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3
"Safety of Thimerosal-Containing Vaccines: A Two-Phased Study of Computerized Health Maintance Organization Database"
Pediatrics, Thomas Verstraeten, MD (November 2003)

Headline:

A disaster. The most widely quoted study, and the only study ever done with American data on American children, reached a neutral conclusion, asked the wrong question, and the author left to join a vaccine company before its publication. And, the world's most incriminating and public "secret meeting" calls the entire study into question. If this is the CDC's best work, we're all in trouble. Recently, the former CDC Director called this study "unhelpful and potentially misleading."

Actual Question This Study Asked & Answered:

Q: Do children receiving more thimerosal in their vaccines have different neurological outcomes from children receiving less thimerosal in their vaccines?

A: Additional investigation is required, an answer could not be found. Nuetral outcome.

Did the study look at unvaccinated children?

No.

Conflict of Interest:

Written by the Centers for Disease Control, the federal agency in charge of the vaccine program. The lead author, Thomas Verstraeten, left to take a job with Glaxo SmithKline -- a vaccine manufacturer -- after the study was written and before it was published. The U.S. Congress later cited this as an ethical violation.

Ability to Generalize:

The study had a robust dataset, with more than 140,000 children analyzed. But, the original data has apparently been lost by the CDC, and the Vaccine Safety Datalink data that the CDC used is unavailable to other researchers, so its impossible to confirm using neutral researchers.

Post-Publication Criticism:

Extreme, the most of any study, including criticism from the study's author for how the study has been mischaracterized in the media.

Scoring (Out of 40 possible points):

Asked the Right Question: 1

Ability to Generalize: 2

Conflict of Interest: 0

Post-Publication Criticism: 0

Total Score: 3

Choice Excerpt from the Study:

"The biological plausibility of the small doses of ethylmercury present in vaccines leading to increased risks of neurodevelopmental disorders is uncertain."

Guest Critic #1: Julie Gerberding, Former Director of the CDC

CDC: Vaccine Study Design "Uninformative and Potentially Misleading" By David Kirby, The Huffington Post

Excerpt from this great article:

"CDC Director Dr. Julie Gerberding has delivered a potentially explosive report to the powerful House Appropriations Committee, in which she admits to a startling string of errors in the design and methods used in the CDC's landmark 2003 study that found no link between mercury in vaccines and autism, ADHD, speech delay or tics."

Guest Critic #2: Dr. Guest Critic: Dr. Mark Geier (re-printed from a letter published in Pediatrics)

Study Misses Link Between Thimerosal and Neurodevelopmental Disorders

Letter to the Editor:

The recent article, "Safety of Thimerosal-Containing Vaccines: A Two- Phased Study of Computerized Health Maintenance Organization Databases," by Verstraeteten et al. [1], which failed to find a consistent association between thimerosal in childhood vaccines and neurodevelopmental disorders, has a number of issues that need to be further addressed.

First, the head author, Dr. Thomas Verstraeten, has for the past several years worked for GlaxoSmithKline, a vaccine manufacturer of thimerosal-containing vaccines. In addition, Nancy Pekarek, a company spokeswoman for GlaxoSmithKline, has written that Verstraeten, since leaving the Centers for Disease Control and Prevention (CDC), has worked as an adviser as the study was finalized and prepared for publication. Presently, GlaxoSmithKline, potentially, faces a large number of lawsuits on the very issue that the paper discusses.

Second, this very study was the topic of secrete-closed meetings between members of the CDC and other government organizations, as well as members of the vaccine manufacturers held at Simpsonwood, Georgia from 7-8 June 2000. The transcript of this meeting has been obtained under the Freedom of Information Act. This transcript reveals that the study initially found statistically significant dose-response effects between increasing doses of mercury from thimerosal-containing childhood vaccines and various types of neurodevelopmental disorders. The transcript documents that the data was real and statistically significant for many types of neurodevelopmental disorders, but that the meeting participants expressed that the data had to be "handled." Despite, discussion about how to "handle" the data, some participants expressed concern that the work that had already been done would be obtained by others through the Freedom of Information Act. In this event, even if professional bodies expressed the opinion that there was no association between thimerosal and neurodevelopmental disorders, it was already too late to do anything. In addition, other participants expressed that the vaccine manufacturers were in a horrible position to be able to defend any lawsuits alleging a relationship between thimerosal and neurodevelopmental disorders, since no one would say with the available data that there was no relationship between thimerosal and neurodevelopmental disorders. Even Verstraeten, in an email following the Simpsonwood meeting, expressed surprise that the data was to be manipulated, stating that ones desire to disprove an unpleasant theory should not interfere with sound scientific methods to evaluate the relationship between thimerosal and neurodevelopmental disorders.

