Apr. 15, 2010 This week, the British Medical Journal questions the existence of a new bowel condition in autistic children dubbed "autistic enterocolitis" by Dr Andrew Wakefield and colleagues in a now infamous and recently retracted paper published by the Lancet in 1998.
In a special report, journalist Brian Deer tries to unravel the journey of the biopsy reports that formed the basis of the study, while an accompanying editorial asks does autistic enterocolitis exist at all?
In 1996, Dr Andrew Wakefield was hired by a solicitor to help launch a speculative lawsuit against drug companies that manufactured MMR vaccine to find what he called at the time "a new syndrome" of bowel and brain disease caused by vaccines.
Deer reveals that biopsy reports from the Royal Free Hospital's pathology service on 11 children included in the Lancet study showed that eight out of 11 were interpreted as being largely normal. But in the paper, 11 of the 12 children were said to have "non-specific colitis": a clinically significant inflammation of the large bowel.
So how did the mismatches occur?
Apparently, the biopsies were first reported on by Dr Susan Davies, a consultant histopathologist and co-author on the study, but they were also seen and interpreted by three other co-authors before final publication.
When Dr Davies was cross examined before the General Medical Council she said that she had initially been concerned about the use of the term "colitis" in the Lancet paper because she herself had found nothing abnormal in the biopsy sections. But she was reassured, she said, by the "formalised review" of the biopsies by her three colleagues.
This apparent concurrence of four pathologists gave strength to the finding of a new bowel disease, writes Deer. But there is no suggestion in the paper that the second assessment caused findings to be substituted or changed.
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, he asks?
Professor David Candy, paediatric gastroenterologist at St Richard's Hospital, Chichester, who reviewed the paper in 1997, said "no": he wouldn't have felt comfortable. "That's an example of really naughty doing -- to exclude the original pathology findings."
So what should we make of all this, asks Deer? The biopsy slides are no longer available, and cannot be re-assessed. All we have are Dr Davies' pathology reports, and independent specialists seem to agree that she regarded what they showed as largely unremarkable.
Professor Tom MacDonald, dean of research at Barts and the London School of Medicine and co-author of Immunology and Diseases of the Gut said: "If I was the referee and the routine pathologists reported that 8/11 were within normal limits, or had trivial changes, but this was then revised by other people to 11/12 having non-specific colitis, then I would just tell the editor to reject the paper."
In an accompanying editorial, Sir Nicholas Wright also from Barts and the London points out that all histopathological interpretation is a matter of opinion, but we should always ask how reliable that opinion is.
In terms of whether autistic enterocolitis exists, several studies have shown an association between inflammatory pathology and autistic spectrum disorder, but he believes that, in view of the limited data, any firm conclusion would be inadvisable.
"We should remember, as recent experience in several fields has shown, that although science has its defects, it is a self correcting process. Time is, perhaps, the wisest counsellor of all," Wright concludes. "In the meantime, this case offers a salutary reminder for researchers and journal editors alike that coauthorship means bearing responsibility for what is written."
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- Brian Deer. Wakefield's "autistic enterocolitis" under the microscope. BMJ, 2010; 340 (apr15 2): c1127 DOI: 10.1136/bmj.c1127
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