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Part 3: Vaccines and Autism - What Do Epidemiological Studies Really Tell Us?

Posted Jul 01 2011 12:00am

Special_Report

(Managing Editor's Note: Read  Part 1 and  Part 2 . Also, this report is available in in full .pdf (Vaccines and Autism Epidemiology HERE )

“We have 16 studies already that clearly state that vaccines do not cause autism.”

-- Amy Pisani, Executive Director, Every Child By Two

“16 studies have shown no causal association between vaccines and autism, and these studies carry weight in the scientific industry.”

-- Dr. Nancy Snyderman, NBC Today Show Medical Editor


“The science is largely complete. Ten epidemiological studies have shown MMR vaccine doesn’t cause autism; six have shown thimerosal doesn’t cause autism.”

-- Dr. Paul Offit, “Autism’s False Prophets”

----------------------------

A NOTE FROM SAFEMINDS:

There are 16 epidemiological studies here on MMR vaccines, thimerosal and autism. These studies represent the most often cited papers by scientists, public health officials and members of the media when trying to refute any evidence of an association between vaccinations and autism.

There are serious methodological limitations, design flaws, conflicts of interest or other problems related to each of these 16 studies. These flaws have been pointed out by government officials, other researchers, medical review panels and even the authors of the studies themselves. Taken together, the limitations of these studies make it impossible to conclude that thimerosal and MMR vaccines are not associated with autism.

SafeMinds would like to acknowledge the previous work in this regard gathered by the “Fourteen Studies” project at Generation Rescue: http://www.14studies.org/about.html

One additional study on autism and thimerosal was published in September 2010 while this paper was in completed draft form. This study’s methods produced a result that demonstrated that thimerosal exposure was protective against autism. Further analysis of this study is forthcoming but not included here.

PART 3

FLAWS AND LIMITATIONS OF THIMEROSAL-AUTISM EPIDEMIOLOGY STUDIES

There has only been one major scientific review of the main epidemiological studies to examine a potential association between thimerosal containing vaccines (TCVs) and autism spectrum disorders: The Institute of Medicine Immunization Safety Committee Report, issued in May, 2004. [37]

The IOM report focused almost exclusively on large, population-based epidemiological studies based on health records. The committee chose to minimize the importance of several biomedical thimerosal studies conducted in laboratories and animal models. Today, a much larger body of medical literature has been amassed which clearly demonstrates the powerful neurotoxic effects of thimerosal. These are joined by other studies demonstrating the increased risks of simultaneous administration of certain vaccines on the current childhood schedule.

WHAT THE IOM CONSIDERED:

The IOM committee reviewed epidemiological studies examining TCVs and autism, including three controlled observational studies (Hviid et al., 2003; Miller, 2004; Verstraeten et al., 2003) and two uncontrolled observational studies (Madsen et al., 2003; Stehr-Green et al., 2003). The published papers “consistently provided evidence of no association between TCVs and autism, despite the fact that these studies utilized different methods and examined different populations (in Sweden, Denmark, the United States, and the United Kingdom),” the committee wrote.

IOM MAIN CONCLUSIONS:

■ “Based on this body of evidence, the committee concludes that the evidence favors rejection of a causal relationship between thimerosal-containing vaccines and autism.”

■ “In the absence of experimental or human evidence that vaccination (either the MMR vaccine or the preservative thimerosal) affects metabolic, developmental, immune, or other physiological or molecular mechanisms that are causally related to the development of autism, the committee concludes that the hypotheses generated to date are theoretical only.”

LIMITATIONS OF THE IOM REVIEW:

■ Because the “vast majority” of ASD cases cannot be accurately sub-classified, “if there is a subset of individuals with autism syndrome triggered by exposure to vaccines, our ability to find it is very limited in the absence of a biological marker.”

■ In fact, the committee admitted, trying to find a cause of autism using population-based epidemiological analyses “requires either a well-defined at-risk population or a large effect in the general population.”

■ But without any known biomarkers, well-defined risk factors, or large effect sizes, “the committee cannot rule out, based on the epidemiological evidence, the possibility that vaccines contribute to autism in some small subset or very unusual circumstances.”

NOTE: Knowledge of biomarkers and risk factors in ASD has increased considerably since the release of the 2004 IOM report.

CRITIQUES OF THE IOM REVIEW

Mark D. Noble, PhD - Professor of Genetics and of Neurobiology and Anatomy, University of Rochester Medical Center [38]

It is easy to understand why people are not believing the scientific community. It reduces confidence in the scientific enterprise when it turns out that the CDC had information on early versions of the studies of Verstraeten et al. that demonstrated a linkage between thimerosal exposure and autism, that these studies were never published, and that no one has ever explained satisfactorily why different analyses were conducted and why they were changed. But all of these studies have equally debilitating flaws that invalidate any conclusions drawn from them on thimerosal safety. And if it turns out that that there is a subset of children for whom additives in vaccines are a problem, then this is important to know. For then we can focus on how to identify these children in advance. The conclusions I have drawn are that we are not going to solve this problem by ignoring it. So let’s embrace it. Let’s get the data.

Irva Hertz-Picciotto, PhD, MPH, Chief of the Division of Environmental and Occupational Health, University of California, Davis School of Medicine – [39]

Several large studies finding no association are far from robust, as they suffer from numerous biases that seriously limit their definitiveness. These include: noncomparable sources for ascertainment of cases, uncontrolled confounding, unrepresentative sample due to selective exclusions, and an as-yet unexplained pattern whereby children with earliest vaccines are the least likely to have developmental deficits. Thus, the body of evidence at this point is inadequate to draw conclusions… Several investigations have been ecologic studies, widely known to be the weakest possible epidemiologic design. Even restricting discussion to the individual-level designs, published studies conducted in Denmark, the UK, and the US are characterized by serious, even fatal, flaws. To regain the confidence that we in the medical/public health/scientific community need in order to fulfill our mandate to protect health, we cannot avoid facing these tough scientific questions head-on. This means funding solid scientific research into vaccines, thimerosal, and the related issues of susceptibility at the population level.

Richard Deth, PhD, Professor of Pharmacology, Northeastern University – [40]

The report aims to close the door on concerns that mercury-containing vaccines might have contributed to the increased frequency of autism. Unfortunately it is obvious that the need to close the door was given a higher priority than reaching reliable scientifically-based conclusions. This is particularly evident when the report shockingly takes a hard-line against further research into this important question … From the very outset, (IOM committee chairwoman) Dr. Marie McCormick displayed a pugnacious and adversarial attitude toward the presentation of information suggesting a thimerosal/autism link, as opposed to that of a neutral investigator… The report reflects a similar adversarial tone, with a welcoming, uncritical presentation of those epidemiological studies which failed to find a link contrasted to a hypercritical, dismissive approach toward data supportive of a link. The IOM clearly valued the epidemiologic approach and de-valued results derived from autistic individuals. The report was a biased effort at damage control.

Dr. Joachim Mutter, FA, Institute for Environmental Medicine and Hospital Epidemiology, University Hospital Freiburg, Germany and US and UK colleagues – [41]

Epidemiological studies which do not consider genetic susceptibility factors, autoimmunity reactions and mercury exposure during pregnancy (amalgam, thimerosal), are not able to detect a statistically significant effect, even if there is one. (NOTE: None of the epidemiological studies reviewed by the IOM committee considered any of those factors.)

Rep. Dave Weldon, MD (Congressman from FL at the time) – [42]

Today's report is premature, perhaps perilously reliant on epidemiology, based on preliminary incomplete information, and may ultimately be repudiated…Unfortunately, the epidemiology studies that the IOM bases its findings on are not immune from conflicts or controversy.  Many of the authors have conflicts of interest including funding from vaccine manufacturers, employment by manufacturers, or conflicts in that they implemented vaccine policies that are now being investigated.  Furthermore, the studies were designed to examine entire populations and would miss subgroups of genetically susceptible populations.

Boyd Haley, PhD, Professor of Chemistry and Bioorganic Chemistry, University of Kentucky – [43]

It appears very solid that autistic children do not biochemically handle mercury as do normal children. This is not theoretical, this is biochemical fact -- the IOM members just chose to ignore it as it does not fit into what they wanted to report. (Some) data clearly show that a small subset of the population is being affected by mercury that would be somewhat difficult to detect with a less than elegantly designed epidemiological study, and easy to miss or cover up. This biochemical data does not totally prove thimerosal is causal for autism, but it certainly should have prevented the IOM from saying they ‘conclusively’ proved thimerosal was not involved. If you do not believe in a hypothesis you replace it with another. That is how science is done.

Coalition for SafeMinds – [44]

This committee clearly chose to ignore groundbreaking scientific research on the mercury-autism link, and instead the IOM has issued a flawed, incomplete report that continues to put America's children at risk. The problem with this report begins with its violation of nearly every tenet of medical science. Respected researchers everywhere do not support the IOM belief that proof can be solely found in epidemiology... Disclosure of potential conflicts of interest is an essential tenet to good science, but here we have a situation where authors of ‘studies’ are probably quite literally writing to preserve their jobs. The IOM gave unusual weight to several authors from the Statens Serum Institut (SSI) in Denmark. What the American public needs to know is that the SSI is not only the Danish version – and frequent collaborative partner – of the CDC, but also that country’s largest vaccine manufacturer.

WHAT IOM COMMITTEE MEETING MINUTES SUGGEST:

On January 12, 2001, the IOM’s Immunization Safety Review Committee held a closed-door meeting convened by Committee Chairwoman Dr. Marie McCormick and Study Director Kathleen Stratton. During the meeting, members discussed their charge from the CDC, which commissioned the review. The minutes were leaked to attorneys for families of children with autism. [45]

At one point, Dr. McCormick seems to imply that CDC officials expect certain pre-ordained results from the study they are sponsoring and paying for:

Dr. McCormick: “CDC wants us to declare, well, these things (vaccines) are pretty safe on a population basis.”

And Dr. Stratton announces to the committee what they WON’T be finding or recommending, before a single page of evidence has been presented:

Dr. Stratton: “The point of no return, the line we will not cross in public policy, is pull the vaccine, change the schedule. We could say it is time to revisit this, but we would never recommend that level. Even recommending research is recommendations for policy. We wouldn't say compensate, we wouldn't say pull the vaccine, we wouldn't say stop the program.”

Later, Dr. McCormick also announces a predetermined finding:

Dr. McCormick: “We are not ever going to come down that [autism] is a true side effect.”

SUMMARY: The IOM Committee gave far more emphasis to epidemiological (population based) studies than biological studies, such as clinical studies in children, laboratory studies, and animal model studies. Since the IOM report was released in May, 2004, a large amount of biological data have been generated from several published studies to support an association between thimerosal and ASD. A new IOM review that includes these studies is needed.

INDIVIDUAL THIMEROSAL STUDIES

1)

Authors: Stehr-Green P, Tull P, Stellfeld M, Mortenson PB, Simpson D.

Publication & Date: American Journal of Preventive Medicine, August, 2003

Abstract online at:  http://www.ncbi.nlm.nih.gov/pubmed/12880876?dopt=Abstract  

Details The authors compared thimerosal exposures and autism rates among children in Denmark, Sweden, and California. In California thimerosal use in childhood vaccines had continued until 2003, while Sweden and Denmark eliminated it in 1992-1993.

California - The authors examined data that SafeMinds member Mark Blaxill had presented to the IOM Immunization Safety Committee in June, 2001, which showed a time correlation between rising exposure levels and rising case numbers. But “as with most ecologic analyses,” they wrote, “the data that Blaxill had compiled had several limitations.” For example, the autism definition used by the California Department of Developmental Services (DDS) was somewhat “vague” and difficult to verify, the authors said. Any reported increase might have been caused by greater awareness and changes in diagnostic criteria, including the addition of autistic related illnesses, such as Pervasive Developmental Disorder (PDD), the study asserted, adding that, “These subcategories of PDD accounted for the largest increases in the reported California cases reflected in the data used.”

