Fwd: Part 4 - REGRESSIVE AUTISM AND MMR VACCINATION

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http://www.redflagsweekly.com/yazbak/2003_nov01_4.html

 

 

REGRESSIVE AUTISM AND MMR VACCINATION

 

By RFD Columnist, F. Edward Yazbak, MD, FAAP.

 

TL Autism Research

Falmouth, Massachusetts

 

E-mail: tlautstudy

 

Part Three here

 

 

 

 

The Kaye Study

 

Mumps, measles, and rubella vaccine and the incidence of autism recorded by

general practitioners: A Time Trend Analysis, by Dr. James Kaye, was published

in 2001, in the BMJ. (22)

 

The study did not receive funding. Dr. Kaye is a member of the Boston

Collaborative Drug Surveillance Program, which is supported in part by grants

from AstraZeneca, Berlex Laboratories, Boehringer Ingelheim Pharmaceuticals,

Boots Healthcare International, Bristol-Myers Squibb Pharmaceutical Research

Institute, GlaxoWellcome, Hoffmann-La Roche, Janssen Pharmaceutica Products, R

W Johnson Pharmaceutical Research Institute; McNeil Consumer Products, and

Novartis Farmaceutica.

 

It is not clear from the article why a group of researchers from Boston chose to

do a study based on data from the UK general practice research database.

 

Kaye claimed there was no MMR - autism connection because the incidence of

autism in children in the UK continued to increase even after MMR take-up was

constant at around 97%. The study did attest that autism increased sevenfold

from 0.3 per 10,000 (1988) to 2.1 per 10,000 (1999) and almost fourfold, from 8

per 10,000 for boys born in 1988, to 29 per 10,000 for boys born in 1993. Again,

the MMR campaign in the UK started in 1988.

 

The authors acknowledged that the study design was not ideal because it would

have been better to examine the autism incidence in vaccinated and unvaccinated

groups of children. But this, they added, was impossible because of the small

number of unvaccinated children. They also acknowledged that time trend analysis

is a " relatively crude method " and speculated that the detected increase in

autism " could be due to increased awareness of the condition among parents and

GPs, changing diagnostic criteria or environmental factors.”

 

The Kaye study precipitated multiple letters to the British Medical Journal. In

my published letter, (23) I commented that:

 

§ A cohort of children born in the years 1988-1993 was chosen. MMR was

introduced in the UK in 1988 and therefore it is unlikely that an uptake of

90-95% was achieved from year one.

 

§ By their selection, Kaye et al effectively excluded children born before

1988, who were vaccinated in/after 1988.

 

§ The restriction of the cases in the main analysis to 114 boys is of

concern. A breakdown of the 290 children in the 1990-1999 birth cohorts by sex

and year of birth would have been informative. A larger proportion of girls

among the 176 cases excluded might have been relevant to the completeness of the

autism figures.

 

§ The fact that neither DSM-IV nor IC-10 was systematically used in the

U.K. creates further doubts as to the significance of the reported findings.

 

I concluded that 1. Kaye cannot exonerate MMR without offering a reasonable

explanation for the increase in autism after 1988 and 2. That until safety

studies on

 

MMR are comprehensive and independent of drug companies and until researchers

review with parents the documented adverse reactions of bowel disease and

autism, the triple jab remains suspect.

 

Clearly, there were serious questions about the autism portion of the MMR-Autism

equation in that study.

 

Another critique by Branell (Sweden) points to serious flaws in the other part

of the equation in the Kaye study, the MMR vaccination rates. (24) It was also

published in the BMJ and was titled “How was the “MMR Prevalence” estimated?

In a short but careful analysis, Branell criticized Kaye’s assertions relative

to MMR vaccination rates in different years and concludes by stating: “Instead

the data shows that as more kids get MMR-vaccine rises the autism rate.”

The Dales California Study

“Time Trends in Autism and in MMR Immunization Coverage in California”, by

Loring Dales, MD et al. in 2001 in JAMA (The Journal of the American Medical

Association.) (25)

 

Dr. Dales and Associates are employed by the California Department of Health

 

Dr. Dales stated: “ Essentially no correlation was observed between the secular

trend of early childhood MMR immunization rates in California and the secular

trend in numbers of children with autism enrolled in California's regional

service center system. For the 1980-1994 birth cohorts, a marked, sustained

increase in autism case numbers was noted, from 44 cases per 100,000 live births

in the 1980 cohort to 208 cases per 100, 000 live births in the 1994 cohort (a

373% relative increase), but changes in early childhood MMR immunization

coverage over the same time period were much smaller and of shorter duration.

