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There have been many studies investigating whether the MMR vaccine causes autism. These studies were generally in response to Wakefield’s article in 1998 and hypothesis that the MMR vaccine may cause gastrointestinal disease and autism.

The MMR vaccine is the only vaccine that has been studied in relation to autism. And all the MMR-autism studies are poorly controlled.

Because other vaccines have generally not been studied as a cause of autism, the claim that “vaccine do not cause autism” has not been proven, or even substantially supported. There is only evidence that MMR does not cause autism, and as we will see, this evidence is weak.

Due to the lack of controls, the MMR-autism studies can only show that MMR is probably not more dangerous than other vaccines.The MMR vaccine does not contain aluminum, so may explain why its not more likely to cause autism compared to other vaccines. At VP, we think this is likely. MMR is almost certainly no more likely to cause autism than other vaccines. But that’s not saying much.

Madsen et al., 2002

Some of the MMR-autism studies are better than others. The Madsen et al. study from the New England Journal of Medicine in 2002 is widely considered to be one of the best. So, as an illustrative example, we are going to critically examine Madsen et al. The full paper is available here: A Population-Based Study of Measles, Mumps, and Rubella Vaccination and Autism

At VP, we don’t argue against straw men. We take the absolute best science from vaccine advocates, and analyze that. Madsen et al. is an excellent example.

After a process of elimination, the Institute of Medicine (IOM) regarded Madsen as one of the 5 best studies on MMR-autism. The IOM states:

“The five remaining controlled studies (Farrington et al., 2001; Madsen et al., 2002; Mrozek-Budzyn et al., 2010; Smeeth et al., 2004; Taylor et al., 1999) contributed to the weight of epidemiologic evidence and are described below.”—IOM, Adverse Effects of Vaccines: Evidence and Causality, 2012, page 145

Over 537,000 subjects were used in the study, with data on individual subjects and 96,648 unvaccinated controls that did not receive MMR. Sounds really impressive, right? It’s a big study with lots of subjects. A study with 537,303 subjects is big by anyone’s standards.

But the Madsen study has serious problems:

1) The study period ended too early. The study period ended before many subjects would be diagnosable with autism. Autism is most often diagnosed at about age 3, with a median diagnosis age of about 4.6 years old. Diagnosis of autism also commonly occurs as late at age 6 or 8. Below is a chart showing age of diagnosis from a study in the British Medical Journal from 2001, covering 1988-1999, approximately the same time period studied by Madsen.

In view of this chart, consider these quotes from Madsen:

“We designed a retrospective follow-up study of all children born in Denmark during the period from January 1, 1991, to December 31, 1998.” “We retrieved information on vaccinations from 1991 through 1999. ” “Follow-up for the diagnosis of autistic disorder or another autistic-spectrum disorder began for all children on the day they reached one year of age and continued until the diagnosis of autism or an associated condition (the fragile X syndrome, Angelman’s syndrome, tuberous sclerosis, or congenital rubella), emigration, death, or the end of follow-up, on December 31, 1999, whichever occurred first.” (emphasis added)

See the problem here? The study period ended before many children were old enough to be diagnosed! Consider a child born in June 1997. This child would be 2.5 years old at the end of the study, and therefore very unlikely to contribute an autism case to the study, even if the child ultimately becomes autistic.

Also hypothetically consider that this child received the MMR vaccine at age 15 months. With no diagnosis of autism by age 30 months (Dec 1999), this subject would be counted as one that received the MMR but did not become autistic. This subject would contribute “risk-time” to the vaccinated group. This will artificially suppress the number of autism cases associated with the vaccinated group, while boosting the “risk-time” contributed to the vaccinated group.

By ignoring all autism diagnoses that occur after Dec 31, 1999, relevant autism diagnoses are omitted. And since the autism rate was much higher (about 5x) at the end of the study period, these omitted cases will tend to conceal an association between MMR and autism.

2) A person-time analysis is not appropriate for this study

Person-time analysis is a common technique in epidemiology for measuring the effect of a risk factor that accumulates over time, or outcomes that occur repeatedly. For example, person-time analysis is designed for things like the risk of asthma attacks or colds, or the risk of occupational accidents (where each day at work produces an incremental risk increase). Critically, it is important for person-time analysis to be used only for risks that are the same at all times-i.e. no time period is riskier than another. But the risk of autism diagnosis is dramatically highest in the age range 3-4 years. The time elapsed since vaccination does not accumulate risk of autism diagnosis at a constant rate.

Consider these quotes from two well-known textbooks on epidemiology:

“Person-time methods are useful if the risk of death or some other outcome does not change greatly over the follow-up period. If the risk of death does change with the amount of time elapsed since baseline (e.g., amount of time since diagnosis of a disease or since entry into a study), person-time methods are not helpful. For example, certain cancers tend to kill quickly if they are going to be fatal, so the amount of risk per person-time depends on whether most of the years of observation were soon after diagnosis or much later. As mentioned in Chapter 2, person time methods are especially useful for studies of phenomena that can occur repeatedly over time, such as otitis media, bouts of angina pectoris, and exacerbations of asthma.”

