Rapid Responses to:

PAPERS: James A Kaye, Maria del Mar Melero-Montes, and Hershel Jick Mumps, measles, and rubella vaccine and the incidence of autism recorded by general practitioners: a time trend analysis BMJ 2001; 322: 460-463 [Abstract] [Full text]

Rapid Responses: Submit a response to this article

Rapid Responses published:

MMR could still be the cause of some autism.

Peter Allmark   (23 February 2001)

MMR vaccine

J K Anand   (24 February 2001)

Autism - Could it be drug induced?

Mary Reid   (24 February 2001)

What's next?

Michel Odent   (26 February 2001)

The Effect of Improved Case Ascertainment on Autism / MMR studies

A J Ferraro   (27 February 2001)

Another Seriously Flawed Study?

John P Heprtonstall   (28 February 2001)

Re: What's next?

Mary Reid   (2 March 2001)

Response to Rapid Responses

James A Kaye   (3 March 2001)

Re: Response to Rapid Responses

John P Heptonstall   (5 March 2001)

Public disquiet remains

Christine Miller   (7 March 2001)

Re: Re: Response to Rapid Responses

James A Kaye   (8 March 2001)

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

Nicola Ellis   (8 March 2001)

'Social' causes for changes in incidence of autism. Were other childhood disorders on the increase?

Ronan Ryan, Bernadette Purcell   (11 April 2001)

Re: 'Social' causes for changes in incidence of autism. Were other childhood disorders on the increa

Lisa Blakemore-Brown   (12 April 2001)

Autism: Changes in diagnosis or increase in prevalence- Evidence from the 1970 cohort

Helen Heussler   (15 May 2001)

MMR is the open door

Karen Montrose   (28 May 2001)

The numbers don't match

Adrian Thewlis   (24 August 2001)

Re: The numbers don't match

James A Kaye   (31 August 2001)

Correlation with other vaccinations

Russell Welch   (10 November 2001)

How was the "MMR Prevalence" estimated?

Ulf C Brånell   (10 February 2002)

Re: Re: Re: Response to Rapid Responses

Chris A Johnson   (24 May 2002)

MMR/AUTISM ONE YEAR ON

Michael D Innis   (7 June 2002)

Re: MMR/AUTISM ONE YEAR ON

David N. Andrews   (9 June 2002)

CLARIFICATION SOUGHT FROM AUTHORS TO ESTABLISH EVIDENTIAL VALIDITY OF THIS PAPER

Clifford G. Miller   (17 April 2004)