Sweden – The authors reported that autism rates continued to climb after thimerosal was removed from Swedish pediatric vaccines in 1993. Looking only at autism patients in Sweden who were diagnosed in an inpatient (hospital) setting, they found that autism numbers rose and fell in an erratic pattern during 1980-1997, but still had an upward trend over the period. Case rates went from 5 or 6 cases “per 100,000 person-years” before 1985, to a peak of 9.2 per 100,000 person years in 1993. “This was generally similar to the trend in California during the same time period,” the authors said:

Denmark - Case rates in Denmark also went up after thimerosal was removed, in 1992. But this increase was linear, and much more pronounced. Prior to 1992, Danish children were exposed to up to 125 micrograms mercury by age ten months, but reported autism rates during this period remained level, at about 10 new cases a year. By 1999, however, after thimerosal was removed, the reported number of new autism cases had climbed to about 200 – an astonishing 20-fold increase.

Results: “In all three countries, the incidence and prevalence of autism-like disorders began to rise in the 1985-1989 period, and the rate of increase accelerated in the early 1990s,” the authors wrote. But ethylmercury exposure levels were significantly different. The average dose from TCVS increased throughout the 1990s in the United States, but in Scandinavia, thimerosal was removed in the early 1990s.

Authors’ Conclusions: Results from Scandinavia provided “compelling evidence in sharp contrast to the alleged association observed in California” against a thimerosal-autism association, the study said. “The body of existing data, including the ecologic data presented herein, is not consistent with the hypothesis that increased exposure to Thimerosal-containing vaccines is responsible for the apparent increase in the rates of autism in young children being observed worldwide.” More plausible explanations for the increase included: “increased recognition of the disorder, and/or other as-yet-unidentified environmental or genetic factors.”

CRITIQUES OF THE STUDY

Critics point to this study’s most glaring flaw, which appears in the Denmark section. The authors relied on autism prevalence data as reported in the Danish Psychiatric Central Register. But the way in which Denmark diagnosed and tracked autism patients had changed radically over the course of their investigation. This created an important alteration in the study’s entry criteria midway through the study period.

Changing Danish Population - From 1983-1992, the Danish register only listed autism cases that were diagnosed in an inpatient (hospital) setting. But in 1992 data from a large, state-of-the-art autism clinic in Copenhagen, which was diagnosing about 20% of all cases in the country was added to the national register. That year, the same year that thimerosal was removed from childhood vaccines, the number of reported autism cases, not surprisingly, saw a significant spike.

Adding Outpatient Cases - In 1995, for reasons that went unexplained, the national register began including all autism cases diagnosed in Denmark, including those diagnosed in outpatient settings. Most people with autism are diagnosed in clinics and private offices, not in hospitals. SafeMinds and other organizations point to a large 2002 study in Denmark - on autism and the MMR vaccine by Madsen et al. (see MMR section) – showing that outpatient-diagnosed cases outnumbered inpatient cases by a 13.5-to-1 ratio in Denmark, accounting for 93% of all autism cases. [47]

New Diagnostic Criteria - A third change in methodology occurred during the study period as well. In 1993, Denmark updated its psychiatric diagnostic codes and adopted new diagnoses for autistic-related disorders. Government workers conducted training seminars with clinicians in order to promote the new coding system, and an increase in autism and other reported diagnosis was to be fully expected. 

Denmark: An Artificial Increase? This study “manipulates the incidence of autism in an attempt to clear thimerosal-containing vaccines of any role in the etiology of the disease,” a SafeMinds said in a statement. The increase reported in Denmark was “falsely created by the authors’ use of techniques which artificially boosted the number of cases identified.”

Sweden: Inpatient Cases Only - By counting only inpatient cases in Sweden, the reliability of that country’s data is also called into question. This limitation (counting a minority of the total number of cases) likely accounted for the erratic swings in the annual numbers of autism cases reported in that country.

California: Increase is Real - Sterh-Green et al. erred by writing that California’s Department of Developmental Services used a “vague” and difficult to verify autism definition. Their speculation that “changes in diagnostic criteria,” including PDD, “accounted for the largest increases” is not supported by the evidence. California’s data included only full-blown cases of autism, and not PDD. If anything, diagnostic criteria for “classic” autism became narrower over the years. And the suggestion that changes in criteria or “diagnostic substitution” (from mental retardation to autism) could explain the reported 800% increase in California has been disproven in several published papers. No retraction or correction of the authors’ erroneous claims was made.

WHAT THE STUDY SAID

Inpatient v Outpatient Cases - The authors noted that the switch from counting inpatient cases only, to counting all cases “Changes over time in the rates of diagnosis of autism-like disorders in inpatient versus outpatient settings may have affected the ascertainment of cases,” the authors said, adding that these very significant changes “may have spuriously increased the apparent number of autism cases.”

Weakness of Ecological Studies - The authors also noted the inherent weaknesses of relying on large epidemiology investigations called “ecological” studies, in which the unit of analysis is a population group and not individuals. They conceded that these studies are inherently limited in their ability to prove or disprove causation. “Such studies can be useful in exploring possible associations, (and) searching for areas of possible further study,” they wrote. “However, the greatest difficulty in interpreting ecologic studies is that of adequately controlling confounding factors due to unavailability of data and/or methodological limitations.”

WHAT THE CDC SAID ABOUT ECOLOGICAL STUDIES

An unpublished 2008 report from the CDC to the US House of Representatives Appropriations Committee concurs that ecological studies are far from ideal when using computerized population data - in this case the federal Vaccine Safety Datalink (VSD) - to determine an association between vaccines and autism. [48]

“CDC concurs that conducting an ecologic analysis using VSD administrative data to address potential associations between thimerosal exposure and risk of AD/ASD is not useful,” said the CDC paper, which was signed by then Director Julie Gerberging, MD, now President of the Vaccine Division at Merck & Co., Inc. Such an evaluation, she added, “would be uninformative and potentially misleading.

WHAT THE IOM COMMITTEE SAID:

Shifting Study Population – In its 2004 report, the Immunization Safety Review Committee agreed that “possible reasons” for the autism increase in Denmark “may be due to the changes in the inclusion criteria in the national register, diagnostic changes (from ICD-8 diagnostic coding to ICD-10), and the fact that, prior to 1992, cases diagnosed in one large clinic (about 20 percent of all cases) were not included.”

Weakness of Ecological Studies - The committee likewise conceded that “The ecological nature of the study limits the study’s contribution to causality.”

Swedish Contribution is Limited - As for the Swedish data, “which only reflected cases diagnosed in inpatient settings” the IOM committee admitted that the reported increase might have been caused by “changes in diagnostic criteria and increasing awareness of autism and related disorders.” The Sweden section, likewise, was an ecological analysis, which again “limits the study’s contribution to causality.”

CRITIQUE BY MARK D. NOBLE - PROFESSOR OF GENETICS AND OF NEUROBIOLOGY AND ANATOMY, UNIVERSITY OF ROCHESTER MEDICAL CENTER [49]

One hypothesis to explain the sudden increase in prevalence is that changes in diagnosis and increased interest in autism caused an enhanced recognition of children with these syndromes.  Thus, we know that the reported prevalence from 1971 to 1990 is artificially low, because it doesn’t include children who were given a different diagnosis.  That means that in its current form, the comparison between the 1971-1990 cohort and later cohorts is fundamentally flawed, because they represent different kinds of information.  There is quite an explosive change that is going on between 1995 and 2000. What could explain this? When you read the actual details of this manuscript (Madsen et al., 2003) you find out that, in 1995, a change was made in the information contained in the Danish registry. Prior to 1995 this registry only contained inpatient data, but after 1995 it also included data from outpatients. 

In fact, the paper states that this change introduced 4-6 times as many total individuals into the registry. But it did not increase for a biological reason – it increased because they simply were obtaining cases from 4-6 times as many total people. At least in the years 1991-1998, 93.1% of the autism cases were treated only as outpatients. Thus, the addition of outpatients to the analysis in 1995 may have added 13.5 times as many cases of autism to the number of cases reported. If we apply even the most conservative correction factor for non-biological contributions, then a reasonable interpretation … is that the biological prevalence of PDD fell by 30-40% after the removal of thimerosal from vaccines. Even the application of the lower end of the possible correction factors leads to the conclusion that there was a fall in autism prevalence after thimerosal was removed from vaccines. 

SUMMARY:  This weak review analyzed data from three different countries where mercury exposures were vastly different, and where autism cases were counted in very different ways. In addition, over the study period, the Danish autism registry switched from counting only inpatient-diagnosed cases (about 13% of the total) to counting both inpatient and outpatient cases (100% of the total). This accounted for most if not all of the “increase” in cases observed after the removal of thimerosal from Danish vaccines.

.” [50]  

Authors: Madsen KM, Lauritsen MB, Pedersen CB, Thorsen P, Plesner AM, Andersen PH, Mortensen PB.

Publication & Date: Pediatrics, September, 2003

Online at: http://pediatrics.aappublications.org/cgi/content/full/112/3/604

Details: As in Stehr-Green, the authors looked into “whether discontinuing the use of thimerosal-containing vaccines in Denmark led to a decrease in the incidence of autism. This studied also relied on data from the Danish Psychiatric Central Research Register on all psychiatric inpatient admissions since 1971, and all outpatient contacts in psychiatric departments in Denmark since 1995. The patient population included all children between 2 and 10 years old diagnosed with autism from 1971-2000.

Results: A total of 956 children were diagnosed with autism during the period. “There was no trend toward an increase in the incidence of autism during that period when thimerosal was used in Denmark, up through 1990,” the authors wrote. But from 1991 until 2000, the incidence increased and continued to rise after the removal of thimerosal from vaccines, including increases among children born after the discontinuation of thimerosal”

Authors’ Conclusions: Because the reported rate of autism continued to rise after the removal of thimerosal from vaccines in Denmark, the authors said, “Our ecological data do not support a correlation between thimerosal-containing vaccines and the incidence of autism.” 

CRITIQUES OF THE STUDY

The Same Danish Database - Critics stated the obvious: This study was little more than a second version of the Danish section included in the Stehr-Green paper, which was published one week earlier. The main flaw in that study, of course, was the major change in the Danish registry – from including inpatient only cases, to including both inpatient and outpatient cases.

Repeating the Swedish Mistake in Denmark - In order to address the issue of adding outpatient cases in 1995, Madsen et al. went back and looked at inpatient cases only. Among this small minority of cases, they reported “the same trend with an increase in the incidence rates from 1990 until the end of the study period.” The authors failed to provide these data in their study. And the sampling was essentially identical to the Swedish analysis, in which the IOM committee (in addition to the authors) conceded that the apparent increase in autism incidence could be due to “changes in diagnostic criteria and increasing awareness of autism and related disorders.”

Weakness of Ecological Studies – This was another ecological analysis which, as the Director of the CDC, Dr. Julie Gerberding, wrote to Congress: the contributions of such studies toward establishing causality are “limited.”

A Very Low Autism Rate - Even if autism rates were shown to actually be increasing in Denmark, they were remarkably low both before and after thimerosal was removed. According to the Madsen study, Denmark’s prevalence rate was a tiny 1-per-10,000 - one of the lowest rates ever reported - before thimerosal’s removal. By 1999 (with the addition of outpatient cases) the rate “rose” to 4-6 per 10,000 - still very low - comparable to US rates before thimerosal exposures in that country tripled, around 1990. The rate was also at least ten times lower than the estimated 2000 US rate, 60-per-10,000.

Undisclosed Conflicts of Interest - SafeMinds and others criticized the inherent conflicts of interest among some of the study authors. Two of them worked for the Statens Serum Institut, a Danish manufacturer of thimerosal containing vaccines. According to its mission statement, “Statens Serum Institut is a public enterprise operating as a market-oriented production and service enterprise. In 2002, more than 80% of SSI profits came from vaccines.” Still, this conflict was not disclosed by Pediatrics.

WHAT AN INTERNATIONAL TEAM OF SCIENTISTS SAID

In 2005, Joachim Mutter of the Institute for Environmental Medicine and Hospital Epidemiology, in Freiburg, Germany and colleagues in the UK and US published a paper in Neuroendocrinology Letters that included a serious indictment of the study. It echoed many of the same points made by SafeMinds and others, namely: [51]

● Autism counts were based on hospitalized, inpatient records in the first cohort and then changed in the middle of the study period (1995) to include outpatient records. Therefore, the purported increases after 1994 may be explained by the additional recruitment of an existing autism population that did not require hospitalization.

