Stories and Grievances: Special Education
Red Flags in Autism Research
From the Editor: Please go to the link for additional references and information (Betsy Combier)
MMR – Autism Epidemiological Studies:
Just a distraction.
By Red Flags Columnist, F. Edward Yazbak, MD, FAAP
Falmouth, Massachusetts, USA
A new MMR-Autism epidemiological study from Japan has just been published.
No effect of MMR withdrawal on the incidence of autism:
a total population study
Honda H, Shimizu Y and Rutter M
Epidemiology cannot disprove causation
Epidemiological studies have come and gone
The recently-published Japanese research is irrelevant
The Red Flags Raspberry Award is justified
In February 1998, Andrew Wakefield and his team published a study in the Lancet in which they reported the investigation of a consecutive series of 12 children (11 boys) aged 3 to 10, with chronic enterocolitis and developmental regression. (1)
All children underwent ileocolonoscopy (with biopsy), electroencephalography (EEG), magnetic-resonance imaging (MRI) and cerebrospinal fluid, blood and urine examinations. Some had barium follow-through intestinal X-Rays.
The parents of eight of the 12 children reported that their children's behavioral changes and autistic regression happened after they had received a measles, mumps, and rubella (MMR) vaccination.
Dr. Wakefield carefully stated: "We did not prove an association between measles, mumps, and rubella vaccine and the syndrome described...We have identified a chronic enterocolitis in children that may be related to neuropsychiatric dysfunction. In most cases, onset of symptoms was after measles, mumps, and rubella immunization. Further investigations are needed to examine this syndrome and its possible relation to this vaccine.
Up to Jan 28, a further 40 patients have been assessed; 39 with the syndrome.
Since then, the Regressive Autism-MMR connection has been further investigated by other CLINICIANS who have identified similar intestinal findings as those described by Wakefield, in hundreds of affected children. Evidence of measles virus genomic RNA was detected in many intestinal biopsies and in cerebrospinal fluid samples. (2) Specific serological testing has also confirmed the co-existence of measles and or MMR antibodies with Myelin Basic Protein (MBP) auto-antibody in the majority of the examined affected children but not in the controls. (3)
Challenge-Dechallange-Rechallange, the fact that some children regress after their initial MMR vaccination, improve and regress again after the MMR booster, has also been documented in many children, further suggesting a vaccine-autism connection.
The present epidemic increase in autistic regression cannot obviously be due to genetic causes. It has been estimated that MMR vaccination could potentially be a precipitating factor in 5 to 10% of cases. The CDC and the British medical authorities deny any such connection and claim that if indeed it was proved, its impact would be extremely negligible - when compared to the benefits of vaccination.
Parents, including doctors, nurses and scientists, who have children and grandchildren with regressive autism, disagree.
Persecuting decent and brilliant researchers is not new. The Austrian physician who suggested that doctors should wash their hands before delivering babies was ostracized as well as the Australian doctor who dared say that stomach ulcers were caused by bacteria.
The anti-Wakefield campaign started immediately after the Study of 12.
It is safe to say that no decent researcher in recent history has been as viciously attacked, personally and professionally as Dr. Wakefield. He has remained focused and dignified.
His courage and resilience are an inspiration.
"All truth goes through three stages.
First it is ridiculed.
Then it is violently opposed.
Finally, it is accepted as self-evident."
Substantial funds (over £3 million) were spent in the United Kingdom on a pro-MMR campaign. Much effort was also invested in order to negate the Study of 12.
The few weak clinical studies that were reported raised negligible interest.
The many epidemiological studies that were published since 1998 had much more impact. Their release was invariably surrounded by intense publicity and celebrated by multiple accolades from other local or distant "experts". The studies were always referred to in the superlative. They were "final", "conclusive", "and convincing" or "the last word", they were "the large 14-year study from Finland" and the "BIG study from Denmark" and they were to be believed just because Wakefield's sample was SMALL.
Strangely enough, the Study of 12 stood the test of time and the big ones quietly faded away. "Bigger and Better" studies were constantly needed and some expert could always be found to produce them. A British MMR-Autism epidemiological study published in early September 2004(4) received little attention and only for a short while.
The new study from Japan is enjoying a nice honeymoon –so far.
