Monday, June 02, 2014

Australian "Vaccines Do Not Cause Autism" Study Debunked

 
A new study based out of Australia supervised by epidemiologist Guy Eslick, and primarily conduced by two researchers Taylor, and Swerdfeger (excluded credentials) is now circulating the Internet.  Let us review the details...

Study

Taylor, L., Swerdfeger, A., Eslick, G. (2014). Vaccines are not associated with autism: An evidence-based meta-analysis of case-control and cohort studies. Vaccine. Retrieved from https://dl.dropboxusercontent.com/u/20127097/Vaccines_Autism.pdf

Corresponding author: guy.eslick@sydney.edu.au (G.D. Eslick).

Inclusion Criteria

The inclusion criteria was extremely narrow and contradicts the study’s title “Vaccines”, which by presumption include thefull compliment of the 71 doses of vaccine prior to 18 years of age in the United States (CDC, 2014).  The study only looked at thimerosal containing, and MMR vaccines, which excluded; rotavirus, haemophilus influenzae type b (HIB), pneumococcal, poliovirus, partial influenza doses, varicella, hepatitis A, human papillomavirus (HPV), and parital meningococcal.  The old studies did include some of the Hepatitis B, and DTP, which included cumulative Hg dosage, and the MMR, however left out the subsequent nine vaccines.  Further, these vaccines are only recommended among the pediatric population in the United States, additional vaccines are recommended among the broader adult, and immigrant populations.  ASD diagnosis had to be included in the research study in correlation with the MMR vaccine and cumulative mercury (Hg) dosage.  This study repeatedly speaks of "cumulative mercury dosage", meaning that there was not a comparison between vaccinated verses unvaccinated.  They simply studied individuals that had some mercury compared with other groups that had more.  For example, smoking a few cigarettes a day, compared to those that smoke a pack a day shows no correlation to lung cancer, therefore smoking is safe.  This was their inclusion criteria in a nutshell...

Exclusion Criteria

The exclusion criteria was broad.  Studies that focused on the other nine vaccines were removed from the review.  Many of these studies have been directly linked with autism like HIB, but were purposefully excluded  (Richmand BJ., 2011).  All data collected from VAERS was also excluded, however the supervising contributor Guy Eslick in a contradiction encouraged parents to report adverse events in this study even though he discounts those reports. 

Results

929 studies were primarily selected from four data banks; Medline, PubMed, Embase, and Google Scholar.  Only 5 made the inclusion criteria; Andrews, Hviid, Madsen, Uchiyama, and Verstraeten.  The authors claim that all of the studies prove vaccines (MMR, & thimerosal) do not cause autism.  Two studies focused on the MMR vaccine, two on cumulative Hg dosage, and one study looked at two data sets of Hg exposure. 
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p-Values

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After viewing the p-value results I immediately know that the researchers must have set the “level of statistical significance” or alpha higher than 0.05 (Burns, B., Grove, S., pg. 377).  I would have preferred all the p-values to be < 0.01 especially when consenting to a medical procedure (vaccination) due to the known risks involved (autism).  Decreasing alpha to 0.01 will decrease Type I errors and increase Type II errors.  A Type I error states; “something is significant when it is not” (Burns, B., Grove, S., pg. 377).  Inversely a Type II error would say that something was not significant when it was, so it would err on the side of caution especially when using pharmaceuticals as your independent variable.  So in these articles that would translate as a Type I error showing that vaccinations were statistically significant in not being causal in autism when in fact they were. 

Limitations

The authors admit that two of the Denmark studies capture the same data cohort, creating sampling duplication.  Further, they also state the Uchiyama and Madsen study are biased.  Closer observations of four studies are discussed below.  The authors not only focused their meta-analysis on only one vaccine and one ingredient, they also did not include any studies looking at outcomes from vaccinated verses unvaccinated populations. 