Third, there are also significant issues about the methods used to determine the mercury dose that children received from thimerosal- containing vaccines. The authors, in Table 1 of their manuscript, completely fail to mention that there were large numbers of thimerosal- free Diphtheria-Tetanus-acellular-Pertussis (DTaP) vaccines administered to children in the Health Management Organizations (HMOs) analyzed. Thimerosal-free DTaP vaccine has been produced by GlaxoSmithKline since 1997. We have personally analyzed the Vaccine Safety Datalink (VSD) database determining that approximately one-third of the children receiving DTaP in the VSD from 1997 through 2000 were immunized with this vaccine, and that the children received thimerosal-free DTaP vaccines in various combinations, with some receiving four doses of thimerosal-free DTaP, some receiving three doses of thimerosal free DTaP and one dose of thimerosal-containing DTaP, some receiving two doses with and two doses without thimerosal, some receiving three with and one without thimerosal, and some receiving all four doses of thimerosal-containing DTaP. In order to evaluate whether Verstraeteten et al., did or did not take this into account, we analyzed Table 1 from their study for the possible cumulative mercury exposures at the various ages of immunization. At one month, the possible mercury exposure was 12.5 micrograms of mercury according to the authors, which is appropriate because there was no potential thimerosal- free DTaP vaccine to take into account. At 2-3 months, the possible cumulative mercury exposure was 37.5-75 micrograms of mercury according to the authors. These potential possible cumulative mercury exposures could be generated by DTP and Hib vaccine separated or combined, or by thimerosal-free DTaP vaccine and Hib (i.e. both DTPH or thimerosal-free DTaP vaccine and Hib vaccine, resulted in children being exposed to 25 micrograms of mercury). At 5-6 months, the possible cumulative mercury exposure was 75 or 125 micrograms according to the authors. The fact that the authors only list these two potential possible cumulative mercury exposure doses show that the authors failed to take into account the thimerosal-free DTaP vaccine made by GlaxoSmithKline, since children receiving one thimerosal-containing DTaP followed by one thimerosal-free DTaP vaccine, in addition to their two doses of hepatitis B vaccine and two doses of Hib vaccine received 100 micrograms of mercury, a mercury dose not mentioned in the table. At 6-7 months, the possible cumulative mercury exposure was 112.5 micrograms of mercury or 187.5 micrograms of mercury according to the authors. These potential possible cumulative mercury exposures show overwhelmingly that there is a significant error in the study. The intermediate mercury values children were exposed to also included: two thimerosal-containing and one thimerosal-free DTaP vaccine, with three doses of hepatitis B vaccine and three doses of Hib vaccine, for a total of 162.5 micrograms of mercury; and two thimerosal-free DTaP and one thimerosal-containing DTaP vaccine, with three doses of hepatitis B vaccine and three doses of Hib vaccine, for a total of 137.5 micrograms of mercury. These calculations indicate that Verstraeteten et al. did not take thimerosal-free DTaP vaccine into account in their study, or if they did, then their paper, as it stands, is replete with inaccurate information.

