy in Children with Autistic spectrum Disorder and Chronic Gastrointestinal symptoms. Autism Insights 2010:2 1-11.

Gonzalez, L., et al., Endoscopic and Histological Characteristics of the Digestive Mucosa in Autistic Children with gastro-Intestinal Symptoms. Arch Venez Pueric Pediatr, 2005;69:19-25.

Balzola, F., et al., Panenteric IBD-like disease in a patient with regressive autism shown for the first time by wireless capsule enteroscopy: Another piece in the jig-saw of the gut-brain syndrome? American Journal of Gastroenterology, 2005. 100(4): p. 979-981.

Balzola, F., et al., Autistic enterocolitis: Confirmation of a new infammatory bowel disease in an Italian cohort of patients. Gastroenterology 2005;128(Suppl. 2);A-303.

Galiatsatos, P., et al., Autistic enterocolitis: Fact or fiction. Canadian Journal of Gastroenterology. 2009;23:95-98.

Let’s look at number 1, Krigsman et al. The name sounds vaguely familiar. In fact, anyone who has read a little about the MMR-autism affair will know Arthur Krigsman as the clinical director of Thoughtful House, which happens to be the same Texas Clinic out of which Andrew Wakefield practises. One editor of “Autism Insight”, the journal in which this “independent confirmation” was published, is Andrew Wakefield (another one the senior author of the study, Carol Stott). Gosh, I bet peer review was harsh for this one.

Gonzales et al, number 2, has been published in “Arch Venez Pueric Pediatr” which stands for Archivos Venezolanos de Puericultura y Pediatría. It was a bit tricky to get my hands on the paper, especially since the citation was not quite right, but I did manage and was not surprised to find that indeed the authors cannot replicate Wakefield’s 1998 “findings” of a distinct autistic enterocolitis, although they do report a higher incidence of gastrointestinal problems in their autistic group.

Balzola et al, number 3, is a case report of one adult autistic patient with inflammed bowel.

Similarly, Balzola et al, number 4, is a meeting abstract that never saw the light of day as a peer reviewed study.

Autistic enterocolitis: confirmation of a new inflammatory bowel disease in an Italian cohort of patients.
Federico Balzola, Clauser Daniela*, Alessandro Repici, Valeria Barbon, Anna Sapino***, Cristiana Barbera**, Pier Luigi Calvo**, Marina Gandione*, Roberto Rigardetto*, Mario Rizzetto.

Dept of Gastroenterology. University of Turin. Molinette Hospital Turin, Italy

*Dept of Neuropsychiatry for Children. University of Turin Regina Margherita Pediatric Hospital, Turin, Italy ** Dept of Pediatric Gastroenterology. University of Turin Regina Margherita Pediatric Hospital, Turin, Italy *** Dept of Biomedical Science and Human Oncology University of Turin

Although the causes of autism are largely unknown, this long-life developmental disorder is now recognised to affect as many as 1 to 500 children. An upper and lower intestinal disease has been recently described in these patients (pts) in spite of gastrointestinal symptoms have been reported by the parents back more many years. This disorder comprising ileo-colonic lymphoid nodular hyperplasia (LNH) and chronic inflammatory colonic disease was called autistic enterocolitis: an association between autism and bowel disease was then proposed.

Nine consecutive male pts (mean age 18 years, range 7-30 years) with a diagnosis of autism according to ICD-10 criteria that showed chronic intestinal symptoms (abdominal pain, bloating, constipation and/or diarrhoea) were enrolled. After routinely blood and stool tests, gastroscopy and colonoscopy with multiple biopsies were performed under sedation. A wireless enteroscopy capsule was also performed in 3 adult pts.

