Faculty Bibliography

The nested case-control (NCC) design is a cost-effective sampling method to study the relationship between a disease and its risk factors in epidemiologic studies. NCC data are commonly analyzed using Thomas' partial likelihood approach under Cox's proportional hazards model with constant covariate effects. Here, we are interested in studying the potential time-varying effects of covariates in NCC studies and propose an estimation approach based on a kernel-weighted Thomas' partial likelihood. We establish asymptotic properties of the proposed estimator, propose a numerical approach to construct simultaneous confidence bands for time-varying coefficients, and develop a hypothesis testing procedure to detect time-varying coefficients. The proposed inference procedure is evaluated in simulations and applied to an NCC study of breast cancer in the New York University Women's Health Study

Cytokines play important roles in B-cell activation, proliferation, and apoptosis, thus may be etiologically related to risk of B-cell non-Hodgkin lymphoma (B-NHL). However, the association between circulating levels of cytokines and B-NHL risk has not been prospectively studied in non-HIV populations. The objective of this study was to assess this association by conducting a case-control study nested within a prospective cohort of non-HIV-infected, healthy women. Fifteen cytokines were measured in samples collected a median of 8.2 years prior to diagnosis in 92 cases and two matched controls per case. Only cytokines that showed adequate temporal reproducibility over a two-year period were included. The odds ratio (OR) for the highest tertile relative to the lowest was elevated for soluble IL-2 receptor (sIL-2R) (OR = 2.5, 95% CI = 1.4-4.7, p (trend) < 0.01) and decreased for IL-13 (OR = 0.5, 95% CI = 0.2-1.0, p (trend) = 0.05). Three other cytokines were marginally associated with risk of B-NHL: TNF-alpha (OR = 1.7, 95% CI = 0.9-3.3, p (trend) = 0.11), sTNF-R2 (OR = 1.9, 95% CI = 0.9-3.5, p (trend) = 0.06), and IL-5 (OR = 0.5, 95% CI = 0.3-1.0, p (trend) = 0.06). No association was observed between B-NHL risk and levels of the other cytokines measured (IL-1beta, IL-1RA, IL-2, IL-4, IL-6, IL-10, IL-12, IL-12p70, CRP and sTNF-R1). This study suggests that dysregulated cytokines may be involved in B-NHL development

Background: Insulin-like growth factor 1 (IGF1) stimulates mitosis and inhibits apoptosis. Some published results have shown an association between circulating IGF1 and breast-cancer risk, but it has been unclear whether this relationship is consistent or whether it is modified by IGF binding protein 3 (IGFBP3), menopausal status, oestrogen receptor status or other factors. The relationship of IGF1 (and IGFBP3) with breast-cancer risk factors is also unclear. The Endogenous Hormones and Breast Cancer Collaborative Group was established to analyse pooled individual data from prospective studies to increase the precision of the estimated associations of endogenous hormones with breast-cancer risk.
Method(s): Individual data on prediagnostic IGF1 and IGFBP3 concentrations were obtained from 17 prospective studies in 12 countries. The associations of IGF1 with risk factors for breast cancer in controls were examined by calculating geometric mean concentrations in categories of these factors. The odds ratios (ORs) with 95% CIs of breast cancer associated with increasing IGF1 concentrations were estimated by conditional logistic regression in 4790 cases and 9428 matched controls, with stratification by study, age at baseline, and date of baseline. All statistical tests were two-sided, and a p value of less than 0.05 was considered significant.
Finding(s): IGF1 concentrations, adjusted for age, were positively associated with height and age at first pregnancy, inversely associated with age at menarche and years since menopause, and were higher in moderately overweight women and moderate alcohol consumers than in other women. The OR for breast cancer for women in the highest versus the lowest fifth of IGF1 concentration was 1.28 (95% CI 1.14-1.44; p<0.0001). This association was not altered by adjusting for IGFBP3, and did not vary significantly by menopausal status at blood collection. The ORs for a difference in IGF1 concentration between the highest and lowest fifth were 1.38 (95% CI 1.14-1.68) for oestrogen-receptor-positive tumours and 0.80 (0.57-1.13) for oestrogen-receptor-negative tumours (p for heterogeneity=0.007).
Interpretation(s): Circulating IGF1 is positively associated with breast-cancer risk. The association is not substantially modified by IGFBP3, and does not differ markedly by menopausal status, but seems to be confined to oestrogen-receptor-positive tumours.
Funding(s): Cancer Research UK.

