(Managing Editor's Note: We ran Part 1 earlier this week. 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.
FLAWS AND LIMITATIONS OF MMR STUDIES
Major Reviews – There have been at least two major reviews of the main studies claiming to examine a potential association between MMR vaccine and autism spectrum disorders. They are the 2005 Cochrane Review and the 2004 Institute of Medicine Immunization Safety Committee Report.
1) The Cochrane Review: “Vaccines for measles, mumps and rubella in children.” October 2005.
According to their sponsors, the Cochrane Reviews report on published (and sometimes unpublished) studies which investigate the effects of interventions for prevention, treatment and rehabilitation in a healthcare setting. Most Cochrane Reviews focus on randomized controlled trials, but other types of evidence may also be taken into account. The reviews are considered by most experts to provide the gold standard of evidence-based medical science.
In 2005, Cochrane published a review of published studies on the safety and efficacy of MMR vaccine. Their search revealed more than 5,000 papers on the subject, though only 139 of them “possibly satisfied” the reviewers’ inclusion criteria. In the end, they reported on and summarized about 31 studies, only a few of which pertained to autism spectrum disorders (ASD).
Main results - MMR was “likely to be associated” with febrile convulsions within two weeks of vaccination, but “unlikely to be associated” with Crohn's disease, ulcerative colitis, mumps or autism.
General Limitations: the authors concluded that:
■ There was a moderate-to-high probability of bias in all but one of the cohort studies.
■ The internal validity of some studies was problematic, and the presence of selection, performance, attrition, detection and reporting biases influenced the reviewers’ confidence in these findings. The most common type of bias was selection bias.
■ There was only limited evidence of MMR’s safety compared to single component vaccines from studies with a low risk of bias. The few studies least likely to be affected by systematic error pointed to a likely association with increased febrile convulsions in the first two weeks post-vaccination.
■ The cohort studies’ conclusions “that MMR is ‘safe,’ ‘equally safe,’ ‘well-tolerated,’ or has ‘low-reactogenicity,’ need to be interpreted with caution given the potential for confounding.
■ In the cohort studies, the validity of the conclusions was affected by selective reporting in the comparative analysis, with just over half the responses from participants in some cases.
■ There was a lack of clarity in reporting and systematic bias which made it “impossible” to compare the various studies through quantitative synthesis of data.
■ There were general difficulties in ascertaining adequate numbers of unexposed children due to the high uptake of vaccines and the extent of vaccination programs. This is a methodological problem likely to be encountered in all comparative studies of established childhood vaccines.
■ There was a “lack of adequate description of exposures (vaccine content and schedules)” in all cohort studies.
■ The failure of any study to provide descriptions of all outcomes was a recurring problem.
■ Some reports offered inadequate explanations for missing data, accepting as ‘adequate’ explanations such as ‘nonresponse to questionnaire’ and ‘medical records unavailable’.
■ The external validity of the studies was low. Descriptions of the study populations, response rates, vaccine content and exposure - all important indicators of generalizability - “were poorly and inconsistently reported.”
■ There were inadequate and inconsistent descriptions of reported outcomes, limited observation periods (maximum 42 days) and selective reporting of results. All of these problems contributed to the reviewers’ decision not to attempt pooling data by study design
SUMMARY – Although the reviewers determined that MMR vaccine was “unlikely to be associated” with autism, they concluded that “meaningful inferences from individual studies lacking a non-exposed control group are difficult to make.” They added that there were disappointed by their inability to identify effectiveness studies with population or clinical outcomes.
Many critics question how the authors of Cochrane’s MMR Review could find an “unlikely” association with autism when - in the very same paper - they also concluded that:
(a) the design and reporting of safety outcomes in MMR vaccine studies, are largely inadequate and
(b) that critical design and reporting flaws need to be improved and standardized definitions of adverse events adopted.
Sallie Bernard, of SafeMinds, wrote that the Cochrane Review “gives MMR a free pass.” She said the review “Assumes that this version of vaccine is as safe as can be, and so beneficial there is no need to worry about the fact that the safety studies are inadequate. Would this happen for any other drug? Isn’t it possible, even probable, that the vaccine is effective but still has safety lapses and could be improved?”
In a review presented at the International Meeting for Autism Research (IMFAR) Carol Stott, a UK epidemiologist and Chartered Psychologist, wrote that, given the Cochrane Review’s conclusions, it is important to examine the extent to which the various clinical and population studies have been designed appropriately and with specific reference to the original hypothesis and, thus, to examine the extent to which claims of the hypothesis being refuted or supported are valid.
2) Institute of Medicine, “Immunization Safety Review: Vaccines and Autism.” May, 2004
In February 2004, the IOM’s Immunization Safety Committee held a hearing on the possible association between MMR, thimerosal and autism. The committee reviewed all published and unpublished epidemiological studies on causality as well as potential biologic mechanisms to explain a possible vaccine-autism causal association. Its findings were released in a May, 2004 report. The committee’s conclusions hold wide sway over many scientists, physicians and much of the media to this day.
Main Results: The committee concluded that the body of epidemiological evidence “favor” rejection of a causal relationship between the MMR vaccine and autism,” further stating that studies examining the association between MMR and autism consistently showed evidence of no association between the MMR vaccine and autism.
■ 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.
■ Although there is no convincing evidence to date that a clearly defined subgroup with susceptibility to MMR-induced autism has been identified, genomics and proteomics could reveal in the future whether or not any genetic susceptibility to vaccine-induced autism exists.
■ A lack of unexposed children is another limitation. The committee noted that they had previously called for studies to enroll children whose families opted against the MMR vaccine, but so far, this type of study has been difficult to do with sufficiently large numbers.
■ The committee also noted that its 2001 report did not exclude the possibility that MMR “could contribute to autism in a small number of children because the epidemiological studies lacked sufficient precision to assess rare occurrences.”
■ They also noted that it was possible that epidemiological studies would not detect a relationship between autism and MMR vaccination in a subset of the population with a genetic predisposition to autism.
The latter two points are covered in the introduction to this document. While the points are well received, it is important to note that ‘epidemiological’ studies lack neither precision nor accuracy simply by virtue of them being ‘epidemiological’. It is entirely possible to design population based studies to maximize the likelihood of identifying small effect sizes; the fact that this hasn’t yet been achieved in the vaccine-autism debate is the fault of the workmen, not the tools.
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 vaccines – including MMR - and ASD. A new IOM review that includes these studies is needed.
INDIVIDUAL MMR STUDIES