MMR vaccination is not associated with autism, take ∞

The last few months have been rough for antivaxers. There have been several large measles outbreaks associated with low MMR vaccine uptake around the US. According to the CDC, thus far in 2019 there are six outbreaks, three in New York (New York City, Rockland County, and Monroe County), as well as outbreaks in Washington, Texas, and Illinois, for a total of 206 cases thus far this year. As a result, there has been a backlash against them, with antivaxers have been getting a lot of criticism, and the press and politicians are turning against them. Their recent ranting (in November and just last week) s at the CDC Advisory Committee on Immunization Pratices (ACIP) are being portrayed as unhinged cranks harassing scientists (which they are). States like Washington are considering bills to eliminate philosophical exemptions to school vaccine mandates, while pressure from the public and legislators has resulted in social media platforms trying to limit the spread of antivaccine movement and streaming services like Amazon Prime and YouTube removing or demonetizing antivaccine content. Just yesterday, Ethan Lindenberger whose parents were antivaccine and didn’t have him vaccinated as a child and who, upon turning 18, got himself caught up on the vaccines he had missed, testified in front of the Senate Committee on Health, Education Labor, and Pensions, which was holding a session on measles outbreaks and vaccine hesitancy. To top it off, just yesterday yet another in a long line of studies has emphatically shown that there is no detectable correlation between the MMR vaccine and autism.

Not surprisingly, this study was not received warmly by antivaxers, probably because it was very much like the proverbial adding insult to injury. After all, we already knew that MMR doesn’t cause autism. There are lots of studies that failed to find a link, lots of excellent studies. The timing of this study, however, although probably coincidental. For instance, antivaxer James Lyons-Weiler (whom I’ve written about before on this blog several times before) laid down a huge swath of burning stupid criticizing the study that will be very fun to deconstruct. First, however, let’s look at the study itself. It’s a particularly damning study to the antivaccine fantasy started by lawyers seeking to sue vaccine companies in the UK in the 1990s and stoked to the pseudoscience that launched a thousand antivaccine quacks (at least) 21 years ago with Andrew Wakefield’s fraudulent case series published in The Lancet.

The first thing you should know is that this is a followup study to a an earlier large study from Denmark published in the New England Journal of Medicine in 2002 that failed to find a correlation between MMR vaccination and autism, a study colloquially known in the vaccine world as the “Danish study.” One of the advantages that Denmark has when it comes to doing studies like this is that it has a national health system and database that allows researchers to examine data from every single child in the country. In brief, the design of this study was a cohort study of all children born in Denmark of Danish-born mothers from 1 January 1999 through 31 December 2010. Researchers sourced the study cohort from the Danish Civil Registration System, which assigns a unique personal identification number to all people living in Denmark and keeps track of basic demographic information for each person. Because this unique identifier is use in all other Danish national registries, it allows for individual-level linkage of health related information. In this case, the linkage was between vaccinations and autism diagnoses. The Danish vaccination schedule involves a first dose of MMR at 15 months and a second dose at 12 years of age. Since 2008, that second dose has been given at 4 years of age.

Autism on autism spectrum disorder diagnoses in the study period was obtained from the Danish Psychiatric Central Register, which the authors described thusly:

Child psychiatrists diagnose and assign diagnostic codes for this register, which contains information from psychiatric hospitals and psychiatric wards (inpatients and outpatients in the study period). The coding classification used in the study period was the International Classification of Diseases, 10th Revision; we used the codes F84.0 (autistic disorder), F84.1 (atypical autism), F84.5 (Asperger syndrome), F84.8 (other pervasive developmental disorder), and F84.9 (unspecified pervasive developmental disorder). We defined our main study outcome of autism as a diagnosis of any of these autism spectrum disorders.

