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Vaccine journal homepage: www.elsevier.com/locate/vaccine

Letter to the Editor Autism and vaccination: The value of the evidence base of a recent meta-analysis 1. Introduction Taylor et al. undertook a meta-analysis aimed “to quantitatively assess the available data from studies undertaken in various countries regarding autism rates and childhood vaccination so that the relationship between these two, whatever its significance, can be adequately substantiated” [1]. They finally selected five cohort studies involving 1,256,407 children, and five case-controlled studies involving 9920 children to analyze. The authors concluded that “The findings of this meta-analysis suggest that vaccinations are not associated with the development of autism or autism spectrum disorder”. The purpose of this analysis is to evaluate the 10 articles included in the Taylor meta-analysis, and assess the impact of their methods on the finding of the meta-analysis. 2. Method Most cohort studies examining the link between vaccination and autism limit their analysis to a comparison of vaccinated children who have been given either the MMR vaccine or thimerosal-containing-vaccines and vaccinated children who have not been given these vaccines. Such analyses permit conclusions relating to the relative safety of MMR and thimerosal containing vaccines. This approach facilitates data collection as the significant majority of children are vaccinated in the communities being studied, and it eliminates any ethical dilemma involved in denying certain vaccines to children (although this is not an issue in retrospective studies). However it means that studies comparing vaccinated (V) and completely unvaccinated children (CUV) have not been undertaken. In this review the ten studies accepted into the Taylor metaanalysis were examined to identify (i) whether comparisons between completely vaccinated and fully unvaccinated children were made, (ii) whether the conclusions made by the authors were justified and (iii) whether the true findings of each study affected the final conclusions made by Taylor. 3. Results The 10 studies included in the Taylor meta-analysis are listed in Table 1. The V:CUV column shows whether a comparison between fully vaccinated and completely unvaccinated children was made. The conclusions made by the authors are then shown and compared to the conclusions that are justified by the analysis. Assessment comments made by the Institute of Medicine in 2012 stated that the studies by DeStefano et al. [7] and Uchiyama

et al. [5] “Had very serious methodological limitations that precluded their inclusion in this assessment. Did not provide sufficient data on whether autism onset or diagnosis preceded or followed MMR vaccination” (p. 145) [12]. 4. Discussion The Taylor meta-analysis included 10 studies, nine of which did not compare fully vaccinated and completely unvaccinated children. The tenth study [8] did not state clearly whether or not the 9 (of 288) children who were not vaccinated against measles were vaccinated against other diseases although the small number of possibly unvaccinated children would not permit a substantive conclusion. Thus the studies, and by extension the Taylor meta-analysis, did demonstrate that the incidence of ASD is similar in children who were vaccinated with any combination or number of vaccines, but failed to demonstrate whether completely unvaccinated children were more or less likely to develop ASD than vaccinated children. It is imperative that CUV be compared to V, given that (i) a study involving such a comparison is needed to definitively demonstrate the long-term safety of vaccines, and (ii) failure to address this question is what prevents at least some of those parents who question vaccine safety from being convinced by orthodox assurances of safety. There are sufficient numbers of unvaccinated children in most communities to permit significantly sized retrospective cohort studies or appropriately matched case–control studies to be undertaken without ethical concerns surrounding denial of vaccination. For example, Bachmair collected data on 13,753 unvaccinated children in a web-based survey [13], and Generation Rescue collected data on 16,683 vaccinated and 991 unvaccinated children in nine counties in California and Oregon in the USA [14]. These are small, “private” studies. Any “public” study supported by health officials, and especially in co-operation with regional and national education departments thus allowing access to primary school children, would extend these numbers significantly. In Australia, for example, it has been estimated that about 92% of primary school aged children (6–11 years old) are fully vaccinated [15], and about half of the remainder are unvaccinated, around 72,000 children. Most would be in the school system. Golden collected data on 309 unvaccinated children in Australia in part through the support of just a few primary schools [16]. A national government-supported study could access a significant percentage of these 72,000 unvaccinated children. A school-centred approach would also facilitate appropriate data matching of the vaccinated and unvaccinated cohorts and improve levels of homogeneity. Meta-analyses of such studies would provide significant new information regarding long-term vaccine safety, and would either demonstrate that long-term vaccine safety is a real problem or finally put to rest genuine concerns by those parents who feel

http://dx.doi.org/10.1016/j.vaccine.2015.02.002 0264-410X/© 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Turville C, Golden I. Autism and vaccination: The value of the evidence base of a recent meta-analysis. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.02.002

