How Andrew Wakefield invented “autistic enterocolitis”

I’m almost beginning to feel sorry for Andrew Wakefield.

Well, not really. He did bring all the misery that’s poured down upon him like an unending waterfall of woe, such as the British General Medical Council (GMC) finding him guilty of research misconduct and soon very likely to recommend that he be “struck off,” a delightful British term for removing someone’s medical license and thus striking him off the list of licensed physicians. Soon after, the editors of The Lancet retracted his infamous 1998 paper that purported to suggest that there was a link between the measles virus in the MMR vaccine and enterocolitis in autistic children. After all, it was the “research” for this paper that had resulted in the ruling against Wakefield, and no wonder. It was incompetent, trial lawyer-funded research that may very well have been fraudulent. Given these findings, it was virtually impossible for The Lancet to stand by Wakefield’s study any more, although it was at least six years late compared to 10 of the 13 coauthors who had disavowed the paper earlier. Given the GMC’s findings, it was also difficult for the editors of NeuroToxicology not to make like The Lancet and withdraw Wakefield’s infamous “monkey study,” which had been accepted for publication but not yet formally published, although it had been published as an “E-pub ahead of print” on the journal’s website. The final blow came when Wakefield was forced to resign from the house of woo that he had founded, Thoughtful House in Austin, TX. Since then, he’s been looking for a way to bring himself into even further disrepute, but thus far, with only a recent exception or two, flown under the radar.

One of the issues that has been most mysterious about the whole affair has been the issue of scientific fraud. A little more than a year ago, investigative journalist Brian Deer capped off his then five year investigation of Wakefield with a report of compelling evidence that Wakefield had falsified data in his Lancet paper. Fourteen months later, Brian Deer has revisited the topic in a report for the British medical journal BMJ entitled Wakefield’s “autistic enterocolitis” under the microscope. In this article, Deer did something I’ve never seen published in a medical journal before. He went back and looked at the original clinical data from Wakefield’s paper and then had various experts look at it again and render opinions. He also talked to at least one of the original peer reviewers who had foolishly approved Wakefield’s paper, told him the results of his investigation, and then asked him if he would have approved the manuscript in light of the new analysis. In putting the story together, Deer paints a picture that shows Wakefield as almost certainly being behind major scientific fraud or gross incompetence, perhaps both.

First, Deer points out the impetus for Wakefield’s original 1998 study:

So what survives of “autistic enterocolitis” after Wakefield’s disgrace and the paper’s retraction? The answer requires an understanding of Wakefield’s mission, which was to discover precisely such a disease. Two years before the paper was published he was hired by a solicitor to help launch a speculative lawsuit against drug companies that manufactured MMR vaccine. And the instrument of their attack was to find what he called at the time “a new syndrome” of bowel and brain disease caused by vaccines.

Yes, Wakefield was a loyal minion of the trial lawyers to the tune of hundreds of thousands of pounds. He needed evidence, and he went looking for it. Unfortunately, reality did not cooperate:

But when the children were brought in to the Royal Free for ileocolonoscopy, between July 1996 and February 1997, a snag in Wakefield’s project emerged. The hospital’s pathology service repeatedly judged colonic biopsy samples to be unexceptional, and thought bowel disease was a possibility in only one child

In almost all cases, histopathologists reported a typical mix of cell types and numbers in the biopsy specimens. “Large bowel-type mucosa within normal histological limits,” said, for example, the report for child 3 in the series. “No evidence of architectural distortion or increase in inflammatory cells in the lamina propria,” said child 4’s.

The lead pathologist for the Wakefield project, and an author of the now retracted paper, was Susan Davies, now at Addenbrooke’s Hospital, Cambridge. At weekly meetings with paediatricians, the unexceptional results were confirmed.

For four of the 12 she made additional notes recording the position more bluntly: “no abnormality detected.”

AFter reading this, I’m guessing that you’re wondering: So what? Why not just go back and look at the original slides. Unfortunately, that is not possible. The original slides, for unexplained reasons, are no longer available. I don’t know what hospital pathology departments are like in the U.K., but here in the U.S., they keep the slides and the paraffin-embedded blocks used to make the slides for considerably longer than 12 years. I find it curious indeed that none of the slides from the original 12 “Wakefield children” is available for re-review by expert pathologists. It stinks. It stinks to high heaven.

Stymied in this, Deer did the next best thing, although it is not nearly as satisfying. He got the hospital pathology reports together and followed their trail through Wakefield’s study. What he found was the perfect confluence of incompetence mixed with what appears to be dishonest. For one thing, eight out of eleven of the children for whom pathology reports could be located had pathology reports that were stone cold normal. Contrast this to Wakefield’s paper, which reported “nonspecific colitis” in 11/12 children. How could this mismatch have come about. That is what Deer tried to find out.