● After 1992, the register added in patients from a large Copenhagen clinic, which accounted for 20% of the caseload in Denmark. The patients from this clinic were excluded prior to 1992.

● The diagnostic category changed after 1993 from “psychosis proto-infantilis” of ICD-8 (code 299) to “childhood autism” of ICD-10. Another paper using the same inpatient register reports that the psychosis proto-infantilis category includes inpatient cases that do not fulfill the criteria for autism.

● Many of the children were between 7–9 years old, and most were over 4 years old, when recorded. But the onset of autism must occur, by definition in the diagnostic criteria, before three years of age. The most widely used approach to assessing autism trends is to use year of birth as the “incidence time” and to assess trends in autism rates based on birth year of the study population rather than time at diagnosis or some other measure of incidence. 

● Another recent study performed by Madsen et al. reported Danish autism rates of 6 per 10,000 for children born in the 1990s. [52] These Danish rates are very low in the 1990s compared to the United States.  Madsen et al. also report inpatient rates for the pre-1993 “psychosis proto-infantilis” at well below 1 per 10,000. This low rate would contradict the single published survey of autism rates from Denmark, which indicated an autism rate of over 4 per 10,000 as far back as the 1950s.

● Additional confounders were present in the U.S. with high prevalence of autism that were not present in Denmark: Between 1970–92, the only childhood vaccine given in Denmark until 5 months of age was the monovalent pertussis vaccine. In the United

States, children were exposed to multiple doses of diphtheria, pertussis, tetanus, polio, hepatitis B and haemophilus influenza B (Hib) vaccines before five months of age in the 1990s.

WHAT THE MEDIA SAID:

The mainstream media portrayed the Madsen study as definitive. The New York Times declared: “Study Casts Doubt on Theory of Vaccines' Link to Autism” and quoted the CDC’s Dr. Robert Davis as saying the evidence was “clear-cut: If you remove cars from highways, you'll see a marked decrease in auto-related deaths. If thimerosal was a strong driver of autism rates, and you remove it from vaccines, you should have seen some sort of decline — and they didn't." [53]  

The Times also quoted Dr. William Schaffner, Chairman of Preventive Medicine at Vanderbilt University in Nashville, as claiming that the study added to “the whole mosaic of studies that have addressed this. Each is imperfect, but they all add up to this theme: thimerosal is not the culprit.”

The paper included a SafeMinds statement asserting that the researchers “artificially boosted the number of cases by adding outpatients and those at a large Copenhagen clinic to earlier inpatient figures.” It also reported that two authors worked for a Danish vaccine maker, “suggesting a conflict of interest.”

WHAT THE AUTHORS SAID:

Outpatients “May Exaggerate Incidence” - The authors conceded that, “because many patients with autism in former years have been treated as outpatients this may exaggerate the incidence rates simply because a number of patients attending the child psychiatric treatment system before 1995 were recorded for the first time, and thereby counted as new cases in the incidence rates.”

Greater Awareness, New Diagnostics Can Boost Numbers - The reported increase in autism in Denmark “may be attributable to more attention being drawn to the syndrome of autism and to a change in the diagnostic criteria from the ICD-8 to the ICD-10 in 1994.”

Exposure Levels Were Lower Than US - Echoing criticism that the Danish data are not comparable to other countries, such as the US where mercury exposures were greater, the authors wrote: “Our data cannot, of course, exclude the possibility that thimerosal at doses larger than used in Denmark may lead to neurodevelopmental damage.”

WHAT THE IOM REVIEW SAID: 

Limited Contribution - Adding additional outpatient cases into the Danish register was noted as a potential problem. “A reanalysis was conducted, limiting itself to inpatient data only, and the authors found similar trends in autism rates, although the data were not shown,” the IOM wrote. “However, despite the reanalysis the authors stated that autism incidence after 1995 may have been exaggerated due to the change in including outpatient cases into the Danish Psychiatric Central Register. This limits the study’s contribution to causality.

SUMMARY: This study is perhaps the least informative of all the thimerosal studies. The shifting definition of cases and limitation, at any point, of only autism cases that were admitted to hospitals make this analysis thoroughly unreliable from the outset. 

Authors: Hviid A, Stellfeld M, Wohlfahrt J, Melbye M.

Publication & Date: Journal of the American Medical Association, October 1, 2003

Online at: http://jama.ama-assn.org/cgi/content/full/290/13/1763

Details: The authors conducted a population-based cohort study of all 467,450 children born in Denmark from January 1, 1990, until December 31, 1996. They compared those children who received a thimerosal- containing vaccine with children who were given a thimerosal-free version of the same vaccine.

Results: During “2,986,654 person-years,” the investigators identified 440 cases of autism and 787 cases of other autistic-spectrum disorders. “The risk of autism and other autistic-spectrum disorders did not differ significantly between children vaccinated with thimerosal-containing vaccine and children vaccinated with thimerosal-free vaccine,” they wrote. “Furthermore, we found no evidence of a dose-response association,” an increase in the relative risk for every 25 micrograms of mercury exposure.

Authors’ Conclusions: “The results do not support a causal relationship between childhood vaccination with thimerosal-containing vaccines and development of autistic-spectrum disorders.”

CRITIQUES OF THE STUDY

Mercury Cannot Be “Protective” - The data in this study show that mercury is beneficial to infant children. Those in the thimerosal group had a relative risk of 0.85 for autism, compared with the mercury free group, suggesting a substantial (though not significant) protective effect for thimerosal. This finding is suspicious, and runs counter to all knowledge, science and common sense. More to the point, the outcome suggests the presence of unexamined or unreported bias in the study design and data management that suggest the researchers were prejudiced in a way that makes them unreliable investigators.

Older Children’s Records Missing - SafeMinds identified a flaw that could well have produced a significant loss of autism case records from the Danish register, rendering the Hviid et al. findings invalid. “The registry allows 10-25% of diagnosed autism cases to be lost from its records each year,” the group wrote in a letter to JAMA. [55] “The effect of this loss is such that the records will disappear from older age groups to a much greater degree than from younger age groups in any given registry year.” Older children were underrepresented in the cohort, even though they were the ones who received thimerosal-containing vaccines before 1992.

Reanalysis Finds More Autism in Exposed Children – In the same letter to JAMA, SafeMinds reanalyzed the Denmark data using an alternative method to avoid the “record removal bias.” Instead, they looked at same-age children – 5-to-9 year olds - but from two different registry years: 1992, when all of the children received thimerosal-containing pertussis vaccines; and 2002, when none of the children received thimerosal. “After adjusting for the lack of outpatient records in the 1992 registry, the analysis found a 2.3 times higher number of autism cases among the 1992 thimerosal-exposed group relative to the 2002 non-exposed group,” SafeMinds said.

No Tracking of Birth Cohorts - The researchers failed to classify autism cases by birth year. There is often a gap between the number of children diagnosed with autism from any given birth cohort and the number of autism cases reported in any given calendar year. Analyzing the data according to birth cohort would have painted a far more accurate picture, because it would have reduced or eliminated the gap between diagnoses of ASD and reporting of cases.

Undisclosed Conflict of Interest - “In the Hviid study in JAMA we can clearly see how the data was misinterpreted so a conclusion could be drawn to clear thimerosal from any role in autism,” a SafeMinds statement said. “This misinterpretation is not surprising, given the authors’ employment at Statens Serum Institut, a conflict of interest that should have been disclosed.”

WHAT THE AUTHORS SAID

The authors wrote that a “possible weakness” of their paper was that “the date of diagnosis used as the incidence date may differ significantly from the ‘onset of symptoms’ date.” Diagnosis autism is often “a lengthy process,” they wrote, and this is “reflected in the mean ages of diagnoses in this study (4.7 years for autism and 6.0 years for other autistic-spectrum disorders).” Such a limitation, however, “is more likely to be a problem in an incidence study than in a risk factor study.”

WHAT THE IOM SAID

Although the committee considered the study as having “strong internal validity” it also identified various limitations, “including its time-series design,” (as pointed out by SafeMinds), and the “generalizability of the study’s findings to the U.S. situation, especially with regard to the different dosing schedule used in Denmark and the relative genetic homogeneity of the Danish population.”

SUMMARY: This study was marked by missing records, a failure to track birth cohorts, and undisclosed conflicts of interest. Reanalysis of the data actually showed an increased risk of ASD following thimerosal exposure. It also concluded that mercury had a protective effect on the neurodevelopment of children, which flies in the face of all logic and all previous studies of mercury and children.

Authors: Verstraeten T , Davis RL , DeStefano F , Lieu TA , Rhodes PH, Black SB , Shinefield H , Chen RT ; Vaccine Safety Datalink Team .

Publication & Date: Pediatrics, November, 2003

Online at:  http://www.ncbi.nlm.nih.gov/pubmed/12880876

Details – This study, conducted by investigators at the CDC using the Vaccine Safety Datalink (VSD) of computerized HMO databases was a two-part “retrospective cohort study.” The first phase looked at potential associations between neurodevelopmental disorders (NDDs) - including autism, ADD, speech and language delay and tics - and thimerosal among 124,170 US children born from 1992 to 1999 at one of two HMOs (A and B).

Because Phase I failed to find a consistent, statistically significant “signal” for autism or ADD, these disorders were excluded as study endpoints in Phase II. In that phase, the most common disorders associated with exposure in phase I (tics, speech delay and ADHD) were assessed among 16,717 children born from 1991 to 1997 in a third HMO (C). Relative risks for neurodevelopmental disorders were calculated for each 12.5 microgram increase of estimated thimerosal exposure in the first, third, and seventh months of life.

Results: In phase I at HMO A, exposure at 3 months of age was associated with an increased risk of tics.” The relative risk for tics was 1.89, meaning exposed children were nearly twice as likely to develop the disorder. At HMO B, there was an increased risk of language delay for exposure at 3 months (RR: 1.13) and 7 months (RR: 1.07). However, in Phase II at HMO C, “no significant associations were found,” and “In no analyses were significant increased risks found for autism or attention-deficit disorder.”

Authors Conclusions: “No consistent significant associations were found between TCVs and neurodevelopmental outcomes. Conflicting results were found at different HMOs for certain outcomes. For resolving the conflicting findings, studies with uniform neurodevelopmental assessments of children with a range of cumulative thimerosal exposures are needed.”

A “SIGNAL” DISAPPEARS ACROSS FIVE GENERATIONS OF STUDY

Critics of the Verstraeten paper question the process under which the data were managed across at least five different generations of analysis that lasted more than four years before the official version was published in Pediatrics. They charge that the data were put through a rather torturous process of statistical manipulation designed to get the results so badly desired by CDC: Namely, no association between thimerosal and negative outcomes.

Whether done intentionally or not, the various generations of analysis clearly show how an extremely strong “signal” between thimerosal and autism, ADD and other NDDs in the first generation was reduced to almost nothing in the fifth and final published version.

It is important to note that the first four analyses would never have come to light without documents obtained by SafeMinds through the FOIA. The group’s FOIA efforts likewise yielded unpublished minutes from a secret, two-day conference held in June 2000 near CDC headquarters outside Atlanta, known as the Simpsonwood Meeting. It is clear from the transcript that many industry and public health experts at Simpsonwood were alarmed by the possible harm being caused by thimerosal – but even more worried about the possible damage that any bad publicity would have on the national and global vaccine programs. Participants voted to keep the meeting secret, and it remained so for two years, when the minutes were delivered to SafeMinds. (See Below).

It is also important to note that Verstraeten himself presented results from some of the earlier VSD analyses – in which the thimerosal signal was still quite significant - to the CDC’s Advisory Committee on Immunization Practices Institute (ACIP) in 2000 and to the Institute of Medicine in 2001 without dismissing the data as being “preliminary” and therefore unreliable (also discussed below)

FIRST ANALYSIS – December, 1999 -- Autism Relative Risk = 7.62

In the very first run of the VSD data on thimerosal, lead author Thomas Verstraeten divided all of the children in HMO A and B into four groups: Those who had received zero micrograms of mercury in vaccines by one month of age, those who had received 12.5mcg, those who received 25mcg, and those exposed to more than 25mcg by one month of age.