Additionally, the fact that the VSD data contained large numbers of children who took thimerosal-free DTaP vaccine and large numbers of children who took thimerosal-containing DTaP vaccine allows a much more direct and powerful way to do the study by comparing these two groups, since this type of analysis would allow for overall evaluation of the effects of increasing doses of mercury from thimerosal in comparison to considerably lesser doses of mercury from thimerosal. We have done just such a study in VSD and found an association between increasing doses of thimerosal and neurodevelopmental disorders. We have previously epidemiologically examined the Vaccine Adverse Event Reporting System (VAERS) for children receiving thimerosal-containing DTaP vaccines in comparison to thimerosal-free DTaP vaccines and the US Department of Education dataset, and both showed an overall and dose-response statistically significant link between increasing doses of thimerosal and neurodevelopmental disorders [2-5]. It also has been observed that children with autism fail to excrete mercury in their hair and show large increases in the amount of mercury in their urine following chelation therapy in comparison to controls [6,7]. These finding are particularly troubling in light of the fact that many authors including Slikker [8] from the Food and Drug Administration have published that thimerosal crosses the blood-brain and placental barriers and results in appreciable mercury content in tissues including the brain, and because it has been shown by Baskin et al. [9] that micromolar concentrations of thimerosal are capable of causing significant damage to neurons. A recently published report from Northeastern University, the University of Nebraska, the USDA, and the Johns Hopkins University has found that thimerosal at picomolar concentrations is a potent neurotoxin since it inhibits the insulin growth factor-1 and the dopamine-stimulated methlyation synthase pathways providing a potential molecular mechanism of how the link between thimerosal in vaccines and neurodevelpmental disorders, reported in our studies, actually increased the incidence of autism and how thimerosal in vaccines through its interaction with the D4 receptor gene may even account for the increase in ADHD as well [10]. It also is in keeping with the many hundreds of peer-reviewed articles published over many decades and from many fields of medicine and science reporting on the harmful effects of thimerosal in humans, animals, isolated neurons, and other systems.

Fourth, there is also a significant issue regarding the inclusion of children who received whole-cell Diphtheria-Tetanus-Pertussis (DTP) vaccine and DTaP vaccine. The Institute of Medicine of the United States' National Academy of Sciences has determined that the evidence is consistent with a causal relationship between whole-cell DTP vaccine and permanent brain damage [11, 12]. In addition, despite the claim by Verstraeteten et al. that encephalopathies following whole-cell DTP occur only rarely, and therefore, this would be unlikely to have influenced the results of the study, some authors, such as Strom [13] reported that 1 in 6,000 children developed a neurological reaction and 1 in 17,000 children died or were left with a permanent neurological defect, and Pollock and Morris [14] who reported that 1 in 8,500 children died or had a neurological disorder following whole-cell pertussis vaccination. Therefore, it is clear that the assumption by Verstraeteten et al. that whole-cell DTP vaccine would have limited effects upon the results of their study seems incorrect, but rather points to a serious confounder present in their study that makes evaluation of the effect of thimerosal more difficult to discern.

In conclusion, because of a number of very serious issues have been raised and the critical importance of the issue as to whether thimerosal causes neurodevelopmental disorders, we respectfully request that Verstraeten et al. consider withdrawing this study. In order to restore the badly damaged confidence in our much needed vaccine program, it is necessity that past errors be admitted, and that open investigations be conducted on vaccines issues. It is also essential that future vaccine decisions are made by physicians and scientists without even the appearance of conflicts of interest.

Dr. Mark R. Geier has been a consultant and expert witness in cases involving vaccine adverse reactions before the National Vaccine Injury Compensation Program and in civil litigation.

David A. Geier has been a consultant in cases involving vaccine adverse reactions before the National Vaccine Injury Compensation Program and in civil litigation.

Additional History:

This lengthy but thorough history was reprinted with permission from www.putchildrenfirst.org:

At 4:15 pm Eastern time on a Friday afternoon in July 1999, a joint statement by the AAP and Public Health Service was released to the press advising Americans that the amount of mercury in vaccines administered to children, through a preservative called Thimerosal, exceeded Federal Health guidelines. This statement did not reveal the amount of panic, backdoor negotiating, and concern federal health officials had been engaged in for the past few weeks, after the levels of mercury had been calculated by dumbfounded federal officials reviewing submissions from vaccine manufacturers responding to a broad FDA inquiry regarding mercury in consumer products. While this article from Pediatrics ultimately looks at the policy makers favorably, it does help explain how frenetic the process was.

How could July 1999 be the first time Federal Officials realized there was mercury in vaccines exceeding our own safety standards? There are many answers to this question. For some officials, this was the first time they had learned mercury was even in vaccines. Others clearly knew and had been concerned for some time, and at least one vaccine manufacturer realized the levels were high eight years earlier, in 1991.