They also excluded syndromes and conditions with an inherent increased risk for autism (fragile X syndrome, tuberous sclerosis, Angelman syndrome, Down syndrome, DiGeorge syndrome, neurofibromatosis, Prader–Willi syndrome, and congenital rubella syndrome) if the condition was diagnosed before their first birthday. In addition, extensive adjustment was made for confounders based on a literature review of risk factors for autism, which ended up including maternal age, paternal age, smoking during pregnancy, method of delivery, preterm birth, 5-minute Apgar score, low birthweight, and head circumference. Again, one of the advantages of the Danish medical system is that these variables could be obtained from the Danish Birth Registry, which includes information on the parents and the newborn, pregnancy, date of birth, multiple births, gestational age, and vital status and other physical characteristics of the newborn.

One of the strengths of this study is how the authors were able to examine subgroups of children. It’s almost as though they were aware of the common antivaccine argument used to explain away the results of studies that failed to find a correlation between vaccination and autism. You’ve probably heard it before, the claim that there are certain “susceptible groups” who are at risk for “vaccine-induced autism” that aren’t picked up in large population-based epidemiological studies. Hence:

The main goal of our modeling strategy was to evaluate whether the MMR vaccine increases the risk for autism in children, subgroups of children, and time periods after vaccination. We defined subgroups according to 1) sibling history of autism (“genetic susceptibility”), sex, birth cohort, and prior vaccinations in the first year of life and 2) a summary index estimated from a disease risk model combining multiple environmental risk factors. The motivation for a summary index was that the combination of several factors each associated with only a moderate risk increase in autism had the potential of identifying children at higher risk through multiple risk factors, in contrast to many stratified analyses of single moderate risk factors.

So what were the results? Well, first, remember how big this study was, involving, as it did, a cohort of 657,461 January 1, 2000 through August 31, 2013. During that time, 6,517 children were diagnosed with autism (incidence rate, 129.7 per 100,000 person-years). Second, the overall result kind of amused me:

Comparing MMR-vaccinated with MMR-unvaccinated children yielded a fully adjusted aHR of 0.93 (95% CI, 0.85 to 1.02). The test for homogeneity of aHRs in the age intervals 1 to 3, 3 to 5, 5 to 7, 7 to 10, and more than 10 years of age yielded a P value of 0.138.

Basically, the overall result found a 7% decreased risk of autism in children vaccinated with MMR. Of course, this doesn’t mean that the results show that vaccines protect against autism. For one thing the result was not statistically significant, although even if it were it wouldn’t necessarily mean that the MMR protected against autism. What it does mean is that in this study there really, really, really wasn’t an association between MMR vaccination and autism. They also found no time period after vaccination during which there was an increased risk of autism associated with MMR vaccine.

Basically, there was also no correlation between MMR vaccination and autism in any of the subgroups, either. These subgroups were defined according to sibling history of autism, autism risk factors (based on a the aforementioned disease risk score), or other childhood vaccinations, or during specified time periods after vaccination. Basically, there was not a whiff of a hint of suggestion of a correlation between MMR vaccination and autism diagnoses—not in the whole population, not in any of the high risk subgroups. This study produced zero, zilch, nada in the way of support for a link between vaccination with MMR and autism. This is about as resoundingly negative a study as you can imagine.

As the authors concluded:

We found no support for the hypothesis of increased risk for autism after MMR vaccination in a nationwide unselected population of Danish children; no support for the hypothesis of MMR vaccination triggering autism in susceptible subgroups characterized by environmental and familial risk factors; and no support for a clustering of autism cases in specific time periods after MMR vaccination.

Next, they addressed criticisms by antivaxers, and they did it so well that I think it worth quoting rather extensively:

A concern about observational studies is that they do not often take into account the possibility of MMR vaccination triggering autism in susceptible subgroups of children. The large number of cases in our study allowed us to define subgroups with sufficient statistical power for useful inference. Specific definitions of susceptible subgroups have been lacking. We defined subgroups according to environmental and familial risk factors for autism. We are only aware of 1 previous study taking a similar approach: A U.S. study by Jain and colleagues (3) evaluated the association between MMR and autism according to sibling history of autism. Those researchers found no support for an association in children with a sibling history of autism, but identified lower MMR uptake rates in children with affected siblings, a potentially important public health issue with increasing autism prevalence and supported by other studies (21).