MMR could still be the cause of some autism. 23 February 2001
Peter Allmark, Nursing lecturer Sheffield University Send response to journal: Re: MMR could still be the cause of some autism.	Kaye et al's statistical analysis offers good evidence that MMR is unlikely to be the sole cause of the huge increase in autism that has occurred over the last twenty years or so. However, as far as I am aware, those who suggest that there may be a link between MMR and autism are not necessarily making such a suggestion. What they are saying is that there is strong anecdotal evidence that MMR may be the trigger to autism in some cases, and that there is a plausible explanatory mechanism whereby it could be such a trigger. I have spoken to the parents of three children in whom the MMR vaccination was followed by an immediate, quite severe, reaction and a sudden subsequent descent into autism. Large scale epidemiological proofs that MMR cannot be the sole cause of autism are, I presume, insufficient to gainsay them entirely.
MMR vaccine 24 February 2001
J K Anand, Retired public health physician Send response to journal: Re: MMR vaccine	Dear Editor Four questions- Firstly, could I please ask Kaye et al whether they have also carried out a similar time trend analysis in California and in Boston? Secondly, have they studied also the relationship, if any, between MMR vaccination and ileal lymphoid nodular hyperplasia? Thirdly, have our paediatric psychiatrists any information or views on the subject? Finally, I would ask paediatric gastroenterologists whether they have encountered ileal lymphoid hyperplasia following MMR. If so, what is the incidence, please? JK Anand
Autism - Could it be drug induced? 24 February 2001
Mary Reid, Private researcher Jamboree Hts Send response to journal: Re: Autism - Could it be drug induced?	The Kaye et el statistical analysis leaves us now with the task of determing what has changed environmentally or mode of treatment which might account for this rapid rise in the diagnosis of autism. Might I suggest it could be time to look at the rising use of H2 blockers and proton pump inhibitors for gastric reflux which many of these children have suffered prior to the diagnosis of autism. I note that usage of the first of these drugs commenced in the late 70's. The fact that some children are secretin responders might alert us to the fact that reducing these levels as a consequence of drug treatment is inadvisable. Mary Reid
What's next? 26 February 2001
Michel Odent, Director. Primal health Research Centre London NW3 2NP Send response to journal: Re: What's next?	The study by James A Kaye and colleagues (1) clearly indicates that the fast and gradual rise in risk of diagnosed autism for boys born from 1988 to 1993 cannot be explained by changes in the prevalence of MMR vaccination in the UK. The practical conclusion is that we must look at early environmental factors that have been actually altered during this 6 year period. This was the very time when the rates of births in physiological conditions have been gradually and rapidly shrinking (rising rates of epidural anaesthesia and caesarean sections). Today it would be relevant to save from oblivion studies suggesting that there are risk factors for autism in the perinatal period (2,3). I previously instanced such studies to introduce the concept of "cul-de-sac epidemiology" (4). Who will break through the dead end of the cul-de-sac? References: -1- Kaye JA, Melero-Montes M, Jick H. Mumps, measles, and rubella vaccine and the incidence of autism recorded by general practitioners: a time trend analysis. BMJ 2001; 322: 460-3. -2- Tinbergen N, Tinbergen A. Autistic children. Allen and Unwin. London 1983. -3- Hattori R, Desimaru M, Nagayama I, Inoue K. Autistic and developmental disorders after general anaesthetic delivery. Lancet 1991; 337: 1357-58. -4- Odent M. Between circular and cul-de-sac epidemiology. Lancet 2000; 355: 1371.
The Effect of Improved Case Ascertainment on Autism / MMR studies 27 February 2001
A J Ferraro, Medical SHO Queens Medical Centre Send response to journal: Re: The Effect of Improved Case Ascertainment on Autism / MMR studies	Kaye et al. argue that the increase in the detected incidence of autism in the UK, at a time of steady "ceiling" uptake of MMR vaccine, provides evidence against a causal link between them. Whilst their data certainly does not confirm any such link, it may simply be evidence of improved case ascertainment (i.e. diagnosis) of those with autism. The current climate of concern about MMR vaccination ironically may create a much better study environment in which to prove or disprove any link. In the coming years one can expect to see declining vaccine uptake - especially amongst those at possibly increased pre-existing risk of the disease (younger siblings of autistic children). At the same time case ascertainment rates of autism should continue to improve (or at least plateau). Only under that situation can a continual rise in the recorded incidence of autism truly be used as an argument against the link - whilst a drop in observed incidence rates would be stronger evidence in its favour
Another Seriously Flawed Study? 28 February 2001
John P Heprtonstall, Director of The Morley Acupuncture Clinic and Complementary Therapy Centre West Yorkshire Send response to journal: Re: Another Seriously Flawed Study?	Editor Kaye et al state that during 1988 to 1999 there was a serious increase in the diagnosis of autism but an almost level rate for MMR vaccine uptake, that rate being about 95% according to the General Practices database. I would dispute this, and add that their statistics actually provide grand evidence for a link between autism and MMR vaccines; this despite corresponding increases in the earlier diagnosis of autism, plus additional vaccines entering the '90s equation (eg Hib in 1992). If the autism rate quantified, by year, bears direct relevance to the cause of autism that year, there appear to be significant time/trend effects demonstrated by the author's tables. 1. 1988/99 saw the nationwide introduction of MMR1 vaccine, autism increased dramatically through 1990 and 1991. 2. Late 1992 saw the nationwide 'mass vaccination' campaign of MMR (which was cut short when a number of children developed menigitis from the Urabe strain of the mumps portion); the annual autism rate recorded by Kaye et al shows another dramatic jump in 1993, maintained to 1994. 3. Late 1994 saw another nationwide mass-vaccination campaign, this time with MR vaccine; autism figures are shown to rise again dramatically in 1995, maintained to 1996. 4. Late 1996 saw the nationwide MMR2 campaign begin; autism rates again rose dramatically in 1997. Am I imagining things, or has the eminent bunch of pharmaceutical industry-sponsored researchers failed to acknowledge a significant increase in MMR dosage rates per UK child through the mass-vaccination campaigns of 1992, 1994 and 1996? I saw nothing in the study which suggested that the effects of these MR and MMR1 & 2 campaigns had been considered; therefore nothing of the potential effects on children vaccinated unnecessarily again and again, perhaps two and three times or more, or any seroconversion data or resultant potentially damaging high titre values known to be associated with measles vaccines for those children. Revaccination was encouraged by the Department of Health; did they ensure that seroconversion took place, or that children vaccinated again and again did not assume dangerously high titre levels for any vaccine? I think not. The authors' use of '95% coverage with MMR' probably does little justice to the truth, and seems rather meaningless without qualification of how many times each child was vaccinated and revaccinated with various vaccines and vaccine batches (MMR Urabe, MMR1, MR and MMR2)and whether any of those childeren were checked for seroconversion prior to each revaccination? Is the MMR vaccination AND revaccination policy responsible for the enormous rise in autism seen in the last decade at home and abroad? The authors' statistics certainly show sudden hikes in autism diagnosis rates coincident with very recent mass-vaccination campaigns with MMR vaccines; have the authors and our public health watchdogs missed this vital factor? If so our children may still be developing autism through MMR1 and MMR2 unecessarily. Regards John H.
