you quoted 1 comment on the paper...
here are the author's responses to most of the complaints levied at the paper:
Response
To the Editor:
Mr. Crosby repeats the claim that the age-adjustment in our original 2002 paper has “artificially eliminated” an association between MMR and autism. He references an unpublished letter by Dr. Suissa, claiming that the rates in Table 2 of our 2002 paper and our adjusted RRs are incompatible and that this might reflect effect modification. This is incorrect. From Table 2 in our 2002 paper, we can calculate the crude relative risk (RR) of autistic disorder as 1.45 (95% CI, 1.08-1.95). Adjusting for age yields a RR of 0.91 (0.68-1.23). As explained previously, the discrepancy between the crude and age-adjusted RRs is due to the follow-up in the unvaccinated group comprising person-time from 1 year of age until age at MMR vaccination from all the MMR vaccinated children. Now, if we start follow-up at 2 years of age instead of 1 year of age we get a crude RR of 0.90 (0.66-1.22) and an age-adjusted RR of 0.88 (0.65-1.19). Clearly, starting follow-up at an age where the unvaccinated and vaccinated groups have similar age distributions yields almost identical results as the main result in the paper; we maintain that adjustment for age is both appropriate and necessary with follow-up from 1 year of age. Similarly, for our current study, we repeat our previous response: In Figure 2, we present cumulative incidences according to age; there is absolutely no suggestion of any age interval where vaccinated children have a higher rate of autism than unvaccinated children, and a test of homogeneity yielded a P-value of 0.138 (see Results).
Mr. Crosby claims that there is clear evidence of an interaction between sibling status and MMR vaccination. We tested this and found no such evidence P>0.20 (see Figure 3). Mr. Crosby also claims that analyzing sibling status, as a time-varying variable is inappropriate. This, too, is not correct. By continually updating sibling status in the event of a sibling receiving an autism diagnosis, all information this variable can supply as a proxy for genetic susceptibility is utilized. Our claim that the two approaches measure the same attribute with differing degrees of statistical precision is supported by a comparison of autism HRs: status at study start HR 7.32 (5.29-10.12) and time-varying status HR 7.64 (6.77-8.62) (Table 3, Supplementary Material).
In conclusion, we maintain that we have analyzed the current study and our 2002 study using appropriate statistical methods, finding no support for an association between MMR vaccination and autism risk, a lack of an association that also applied in children with autistic siblings.
Sincerely,
Anders Hviid, Jørgen Vinsløv Hansen, Morten Frisch, Mads Melbye.
Anders Hviid, Jørgen Vinsløv Hansen, Morten Frisch, Mads MelbyeStatens Serum Institut11 March 2019
Authors' Response
To the Editor:
We appreciate the massive, global attention our paper has received and have carefully evaluated all comments. Below, we address the major claims made by some of our critics.
Mr. Arumugham lists a number of specific biological mechanisms hypothesized to be involved in the etiology of autism, and he rightfully claims that epidemiological studies are not capable of addressing such mechanisms. However, Mr. Arumugham ignores the central message from our present and prior well-conducted epidemiological investigations, namely that regardless of which biological mechanisms lead to autism, there is no difference in autism risk between MMR-vaccinated and MMR-unvaccinated individuals. In this light, it seems illogical and futile to continue the quest to understand the biology of autism by focusing on theoretical adverse effects of a vaccine that seems, rather compellingly, to be safe both overall and, specifically, in relation to autism risk.
Professor Exley wants to know if we took prior exposure to aluminium, for example in vaccinations that include an aluminium adjuvant, into account. Indeed, we did. According to Figure 3 in the paper, MMR vaccination was not associated with autism risk, whether children had been vaccinated with aluminium-adjuvanted vaccines (DTaP-IPV/Hib) in infancy or not.
In response to Mr. Crosby’s comment it should be noted that sibling status at 1 year of age was not an effect modifier (Figure 3, p>0.20), and the confidence interval for the “Siblings with autism” effect estimate overlaps HR=1.00. In Figure 2 of the Supplementary Material, we transparently provide the unadjusted cumulative incidences according to age and vaccination status, and stratified according to child’s sex and sibling history of autism; these supplementary analyses do not support an association in children with autistic siblings. Sibling status at 1 year of age is a conservative measure of “Siblings with autism” with only 5 unvaccinated and 32 vaccinated cases (Figure 3). If we consider sibling history as a time-varying variable, that is, each child’s “sibling status” is updated during the study period, e.g. if a sibling is diagnosed with autism, we gain statistical power. In this analysis, MMR vaccination was also not associated with autism risk in children with autistic siblings (HR, 1.15, 95% CI, 0.71-1.87) (see Results).
The further claim by Mr. Crosby that we “artificially eliminated” an association between MMR vaccination and autism by adjusting for age in our 2002 study is false and reveals an incomplete understanding of survival analysis. Our 2002 study and the current study share many similarities in study design, and thus, the concept of confounding by age is clearly illustrated in Figure 1 of the Supplementary Material, where the distribution of time and autism cases according to vaccination status and age is visualized; here we show that unvaccinated children are younger, and since younger children have lower rates of autism the crude rate ratio is confounded by age. Consequently, adjustment for age is required. In Figure 2, we present cumulative incidences according to age; there is no suggestion of any age interval where vaccinated children have a higher rate of autism than unvaccinated children, and a test of homogeneity yielded a P-value of 0.138 (see Results).
In conclusion, we maintain that we have analyzed the current study as well as our 2002 study using appropriate statistical methods, finding no support for an association between MMR vaccination and autism risk, a lack of an association that also applied in children with autistic siblings.
Sincerely,
Anders Hviid, Jørgen Vinsløv Hansen, Morten Frisch and Mads Melbye
This is 1 of a large body of peer-reviewed papers (others of which i have also posted links to) that all investigate links between MMR and autism with various different methodologies - not 1 has found any link between the 2 - nor has any vaccine study - including of the risks of a so-called "vaccine overload" theory that is even less substantiated than the rest