The results were astonishing. The children exposed to more than 25mcg had extremely elevated relative risks for:

● ADHD: 11.35 times more likely

● Autism: 7.62 times more likely

● ADD: 6.38

● Tics: 5.65

● Speech and Language Delay: 2.08

SECOND ANALYSIS – February, 2000 -- Autism Relative Risk = 2.48

Within two months, Verstraeten had reanalyzed the data, incorporating methodological changes suggested by colleagues at the CDC. In the second version, completed in February 2000, the estimated relative risk for autism had fallen considerably – though it was still worryingly high. Children in the two HMOs exposed to the most mercury (62.5mcg) at three months of age were almost two and half times more likely to develop autism (RR=2.48). This calculation was just short of statistical significance because the low end of the margin of error fell slightly below the risk of 1.0. It’s worth noting that Verstraeten excluded children who had been treated with hepatitis B immune globulins “as these were more likely to have high exposures and high outcomes.” Most formulations of immune globulins were preserved with thimerosal at that time. These infants were among the most heavily exposed patients and also had dramatically higher rates of autism and other disorders, and yet they were excluded from the analysis at this stage.

Relative risk of from thimerosal exposure at 3 months of age:  

SOURCE: Internal CDC report, February 2000 – Obtained through the Freedom of Information Act (FOIA).

Verstraeten was nonetheless alarmed. On December 17, 1999 he sent an email to colleagues Robert Davis and Frank DeStefano under the subject line “It just won’t go away,” by which one presumes he meant the association between thimerosal and NDDs. “Some of the relative risks increase over the categories, and I haven’t yet found an alternative explanation,” he said. “Please let me know if you can think of one.” 

In this second analysis, Verstraeten, Davis and DeStefano candidly wrote that they had associated “increasing risks of neurological developmental disorders with increasing cumulative exposure to thimerosal.” They also found “similar increases” for the risk of developmental speech disorder, autism, stuttering and attention deficit disorder, though these increases were not statistically significant. “We can state that this analysis does not rule out that receipt of thimerosal containing vaccine in children under three months of age may be related to an increased risk of neurological developmental disorders.”

THIRD ANALYSIS – June, 2000 -- Autism Relative Risk = 1.69

On March 9, 2000, Verstraeten sent another email, obtained through FOIA, about his work on the third generation of analyses. He wrote that the risk of developmental delay began to drop among children who missed their first thimerosal-containing HiB and DTP shots before three months of age. This confirmed his “hypothesis” that “What matters is not getting it before the third month, after which the implications gradually diminish.”

Verstraeten also looked at exposure rates and outcomes among 10 premature infants and found that those exposed to 200mcg mercury were five times more likely to have an NDD than preemies exposed to 100mcg. “These findings are very extreme and warrant closer examination,” he wrote.

By this time, Verstraeten et al. were preparing a third analysis of the VSD data, incorporating even more changes (i.e. entry criteria, stratification of population groups, etc) to their methodology. Critics say these changes were made deliberately to eliminate the “signal” that would “not go away” (discussed below) while CDC officials have insisted they were just trying to get the “cleanest” and most reliable data possible.

In June, 2000, Verstraeten presented the third analyses at a meeting of the CDC’s Advisory Counsel on Immunization Practices (ACIP) and at the Simpsonwood conference. This time, the relative risk for autism among children given more than 62.5 mcg by three months of age had fallen - from 2.48 to 1.69:

This still-elevated autism finding was not considered statistically significant because the margin of error dipped below a relative risk of 1.0. But the team did find “statistically significant associations between thimerosal and neurodevelopmental disorders” other than autism. These included:

Relative Risk for All NDDs Combined: The RR for this umbrella category of outcomes among children exposed to 62.5mcg at three months was 1.64, meaning these children were 64% more likely to have any NDD than children exposed to 0mcg. The risk was considered statistically significant because the margin of error remained above 1.0. And increased risk was completely linear and dose-dependent: It increased by 0.7% for every microgram of mercury exposure:

Relative Risk for Developmental Language Disorder: Statistically significant increased risks for language disorder were found at 3 months (2.1% per mcg). The RR for children receiving 50mcg mercury or more by 3 months of age was especially high. Children who received 62.5mcg had a relative risk of 2.10 compared with children who received 12.5 mcg.

 Relative Risk for Attention Deficit Disorder: There was a statistically significant, dose-dependent response at six months of age of 0.6% for each microgram of exposure. At 62.5mcg, the RR was 1:30, or 30% more likely to develop ADD.

Other Elevated risks: Increased risks per mcg of exposure were found for:

Speech delay: 1 month (RR: 1.011), 3 months (RR:1.008), 6 months (RR:1.002)

Unspecified Delays: 2 months (RR: 1.005), and 3 months (RR:1.007)

Tics: 3 months: (RR: 1.021)

“Some of these are borderline statistically significant,” Verstraeten told the ACIP meeting. “Some of them are highly statistically significant. What these estimates suggest is that there seems to be an increasing trend, an increasing risk for any of these neurological developmental outcomes, with increasing thimerosal exposure.”

THE SIMPSONWOOD CONFERENCE – June 2000

The same month as the ACIP meeting – June, 2000 - the CDC convened an invitation-only conference at a retreat outside Atlanta called Simpsonwood, where dozens of public health officials, physicians, scientists, and industry executives gathered for a two-day, supposedly off-the-record discussion of the Verstraeten findings. The meeting was not announced to the public, and the transcript was not meant for public consumption. It was, however, included in a FOIA request packet that was delivered to SafeMinds. Members of the public were patently excluded at Simpsonwood, and industry representatives outnumbered panel members.

The task at hand was to review the VSD analysis and determine if a “signal” between TCVs and developmental disorders was there. Participants were also asked for ideas on how to proceed in the ongoing investigation, which was in its first year of what would become four years of analysis and reanalysis. Among the revelations: [57]

Troubling data - Many attendees knew they had a problem. “What if the lawyers get hold of this?” asked one. “There’s not a scientist in the world who can refute these findings.”

● Deference to industry - It is clear that the CDC would not recall any mercury containing vaccines, regardless of the risks, out of concern for the financial interests of the vaccine industry. “CDC is not in favor of expressing a preference for a particular vaccine (i.e. thimerosal-free) for fear of alienating the other manufacturers and disrupting a free market economy,” one participant wrote to colleagues after the meeting.

● Dr. Paul Stehr-Green, an associate professor of epidemiology at the University of Washington and lead author of the Danish-Swedish thimerosal study, summarized the meeting in a memo obtained through FOIA. He wrote that, despite a prolonged “re-analyses,” the data still showed a “slight tendency for groups with higher exposure to thimerosal-containing vaccines to have higher rates of the same neurobehavioral outcomes.” But, he insisted, the level and consistency of statistical significance of these findings was “unimpressive.” The results did not “offer adequate evidence to support or refute the existence of causal relationship.          

● Dr. Philip Rhodes (a CDC statistician) spoke of a certain way that researchers could suppress the signal through changing the exclusion criteria: Restore thousands of children with congenital disorders who were excluded from the study, “which would serve to add ‘noise’ that could obscure the signal. All those kids that Tom (Verstraeten) has excluded, I have thrown them in. I think there is a clear argument that is going too far, but that further brings things down,” Rhodes said. “So you can push, I can pull. But there has been substantial movement from this very highly significant result, down to a fairly marginal result.”

Eventually, those previously excluded children with congenital disorders would indeed be added back into the patient population under study.

● Dr. Thomas Verstraeten discussed many of the study’s flaws, including the large number of young children. “One thing that is for sure, there is certainly an under-ascertainment of all of these cases,” he said. “Some children are just not old enough to be diagnosed. So the crude incidence rates are probably much lower that what you would expect, because the cohort is still very young.” As for the most common disorder found, speech delay, Verstraeten said the trend had been “highly statistically significant.” He added that the hypothesis was “biologically plausible.”

Verstraeten was very clear on one central point, however. Despite the changes in methodology and stratification of the data, the signal between thimerosal and NDDs simply would not vanish. “You can look at this data and turn it around,” he said, “and look at this, and add this stratum, and I can come up with very high risks. And I can come up with very low risks, depending on how you turn everything around. You can make it go away for some and then it comes back for others,” he concluded. “So the bottom line is, okay, our signal will simply not just go away.”

Dr. William Weil, who represented the American Academy of Pediatrics, lectured his colleagues for believing that the signal was weak and not significant:

The number of dose related relationships are linear and statistically significant. You can play with this all you want. They are linear. They are statistically significant. The increased incidence of neurobehavioral problems in children in the past few decades is probably real. Like many repeated acute exposures, if you consider a dose of 25 mcg on one day, then you are above threshold. And then you do that over and over to the same neurons. It is conceivable that the more mercury you get, the more effect you are going to get. The brain and central nervous system are not fully developed at birth. The earlier you work with the central nervous system, the more likely you are to run into a sensitive period for one of these effects. It changes enormously the potential for toxicity. There’s a host of neurodevelopmental data that would suggest that we’ve got a serious problem. To think there isn’t some possible problem here is unreal. The number of kids getting help in special education is growing nationally and state by state at a rate we have not seen before. The rise in the frequency of neurobehavioral disorders is much too graphic. We don’t see that kind of genetic change in 30 years.
      
After the meeting, Verstraeten sent an email to colleagues complaining of the indifferent stance that most of the participants took toward the thimerosal signal that “won’t go away.” Their attitude seemed to be that, “if nothing is happening in these studies, then nothing should be feared of thimerosal,” he wrote. “I do not wish to be the advocate of the anti-vaccine lobby and sound like being convinced that thimerosal is or was harmful, but at least I feel we should use sound scientific argumentation and not let our standards be dictated by our desire to disprove and unpleasant theory.”

FOURTH ANALYSIS – July, 2001 -- Autism Relative Risk = 1.58

In this fourth analysis, presented at the July 2001 meeting of the IOM’s Immunization Safety Review Committee, the VSD team had decided to divide HMO A and B and examine their data separately.

But HMO B, with some 15,000 patients studied, was considerably smaller than HMO A, which had 115,000 patients. After breaking them into two subpopulations, they found that data from the smaller HMO were no longer statistically significant. The smaller HMO simply lacked the “statistical power” of the larger HMO and therefore, results from the two HMOs were no longer “consistent.” The same was true for speech and language delays.

Even so, for some of the estimates, “we found high statistical significance,” Vertraeten told the IOM. “Some of these associations are biologically plausible, and for some, we saw a dose response.”

By now, the team had also completed Phase II of the study, which was to compare results from HMOs A and B with a third, independent HMO, in this case, Harvard Pilgrim of Massachusetts. And though Phase I had found “several significant associations between thimerosal and neurodevelopmental disorders,” Verstraeten said, “in an analysis in a smaller and independent data set, we could not confirm those associations for speech or language delay and ADHD.” And given the lack of statistically significant risk for autism, the team had stopped looking at that outcome altogether in the Harvard Pilgrim data.

The reliance on HMO C to discount the entire study was criticized by Neal Halsey (title here) “Some people who have seen the third HMO, which is Harvard Pilgrim, have said there is no effect there, therefore that disproves the hypothesis,” he testified at IOM. “Well, that is really not true. I don't know what the real power is of that study to say that there really isn't an effect there. Power is a very important factor in studies that don't show an effect.”

The data were inconclusive, but “still suggestive of an effect from thimerosal,” he said.

FINAL ANALYSIS – November, 2003 -- Autism Relative Risk = N/A

By the time the study was published in 2003, the authors found just one increased risk for tics in phase I: At HMO A, exposure at 3 months the relative risk was 1.89. At HMO B, B, there was an increased risk of language delay for exposure at 3 months (RR: 1.13) and 7 months (RR: 1.07). But in Phase II at HMO C, “no significant associations were found.” And “in no analyses were significant increased risks found for autism or attention-deficit disorder.”

This was untrue. In the first analysis, there were significant increased risks for autism and ADD, and in the second analysis, there was a significant increased risk for ADD.