The CDC-funded Madsen MMR study (5) "The BIG study from Denmark" was published in November 2002. It attracted a lot of attention and "had a great run". It is likely that it was a major consideration in the 2004 IOM Special Committee decision that an MMR-Autism connection did not exist. In the UK, the Madsen study, among other things, provided justification for the interruption of Legal Aid to the parents involved in the MMR litigation.
Promptly after the Madsen study was published, Professor S. Suissa, a McGill University epidemiologist reported her serious concerns about the epidemiological analysis of the vaccinated and unvaccinated cohorts to the editor of the New England Journal of Medicine (NEJM). Her letter was never published.
In September 2004, Goldman and Yazbak published "An Investigation of the Association between MMR Vaccination and Autism in Denmark" in the fall issue of the Journal of American Physicians and Surgeons (JPS). (6) The study was the first to show that autism had increased in Denmark after the introduction of the MMR vaccination in 1987; more specifically, that a statistically significant increase in autism among 5 to 9 year olds had occurred from 1990 to 1992, prior to any change in classification or enrollment.
In their invited Commentary in the same issue of JPS, Stott, Blaxill and Wakefield agreed that an increase in autism indeed occurred in Denmark after 1987 and published Dr. Suissa's review of the epidemiological analysis of the Danish data.(7)
To date, there have been no comments by Dr. Madsen.
In the second paragraph of his paper, Madsen stated: "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).
The studies that Madsen referred to as having insufficient statistical power to detect an association were:
(10) The Taylor study in The Lancet 1999
(11) The Kaye study in the British Medical Journal (BMJ) 2001
(12) The Dales study in the Journal of the American Medical Society (JAMA) 2001
(13) The Fombonne study in Pediatrics 2001
(14) The Patja study in the Journal of Pediatric infectious diseases 2000
(15) The Peltola study in the Lancet in 1999
(16) The Taylor study in the BMJ 2002
Interestingly, when they were released, every one of these studies was hailed as the best yet and a definite proof that the Study of 12 was wrong. To date, Madsen's criticism that all these studies had weak statistical power has remained unchallenged by the CDC, the British medical authorities and the authors of the listed studies themselves.
The studies mentioned by Madsen had the following potential conflicts:
The two Taylor studies were ordered and financed by the UK Medicines Control Agency and the Public Health Laboratory Service. Two co-authors were employed by the Immunisation Division, Public Health Laboratory Service Communicable Disease Surveillance Centre.
The Peltola and Patja studies from Finland were supported by a grant from Merck.
Dr. Kaye disclosed: "Funding: No specific funding. Competing interests: The Boston Collaborative Drug Surveillance Program is supported in part by grants from Astra Zeneca, Berlex Laboratories, BoehringerIngelheim 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."
Dr. Dales was employed by the California Department of Health.
Dr. Fombonne was a consultant for Aventis Pasteur in its legal fight against parents of children with autism.
Concerning the recent study from Japan: Honda, Shimizu and Rutter concede (page 7 paragraph 2) that: "Epidemiological data, however, cannot test the very different hypothesis that MMR might involve an increased risk of ASD in a very small number of children who, for some reason, are unusually susceptible to damage from the vaccine." (8)
If the better and more accurate epidemiological studies cannot disprove a causal link between MMR vaccination and a small number of cases, then one must wonder why the medical authorities continue to request and support epidemiological studies to disprove an adverse vaccine reaction- a clinical event? And how can epidemiological studies be relevant-medically and/or legally- in the assessment of adverse reactions of individual children to a certain vaccine?
When it comes to MMR and autism:
Epidemiology is irrelevant to the issue of causation.
The Epidemiological Study du Jour
No effect of MMR withdrawal on the incidence of autism:
a total population study
Honda H, Shimizu Y and Rutter M
Journal of Child Psychology and Psychiatry 2005
In their Commentary on Red Flags (March 7, 2005) entitled "Japanese study is the strongest evidence yet for a link between MMR and autism" Drs. Wakefield and Stott, reviewing the epidemiological research of the Japanese study, showed that the conclusions of the authors were not justified and that in fact, an opposite conclusion was more viable.
1. Funding: None mentioned. If the study was not funded, then a statement to that effect should have been made.
2. Conflict of interest: None mentioned. Conflicts of interest of the authors and of their place of work should be listed. NONE would be appropriate if none existed.
3. The role of Professor Rutter: It is not clear why a British psychiatrist co-authored this Japanese study.
A Medline search reveals that Drs Honda and Shimizu co-authored three other studies without the help of Professor Rutter including one just published in January 2005. The previous two were published in September 2002 and August 1996.
