Reply to D.C. Sokal et al.

The impetus for the Siddiqui et al study was to address appropriate concerns that positive associations between vasectomy and prostate cancer in prior epidemiologic studies could be attributed to bias. Using data from the Health Professionals Follow-Up Study (HPFS), we carefully considered bias resulting from intensity of prostatespecific antigen (PSA) screening as well as confounding resulting from potential differences among men with and without vasectomy. Here we address concerns raised by Sokal et al about this study. Sokal et al point to differences in relative risks between the original HPFS study published in 1993 and the report by Siddiqui et al. There was a critical factor introduced in the United States between the timing of these two publications: PSA screening. Before widespread screening started in the early 1990s, a higher proportion of men were diagnosed with advanced prostate cancer. In the PSA era, screening dramatically increased overdiagnosis of indolent prostate cancers. Thus, the investigation of overall prostate cancer risk is quite different in these two settings. Of note, our findings regarding vasectomy and risk of advanced prostate cancer are consistent with the 1993 results. PSA screening has had broad effects on epidemiologic studies of prostate cancer, because there is evidence delineating lifestyle factors specifically for risk of aggressive disease. We were transparent in describing inclusion and exclusion criteria and follow-up procedures for both studies. The small differences in baseline sample size were the result of the exclusion of men with missing dietary data in the 1993 study, because those variables were adjusted for in analyses, whereas we adjusted for a more limited set of dietary variables in the current study. If we apply the additional exclusions in the current analysis, the results are unchanged. Loss to follow-up is a minimal concern within HPFS; even 24 years into the study, an impressive 93% of men complete a questionnaire in a given cycle. Furthermore, follow-up for cancer incidence ( 96%) and for mortality ( 98%) are high. There are three criteria for a factor to be a confounder: prevalence of the factor varies with the exposure of interest (vasectomy), the factor is independently associated with disease risk (advanced or lethal cancer), and prevalence of the factor should be sufficiently high in the population. Sokal et al incorrectly state that we did not investigate the role of tomatoes (lycopene) or religion, because we state that “geographical region, religion, self-reported history of gonorrhea and syphilis, frequency of ejaculation, intakes of tomato sauce . were not included in the final models because they were not associated with vasectomy and had little effect on the RR [relative risk] estimates. ” Religion and tomato sauce intake do not meet all criteria for confounders. The relative risks of vasectomy and lethal prostate cancer were virtually identical in the analyses with (hazard ratio, 1.56) and without (hazard ratio, 1.55) adjustment for tomato sauce and religion. We reported on finasteride in HPFS and found no association with risk of advanced or lethal cancer, a noteworthy finding in that it recapitulates the mortality results within the Prostate Cancer Prevention Trial and supports our ability to properly control for confounding. We acknowledge that there still may have been unmeasured confounding, although given the number of factors considered, it is unlikely that this bias would have meaningfully influenced risk estimates. Sokal et al raise issues that are not methodologically sound. First, the comparison of crude cumulative incidences by vasectomy status is biased. Such risks do not account for the considerable differences in age and PSA screening patterns by vasectomy status, nor do they account for follow-up time. It would not have been valid to compare the relative risks for the highly screened group, which optimally accounts for diagnostic bias, with a non–highly screened cohort in which residual confounding resulting from PSA screening differences could remain. Such a comparison would have been biased, because a test for interaction between two groups assumes a causal association in both subgroups. Our current strategy was similar to that in our lycopene study, although we limited the analysis to men who had two—rather than one—PSA tests. Our results showing a positive association between vasectomy and advanced prostate cancer have generated lively discussions within the scientific community, and we welcome critical evaluations of the methodology and findings. Our investigation integrated the most detailed information of any prior study, and the results are methodologically sound. As we previously stated, a man’s decision to opt for vasectomy is a highly personal one, and one that should be discussed with his family and physician in light of the totality of evidence.