CRITIQUES OF THE STUDY

How did the relative risk for autism tumble from 11.35 to null? The four-year, five-generation analysis has been examined closely by many critics, both inside the autism community and among respected scientists, physicians and members of Congress. The many methodological flaws they have identified include:

Inclusion of Young Children - Researchers included young children, from 0-3 years old, even though the average age of an autism diagnosis was 4.4 years. A diagnosis in the first years of life was rare, so including these children would tend to drive down the overall relative risk. Because they were not yet diagnosed, all of them would have been misclassified under the normal group. But the CDC assumed that autism is diagnosed as frequently in 1-year-olds as five-year-olds. 

■ No Autism Diagnoses Among Youngest Children - Among the youngest children, who made up 40% percent of all kids in the study, not a single case of autism was reported, which means that 40% of the sample was misclassified.

Underreporting of Autism Cases - The researchers identified relatively few kids with autism compared to what one would expect to find in the general population. In California at the time, the autism rate (excluding PDD and Aspergers) was around 50-100 per 10,000 children. But the average rate at the two California HMOs was just 11.5 per 10,000. Had they missed, or somehow eliminated four out of five cases? What else could explain this dramatic under-ascertainment? This undercount clearly also means that these cases were misclassified. 

■ Exclusion of ASD cases other than “autism” - The researchers did not look for outcomes like PDD-NOS and Asperger’s Syndromes, even though they are autism spectrum disorders. This meant that higher-functioning children were not included in the risk ratios.■ Stratification of Data – The authors not only separated HMO A and B to find that data from the smaller HMO alone lost statistical power, they even broke up the larger HMO into subgroups comprised of individual clinics in the network. This “stratification” helped eliminate any consistent statistically significant risk of ADHD or speech disorders that were found within the larger HMO as a whole. Smaller population subgroups have less “statistical power,” and increase the possibility that statistical significance will not be attained.

■ Elimination of the combined “NDD” Outcome - By breaking this generalized umbrella outcome into individual categories like ADHD, speech delay and tics, the relative risks and statistical significance of most outcomes were reduced or eliminated. Again, the smaller the stratified subgroup, the greater the chance of reducing statistical power and thus statistical significance.

Elimination of cases diagnosed outside the HMOs – The authors chose to include only those cases confirmed by a behavioral specialist. But if that specialist was outside the HMO, the diagnosis was not counted. This provided the opportunity to “cherry pick” cases out of the original data set. Among the ADD/ADHD cases, 60% were eliminated because they were not made by an in-network specialist. For speech and language delay, 50% were excluded and for autism, 20% were eliminated.

Higher risk with increased vaccination - Generally speaking, among the three HMOs studied, the higher the vaccination rate, the greater the risk of adverse outcomes. During the third generation of analysis, for example, HMO C had the highest full vaccination rate, at 65%, and also the highest speech delay rate. Meanwhile, at HMO A, the fully vaccinated rate was 60%, or four times greater than compliance at HMO B (15%), while the rate of all NDDs at HMO A was 5.7%, four times greater than the 1.3% rate found at HMO B.

■ Problems at Harvard Pilgrim - There were questionable record keeping practices at Harvard Pilgrim (HMO C), and Massachusetts had been forced to take over after it declared bankruptcy. Even worse, the HMO used different diagnostic codes than the other two HMOs in Phase I. It wasn’t surprising that the Harvard Pilgrim data was inconsistent. Also, the study population at Harvard Pilgrim was significantly smaller (15,000 kids). The smaller the population studied, the greater the margin of error, which lowers the study’s “statistical power” and weakens the signal for outcomes.

■ Undeclared conflict of interest. After Verstraeten began work at GlaxoSmithKline, “the data, sampling and methodology of the study were altered, so that results would point to enough inconsistencies to cast doubt that mercury in vaccines causes autism,” critics alleged. Verstraeten had not been named as a GSK employee in the study and was misidentified as an employee of the CDC. It must be noted that GSK made thimerosal- containing vaccines included in the study, such as Hepatitis B and DTaP vaccines.

■ Unavailability of data - “The current practice of restricting access to the database to a limited group of possibly biased individuals is not acceptable,” SafeMinds declared. Their statement added that the Pediatrics report “cannot be accepted as final.” CDC rules had made the approval process long and arduous. Those who did gain access (the Geiers) could only “utilize a limited portion of the VSD data set, and their examination of the data is subject to constant monitoring by CDC staff.”

WHAT THE MEDIA SAID

Associated Press – Co-author Frank DeStefano “acknowledged that the early results suggested stronger links with some disorders, though not autism, but denied that there had been pressure or a cover-up. He said the final data reflect a more thorough recent analysis. Verstraeten, who left the CDC in July 2001, did not respond to an email request seeking a response, and company spokeswoman Nancy Pekarek said he did not wish to discuss the results, but provided a statement in which Verstraeten said that ‘since leaving the CDC he was only an adviser as the study was finalized and prepared for publication.’” [58]

WHAT THE CDC SAID

CDC spokesman Von Roebuck told Insight on the News magazine that, “We pretty much looked into that [the manipulation of data] in the sense of how the information was presented, and we do stand behind it.” As for Verstraeten’s undisclosed employment at vaccine maker GSK, he said. “The one thing that we would want to happen differently is that would have been known before. But the work that Dr. Verstraeten did was for the CDC at the time the work was produced – the work that he did for the study was done when he worked for the CDC."

WHAT LEADING VACCINE EXPERTS SAID

Dr. Neal Halsey, the national vaccine expert, along with colleagues Daniel A. Salmon and Lawrence H. Moulton, published a letter in the journal Pediatrics calling for further analysis of the data which included the following critiques: [59]

■ Changing Criteria - By eliminating the combined umbrella outcome of NDDs, and dividing it into separate diagnoses, the authors “may have substantially reduced the power to find important relationships,” Halsey et al. said, adding that the later entry criteria “appear to have been more lax” than in a previous version.

■ Excluding Diagnoses - The requirement that diagnoses be made by an in-network specialist was also questioned. “Were diagnoses that were not made by a specialist excluded from analyses?” they asked, noting that primary care doctors are quite “capable of diagnosing ADD without input from a sub-specialist.”

■ Unequal Population Sizes – Halsey et al. also criticized the comparing of data from a large HMO with two much smaller ones.

WHAT VERSTRAETEN SAID

In a letter published in the April, 2004 issue of Pediatrics, Verstraeten wrote that, while his team had found a positive association between thimerosal and certain outcomes in Phase I, these findings could not be replicated in the second phase. [60]

But this in no way disproved an association (at least for NDDs other than autism), he insisted in a declaration that is seldom, if ever quoted today. “The perception of the study changed from a positive to a neutral study,” he said. “Surprisingly, however, the study is being interpreted now as negative by many, including the anti-vaccine lobbyists. 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.”

“Did the CDC water down the original results?” Verstraeten asked, and then answered: “It did not.” Despite the fact that vaccine safety activists were charging that a “positive” study had been manipulated into a “negative” one, the study results were neutral; they proved nothing for either side of the debate. Presumably, the point he was making is that a deliberately manipulated study would have yielded a negative result, and not a neutral one

“Did the CDC purposefully select a second phase that would contradict the first phase?” Verstraeten also asked. “Certainly not. The push to urgently perform the second phase at (Harvard Pilgrim) came entirely from myself, because I felt that the first-phase results were too prone to potential biases to be the basis for important public health decisions. (It) was the only site known to myself and my coauthors that could rapidly provide sufficient data that would enable a check of the major findings of the first phase in a timely manner.

And he added this:

The bottom line is and has always been the same: an association between thimerosal and neurological outcomes could neither be confirmed nor refuted, and more study is required.

WHAT A SPECIAL PANEL OF THE NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES SAID

On August 24, 2006, a special panel appointed by the NIEHS issued a report titled “Thimerosal Exposure in Pediatric Vaccines: Feasibility of Studies Using the Vaccine Safety Datalink.” [61] Among other things, the panel was asked to “Identify the strengths and weaknesses of the VSD for evaluating the possible association between exposures to thimerosal-containing vaccines and AD/ASD”

According to the panel, “a number of gaps were identified in the information available at the meeting. These involved business and medical practices at the MCOs that might impact data quality and interpretation of study results, and more generally, the completeness and validity of exposure and diagnostic data in the VSD and the ability to link across family members.” The panel recommended that these gaps be addressed prior to consideration of further studies of ASD and thimerosal using the VSD.

The panel also “identified several areas of weakness,” the report said. “The cumulative effect of these weaknesses was judged to reduce the usefulness of the VSD for addressing the potential association between exposure to the vaccine preservative thimerosal and risk of AD/ASD.”

The weaknesses of primary importance are summarized below.

Case ascertainment - “Of particular interest to the panel was the large proportion, around 25%, of births excluded from the analyses in the Verstraten study. These exclusions were intended to decrease confounding. The panel noted that these children may represent a susceptible population whose removal from the analysis might have had the unintended consequence of reducing the ability to detect an effect of thimerosal. A VSD study that relies exclusively on administrative data to identify cases of ASD is subject to both false positives and missed cases. This stems in part from the original design of the data systems that support the VSD; these systems were designed for administrative rather than research purposes. For example, the administrative record created for an outpatient visit of a child with AD/ASD who is being treated for another medical condition will reflect that other condition rather than the presence of autism. Entries of this type would lead to under-ascertainment of cases.”

Heterogeneity in business practices across and within MCOs (HMOs) – “Eight MCOs currently participate in the VSD and each relies on data systems designed to meet the specific business requirements of the MCO. In addition to obvious differences among MCOs in enrollment size and geographic location of the populations served, many other aspects of service delivery and tracking vary (e.g., developmental screening practices and specialist referral guidelines). Differences across clinics and other service providers affiliated with an individual MCO occur as well. The panel noted that these variations within and among VSD sites would complicate interpretation of a VSD study that combined data across clinics and sites by introducing heterogeneity in the completeness and quality of case ascertainment. Moreover, membership in an MCO might be influenced by an AD/ASD diagnosis. This could occur, for example, if children presenting with problems predictive of the development of AD/ASD (e.g., speech delay) are more likely to leave a MCO-administered plan because the parents believed that another model of service delivery would be more beneficial.”

Systematic changes over time – “The systems for creating medical records at the VSD sites are dynamic and change frequently in response to the evolution of the individual MCO business model. The panel noted that at least some of these changes would be expected to affect the observed rate of autism and could confound a trend analysis. One such change was the transition from paper to electronic medical records. This change occurred at different times for each of the participating MCOs.”  

Estimation of mercury burden. “Panel members expressed a concern that thimerosal dose, administered through a series of vaccinations, may provide a poor surrogate measure of the cumulative exposure of a child to organic mercurials. Exposures through diet or other environmental sources would not be documented reliably in either the VSD administrative data or medical charts.”

Transparency and Public Access – “The panel recognized the perception by some members of the public and the advocacy community that previous VSD analyses have not been conducted in an open manner. The panel recommended that the AD/ASD advocacy community participate meaningfully in all aspects of any future VSD study of AD/ASD, including design, analysis and interpretation.”

CRITIQUE BY IRVA HERTZ-PICCIOTTO, PHD, MPH, CHIEF OF THE DIVISION OF ENVIRONMENTAL AND OCCUPATIONAL HEALTH, UNIVERSITY OF CALIFORNIA, DAVIS SCHOOL OF MEDICINE 

“The appropriateness of exclusions that amounted to nearly 25% of the birth cohort in the investigation by Verstraeten et al. (2003) was questioned in the NIEHS expert panel report, and (CDC Director) Dr. Julie Gerberding concurred that further work should be done using the VSD to address this weakness.” [62] The VSD study "was not the last word... things need to be looked at again, perhaps with different methodology." [63]

WHAT A LEADING CRITIC IN CONGRESS SAID

Former Rep. Dave Weldon, MD (R-FL), who served as only one of two physician members of Congress, wrote to CDC Director Dr. Julie Gerberding about his “serious reservations about the four-year evolution and conclusions of this study.” [64]

“I have read various emails from Dr. Verstraeten and coauthors. I have reviewed the transcripts of a discussion at Simpsonwood. I found a disturbing pattern which merits a thorough, open, timely and independent review by researchers outside of the CDC, HHS, the vaccine industry, and others with a conflict of interest in vaccine related issues (including many in University settings who may have conflicts), he wrote.