Immunization coverage by the age of 24 months increased from 72% to 82%, a

relative increase of only 14%, over the same time period”.

 

Dr. Dales himself acknowledged the following weaknesses in the study:

 

§ “Diagnosis is not always straightforward.

 

§ The California Department of Developmental Services’ report stresses that

its patient caseload data cannot be used as a true measure of changes over time

in autism incidence because other factors can affect trends in system case

numbers

 

§ Observation of parallel trends over time or across geographic locations

for 2 events, generally do not constitute strong evidence for a causal

association between the 2 events

 

§ As the system expanded and matured over time, the proportions of

California children enrolling and the distribution of ages at enrolment likely)

changed over time as a result.

 

§ Also, the proportions of children enrolling in the system who were born

outside California may have changed over this time period.

 

§ The data presented herein have some limitations. It would have been

useful to examine individual immunization and autism records on the same

children; however, these could not be linked.

 

§ Further, the childhood immunization coverage data used in this study do

not provide precise quantification of the percentage of children who received

the combined MMR vaccine product vs. separate injections.

 

Clearly, Dr. Dales states that one of the two elements examined in the

statistical comparison is flawed.

 

After listing all these difficulties, the authors of the study state that they

were " unable to demonstrate a correlation between secular trends in early

childhood MMR immunization coverage and autism caseload. "

 

Drs. Edwardes and Baltzan, (26) both from McGill University promptly responded

in JAMA to the Dales study: “Dr. Dales and colleagues reported that there was

“essentially no correlation” between rates of autism and measles-mumps-rubella

(MMR) vaccine, but this conclusion is based on their Figure, which seems to be

an optical illusion. We took the y-axis values directly from the Figure and

computed the correlation coefficients, which are 0.73 and 0.90 between the total

number of autism cases and the percentage of children receiving immunization by

24 months and 17 months respectively. The illusion of no relationship is due to

vertically compressed graph...Furthermore their data show that the age of

immunization was becoming younger between 1981 and 1993. In Figure 1, we plot

the ratio of children immunized before 17 months with those immunized between 17

and 24 months. The ratio increased 200% from 1981 to 1993. Thus, if the total

number of autism cases divided by the total number of

births are near the true incidence rates for California, the data also suggest

that the rate of early MMR immunization is correlated with the incidence of

autism.

 

So in summary, Dales could not and should not have concluded that no correlation

existed between MMR vaccination and the incidence of autism in California.

Actually, his study seems to suggest that such a correlation exists.

The MMR Study from Denmark

A Population-Based Study of Measles, Mumps and Rubella vaccination and Autism,

by Dr. Kreesten Meldgaard Madsen and Associates is presently the most quoted

anti-Wakefield study. It was funded by the CDC and published in the New England

Journal of Medicine (NEJM) on November 7, 2002.

 

Immediately, in the second paragraph, Madsen states: “Studies designed to

evaluate the suggested link between MMR vaccination and autism do not support an

association, but the evidence is weak and based on case-series, cross-sectional,

and ecologic studies, No studies have had sufficient statistical power to detect

an association, and none has a population-based cohort design” (References

10-16).

 

Reference 10 in the Madsen bibliography is the Taylor study; Reference 11 is the

Kaye study and Reference 12 is the Dales study discussed above. Madsen is

therefore stating that the studies by Drs. Taylor, Dales and Kaye could not have

detected an association between MMR and autism.

 

In the last paragraph, Madsen reported: “The prevalence rates among 8-year-old

children in our cohort were 7.7 per 10,000 for autistic disorder and 22.2 per

10,000 for other autistic-spectrum disorders. These rates are similar to the

prevalence rates of 5.4 per 10,000 for autistic disorder and 16.3 per 10,000 for

other autistic-spectrum disorders in a cohort of 325, 347 French children

(ICD-10 criteria), reported by Fombonne et al. …”

 

Choosing this particular Fombonne study was interesting. Fombonne’s earlier

claim to fame was his insistence that autism had not dramatically increased and

that any perceived increase was due to changing diagnostic criteria and improved

methods of case finding. Professor Fombonne who started his career in France

moved to England for a while and is now at McGill University, in Montreal.

 

The Fombonne publication quoted by Madsen was based on an epidemiological survey

from INSERM (Institut National de la Sante et de la Recherche Medicale, Paris).

Though reported in 1997 the study investigated children born between 1976 and

1985..

 

Madsen could have quoted more recent and pertinent data by Fombonne, such as

that presented in November 2001 at the International Meeting for Autism Research

(IMFAR). At that conference, Dr. Fombonne stated that though in 50 previously

published epidemiological studies, he and others had established the prevalence

rate of autism at between 2 and 10 per 10,000, his most recent research points

to a prevalence at present, of 68 per 10,000 or 1 in 147. This is an increase

of 600 to 3400% in 25 years.

