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14 Studies Later*

First off, I have deliberately not read the entries on Fourteen Studies by fellow bloggers on SBM. I wanted to go through the information on the site myself. So if some of the information is repetitive, sorry.

Second, in the interest of openness and transparency, I will state my conflicts of interest up front: none. I have not talked to a drug rep in at least 20 years. Outside of a trip to San Francisco as a fellow, paid for by the company who was funding a drug study my boss was participating in, I have accepted no gifts or money of any kind from big (or little) pharma since I was a medical student. Nothing. I don’t even eat the pizza at conferences (1).

Third, I am a hospital based adult Infectious Disease doctor. I make zero money from vaccines. In fact, I only make money if people get sick with infections. For my bottom line, giving vaccines to prevent disease is counter productive to my bottom line.

Why 14 studies?

Fouteen Studies is child (8) of Generation Rescue, one of the autism organizations that, among other things, promotes a link between vaccines and autism. The web site opens with Amanda Peet, my favorite actress (2), who generated a brouhaha when she suggested that vaccines were safe. As the top of the home page of fourteenstudies.org quotes:

“Fourteen studies have been conducted (both here in the US and abroad), and these tests are reproducible; no matter where they are administered, or who is funding them, the conclusion is the same: there is no association between autism and vaccines.”

Fourteen Studies refers to Ms. Peet as “Spokesperson for Sanofi Aventis, a vaccine manufacturer.” They imply she is a shill for big pharma. As best I can tell she is a spokesman for Vaccinateyourbaby.org, a site by Every Child by Two.

Every Child By Two (ECBT) was founded by former First Lady Rosalynn Carter and former First Lady of Arkansas Betty Bumpers in 1991 as a result of the measles epidemic that killed nearly 150 people.

I am convinced. Whenever I think of Rosalyn Carter, I think evil incarnate. Don’t you?

Ms. Peet is a spokesman for Vaccinate Your Baby, which gets support from the vaccine maker sanofi pasteur.

Every Child By Two’s Vaccinate Your Baby campaign is made possible through an unrestricted, educational grant from sanofi pasteur (9).

However:

Amanda Peet is generously volunteering her time to support this cause and does not receive compensation for her time and effort.

Anyone besides me think this is cheesy? But this site is more about implying financial impropriety and bias, than evaluation of science. Anyone mind if I continue the theme of being a financial shill?

The papers discussed at Fourteen Studies like the Vaccinateyourbaby.org website, have some openness and transparency. Both at least let you know where the funding comes from (4).

Generation Rescue, like the Age of Autism website, is rife with advertisements yet nowhere can I find a statement of any financial conflicts of interest they might have. It is a small thing, but in the interest of openness and transparency, it would be nice to know how much they take in from advertisements, on line sales and speaking fees. Generation Rescue is a tax exempt charity, but I cannot find their financial statement on line. It would help put their position into context, at least as far as financial bias goes. Maybe its nothing.  Maybe it is a dollar a year, like what Apple pays Steve Jobs. Jobs appears to be doing OK. Maybe they make a good living from the proceeds.

Fourteen Studies often in its criticisms links to other sites that also do not mention any potential financial conflicts of interest. Which they probably don’t have. We all blog out of the intrinsic goodness of out hearts, after all. But when someone asks “Amanda Peet, How Much Are They Paying You?” on a web page with 12 sponsors and advertisers of autism treatments, the moral high ground slumps into the Marianas Trench.

(A later in the day addendum.  I found the 990′s. The founders of GR are paid nothing.  They spend the 400K a year they take in mostly on market research and advertising. No research. A breakdown of the source of income is not available).

What they do at the Fourteen Studies is rate each study (and there are more than 14 studies) with the following criteria, each worth up to 10 points: “Asked the Right Question,” “Conflict of Interest,” “Ability to Generalize,” and “Post-Publication Criticism.” 40 points would be the highest possible score. The highest score two studies received was a 5. Several received negative numbers suggesting either that those doing the scoring either did not know how to apply their own criteria, do not know how to correctly add together 4 positive numbers, or that the whole scoring system is bogus.

They say “We ranked all of the studies on a forty point scale.” Who the ‘we’ is who are doing the scoring is not mentioned. In each of the studies evaluated on the website, you know who did the work. Not fourteen studies. Transparency and accountability do not appear to be the strong suit of this site.

The first click to take you to the 14 studies gives a list of the studies and the only flaw they mention is the conflict of interest in each study. I have written before on this blog about the perils of funding and the results of clinical trials. It is not a trivial issue, but is, in and of itself, not a reason to dismiss a study. In the end the study has to rise and fall on the merits of its science and its reproducibility. Key concept. Reproducibility. The more a study is reproduced, the more reliable its underlying premise and the results.

The page does give the impression that there is a widespread, well funded, conspiracy between researchers, industry and government to suppress the truth about the side effects of vaccines.

Which is not true. As we all know that the REAL widespread, well funded, conspiracy between researchers, industry and government is suppress the truth about the Kennedy assassination. And man made global warming. And the Trilateral Commission. And the Holocaust. And UFO’s. And Big Foot. And Homeopathy. And Fluoridation. And the Loch Ness Monster. And and and and…

High quality studies take time and money to complete and are not easy to do. Someone has to do them, and the only people with the resources to fund biomedical research are the government and industry. Funding bias is a two edged sword, so if we look at the studies in peer reviewed, high impact journals funded by Generation Rescue we find, well, I can’t find any published studies Generation Rescue has funded. But if they do fund a published study that shows a link between autism and vaccines, by their own standards it will be suspect. Unless they are good guys, and so, as good guys, are resistant to funding bias. Of course, everyone thinks they are the good guy. Except me. I am totally prone to be influenced (1).

There is a page on the website called “Our Studies,” but they are not “their studies” because Generation Rescue is responsible for the studies, but because they support Generation Rescue’s position. That is the approach of Fourteen Studies: A good study is one that supports a vaccine/autism connection and a bad study is on that contradicts the connection. If, in the end, reality does not support your position and you do not change your opinion based on reality, then all you are left with is being a crank. I suspect that Generation Rescue is destined for crankdom.