Interesting Notes

Researchers Mention:
  1. Vaccine Induced Herd Immunity - Vaccine induced immunity wanes, which is well understood in the scientific literature.  Natural immunity is life-long and it is under this basis that the theory of herd immunity exists.  Peer-review also shows that boosters are shorter lasting then initial injections so if the MMR only last 2 to 10 years (if at all) then the booster would last much less.  Patients who are 50 should have at least 4 to 6 injections of the MMR to be considered immune.  There are very few in this population (baby boomers) that are compliant with the CDC’s requirements.  This subpopulation makes up 50% or more of the U.S. population and yet there is not a measles epidemic in the United States as promised by vaccine promoters.  Vaccine derived herd immunity has not persisted in the United States for at least 40 years, and we have not seen a resurgent of massive infectious disease epidemics.  Vaccine induced herd immunity is used by public-health officials and providers to frighten those to adhere to a vaccine policy that is not even grounded in the belief system they propagate.  This proves that there is no justification in forced vaccination.  In a recent outbreak the issue of measles spreading to adults with no immunity is discussed.  The population that they presume is the least immune to measles are those born between 1970 and 1985 (Frketich, 2013).  This is blamed on the “youngish adults” not having had the natural infection and not being vaccine compliant.  So here again we find the level of presumed “herd immunity” well below the needed rate to prevent massive disease outbreaks and yet the disease is relatively non existent.
  2. MMR Vaccine Benefit Outweighs Risk - They ignored data, which states; Vaccine induced autism risk (0.6%) calculated against the risk of natural measles mortality (0.1-0.3%), which demonstrates undue risk through the overuse of vaccines (Ewing, G., 2009).
  3. Cochrane Review Claims No Link Between MMR And Autism - It appears the authors did not weight the interpretation by the quality of the evidence Cochrane presented instead they simply quoted anything that supported their theory.  Cochrane's conslusions were; "The design and reporting of safety outcomes in MMR vaccine studies, both pre- and post-marketing, are largely inadequate.  The evidence of adverse events following immunisation with the MMR vaccine cannot be separated from its role in preventing the target diseases" (Demicheli et al., 2012).  This is a far cry from a simplistic definitive statement that there is no link between vaccine/autism causation. 
  4. Verstraeten Study - The authors claim that the Verstraeten study shows no correlation between vaccines and autism, but Verstraeten himself disagrees with their conclusion.  In a letter to the journal of Pediatrics Dr. Vestraeten expresses concerns that his study is being used to prove no correlation between thimerosal and neurodevelopmental delays."Surprisingly, however, the study is being interpreted now as negative [where ‘negative’ implies no association was shown] by many…. The article does not state that we found evidence against an association, as a negative study would. It does state, on the contrary, that additional study is recommended, which is the conclusion to which a neutral study must come… A neutral study carries a very distinct message: the investigators could neither confirm nor exclude an association, and therefore more study is required" (Verstraeten, T., 2004).

Summary

This is a failed attempt in gaining public confidence in vaccine policy.  The authors used flawed data to create a perception of safety, which is not only dishonest, but dangerous.

Guest Spot: Valerie Foley

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Valerie Foley, the writer for "Information about autism" also wrote a piece relating to this article, which I find enlightening!  She discusses the background of the researchers that I think all of us will enjoy to note as well as some aspects of what I touched upon.  Enjoy!

Foley, V. (2014). Surely we can do this better. Information about autism. retrieved from http://infoaboutautism.com/2014/05/22/surely-we-can-do-this-better/comment-page-1/#comments

Independent Study Critiques of Individual Articles Included In This Meta-Analysis

Andrews Study Critiques

Andrews et al. (2004). Thimerosal exporure in infants and developmental disorders: a retrospective cohort study in the United kingdom does not support a causal association. Pediatrics. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/15342825
What Other Scientists Have Said
  • Mercury is Not Protective - Many observers felt that the "protective effect" of organic mercury exposure found in young children was biological 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 a 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 complete 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 wnad competes with the exposure variable.  Instead, the Andrews model assumes implicitly that increased autism rates are do 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.  
  • Potential Conflicts of Interest - Some of the authors have ties to vaccine manufactures 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 U.S. -  Were 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 findings 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 recieved a maximum of 50 mcg of mercury at 3 months of age and 75 mcg of mercury at 4 and 6 months of age.  This amount is less then the maximum amount recieved by US children.  US children could have recieved 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 recieved 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.
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 undisclsed conflicts of interest among all the thimerosal ASD epidemiological investigations.
Source Credit:  This careful review was conducted by multiple scientists and medical doctors.