Thimerosal was first used as a preservative in vaccines in the late 1930s, long before we understood the extreme neurotoxicity of mercury. As the FDA ratcheted up safety standards, Thimerosal was grandfathered through due to its history without ever having to undergo any safety testing. We may not be reading so much about Thimerosal today if the CDC hadn't embarked upon an aggressive plan to add vaccines to the Recommended Childhood and Adolescent Immunization Schedule in the late 1980's. In 1988, the Haemophilus Influenzae type B (Hib) vaccine was added to the schedule, followed by the Hepatitis B (HepB) vaccine in 1991. Together, these two vaccines added six shots to the schedule, and tripled the amount of mercury children born after 1991 received compared to the previous generation.

The joint statement above downplayed the risk of mercury injected in newborns, and it downplayed the degree to which mercury exceeded federal safety standards. Doing the simple math, a child following the recommend schedule and receiving vaccines at birth, 2 months, 4 months, and 6 months was receiving mercury in excess of the EPA safe standards by a factor of 36x, 120x, 77x, and 66x, respectively. That's 120 times the safe Federal standard!! (See chart).

The start of the sharp increase in autism and other neurodevelopmental disorders matches the change in the vaccine schedule. In the 1980s the incidence of autism was somewhere between 1 in 10,000 and 1 in 5,000, today it is 1 in 110. (See chart).

"The Food and Drug Administration (FDA) Modernization Act of 1997 called for the FDA to review and assess the risk of all mercury containing food and drugs. In line with this review, U.S. vaccine manufacturers responded to a December 1998 and April 1999 FDA request to provide more detailed information about the thimerosal content of their preparations which include this compound as a preservative," said the statement.

The Federal Health authorities were well aware of the potential damage their public announcement could cause to the National Immunization Program, and they did their best to downplay risks, slow down change, and avoid blame or liability. Perhaps most astonishing of all, there is still Thimerosal, at high levels, being injected in our children before their first birthday, 7 years after this joint statement was released.

"The number of dose related relationships [between mercury and autism] are linear and statistically significant. You can play with this all you want. They are linear. They are statistically significant." - Dr. William Weil, American Academy of Pediatrics. Simpsonwood, GA, June 7, 2000

"The issue is that it is impossible, unethical to leave kids unimmunized, so you will never, ever resolve that issue [regarding the impact of mercury]." - Dr. Robert Chen, Chief of Vaccine Safety and Development, Centers For Disease Control, Simpsonwood, GA, June 7, 2000

"Forgive this personal comment, but I got called out at eight o'clock for an emergency call and my daughter-in-law delivered a son by c-section. Our first male in the line of the next generation and I do not want that grandson to get a Thimerosal containing vaccine until we know better what is going on. It will probably take a long time. In the meantime, and I know there are probably implications for this internationally, but in the meanwhile I think I want that grandson to only be given Thimerosal-free vaccines." - Dr. Robert Johnson, Immunologist, University of Colorado, Simpsonwood, GA, June 7, 2000

"But there is now the point at which the research results have to be handled, and even if this committee decides that there is no association and that information gets out, the work has been done and through the freedom of information that will be taken by others and will be used in other ways beyond the control of this group. And I am very concerned about that as I suspect that it is already too late to do anything regardless of any professional body and what they say…My mandate as I sit here in this group is to make sure at the end of the day that 100,000,000 are immunized with DTP, Hepatitis B and if possible Hib, this year, next year and for many years to come, and that will have to be with thimerosal containing vaccines unless a miracle occurs and an alternative is found quickly and is tried and found to be safe." - Dr. John Clements, World Health Organization, Simpsonwood, GA, June 7, 2000

Soon after the joint statement by the AAP and Public Health Service was released, all hell broke loose, and the CDC moved into damage control mode, where they remain today, seven years later. (Here's a great article from the Hepatitis Control Report on the panic.) Parents of autistic children began to compare the symptoms of autism to the symptoms of mercury poisoning, and a feisty Congressman from Indiana with an autistic grandson, Dan Burton, started using his pulpit as head of the Committee on Government Reform to ask very tough questions. By August, two months after the joint statement, his committee was in a full-scale investigation of conflict in vaccine policy, which the CDC knew.