Deer concludes (reasonably, based on my reading of the evidence) that the mismatch came about through ambiguities in the use of the term “inflammation” and “colitis.” Remember, we’ve discussed before, part of the reason that the GMC ruled against Wakefield is that he had children subjected to colonoscopies that were not medically indicated. A colonoscopy is an invasive procedure, and it is not to be taken lightly, even for valid medical reasons. Biopsies were then obtained. What needs to be understood is that some degree of inflammation is very common and not necessarily abnormal in the colon, particularly if you are looking for it. The more you look, the more you will find, and Wakefield’s group found a lot as they reexamined the slides for all the children, particularly the ones that had previously been described as “normal.” This resulted in:

“It was decided that the senior consultant histopathologist with expertise in intestinal disease (Dr Dhillon) should review all biopsies from autistic children, and that pathology should be graded on a pro forma (or grading sheet) designed by him,” Wakefield said last March, in a now suspended complaint to the UK Press Complaints Commission about one of my Sunday Times reports.

Notice how Wakefield says “inflammation,” not colitis. Why does this make a difference? Because the two are not the same thing:

As for the histological grades produced in any second review the published paper includes nothing of these. In any case, specialists I’ve consulted say that grading sheets are research tools and don’t generate clinical diagnoses such as colitis. Applying such terminology is a clinical decision: somebody must make a judgment. Moreover, in 1997, the British Society of Gastroenterology said that “inflammation requiring further investigation” to reach “a specific disease category” should be called “inflammation–unclassified.”15 Not colitis. Would the Lancet have published on just “inflammation–unclassified”? Would any claim of a new syndrome have sounded credible? And how many peer reviewers would have felt comfortable approving the paper if they had known that the hospital pathology service reported biopsy specimens as largely normal, but they were then subjected to an unplanned second look and reinterpreted?

The response from one of the Lancet’s peer reviewers of the Wakefield paper was “no”: he wouldn’t have felt comfortable. “I’m surprised the GMC didn’t make more of this,” said David Candy, paediatric gastroenterologist at St Richard’s Hospital, Chichester, who reviewed the paper in 1997. “That’s an example of really naughty doing–to exclude the original pathology findings.”

In any case series (which is what Wakefield is now calling his paper in a futile attempt to make it sound as though he wasn’t doing research and thereby avoid charges of research misconduct), omitting the original pathology findings is indeed a definite no-no. It’s just not done. Moreover, “reinterpretations” of any pathology findings must be thoroughly explained to the satisfaction of peer reviewers that the reinterpretation is not generating desired results, rather than looking at objective indices. It would indeed be a huge red flag to see a study in which the original pathology reports virtually all did not agree with the final research pathology reports. Any peer reviewer worth his or her salt wouldn’t approve a paper like that.

The big question, then, is: How were the findings of mild focal inflammation in many of the patients end up being translated to “nonspecific colitis”? Brian Deer makes a compelling case that it was Andrew Wakefield who “translated”:

Wakefield last year offered a glimpse into how this happened. He gave a detailed explanation for child 8–the only girl in the Lancet series. This 3 year old’s clinical notes said: “Histology normal.” The pathology service reported three large bowel biopsy specimens: “All pieces of normal colonic-type mucosa containing occasional lymphoid aggregates,” a consultant reported. “Minimal inflammatory changes. May be result of operative artefact.”

Wakefield wrote: “When the biopsies were reviewed and scored by experts in bowel pathology–namely, Drs Dhillon and Anthony–these doctors determined that there was mild inflammation in the caecum, ascending colon, and rectum,” he said. “This was correctly reported as non-specific colitis in the Lancet.” In other words, it looks like it was Wakefield who translated the scores.

Unfortunately, this is not an acceptable practice. Deer points out that minimal or mild inflammatory changes, in and of themselves, should not be reported as colitis. The reason is that the diagnosis of colitis actual evidence of injury to the lining of the colon. It is not enough simply to have an influx of inflammatory cells. Wakefield wasn’t a pathologist; so perhaps he didn’t know that. One wonders why the pathologists on the study weren’t more insistent on expressing their misgivings.

Sadly, BMJ apparently didn’t have the courage of its convictions in publishing the Brian Deer article. It had to go and present some “balance” by publishing a companion editorial by Professor Sir Nicholas Wright of Barts and the London School of Medicine and Dentistry, Queen Mary University of London. As Sullivan points out, Sir Wright has testified as a character witness for Professor John Walker-Smith, one of the faculty who worked with Wakefield and came under the gaze of the GMC. His editorial, Does Autistic Enterocolitis Exist?, is a jumbled mess that doesn’t really define “autistic enterocolitis” and isn’t clear on whether Wright is examining the question of whether there is a form of enterocolitis unique (or nearly so) to autistic children or whether autistic children have higher rates of enterocolitis than children without autism. In both cases, the evidence leans more towards an answer of “no,” but Wright clings to the possibility that “autistic enterocolitis” exists as an identifiable entity while acknowledging that a recent consensus statement does not support the existence of “autistic enterocolitis.” Unfortunately, scientific journals can sometimes be as prone to the “tell both sides” technique that I complain about so much as any newspaper.

In the end, it’s not entirely clear to me whether Wakefield’s apparent “translation” of inflammation into colitis was due to incompetence, wishful thinking, or clear cut fraud. What is clear to me is that, whatever the reason, whatever forces led Andrew Wakefield to produce such a scientifically worthless and deceptive paper, this was a failure on many levels. It was a failure of Wakefield, but it was also a failure of the peer review system. The warning signs were there, but not heeded. An incompetent and possibly dishonest “researcher” (and I do use the term loosely) took advantage, and the results were disastrous.