Re: What's next? 2 March 2001
Mary Reid, Private researcher Jamboree Hts Send response to journal: Re: Re: What's next?	I find Michel Odent's reply most interesting and would like to pursue this issue he raises regarding the frequency of caesareans these days and a possible relationship with autism. Further to my previous post that many of those with autism suffer gastric reflux, I would like to propose a possible connection. The research by Lechner and Bergant(1), that metoclopramide hydrochloride actually has not a tonifying effect, but a relaxant effect on the uterus is of interest. Could we expect that those mothers who take metoclopramide during pregnancy have a greater chance of needing a caesarean section? Could we take it one step further, and wonder whether it predisposes the neonate to gastric reflux and a possible drug dependence? We then prescribe the child H2 blockers and proton pump inhibitors or maybe dopamine receptor antagonists which quite likely result in bacterial and yeast overgrowth, not to mention the production of ethanol with its ramifications. The same could be said of the overprescription of antibiotics. It has been brought to my attention that Reglan - metoclopramide hydrochloride has been prescribed for children with reflux, and after reading of the possible side effects, I would have to question this practice. Many of the possible side effects of this drug are similar to symptoms we may see in autism. Is this a line we can afford to ignore? Mary Reid (1) Z Geburtshilfe Neonatol 2000 May-Jun;204(3):114-6 [Effect of the dopamine antagonist metoclopramide on uterine contraction]. Lechner W, Bergant A Universitatsklinik fur Frauenheilkunde, Innsbruck.
Response to Rapid Responses 3 March 2001
James A Kaye, epidemiologist Boston Collaborative Drug Surveillance Program, Boston University School of Medicine Send response to journal: Re: Response to Rapid Responses	Response to Rapid Responses We appreciate the attention given to our recent study on autism and the measles, mumps, and rubella vaccine (1) and wish to respond to several of the questions and comments submitted by readers. To Peter Allmark: One of the main reasons we undertook our study is indeed that data from California and London were interpreted by Wakefield as showing "identical temporal trends" with "the rise in autism from a steady baseline value, coinciding with the introduction of MMR vaccine." (2) Although epidemiologic studies can never exclude causality in individual cases, our judgment is that the data and analysis we presented indicate that the introduction of the MMR vaccine is not a plausible explanation for the observed rapid increase in the diagnosis of autism recorded by general practitioners during the period we studied. To JK Anand: No, we have not studied the time trend of MMR vaccination and autism incidence in California or Boston. To date we have not studied any possible relationship between MMR vaccination and ileal nodular hyperplasia, but we are interested in further studying the occurrence of gastrointestinal disease in children with a diagnosis of autism. To Mary Reid and Michel Odent: We agree that further study of possible etiologic factors in the development of autism is needed. To Dr A J Ferraro: We certainly do not know whether vaccine uptake will decline or whether case ascertainment for autism will "continue to improve (or at least plateau)," but we disagree that "only under that situation can a continual rise in the recorded incidence of autism be used as an argument against the link [between autism and the MMR vaccine]." While there are several possible reasons for the increased diagnosis of autism, as we discussed in our paper (1), introduction of the MMR vaccine is not a likely explanation for the birth cohorts we analyzed. To John P. Heprtonstall: The table in our paper (1) shows crude incidence rates for the recorded diagnosis of autism by general practitioners among children age 12 and younger. The reason we presented these rates was simply to provide background data on the overall incidence of a recorded diagnosis of autism during the period covered by the General Practice Research Database. It is a mistake to try to attribute the pattern of changes from one year to the next to specific causes. The incidence data for a particular year are contributed by children of various ages (through age 12), and there is no simple or direct relation between the year a child was diagnosed and the year the child was vaccinated. That is the reason we did a birth cohort analysis (presented in figure 2). In the birth cohort analysis, we could analyze children born in the same year; these children would have had the same opportunity to receive vaccination in each subsequent year of their lives. In other words, they would have the same potential for "exposure" to the vaccines that were available at any given time. It was also important to define a specific period of risk for the diagnosis being recorded (through age 5 in our study) so that all children in the birth cohort have the same duration of follow-up time. (In the table showing crude incidence rates, for example, a 2-year old child in 1988 would have regularly been followed until age 5 in the GPRD, but it would be impossible for a 2-year old child in 1999 to have the same duration of follow-up). Our study was designed to address the hypothesis that the rapid increase in autism diagnosis in the 1990's was linked to the introduction of the MMR vaccine in 1988. Your letter seems to raise several other hypotheses that we did not set out to study: (a) that autism may be caused by repeated vaccination with MMR; (b) that autism may caused by vaccinating children who already have immunity to measles; and (c) that autism may be caused by some MMR preparations and not by others. With regard to the first possibility, we reviewed the computer-based records of the 114 cases we identified for our birth cohort analysis. We found that only 12 received more than one MMR vaccination before diagnosis, and none received more than 2. We would also point out in response to one of the statements in your letter that we did not receive any pharmaceutical industry funding to conduct this study and that we are also supported by a grant from the US Food and Drug Administration. References: 1. Kaye JA, Melero-Montes MM, Jick H. Mumps, measles, and rubella vaccine and the incidence of autism recorded by general practitioners: a time trend analysis. BMJ 2001;322:460-463 2. Wakefield AJ. MMR vaccination and autism. Lancet 1999;354:949-950 James A. Kaye, epidemiologist; Maria del Mar Melero-Montes, epidemiologist; Hershel Jick, Associate Professor of Medicine; Boston Collaborative Drug Surveillance Program, Boston University School of Medicine, 11 Muzzey Street, Lexington, MA 02421, USA.
Re: Response to Rapid Responses 5 March 2001
John P Heptonstall, Director of The Morley Acupuncture Clinic and Complementary Therapy Centre West Yorkshire Send response to journal: Re: Re: Response to Rapid Responses	Editor I thank James Kaye for the response. It begs more questions:- 1. You say the study was 'designed to address the hypothesis that the rapid increase in autism diagnosis in the 1990's was linked to the introduction of the MMR vaccine in 1988"; your paper states the objective to be "to estimate changes in the risk of autism and assess the relation of autism to the MMR vaccine". The above two declared 'objectives' appear to contain 3 separate criteria:- A. is rapid INCREASE IN DIAGNOSIS OF AUTISM linked to introduction of MMR in 1988? B1. an estimation of CHANGES IN RISK OF AUTISM with MMR vaccine. B2. assessment of the RELATION OF AUTISM TO THE MMR vaccine I realise semantics plays a part but they are not necessarily the same. I do not think any of these questions can be answered with any degree of certainty by the study. The paper relied on the GPRD which the authors state is 'of high quality and completeness' using data stored from 1988 to 1999; I think many GPs will laugh at this statement, most of them do not use computers nor have assured entry of much useful data; any 'useful' data collected would be relatively recent, surely a system capable of recording and storing such information is relatively new in the