Talk:Lancet MMR autism fraud/Wakefield 1998 Paper Fraud

This was originally a declined draft. It was moved here to allow for research.

Wakefield 1998 Paper Fraud

On 28 February 1998, Andrew Wakefield was the lead author on a paper in the British medical journal Lancet titled "Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children". which reported an association in 12 children between treatment with the Measles-Mumps-Rubella vaccine and subsequent development of colitis and autism. The history of the controversy surrounding this paper is treated in the article on Andrew Wakefield. This article discusses in detail the falsifications and fabrications in the 1998 paper which caused it to be identified as fraudulent and retracted.

Definition of Scientific Fraud
For these purposes, scientific fraud, or scientific misconduct, will be defined per the US Office of Research Integrity (ORI) as "fabrication, falsification, or plagiarism in proposing, performing, or reviewing research, or in reporting research results." The ORI further defines "(a) Fabrication is making up data or results and recording or reporting them. (b) Falsification is manipulating research materials, equipment, or processes, or changing or omitting data or results such that the research is not accurately represented in the research record."

Six Fabrications and Falsifications
The primary fabrications and falsifications in the paper occur in 5 main areas. There is a 6th form of falsification which occurred in Wakefield's response to criticisms of the paper which will be discussed later. The first 3 areas of falsification and fabrication concern the reporting of the scientific findings in the article.

Fraud 1. Findings of Non-specific Colitis
The paper reported in Table 1 that 11 of the 12 children examined had "non-specific colitis". This was apparently a phrase used by Wakefield in final revisions to summarize the results of the histopathogical examination of the biopsies collected during ileocolonoscopy.

These slides were originally examined by the clinical pathologists at the Royal Free Hospital in London and were determined to be essentially normal. Given this result, the research team decided to have the slides re-examined by medical school faculty. In this review, specific histological findings were scored on a 0-3 scale by Dr. Dhillon and there was also a checkbox at the bottom for other findings, such as 'non-specific' or 'normal'. In 11 of the 12 children, the 'non-specific' box was checked for at least one biopsy site.

Evidently the checking of these boxes was then reported as 'chronic non-specific colitis' by Wakefield in making final revisions to the paper. The checkbox on the form filled out by Dr. Dhillon, however, may have simply meant that the findings on the slide were of uncertain significance.

When reviewed by two independent specialists in 2011, Geboes reported that “I see no convincing evidence of “enterocolitis,” “colitis,” or a “unique disease process”. Bjarnason reported that he and his colleagues “came to an overwhelming and uniform opinion that these reports do not show colitis”.

The direction of each of the 11 errors is consistent in tending to overstate the association and unlikely to be due to chance. The errors also included technical medical terminology implying a particular condition is present when it was not in most cases, though Wakefield was a gastroenterologist who knew the meaning of these terms.

It thus appears that Wakefield falsified the results presented in Table 1 of the paper by stating these were examples of non-specific colitis when in fact the totality of the data available at that time indicated something non-specific or of uncertain significance was present.

Fraud 2. Timing of MMR Vaccine Administration and First Behavioral Symptoms
The paper's Table 2 lists the "Interval from exposure to first behavioral symptoms". In one case this is listed as "immediately", 2 cases within 24 hours, 1 case within 48 hours, 2 cases within 2 weeks, 1 case within 1 month and 1 case within 2 months. These reported temporal associations were used in the paper to bolster the case that there was an association between vaccine administration and subsequent development of behavioral problems, such as autism.

Brian Deer reviewed the hospital admission notes and the Medical Research Council (MRC) hearing transcripts and reported that of the 8 of 12 cases which were reported as having first behavioral symptoms within 1 week, only 2 could be confirmed in the records. In some cases, such as Child 11, where Table 2 of the paper stated behavioral symptoms developed 1 week after vaccine administration, the hospital discharge note stated that behavioral symptoms began 1 month before administration of the MMR vaccine.

The direction of all 8 of these errors is consistent in tending to indicate a temporal association. It is unlikely that this was simply accidental copying errors and indicates that the authors falsified the temporal associations between MMR vaccine administration and development of behavioral symptoms.

Fraud 3. Findings of Regressive Autism
Table 2 in the paper also lists for all 12 children their "Behavioral Diagnosis". This table lists 9 of the 12 children as having autism and 1 additional child as possibly having autism.

Per reports reviewed by Deer, including the MRC hearing transcripts , only one child clearly had a diagnosis of regressive autism. 6 of the 9 listed as having regressive autism did not have this diagnosis and 5 of the 9 so listed had uncertain behavioral diagnoses.

The lack of underlying documentation of the majority of the children listed in Table 2 as having regressive autism, when this is one of the main points of the paper, arguably rises to the level of fabrication of these results, insofar as documentation is just missing. Certainly it points to falsification of the data presented in Table 2.

There are two additional areas of fraudulent representations within the 1998 Wakefield et al. paper which are not in the scientific findings but having to do with other scientific publication issues.

Fraud 4. Ethics Consent Statement
The paper stated that "Ethical approval and consent investigations were approved by the Ethical Practices Committee of the Royal Free Hospital NHS Trust, and parents gave informed consent." A statement of this type is required for all medical and scientific publications in order to help prevent abuse of subjects in human subject research studies.

After questions were first raised by Deer and others regarding the nature of the investigations and whether they had been approved by the appropriate ethical practices committee, Murch, one of the co-authors, stated that "The protocol for the 1998 Lancet paper was submitted on September 16, 1996" and "This protocol formed the basis for all children investigated in the 1998 Lancet paper, and all were investigated". Hodgson stated that "the investigation of these children was properly submitted to and fully discussed by the Ethical Practices Committee at the Royal Free Hampstead in 1996."