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2 Table 1 Analysis of 10 studies included in the Taylor meta-analysis. Study

V:CUV

Authors’ conclusion

Conclusion that is justified

Cohort studies Andrews et al. [2] (United Kingdom)

No

“With the possible exception of tics, there was no evidence that thimerosal exposure via DTP/DT vaccines causes neurodevelopmental disorders”

Hviid et al. [3] (Denmark)

No

Madsen et al. [4] (Denmark)

No

Uchiyama et al. [5] (Japan)

No

“The results do not support a causal relationship between childhood vaccination with thimerosal-containing vaccines and development of autistic-spectrum disorders” “This study provides three strong arguments against a causal relation between MMR vaccination and autism. First, the risk of autism was similar in vaccinated and unvaccinated children, in both age-adjusted and fully adjusted analyses. Second, there was no temporal clustering of cases of autism at any time after immunization. Third, neither autistic disorder nor other autistic-spectrum disorders were associated with MMR vaccination” “Our results cast additional doubt on the hypothesis that developmental regression in children with ASD is associated with MMR”

There is no apparent difference in the incidence of neurodevelopmental disorders in children vaccinated with vaccines including thimerosal and vaccines excluding thimerosal There is no apparent difference in the incidence of autistic-spectrum disorders in children vaccinated with vaccines including thimerosal and vaccines excluding thimerosal There is no apparent difference in the incidence of autism or autistic-spectrum disorders in children vaccinated with vaccines including the MMR vaccine and vaccines excluding the MMR vaccine

Verstraeten et al. [6] (France)

No

“In our analyses of computerized HMO data, we found no consistent significant associations between TCVs and neurodevelopmental outcomes”

Case–control studies DeStefano et al. [7] (USA)

No

Mrozek-Budzyn et al. [8] (Poland)

Not known

“We found that, overall, the age at time of first MMR administration was similar among case and control children” “The study provides evidence against the association of autism with either MMR or a single measles vaccine”

Price et al. [9] (USA)

No

Smeeth et al. [10] (United Kingdom)

No

Uno et al. [11] (Japan)

No

“In our study of MCO members, prenatal and early-life exposure to ethylmercury from thimerosal-containing vaccines and immunoglobulin preparations was not related to increased risk of ASDs” “We have found no convincing evidence that MMR vaccination increases the risk of autism or other PDDs. No significant association has been found in rigorous studies in a range of different settings” “There were not any convincing evidences that MMR vaccination and increasing the number of vaccine injections were associated with an increased risk of ASD in a genetically homogeneous population”

that until the comparison between vaccinated and completely unvaccinated children is made that definitive proof of long-term vaccine safety does not exist. 5. Conclusions Whilst the Taylor meta-analysis reinforced previous findings which showed that the incidence of ASD is similar in groups of differently vaccinated children, it failed to compare the incidence of ASD in vaccinated and completely unvaccinated populations. It is recommended that this final piece in the “vaccine safety puzzle” be directly addressed by appropriate research and all findings published. References [1] Taylor LE, Swerdfeger AL, Eslick GD. Vaccines are not associated with autism: an evidence-based meta-analysis of case–control and cohort studies. Vaccine 2014;32(29):3623–9. [2] Andrews N, Miller M, Granty A, Stowe J, Osborne V, Taylor B. Thimerosal exposure in infants and developmental disorders: a retrospective cohort study in the United Kingdom does not support a causal association. Pediatrics 2004;114(3):584–91. [3] Hvid A, Stellfeld M, Wohlfahrt J, Melbye M. Association between thimerosalcontaining vaccine and autism. J Am Med Assoc 2003;290(13):1763–6.