BACKGROUND: Ionizing radiation is a known mutagen and an established breast carcinogen. The ATM gene is a key regulator of cellular responses to the DNA damage induced by ionizing radiation. We investigated whether genetic variants in ATM play a clinically significant role in radiation-induced contralateral breast cancer in women. METHODS: The Women's Environmental, Cancer, and Radiation Epidemiology Study is an international population-based case-control study nested within a cohort of 52,536 survivors of unilateral breast cancer diagnosed between 1985 and 2000. The 708 case subjects were women with contralateral breast cancer, and the 1397 control subjects were women with unilateral breast cancer matched to the case subjects on age, follow-up time, registry reporting region, and race and/or ethnicity. All women were interviewed and underwent full mutation screening of the entire ATM gene. Complete medical treatment history information was collected, and for all women who received radiotherapy, the radiation dose to the contralateral breast was reconstructed using radiotherapy records and radiation measurements. Rate ratios (RRs) and corresponding 95% confidence intervals (CIs) were estimated by using multivariable conditional logistic regression. All P values are two-sided. RESULTS: Among women who carried a rare ATM missense variant (ie, one carried by <1% of the study participants) that was predicted to be deleterious, those who were exposed to radiation (mean radiation exposure = 1.2 Gy, SD = 0.7) had a statistically significantly higher risk of contralateral breast cancer compared with unexposed women who carried the wild-type genotype (0.01-0.99 Gy: RR = 2.8, 95% CI = 1.2 to 6.5; > or =1.0 Gy: RR = 3.3, 95% CI = 1.4 to 8.0) or compared with unexposed women who carried the same predicted deleterious missense variant (0.01-0.99 Gy: RR = 5.3, 95% CI = 1.6 to 17.3; > or =1.0 Gy: RR = 5.8, 95% CI = 1.8 to 19.0; P(trend) = .044). CONCLUSIONS: Women who carry rare deleterious ATM missense variants and who are treated with radiation may have an elevated risk of developing contralateral breast cancer. However, the rarity of these deleterious missense variants in human populations implies that ATM mutations could account for only a small portion of second primary breast cancers

OBJECTIVE: To investigate the degree to which ionising radiation confers risk of mortality from heart disease and stroke. DESIGN: Prospective cohort study with more than 50 years of follow-up. SETTING: Atomic bomb survivors in Hiroshima and Nagasaki, Japan. PARTICIPANTS: 86 611 Life Span Study cohort members with individually estimated radiation doses from 0 to >3 Gy (86% received <0.2 Gy). MAIN OUTCOME MEASURES: Mortality from stroke or heart disease as the underlying cause of death and dose-response relations with atomic bomb radiation. RESULTS: About 9600 participants died of stroke and 8400 died of heart disease between 1950 and 2003. For stroke, the estimated excess relative risk per gray was 9% (95% confidence interval 1% to 17%, P=0.02) on the basis of a linear dose-response model, but an indication of possible upward curvature suggested relatively little risk at low doses. For heart disease, the estimated excess relative risk per gray was 14% (6% to 23%, P<0.001); a linear model provided the best fit, suggesting excess risk even at lower doses. However, the dose-response effect over the restricted dose range of 0 to 0.5 Gy was not significant. Prospective data on smoking, alcohol intake, education, occupation, obesity, and diabetes had almost no impact on the radiation risk estimates for either stroke or heart disease, and misdiagnosis of cancers as circulatory diseases could not account for the associations seen. CONCLUSION: Doses above 0.5 Gy are associated with an elevated risk of both stroke and heart disease, but the degree of risk at lower doses is unclear. Stroke and heart disease together account for about one third as many radiation associated excess deaths as do cancers among atomic bomb survivors.