UK? One GP suggested to me that much data collected on the GPRD may be more a 'wish list' and not an accurate reflection of trends. Finding any cohort with 'over 95% uptake of MMR', in a nation where I suspect few health authorities would claim even a 90% annual uptake since 1988, suggests the GPRD data is unrepresentative of national figures. McColl et al BMJ 1998 Jan 31st; 316(7128): 361-5 suggest just how interested GPs are in supporting databases nationally: Only 302 of 452 GPs answered a questionnaire designed to assess their perceptions of Evidence Based Medicine (EBM); Only 40% knew what the Cochrane Database is; of those aware, many did not use it; only 20% had access in their surgeries to bibliographic databases; only 17% had access to the www - Not a cohort illustrating physical interest or technical prowess in database recording and reading procedures as an Evidence Base for what they do; how can one then claim a General Practices Research Database would be 'high quality and complete' from 1988 to the present time when data collected would depend so much on GP interest, productivity and accuracy? Information collected would be further dependent on GPs recording practices; it is well known that ADR-reporting, essential for continual evaluation of efficacy and safety of all medical interventions, is abysmal (MORIDE et al 1997, say GPs are underreporting by as much as 24,500 times!). Why should the public trust data from the GPRD said to be 'of high quality and completeness' only by comment in the Lancet, and a letter in the Br J Gen Pract, and both made by one of the authors of this paper? The conclusion in this paper is "that the data provides EVIDENCE THAT NO CORRELATION EXISTS BETWEEN THE PREVALENCE OF MMR VACCINATION AND THE RAPID INCREASE IN THE RISK OF AUTISM OVER TIME". Table 1 - James says this was merely included to "provide background data on overall incidence of a recorded diagnosis of autism over period in GPRD" and one "cannot attribute pattern of changes from one year to next to specific causes" as "there is no direct information of year vaccinated for any specific child with year diagnosed. It is an interesting COINCIDENCE therefore that the year following each 'MMR campaign' shows the greatest jump in incidence of autism in every case! Could James explain why this is? I realise that the data collected and analysed may not be able to explain this anomaly, but its very presence "suggests a link between MMR vaccination campaigns and a rapid increase in autism diagnosis" not adequately explained away by the data which admittedly cannot answer the question until year of child and year of vaccination are provided to study correlation. It may be an anomaly thrown up by the GPRD, that bears some other relationship to the MMR campaigns, or not. James says that only 12 of the 114 male cohort had been revaccinated. This is 10%, of a small cohort that was split over several years which includes vaccine campaign years; perhaps the data should be examined to remove any doubt? Of the 3 alternative hypotheses James mentions I have suggested:- The first - that the years 1992, 1994 and 1996 which were immediately followed by a dramatic hike in incidence of autism diagnoses, has not been disproved by the study and table 1 figures, though not specifically adressing this point, do show consistency with the hypothesis so the authors cannot conlude that their results negate a causal link between autism and MMR vaccine until the anomaly is resolved. The second - 'that autism may be caused by repeated vaccination of children who are already immune to measles'; this is not correct as MMR is three in one, not only measles; therefore seroconversion with any or all of the vaccine pathogens may be suspected as contributing, if at all, to autism. This has not been tested by the team, so again they cannot claim to have removed doubt as to causality of autism through vaccination with MMR until the matter of revaccination of seroconverted children is cleared up. The third - that autism may be caused by some MMR preparations and not others must be a prime consideration; especially in light of the Urabe 'mumps vaccine virus causing meningitis' findings (ironically through administration of MMR vaccines!). JABS, the UK organisation dedicated to making parents aware of vaccination issues, produced charts of anecdotal data showing that different batches, and different types, of vaccine virus may cause serious effects such as autism. Failure to consider these options makes any conclusion less viable; the data and methodology are in no way comprehensive, and are based solely on the potentially inaccurate GPRD; one can only say that, with the limited information available, no consideration of the apparent rising step-effect for autism diagnosis figures, nor revaccination cases, nor specific batches of vaccine or vaccine virus types, the study suggests that there may be no direct relationship between diagnoses of autism and MMR vaccination rates during the period 1988 to 1999. Table 3, for 114 boys aged 2-5 when diagnosed between 1990-99, again shows the characteristic (of Table 1) sudden hike in diagnoses at 1993, the year after the 1992 campaign with 'meningitis-inducing Urabe MMR'. The dramatic rise in diagnoses of autism (and 'estimated incidence') seems, from the limited data shown, to follow the same two year pattern as Table 1 figures derived from all 305 children. If not significant, why not? Before authors claim to have shown non-causality I would prefer that they either use the data to cover all possible questions or admit that current databases cannot provide them with sufficient data to be able to produce the evidence required to answer general questions of causality with any real degree of certainty. In this case I believe they have merely attacked one layer of a problem, using a far from 'high quality' database in an attempt to provide useful data for an 11 year period, a relatively small and very mixed cohort of children, in a study that cannot possibly be extrapolated to a national picture where MMR vaccination rates are inaccurate and vary considerably from district to district, where diagnoses of autism in children were notoriously poor and varied considerably by authority, for a wide spectrum disorder, whilst using a 'base population' rate which could contain a large proprtion of autistic perons not yet diangosed (in 1990, 4 per 10,000 'classically autistic' was a figure well used, by 1997 this had altered to 1 in 100 children allegedly displaying 'autistic traits' said Sweden and Britain). Perhaps the team could source and provide more detail eg. of ages, years of vaccination, if/when revaccinated, districts where vaccinated, any siblings with autism, how many different batches/vaccine types were used and by which children to clarify matters more? Regards John H.
Public disquiet remains 7 March 2001
Christine Miller Send response to journal: Re: Public disquiet remains	Editor, "Stoking peoples' fears is a way to sell newspapers" wrote the Editor when the media attack on MMR vaccine was at its height (1). For the moment the attack has stopped but public disquiet remains. It is particularly cruel for parents of autistic childrten who have been gulled into into feeling guilt because they accepted MMR vaccine. The two welcome BMJ papers (2,3) provide strong reassurance that Wakefield's alleged "link" (4) was unfounded. An earlier report (5) shows how much reassurance is also needed by professionals. In that study a substantial proportion of practice nurses believed there was a link between MMR vaccine, autism, and Crohn's Disease, despite published evidence to the contrary (6) of which they were unaware. If professionals continue to accept media alarms without question there is likely to be a repeat of the pertussis vaccine collapse of the 1970's. The hope this time is the strong and prompt evidence from the above studies which refutes the alleged dangers. Will it reach those most involved, restore their confidence and enable them to allay the public's fears? If not the consequence could be the return of three preventable diseases with all their potential danger Christine Miller retired epidemiologist London NW3 1NT 1. Editor's Choice. Making and breaking news. BMJ 2001;322. 2. Elliman D, Bedford H. MMR vaccine: the continuing saga. BMJ 2001;322:183-4. 3. Kaye James A, del Mar Melero-Montes Maria, Herscel Jick. Mumps, measles and rubella vaccine and the incidence of autism recorded by general practitioners: a time trend analysis. BMJ 2001;322:460-3. 4. Wakefield AJ. MMR vaccine and autism. Lancet 1999;354:949-50. 5. Petrovic M, Roberts R, Ramsay M,. Second dose of measles, mumps and rubella vaccine: questionnaire survey of professionals. BMJ 2001;322:82-5. 6. Taylor B, Miller E, Farrington P et al. Autism abd measles, mumps, and rubella vaccine: no epidemiological evidence for a causal association. Lancet 1999;353:2026-9.