 

Obviously comparing the Danish results with those of an old French study was a

good way to suggest that there had been little or no increase in autism in

Denmark after the introduction of the MMR vaccine.

 

Madsen’s study had several problems. As a clinician, I did not believe that the

findings were very relevant to the situation in the United States. Professor

Walter O. Spitzer M.D., M.P.H., F.R.C.P.C, Emeritus Professor of Epidemiology at

McGill University and Emeritus Editor, Journal Of Clinical Epidemiology also had

many questions about the statistical and epidemiological aspects of the

research.

 

In sworn testimony at the December 10, 2002 Hearing of the Government Reform

Committee, Professor Spitzer stated: “

 

Only 40 cases (13%) were reviewed. That is very inadequate especially if done

for validity purposes only. To fail to examine all records among the 787

children in the numerators of the cohort (738 in Table 2), with a clinical

multidisciplinary approach leaves the project wide open to errors and

misclassification.

 

Review of all cases could have easily been done as it was done in an English

study of autism where 7 medical professionals reviewed records of 493 affected

children in one month.

 

Assume hypothetically that there is a vulnerability to MMR-induced disease in a

subgroup of 10% of the autistic cases. Assume further that in the main autism

group 80% have been vaccinated and 95% vaccinated in the subgroup. In a nested

case control design within the Danish cohorts, the odds ratio (OR) for MMR in

the subgroup would be 4.17; combining all autistics the OR would be 0.97 masking

the strong association in a small subgroup”.

 

According to Dr. Spitzer, the percentage of cases of regressive autism, in an

unselected series is likely to be between 10% and 15%. Dr. Spitzer calculated:

“Conservatively, 10% would represent approximately 50,000 children in the U.S.

alone with a yearly burden of $1.25 billion.”

 

He goes on to add that Madsen described a very important subgroup in the

introduction but did not examine it specifically and did not or could not test

the most relevant hypothesis proposed by Wakefield et al.

 

Dr. Spitzer then went on to raise several questions in reference to analytic

issues:

 

a. Why did Madsen et al do an adjustment to the sub-cohort that removed 6

autistic (and a total of 13 cases of progressive developmental disorder) cases

from the vaccinated sub-cohort and placed them in the unvaccinated one? This

single adjustment reduces relative risk of autism due to MMR vaccination by 17%,

from 1.26 to 1.09.

 

b. Why did Madsen et al not simply exclude all cases involving early

(non-regressive) diagnoses of autism? If they had removed all cases diagnosed

before two years of age from both sub-cohorts, the relative risk would have

risen from 1.26 to 1.28.

 

He then discussed what he called a “classical problem of computerized

databases”: Data gathered for other purposes, are rarely adequate to examine a

problem, which was not investigated originally, because of variables that cannot

be examined.

 

Professor Spitzer then discussed the ethical aspects of the study: “The concerns

are about the process of funding, the interaction of sponsors with protocol

formulation and approval, compliance with protocol, the role of investigators

vis-a-vis sponsors in the actual conduct of research and the input of CDC

epidemiologists in the preparation of the report with its conclusions:

 

a) Was there a protocol?

 

b) Who approved it?

 

c) Were there changes as the study progressed?

 

d) Who approved the changes?

 

e) Who monitored work-in-progress?

 

f) Who approved the final report?

 

g) Was there a Scientific Advisory Board?

 

h) What exactly was the role of the CDC and its professionals?”

 

Professor Spitzer also touched on the mercury in preceding vaccines:

 

“The immature infant immune system is biased towards an allergic response. As

the immune system matures it becomes better able to deal with and clear viral

infections. Impairing this immune system maturation (e.g. with heavy metals) may

increase the susceptibility to an adverse event from a live viral vaccine.”

 

He then went on to describe the possible synergistic adverse effects of MMR and

Thimerosal, upon the immune system of susceptible children triggering allergy,

autoimmunity and eventually autism. “There is no mention of the role of heavy

metals in a likely multi-factorial causal situation. This is not the fault of

the investigators; it just can’t be done with the data sources available”.

 

For “Total Transparency” Dr. Spitzer advocated:

 

1. That the main protocol should be published in advance of the

fieldwork, notably including the analysis plan with attendant definitions

declared in advance.

 

2. A Scientific Advisory Board be created to monitor all phases

especially protocol changes in progress and proposed publications.

 

3. A Community Advisory Board to look at conflicts of interest in

finances.

 

 

 

 

 

 

 

 

 

 

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