Hviid Study Critiques

Haviid et al. (2003). Association between thimerosal-containing vaccine and autism. Journal of the American Medical Association. Retrieved from http://jama.ama-assn.org/cgi/content/full/290/13/1763
What Other Scientists Have Said
  • 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 acknowledged several limitations in their study:
  • The authorswrote that a possible weakness of their paper was that the date of diagnosisused as the incidence date may differ significantly from the onset ofsymptoms 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 incidencestudy 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 bymissing records, afailure to track birth cohorts, and undisclosed conflicts of interest. Reanalysis of the data actually showed an increased risk ofASD 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.
Source Credit:  This careful review was conducted by multiple scientists and medical doctors.

Madsen Study Critique

Madsen et al. (2002). A population-based study of measles, mumps, and rubella vaccination and autism. New England Journal of Medicine. Retrieved from http://content.nejm.org/cgi/content/full/347/19/1477
What Other Scientists Have Said
  • Walter Spitzer, Professor Emeritus of Epidemiology, McGill University et al., in a letter published in the March, 2003 issue of the NEJM, noted that there were still some methodological problems outstanding with regard to the Danish study.  Spitzer charged that researchers did a clinical record review of just 40 cases (13%), which he claimed was inadequate, especially if the purpose was only to validate an existing diagnosis. Spitzer claimed that …without a multidisciplinary review of original lifetime records as well as double verification in a large descriptive single cohort, important errors would have been unavoidable, both in classification and numbers for the numerators. Spitzer et al. also raised the question of whether pediatric clinical psychologists, pediatric neurologists and speech therapists were involved in the review and whether the reviewers were blind as to exposure status.

    Though the power of the published study was high, it was misleading, Spitzer et al. claimed. In elaborating this point Spitzer et al. explained that if, for example, one assumed a vulnerability to MMR-induced disease in 10% of the regressive ASD cases, with 95% of this group being vaccinated, and if 80% of the non-regressive ASD cases were also assumed to be vaccinated, then the odds ratio for MMR as a risk factor for regressive autism would be 4.17.  However, if children with autism, regardless of sub-types, were combined and compared against non-affected controls, the odds ratio would plummet to just 0.97. Thus a small non-statistically significant reduction in uptake of MMR in the 90% of non-regressive autistic children would mask a strong causal association in a small subgroup,‖ Spitzer et al. Whilst the sub-group might be small, they claim, …conservatively the 10% would represent 50,000 children in the U.S. alone with a financial burden of disease to parents and government of at least $1.25 billion per year.
  • Goldman and Yazbak, in a letter published in the Journal of American Physicians and Surgeons, pointed out the substantial under representation of autism diagnoses and vaccination status for children born in the later study years.5‖ Children with ASD in Denmark are diagnosed at about 5 years old; many were simply too young to receive an ASD diagnosis by the end of the study period. This would apply to all children under the age of 36 months and, in a practical sense, to many of the 3-5 year olds. Among children born in 1997 and 1998, who made up a substantial proportion (39%) of the total years of observation time, many had yet to even receive an MMR vaccine all.

