Tag Archives: autism

Elsevier Makes Good: Original Wakefield Takedown Now Free

Awhile back, I blogged about a particularly insidious glitch in the biomedical literature, in which a fraudulent study that caused enormous harm was available for free, while a contemporary – and strikingly prescient – commentary that eviscerated that study was locked behind a paywall. Now, thanks largely to the perserverance of TWiV co-host Rich Condit, this situation has been fixed.

Rich followed up on his original request, pulling strings with several contacts he’d made at Elsevier. He forwarded the conclusion of the saga this morning:

Dear Professor Condit

On behalf of Dr Astrid James, I can confirm that both the commentary and article in question are now free to access, subject to (free) registration on www.thelancet.com

Many thanks.
Richard Lane
Web Editor
The Lancet

Now, not only can the general public read the infamous and now retracted paper from Andrew Wakefield, which purported to show a link between MMR vaccination and autism, but also the brief, thorough debunking of that paper by Robert Chen and Frank DeStefano. Thank you Rich, and thanks to the folks at Elsevier who finally got the point.

The only remaining question is why, in light of Chen and DeStefano’s analysis, The Lancet even published Wakefield’s paper in the first place.

Our Cross to Bear

I’m an atheist, but for social reasons I occasionally have to sit through a church service. This past Easter, I did it again, and found the sermon particularly interesting, though not in the way the pastor intended. Visiting a common theme, she talked about how preposterous Easter is: the idea of someone rising from the dead, the shortage of witnesses to the event, and the questionable credibility of the few who did supposedly see it. The lesson was supposed to be that only someone of great faith would believe such a story, thus proving that Christians are the most pious people.

Instead of a religious epiphany, though, I had an anthropological one. Believing in something absurd is a good way to be ridiculed – and that’s exactly the point. By professing their beliefs, the faithful are not really trying to convince outsiders of anything. The entire purpose is to incur derision, so that they can point to it as proof of their faith.

Crosses. Courtesy Flickr user istolethetv.

This is the whole point, apparently.

“Look at what I endured for our beliefs,” they want to say. It cements their position in the community of their faith, and also challenges others in that community to outdo them. Someone else then professes the absurd beliefs to an even larger crowd, incurring even more ridicule, and earning even more esteem among the faithful. If they make enough of a nuisance of themselves to get arrested, injured, or killed, they’ll be made into saints.

Arguing with these faith-based absurdities is not only unproductive, it’s actively counterproductive. Believers want to hear someone elaborate all the ways their beliefs are wrong. They thrive on the rational disproofs of their position. They crave the scorn.

As interesting as that insight was, I didn’t think it applied to anything beyond traditional organized religion. This week, I suddenly realized that an entirely new kind of religion has quietly sprouted over the past few years, and that its tendrils now extend into a wide range of scientific topics. I don’t have a name for these new religions yet – maybe Forum Faiths, or E-tribes, or Chatroom Counterfactuals would work. Regardless of the terminology, the pattern is always the same.

Start with a controversial but completely testable statement – a hypothesis. This frames the discussion as a scientific one, even though you have no intention of pursuing it scientifically. Say that vaccines cause autism, or that a newly discovered retrovirus causes chronic fatigue syndrome, or that people with delusional parasitosis are actually infected with real parasites. The specifics don’t matter, all that matters is that you pick a topic someone will care about, and make a surprising claim that some people will want to believe.

Now present a tiny shred of data supporting the hypothesis, but tell everyone that you’re sure it’s going to turn out to be true. This establishes the faith. True believers will immediately sort themselves out from the crowd, latching onto the hypothesis and proclaiming it as fact, even though (or perhaps especially because) the data are so scanty.

From that point forward, every new piece of evidence against the hypothesis will only reinforce the faith. Some of the early adopters, who were misled by thinking this was an actual scientific exercise, will abandon the group once the new data come along. The true believers, though, will become more adamant. They’ll meet in online forums every time a new refutation comes along, so they can agree on talking points to answer it. They will then spam every blog, forum, and news site with comments that appear to be arguments, but which are actually protestations of their faith.

As unbelievers respond to those comments, the believers will persist until their arguments are completely absurd. Then they’ll be ridiculed for their irrationality, at which point they’ve won. They can return to their groups and point to the suffering they’ve felt for the faith. Their esteem among the faithful will rise, even as the rest of the world considers them idiots.

Meanwhile, the charismatic leader of the faith – The One who originally presented the shred of data – will follow the same pattern but in the professional world. He or she will argue with the scientists whose data don’t support the hypothesis, until the arguments become absurd. The scientific community will then marginalize and ignore The One, because they don’t have time to deal with willful idiocy. Of course, to the faithful this only proves that The One is a true martyr, and that the unbelievers are conspiring against them.