Another frequent criticism of observational studies of MMR vaccination and autism is a perceived failure to take into account the existence of specific autism phenotypes associated with vaccination, such as regressive autism. Our analysis of specific time periods after vaccination does not support a regressive phenotype triggered by vaccination with excessive clustering of cases in the subsequent period, and no other studies have been able to substantiate the existence of this phenotype (22).

A general criticism of observational vaccine effect studies is that they do not include a completely unvaccinated group of children (23). The number of children completely unvaccinated throughout childhood will be low in a country such as Denmark. We evaluated the association between MMR and autism in children with no DTaP-IPV/Hib vaccinations in the first year of life; we found no support for an association in this vaccine-naive subpopulation.

That’s gonna leave a mark.

Of course, antivaxers gonna antivax, and it wasn’t long before James Lyons-Weiler, who’s known for his antivaccine stylings, his participating in a “vaxed versus unvaxed” study in a state in the midst of a large measles outbreak, took part in an antivaccine quackfest recently, and, hilariously, once battled Leslie Manookian for the title of most antivaccine crank. Less than a day after the study hit the press, he published what he called An Autopsy on Hviid et al. 2019’s MMR/Vaccine Science-Like Activities. it’s an example of handwaving at its finest. Hilariously, the term “science-like activity” doesn’t even apply to Lyons-Weiler, because what he does isn’t even science-like:

The burnt ends on this brisket are obvious. Just like all the past studies on the MMR/autism question, the study focuses on one vaccine. This is a problem because the variable they call “genetic risk” (having an older sibling), which is the most significant variable, is confounded with health user bias (there is no control over vaccine cessation). It’s an important variable, but genetic risk of what? Of autism? Or of autism following vaccination? It’s impossible to tell because the study never tests a VACCINE x FAMILY HISTORY interaction term. Or any other interaction term that includes vaccines.

This is very much like what antivaxers do when they invoke the “toxins” gambit. If one individual toxin is found not to be a risk factor for autism, they start demanding that every possible combination of the “toxins” in vaccines be analyzed. If the authors had done exactly the analysis that Lyons-Weiler said they didn’t do, he would have come up with another one. As for controlling for “vaccine cessation,” that’s just a diversion that makes the assumption that ceasing vaccines will decrease the risk of autism. As for the rest, it’s very predictable. The authors looked at high risk categories for autism because antivaxers frequently say that there are subgroups at high risk for “vaccine-induced autism.” The groups chosen by the authors were the most reasonable to start with.

Here’s the absolute dumbest part of Lyons-Weiler’s article:

The smoking gun is the study-wide autism rate of 0.9-1%. The rate of ASD in Denmark is 1.65%. Where are the missing cases of ASD? Given past allegations of this group’s malfeasance and fraud, the rest of the study cannot be accepted based on this disparity alone: the study group is not representative of the population being studied.

My first question was: Where did he get this number? Well, if you divide all the cases (6,517) found over the study period by the total number of children studied (657,461), producing an incidence rate of 0.99%. I note that the link he cites found that the prevalence of autism in Danish 10 year olds in 2016 was 1.65%. The two populations aren’t comparable. Also, if you look at this graph, you’ll find that the autism cumulative incidence in ten year olds in the study was—you guessed it!—around 1.4%, which is not too far off from 1.65%, particularly remembering that this study covers over a decade, a period of time when autism prevalence was rising. Check it out for yourself

I was half-tempted to stop there, given that anyone who makes such a simplistic calculation and dumb mistake in one important area is likely to have made others. For example:

They did not consider anything about >1 vaccine per visit when the MMR was given. Comment below if your child regressed into ASD following receipt of the MMR + other vaccines (“MMR + OTHER”). Here’s an interesting question: Comment below if your child regressed into ASD following receipt of MMR alone after having received no prior vaccines (“MMR ALONE NO PRIOR”). Comment below if the situation was “MMR ALONE WITH PRIOR VACCINES”).