None of “their studies”, save the Lancet MMR article by Wakefield, are high impact journals. Two studies were funded by Cure Autism Now Foundation. Does that invalidate them? Two are partially funded by the NIH? I thought the government were the Bad Guys. One (besides Wakefield’s) is by researchers who testify as experts on the damage caused by vaccines. Many do not mention conflicts of interest at all. Thanks to an apparent disregard for copyright/intellectual property (5), you can download all the references yourself from the fourteen studies website. Not that I would encourage you to do that. I got my copies through my hospital’s library.

In residency (and sometime beyond if you practice in a teaching hospital as I do) you have to suffer though, I mean, participate in Journal Club. In Journal Club an article is chosen and then carefully analyzed line by line. You look carefully for the strengths and weaknesses of the paper to learn how to read a paper critically. The one take home from years of participating in Journal Club is that all studies have flaws. All of them. Our studies and their studies are have flaws and bias. That is why most studies need to be repeated and all studies need to be taken in context. Clinical trials are messy and an individual study is rarely definitive.

Lets do a modified Journal Club with the 14 (actually 19) studies. These are all downloadable from Fourteen Studies, again, not that I suggest you violate copyright laws.

1) “Safety of Thimerosal-Containing Vaccines: A Two-Phased Study of Computerized Health Maintenance Organization Database”
Pediatrics, Thomas Verstraeten, MD (November 2003)
They gave it a 3. Their main issue with the paper was the politics and bias behind it. What about the science?

In this study they looked at HMO records of 124,170 infants for associations between neurodevelopemental disorders and thimerosal exposure. They then reevaluated the same disorders on another 16,717 children in another HMO. They found different associations between neurodevelopemental disorders and thimerosal exposures at the two HMO’s. And when it came to autism and attention deficit disorder, there were no increased risks that they could determine.

The discussion is a sober and reasonable evaluation of the potential confounding issues in the study that make it difficult to make a definitive statement that thimerosal does not cause autism. It is also one of those studies that makes your brain hurt trying to wrap your brain around it. In the conclusion they say “Although the lack of consistency between the 2 phases argues against a thimerosal effect, we believe that additional investigation is required.” It is typical of the calm, considered discussions found in all fourteen studies of the limitations of the study in question.

It is an article that demonstrates how difficult it is to tease out risk from a single exposure in a large population using epidemiology studies. The website suggests what is needed is a study that compares autism rates in vaccinated vrs unvaccinated children. Given the benefits of vaccines, such a study could never be ethically done. To deliberately randomize children to not getting vaccines would be immoral to do and impossible to get past an IRB.

That study will be possible in the future, thanks to the anti-vaccine and alternative vaccine schedule proponents. We will be able to compare disease, death and autism rates in vaccinated and unvaccinated populations. I predict that the unvaccinated group may have a slightly higher autism rate. If autism is mostly genetic, families where vaccines are not given due to prior autism cases will have more cases of autism when compared to vaccinated groups.

Where fourteen studies sees ethical malfeasance, I see a typical epidemiologic study. Messy, but helpful. It is one brick in the wall.

2) “Thimerosal and the Occurrence of Autism: Negative Ecological Evidence from Danish Population-Based Data”
Pediatrics, Kreesten M. Madsen, MD (September 2003)
According to fourteen studies, who gave it a 1, “Written by a Danish vaccine company, the study made a mockery of the data, a problem the authors themselves warned of. And, the CDC engineered the entire study. This one goes beyond useless, it was fraudulent to run the numbers this way, and they knew it.”

In this study they look at autism rates in Denmark during the use of thimerosal and after it was removed from the vaccines. The rates of autism diagnosis were stable during the thimerosal era and increased once thimerosal was removed. Suggesting that thimerosal is not associated with the development of autism (and maybe protective? (6)).

The mockery and fraud? I can’t mockery or fraud in the study. They recognise the confounding factors that both the criteria for diagnosis and the ability to find cases changed during the study period and may be a confounding variable.

I thought a nice study, and, for a retrospective epidemiologic study, fairly clean.

3) “Continuing Increases in Autism Reported to California’s Developmental Services System”
Archives of General Psychiatry, Robert Schechter, MD (January 2008) They gave it a 1.

“The entire study is based on the false premise that children’s vaccines no longer contain mercury. ” Not true. The premise was that mercury exposure declined over time.

This study looked at the prevalence of autism from 1995 to 2007. From 1999 to 2001, when most of the thimerosal was removed from the vaccine schedule, From 1995 to 2007 autism rates rose. Again, demonstrating that thimerosol is protective?

Another relatively clean and compelling epidemiologic study. The “Bad” studies that show an no association between vaccines and autism are all messy, as life is messy. They are several logs better than “Our” studies. The best study, a randomized, prospective, blinded trial can never ethically be done.

4) “Neuropsychological Performance 10 Years After Immunization in Infancy With Thimerosal-Containing Vaccines” Pediatrics, Alberto Eugenio Tozzi, Patrizia Bisiacchi (February 2009). A negative 2. It is concerning that the those at Fourteen studies can take a 0 to 10 scale and, after adding 4 positive numbers, get a negative number. Next thing you know, they will say a study that demonstrates no association between a vaccine and autism actually shows such an association (11). They gave it a negative two due to “such extreme fraud”

In medicine, there is a dose response curve. More drug, more effect, less drug, less effect. The assumption, reasonable outside of the world of homeopathy, is that if groups of kids who get less thimerosal (62.5 mcg) are compared to kids who had more thimerosal, (137.5 mcg), there should be a less toxicity in the group that received less thimerosal.

Not so in this study. There was (mostly) no difference in the two groups.

“Nearly 70% of the invited subjects participated in the neuropsychological assessment (N = 1403). Among the 24 neuropsychological outcomes that were evaluated, only 2 were significantly associated with thimerosal exposure. Girls with higher thimerosal intake had lower mean scores in the finger-tapping test with the dominant hand and in the Boston Naming Test.”