I don’t have a solution to this. Ignoring these counterfactual religions won’t work, particularly when they make claims that can profoundly affect public health, and arguing with them obviously isn’t going to help either. Science is ultimately self-correcting, so poorly-controlled, fraudulent, or simply erroneous results will eventually be expunged and most of the world will move on. The true believers, isolated in their little cul-de-sacs of falsehood, may gradually dwindle over time. All that will be left will be the damage: kids maimed and killed by vaccine-preventable diseases, sick patients made sicker from drugs that never could have helped them, families destroyed by untreated psychoses.

As religious casualties go, I suppose it could be worse. But in the twenty-first century, I wish we could do better.

New Elsevier Slogan: “It’s All about The Benjamins”

Regular readers of this blog (both of you), and regular listeners of This Week in Virology (all 10,000-plus of you) are by now quite familiar with a fellow named Andrew Wakefield, and the epic and ongoing public health catastrophe he perpetrated. That story began in 1998, when Wakefield and several coauthors published a paper in The Lancet that purported to show a link between autism and vaccination with the measles-mumps-rubella (MMR) shot. If you don’t know what happened after that, or how utterly that notion has been discredited, take a few minutes to read up on it. I’ll wait.

As we all now know, Wakefield’s original study was not only tiny, unrepresentative, poorly controlled and vastly overclaimed in the media, it was also unethical and fraudulent. Indeed, all of the authors except Wakefield have since repudiated the work, and The Lancet has retracted the paper.

However, some sharp researchers actually foresaw much of this and wrote a commentary to that effect in the very same issue of the journal where Wakefield’s paper appeared. Had that commentary been given the same media exposure as the paper, much of the ensuing disaster could have been avoided. If we’re going to derive any benefit at all from this whole tragedy, then everyone should go and read that commentary. It provides a perfect case study of the importance of critically analyzing clinical data.

Unfortunately, unless you’re at a university that already subscribes to The Lancet, you’ll have to pay a hefty fee to Elsevier, the journal’s publisher. That’s right: this critically important document from one of the most damaging and costly frauds in the history of science is locked in a vault.

In the spirit of full disclosure, I’ve done some work for Elsevier subsidiaries over the years – they previously owned Drug Discovery and Development and Bioscience Technology, two journals for which I write regularly. That said, I’ve sometimes disagreed with the company’s decisions, and this is one of those times.

Thinking it was merely an oversight, one of my TWiV co-hosts, Rich Condit, decided to send a polite request for Elsevier to open this particular paper to the public:

To whom it may concern:

I am writing to request that the 1998 Lancet comment by Chen and DeStefano on the Wakefield autism/MMR vaccine article in the same issue be made open access on your site. The reference for the comment in question is:

Lancet. 1998 Feb 28;351(9103):611-2.
Vaccine adverse events: causal or coincidental?
Chen RT, DeStefano F.

My reasons for the request follow:

I am a co-host on a podcast called “This Week in Virology” (www.twiv.tv). Each week we discuss topics of interest in virology. We also post “science picks of the week”, miscellaneous items that we think may be of interest to our listeners. I would like to use the Chen and DeStefano article as a pick of the week, but it is behind a paywall so that our listeners would not be able to access it, and posting the pdf would be a copyright violation.

This comment essentially debunks the now famous and retracted article by Andrew Wakefield and colleagues linking autism with the MMR vaccine. The comment is of considerable public interest because it quite accurately discredits the Wakefield report and also anticipates the damage it would do, and is published in the same issue of Lancet that contained the Wakefield article. It was apparently essentially ignored and yet was prescient. I would like the public to be able to have free access to this important comment as a lesson in how these things might be avoided in the future.

TWiV has about 7000-10,000 regular listeners so this is a good way to communicate this important message.

Thank you for your consideration.

Sincerely,

Richard Condit
Professor
Department of Molecular Genetics & Microbiology
University of Florida
Gainesville, FL

Rich got a prompt reply from an autoresponder script, which informed him that all requests regarding rights and permissions had to be filed through a particular web site. He did that, and got a receipt indicating that his request had been submitted, presumably for an actual human to review. A short time later, he got this:

Dear Dr. Richard Condit,

Your order 500611163 has been denied as a result of the following: Permission Denied . You will not be charged for this order and a credit will be issued for any monies submitted in this regard to date.