Cumulative vaccine exposure is the variable that might reflect risk better, as would “>1 vaccine received on date of MMR vaccination”. It is meaningless to study a single vaccine exposure in a population that is being vaccinated so many times before the MMR.

Again, this is a silly criticism based on the antivax trope of “too many too soon.” This is not the question the authors were studying; so it’s misleading to bring this up as a criticism. The authors were asking a simple question: Is vaccination with MMR associated with autism, either in the whole population or in certain high risk subgroups. The answer was a resounding no. They were not studying whether overall cumulative vaccine dosage is associated with autism.

Now here’s a rather obvious dodge:

Apparently vaccine risk in immigrants do not matter because the study required that individual have a valid entry in the Denmark birth registry. Why would that matter? Because the odds of receiving many vaccines at once upon entry into Denmark is very, very high. Oddly, without explanation, the study excluded 11 people with autism. To avoid translational failure, the MMR should not be used on any of the clinical groups that were excluded from the study.

Immigrants don’t have complete data from birth in the database because by definition they weren’t born in Denmark! Also, regarding the claim that immigrants are at high risk of receiving many vaccines at once, my response is: citation required. Even if this were true, again, whether receiving many vaccines at once is associated with autism was not the question the study was asking. As for the eleven cases of autism excluded, the reason was right there in the study flow diagram and in the methods section. Children diagnosed with autism before one year of age were excluded because they don’t get their first dose of MMR until 15 months of age. Seriously, Mr. Lyons-Weiler, read the damned study! Here’s the flow diagram if you don’t believe me:

His fourth complaint is that the authors didn’t use his preferred unvalidated models that he published in Cures vs. Profits. My answer: Why would they do that?

Finally, Lyons-Weiler makes a “well, duh!” statement and then totally misinterprets a simple observation:

Association studies do not test causality. Had this study reported a positive association, it would have fallen short under IOM standards, of providing sufficient evidence for causality. Thus, it cannot be used rule out causality. It’s not testing that hypothesis.

Later he says:

Once again, epidemiology is the WRONG TOOL for studying vaccine risk.

Not exactly. Actually, no. Epidemiology is the correct tool for studying vaccine risk. Surely Lyons-Weiler isn’t claiming that a randomized, double-blind, placebo-controlled study is the best way, given that such a study would be quite unethical for existing vaccines that are standard of care—like MMR.

In any event, it is true that association studies do not demonstrate causality (i.e, correlation does not necessarily equal causation). However, if an association is found, it might indicate causation, and if the association found is strong enough and robust enough, it can strongly suggest causation. I like to use the example of smoking and lung cancer. The correlation between smoking and lung cancer is very strong, very robust (having been demonstrated in many studies), and has a clear dose-response curve. Because it’s unethical to do a randomized, controlled trial of smoking versus not smoking, epidemiology had to be enough to support causation for a long time before mechanistic studies started to show how smoking predisposes to lung cancer. Finally, if there is no association found in a huge study like this, including no association found in any subgroup studied, it can’t absolutely rule out causation, but it sure as hell can tell us that, if there is a correlation, it must very, very tiny indeed. That’s not what antivaxers have been saying about a link between MMR and autism. They’ve been saying that MMR has been causing autism in a lot of children, huge numbers. This study refutes that claim quite conclusively.

Finally, what antivax rant would be complete without accusations of COIs?

The bottom line is that this is a well-designed, very large, and very well executed epidemiological study. Its results were about as negative as negative can possibly be for a correlation between MMR vaccination and autism and adds to the already huge volume of evidence that, given its quantity and quality, has gotten to the point where we can safely say that the MMR vaccine does not cause autism. Lyons-Weiler can rant all he wants about the study, but that’s because he can’t refute it.