    In fact, ASD prevalence among children aged 5-9 years increased from a mean of 8.38/100,000 in the pre-licensure era (1980-1986) to 71.43/100,000 in 2000, making the adjusted prevalence rate-ratio 4.7 for the post-licensure period compared with the pre- licensure period. This suggested a temporal association between the introduction of MMR vaccination in Denmark and an almost five-fold increase in autism cases.
What Cochrane Said
  • Follow up on medical records terminated just one year after thelast day of admission to the cohort.Because ofthe length of time from birth to diagnosis, the Cochrane reviewers felt it became‘… increasingly unlikely that those born later in the cohortcould have a diagnosis.
  • The study was judged to have a moderate probability of bias.
  • Interpretation of the study was made difficult by the unequal length of follow up for younger cohort members and the use of date of diagnosis rather than onset of symptoms for autism.
  • The study failed to report complete vaccine identification information, including lot numbers, adjuvants, preservatives, strains, product and manufacturer.
  • There was inadequate description of exposures, such as vaccine content and schedules.
  • The study suffered from clearly missing unintended-event data‖ and many participants were missing for adverse event monitoring. Adverse event data were missing in up to 1- in-5 participants (20%). 
  • The study failed to provide descriptions of all outcomes monitored
Summary
  • Madsen et al. argue no effect of MMR vaccination on autism in Danish children and even suggest there might bea protective effect to MMR exposure. Unfortunately, their study is plagued with questionable methodological choices, unexplained data anomalies and biased adjustments. In any study that asks a fundamental question about relativeproportions of exposure in affected vs. unaffected groups, accurate definitions and classifications of (a) exposure and (b) affected status are crucial to the validity of any conclusions drawn from the data. Numerous criticisms of Madsen et al. highlight a source of error in one or another of these classifications. Methodology questions aside, more straightforward approaches to the population data they report suggest an increased risk of autism in Danish children based on MMR exposure, especially when adoptinga case- based approach rather than relying on person-years. A simple comparison of autism rates by birth year shows a clear increase in autism rates after the introduction of MMR in Denmark. These analyses demonstrate that frequent references made based on Madsen et al. regarding the safety of MMR are incorrect.
Source Credit:  This careful review was conducted by multiple scientists and medical doctors.

Verstraeten Study Critique

Verstraeten et al. (2003). Safety of thimerosal-containing vaccines: a two-phased study of computerized health maintenance organization databases. Pediatrics. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12880876

Study was revised five times prior to publication.

What Other Scientists Have Said
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 autismcommunity and amongrespected scientists, physicians and members of Congress.The many methodological flaws they haveidentified 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 DiagnosesAmong 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 under count 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 theHMOs The authors chose to include only those cases confirmed by a behavioral specialist. But if that specialist was outside the HMO, the diagnosiswas 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 madeby an in-network specialist. For speech and language delay, 50% were excluded and forautism, 20% were eliminated.
  • Higher risk with increased vaccination - Generally speaking, among thethree 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 thehighest 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 HMOB.
  • 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
  • AssociatedPress 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 theCDC 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 provideda statement in whichVerstraeten said that since leaving the CDC he was only an adviser as the study was finalized and prepared for publication.‘
What The CDC Said
  • CDC spokesman Von Roebucktold Insight on the News magazine that, We pretty much looked into that [the manipulation of data] in the sense of how theinformation was presented, and we do stand behind it.  As for Verstraeten‘s undisclosed employment at vaccinemaker GSK, he said. The one thing that we wouldwant 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 heworked for the CDC."
What Vaccine Experts Said
Dr. Neal Halsey, the national vaccine expert, along with colleagues Daniel A. Salmon and Lawrence H. Moulton, published a letter in thejournal Pediatrics calling for further analysis of the data which included the following critiques:

  • 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 previousversion.
  • 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. Among other things, the panel was asked to Identify the strengthsand 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 practicesat 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 thevaccine 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 birthsexcluded from the analysesin the Verstraten study. These exclusions were intended to decrease confounding. The panel noted that these childrenmay represent a susceptible population whoseremoval 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 reflectthat 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 practicesand specialist referral guidelines). Differences across clinics and other service providersaffiliated 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 byan 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 leavea 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 beexpected 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 aseries of vaccinations, may provide a poor surrogate measure of thecumulative 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.
  • Transparencyand 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 studyof AD/ASD, includingdesign, analysis and interpretation.
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 amountedto 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. JulieGerberding concurred that further work should be done using the VSD to address this weakness. The VSD study "was not the last word...things need to be looked at again, perhaps with different methodology."
What Congress Said
Former Rep. DaveWeldon, MD (R-FL), who served as only one of two physician members of Congress, wrote to CDC DirectorDr. Julie Gerberding about his serious reservations about the four-year evolution and conclusions of this study.