Anemia and fecal blood positive test were found in 2 pts and 3 pts, respectively. Gastroscopy revealed mucosal gastritis in 4 pts, esophagitis in 1 and duodenitis in 1 pts. Histological findings showed a chronic inflammation of the stomach and duodenum in 6 pts (66%) but inconsistent with celiac disease. Macroscopic mucosal abnormalities (aphtoid ulcerations and loss of vascular pattern) were found in 1 pts (11%) at colonoscopy and a LNH in the terminal ileum in 4 pts. (44%) Microscopic colitis with intraepithelial lymphocytes and eosinophils infiltrations, mucosal atrophy and follicular hyperplasia was histologically present in all the pts (100%) whereas a chronic inflammation with iperemia and villous shortening of the terminal ileum was shown in 6 (66%) pts. The wireless capsule revealed areas of bleeding or patchy erythema, mucosal erosions and ulcers in both jejunum and ileum in 1 patients whereas a particular chronic jejunum and ileal erosive pattern was evident in the other two.

These preliminary data are strongly consistent with previous descriptions of autistic enterocolitis and supported a not-coincidental occurrence. Moreover, they showed for the first time a small intestinal involvement, suggesting a panenteric localisation of this new IBD. The treatment to gain clinical remission has still to be tried and it will be extremely important to ameliorate the quality of life of such pts who are likely to be overlooked because of their long-life problems in the communication of symptoms.

These findings do not support a distinct pathology unique to autism. Additionally, Wakefield's original claim was essentially, 'MMR vaccination, then appearance of gastrointestinal symptoms, then regression into autism'. So not only was Wakefield's original claim roundly disproven, but Balzola et al.'s findings do not indicate anything remotely descriptive of Wakefield's original claim. This abstract also remains just that, i.e. an abstract presented at a meeting 5 years ago and has not gone through any peer-review, nor publication.

Finally, number 5, Galiatsatos et al., is a case report, featuring two adult patients with gastrointestinal problems and an ASD diagnosis. The authors call for “more investigations” in their discussion.

So what do we have here? Three (3) genuinely published cases of autistic adults who had consulted a doctor for gastrointestinal problems and were found to have gastrointestinal problems. One conference report from April 2005 that has not gone through peer review and has not appeared in a real journal in the 5 years since the conference. One real study looking at over 50 autistic children which does not confirm Wakefield’s findings. And finally, one study by Wakefield’s buddies in a freshly founded journal run by Andrew Wakefield and his buddies, to say that their buddy Andy was really right all along – how is that for "independent" confirmation?!

Edited on 19 January 2011 to add a find that Sullivan from LBRB led me to - it appears that the 2007 and 2008 tax forms (990) from Thoughtful House mention a "VENEZUELA COLLABORATION" under the projects they fund - a bit of thoughtful googling produced this gem

Gastrointestinal Pathology in Autism Spectrum Disorders: The Venezuelan Experience by Lenny G. Gonzalez, MD

Meet Lenny Gonzales, another Wakefield "buddy".

GMC ruling on Andrew Wakefield in and a reminder why MMR is important

The General Medical Council (GMC) announced its ruling (ETA link, hat tip to Kev) on the "Fitness to Practise" case of Dr. Andrew Wakefield today. They state that Wakefield "failed in his duties as a responsible consultant" and showed a "callous disregard" for the suffering of children involved in his research (as quoted from The Guardian). Undoubtedly, we will see more analyses and interpretations of this ruling in the days to come, so I wanted to take the opportunity to remind readers why it is important that children do not get measles:

In 2006, there was a measles outbreak in Nordrhein Westfalen, with a total of 1700 reported cases. Two toddlers died of encephalitis/MIBE at the time. Last year, a 4 year old girl, Michaela, who had caught measles at the age of 4 months in that outbreak, came down with SSPE. She has been in a wake coma since the Summer and no one knows how long it will be until she dies. The other two SSPE victims we blogged about have been in this state since 2005/6.

1700 cases, 3 dead/dying children...