I can’t even count how many ways this is wrong. The now-retracted Wakefield article is available free of charge, and has been for awhile. It requires signing up for The Lancet’s site, but costs nothing. Meanwhile, Chen and DeStefano’s thorough and prescient analysis of this steaming pile of crap is behind a paywall, and apparently Elsevier has no intention of changing that. The fraud is free, the truth is locked up, and that’s how the publisher wants it.

The Epidemic That Still Isn’t: Autism Rates and Case Definitions

A paper that came out yesterday in the American Journal of Psychiatry has generated a lot of press coverage of the “autism epidemic,” as it purportedly shows that one in every 38 South Korean children is autistic. That’s more than double the incidence previous epidemiological studies have found. I have no doubt that this result, completely devoid of its larger context, will now be picked up by all manner of woo-woo peddlers as indisputable proof of whatever nonsense they’re selling. What the paper really shows, though, is how slightly different interpretations of case definitions can produce radically different results.

First, let’s dispense with the most obvious flaw in much of the news coverage of autism: there is no “epidemic.” As numerous epidemiologists have found every time they’ve looked at this issue, the apparent rise in the rate of autism spectrum disorder (ASD) tracks perfectly with changes in the diagnostic and special education criteria for the disease. It’s not rising, just being identified more often.

One particularly telling point is that the supposed increase in ASD doesn’t age well. Autism appears in childhood, but many folks seem to forget that children grow up, and the disease doesn’t go away when they do. That means that if ASD rates are genuinely increasing, there should be more autistic kids than autistic adults. But as a paper last week in Archives of General Psychiatry showed, there aren’t.

A Reuters story on that paper explained the key finding nicely:

Researchers found nearly one percent of Britons older than 16 years have autism, a rate that is similar to that seen in children. Younger people were no more likely to be affected than older ones, however, which would have been expected if the condition were truly on the increase.

“It was surprising to all of us,” said Dr. Traolach Brugha, a psychiatrist at the University of Leicester, who worked on the study. “If this study is correct, it does put a big question mark over the autism epidemic.”

Not so much a question mark as a stake through the heart. Brugha’s team found that the adults with ASD were less likely to have been diagnosed previously than kids with it, pretty much proving that the rising rates are due to increased diagnosis and awareness. Nor is Brugha’s report the first in this genre. For example, Orac at Respectful Insolence has an excellent post about a 2006 study that essentially proved the same point using a different method.

So case rates aren’t rising. But are they really only 1%? That’s what Kim et al. wanted to determine in the new South Korean study. I encourage everyone to read the whole paper, which Am J Psych has made available for free. It’s an impressive piece of work.

First, the researchers identified a South Korean community that was demographically diverse, and set out to sample all 7- to 12-year-old kids in that region. There were 55,266 of them. Before I start my criticism of this study, I have to congratulate the authors on the dedication, organization, and plain hard work that they put in to tackle such a huge job. As I said, it’s an impressive paper.

Kim’s team broke their sample into two groups: those who received special education or other psychiatric help (the “high-probability group”), and those who were in the general school population. That ensured that their sample wouldn’t be skewed by accidentally pulling too many kids from special ed. Between the two groups, they found a whopping 2.64% prevalence for ASD, or about 1 in 38 kids. That’s the conclusion that’s been plastered all over the headlines, and the one that I predict will launch a thousand quacks.

As often happens, though, the Abstract giveth while the Results taketh away. Let’s start with the autism rates in the high-probability group, which were, unsurprisingly, very high:

In the high-probability group (those in the Disability Register, those in special education schools, and those in regular schools who had psychiatric or psychological service use) 97 of 114 children were confirmed to have autistic disorder (N=74) or other ASDs (N=23). The high- probability group contributes 0.18% for any ASD to the total population prevalence (autistic disorder=0.13% and other ASDs=0.05%; the ratio of autistic disorder to other ASDs was 2.6:1).

I’ll parse that. In ASD, the middle letter is critical: autism occurs on a spectrum. Contrary to popular belief, not everyone with ASD is Rain Man. In fact, the cases depicted in movies are generally the extreme end of the spectrum, people with the biggest problems. Milder cases extend from there all the way through (according to many researchers) Asperger Syndrome. There are no bright lines dividing these folks. Indeed, there’s no reason to believe that there’s even a clear boundary between “sick” and “well” here. Extremely autistic individuals clearly need help, but what about high-functioning folks with Asperger’s? At what point does one divide someone with very mild ASD from someone who’s just socially awkward? Like most psychiatric case definitions, it’s murky at the edge.

What Kim et al. found in the special ed group was a lot of ASD, with the majority of diagnoses in the “autistic” category rather than in milder categories. These are the sickest kids. Presumably that’s why they’ve been singled out for special help. So far, so good.