There is no apparent difference in the incidence of regression within autistic children vaccinated with vaccines including the MMR vaccine and vaccines excluding the MMR vaccine There is no apparent difference in the incidence of neurodevelopmental disorders in children vaccinated with vaccines including the MMR vaccine and vaccines excluding the MMR vaccine Excluded all children who had not had 1 MMR by 4y/o. Age profile at vaccination of autistic and non-autistic children is similar 9 children were not vaccinated against measles, but it was not specified if they received other vaccines. Thus the true conclusion cannot be confirmed There is no apparent difference in the incidence of autistic-spectrum disorders in children vaccinated with vaccines including thimerosal and vaccines excluding thimerosal There is no apparent difference in the incidence of autism or PPD disorders in children vaccinated with vaccines including the MMR vaccine and vaccines excluding the MMR vaccine There is no apparent difference in the incidence of autistic-spectrum disorders in children vaccinated with vaccines including the MMR vaccine and vaccines excluding the MMR vaccine, or in children receiving different numbers of vaccines

[4] Madsen KM, Hviid A, Vestergaard M, Schendel D, Wohlfahrt J, Thorsen P, et al. A population-based study of measles, mumps, and rubella vaccination and autism. N Engl J Med 2002;347(19):1477–82. [5] Uchiyama T, Kurosawa M, Inaba Y. MMR-vaccine and regression in autism spectrum disorders: negative results presented from Japan. J Autism Dev Disord 2007;37(2):210–7. [6] Verstraeten T, Davis RL, DeStefano F, Lieu TA, Rhodes PH, Black SB, et al. Safety of thimerosal-containing vaccines: a two-phased study of computerised health maintenance organization databases. Pediatrics 2003;112(5):1039–48. [7] DeStefano F, Bhasin TK, Thompson WW, Yeargin-Allsopp M, Boyle C. Age at first measles–mumps–rubella vaccination in children with autism and schoolmatched control subjects: a population-based study in metropolitan Atlanta. Pediatrics 2004;113(2):259–66. [8] Mrozek-Budzyn D, Kieltyka A, Majewska R. Lack of association between measles–mumps–rubella vaccination and autism in children: a case–control study. Pediatr Infect Dis J 2010;29(5):397–400. [9] Price CS, Thompson WW, Goodson B, Weintraub ES, Croen LA, Hinrichsen VL, et al. Prenatal and infant exposure to thimerosal found from vaccines and immunoglobulins and risk of autism. Pediatrics 2010:656–64. [10] Smeeth L, Cook C, Fombonne E, Heavey L, Rodrigues LC, Smith PG, et al. MMR vaccination and pervasive developmental disorders: a case–control study. Lancet 2004;364:963–9. [11] Uno Y, Uchiyama T, Kurowasa M, Aleksic B, Ozaki N. The combined measles, mumps, and rubella vaccines and the total number of vaccines are not associated with developmental autism spectrum disorder; the first case–control study in Asia. Vaccine 2012;30:4292–8. [12] I.O.M. (Institute of Medicine). Adverse effects of vaccines: evidence and causality. Washington, DC: The National Academies Press; 2012. [13] Bachmair A. State of health of unvaccinated children; 2012. www. vaccineinjury.info/ (accessed 29.01.15).

Please cite this article in press as: Turville C, Golden I. Autism and vaccination: The value of the evidence base of a recent meta-analysis. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.02.002

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[14] Generation Rescue. Cal-Oregon unvaccinated survey; 2007. http://www. generationrescue.org/resources/vaccination/cal-oregon-unvaccinated-survey/ (accessed 29.01.15). [15] Hull BP, Dey A, Menzies RI, Brotherton JM, McIntyre PB. Immunisation coverage, 2012. Commun Dis Intell 2014;38(3):E208–31. [16] Golden I. The potential value of homeoprophylaxis in the long-term prevention of infectious diseases, and the maintenance of general health in recipients. Melbourne, Australia: Swinburne University Press; September 2004. p. 169.

Christopher Turville International and Partnerships, School of Applied and Biomedical Sciences, Faculty of Science and Technology, Federation University of Australia, Australia

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Isaac Golden ∗ Centre for Informatics and Applied Optimization (CIAO), Faculty of Science and Technology, Federation University of Australia, Australia ∗ Corresponding author. Tel.: +61 354270880. E-mail address: [email protected] (I. Golden)

23 September 2014 Available online xxx

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