Michaela in December 2009 (source: Bild Zeitung)

20 Monkeys

Last Wednesday (9.30.09), Age of Autism posted an unsurprising announcement of a soon-to-be published study by Hewitson et al., Delayed Acquisition of Neonatal Reflexes in Newborn Primates Receiving a Thimerosal-Containing Hepatitis B Vaccine: Influence of Gestational Age and Birth Weight in an upcoming issue of Neurotoxicology. Naturally, the author, Mark Blaxill not only inflates the results of the study but also manages to implicate influenza vaccines too:

Consequently, the finding that early exposure to potentially toxic vaccine formulations can cause significant neuro-developmental delays in primates has explosive implications for vaccine safety management. These implications go far beyond the domestic HBV program and raise concerns about HBV formulations sold abroad as well as the domestic influenza vaccine program. Most influenza vaccines, including the vaccines in the upcoming swine flu program, contain thimerosal and are routinely administered to pregnant women and infants.

Primate studies are not trivial to perform and it is imperative to implement a robust study design with sufficient statistical power. This is why we discuss the study design in more detail here. Before we dive into this study, let's backtrack a bit. Back in May of 2008, Hewitson et al. presented 3 posters at the International Meeting for Autism Research (IMFAR). Dr. David Gorski provided and excellent summary of these 3 abstracts on Science-Based Medicine so there is no need to discuss these at length here and now. We mention these abstracts since they are clearly parts of a single study that this Hep B/thimerosal study is also part of and there are discrepancies between them.

The authors claim that the animals were selected on a "semi-random" basis to receive either thimerosal-containing Hepatitis B vaccines at birth (TCV or thimerosal-containing vaccine) (n=13), a saline placebo (n=4), or no injection (n=3). We would like to point out that there isn't any accepted term such as "semi-random". Selection is either random or non-random and while there are numerous ways to randomise ones' selection randomisation is never a sliding-scale. Next, the 3 aforementioned abstracts state that there were 13 treatment animals (TCV) and 3 receiving saline placebo. Since these animals are all undoubtedly from the same group and protocol, that means that either 4 animals (1 saline placebo and 3 no injection) were not used for inclusion on the abstract results or that 4 animals were added for the purposes of this study. This discrepancy, along with their "semi-random" selection require explanation since they could certainly affect the results and subsequent interpretation.

Given the authors' hypothesis, i.e. ethylmercury affects infant (macaque) neurodevelopment, and to ensure they are controlling for all conceivable bias, it is puzzling as to why their treatment and control group sizes were alloted in the manner they were. The Hep B vaccine, with or without thimerosal will have a physiological effect upon recipients, which may easily manifest in outward symptomology e.g. fever, fussiness and/or injection site swelling and soreness. A more robust study design would have, for example, been TCV Hep B (n=10), thimerosal-free Hep B (n=5) and saline placebo (n=5). This would have controlled for the absolute effects between the TCVs, Hep B and placebo.

The authors also describe how the animals were divided into peer groups such that each group contained animals from either exposed or unexposed study groups for later "social testing". Not only is this social testing never mentioned again in the present paper, but placing the animals in such groupings introduced observer bias for the reasons mentioned above. Even though the animals were in separate cages, the cages containing exposed or unexposed animals were grouped together. An observer could subconsciously note that an animal was fussy and had visible swelling at the injection site and thus, be able to guess that the rest in the group were also TCV-exposed. Conversely, animals in the unexposed peer groups would likely be behaving differently and no outward signs of having received a vaccination.

Appropriate randomisation and blinding of the observer to the treatment are essential elements of a good study, animal studies that do not utilize randomisation and blinding are up to 5 times more likely to report a difference between study groups than studies that employ these methods. Neither were apparently done properly in the present paper.

The neonatal assessments for reflexes, perceptual and motor skills were carried out by a single assessor, L.A.H. On at least 2 other studies of neonatal Rhesus Macaque behaviour using the same metrics, i.e. the Brazelton Neonatal Behavioral Assessment Scale, co-authored and authored by some of the same investigators as this study, multiple assessors were used. From Sackett et al. (2006):

Reflex and sensory motor responses were measured 5–6 days per week from birth through 30 days. The purpose was to assess neural integrity during the neonatal period, as reflected in the development of motor and sensory reflexes required for the survival of macaque monkeys in a natural environment. Similar procedures for a similar purpose have been used to assess both humans (Brazelton, 1973) and rhesus monkeys (Schneider & Suomi, 1992).