And the association could have been due to chance as often happens in studies that look at multiple endpoints. Natural noise in biologic outcomes results in the occasional outlier looking significant. It is why studies need to be reproduced.

The Italians had only one autism case in the study, so, while interesting on the potential for other neurotoxicities from thimerosal, it does not directly address the issue of autism. But extreme fraud? Nope. I can’t find any. I half expect Fourteen studies to say “The CDC is infested with Vaccinationists. I have here in my hand a list of 205—a list of names that were made known to the Secretary of Health as being members of the Vaccinationist Party and who nevertheless are still working and shaping policy in the CDC (9).”

5) “Autism and Thimerosal-Containing Vaccines: Lack of Consistent Evidence for an Association”
American Journal of Preventive Medicine, Paul Stehr-Green, DrPh, MPH (August 2003). A zero score.

In this study they “compared the prevalence/incidence of autism in California, Sweden, and Denmark with average exposures to Thimerosal- containing vaccines.”
They found that as the use of thimerosal declined, the rates of autism rose in all three areas. The Swedes have much less autism than the US, whether real or diagnosed, I cannot say, but the results are as compelling as epidemiologic data gets. And there is a pattern in the studies.

6) “Thimerosal Exposure in Infants and Developmental Disorders: A Prospective Cohort Study in the United Kingdom Does Not Support a Causal Association” Pediatrics, John Heron and Nick Andrews, PhD (September 2004). This study received a -4, the worst score and worst addition in the group. Why the low score?

They looked at 14,000 kids, when they received a vaccine, then calculated the amount of thimerosal they received, and were “compared with a number of measures of childhood cognitive and behavioral development covering the period from 6 to 91 months of age.” They did not specifically look at autism.

Annoying for Fourteen studies, and perhaps the real reason it received a -4, is the explicitly stated result that the exposure of thimerosal was beneficial:

“Contrary to expectation, it was common for the unadjusted results to suggest a beneficial effect of thimerosal exposure. For example, exposure at 3 months was inversely associated with hyperactivity and conduct problems at 47 months; motor development at 6 months and at 30 months; difficulties with sounds at 81 months; and speech therapy, special needs, and “statementing” at 91 months.”

So mercury is good for you? I doubt it. It demonstrates the difficulties in retrospective epidemiologic studies, that occasionally the data has what are probably not real results. To be believed, it need to be reproduced.
How about adverse effects from thimerosall? No.

“We could find no convincing evidence that early exposure to thimerosal had any deleterious effect on neurologic or psychological outcome when given according to an accelerated schedule.”

Anyone besides me noticing a pattern here? Epidemiologic studies, all coming at a problem from a different angle, all with the same result. Of course, the same result is what you would expect from a high level conspiracy.

7) “Early Thimerosal Exposure and Neuropsychological Outcomes at 7 to 10 Years”
New England Journal of Medicine, Thompson WW et al. (September 27, 2007). Highest score with a 5 out of 40. No one, not even Fourteen studies, would dis the NEJM. It is not that different from study 4 that received a -2.

They looked at “1047 children between the ages of 7 and 10 years and administered standardized tests assessing 42 neuropsychological outcomes. (We did not assess autism-spectrum disorders) ” and how much thimerosal they received in vaccines. They found that mercury exposure in vaccines was probably not a neurotoxin.

“The weight of the evidence in this study does not support a causal association between early exposure to mercury from thimerosal containing vaccines and immune globulins administered prenatally or during infancy and neuropsychological functioning at the age of 7 to 10 years. The overall pattern of results suggests that the significant associations may have been chance findings stemming from the large number of statistical tests that we performed. “

8) “Association Between Thimerosal-Containing Vaccine and Autism”
Journal of the American Medical Association, Anders Hviid, MSc (October 2003). A score of 1.

The study looked at all children born in Denmark from 1990 and 1996 and found no difference in the rates of autism in kids vaccinated with vaccines that contained thimerosal and those that were vaccinated with vaccines that did not contain thimerosal.

As best they could tell, no relation between thimerosal and autism. They also found that as the use of thimerosal declined, the rates of autism increased.

The data was reanalyzed by Safe Minds on the assumption that cases of autism were lost and if that was factored in, autism rates declined when thimerosal was removed. The authors disagreed with this approach, and, in an exchange in the letters sections of JAMA (curiously not mentioned at 14 studies) said they checked with the source of the data, that the numbers used were not prevalence measurements, and that cases were not lost, invalidating the analysis of Safe Minds (3).

9) “Mercury concentrations and metabolism in infants receiving vaccines containing thimerosal: A descriptive study”
The Lancet, Michael Pichichero, MD (November 2002). Rated zero.

An interesting study that looked at mercury levels in children who received thimerosal containing vaccines and compared it to mercury blood levels in children who received thimerosal free vaccines. The mercury in the blood of the vaccine children was about twice that of controls, but well with in what is considered safe. And 12 of the samples in the vaccine group had no detectable mercury. It does not address the issue as to whether near homeopathic blood levels of mercury are associated with autism, but is an interesting basic science. I would, as mentioned above, expect a dose response effect of mercury and, if the levels after vaccine are low to undetectable after vaccine, I would be skeptical, on the basis of basic pharmakotoxicity, that mercury is a cause of autism.

Fourteen studies take? “One of the sillier studies ever performed, and the lead author is a vaccine patent-holder, no less. Absurd that this study appears on lists of studies exploring the relationship of vaccines to autism, as it doesn’t even address the topic. More absurd is the author’s complete misunderstanding of how mercury is excreted from the body.”

I can’t see why this is silly. If you are to understand how ethylmercury is toxic, in part you need to understand its pharmakokinetics, how it is excreted and where it goes in the body. Which is what this study investigated and reported.  Based on the critics, I imagine they would only be satisfied if brain biopsies were done to measure mercury level in the CNS.  If you think the return of polio is ok, probably a brain biopsy would not be so bad (12).

