Breast cancer, birth cohorts, and Epstein-Barr virus: methodological issues in exploring the "hygiene hypothesis" in relation to breast cancer, Hodgkin's disease, and stomach cancer.

To address methodological issues in exploring a variant of the "hygiene hypothesis" that posits delayed infection by Epstein-Barr virus contributes to rising rates of breast cancer and Hodgkin's disease, we examined birth cohort trends in the incidence of both cancers plus stomach cancer, building on previously reported year-of-diagnosis cross-sectional associations of age-standardized rates. Using published data from the United States Connecticut state cancer registry (1935-1998) for women for each cancer site, we obtained age-specific incidence rates by birth cohort (1870-1874 to 1970-1974), along with age-standardized incidence rates for selected calendar years (1935-1939, 1940-1944,., 1990-1994, 1995-1998). Clear secular trends in incidence rates, in the opposite direction, were evident for: (a) breast cancer and for Hodgkin's disease in young adults (increasing), and (b) stomach cancer (decreasing). Correlations between the incidence of breast cancer among women ages 50-54 and Hodgkin's disease among young adults (ages 20-24) were stronger for birth cohort (Pearson correlation, 0.85) than for cross-sectional analyses (Pearson correlation, 0.68). Stronger associations between the incidence of breast cancer and non-Hodgkin's disease were evident for birth cohort compared with cross-sectional analyses, findings consonant with (but not "proof" of) the hygiene hypothesis. One methodological implication is that tests of the hygiene hypothesis must take into account birth cohort effects and age at incidence of the outcomes under study; age-standardized cross-sectional analyses may be misleading.