Reliability was assessed from the simultaneous observations of pairs of testers for each response that could be scored simultaneously and by immediately repeated observations by the second tester for items requiring handling the neonate by the tester. The latter values combine reliability with response repeatability. Periodic retesting maintained reliability at 80% or better on each type of scoring.

And from Dettmer et al. (2007):

Neonatal assessment and social data were collected by multiple observers. Interrater reliability for social behavior was achieved by computerized calculation of a kappa score (k) of .80 or above for each of five consecutive randomized focal animal sessions. Reliability for nursery assessments was achieved when observers obtained an 89% agreement on three consecutive randomized assessments.

Now given the intense scrutiny most of the authors had to know this study would be given, why use just one assessor? What was the possible observer error of one assessor if such a high discordance is acceptable for 2 or more observers?

The authors state that they had to right-censor the data because a further intervention on day 14 precluded them from assessing the animals longer (right-censoring data is a statistical technique to account for subjects that don't reach the a threshold value by the end of the study period). But not only do they fail to mention what this intervention was, but it appears as though they did assess the animals until at least day 30, as indicated in one of their IMFAR abstracts. Why was this data not reported in the present paper? authors also did not include any biochemical analyses, such as baseline and post injection blood-mercury levels. If they went to such considerable effort to prepare and verify TCVs for this study, it seems almost absurd to ignore the relatively easily-obtainable data points that mercury testing and a chemistry panel could provide.

In summary, the present study has significant flaws in experimental design. Groups size varied greatly, animals were not randomised properly, and the observer was not properly blinded. These are all conditions under which the likelihood of finding a significant difference between groups (a 'false positive') is artificially increased. Furthermore, 4 animals seem to have been added long after the initial study (as reported at the 2008 IMFAR meeting). While this may have been to satisfy reviewer requests, it certainly contributed to the problems mentioned above. These problems will also carry through to all subsequent studies reporting on the same cohort of monkeys.

There are further problems in the data reported and how they are presented and interpreted. According to the results:

All infants remained healthy during the study testing period reaching all criteria for maintaining health including appetite, weight gain, and activity level, and achieved temperature regulation by Day 3.

Neonatal reflexes and sensorimotor responses were measured daily from birth until post-natal Day 14. Datasets from the two unexposed groups (with or without a saline injection) were combined when no differences were found for all measures (p>0.5). There was a significant delay in time-to-criterion for exposed vs. unexposed animals for three survival reflexes including root (Fig. 1A; p=0.004), suck (Fig. 1B; p=0.002) and snout (Fig, 1C; p=0.03) and approached significance for startle (p=0.11). The effect of exposure also approached significance for grasp hand (p=0.07), one of the motor reflexes. There were no reflexes for which the unexposed animals took significantly longer to reach criterion than the exposed animals (Table 2).

So for all of the thirteen measurements, only 3 reached statistical significance. And one of these, snout, the unadjusted main effects of exposure, did not maintain significance using the Cox regression models, nor did it reach statistical significance when exposure was measured against gestational age (GA). The data from Tables 3 and 4 were sufficiently explained in the body of the text, and since they were attempts to squeeze every last bit of possible associations between TCV exposure and development, the tables themselves were redundant. It would have been far more interesting and informative to have instead included a table that had animals, exposure and assessment results for each measurement. It is also worth noting that all animals in the exposed groups reached root, suck and snout criterion well-prior to reaching censor and unexposed animals did not reach criterion for some measurements prior to censor.

Three measurements out of 13 were statistically significant when comparing TCV exposed and unexposed animals but are they biologically important? Maybe, maybe not; it's difficult to say due to the low quality of the study design in terms of control groups and observation. It is worth noting this gem from Mark Blaxill about the results interpretation:

To make the point more simply, it would have taken only modest differences in the management of the data analysis to make over half of the measured reflexes show significant delays instead of a third of them. Pointing this out is not intended as a criticism of the study, however, but rather a demonstration of how conservative the authors were in their interpretation of the results.