10)  “Thimerosal and Autism?” Pediatrics, Karen Nelson, MD (March 2003). Rated zero.

A nice review that concludes, based on 60, yes 60 (when I count postive numbers, I get a postive number), which, in my world of numbers, is greater than 14, papers that there is no link between thimerosal and autism.

11) “Lack of Association Between Rh Status, Rh Immune Globulin in Pregnancy and Autism”
American Journal of Medical Genetics, Judith H. Miles and T. Nicole Takahashi (May 2007). Another zero.

Looks at whether Rh Immune Globulin, which contains thimerosal, is associated with autism. It isn’t. While not a vaccine, it is a mercury exposure, and does concern the issue as to whether or not thimerosal is toxic.

That’s the 11 articles that address thimerosal and autism. A very compelling series of articles that, when taken as a whole, are convincing that there is no relation between mercury and autism. I had read the articles piecemeal before, but, like evolution, when read in total, are an excellent argument that thimerosal is not associated with autism.

Lets move on to the 7 articles concerning MMR and autism

Wakefield had a study published in Lancet titled ” Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children,” that has had some issues.

This study demonstrated that “Onset of behavioral symptoms [autism] was associated, by the parents, with measles, mumps, and rubella vaccination [MMR] in eight of the 12 children, with measles infection in one child, and otitis media in another…We identified associated gastrointestinal disease and developmental regression in a group of previously normal children, which was generally associated in time with possible environmental triggers.”

The response of fourteen studies is that “This relatively straightforward conclusion, that the MMR may in fact be related to autism, set off a worldwide controversy and a mini-industry of bogus scientific reports trying to refute the idea that MMR and autism are related. You will see many of the studies below.”

If true, the Wakefield needs to be reproduced, if not true, that also needs to be determined. The first study that looked at high dose steroids and sepsis showed benefit. Multiple subsequent studies (or should I say a mini-industry of bogus scientific reports trying to refute the idea that steroids were helpful) showed harm and no benefit. A typical and annoying feature of the medical literature is differing results. It is why it is important to consider both biologic plausibility and the results of the preponderance of studies.

The following studies, unlike the Wakefield study, are bogus. Hm.

12) “Lack of Association Between Measles Virus Vaccine and Autism with Enteropathy: A Case-Control Study”
PLoS One, Mady Hornig, Thomas Briese T, et al. (September 2008). Rated 1.

The secret to believable medical information is reproducibility. Cold fusion died because no one can reproduce it. So an association between MMR and autism will have to be reproduced to be compelling.

They tried, in part, to repeat the Wakefield study, They did not get the same results. “However, it made one critical distinction from the Wakefield approach: it didn’t recruit for the subset of children with autism who regressed after MMR vaccination.” Evidently, neither did Wakefield.

“The sample was an age-matched group of US children undergoing clinically-indicated ileocolonoscopy. Ileal and cecal tissues from 25 children with autism and GI disturbances and 13 children with GI disturbances alone (controls) were evaluated by real-time reverse transcription (RT)-PCR for presence of MV RNA in three laboratories blinded to diagnosis, including one wherein the original findings suggesting a link between MV and ASD were reported. The temporal order of onset of GI episodes and autism relative to timing of MMR administration was examined. We found no differences between case and control groups in the presence of MV RNA in ileum and cecum. Results were consistent across the three laboratory sites. GI symptom and autism onset were unrelated to MMR timing.”

This study had the advantage over the Wakefield study in that the data was not made up or falsified.

13) “MMR Vaccination and Pervasive Developmental Disorders: A Case-Control Study” The Lancet, Liam Smeeth, MRCGP, Eric Fombonne, MD (September 11, 2004). Rated a 2.

In medicine, if you want to see if there is a risk of disease in a population, you do a case control study. The two groups differ in (hopefully) one variable. In this study they compared “1294 cases and 4469 controls were included. 1010 cases (78·1%) had MMR vaccination recorded before diagnosis, compared with 3671 controls (82·1%) before the age at which their matched case was diagnosed.”

They could find no association between the MMR and autism. Fourteen studies argues that the MMR causes regression of autism, which was not the point of the study, and therefore the study is no good because it looked at the ‘wrong’ question. It is an easy and typical criticism throughout Fourteen studies: the study looked for and found no association using a given methodology. The study is no good because it didn’t look at the information Fourteen studies thought it should. Given that most studies try for a narrow focus, there will always be a component not evaluated. A common straw man argument throughout the website.

Within the context of the study, it is reasonable to conclude that the MMR is not associated with developing autism.

14) “Pervasive Developmental Disorders in Montreal, Quebec, Canada: Prevalence and Links With Immunizations”
Pediatrics, Eric Fombonne, MD (July 2006). Another issue with addition, it is rated -2.

The negative number may come from the finding that “The prevalence of pervasive developmental disorder in thimerosal free birth cohorts was significantly higher than that in thimerosal-exposed cohorts (82.7 of 10 000 vs 59.5 of 10 000).” Curious we now have several studies that showed thimerosal to be protective. Ouch.

To add insult to injury, they also found

“Pervasive developmental disorder rates significantly increased when measles-mumps-rubella vaccination uptake rates significantly decreased. In addition, pervasive developmental disorder prevalence increased at the same rate before and after the introduction in 1996 of the second measles-mumps-rubella dose, suggesting no increased risk of pervasive developmental disorder associated with a 2–measles-mumps-rubella dosing schedule before age 2 years.”

Now I feel like Truedeau. The vaccination information THEY don’t you to know: MMR and thimerosal are protective for developing autism.

They derived this information looking at 27,000 kids, 180 of whom had a pervasive developmental disorder, including autism and comparing rates of autism (which went up) with thimerosal and MMR use (both of which went down).

15) “No Evidence for a New Variant of Measles-Mumps-Rubella-Induced Autism”
Pediatrics, Eric Fombonne, FRCPsych (October 2001). A one rating.

