Hepatitis B vaccine and risk of multiple sclerosis

We are writing regarding the commentary by Hernan and Jick in response to our reanalysis of our study on hepatitis B vaccine and risk of multiple sclerosis reported in a letter to the editor of Neurology. The commentary raises several pertinent questions about our analysis that wewere not able to address within the limited length of our previously published letter. Before addressing Hernan and Jick’s specific concerns, we wish to present some additional results that were not included in our letter. To be most consistent with the General Practice Research Database (GPRD) analysis, we compared the risks associated with vaccination 3 years before the index date versus >3 years or never vaccinated; the odds ratios (95% confidence interval) were 0.7 (0.3–1.4) using medical records plus interview data and 0.2 (0.03–1.5) using medical records data only. Turning to Hernan’s and Jick’s specific concerns, they first note that over 30% of the selected controls were not included in our study, which may have introduced selection bias. Since we did not find an increased risk of MS associated with hepatitis B vaccination, the concern would be that controls who participated had higher vaccination rates than those who did not, thus resulting in a downward bias of the relative risk estimates. Levels of hepatitis B vaccine coverage in the general adult population could provide evidence on this possibility, but such data are not available. In our original study, we evaluated several vaccines and found that the odds ratios for most were less than 1.0. Thus, we have to consider the possibility that the controls who participated may have been more likely vaccinated than the general population of health maintenance organization (HMO) members. This concern would be most pronounced for tetanus toxoid-containing vaccines, where we found significantly decreased risks of demyelinating diseases. We compared the self-reported tetanus vaccination histories of the controls in our study, who were interviewed in 1999 and 2000, against similar selfreported vaccination data from a sample of US adults in the 1995 National Health Interview Survey (NHIS). Receipt of tetanus toxoid vaccine in the previous 10 years was reported by 65% of adults 18–49 years of age in the NHIS compared with 48% in our study. Although the time periods are not strictly comparable, the substantially lower tetanus vaccination coverage in the controls in our study suggests that they were not a more highly vaccinated group than the general population. Second, Hernan and Jick question the accuracy of the MS onset dates in our study compared with their study that was based on GPRD records. Their concern is two-fold: (1) in our analyses in which we included self-reported information, the retrospective recall of dates may have been inaccurate; and (2) in the analyses restricted to medical records data, we may have had incomplete information because some of the participants may have not been enrolled for at least 3 years prior to their index date. The GPRD study relied solely on computerized or paper medical record data; thus, the availability of data from the computerized records of the medical practices was necessary to obtain historical vaccination information for at least 3 years prior to disease onset. In our study, we obtained this information from the patient interviews if it was not available in the HMO records. When we limited our analysis to medical records data, we identified only three vaccinated cases among the 119 MS cases eligible for the analysis. Nonetheless, the results of analyses that were restricted to vaccination and symptom data recorded in the medical records were similar to the results from analyses that included self-reported information. The usual concern with case-control studies that include interview data is that the cases may have more pharmacoepidemiology and drug safety 2007; 16: 705–708