Faculty Bibliography

A case-control analysis was conducted to determine the relationship between height and mortality among patients enrolled in the already completed Beta Blocker Heart Attack Trial (BHAT). In a basic model including height (continuous) and relevant covariates the relative risk (RR) per 4-inch reduction in height (approximately 1 standard deviation) was 1.18 (95% confidence interval, 0.92 to 1.51). When sex was considered, the effect of short stature on mortality was found to be restricted to male subjects. The male RR per 4-inch reduction in height was 1.26 (0.96 to 1.63) whereas for women it was 0.89 (0.49 to 1.59). In males not randomized to propranolol (untreated) the effect was further modified with a RR per 4-inch reduction in height of 1.41 (1.00 to 1.99). It is hypothesized that short stature could be a marker for factors operating as far back as childhood that predispose males to mortality from coronary heart disease in later life

The thyroid gland of children is especially vulnerable to the carcinogenic action of ionizing radiation. To provide insights into various modifying influences on risk, seven major studies with organ doses to individual subjects were evaluated. Five cohort studies (atomic bomb survivors, children treated for tinea capitis, two studies of children irradiated for enlarged tonsils, and infants irradiated for an enlarged thymus gland) and two case-control studies (patients with cervical cancer and childhood cancer) were studied. The combined studies include almost 120,000 people (approximately 58,000 exposed to a wide range of doses and 61,000 nonexposed subjects), nearly 700 thyroid cancers and 3,000,000 person years of follow-up. For persons exposed to radiation before age 15 years, linearity best described the dose response, even down to 0.10 Gy. At the highest doses (> 10 Gy), associated with cancer therapy, there appeared to be a decrease or leveling of risk. For childhood exposures, the pooled excess relative risk per Gy (ERR/Gy) was 7.7 (95% CI = 2.1, 28.7) and the excess absolute risk per 10(4) PY Gy (EAR/10(4) PY Gy) was 4.4 (95% CI = 1.9, 10.1). The attributable risk percent (AR%) at 1 Gy was 88%. However, these summary estimates were affected strongly by age at exposure even within this limited age range. The ERR was greater (P = 0.07) for females than males, but the findings from the individual studies were not consistent. The EAR was higher among women, reflecting their higher rate of naturally occurring thyroid cancer. The distribution of ERR over time followed neither a simple multiplicative nor an additive pattern in relation to background occurrence. Only two cases were seen within 5 years of exposure. The ERR began to decline about 30 years after exposure but was still elevated at 40 years. Risk also decreased significantly with increasing age at exposure, with little risk apparent after age 20 years. Based on limited data, there was a suggestion that spreading dose over time (from a few days to > 1 year) may lower risk, possibly due to the opportunity for cellular repair mechanisms to operate. The thyroid gland in children has one of the highest risk coefficients of any organ and is the only tissue with convincing evidence for risk about 1.10 Gy

Epidemiologic studies have focused on the association between diet and breast cancer with conflicting results. Whereas a majority of case-control studies indicate a role for the intake of total fat and saturated fat, most prospective cohort studies either are negative or indicate very modest associations. Only a few authors have examined the role of meat intake in relation to breast cancer risk. The aim of this study was to examine the relation between risk of breast cancer and dietary intake of meat, animal products, fat, and protein. Between 1985 and 1991, we recruited 14,291 New York City women in a prospective cohort study of endogenous hormones, diet, and cancer in which they reported on their recent diet using a food frequency questionnaire self-administered at enrollment. From the cohort, 180 invasive breast cancer cases diagnosed before December 1990 and five times as many controls, individually matched by age, calendar time at enrollment, menopausal status, and, if premenopausal, phase of menstrual cycle, were included in a nested case-control study. There was an evident increase in the relative risk (RR) of breast cancer for increasing consumption of meat. Women in the upper quintile of meat consumption, as compared with the lowest quintile, had an energy-adjusted RR of 1.87 (95% confidence interval = 1.09-3.21). There was a modest RR increase in the upper quintile of total and saturated fat and no apparent association for other types of fat, protein, dairy products, poultry, or fish.(ABSTRACT TRUNCATED AT 250 WORDS)

Estradiol (E2) circulates in the blood in three states: unbound (U-E2), bound to sex-hormone binding globulin (SHBG-E2), and bound to albumin. There is evidence to support the concept that only U-E2 and albumin-bound E2, are bioavailable (i.e., rapidly extracted by tissues). A case-control study nested within a large cohort of women, in which we are examining the effect of estrogens on breast cancer risk, offered the opportunity to assess the reliability of measurements of E2, the percentage of SHBG-E2, and the percentage of U-E2 based on multiple annual serum specimens. Long-term (1-2 year) reliability, as estimated by the intraclass correlation coefficient, was assessed in a subgroup of 71 premenopausal and 77 postmenopausal controls for whom two or three serum specimens were assayed. In postmenopausal women the intraclass correlation coefficient for a single measurement of total E2 was only 0.51. As for the percentage of SHBG-E2, intraclass correlation coefficients were 0.83 and 0.94, and for U-E2, 0.72 and 0.77 in the premenopausal and postmenopausal groups, respectively. These data suggest that, whereas single determinations of total E2 are insufficient to reliably estimate a woman's true mean level, a single measurement of the percentage of SHBG-E2 or U-E2 is adequate to assess bioavailability of E2 in an epidemiological study, irrespective of day of the menstrual cycle

Levels of total estradiol in premenopausal women vary widely over the course of the menstrual cycle with a spike at the time of ovulation and dissimilar patterns pre- and post-ovulation. Evaluating the association between breast cancer and premenopausal measurements of total estradiol when the measurements cannot be taken on a uniform day of the cycle is therefore a difficult methodological challenge. In a matched case-control study of breast cancer nested within a prospective study, premenopausal serum samples obtained up to 7 years before breast cancer diagnosis were available for total estradiol assay. By fitting a three-piece spline model that regressed the logarithm of total estradiol (ln estradiol) on day of menstrual cycle, the authors were able to adjust the measurements for day of the cycle on which they were collected by expressing them in terms of the number of standard deviations above or below the fitted ln estradiol value for that day. Applying the adjusted measurements to the nested case-control study, they found evidence of a 1.5 to 2-fold risk for women in the upper two tertiles of ln estradiol relative to women in the lowest tertile. Conditional logistic regression analysis for day-of-cycle-adjusted ln estradiol treated as a continuous variable resulted in a relative risk estimate of 1.19 (95% confidence interval 0.91-1.55) per standard-deviation increase in adjusted ln estradiol