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Fourteenstudies.org: Study Analysis

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2
"MMR Vaccination and Pervasive Developmental Disorders: A Case-Control Study"
The Lancet, Liam Smeeth, MRCGP, Eric Fombonne, MD (September 11, 2004)

Headline:

Sloppy, very few cases used, and the same issue with the study above: it did not focus on children who had regressed after MMR. May also win the award for most conflicts.

Actual Question This Study Asked & Answered:

Q: Do children who got MMR vaccine before autism diagnosis have higher autism rates?

A: No

Did the study look at unvaccinated children?

No.

Conflict of Interest:

"E Fombonne has provided advice on the epidemiology and clinical aspects of autism to scientists advising parents, to vaccine manufacturers (for a fee), and to several government committees. A J Hall received a financial contribution from Merck towards research on hepatitis B vaccination in 1998. He is also a member of the Joint Committee on Vaccines and Immunisation (2002 - present)."

Ability to Generalize:

Group was too small: "even if they had studied the correct group - regressive autism - the study would need to have included at least 3,500-7,000 children with autism - 3 to 6 times the actual number examined - in order for the study to have any validity at all." (see below)

Post-Publication Criticism:

High due to poor methodology.

Scoring (Out of 40 possible points):

Asked the Right Question: 0

Ability to Generalize: 0

Conflict of Interest: 0

Post-Publication Criticism: 2

Total Score: 3

Guest Critic #1: Thoughtful House, Dr. Andrew Wakefield

Re: The study: "MMR Vaccination And Pervasive Developmental Disorders: A Case Control Study." By Liam Smeeth, Claire Cook, Eric Fombonne, Lisa Heavey, Laura C Rodriques, Peter G Smith, Andrew J Hall. Lancet 2004;364:963-969.

The above paper has many failings. Two in particular are of such significance as to invalidate the conclusion; that MMR vaccine is not associated with onset of autism in children.

On page 967, first column, penultimate paragraph the authors state: "We were not able to separately identify the subgroup of cases with regressive symptoms to investigate the hypothesis that only some children are vulnerable to MMR- induced disease and that this is always regressive (27).

In this single statement the authors make it perfectly clear that they have not conducted an investigation of what has been referred to by the Department of Health and press commentaries as "the Wakefield hypothesis".

This hypothesis has remained unchanged since 1999, when we first described it in detail in a paper that was later published in the Israeli Medical Association Journal (IMAJ;1999:Vol1,1-5). The original hypothesis is restated below in lay form.

There exists a subset of children who are vulnerable to developing a particular form of regressive autism following previously normal development in combination with a novel form of inflammatory bowel disease. Onset may occur over weeks or sometimes months, and is triggered by exposure to a measles containing vaccine, predominantly the measles mumps rubella vaccine (MMR), that is in use in much of the world today. This exposure leads to long term infection with measles virus within key sites, including the intestine where it causes inflammation.

Smeeth and colleagues were aware of the question that needed answering since they had consulted with epidemiologist, Dr Scott Montgomery and Dr Wakefield several years ago, when they were designing the current study. We made it absolutely clear then that they should specifically look at the children with regressive autism. They ignored this explicit advice.

Secondly, epidemiolgists in Sweden and Cambridge have confirmed that even if they had studied the correct group - regressive autism - the study would need to have included at least 3,500-7,000 children with autism - 3 to 6 times the actual number examined - in order for the study to have any validity at all.

On this basis the paper cannot be said to have concluded anything of relevance to the hypothesis summarised above and has been grossly over-interpreted.

Moreover, in their conduct of the study, the authors do not even meet their own criteria set out in their previous paper 'A Case-Controlled Study of Autism and Mumps-Measles-Rubella Vaccination Using the General Practice Research Database: Design and Methodology', published in BMC Public Health (2001)1:2.

In that paper they stated in their abstract that "Children with a possible diagnosis of autism will be identified from their electronic health records. All diagnoses will be validated by a detailed review of hospital letters and by using information derived from a parental questionnaire". The second and third steps were not performed. Only 25% of cases had their records examined and no questionnaire was used. There were other substantial changes in the methodology which were also not explained in the present paper. This paper, therefore, meets neither the criteria for testing the original question nor those laid-down by the authors themselves.

The Government has chosen to rely on a series of epidemiological studies that, when subject to re-analysis, have been comprehensively criticised.

For example, readers should consider the two papers recently published in the Journal of American Physician and Surgeons, one by Dr Goldman and one by Dr Stott. These papers, demonstrated the unreliability of the recent Danish study, which was also heralded by the authorities as demonstrating the safety of the MMR vaccine.

The graph below has been reproduced from the second of these papers. It demonstrates a striking change in the number of children developing autism following the introduction and progressive increase in uptake of MMR in Danish children.