Their insightful analysis of the article starts “What is it with Eric Fombonne and Pediatrics? ” I do not think they approve of Fombonne. Next they will accuse him for something he didn’t do (11).  Not a sign of compelling science analysis and they do not give a reason for the 1 rating, the link takes one to another site for analysis. Suggesting again a mini-industry of bogus scientific ratings trying to refute the idea that MMR and autism are not related.

This study, with small numbers, compared 96 children with MMR and autism to data from other studies of children with autism before and after an MMR. Not the most compelling of methodological design (more cases are always better, especially if looking for very rare events) and looked to support 6 hypothesis:

“1. Childhood disintegrative disorder might have become more frequent;
2. The mean and distribution of age at which parents become concerned has changed and is closer to the mean immunization age than in children who were not exposed to MMR;
3. Regression in the development of children with autism has become more common;
4. The age of onset of symptoms for autistic children with regression clusters around the immunization date and is different from that of autistic children without regression;
5. Children with regressive autism may have distinct symptom and severity profiles; and
6. Regressive autism is associated with gastrointestinal symptoms, and children with regressive autism may exhibit increased frequency of inflammatory bowel disorders. “

Their data comparisons did not support any of the above. Not the most convincing data set, but in the context of the above studies, ok conclusions.

16) “No effect of MMR withdrawal on the incidence of autism: a total population study”
Journal of Child Psychology and Psychiatry, Hideo Honda, Michael Rutter. A five.

Highest score in the group. Why?

We gave this study our highest score because it appears to actually show that MMR contributes to higher autism rates.
The key phrase in the whole site. Data that supports their position is good, data that doesn’t is bad. What makes a study good is not its methodology or its rigor, but if it supports vaccines casing autism. Bass Ackwards thinking.
The position that vaccines cause autism is determined, then you look for data that supports the position. When you read the studies, they do not support the position that the MMR is associated with autism.

It is doubly odd in that the paper’s conclusion is that

“The MMR vaccination rate in the city of Yokohama declined significantly in the birth cohorts of years 1988 through 1992, and not a single vaccination was administered in 1993 or thereafter. In contrast, cumulative incidence of ASD up to age seven increased significantly in the birth cohorts of years 1988 through 1996 and most notably rose dramatically beginning with the birth cohort of 1993.”
Remember reference 4? Foreshadowing.

In Yokohama they gave ZERO MMR’s after 1993. Zip. The result?

Kind of hard to argue that MMR leads to autism when autism rates continue to increase after no more MMR is given. One explanation link as to why black is really white leads to ’404 not found error,’ the other links to a web page where, as best I can gather, they argue that the MMR withdrawal lead to a decrease in autism because there was actually an increase in autism due to increase in the use of Japanese encephalitis and single measles vaccines. Which demonstrates that the increased autism rates that followed MMR removal were a decline in autism rates. I may have that wrong. Read it and let me know. Maybe the 404 site explained it better.

17) “Measles Vaccination and Antibody Response in Autism Spectrum Disorders”
Archives of Disease in Childhood, Gillian Baird (February 2008). Rated a one, they must have become distracted in the MMR section as they do not give a breakdown of how the score was derived for the last five studies.

They looked at antibody to measles as a result of MMR in autism cases and controls and found no correlation. This one study adds little to the data. It supports the lack of correlation between MMR and autism, but the last study is far more compelling.

18) “Neurologic Disorders After Measles-Mumps-Rubella Vaccination”
Pediatrics, Annamari Makela, MD (November 2002). Another zero without reason.
This study looked at 535, 544 children for neurologic events after MMR. It was more to look at encephalitis and meningitis, which were not increased as a result of the vaccine. Autism was not also seen, but, as legitimately pointed out (the one and only legitimate sentence in the whole web site) “it used “hospitalizations” as a criteria for finding children with autism.” Not a good way to find autism cases, I agree.

The last paper in the group,
Association of Autistic Spectrum Disorder and the Measles, Mumps, and Rubella Vaccine”
Archives of Pediatrics & Adolescent Medicine, Eric Fombonne, FRCPsych (July 2003) is a structured review of 28 papers that fails to demonstrate a relationship between the MMR and autism.

This is really odd. Their ‘headline’ is “Fombonne again.”
But the authors of this reference are Kumanan Wilson, MD, MSc, FRCP(C); Ed Mills, DPH; Cory Ross, MSc, DPH, CHE; Jessie McGowan BMus, MLIS; Alex Jadad MD, DPhil, FRCP(C). I cut and pasted it from the reference.

For posterity’s sake, here is a screenshot before they change it:

Are they even reading the damn articles?
The full title of the article is “Association of Autistic Spectrum Disorder and the Measles, Mumps, and Rubella Vaccine
A Systematic Review of Current Epidemiological Evidence.”

The key words, left out by Fourteen studies, are ” Systematic review.” For those who do not have to read the medical literature (bold added by me),

“Systematic reviews are scientific investigations in themselves, with pre-planned methods and an assembly of original studies as their “subjects.” They synthesize the results of multiple primary investigations by using strategies that limit bias and random error. These strategies include a comprehensive search of all potentially relevant articles and the use of explicit, reproducible criteria in the selection of articles for review. Primary research designs and study characteristics are appraised, data are synthesized, and results are interpreted.”

“A systematic review involves the application of scientific strategies, in ways that limit bias, to the assembly, critical appraisal, and synthesis of all relevant studies that address a specific clinical question. (7)”

A well done Systematic review is more that a review, it is a valuable, if less than perfect, way to evaluate a literature that tries to correct for bias and for variation in study methodologies.

Finally, if you want another excellent (free) review, try Vaccines and Autism: A Tale of Shifting Hypothesis.

I read over 100 or so journal articles a month just for my Infectious Disease podcast. Plus those I read for patient care, for general interest, for the blogs. They are of variable quality, from the ground breaking to the incomprehensible. The ‘bad’ references on the fourteen studies site are by and large pretty good, especially given the methodologic, logistic and ethical problems in doing large epidemiologic studies.