Re: Re: Response to Rapid Responses 8 March 2001
James A Kaye, epidemiologist Boston Collaborative Drug Surveillance Program, Boston University School of Medicine Send response to journal: Re: Re: Re: Response to Rapid Responses	Response to John Heptonstall Your letter reflects a lack of knowledge about the General Practice Research Database. Most of the general practitioners who contribute to the GPRD have been using computerized medical record systems for over a decade. They were trained in recording information by the general practitioners who developed the software; they use the computer system to produce prescription authorizations (thereby automatically providing a complete record of the medications they prescribe); and they use the system not to "report ADRs" per se but rather to record their patients' complaints and diagnoses on an ongoing basis in the course of daily medical practice. We and others have conducted validation studies showing that the information recorded in the database is supported by other office records (letters from consultants, hospital discharge summaries, etc.), and more than a hundred publications by various investigators have resulted from work based on the GPRD. While our group has contributed a substantial number of these publications, it is wrong to suggest that we are the only investigators who have found the data to be of high quality and consistency. The database is now administered by the UK Department of Health. For further information, please see http://www.gprd.com. If you want to contact us directly, we would also be glad to provide you with a list of publications by our group, many but not all of which are based on data from the GPRD. You have pointed to an "apparent rising step effect" of autism diagnoses in our study (1) and related this pattern to specific "MMR campaigns." Although the overall increasing trend in autism diagnosis shown in Figure 2 of our report is statistically significant, the individual year-to-year changes are not. For this reason, and because temporal association is not sufficient to demonstrate causation anyway, we cannot attribute apparent year-to-year changes to specific events. We agree that further investigation of the cases with a diagnosis of autism recorded in the GPRD may be useful, and our group is collecting for future study additional information on the children we identified. We also understand that a research team led by Liam Smeeth at the London School of Hygiene and Tropical Medicine is conducting a study of autism and its potential causes using data from the General Practice Research Database (2). References: 1. Kaye JA, Melero-Montes MM, Jick H. Mumps, measles, and rubella vaccine and the incidence of autism recorded by general practitioners: a time trend analysis. BMJ 2001;322:460-463 2. Smeeth L, Hall AJ, Fombonne E, Rodrigues LC, Huang X, Smith PG. A case-control study of autism and mumps-measles-rubella vaccination using the general practice research database: design and methodology. BMC Public Health 2001;1:2 James A. Kaye, epidemiologist Maria del Mar Melero-Montes, epidemiologist Hershel Jick, Associate Professor of Medicine Boston Collaborative Drug Surveillance Program, Boston University School of Medicine, 11 Muzzey Street, Lexington, MA 02421, USA
Mumps, measles, and rubella vaccine and the incidence of autism recorded by general practitioners 8 March 2001
Nicola Ellis, Senior Rersearch Associate Centre for Health Services Research, University of Newcastle upon Tyne Send response to journal: Re: Mumps, measles, and rubella vaccine and the incidence of autism recorded by general practitioners	Sir, The disputed relationship between MMR vaccination and autism is one where the epidemiological data has been called into question across a wide range of media. In his response to Kaye et al, Dr Ferraro has suggested that the observed increase in the detected incidence of autism in the UK “may simply be evidence of improved case ascertainment”. In other words, more cases are being diagnosed. The evidence for this change in diagnostic behaviour has been derived from data collected in the General Practice Research Database (GPRD). Our view is that this apparent increase in incidence during the time period in question (1988-1993) is only partly explained by rising numbers of diagnoses. We believe that the ways that clinical data is recorded has also played an important part in this process. The GPRD uses data from the VAMP Research Database. The latter was created from data submissions from General Practices. These received payments for providing data that were conditional on improving their quality in a number of ways. Importantly, one of these was that all events resulting in a referral to any specialist must be recorded. The implication of this is that patterns of data collection have changed, and that this database may have become more comprehensive. Consequently it is not possible to be certain that the observed increase in the incidence of autism recorded in the GPRD during this time period is reliable. It is more likely that the increase in incidence can be explained by changes in diagnostic behaviour (there has been abundance debate about the wider reasons for this) and more comprehensive data collection by participating practices over time. Our view is that it is difficult to draw solid conclusions about the changing incidence of autism on the basis of this data. Apparent changes in the level of detection may be driven by socio-technical factors related to diagnosis and recording rather than a real change in prevalence. Dr N T Ellis Senior Research Associate Centre for Health Services Research, University of Newcastle upon Tyne. B Ellis Practice Manager Ash Trees House Surgery, Kirkham. Professor CR May Centre for Health Services Research, University of Newcastle upon Tyne.
'Social' causes for changes in incidence of autism. Were other childhood disorders on the increase? 11 April 2001
Ronan Ryan, Research Officer, Morbidity and Health Care Team; Specialist Registrar in Public Health Office for National Statistics, Bernadette Purcell Send response to journal: Re: 'Social' causes for changes in incidence of autism. Were other childhood disorders on the increase?	The GPRD is a rich source of information on the health of the UK population, containing records gathered from GPs' day to day work. The activities of the participating doctors and patients are influenced by changes in the roles and responsibilities placed upon doctors and eligibility requirements for state benefits, for example changes to the GPs' role with the advent of sick certification. In the interpretation of the findings of Kaye we would like to draw attention to relevant changes in policy during the study period.