This issue was the focus of much investigation in the MRC hearings, because many of the subjects in the paper were admitted to the hospital for studies prior to the date, 18 December 1996, on which that research protocol was approved. On the basis of this and other ethical and practice violations, the General Medical Council struck (or revoked) the medical licenses of both Drs. Andrew Wakefield and John Walker-Smith. While both initially appealed these findings to the High Court of Justice Administrative Court, Wakefield dropped out of the appeal. The primary argument in Walker-Smith's defense on appeal was that no such ethics committee approval was required because the investigations were for the clinical benefit of the children and were covered by a prior study approval for his work. This defense directly contradicts the statements of both Murch and Hodgson in 2004. Nonetheless, based on other evidence, Mr. Justice Mitting determined on appeal that it was not proven to the requisite criminal standard of proof that Walker-Smith had carried out the investigations without ethics board approval.

Regarding the ethics approval statement in the paper, however, Mr. Justice Mitting found "This statement was untrue and should not have been included in the paper".

In finalizing the paper, there was a discussion of the wording of the ethics consent statement amongst the authors. Following this Wakefield evidently inserted this standard language of an ethics consent approval statement. This was a falsification of the actual record in order to facilitate publication of the paper.

Fraud 5. Conflict of Interest Statement
In 1998, at the time of the paper's submission, Lancet, like most medical journals, required that the authors sign a statement disclosing any conflicts of interest, either real or any items which could be perceived as a conflict of interest. Wakefield declared no conflicts of interest with respect to the publication.

Unbeknownst to the editors or readers at the time, however, Andrew Wakefield had filed a patent for virological testing in 1995. He had been engaged as an expert by lawyer Richard Barr since February 1996 to work on a potential lawsuit against virus manufacturers. He was paid in total 435,643 pounds for this work

Both the editor of Lancet, Horton, in 2004 and Hodgson, as a Vice Dean of the Royal Free and University College School of Medicine, stated in writing that this conflict should have been disclosed.

Failing to disclose such an obvious potential monetary conflict of interest in the outcome was a form of falsification of the record in order to facilitate publication and improve the perceived impact of the findings.

There was a last form of fraud committed by Andrew Wakefield in connection with this paper, but it was not in the paper itself.

Fraud 6. Methods of Patient Referral
Immediately after the paper was published criticisms were raised regarding a possible strong bias in patient selection. Nearly all the patients were originally contacted through an anti-vaccine campaign and the solicitors attempting to sue the vaccine manufacturers

In the paper itself, this was described as "We investigated a consecutive series of children with chronic enterocolitis and regressive developmental disorder" and "12 children, consecutively referred to the department of paediatric gastroenterology..."

In a subsequent response to this critique, Wakefield stated that "These children have all been seen expressly on the basis that they were referred through the normal channels (eg, from general practitioner, child psychiatrist, or community paediatrician) on the merits of their symptoms."

When this was examined in detail during the MRC hearings, the committee found that Wakefield's statement in the response were dishonest and irresponsible. The case of referral of Child 12 was examined in detail as the mother testified and revealed that the mother was supplied with a "fact sheet" written by Wakefield prior to being seen. The levels of biasing the findings for that child as revealed in the MRC transcripts are discussed in detail on the lbrb blog.

This issue was also addressed with respect to Wakefield's co-author, Dr. Walker-Smith, during the appeal of the MRC findings. In that appeal, Mr. Justice Mitting found that the finding of the MRC panel was not correct with respect to Dr. Walker-Smith's co-authorship of the paper. It is important to note that this finding on appeal did not address the MRC finding with respect to the dishonesty of Wakefield's separate response to criticism of the paper.

The significance of the findings in the paper depended on the route of referral. The findings would be stronger if they were found in a consequetive series of children come to the clinic; they would be weaker if they were found in a set of children chosen to potentially have the significant findings. By claiming that the referrals were through normal channels, when in fact the cases were selected for the findings prior to referral and the parents were prompted with the desired findings, Wakefield falsified this aspect of the scientific record.

Other Types of Fraud
Commentators often simply state that Andrew Wakefield committed fraud in the study which was published in 1998. Other than the scientific fraud discussed above, there are other common meanings of the term. Fraud often refers to either criminal fraud or civil fraud, a tort. Wakefield was never tried for either type with respect to the 1998 paper and study.

Criminal Fraud
Criminal fraud has several elements that must be proved to support a conviction (which depend in detail on the jurisdiction in question). These are 1) Misrepresentation of a material fact; 2) By someone who knows that the material fact is false; 3) With intent to defraud; 4) To a person or entity who justifiably relies on the misrepresentation; and 5) Actual injury or damages result from that reliance on the false representation. In both the US and the UK, each of these elements would have to be proven beyond a reasonable doubt.

In the case of the 1998 paper, it is unclear who the parties would be that were injured or damaged by the scientific frauds in that paper. Assuming such parties existed, it seems it would be difficult to prove beyond a reasonable doubt the 3rd element, that Wakefield engaged in the fraud with the intent to defraud the person injured.

Civil Fraud
Civil fraud as a tort has as requisite elements generally the intentional misrepresentation or concealment of an important fact upon which the victim is meant to rely, and in fact does rely, to the harm of the victim.

People who invested money in Wakefield's business proposal or the attorneys who paid him a large amount of money as a consultant for their lawsuits might have some claim for a monetary injury. Since the standard of evidence in a civil case is simply the preponderance of the evidence, the review of the scientific frauds above suggests such a lawsuit may have succeeded; however, none was ever brought.

DO NOT ATTEMPT TO MERGE THIS CONTENT INTO THE ARTICLE
It has been rejected as OR based on SYNTH of primary sources, but it is kept here for study. -- BullRangifer (talk) 22:42, 14 January 2020 (UTC)