In medicine, as in all of science, no single study is definitive. Epidemiologic studies in medicine are particularly messy, and researchers never do a perfect study. I am always impressed with the ingenuity and hard work on the part of epidemiologists to get good information out of complicated and incomplete data sets. You have to read all the studies in context of biologic plausibility, the flaws in a given study, reproducibility, and, yes, the financial bias of the researcher.

I would like to thank the Fourteen studies for their website. Anyone who takes the time to read all the articles will come away convinced of the safety of both thimerosal and the MMR vaccine, especially in contrast to the quality of ‘our’ studies that purport a causation. The moving target of the cause of autism appears to be shifting to aluminum and too much too soon. I’m skeptical on biologic plausibility grounds. I am as certain as I can be (i.e. I am one, preferable more, high quality studies in a high impact journal from changing my mind) that the vaccines, both separately and together, are many logs safer than the diseases they prevent.

Now I get to read the other blog entries on the topic. About time.

========

References

*I love the movie 28 Days Later and its sequel. Something about fast, mindless, infected zombies running amok, producing more mindless zombies with the resultant body count appeals to me. I didn’t care for Shawn of the Dead, which didn’t work as either a comedy or a zombie movie for me. But do read World War Z if you are a zombie fan.

(1) Not that I do not want to sell my soul. I do. I just set the price higher than most want to pay.

(2) In the spirit of transparency, I will admit she isn’t. A review of the Internet Movie Database suggests I have never seen her perform, but most movies I see are with my 11 year old and are animated.

(3) JAMA letters Vol 291, No 2, page 181

(4) Not enough for my taste, but I am a crank on the topic. I think everyone should have to list, in dollar amounts, all direct and indirect (travel, food etc) support they receive if they give CME accredited lectures or publish in journals

(5) I can’t download the Lancet references with paying first. I doubt the publishers will complain as it would look like they are in cahoots with Big Pharma to suppress information.

(6) I don’t really think that. It is what the data would suggest, but I can’t really see the plausibility.

(7) http://www.annals.org/cgi/content/full/126/5/376

(8) A child evidently vaccinated against reality.

(9) They do not capitalize their title, very hip edgy. For a drug company. To be really Web 2.0 it needs a random capital and a vowel removal: snoFi psTeur.

(10) Modified from Joseph McCarthy, US Senator.

(11) A literary device called foreshadowing.

(12) “I do believe sadly it’s going to take some diseases coming back to realize that we need to change and develop vaccines that are safe. If the vaccine companies are not listening to us, it’s their f___ing fault that the diseases are coming back. They’re making a product that’s s___. If you give us a safe vaccine, we’ll use it. It shouldn’t be polio versus autism.” http://www.time.com/time/health/article/0,8599,1888718,00.html

Posted in: Public Health, Science and the Media, Vaccines

Leave a Comment (37) ↓

37 thoughts on “14 Studies Later*

  1. Erika says:

    You know, as a librarian, and a fan of open access, I’m generally really reluctant to take the side of publishers–but I looked at those studies hoping against all hope that at least one of them was in an Elsevier journal. They don’t take so kindly to free and open sharing of their material. (They also are more or less free of the ties to professional organization that “taint” the AAP and AMA journals.)

  2. DoctorLaw says:

    “The website suggests what is needed is a study that compares autism rates in vaccinated vrs unvaccinated children. Given the benefits of vaccines, such a study could never be ethically done. To deliberately randomize children to not getting vaccines would be immoral to do and impossible to get past an IRB.”

    I think such a study could be done by attempting to enroll as participants the children of those parents who don’t vaccinate for religious or other reasons. They’re out there, in big numbers.

  3. DoctorLaw says:

    Sorry, by the time I finished reading the post I had completely forgotten your very next paragraph, and your interesting conjecture.

    My bad.

  4. Dr Benway says:

    Why thimerosal might appear protective:

    Nutty parents may be prone to believe conspiracy theories about vaccinations, and so may vaccinate less.

    Nutty parents may have higher rates of mental disorders, including autism, among their children.

  5. David Gorski says:

    I think such a study could be done by attempting to enroll as participants the children of those parents who don’t vaccinate for religious or other reasons. They’re out there, in big numbers.

    No, it couldn’t, at least not easily. It would have a ton of confounders, because there are many socioeconomic differences between parents who don’t vaccinate and those who do. It would also take a lot of subjects. Prometheus wrote an excellent discussion of what, precisely, it would take to do a “vaxed versus unvaxed” study:

    http://photoninthedarkness.com/?p=154

    Of course, the antivaccinationists’ insistence on a “vaxed versus unvaxed” study is based on a highly simplistic understanding of clinical trial methodology. They really think that the only way to answer a question is to do a randomized, double-blinded placebo-controlled clinical trial, and many of them insist on such a trial as the only thing that would convince them that vaccines don’t cause autism. As Mark points out, however, such a trial would be utterly unethical because it would deny the control group protection against common vaccine-preventable diseases. In the bizarro world of the antivaccinationist, though, such a randomized study is ethical because anti-vaccine zealots honestly believe that vaccines are as risky and harmful as the diseases they prevent, if not more so. That’s one main reason that it’s clear to me that, even if such a trial were done and the rates of autism were exactly identical in the vaxed and unvaxed groups, it still wouldn’t convince them. They’d come up with some reason to dismiss the study.

    In fact, a while back, J.B. Handley wrote a hilariously inept defense of the randomized, double-blind “vaxed versus unvaxed” study against my pointing out how unethical it would be and how he does not understand clinical trial ethics. He tortured the Helsinki Declaration to try to demonstrate that such a trial would be ethical. Since we’re dumping on Generation Rescue (which richly deserves it), perhaps I should answer him next week, seeing how he never responded to my three posts on Generation Rescue’s intellectually dishonest propaganda tactics and his ad hominem attack on Steve.

    Or maybe not. I’m getting tired of dealing with these clowns again and again. I need a break. :-)

    BTW, Mark, I liked Shaun of the Dead (particularly the part where they were trying to drive off a zombie by throwing their old LPs at it and the part where they all pretend to be zombies in order to try to make it to the bar that they turned into their ill-advised fortress. However, if you want the greatest, most hilariously warped zombie movie of all time, you need to rent Return of the Living Dead from back in 1985. You won’t regret it. Best line: “Send more paramedics.”