Figure 1. Autism prevalence in Denmark by year of birth, 1982-1992. Lines of best fit are shown for birth years 1982-1986 and from 1986 to 1992. Children born in 1986 were first to receive MMR in Denmark. The annual growth before MMR was -0.5% [trend = -15%;95% CI, (-1.06) - (-0.76),ns], compared with +14.98% after MMR introduction (t = 6.94, p<0.001; trend 1.54, 95% CI, ).97 - 2.11). Source: Danish Psychiatric Central Register Data, with gratitude to SafeMinds.

**

The Visceral research program involves the meticulous clinical investigation of individual affected children, which is a far more accurate and precise way of investigating the possible relationship between MMR and regressive autism.

Guest Critic #2: Whale.to/vaccines

"MMR Vaccination And Pervasive Developmental Disorders: A Case Control Study." By Liam Smeeth, Claire Cook, Eric Fombonne, Lisa Heavey, Laura C Rodriques, Peter G Smith, Andrew J Hall. Lancet 2004; 364:963-969.

This was an important paper in that it claimed to have looked at a very large number of child health records, giving it considerable claimed authority. The study had been set up in the UK in the light of strong public concern (and probably a degree of internal UK Government unease) over the safety of MMR vaccination. Data were abstracted from the UK General Practitioer Research Database.

The study found that:

  • MMR vaccination was not associated with an increased risk of subsequent PDD diagnosis. The study found "no convincing evidence" that MMR vaccination increased the risk of autism or other pervasive developmental disorders
  • The "odds ratio" associated with MMR vaccination varied according to the age at which a person joined the GPRD. In particular, the odds ratio associated with MMR vaccination was higher among children who joined the GPRD at birth or before their first birthday. This was dismissed as possible selection bias or a "chance result"
  • Research into the cause(s) of autism was urgently needed The study included over 1,000 cases with a diagnosis of PDD. Despite its size, the study had a number of drawbacks, some of which the study authors admitted:
  • some recording of previous vaccination history, where children came onto a GPRD after date of vaccination, was acknowledged to be possibly incomplete
  • the study admitted that it was not able to separately identify the subgroup of cases with regressive symptoms, so as to be able to investigate the hypothesis that only some children were vulnerable to MMR-induced disease and that this was always regressive. This was a crucial failing, as this hypothesis lies at the very heart of the allegations of parents and the views of researchers such as Dr. Andrew Wakefield. On page 967, the authors stated that "we were not able to separately identify the sub-group of cases with regressive symptoms (so as) to investigate the hypothesis that only some children are vulnerable to MMR-induced disease and that this is always (in those cases) regressive". The authors thereby are admitting that they have not, in fact, conducted an investigation of "the Wakefield hypothesis"
  • The study claimed that its results were similar to a Danish cohort study (the Madsen et al study). However, the use of thimerosalcontaining vaccines in Denmark has not matched that in the UK, and so comparing the two countries’ experiences may be inappropriate

The study also had to declare one serious conflict of interest, specifically that "E. Fombonne has provided advice on the epidemiology and clinical aspects of autism to scientists advising parents, to vaccine manufacturers (for a fee), and to several Government committees."

In plainer language, Fombonne had been a paid adviser to the manufacturers of MMR in the then-impending 1,500-strong class action High Court case in the UK that alleged that MMR had precipitated children’s degeneration into autism. The wisdom of using a paid witness to the manufacturers, as defendants, in a central authorship role in a supposedly independent research paper, might be questioned by many.

This study was heavily criticised:

  • the study is only epidemiological, not clinical. No children were examined
  • the UK GP Research Database, the basis for this study, was not designed to be used for a study such as this
  • there may have been some misclassification of cases (the authors admitted this flaw). In fact, it is understood that no fewer than 73 "controls" were discovered during the course of the study to be "cases", illustrating the difficulty of relying on the GPRD database
  • insufficient controls were used. Although the study, which used 1,294 cases and 4,469 controls, had initially indicated that there would be ten controls per autism case, 594 cases had fewer than three controls, 72 cases had only one control and 25 had none at all. It was not explained why the study’s original protocols had been apparently disregarded
  • only 62% of the children had received MMR before 18 months. Yet the focus of concern needed to be on infants younger than this, 15 months or less. This makes the study less relevant to the core area of concern
  • methodological flaws in the study were pointed out to the study team at early stages of the study, but do not seem to have been taken into account
  • the study deliberately excluded children who did not have a record of seeing their GP in the 12 months prior to the "index date", which was the date at which the children received a diagnosis of PDD. This could have increased the risk of excluding children who had undergone definite regression after MMR

Comment: this study cannot be taken as offering reliable evidence to deny an MMR/autism link, despite the claims made at the time. It is worth reminding readers as to the original "Wakefield hypothesis", as published in the Israeli Medical Association Journal, 1999, Volume I, pp1-5: "There exists a subset of children who are vulnerable to developing a particular form of regressive autism following previously normal development, in combination with a novel form of inflammatory bowel disease. Onset may occur over weeks or sometimes months, and is triggered by exposure to a measles-containing vaccine, predominantly the measles mumps rubella vaccine (MMR) that is in use in much of the world today. This exposure leads to long term infection with measles virus within key sites, including the intestine where it causes inflammation."