Instead of a “good faith effort” to investigate potential harm from thimerosal, “there may have been a selective use of the data to make the associations in the earliest study disappear,” he charged. “I cannot say it was the author’s intent to eliminate the earlier findings of an association. Nonetheless, the elimination of this association is exactly what happened and the manner in which this was achieved raises speculation.” The Simpsonwood transcripts, he added, “clearly indicated how easily the authors could manipulate the data and have reasonable sounding justifications for many of their decisions.”

WHAT THE IOM SAID

The IOM vaccine safety committee was not troubled by the changing criteria for entry and outcomes, nor did the total disappearance of an autism signal concern them.

“The difference in preliminary results can be attributed to three major reasons,” they said:

■ “Investigators updated datasets with extended follow-up periods, which allowed for additional cases to be identified.”

■ “They modified exclusion criteria based on scientific input from the (2001) IOM report and CDC and VSD investigators

■ “They improved adjustments for health-care-seeking behavior.

■ “Other reasons cited for the differences were a modification to the time of exposure, and inclusion of additional variables in the model.

The panel added this:

The committee notes that it is commonplace for large and important studies to be reviewed along the way, with adjustments often made to improve the eventual validity of the results; thus, it finds nothing inherently troubling in the fact that the VSD study underwent this process. The committee also notes that preliminary results are often misleading and can change substantially as methods are adjusted and more cases and controls are assembled. Indeed, the fact that a conference was held to discuss preliminary findings (Simpsonwood) would typically be interpreted as an attempt by researchers and their sponsors to “get it right,” given the high level of interest in the findings.

Under-ascertainment of cases? The IOM panel wrote that, for HMO A, the autism rate was 1 in 635, or 15.7-per-10,000, and HMO B had 1 in 523, or 19-per-10,000). “Several concerns were raised about the possibility of misclassification of cases with autism because of the way the age of the child was handled in the analyses,” they wrote. One worry was that “some cases of autism may have been missed with shorter follow-up.” But, the data “were adjusted for month and year of birth and time of follow-up,” a “statistical-analysis technique” that “should therefore take care of this concern,” the panel said, without explaining how.

Inclusion of younger children – “Another related concern was that inclusion of a younger group (who are less likely to be diagnosed with autism) in the study would bias the thimerosal effect toward zero,” the panel wrote. “Adjusting for age would reduce, but not eliminate, this tendency. However, if there were an effect of thimerosal, one still would anticipate a trend of increasing effect with age. In this study, there was no such association, even in the older age groups.”

Misdiagnosis of younger children – “The authors attempted to address this by determining the association between thimerosal and neurodevelopmental outcomes and found no consistent significant associations,” the panel said. But it conceded this very important point, often overlooked by the media: “If there are multiple pathways leading to these disorders, it would be difficult to detect the effect of any one cause—unless it occurred with high frequency and the sample size was large—because the tendency of misclassification of outcome is to dilute measures of effect.”

General Limitations cited by the IOM

The authors were unable to control completely for other potential confounding factors. In HMO B, the clinic that a child attended may have acted as a confounder.” In other words, inconsistencies between record keeping practices – even within the same HMO – render the data less reliable.

■ “The HMO databases did not provide information on other possible confounders, such as maternal smoking, lead exposure, or fish consumption.” Total accumulated toxic exposure is probably more important that a single type of exposure from a single source (ie, mercury in vaccines). Background exposures should also be included.

■ “Limitations include the study’s ability to answer whether thimerosal in vaccines causes autism because the study tests a dose-response gradient, not exposure versus non-exposure.” This study compared children who received the highest doses of thimerosal with children who received lower doses. Studying exposed versus non-exposed children might yield clearer data.

■ “The small number of cases and instability of some of the risk estimates may affect the findings.” The number of autism cases found was quite low - far lower than what would be expected for such large HMOs.

SUMMARY: This highly controversial study is considered the most important by people who reject any link between thimerosal and ASD, yet it is fraught with severe limitations, methodological weaknesses and questionable analyses. Data collected from the HMO’s was repeatedly re-analyzed – at least five times across three years of study. During that time, entry criteria were changed, children too young to have an ASD diagnosis were added, and other questionable methods of analysis were used. The relative risk for autism fell from 11.35 to zero during that time. As for other NDDs, even the lead author wrote that this was a “neutral” study and could not be used to support or refute a link.<>


5)

Authors: Andrews N , Miller E , Grant A , Stowe J , Osborne V , Taylor B .

Publication & Date: Pediatrics, September, 2004

Online at: http://pediatrics.aappublications.org/cgi/content/full/114/3/584

Details – This study was “designed to investigate whether there is a relationship between the amount of thimerosal that an infant receives via diphtheria-tetanus-whole-cell pertussis (DTP) or diphtheria-tetanus (DT) vaccination at a young age and subsequent neurodevelopmental disorders.” It was a retrospective cohort study of 109,863 children born in the UK from 1988 to 1997. Outcomes studied were general developmental disorders, language or speech delay, tics, attention-deficit disorder, autism, unspecified developmental delays, behavior problems, and others. “Exposure was defined according to the number of DTP/DT doses received by 3 and 4 months of age and also the cumulative age-specific DTP/DT exposure by 6 months.”

Results: “Only in 1 analysis for tics was there some evidence of a higher risk with increasing doses (HR: 1.50 per dose at 4 months). Statistically significant negative associations with increasing doses at 4 months were found for general developmental disorders (HR: 0.87), unspecified developmental delay (HR: 0.80) and attention-deficit disorder (HR: 0.79; 95% CI: 0.64-0.98). For the other disorders, there was no evidence of an association with thimerosal exposure.”

Authors’ Conclusions: “With the possible exception of tics, there was no evidence that thimerosal exposure via DTP/DT vaccines causes neurodevelopmental disorders.” For general developmental disorders, unspecified developmental delay, and ADD, there was an apparent protective effect from increasing thimerosal exposure.

CRITIQUES OF THE STUDY

Mercury is Not Protective - Many observers felt that the “protective effect” of organic mercury exposure found in young children was biologically implausible. According to this study, higher thimerosal exposure at 4 months of age reduced the risk of ADD and unspecified developmental delay by at least 20 percent compared to children with lower exposures. There is no biological evidence to suggest that a known neurotoxin like ethylmercury can be beneficial to neurodevelopment.

A Deceptive Study Design – When researchers try to determine if there is a cause-and-effect relationship between two different things – in this case thimerosal exposure and autism outcomes – they make their calculations using something called a “regression analysis,” which, in its simplest form, most people know of as a “curve.” A simple regression analysis has two variables. In this case, thimerosal (the potential causative agent) would be the “independent variable,” and autism (the potential effect of the agent) would be the “dependent variable.” It is important to note as well that this is not an analysis of exposure or not, but only the timing of vaccination. All of the children in this study were exposed to thimerosal

But in Andrews et al., the authors used a model that was a bit more complicated, something called a “multiple regression analysis,” which had one dependent variable (autism), and multiple independent variables, including two independent variables (thimerosal exposure levels, and year of birth) that were “correlated” with each other, since thimerosal exposures went up with time. This creates a well-known problem in regression known as "multicollinearity" It is illogical to include both variables unless you believe the increases over time are only due to improved awareness. If there is no logic to including a variable in a regression model, it simply doesn’t belong there. In this case, since the time variable and the vaccine exposure variable are correlated, they actually compete to explain the outcome effect. Inclusion of the time variable reduces the significance of the exposure variable. Yet the authors never explained why they included a time variable that correlates and competes with the exposure variable. Instead, the Andrews model assumes implicitly that increased autism rates are due to time trends alone.

Lack of Transparency – The authors have repeatedly declined to make their data available to others for independent verification, and they fail to state why they chose such an erroneous method that would produce multicollineraity. “It’s a flaw of the peer review process, because someone should have called them on it,” said Mark Blaxill of SafeMinds. “But Pediatrics wants the outcome they report, so no one requires them to be transparent.” The AAP and its journal Pediatrics receive millions of dollars a year in advertising and other funds from major pharmaceutical companies, including vaccine makers. This clear conflict of interest was never mentioned in mainstream media coverage of this subject

Potential Conflicts of Interest – Some of the authors have ties to vaccine manufacturers and/or the national immunization program of the United Kingdom. For example, Elizabeth Miller, FRCPath, was the architect of the UK vaccine program and has testified in court in defense of drug companies in vaccine injury lawsuits.

■ Results Not Applicable to US - Where infant exposures to mercury from vaccines was considerably higher.

WHAT THE AUTHORS SAID

The authors acknowledged several limitations in their study:

■ The outcomes measured occurred “at a relatively young age” and were “more likely to be affected by confounding factors that are also associated with delayed or incomplete vaccination.”

■ Another limitation was the “inability to adjust for many potential confounding factors, such as unrecorded medical conditions and socioeconomic factors.”

■ “If the increased risk in the US study were attributable only to the additional thimerosal exposure after 4 months of age, then it is possible that our study may not have been able to detect the risks found in the US study.”

■ Validation exercises found that 20% of the diagnoses were invalid or questionable. “This lack of specificity is a limitation of the study because it biases against finding an association.”

■ As for the risk of minor transient tics, “the possibility of a true effect cannot be ruled out,” although it was more plausible that the association “is a chance effect or the result of confounding.”

WHAT THE IOM SAID

The IOM panel noted the differences in mercury exposure rates in the US and UK vaccines scheduled. “With the (UK’s) 2-3-4 month schedule, children could have received a maximum of 50mcg of mercury at 3 months of age and 75mcg of mercury at 4 and 6 months of age. This amount is less than the maximum amount received by U.S. children. U.S. children could have received 75 mcg of mercury after 3 months, 125 mcg after 4 months, and 187.5 mcg after 6 months.

What Irva Hertz-Picciotto, PhD, MPH, Chief of the Division of Environmental and Occupational Health, University of California, Davis School of Medicine, said:

Andrews et al. (2004) examined a specific hypothesis, namely, that autism risk would be increased from early administration of thimerosal-containing vaccines, based on the number of vaccines received prior to 3 months, prior to 4 months, and the timing and number of vaccines prior to 6 months of age. The unexplained oddity that three of the nine categories of developmental disorders (general developmental disorders, attention deficit disorders, and unspecified developmental delay) were significantly reduced in those with early vaccines would suggest the possibility that confounding (acknowledged by the authors as a problem) could have resulted in a 'healthy vaccinee' effect. In other words, the healthiest babies would be those who were vaccinated at the earliest times. [66]

SUMMARY:  This study used a statistical sleight of hand to make any association disappear. The authors included a time variable that competes with the exposure variable. Such a model assumes a priori that increased autism rates are due to time trends alone. This study also suffered from some of the most serious undisclosed conflicts of interest among all the thimerosal ASD epidemiological investigations. 

6)

Authors: Thompson WW, Price C, Goodson B, Shay DK, Benson P, Hinrichsen VL, Lewis E, Eriksen E, Ray P, Marcy SM, Dunn J, Jackson LA, Lieu TA, Black S, Stewart G, Weintraub ES, Davis RL, DeStefano F; Vaccine Safety Datalink Team.

Publication & Date: New England Journal of Medicine, September 26, 2007

Online at: http://content.nejm.org/cgi/content/full/357/13/1281  

Details: Although autism was not included in this study, it is still presented as evidence against any association between thimerosal in vaccines and certain immune-globulins given during pregnancy and adverse outcomes.

Investigators studied 1,047 children between 7 and 10 years of age enrolled in participating HMOs of the VSD database. The children were given standardized tests for 42 neuropsychological outcomes, including speech and language disorders, verbal memory, achievement, fine motor coordination, visuospatial ability, attention and executive-functioning tasks, behavior regulation, tics, and general intellectual functioning.

Attention, hyperactivity and executive functioning were based on reports from parents and teachers, while motor tics, phonic tics and stuttering evaluations combined ratings by evaluators with reports from parents and teachers.