"Modest difference in the management of the data analysis"?! What exactly are you suggesting here Mr. Blaxill? A little more data massaging would have been justified?

There were 3 authors involved with this study that have considerable conflicts of interest, Dr.s Hewitson, Wakefield and Stott. Here is their COI statement as it appears in the galley of the manuscript:

Prior to 2005, CS and AJW acted as paid experts in MMR-related litigation on behalf of the plaintiff. LH has a child who is a petitioner in the National Vaccine Injury Compensation Program. For this reason, LH was not involved in any data collection or statistical analyses to preclude the possibility of a perceived conflict of interest.

Now here is the COI declaration in Neurotoxicology Instructions to Authors:

All authors are requested to disclose any actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations within three years of beginning the submitted work that could inappropriately influence, or be perceived to influence, their work. See also http://www.elsevier.com/conflictsofinterest.

NeuroToxicology requires full disclosure of all potential conflicts of interest. At the end of the manuscript text (and in the cover letter of the manuscript), under a subheading "Conflict of Interest statement", all authors must disclose any financial and personal relationships with other people or organisations that could inappropriately influence (bias) their work. If there are no conflicts of interest, the authors should state, "The authors declare that there are no conflicts of interest." Signed copies of the NeuroToxicology Conflict of Interest policy form are required upon submission. The Conflict of Interest policy form can be downloaded here. In order to minimize delays, we strongly advise that the signed copies of these statements are prepared before you submit your manuscript. The corresponding author is responsible for sharing this document with all co-authors. Each and every co-author must sign an individual disclosure form. The corresponding author is responsible for uploading their form and those of their co-authors.

None of these 3 authors fully declared their conflicts of interest. Now they may think they have some wiggle room with the way the COI declaration instructions are worded, but they don't. They have certainly violated full disclosure of actual or potential conflicts of interest. Dr. Hewitson has failed to mention her affiliation with DAN! and her husband's employment by Thoughtful House and his associations with decidedly anti-vaccine organisations such as SafeMinds, whom, not-so-coincidentally co-funded this study and may or may not have had significant input into the study design. Dr. Wakefield goes without saying but as the executive director of a medical practise that unabashedly treats autism as vaccine damage, the mission of his organisation has a considerable vestment in any positive results for such studies and should have been declared as such. Dr. Stott is employed by Thoughful House as a Senior Research Associate as well and may still be offering her services as paid 'expert' for 'vaccine injury' litigation.

Dr. Carol Stott has undeclared conflicts of interest, not to mention she has a history of rather deranged behaviour related to the MMR-autism scare originated by Dr. Wakefield (she was disciplined by the British Psychological Society), yet she was allowed to handle the data analyses for this study.
Finally, let's take a look at their funding sources:

This work was supported by the Johnson Family, the late Liz Birt, SafeMinds, the Autism Research Institute, The Ted Lindsay Foundation, the Greater Milwaukee Foundation, David and Cindy Emminger, Sandy McInnis, Elise Roberts and Vivienne McKelvey.

Most of these individuals and organisations have considerable investment in a vaccine-autism association, particularly with regards to mercury. Sally Bernard has demonstrated her vitriolic dedication to the mercury-autism causation claim when she was invited to take part in a CDC study examining TCVs and autism. A study that was published in a 2007 NEJM issue had her input and cooperation until the results were announced; she flounced off, claiming that the study design was poor. Given that SafeMinds is a supporter of Thoughtful House and has funded dubious research such as the "Rain Mouse" study by Hornig et al., it is clear that they exert substantial pressure for results they may want.

Primate studies come with significant financial and ethical costs. These are sentient creatures, their use in animal research should not be broached lightly and their sacrifice should come with a significant contribution to the literature. It is a shame that the design of the current study did not ensure the optimal benefit from this investment.

Please visit Respectful Insolence for Orac's undoubtedly thorough critique of this study.

ETA: The authors of this blogpost, Catherina and Science Mom have absolutely no conflicts of interest either real or perceived to declare.