  6. David Gorski says:

    Nutty parents may be prone to believe conspiracy theories about vaccinations, and so may vaccinate less.

    That may very well be why the “partially vaccinated” cohort in Generation Rescue’s ridiculous phone survey had higher reported rates of autism than the “fully vaccinated” cohort. Parents who think vaccines may have caused their child’s autism stop vaccinating.

    In fact, my guess is that, were a retrospective “vaxed versus unvaxed” study to be done it would actually show higher rates of autism in unvaccinated children. The reason? Because of all the antivaccine fearmongering, parents who had one autistic child decide that “the vaccines done it” and as a consequence stop vaccinating subsequent children. Because autism has a significant genetic component, the subsequent children of such parents (who would be more likely to be unvaccinated or only partially vaccinated) would also be more likely to be on the spectrum.

    It’s a guess, I admit, a speculation, but it’s a reasonable one. It would also be very hard to control for those confounders.

  7. DoctorLaw says:

    David Gorski wrote:

    “Prometheus wrote an excellent discussion of what, precisely, it would take to do a “vaxed versus unvaxed” study:

    http://photoninthedarkness.com/?p=154

    Excellent discussion indeed. Thanks for pointing me in that direction.

  8. Zetetic says:

    What’s the difference between a “Systematic Review” and a “Meta-analysis” ?

  9. DoctorLaw says:

    A “systematic review” may or may not include a quantitaive analysis; a “meta-analysis” always does.

  10. Versus says:

    Dr. C: “Generation Rescue is a tax exempt charity, but I cannot find their financial statement on line.”

    Because Genration Rescue is a 501(c)(c) tax exempt organization, it must make certain information public, including its annual form 990 filed with the IRS (sort of a non-tax return). I’ve gotten these 990s from the IRS before, but you can also request the required public information from the organization itself. You can find out more on the IRS website at http://www.irs.gov/charities/article/0,,id=96430,00.html.

  11. Kev says:

    Generation Rescue have filed 990′s. You can get the data here:

    http://www2.guidestar.org/ReportNonProfit.aspx?ein=20-2063267&Mode=NonGx&lid=100754201&dl=True

    Or if that link breaks just search for Generation Rescue.

  12. Matt says:

    Another place to find GR’s 990′s–

    http://foundationcenter.org/findfunders/990finder/

    They have the 990′s for 2005, 2006, and 2007.

    The budgets were

    $496k 2005
    $353k 2006
    $425k 2007

    Most of the money is spent on advertising, followed by market research.

    Mr. Handley recently noted that he doesn’t get paid (confirmed by the 990) and that he pays his own travel (possible, but some one or some people were paid for travel and conferences in 2005). He also said that he has paid “millions” for the autism cause. If he were floating GR on his own, or substantially, it is possible that he has spent on the order of $2M.

    Pure speculation, but that would explain offloadinig GR to Jenny McCarthy. What has been a liability for Mr. Handley would be more of an asset to Jenny McCarthy. She could pay money to GR–a large expense, but a charitable donation–and at the same time receive significant public relations benefits including promoting her products and books.

    It is also worth noting that in the existing 990′s, there is no evidence of real research being funded. There was their famous survey, which was a total flop scientifically but has been a moderate public relations boost for them. But, nothing that looks like they are supporting actual scientific research.

  13. Matt says:

    “It is a small thing, but in the interest of openness and transparency, it would be nice to know how much they take in from advertisements, on line sales and speaking fees.”

    Speaking fees would likely go to the individuals and not be reported on the org’s 990.

    All the org’s income is from donations, from what I can see.

    It is a fairly safe bet that GR was a financial liability for the Handley’s (and others). They tend to have no funds left over at the end of each year. To me, that indicates that they are pumping money in on an “as-needed” basis.

    Also, the 2007 990 shows that most of the money comes from large donors. While they don’t list the donors, they do have an estimate for “public support”, which is 14% in 2007.

    I would expect that the big donors are the Handley’s themselves, possibly their businesses, and other GR people.

    As noted above, this could be a reason to offload GR to Jenny McCarthy. She would return more from floating the organization in terms of public relations that would Mr. Handley.

  14. Mark Crislip says:

    Thanks. I tried guidestar and foundation center and got nothing. I am not as interweb savvy as I think.

  15. Karl Withakay says:

    “Strangely enough, antivaxers tend to be educated, internet-savvy urban parents. These are precisely those parents who are most likely to seek an autism diagnosis for their child, and have access to the facilities need to obtain such a diagnosis. There is a huge disparity in the apparent rates of autism between rural and urban settings, with many more children diagnosed in urban settings for just these reasons.”

    Yes, confounders abound! That’s why you can’t just find a bunch of unvaccinated people and compare them to the vaccinated population, there’s too many uncontrolled variable to confound.

  16. Mark Crislip says:

    I found the 990′s and since it is post day, added a few lines to the post.

  17. Khym Chanur says:

    Several received negative numbers suggesting … that the whole scoring system is bogus.

    *GASP* Surely you jest!

    I suspect that Generation Rescue is destined for crankdom.

    What, you mean they haven’t arrived there already?

  18. wales says:

    It is interesting that according to these studies the “epidemic” of autism started around 1990. This time frame coincides with a dramatic increase in the number of recommended childhood vaccines and number of doses: pre-1990 recommended childhood vaccination was for 7 diseases via 10 doses; by 1995 that had increased to vaccination for 10 diseases; currently recommended childhood vaccination is for 15 diseases (not including HPV) via 30+ doses, all before the age of 6 (25 doses before the age of 2).

    In a larger context the fourteen studies may amount to a tempest in a teacup. If there is a causal relationship between some vaccine component(s) and autism it could take decades to amass enough evidence to prove causation via observational studies due to the perceived unethical nature of a vaxed vs. non-vaxed study.