Mercury exposure from thimerosal was determined from computerized immunization records, medical records, personal immunization records, and parent interviews. The authors “assessed the association between current neuropsychological performance and exposure to mercury during the prenatal period, the neonatal period (birth to 28 days), and the first 7 months of life.”

Results: Among the 42 outcomes studied, only a few significant associations with exposure to thimerosal were detected. These associations were “small and almost equally divided between positive and negative effects.” For example:

■ Higher prenatal mercury exposure was associated with better performance on one measure of language and poorer performance on one measure of attention and executive functioning.

■ Increasing levels of mercury exposure from birth to 7 months were associated with better performance on one measure of fine motor coordination and on one measure of attention and executive functioning.

■ Increasing mercury exposure from birth to 28 days was associated with poorer performance on one measure of speech articulation and better performance on one measure of fine motor coordination.

Conclusions “Our study does not support a causal association between early exposure to mercury from thimerosal-containing vaccines and immune globulins and deficits in neuropsychological functioning at the age of 7 to 10 years.

Critique by Mark D. Noble, Phd - Professor of Genetics and of Neurobiology and Anatomy, University of Rochester Medical Center: [68]

Poor Confirmation of Cases – “One of the most critical problems with the studies of Andrews et al. is the very poor validation for the data that they analyzed. Validation responses were received from 162 of 166 general practices that were queried, of which it appears that each was asked about a single child.  Of this group, 19% of diagnoses could not be confirmed.  Of those with a confirmed diagnosis, 39% were considered to be transient problems (which is not a description that would normally be applied to autism) and the duration of the problem could not be determined for an additional 35% of cases. Thus, only 26% of the validation attempts established that problems were long-term in children with a confirmed diagnosis.”

Low Number of Unexposed Children – “The number of individuals reported to receive no thimerosal exposure during the first 4 months of life was very low, representing only 3.4% of infants delivered at term and 5.8% of pre-term infants.”

“The small numbers of children with behavioral differences were spread in unspecified distributions across the ten years of information, and attempts at validation provided confirmation of long-term problems in only 20.5% of cases. (This) renders analysis of the data base of Andrews and colleagues fraught with uncertainty.  In the specific context of autism, any decreased representation in the zero-exposure cohort (i.e., less than a total of 3 cases identified) seems unlikely to be suitable for accurate statistical comparisons.”

Mercury As “Neuro-protective”?:  “Claims made that increased exposure to thimerosal was associated with equal or even lower levels of hazard thus appear to be conjectural.  Moreover, children also exposed to hepatitis B and/or influenza vaccinations in the first six months of life were excluded from the analysis, thus excluding those children known to have still higher levels of thimerosal exposure and further limiting the values of the comparisons conducted.”

Critique by Mary Catherine DeSoto, PhD, and Robert T. Hitlan, PhD, Department of Psychology, University of Northern Iowa: [69]

Seven of the authors had received fees from Merck, Kaiser Permanente and other pharmaceutical companies that may have or had an interest in disproving any link to thimerosal and/or mercury exposure and developmental disorders. First, it is important to be very clear that we do not believe that authors would purposefully change their data, or consciously misstate conclusions. Not only would this be unethical, but the stakes are very high. But this does not mean there is no bias; the bias would be subtle and far less nefarious than any sort of purposeful altering of data. If a person has publicly staked his/her career on a certain position being right, it may become harder to keep a truly open mind, even when new data become available and even when the original intent was to be objective. A way this bias might manifest itself is an overstatement or slight misstatement of results. We feel that both sides have been guilty of this, and this happens when a person becomes so confident in the correctness of his/her own view that he/she no longer reviews evidence to the contrary. Unconscious bias may exist even in the best scientists

This is the sort of bias, whether conscious or unconscious, that occurs. Because some of the authors of the Thompson study have publicly aligned with opposing a mercury-autism link (by taking consulting fees), they may be unconsciously more prone to review studies that support their view, less likely to review opposing viewpoints, and may eventually become unaware of relevant research (e.g., Newland et al. 2008). By using 42 measures and finding only a small handful of effects, it is easy to say the obtained relations are chance occurrences. Then, another scholar summarizes the study and slightly changes the results based on a world view that there is no effect of thimerosal, “found no evidence of neurological problems in children exposed to mercury containing vaccines” (Offit 2007, p. 1279). Then this assessment gets quoted by those who do not bother to look carefully at the original study, and scientific advancement becomes stifled.

OTHER CRITIQUES OF THE STUDY

■ The response rate was extremely low. Of 3,648 children selected for recruitment only 1,107 (30.3%) were tested. Among those not responding, 1,026 could not be located, while the mothers of 959 children refused participation. 68% of those refusing cited lack of time, but 13% reported “distrust of or ambivalence toward research

■ Mothers with special needs kids are usually those with the least amount of free time. With such a low response rate, the children studied were likely healthier than the general population.

■ Among a population of 1,026 children, one could expect to find about 45 students on medication for ADD/ADHD. Was that the case? “There were a small number of kids” with ADD/ADHD, Dr. Thompson said, without providing a number.

■ It is possible that low birth-weight kids had increased deficits, but children born below 5.5lbs were excluded from the study.

■ Some children had probably received years of therapy to treat outcomes they were being tested for. An unreported number had been treated with prescription drugs, speech therapy, psychotherapy and/or other forms of treatment. Investigators conceded that prior therapy "may have ameliorated the potential negative effects of thimerosal exposure," and "could have biased the results toward” finding nothing.

■ Despite the mix of positive and negative associations, there remained a “higher likelihood” of motor and phonic tics in boys, something found in previous studies, including Verstraeten (US) and Andrews (UK).

■ Boys exposed to the highest amounts of mercury by 7 months of age were 2.19 times more likely to have motor tics, and 2.44 times more likely to have phonic tics than boys in the lowest exposure rates.

■ The authors failed to differentiate between "transient" tics, which go away within a year, and "chronic" tics, which can last a lifetime. Nor did they distinguish between "simple" and "complex" tics. “We did not categorize them, and some of them may have been chronic,” Dr. Thompson said.

 ■ In fact, “The replication of the (2003) findings regarding tics suggests the potential need for further studies,” the authors wrote.

■ There were also small but negative associations with speech-articulation in children, and lower verbal IQs among girls, which together “suggest a possible adverse association between neonatal exposure to mercury and language development,” the authors said. A similar “increased risk of language delays at one HMO associated with thimerosal-containing vaccines,” was found in Verstraeten’s 2003 VSD study.

■ It is illogical to cite an increased risk for tics (one replicated in a prior study and which may need “further study”) and increased language deficits (also found in the same prior study), but still conclude that there is “no causal association” between thimerosal neuropsychological deficits.

■ Sallie Bernard of SafeMinds, the only consumer representative on the study’s panel of advisors, said the final conclusions were mere “conjecture.” The many limitations “preclude any reasonable determination of the ‘truth.’ The authors’ arbitrary selection of one explanation for their conclusion risks misleading the reader into thinking that the absence of a relationship has been proved.” [70]

■ Dr. Lawrence Rosen, a pediatrician who treats ASD in Tappan, NJ, said the mixed results and severe limitations “make the study kind of worthless. They are picking and choosing what they want to report. It’s not a well-designed study. So either don’t publish it; or do so with all sorts of explanations. You can’t have it both ways. This study doesn’t answer any questions. It makes things even muddier.” [71]

■ Extremely few children received no thimerosal: the investigators largely compared medium-to-high exposures to low exposures, instead of zero exposure.

DEFENSE OF THE STUDY

■ Dr. Ted Schettler, science director of the Science and Environmental Health Network, said there were “only a few significant associations, small and equally divided. When looking at multiple outcomes, some favorable and some unfavorable, it’s very common for authors to conclude that chance variability is the reason.” [72]

■ Dr. Thompson said tics were “likely to be transient,” and not of clinical importance. They were also detected by trained experts, not parents, meaning they were “probably” not severe enough for parents to notice. “And given that kids that age (7-10) have the greatest degree of transient tics,” he added, “we believe these were transient.” [73]

■ Although a 30% response rate “could have an impact on selection bias,” it’s impossible to know which way the bias may have gone. Parents with concerns about their child’s development might be more likely to participate.

SUMMARY: The response rate to this study was extremely low, suggesting possible selection bias in the recruitment of patients. Moreover, the children were examined years after their thimerosal exposure, and many of them had presumably received medical and behavioral treatments in the intervening period. It is illogical to conclude there is “no causal association” between thimerosal neuropsychological deficits, and then cite an increased risk for tics (one replicated in a prior study “further study”) and increased language deficits (also found in the same prior study).

Authors: Schechter R, Grether JK.

Publication and Date: Archives of General Psychiatry, January, 2008

Online at: http://archpsyc.ama-assn.org/cgi/content/full/65/1/19

Details: “The exclusion of thimerosal from childhood vaccines in the United States was accelerated from 1999 to 2001.” This study was designed to see if trends in California’s Department of Developmental Services (DDS) autism client data “support the hypothesis that thimerosal exposure is a primary cause of autism.” The authors investigated trends in autism cases by age and birth cohort in children with autism who were DDS clients from January 1, 1995, through March 31, 2007.

Results: “The estimated prevalence of autism for children at each year of age from 3 to 12 years increased throughout the study period. The estimated prevalence of DDS clients aged 3 to 5 years with autism increased for each quarter from January 1995 through March 2007. Since 2004, the absolute increase and the rate of increase in DDS clients aged 3 to 5 years with autism were higher than those in DDS clients of the same ages with any eligible condition including autism.

Authors’ Conclusions: The DDS data do not show any recent decrease in autism in California despite the exclusion of more than trace levels of thimerosal from nearly all childhood vaccines. The DDS data do not support the hypothesis that exposure to thimerosal during childhood is a primary cause of autism.

CRITIQUES OF THE STUDY

Thimerosal Removal Not Complete Until 2003 – The authors’ statement that “The exclusion of thimerosal from childhood vaccines in the United States was accelerated from 1999 to 2001” is inaccurate. Vaccine makers were asked to voluntarily remove thimerosal from childhood vaccines in July of 1999, a process that took a few years. Likewise, the authors claim their study is inconsistent with a thimerosal association because “the prevalence of autism in children reported to the DDS has increased consistently for children born from 1989 through 2003, inclusive of the period when exposure to TCVs has declined.” The last TCVs (with the exception of the influenza vaccine) were manufactured in 2001, but expired in 2003.

Youngest Cohort Data is Unreliable – The study states that there were more 3-5-year olds in the first quarter of 2007 (children born from 2002-2004) than among 3-5 year olds in the first quarter of 2006 (born from 2001-2003). But diagnoses among younger children can vary, depending especially on the average age of diagnosis in any given area.  This is why the CDC waits until children are 8 years of age in order to conduct its own autism surveillance studies, which are considered to be the most accurate in the United States. Unfortunately, the CDC surveillance system does not include children in California.

Falling Age of Diagnosis Creates Artificial Increase – One reason that CDC waits until children are 8 years of age is because each year, the average age of autism diagnoses goes down. The result is that, each year, more and more three-year-olds are diagnosed as compared to prior years. This is supported by a study published in the December 2008 issue of Archives of Pediatric and Adolescent Medicine. [75]   “Shifts in age at diagnosis inflated the observed prevalence of autism in young children in the more recent cohorts compared with the oldest cohort,” the authors wrote. “This study supports the argument that the apparent increase in autism in recent years is at least in part attributable to decreases in the age at diagnosis over time.”

IOM: California Data Not Reliable For Incidence Studies – In its 2004 report on thimerosal and autism, the IOM Immunization Safety Committee discussed two reports from California’s DDS system (from 1999 and 2003) that showed a large increase in autism cases from 1987 to 2002. Those data were “widely cited as evidence of an increase in the incidence of ASD in the United States,” the panel wrote. But, it cautioned: “The report stresses that the study was not designed to measure trends in autism incidence, and the data should therefore be interpreted with caution. Several methodological limitations have been cited, including the failure to account for changes over time in the population size or composition, in diagnostic concepts, in case definitions, or in age of diagnosis.” (Emphasis added).