Shockingly, CDC received letters in July and September 1999 from Merck and SmithKline Beecham, respectively, letting CDC know that full production of Thimerosal-free vaccines for Hepatitis B and DTaP could be made available almost immediately. To SmithKline, CDC responded with a tepid letter thanking them for the offer, but not taking them up on it. Thimerosal would remain in the vaccines on the Childhood Immunization Schedule for three more years, into late 2002, before Thimerosal-free vaccines were finally available for all vaccines, as this letter from FDA to Congressman Dave Weldon demonstrates. CDC's inexplicable complacency in the face of the July 1999 statement to switch over to Thimerosal-free vaccines was highlighted in this March 2006 article by Robert F. Kennedy, Jr in the Huffington Post.

As part of the FDA Modernization act that spurred the joint statement, FDA was required to commission the Institute of Medicine to review the impact of mercury in vaccines. The IOM's study began in late 1999 with an expected publication date in 2001. For the CDC, the walls were starting to close in, particularly for the man responsible for both vaccine development and vaccine safety, Dr. Robert Chen. The knowledge of a looming IOM review spurred CDC to take matter into their own hands.

Soon after the AAP statement a young CDC epidemiologist, Dr. Thomas Verstraeten, was given the task of comparing neurodevelopmental outcomes of children exposed to Thimerosal using the CDC's internal database, the Vaccine Safety Datalink (VSD). CDC hoped to run their own analysis, establish no relationship between Thimerosal and autism, give the analysis to the IOM, and close this chapter for good. By November of 1999, just 5 months after the joint statement, Dr. Verstraeten was in a near panic as the data he was analyzing was showing a clear, unassailable, ugly truth: there was a statistically significant relationship between the amount of mercury children were receiving through their vaccines and autism. No matter how he tried to run the numbers, he wrote, the association "just won't go away."

In June of 2000, six months after Dr. Verstraeten's analysis revealed a clear correlation, the CDC commissioned a private meeting at the Simpsonwood Conference Center in Atlanta, GA, with representatives from the CDC, other health organization (WHO, FDA) and representatives of vaccine manufacturers to share some startling news: despite six full months of trying to dumb down the data, CDC's analysis was still showing a statistically significant relationship between neurodevlopmental disorders, especially autism, and Thimerosal children received through their vaccines.

The Simpsonwood meeting set that stage for the way the CDC has conducted themselves ever since: control the damage, bury the data, and ensure that the National Immunization Program never misses a beat. The candor and incriminating statements of the Simpsonwood attendees is at times breathtaking, as some of the above quotes demonstrate, and a whole website could be devoted to analyzing the words of the participants. A great summary of the Simpsonwood meeting is available through this excellent article written by Dr. Russell Blaylock. The transcript from the meeting was stamped with the words "Do Not Copy or Release" and "Confidential", but was obtained by parents through FOIA.

Late 2000 and 2001 was a rough time for the CDC. Simpsonwood had already highlighted the challenges CDC faced with the data they were sitting on. In August of 2000, two months after Simpsonwood, Dan Burton's Government Reform Committee released a highly critical document on the conflicts of interest at CDC and FDA for decision made on the Rotavirus vaccine, recently recalled due to intussusception in children (a severe bowel disorder), and critical of vaccine policy making in general.

In January 2001, parents associated with the nonprofit group SafeMinds published an article in a peer-reviewed journal titled Autism: A Novel Form of Mercury Poisoning. Chairman Burton continued to hold hearings, browbeating public health officials over the lapse on thimerosal and what was being done about it. This was followed up that May by a speech by Chairman Burton demanding FDA recall any vaccine containing thimerosal at once (they didn't).

Once it was clear that unsafe levels of mercury were in the vaccine supply, FDA was required to hire the Institute of Medicine to review thimerosal and any role it may play in damaging children. With the weight IOM carried with the scientific community, IOM's conclusions, expected to be published in late 2001, were of grave concern to CDC. By the summer of 2001, CDC was aware of IOM's likely conclusion, which was not particularly favorable to CDC: they were going to say that the notion that thimerosal created neurological disorders was "biologically plausible" and merited further study. CDC had already given IOM their data from the VSD, which had been manipulated enough to neither prove nor disprove an association.