(1) There were at least two additions to the legislation and regulations that cover the education and social security benefits that children with extra needs are entitled to during the period of this study. The Disability Living Allowance (DLA) covers children from three months of age and offers varying rates of support, depending upon the established needs of the child. Some of the DLA benefits that are available from infancy do not require a learning disability to be present. If an impairment in social functioning and severe behavioural problems are present then higher rates of the benefit may be awarded to older children ( www.oneworld.org/autism_uk/factsheet/factsh.html). Secondly, a Code of Practice in the identification and assessment of special educational needs was released as a result of the 1993 Education Act by the Department for Education, along with associated regulations. Statements can be issued for a variety of reasons that can affect the children's schooling - sensory impairments, speech and language difficulties, a learning disability, or emotional and behavioural difficulties. The Annual Schools' Census shows an increase in the incidence of pupils with statements (statutory assessments of special educational needs) in all schools in England from 1993 to 1998 (2.3%-2.9%) ( http://www.dfee.gov.uk/sen/stat98.htm). An additional study, using population based data might add useful information to the debate on the apparent increase in the incidence of autism. Such a study could employ the GPRD to determine if the incidence of other childhood psychological problems increased during the study period. If conditions that share common symptoms with autism such as ADD/ADHD, obsessive-compulsive disorders, anxiety, childhood depression, and elective mutism also increased in the study period, this would suggest the rise in autism may be explained in part by changes like benefits entitlements and the Code of Practice for the identification and assessment of special educational needs. Signed Ronan Ryan Research Officer, Morbidity and Health Care Team Office for National Statistics Bernadette Purcell Specialist Registrar in Public Health Office for National Statistics (1) Kaye J. Mumps, measles, and rubella vaccine and the incidence of autism recorded by general practitioners: a time trend analysis. BMJ 2001; 322: 460-463.
Re: 'Social' causes for changes in incidence of autism. Were other childhood disorders on the increa 12 April 2001
Lisa Blakemore-Brown, Independent Psychologist. Specilaist in Autistic and ADHD Spectrum Disorders UK Send response to journal: Re: Re: 'Social' causes for changes in incidence of autism. Were other childhood disorders on the increa	The good thing about being at the coal face with children rather than in an office looking at figures pertaining to children, is that one can really get a feel of what is changing, if anything. In the mid eighties the highest referred group were the male `ADHD` pre schoolers. Within this group were clearly children with autism. However. The bowel, allergy and intolerance problems were not `in your face`. They are now and they have been since the early nineties. The presentation is DIFFERENT. It is grossly unhelpful to add insult to injury to even imply that perhaps DLA or Special Needs support has led to a change in the way parents describe their child's problems. Undoubtedly, there are people who see a quick buck and go for it. What advantage could there be for people to have to admit that their child is virtually unteachable and virtually uncontrollable? From the vast numbers of brilliant parents I have met, their greatest wish is for a normal child.
Autism: Changes in diagnosis or increase in prevalence- Evidence from the 1970 cohort 15 May 2001
Helen Heussler, Lecturer in Community Paediatrics Nottingham Send response to journal: Re: Autism: Changes in diagnosis or increase in prevalence- Evidence from the 1970 cohort	Recent concerns about an increasing prevalence of Autism in the general population and the patho-physiology behind this have been prominent in the press. Before these concerns can be addressed we need to be sure that this is a true increase in prevalence. A cohort study was felt to be suitable to provide an insight into whether there is a true increase in prevalence of Autistic disorders. In the British Cohort 1970 (BCS70) only 5 children at the age of 5 years were identified with a diagnosis of Autism (and 1 with suspected autism) in disability data files. This gives a prevalence of 6/13135 (0.45/1000) comparable with previous studies(1,2). A focus group consisting of practising consultants experienced in the diagnosis of Autistic disorders from adult and paediatric disciplines, identified a number of diagnostic features from the available data they felt were important in making a diagnosis of autistic spectrum disorder. The aim was to identify whether there were potentially missing/undiagnosed cases with current commonly used diagnostic features. Identified features from the original BCS70 questionnaire included: Age 5 · Restless · Solitary, does things on own · Fearful, afraid of new situations · Fussy or Over-particular Age 10 · Does things on own- rather solitary · Afraid of new situations · Fussy or over particular · Hums or makes odd noises · Obsessional · Requests must be met immediately Where an analogue scale has been used only the most extreme cases were identified i.e. the top 20%. Cases were identified where the child had all features present at both 5 and 10 years. Using this methodology we were able to identify a total of 56 cases from 14904 children studied at 10 years giving a prevalence of 3.76/1000. This would suggest that these children are potentially likely to have a diagnosis of an autistic spectrum disorder using contemporary diagnostic features. This agrees with current lifetime prevalence figures suggested by Powell et al(3). Therefore estimates of prevalence from the early 1970’s may have seriously underestimated the prevalence at that time. Confirmation of this suggestion would require contemporary assessment of the individuals involved. Helen Heussler Lecturer in Community Child Health Corresponding Author Division of Child Health, School of Human Development University of Nottingham, Nottingham NG7 2UH Email: honey.heussler@nottingham.ac.uk Leon Polnay Professor of Community Paediatrics Division of Child Health, School of Human Development, University of Nottingham, Nottingham NG7 2UH Elizabeth Marder Consultant Community Paediatrician Department of Paediatrics, Queens Medical Centre, Nottingham NG7 32UH Penny Standen Reader in Health Psychology and Learning Disability Division of Rehabilitation and Ageing, School of Community Health Sciences, University of Nottingham, Nottingham NG7 2UH Chin Lyn U Formerly Data Manager BCS70 Nottingham Division of Psychiatry, School of Community Health Sciences, University of Nottingham, Duncan MacMillan House Porchester Rd, Nottingham NG3 6AA Neville Butler Senior Research Fellow BCS70 80 Cumberland Road, Hotwells, Bristol BS1 6UG. References: 1. Gillberg C. Wing L. Autism: not an extremely rare disorder Acta Psychiatrica Scandinavica. 1999 99(6):399-406 2. Kaye J. del Mar Melero-Montes M. Jick H. Mumps, Measles, and rubella vaccine and the incidence of autism recorded by general practitioners: a time trend analysis. BMJ 2001 322 (7284): 460-463 3. Powell J, Edwards A, Edwards M, Pandit B, Sungum-Paliwal S, Whitehouse W. Changes in the Incidence of Childhood Autism and other Autistic Spectrum Disorders in Preschool Children from two areas of the West Midlands. Dev Med and Child Neurol. 2000 42:624-628
MMR is the open door 28 May 2001
Karen Montrose Send response to journal: Re: MMR is the open door	I have understood that Dr. Wakefield's work represents MMR as one factor in autism, with other factors being bowel disease, and environmental toxins. My interpretation of this is that the MMR vaccine triggers either an absorption disease within the bowels that is temporary, or permanent, allowing an extreme level of environmental toxins to be absorbed. The result is permanent damage to the brain, which would be very sudden in appearance if the toxins were present in high amounts, and absorbed in totality, or slower, if the toxins were low in the environment or absorbed in lower potency. The variables here are the amount of damage done to the bowel, and the toxins in the environment itself. The MMR vaccine simply opens the door to the problem, and the increase in environmental toxins over time would account for the continued increase in autism occurence.
The numbers don't match 24 August 2001