There are almost 800 articles authored by many other "H. Honda" researchers on a multitude of subjects. I reviewed the first 200 of these articles and found only THREE where any co-author had an occidental surname.
In a newspaper account dated December 23, 2001, Professor Sir Michael Rutter was one of seven "external expert witnesses" who helped guide the course of the MMR inquiry in the United Kingdom. He reportedly was paid to provide reports to help Glaxo Smith Kline, a company that manufactured the MMR vaccine used in England. In the newspaper article, Professor Rutter is quoted as saying: "When there are major issues of this kind to analyze it involves people in the field and inevitably there will be conflicts of interest. It is only unacceptable if these are kept secret." ( Reference available on request )
In 2004, Legal Aid to families of affected children was discontinued and MMR litigation was effectively stopped in the United Kingdom.
Because of all the above information, and the fact that the whole publication was devoted solely to Japanese research, data and information, the last paragraph is a serious concern: "Finally in terms of immunization policy, in countries such as the USA and the UK where the MMR vaccine is still being administered, our findings indicate that simply terminating MMR vaccination programs will not lead to a reduction in the incidence of ASD."
The following statement from the study abstract, not only raises questions concerning motives but is scientifically bewildering: "The significance of this finding is that MMR vaccination is most unlikely to be a main cause of ASD, that it cannot explain the rise over time in the incidence of ASD and that withdrawal of MMR in countries where it is still being used cannot be expected to lead to a reduction in the incidence of ASD."
The uncontestable facts about the three points the authors make are: 1. No one has ever said that MMR is a main cause of ASD. 2. The findings reported by Honda and Associates cannot prove or disprove whether MMR vaccination was/is a factor in the increase in autism and ASD in other countries. 3. Neither can the study findings predict what will happen when MMR is indeed withdrawn in other countries.
For many reasons, the "MMR Japan Experience" cannot be compared with that of the United Kingdom and the United States.
In Japan, the use of the MMR vaccine containing the Urabe strain was banned in 1992 and the single Measles and Rubella vaccines were recommended.
In the UK, when the Urabe-strain MMR was banned in 1993, it was replaced by other formulations of MMR from different manufacturers.
In the United States, the Urabe-strain MMR was never used.
The role and contribution of Professor Rutter to the study are not known.
4. The study findings: Dr. Honda graphically shows the rise in autism and autistic spectral disorders (ASD) in Japan (Figure 1 page 5). Two peaks are demonstrated: The first peak in 1990 and the second larger peak in 1994. In Japan, children aged 12 to 24 months were targeted to receive the MMR. The proportion of children who received the triple vaccine fell from 69.8% in 1988 to 33.6% in 1990. By 1992, only 1.8% of eligible children were vaccinated and none were vaccinated in 1993. Clearly vaccination levels with MMR were quite low even in 1990 and kept dropping after that. If the Honda hypothesis was correct, the incidence of autism should have continued to increase after the first peak and no valley should have occurred between the two peaks. In addition, it should have continued to rise after the second peak and it did not.
5. The IC -10 Classification: A new autism classification (IC-10) was adopted in 1993 and is mentioned by the authors (page 5, paragraph 1). The potential impact of that change was NEVER considered and not even mentioned by the authors in their discussion.
Most noteworthy is the fact that one year after the introduction of IC-10 in Japan the prevalence rate of autism reached 161.3 / 10,000 or 1 out of 62 children. (Table 1) This is the highest prevalence rate ever recorded in a large epidemiological study and as such, it raises serious questions about the accuracy of the screening process used with the new classification.
In addition, the authors did not disclose what classification code was used prior to 1993 and did not reveal what effect the redistricting of 1995 had.
"Autism experts" have traditionally always blamed the increased prevalence of autism on changes in diagnostic criteria. Until months ago and more than a decade after the introduction of the DSM IV classification, "experts" were still saying that there was no real increase in autistic syndromes and that the apparent increase was due to the change in classification.
The same DSM IV argument was also used to try to invalidate the proposition that the introduction of universal Hepatitis B vaccination in the United States and the increasing number of thimerosal-containing vaccines were to blame for some of the spectacular increase in autism in the nineties.
The authors of the study may want to explain why they did not feel that a sudden and spectacular rise in autism shortly after a major classification change was relevant.