I have read various emails from Dr. Verstraeten and coauthors. I have reviewedthe 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‘sintent to eliminatethe earlier findings of an association. Nonetheless, the elimination of this association is exactly what happenedand the manner in which this was achieved raises speculation. The Simpsonwood transcripts, he added, clearly indicatedhow easily the authorscould 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 thechanging 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 nothinginherently 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 andcontrols are assembled. Indeed, the fact that a conference was held to discuss preliminary findings (Simpsonwood) would typically be interpreted asan 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 concernswere raised about thepossibility 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 thereforetake care of this concern, the panel said, without explaining how.

Inclusion of youngerchildren Another related concern was that inclusion of a younger group (who are less likely to be diagnosed with autism) in the studywould bias the thimerosal effect towardzero, 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 ofincreasing effect with age. In this study, there was no such association, even in the older age groups.

Misdiagnosis of youngerchildren  The authorsattempted to addressthis by determining the association between thimerosal and neurodevelopmental outcomes and found no consistent significant associations, the panel said. But it concededthis very important point,often overlooked by the media: If there are multiple pathways leadingto 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 tendencyof 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 attendedmay 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 asingle source (ie, mercury in vaccines). Background exposures should also be included.
  • Limitations include the study‘sability to answer whetherthimerosal in vaccinescauses autism because the study tests a dose-response gradient, not exposure versus non-exposure. This study compared children who receivedthe highest doses of thimerosal with children who received lower doses. Studying exposed versus non-exposed childrenmight 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 beexpected for such large HMOs.
Summary
  • This highly controversial study is considered the most important bypeople 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 ofstudy. During that time, entry criteria were changed, children too young to havean 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 supportor refute a link.
Source Credit:  This careful review was conducted by multiple scientists and medical doctors.

References

Burns, B., Grove, S. (2011). Understanding nursing research – Building evidence based practice (with Evolve access code). 5th ed. Maryland Heights, MO: Elsevier Saunders Inc.

CDC. (2014). Recommended immunization schedule for persons age 0 through 18 years. Centers for Disease Control and Prevention. Retrieved from http://www.cdc.gov/vaccines/schedules/hcp/imz/child-adolescent.html

Demicheli et al. (2012). Vaccines for measles, mumps and rubella in children. Cochrane Database Syst Rev. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/22336803

Ewing, G. (2009). What is regressive autism and why does it occur?  Is it the consequence of multi-systemic dysfunction affecting the elimination of heavy metals and the ability to regulate neural temperature? N Am J Med Sci. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3364648/

Frketich, J. (2013). Measles spreading to adults with no immunity. the spec.com. Retrieved from http://www.thespec.com/news-story/3921529-measles-spreading-to-adults-with-no-immunity/

Richmand BJ. (2011). Hypothesis: conjugate vaccines may predispose children to autism spectrum disorders. Med Hypotheses. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/21993250

Vertraeten, T. (2004). Thimerosal, the Centers for Disease Control and Prevention, and GlaxoSmithKline. Pediatrics. Retrieved from http://www.scribd.com/doc/113833183/Verstraeten-2004-Publication-in-Pediatrics

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Heather White editor of AutismRawData and mother of a vaccine injured child, who has autism.  I have nearly 10 years of clinical experience and am currently continuing my education in Health Science with the hope of developing my own path in research.  I am passionate about God, family, living debt-free, toxin-free, organic food, clean water, whole health and an integrative approach to healthcare.

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