The general population data get more problematic:

For 104 children with ASDs in the general-population sample, among the 172 assessed, the crude prevalence for any ASD was similar to that in the high-probability group (0.19%). However, the ratio of autistic disorder to other ASDs was reversed, with prevalences of 0.05% and 0.14%, respectively (ratio, 1:2.6) (Table 2). Other differences between the high-probability and general-population groups included the ratio of boys to girls, which was 5.1:1 in the high-probability group and 2.5:1 in the general-population sample (p=0.037) (Table 2). Mean performance IQ for individuals with any ASD was 75 (SD=28) in the high-probability group and 98 (SD=19) in the general-population sample (p<0.001)

Now we’re seeing a majority who are on the mild end of the spectrum. How mild? In some cases, quite. The surveys the researchers used to assess ASD, while standard in the field, suffer from the usual drawbacks of any psychiatric survey tool. Does your child have only a few friends? Prefer playing alone? Is he or she easily overwhelmed by extraneous stimuli? There’s lots of wiggle room on questions like these, and the closer you look the more likely you are to start pathologizing mere eccentricity.

Finally, there’s an extrapolation problem. As the numbers in the paragraphs above indicate, the researchers didn’t manage to get detailed diagnostic information on all 55,266 kids in the district. A lot of parents responded to the initial questionnaire, but many didn’t. Of the ones who did, many declined subsequent followups. By the time we get to the most detailed tests, the investigators are down to hundreds rather than thousands of data points. Nonetheless, they extrapolate from this self-selected group to the entire population. If we assume that parents who had some concerns about their children were more likely to follow up with the study – a reasonable assumption – then the extrapolation fails.

I’m not saying the results are completely bogus. The researchers are aware of their tools’ limitations, and they take efforts to control for some of them. Still, we have to ask whether a child who’s enrolled in regular school programs, hasn’t been identified as sick by any of his or her teachers, and seems to be progressing just fine in life needs to be given a diagnosis. Maybe there are a lot of children who aren’t truly “normal,” but who are acting the part well enough to pass. On some level, doesn’t that describe us all?

Brugha, T., McManus, S., Bankart, J., Scott, F., Purdon, S., Smith, J., Bebbington, P., Jenkins, R., & Meltzer, H. (2011). Epidemiology of Autism Spectrum Disorders in Adults in the Community in England Archives of General Psychiatry, 68 (5), 459-465 DOI: 10.1001/archgenpsychiatry.2011.38

Kim, Y., Leventhal, B., Koh, Y., Fombonne, E., Laska, E., Lim, E., Cheon, K., Kim, S., Kim, Y., Lee, H., Song, D., & Grinker, R. (2011). Prevalence of Autism Spectrum Disorders in a Total Population Sample American Journal of Psychiatry DOI: 10.1176/appi.ajp.2011.10101532

Vaccines and Autism: The Bullshit Continues

A news item a few days ago has fired up a new round of the old “vaccines cause autism” nonsense. The story correctly states that the National Vaccine Injury Compensation Program has awarded a substantial amount of money to the family of a girl who appears to have been injured by a vaccine. And that’s about the only thing in the story that’s correct.

Continue reading

Is Autism a Methylation Disease?

What causes autism? It’s a question that has bedeviled researchers for decades, but a new report in BioMedCentral Medicine points to epigenetics for a possible answer:

Researchers at Duke University Medical Center have uncovered a new genetic signature that correlates strongly with autism and which doesn’t involve changes to the DNA sequence itself. Rather, the changes are in the way the genes are turned on and off. The finding may suggest new approaches to diagnosis and treatment of autism.

The researchers found higher-than-usual numbers of gene-regulating molecules called methyl groups in a region of the genome that regulates oxytocin receptor expression in people with autism.

“In both blood samples and brain tissue, the methylation status of specific nucleotides in the oxytocin receptor gene is significantly higher in someone with autism, about 70 percent, compared to the control population, where it is about 40 percent,” said co-lead author Simon G. Gregory, Ph.D., assistant professor in the Duke Department of Medicine.

This is an attractive idea for a lot of reasons. Methylation can change gene expression levels in a way that’s heritable, but not directly encoded in the DNA. That could explain why autism seems to stem from a combination of genetic and environmental (read: unknown) causes. Meanwhile, oxytocin signaling is important in social attachment and emotional development, processes that seem to be derailed in autism.

However, the findings come from a very small population of patients: a total of 119 autism cases, with only one family analyzed in detail. In that family, the mother and one autistic child have a deletion in the oxytocin receptor gene, and the other autistic child has an apparent methylation defect in the gene. In other words, epigenetics might be a cause of autism, but it’s unlikely to be the cause.