6. Vaccination practices in Japan: "A Review of Vaccination Policy in Japan", by Drs. Nakatami, Sano and Iuchi, of the Ministry of Health, Labor and Welfare was published in 2002 in the Japanese Journal of Infectious Diseases (9). The report contains the interesting graph reproduced below showing vaccination coverage from 1962 to 2000.
A spectacular rise in the use of three vaccines, starting in 1993, is very obvious.
The Japanese encephalitis vaccine (JE-Vax) coverage seems to have increased from 43 to 90%, the measles vaccine (MV) from 65 to 95% and the rubella vaccine (RV) from 65% to almost 100%.
The JE-Vax: The increase of over 100% in the use of JE-Vax is of note because this particular vaccine contains Thimerosal as a preservative. (10) Each dose of pediatric JE-Vax contains 17.5µg of mercury.
The JE-Vax pediatric vaccination schedule could be as short as three doses in ONE month (Day 0-7-30) starting anytime after the first birthday. A more accelerated schedule (Day 0-7-14) is permitted in certain circumstances. (11)
The measles vaccine is recommended immediately after the first birthday
The rubella vaccine may be administered anytime between 12 and 36 months
Although the recommendation is that the measles and rubella vaccines be administered a month apart, it is well known that they were and still are administered separately but on the same day. (12)
( As strange as that sounds, something very similar takes place in the United States. The MMR and the chicken pox vaccine are often administered separately on the same day. If they are not, the CDC and the manufacturer recommend that they be administered at least a month apart. In addition, while we are still debating whether it was wise to put three live attenuated viruses together (MMR) the "experts" are working on adding the chickenpox vaccine in the same vial (MMR-V). Obviously very often, the HIB and Hepatitis B vaccine boosters are also often administered that same day.)
It is clear from the above that Japan has had UNIQUE vaccination practices. Dr. Honda should have reviewed and discussed them and specifically commented on the striking increasesin the JE-vax, measles and rubella vaccination ratesin 1993 that coincidedwith the second and highest peak in autism and ASD.
The failure to do so is a major weakness of the study.
7. The 7- year issue: In Japan, autism is usually diagnosed by the age of 5. Drs. Honda, Shimizu and Rutter sought the cumulative incidence up to the age of seven. It is not completely clear whether some of the children who developed autism or ASD and were 5 to 7 year-old when they were diagnosed, had not actually received an MMR vaccine at age 12 months.
8. The comparative increase: According to Honda, the seven year cumulative incidence of ASD went up from 47.6/10,000 in 1988 to 117.2/10,000 in 1996, a 2 ½ fold increase. MMR vaccination went down to zero by 1993.
Kaye reported that after the introduction of MMR into the UK, the incidence of newly diagnosed autism increased sevenfold between 1988 and 1999. "In an annual birth cohort analysis of 114 boys born in 1988-93, the risk of autism in 2 to 5 year old boys increased nearly fourfold overtime..." (13)
It is therefore clearly evident that during the same years, while MMR vaccination rates were high and rising in the UK and low to nil in Japan, autism increased more substantially in the United Kingdom than in Japan. This alone suggests that the MMR vaccine may be a precipitating factor in regressive autism and supports the suspicions raised by the Study of 12. It also clearly indicates that making the single measles, mumps and rubella vaccines available again in the UK –alongside the MMR- and spacing them at safe intervals, as suggested in 1999 by Andrew Wakefield, is a wise decision.
In the United States, the incidence of autism was estimated at 1 in 166 in January 2004. That increase speaks for itself.
Epidemiological studies cannot prove that MMR does not cause autism because even the most accurate studies cannot disprove a causal connection in a relatively small number of cases. Drs. Honda, Shimizu and Rutter agree.
Over a dozen epidemiological studies from every corner of the world have failed. Some included thousands of individuals and some whole populations. Some have extended over many years and undoubtedly some are on-going. They too will be useless.
If just ONE study had been good enough to prove that Wakefield was wrong, the need for others would not exist.
The Study of 12 published by Andrew Wakefield in 1999 still stands.
Hundreds of children with autism have been shown to have Wakefield entero-colitis and many have evidence of measles presence.
Epidemiological MMR-autism research is a waste of time and money.
Independent clinical research is needed.
The recent study by Honda, Shimuzi and Rutter has not proved that an MMR-autism connection does not exist.
Only clinical research is of any value in identifying the causes of regressive autism.
It is time to wake up to that reality.