Adrian Thewlis, Father-to-be C.E.O. Joshua Technology, Inc Send response to journal: Re: The numbers don't match	I am not a medical person, however a study of statistics is a normal part of an engineering degree, and it is from that basis there are some apparent anomalies between the data that Kaye et al have published and other facts that they themselves and others have provided. The first is the MMR prevalence from Fig.2, which remains remarkably static at around 97%. In contrast to that, John P. Heprtonstall mentions the successive imunisation campaigns of 1988, 1992, 1994, 1996. I do not understand how these campaigns, the existence of which Kaye does not dispute, could not effect the measured prevalence of MMR? Surely either the data or the campaigns must be seriously called into question... and, if the data is not to be questioned, given the supposed lack of effect of the first campaign, why three more, equally ineffective campaigns were carried out! Secondly, from Kaye's testimony, amongst the cases and controls, 3% had not had MMR. He then focuses on a group of 110 boys with autism, of whom only one had not had the MMR vaccine, a "non-uptake" of one-third that of the control group. This is a small sample space I agree, and that the difference between the expected 3 and the measured 1 is small. Nevertheless it would be interesting to know of the 305 total cases observed, how many had the MMR vaccine, and whether that is closer to the quoted 97%.
Re: The numbers don't match 31 August 2001
James A Kaye, epidemiologist Boston Collaborative Drug Surveillance Program, Boston University School of Medicine Send response to journal: Re: Re: The numbers don't match	We have not directly studied the effectiveness of MMR vaccine campaigns in the UK. Data produced by the Department of Health show high MMR coverage starting with the cohort of children born in April 1988 to March, 1989 (Figure 2 in Taylor B, Miller E, Farrington CP, et al. Autism and measles, mumps, and rubella vaccine: no epidemiological evidence for a causal association. Lancet 1999;353:2026-29). If the MMR vaccine prevalence we reported is higher than the prevalence documented by the Department of Health during the period of our study, one possible explanation is that using an office computer medical record system (as do all GPs who contribute data to the GPRD) may facilitate compliance with vaccine recommendations. Among the 1988 to 1993 birth cohorts, the 95% confidence interval for the proportion of boys we studied who were vaccinated with MMR (109 of 110) is 0.95 to 1.00, which contains the value of 0.97 we observed for these birth cohorts in the general population followed in the GPRD. It is not meaningful to compare these proportions with the proportion vaccinated among all 305 chldren we identified with a recorded diagnosis of autism because not all of the 305 children had all their medical data recorded in the GPRD from the time of birth (especially those born before 1988), and so vaccines may have been given to some but not recorded in the GPRD. This is part of the reason we focused our analysis on birth cohorts starting in 1988.
Correlation with other vaccinations 10 November 2001
Russell Welch R & R Landscaping Salt Lake City, USA Send response to journal: Re: Correlation with other vaccinations	I have found this research and responces most interesting. It seeems to me that there are several things to consider on this subject. 1. Have any other vaccines been looked at in combination with the MMR. Here in the US, Hep B and DPT are also commonly give to infant children. Both of these vaccines contain thimerosal. Thimersol is inorganic mercury and is 50 times more toxic than methylmercury. The symptoms of mercury poisoning and autism are strikingly similar. When was autism first diagnosed? In the late 1930's, and when was thimersol introduced into vaccines? The 1930's. Why would we inject the worlds third most toxic substance into our children? They have no blood-brain barrier, they can't produce bile, which is necessary to excrete mercury and it accumulates in the brain and nerve cells. Once thimersol is in the nerve cells it is converted into its inorganic form. 2. Since the MMR doesn't contain thimersol, we should look to other aspects of this serious problem. I am not familiar with any research having been done to show that polyvalent vaccinations are safe. Are they? 3. Dr. Andrew Wakefield a British surgeon has shown that at least three quarters of autistics have pathologically blocked bowels, due to the huge swelling of the tissue lining the intestins. This nodular hyperplasiais both an immune, and autoimmune responce that hhas been clearly linked to the presence of the measels virus from the MMR shot. No other virus was found in those cells. (Wakefield and O'leary) Regardless of what research will find as the root cause, autism is an epidemic. I personally get a little leary when there is so much money involved with the pharmicudical companies, and the public health system. Just like the distruction of so much rainforest in the Amazon due to cattle ranching , and public works projects... so much money is funneling through these issues.
How was the "MMR Prevalence" estimated? 10 February 2002
Ulf C Brånell, Selvemploed SIEM, Borred 110, 52026 Trädet, Sweden Send response to journal: Re: How was the "MMR Prevalence" estimated?	This report claims to have found that 1) the incidence rate of autism amongst children 0-12 years has risen from 0,3 to 2,2 during the years 1988-1999 2) During these years the prevalence of MMR-vaccination has been continuosly 90-97% Conclusion: While MMR-vaccination is constant and autism rises, vaccine cannot be cause of autism The table must be read as: In 1988 were 7 cases of autism diagnosed among 255771 children aged 0-12 years. Incidence rate: 7/255 771/10 000 = 0,3 and so on The report says - without further evidence - that in 1988 there was a MMR prevalence of 90%. · Well: we must now ask: : When were these 255771 children (or ”person years”) of 1988 born, and when were they vaccinated with the MMR vaccine? ( The MMR vaccine was introduced in 1988.) · Children 0-12 years 1988 were born the years 1976 -1988. No record has been made that all children 0-12 years were MMR-vaccinated in the single year of 1988. Many of them had earlier got other single-vaccines and it is not probable that they were called back 1988 for another shot of the new combined MMR-vaccine. And if they really were - the vaccination of chilkdren 6,7,8,9,10,11 years is hardly hypothesized by anyone to cause autism., What is in question is if vaccination of small children , according to the vaccine program, is causing autism. · We must conclude that what really happened in 1988 was that 90% of the babies of 1 years age (and possibly those of 4-5 years ) were vaccinated. The other children were not vaccinated. This will NOT make an MMR- prevalence of 90% of the ”person years” but approximately 10-25% .during 1988. · The base of possibly MMR-induced autism during 1988 is then say 25% *255771= 64 000 MMR vaccinated children, most of them born 1987, and possibly 1983-84. During 1988 7 cases of autism were diagnozed, median age 6 years. Almost none of these children can have got the MMR this year. · During these following years the real MMR-prevalence will rise from 25% by approximately one year-cohort (or ca 1/12 = 8% of the person years) every year, until in around 1998-99 almost all children 0-12 years will have got the MMR-shot.according to the official vaccination program. Obviously the ”person years” that are accounted for in the table have very different MMR-status in 1988 compared to e g 1999. This makes the conclusion is not valid. Instead the data shows that as more kids get MMR-vaccine rises the autism rate.
Re: Re: Re: Response to Rapid Responses 24 May 2002
Chris A Johnson, Audiologist Send response to journal: Re: Re: Re: Re: Response to Rapid Responses	Given that "temporal association is not sufficient to demonstrate causation anyway", why have you bothered to use it as your basis for disproving possible causation?
MMR/AUTISM ONE YEAR ON 7 June 2002