DDS: Be Careful Drawing Conclusions – On a webpage titled “Data Interpretation Considerations and Limitations,” the DDS cautions: “Although information published by DDS in the Quarterly Client Characteristics Report is often used by media and research entities to develop statistics and draw conclusions some of these findings may misrepresent the quarterly figures.” In addition, it says, “Increases in the number of persons reported from one quarter to the next do not necessarily represent persons who are new to the DDS system.” [76]

Authors: Findings Must Be Confirmed – The authors concluded that “Continuing evaluation of the trends in the prevalence of autism for children born in recent years is warranted to confirm our findings.”Unfortunately, that will never be possible in California, where entry criteria for DDS services were broadly expanded to include children with PDD-NOS and Asperger’s Disorder in January, 2008. “Information from these new items will not be comparable to prior information,” a DDS statement says. 

SUMMARY – The conclusions of this study rely solely on one year of data in one state among the youngest children who presumably received markedly less thimerosal in their vaccines. Basing such a conclusion on the youngest cohort data is unreliable, partly because the falling age of diagnosis creates an artificial increase. The IOM said the California data is not reliable for incidence studies, the California Department of Developmental Services cautioned against drawing conclusions from the database, and the authors themselves warned that their findings must be confirmed from later data, something that has not happened – and cannot happen.

References:


[37] “Immunization Safety Review: Vaccines and Autism,” Immunization Safety Review Committee Board on Health Promotion and Disease Prevention INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES, THE NATIONAL ACADEMIES PRESS Washington, D.C. Online at: http://www.nap.edu/catalog.php?record_id=10997

 

[38] Mark Noble, PhD, Department of Biomedical Genetics, University of Rochester Medical Center. “The scientific case for re-examining the safety of vaccine additives.” Statement to the Interagency Autism Coordinating Committee on Autism Research (IACC). Washington, DC. February 2, 2009.

 

[39] Irva Hertz-Picciotto, PhD, MPH, Professor and Chief, Division of Environmental Epidemiology, Department of Health Sciences, School of Medicine, University of California, Davis. “Funding for the Study of Vaccines and Autism.” Statement to the Interagency Autism Coordinating Committee on Autism Research (IACC). Washington, DC. February 2, 2009.

 

[40] Statement excerpted from “Evidence of Harm – Mercury in Vaccines and the Autism Controversy, A Medical Controversy,” by David Kirby - Paperback edition, St. Martin’s Press (2006). Pg.358.

 

[41] Joachim Mutter, Johannes Naumann, Rainer Schneider, Harald Walach, Boyd Haley. “Mercury and autism: Accelerating Evidence?” Neuroendocrinology Letters Vol.26 No.5, October 2005 – Online at: http://www.detoxmetals.com/content/AUTISM%20AND%20Hg/autism_reprint.pdf  

[42] “Weldon Calls IOM Conclusions Premature and Hastily Drawn,” Press Release – Office of US Rep. Dave Weldon (FL). May 18, 2004. Washington, DC.

[43] Statement excerpted from “Evidence of Harm – Mercury in Vaccines and the Autism Controversy, A Medical Controversy,” by David Kirby - Paperback edition, St. Martin’s Press (2006). Pg.359.

 

[44] “SafeMinds Outraged that IOM Report Fails American People,” Statement from Coalition for SafeMinds, May 18, 2004.

 

[45] Transcript: “Organizational meeting of: Immunization Safety Review Committee” - CLOSED SESSION. January 12, 2001 National Academy of Sciences, Institute of Medicine, Washington, D.C. – Online at: http://www.coalitionforvaccinesafety.org/docs/IOM%20VSR%20Transcript%20closed%20meeting%201-12-01_OCR.pdf

 

[46] Stehr-Green P , Tull P , Stellfeld M , Mortenson PB , Simpson D . “Autism and thimerosal-containing vaccines: lack of consistent evidence for an association.” American Journal of Preventive Medicine - 2003 Aug;25(2):101-6. Online at: http://www.ncbi.nlm.nih.gov/pubmed/12880876

 

[47] Kreesten Meldgaard Madsen, M.D., Anders Hviid, et. al. “A Population-Based Study of Measles, Mumps, and Rubella Vaccination and Autism.” New England Journal of Medicine, November 7, 2002.Online at: http://content.nejm.org/cgi/content/full/347/19/1477

 

[48] Report from Dr. Julie Gerberding, Director, Centers for Disease Control and Prevention (CDC) to the U.S. House of Representatives Appropriations Committee. 2008. Washington, DC. Online at: http://evidenceofharm.com/VaccineDataLinkReporttoCongressFinal.pdf  

 

[49] Mark Noble, PhD, Department of Biomedical Genetics, University of Rochester Medical Center. “The scientific case for re-examining the safety of vaccine additives.” Statement to the Interagency Autism Coordinating Committee on Autism Research (IACC). Washington, DC. February 2, 2009.

[50] Madsen KM, Lauritsen MB, Pedersen CB, Thorsen P, Plesner AM, Andersen PH, Mortensen PB., “Thimerosal and the occurrence of autism: negative ecological evidence from Danish population-based data.” Pediatrics, September, 2003 Sep;112(3 Pt 1):604-6. Online at: http://pediatrics.aappublications.org/cgi/content/full/112/3/604

[51] Joachim Mutter, Johannes Naumann, Rainer Schneider, Harald Walach, Boyd Haley. “Mercury and autism: Accelerating Evidence?” Neuroendocrinology Letters Vol.26 No.5, October 2005 – Online at: http://www.detoxmetals.com/content/AUTISM%20AND%20Hg/autism_reprint.pdf

 

[52] Kreesten Meldgaard Madsen, M.D., Anders Hviid, et. al. “A Population-Based Study of Measles, Mumps, and Rubella Vaccination and Autism.” New England Journal of Medicine, November 7, 2002.Online at: http://content.nejm.org/cgi/content/full/347/19/1477

[53] Donald G. McNeil Jr, “Study Casts Doubt on Theory of Vaccines' Link to Autism,” The New York Times, September 4, 2003. Online at: http://www.nytimes.com/2003/09/04/us/study-casts-doubt-on-theory-of-vaccines-link-to-autism.html  

 

[54] Anders Hviid, MSc; Michael Stellfeld, MD; Jan Wohlfahrt, MSc; Mads Melbye, MD, PhD  “Association Between Thimerosal-Containing Vaccine and Autism,” Journal of the American Medical Association, 2003;290:1763-1766. Vol. 290 No. 13, October 1, 2003. Online at: http://jama.ama-assn.org/cgi/content/full/290/13/1763

 

[55] “SafeMinds Analysis of Denmark Data Finds Dramatic Drop in Autism Rates After Thimerosal Removal from Vaccines, Finds Flaw in Study Appearing in JAMA, Invalidating its Conclusions.” Statement from the coalition for SafeMinds. October, 2003.

 

[56] Thomas Verstraeten, MD, Robert L. Davis, MD, MPH, Frank DeStefano, MD, MPH, et al.. “Safety of Thimerosal-Containing Vaccines: A Two-Phased Study of Computerized Health Maintenance Organization Databases,” Pediatrics, Vol. 112 No. 5 November 2003, pp. 1039-1048

 

[57] “Scientific Review of Vaccine Safety Datalink Information,” June 7-8, 2000, Simpsonwood Retreat Center, Norcross Georgia – Transcript from US Centers for Disease Control and Prevention. Online at: http://www.autismhelpforyou.com/HG%20IN%20VACCINES%20-%20Simpsonwood%20-%20Internet%20File.pdf

 

[58] “Study disputes vaccine, autism link; little evidence found that vaccinations cause problems,” Associated Press, November 4, 2003. Online at: http://www.msnbc.msn.com/id/3341596 )  

 

[59] Neal A. Halsey, Daniel A. Salmon, Lawrence H. Moulton “Comments on Verstraeten et al., Safety of Thimerosal-Containing Vaccines from Nov 5, 2003,” Letter to Pediatrics, December 17, 2003. Online at: http://pediatrics.aappublications.org/cgi/eletters/112/5/1039#547

[60] Thomas Verstraeten, MD, MSc, “Thimerosal, the Centers for Disease Control and Prevention, and GlaxoSmithKline,” Letter to Pediatrics, Vol. 113 No. 4, April 2004, pp. 932. Online at: http://pediatrics.aappublications.org/cgi/content/full/113/4/932

[61] “Thimerosal Exposure in Pediatric Vaccines: Feasibility of Studies Using the Vaccine Safety Datalink.” Report of the Expert Panel to the National Institute of Environmental Health Sciences. August 24, 2006. Online at: http://www.niehs.nih.gov/health/docs/thimerosal-exposure.pdf

 

[62] Irva Hertz-Picciotto, PhD, MPH, Professor and Chief, Division of Environmental Epidemiology, Department of Health Sciences, School of Medicine, University of California, Davis. “Funding for the Study of Vaccines and Autism.” Statement to the Interagency Autism Coordinating Committee on Autism Research (IACC). Washington, DC. February 2, 2009.

 

[63] Interview with Dan Olmsted, United Press International, September 2006.

 

[64] Letter from Rep. Dave Weldon, MD (R-FL) to CDC Director Julie Gerberding, MD. November, 2003

[65] Nick Andrews, MSc, Elizabeth Miller, MBBS, FRCPath, FFPHM, Andrew Grant, PhD, Julia Stowe, BA, Velda Osborne, BSc, Brent Taylor, PhD, MBCHB. “Thimerosal Exposure in Infants and Developmental Disorders: A Retrospective Cohort Study in the United Kingdom Does Not Support a Causal Association.” Pediatrics, Vol. 114 No. 3. September 2004, pp. 584-591 (doi:10.1542/peds.2003-1177-L). Online at: http://pediatrics.aappublications.org/cgi/content/full/114/3/584

[66] Irva Hertz-Picciotto, PhD, MPH, Professor and Chief, Division of Environmental Epidemiology, Department of Health Sciences, School of Medicine, University of California, Davis. “Funding for the Study of Vaccines and Autism.” Statement to the Interagency Autism Coordinating Committee on Autism Research (IACC). Washington, DC. February 2, 2009.

[67] Thompson WW, Price C, Goodson B, Shay DK, Benson P, Hinrichsen VL, Lewis E, Eriksen E, Ray P, et al., “Early thimerosal exposure and neuropsychological outcomes at 7 to 10 years,” New England Journal of Medicine, September 26, 2007. Online at: http://content.nejm.org/cgi/content/full/357/13/1281

[68] Mark Noble, PhD, Department of Biomedical Genetics, University of Rochester Medical Center. “The scientific case for re-examining the safety of vaccine additives.” Statement to the Interagency Autism Coordinating Committee on Autism Research (IACC). Washington, DC. February 2, 2009.

 

[69] Mary Catherine DeSoto, Robert T. Hitlan, “Sorting out the spinning of autism: heavy metals and the question of incidence.” Acta Neurobiologiae Experimentalis, 2010, 70: 165–176. Online at: http://www.ane.pl/pdf/7021.pdf

 

[70]Evading the evidence,” David Kirby, Mothering Magazine, March 1, 2008

 

[71]Evading the evidence,” David Kirby, Mothering Magazine, March 1, 2008

 

[72]Evading the evidence,” David Kirby, Mothering Magazine, March 1, 2008

 

[73]Evading the evidence,” David Kirby, Mothering Magazine, March 1, 2008

 

[74] Robert Schechter, MD, MSc; Judith K. Grether, PhD, “ Continuing Increases in Autism Reported to California's Developmental Services System – ’Mercury in Retrograde.” Archives of General Psychiatry. 2008;65(1):19-24. Online at: http://archpsyc.ama-assn.org/cgi/content/full/65/1/19

 

[75] Parner ET , Schendel DE , Thorsen P , “Autism prevalence trends over time in Denmark: changes in prevalence and age at diagnosis.” Archives of Pediatric and Adolescent Medicine, 2008 Dec;162(12):1150-6. Online at: http://www.ncbi.nlm.nih.gov/pubmed/19047542

 

Posted by Age of Autism at July 27, 2011 at 5:46 AM in Mark Blaxill , Science , Sponsor News Permalink

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