— Epidemiology, Biostatistics and Preventive Medicine, 2007 ed. By James Jekel MD MPH et al., page 190

Amazon: http://amzn.com/141603496X “Person-time analysis assumes that the two components (numbers of persons and follow-up time) contribute equally to health event rates. This implies, for example, that 10 persons observed for 1 year and 1 person observed for 10 years provide equivalent information for the assessment of health outcomes (i.e., each would contribute 10 person-years of observation). This will usually be true only if the risk of the study event is uniform over the interval(s) analyzed.”

— Epidemiology and Biostatistics, 2012 ed. By J. Hebel et al., page 135

Amazon: http://amzn.com/1449604757



Person-time methods are not an appropriate way to study autism or this data set by Madsen. This is because:

1) Risk of autism diagnosis is not uniform over time. Autism cannot be diagnosed at any age. Its is typically diagnosed in the age range of about 3-4 years. Autism diagnosis almost always happens within a specific age range. Hence the risk of diagnoses rises steeply until the peak, and declines steeply after. The risk of autism diagnosis changes enormously (both increases and decreases) with time. Again, see the chart above. Consequently, person-time analysis is not appropriate in this study, in view of the quoted texts above.

2) The person-time analysis magnifies the weight of the early cases and minimizes the weight of the later cases, when autism rates were 5 times higher (see Comment by Mullins below). This is because the risk of autism is expressed in “person-time” units. And more time is accumulated for subjects born earlier in the study period.

In view of the above, the person-time analysis of Madsen should be expected to produce wrong results. Madsen’s person-time analysis is inappropriate, by conventional, textbook methods of epidemiology. This study appears designed to produce an inaccurate result.

The correct analysis method is to simply compare those that received the MMR vaccine with those that didn’t, and make sure the study period is long enough so that all subjects have an equal chance of being diagnosed. This is a “person analysis” that does not include the time factor (i.e. the length of time since the MMR vaccine was given). This is the correct analysis. Unfortunately, Madsen did not include this simpler, more accurate analysis, or explain why it was not used.

3) Unspecified vaccine exposure in controls

Madsen compared two groups with the following vaccine exposure:

“vaccinated” = MMR + ? vaccines

“unvaccinated” = ? vaccines

For all we know, the so-called “unvaccinated” group may have received more vaccines than the “vaccinated”. And further, the “unvaccinated” group likely received separate measles, mumps and rubella vaccines, which may have comparable (or greater?) autism risk as MMR. The Madsen paper does not disclose the vaccine exposure of the so-called “unvaccinated” group.

For this reason, the only thing that Madsen can reasonably claim, is that the MMR vaccine is not likely to have a much greater risk of autism compared to other vaccines. But even this conclusion is weak, because the number of other vaccines in both groups is not disclosed, or analyzed.

4) The person-years analysis was unbalanced.

The person-time analysis was done in an unbalanced fashion, presumably due to differences in follow-up time. Subjects in the unvaccinated group experienced a mean of 5.0 years of follow-up (482,360 person-years for 96,648 persons); subjects in the vaccinated group experienced a mean of 3.7 yearsof follow up (1,647,504 person-years for 440,655 persons). The longer follow-up in the “unvaccinated” group will tend to find more autism diagnoses in that group. This creates a bias that will conceal and association between MMR and autism.

A letter to the editor of the NEJM, succinctly states some of these flaws with Madsen:

“The admirable attempt by Madsen et al. to evaluate a possible association between the MMR vaccine and autism has multiple flaws that compound the bias toward a finding of no association. First, the use of person-years instead of persons in the analysis magnifies the weight of the early cases (when the prevalence of autism was relatively low) and minimizes the weight of the later cases (when the prevalence was five times that in the early period). Second, the mean ages at diagnosis were 51 months for autism and 63 months for other autistic-spectrum disorders. A child born early in the study period had a higher likelihood of receiving a diagnosis than a child born later in the study period. Finally, children in the unvaccinated group underwent a mean of 5.0 years of follow-up (482,360 person-years for 96,648 persons), as compared with 3.7 years in the vaccinated group (1,647,504 person- years for 440,655 persons). This discrepancy also reduced the likelihood that autism would be detected in a vaccinated child as compared with an unvaccinated child. The authors overstate their conclusion in the abstract by saying, “This study provides strong evidence against the hypothesis that MMR vaccination causes autism.””

—Dr M Mullins, Washington U. School of Medicine

All letters to the editors regarding Madsen, and Madsens non-responsive response are provided here: Measles, Mumps, and Rubella Vaccination and Autism NEJM letters.

In view of the above serious flaws, the Madsen 2002 study is essentially meaningless with regard to the MMR-autism hypothesis. And it provides no evidence whatsoever that vaccines in general do not cause autism.

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