Michael D Innis, Director Medisets International Send response to journal: Re: MMR/AUTISM ONE YEAR ON	Editor, The impulse to seek causes is innate in the soul of man – said Tolstoy; and Kaye says “ …epidemiological studies can never exclude causality in individual cases” unless, that is, you are standing on the shoulders of Dr John Snow.[1] Snow’s famous experiment of removing the handle of the Broad Street Pump established once and for all that causal associations are demonstrable by epidemiological studies. ‘IF pump THEN cholera’ AND ‘IF no pump THEN no cholera’ THEN Cholera If and Only if Pump This was the logic behind Snow’s experiment which banished cholera from London forever. Keep in mind of course the fact that any event may have more than one efficient cause. In this case one can think of the Pump, vibrio Cholera contaminated drinking water and genetically susceptible victims, as the causes of the cholera epidemic. The formula that governs all causal associations of this type is, (If p then q) AND (If not p then not q) THEN (p if and only if q) conceptualised originally by Aristotle[2] and later Francis Bacon[3], Mill[4] and Claude Bernard[5] . Epidemiologists are not going to solve the MMR/Autism controversy until they start a case/control (age, sex, ethnicity because of HLA specificity of some immune reactions) study and compare the number of Autistic children who have been given MMR with the number of Autistic children not given MMR. It will come as no surprise to many, who have followed and understood the work of Wakefield and his colleagues, that a significant positive statistical association will be found to exist between MMR and Autism Some can tell a lion by its Paw – others must wait to hear it Roar. Michael Innis FRCPA; FRCPath. Reference: 1.http://www.ph.ucla.edu/epi/snow 2.Kneale W (1949) Probability and Induction. P 31 London EC 4 Oxford University Press Amen House 3.Bacon F (1960) The New Organon and Related Writings p 51 Indianapolis Edited by Anderson FH . Bobbs-Merrill Company Inc 4.Mill JS (1843) A System of Logic Longmans, Green and Co LTD p 247 5.Bernard C (1957) An Introduction to the study of Experimental Medicine p 55 New York Translated by Green HC Dover Publications Inc. .
Re: MMR/AUTISM ONE YEAR ON 9 June 2002
David N. Andrews, Postgraduate Student/Social Psychologist & Autism Consultant(Freelance) Kapteeninkatu 24 E 115, 48100 KOTKA, Finland Send response to journal: Re: Re: MMR/AUTISM ONE YEAR ON	Hmm....... This thing of vaccines CAUSING autism..... not really! Autism has no actual PHYSICAL form- it is identified and diagnosed BEHAVIOURALLY, and most medical practitioners (including psychiatrists) are not really in possession of psychological competence, even at an undergraduate level (intercalated and previously taken psychology degrees notwithstanding!). Therefore, I am not entirely sure that something like autism is entirely within the medical sphere. I say this from two bases: firstly, I am a social psychologist, and I am therefore very interested in human interaction and its effects on behaviour. Secondly, I am autistic myself, and was not (as far as I can tell anyway!) immunised with the MMR vaccine. There was a very astute psychologist working in the US in the earlier part of the last century, whose work may have much to say on this phenomenon. Kurt Lewin is seen as the "father" of the study of group dynamics in social psychology. In his work he found that there are systems based around any individual one may wish to consider, and these systems - although social in nature - have tensions between the members they comprise (Fontana, 2000). These tensions operate a little like certain types of field phenomena, such as electrostatic fields (from with the model actually seems to be developed). Within these fields, the tensions interact to give rise to behaviour (as people sense and perceive, and then construe - see Kelly, 1955) which forms the reorganisation of the tension system in question. The occurrence of "problem behaviours" might be seen as the end result of a system reorganising in such a way as to "force" a leak of behaviour at the least resistive point. Work by Finnish neuropsychologist Timo Järvilehto seems to uphold such a notion from a "social neuropsychological" viewpoint. His work accentuates the existing neurobiological substrate which can be said to underlie any person's behaviour, but which by the same token cannot possibly be the sole cause of that behaviour (Järvilehto, undated). This being so, we cannot assume that autism is an "illness" with the same types of aetiological factors seen in - for example - haemorrhoids. Autism is best seen as a continual set of possible response states by the individual concerned to inhospitable situational factors with which s/he has to deal: in other words, it is the best possible defensive response by that person to the expectations and attitudes of the society into which that person has been born. It is also pertinent to mention here that an autistic person may behave totally differently in any two different situations, which would seem to uphold the notion of tension systems within that individual's Organism-Environment System (Andrews, 2001). In short, I am of the opinion that biological causes for autism cannot be found, whatever contributory factors may exist in such a substrate. For this reason, I find the whole MMR debate, like so many other similar debates, to be a little tiresome now. The research should be oriented to discovering the types of interactions between the person and his/her environment are that bring about autistic states. Trying to find a root biological cause for it (as if it were a true "disease") is akin to attempting to find a deep psychological basis for piles! Remember - we are BIOLOGICAL creatures in SOCIAL contexts! David N Andrews sosiaalipsykologi, EPiT (psychologist in training) Kotka, Finland References: Andrews D N- (2001) Neurological Aspects of Higher-functioning Autisms (http://edtech.oulu.fi/sampo/00-01/cumu/dna/nahfa.htm) Fontana D- (2000) Personality in the Workplace Kelly G A- (1955) The Psychology of Personal Constructs Järvilehto T - The Theory of Organism-Environment System, parts I to IV (essentially an adaptation in English of his earlier book Ihminen ja Ihmisen Ympäristö 1994) (http://wwwedu.oulu.fi/homepage/tjarvile/indexe.htm) but see also http://cogprints.soton.ac.uk/documents/disk0/00/00/03/62/cog00000362- 00/chap1.htm
CLARIFICATION SOUGHT FROM AUTHORS TO ESTABLISH EVIDENTIAL VALIDITY OF THIS PAPER 17 April 2004
Clifford G. Miller, Lawyer, graduate physicist, former examining university lecturer on law standards ethics Beckenham Kent England BR3 Send response to journal: Re: CLARIFICATION SOUGHT FROM AUTHORS TO ESTABLISH EVIDENTIAL VALIDITY OF THIS PAPER	OPEN LETTER TO THE AUTHORS Dear Mr Kaye, In your paper, "Mumps, measles, and rubella vaccine and the incidence of autism recorded by general practitioners: a time trend analysis" BMJ 2001;322:460-463 ( 24 February ) it is stated "The data provide evidence that no correlation exists between the prevalence of MMR vaccination and the rapid increase in the risk of autism over time." With what degree of confidence would you say this evidence can be relied upon to prove no correlation exists? In asking this question, I am being careful to distinguish 'evidence' from 'proof'. Anything is 'evidence', in that 'evidence' is simply information with goes to support or undermine a disputed proposition, but can fall short of being proof, whereas 'proof' depends upon an assessment of all the relevant evidence in the light of the standard of proof being adopted. The scientific standard of proof being irrefutability. How far would you say this paper goes to establish, irrefutably, that there is or is not a correlation of the kind considered? Is there any assessment available of the reliability (authenticity, accuracy and completeness) of this evidence and the weight to be afforded to it. Is there any other relevant evidence which might have existed at the time of the study which might also have usefully been considered in order to gain a better understanding of whether or not such a correlation existed? Also, the following statements appear in the paper:- 1. "It should be noted that the MMR vaccine is given first at about 15 months of age" 2. "We recognise that the diagnosis of autism in our study was not confirmed from original records but consider that differential misclassification of the diagnosis in vaccinated and unvaccinated children is unlikely to vary over the period of the study." Is there any reference from which the bases for these statements can be verified for the two periods of time during which the study relates and the accuracy of the data upon which they are based, as the samples are quite small? I also assume that the statement ".... autism is not typically diagnosed until age 2 years or later" is based upon the data analysed for this paper. This open letter is sent in the absence of a current email address for the principal author. Competing interests: Close relative with life threatening food allergy.