Perhaps most frustrating about the recommendations of the IOM in October 2001 is that CDC did not pursue any of them. Where IOM recommended further work to assess biologically plausibility (like measuring mercury levels in autistic children), CDC would focus exclusively on epidemiology, a statistical science easily manipulated. Where IOM encouraged CDC to explore the growing reports of autistic children recovering after chelation therapy, a treatment to remove mercury and other metals from the body, CDC never did anything to explore the reports further. Where IOM encouraged CDC to replace any thimerosal containing vaccines immediately, CDC still has vaccines with thimerosal targeted at infants today, five years later.

Luckily for the children, what CDC did not realize was that parents would dig into their own pockets to fund biological research to prove what had been done to their children, as we will discuss in Chapter 5.

CDC was in a bind. They knew what the Generation Zero data had shown and how explosive that information, if released, would be to the National Immunization Program, their jobs, and vaccine manufacturer liability. They also knew IOM was not going to let them off the hook, and that more work and analysis would be recommended. It left only two alternatives for CDC, both of which they continue to follow today:

  1. Never, ever let anyone else see the Generation Zero data nor any of CDC's other internal data. Given all the shortcuts and assumptions CDC made to manage down the risks, independent researchers would most assuredly come to a different conclusion. Even though laws required CDC to share this data publicly, they would become experts at buying time and "losing" data when pressured.
  2. Since the U.S. data shows a high correlation, go to other countries and find willing participants to manufacture data that will "prove" thimerosal and autism are unrelated.

With that strategy in place, a few months prior to the release of the IOM study, CDC employees, under the guidance of their bosses, Dr. Walter Orenstein, Director of the NIP and Dr. Roger Bernier, Associate Director of Science for the NIP, began a world-wide inquiry to find data from other countries that would be used bail them out. Not only would CDC initiate, fund, and structure these studies, but their own employees would also end up as published authors in the studies exonerating thimerosal's role in autism.

Dr. Vestraeten's data, which began with a panic in late 1999 ("It just won't go away"), was published in Pediatrics titled Safety of Thimerosal-Containing Vaccines: A Two-Phased Study of Computerized Health Maintenance Organizations. Perhaps most frustrating about this study is that it is often referenced as "proof" that vaccines do not cause autism when it was actually a neutral-outcome study, as Dr. Verstraeten himself noted, in a letter to Pediatrics:

"Surprisingly, however, the study is being interpreted now as negative [where 'negative' implies no association was shown between Thimerosal and autism] by many...The article does not state that we found evidence against an association, as a negative study would. It does state, on the contrary, that additional study is recommended, which is the conclusion to which a neutral study must come...A neutral study carries a very distinct message: the investigators could neither confirm nor exclude an association, and therefore more study is required."

This study was highly flawed for the following reasons (read SafeMinds' critique here):

The data was manipulated to remove the strong correlation between mercury and autism. As Chapter II discussed, the initial analysis using Vaccine Safety Datalink data (VSD) showed a high correlation between Thimerosal and autism, called "Generation Zero." The CDC used many techniques to dumb-down the numbers including removing comparisons to children who had received no Thimerosal, lowering the age of children available for the analysis, and including a bankrupt HMO, with notoriously faulty data systems, in their final round of analysis. This HMO helped neutralize the findings reviewed at Simpsonwood. As SafeMinds reported:

"The general drift of their design changes was clear, to reduce the statistical power through conscious manipulation of statistical methods, data classifications, and samples."

Dr. Verstraeten, the study's author, had been an employee of Glaxo SmithKline for more than 2 years by the time the study was published. This blatant conflict, with a study author employed by a company being sued by parents for Thimerosal in vaccines, was never noted in the Pediatrics study.

Even with all the manipulation, the study was still a neutral outcome study. Many people would be surprised to know that the study itself cites a correlation between Thimerosal-containing vaccines and both "tics" and "language delay." Beyond that, the study neither proves nor disproves an association between Thimerosal and autism and recommends that more work needs to be done.