    “the famous controversy about whether smoking causes lung cancer” provides a good analogy.

    “……..establishing causation via observational study is much more difficult than via experiment and requires more than mere statistical association, including: having a reasonable model to explain cause and effect, showing that the relationship occurs under various conditions, and ruling out potential confounding variables………Indeed, only in exceptional cases has data from studies other than experiments yielded a broad agreement about causation.”

    “A noted statistician who addressed weaknesses in observational studies was William G. Cochran, who served on the Surgeon General’s committee that analyzed seven large prospective studies started in the 1960’s and that wrote a landmark report (Advisory Committee to the Surgeon General of the Public Health Service 1964) that identified smoking as a cause of lung cancer. “

    Journal of Statistics Education Volume 12, Number 3 (2004), http://www.amstat.org/publications/jse/v12n3/lesser.html
    Section 3.1.2 “Observational Studies”

  19. cheglabratjoe says:

    wales,

    You know another interesting occurrence that coincides with the “epidemic” of autism in the early 90s? The release of the DSM-IV, which drastically expanded the definition of autism.

    Thanks for the large and scary-sounding number of vaccines given nowadays, though. I found those very interesting, because I like disease eradication.

  20. The Blind Watchmaker says:

    This is an interesting side-by-side comparison of studies, 25 studies actually.

    Doesn’t look good for the anti-vaccine crowd.

    Please share this with whomever.

    http://www.immunize.org/catg.d/p4026.pdf

  21. christie says:

    Yet another event that coincided with the “epidemic” was the addition of “autism” on the IDEA list of conditions that receive funding in schools.

  22. Chris says:

    wales, a bit hint on the answer to your question here:
    http://www.unstrange.com/dsm1.html

    (my son was born too soon to be diagnosed, if he were just five years younger he would have been considered autistic)

  23. The Blind Watchmaker says:

    “Yet another event that coincided with the “epidemic” was the addition of “autism” on the IDEA list of conditions that receive funding in schools.”

    You are correct, christie.

    The states that tie funding to the diagnosis have the higher rates of diagnosis of autism. Over time the rates have a high degree of correlation. (see link below).

    Now, correlation is not necessarily causation (indeed, this fallacy is how this whole business got started). However, if other states (with similar populations that do not tie funding to the diagnosis) are used as controls, then funding becomes the main variable. If there are different rates, then causation can be applied.

    http://www.autism-watch.org/general/edu.shtml

  24. The Blind Watchmaker says:

    Also, the higher autism rates have been shown to be a bit false. When uniform, agreed upon criteria are applied to the “high rate populations”, the relative increases seem to go away. The problem is that states seem to be using whatever loose criteria they want. The condition does not even have to be diagnosed by a doctor.

    http://pediatrics.aappublications.org/cgi/content/abstract/117/4/1028

  25. christie says:

    Watchmaker,

    Thanks for the links. Tangential point: I always love it when I face an antivaxer who tells me they live in the “autism capital of the us” (which, depending who you ask, is colorado, north carolina, new jersey, michigan, or rochester, NY). I’m not sure about NJ, but I know the others all have major treatment centers that people with children with autism flock to… of course there’s a greater proportion of people with autism!

    As far as higher rates being false, it’s well understood in psychology circles that you always have to check whether numbers are referring to classic (Kanner) autism or ASDs.

    …and people wonder why we can’t figure out what causes autism… we can’t even seem to agree on what is it! (yes, I know, not the only reason, but still…)

  26. christie says:

    cheglabratjoe wrote: “You know another interesting occurrence that coincides with the “epidemic” of autism in the early 90s? The release of the DSM-IV, which drastically expanded the definition of autism.”

    Actually, the DSM-IV (1994) probably tightened the autism diagnosis, compared to DSM-IIIR (1987) (6 of 12 criteria, compared to 8 of 16 – I know it’s the same ratio, but an MR kid could easily get an autism diagnosis on the DSM-IIIR scale). However, both were substantially more broad than previous DSMs that included autism. What the DSM-IV DID do, however, was include autism in with the other Pervasive Developmental Disorders, more commonly called the Autism Spectrum Disorders, which is a broader category and what the current 1/150 number (from the CDC) is based on.

  27. SF Mom and Scientist says:

    As cheglabratjoe said, I am happy for all these new vaccines (especially being the parent of a young child.)

    wales, since you think the introduction of all these new vaccines is so bad, you should read this.

    http://news.bbc.co.uk/2/hi/health/8015138.stm

  28. SF Mom and Scientist says:

    Another thing to point out is that, even if there was not an ethical issue in performing a prospective study (an idea that is hard to comprehend), it would be next to impossible to find parents who would be willing to enroll their children in such a study. As someone said earlier, the anti-vaxers would not allow the chance that their children be vaccinated. And those of us who understand how important vaccines are would be absolutely horrified at the possibility that our children would be unvaccinated.

  29. Eric Jackson says:

    No! Pay no attention to the complete rewrite of the criteria and definitions of Autism! It has Absolutely Nothing to do with a change in the rates of diagnosis done according to those criteria! And no matter that despite the increase in diseases vaccinated for, the removal of smallpox and polio vaccination has resulted in a major decrease in the number of antigens presented. Neither does a comparison of what got a diagnosis of Autism in say 1975. Don’t look.
    /sarcasm

    No really. Don’t go look. They make most schizophrenia cases look lie they have happy endings.

  30. DLC says:

    Interesting analysis, Dr Crislip, thanks for the write-up.
    Someone needs to pull aside the Curtain of Generation Rescue and show the man pulling the levers and yelling into the loudspeaker. But, J B Handley has commanded that none look behind the curtain.

  31. HelenSan says:

    Re Madsen’s “Thimerosal and the Occurrence of Autism,” I recently used it as a poster child of pseudoscience on my blog. I cannot for the life of me see how anyone can see it as a “nice study” and “fairly clean.”

    http://freedom2question.blogspot.com/2009/05/what-is-pseudoscience.html

    Most of the studies defended by your article would be seen as pseudoscience by real, experimental scientists.

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