The Sister Study Cohort: Baseline Methods and Participant Characteristics.

BACKGROUND: The Sister Study was designed to address gaps in the study of environment and breast cancer by taking advantage of more frequent breast cancer diagnoses among women with a sister history of breast cancer and the presumed enrichment of shared environmental and genetic exposures. OBJECTIVE: The Sister Study sought a large cohort of women never diagnosed with breast cancer but who had a sister (full or half) diagnosed with breast cancer. METHODS: A multifaceted national effort employed novel strategies to recruit a diverse cohort, and collected biological and environmental samples and extensive data on potential breast cancer risk factors. RESULTS: The Sister Study enrolled 50,884 U.S. and Puerto Rican women 35-74y of age (median 56 y). Although the majority were non-Hispanic white, well educated, and economically well off, substantial numbers of harder-to-recruit women also enrolled (race/ethnicity other than non-Hispanic white: 16%; no college degree: 35%; household income <$50,000: 26%). Although all had a biologic sister with breast cancer, 16.5% had average or lower risk of breast cancer according to the Breast Cancer Risk Assessment Tool (Gail score). Most were postmenopausal (66%), parous with a first full-term pregnancy <30y of age (79%), never-smokers (56%) with body mass indexes (BMIs) of <29.9 kg/m2 (70%). Few (5%) reported any cancer prior to enrollment. CONCLUSIONS: The Sister Study is a unique cohort designed to efficiently study environmental and genetic risk factors for breast cancer. Extensive exposure data over the life-course and baseline specimens provide important opportunities for studying breast cancer and other health outcomes in women. Collaborations are welcome. https://doi.org/10.1289/EHP1923.

Lifetime use of nonsteroidal anti-inflammatory drugs and breast cancer risk: results from a prospective study of women with a sister with breast cancer.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to inhibit several pathways in experimental models of breast carcinogenesis, but epidemiological evidence remains insufficient to support their use for breast cancer prevention. We examined the association between use of NSAIDs and breast cancer risk in a prospective cohort. METHODS: The Sister Study is a prospective cohort study of women who had a sister(s) with breast cancer. As of December 2013, 2118 incident breast cancers were ascertained from 50,884 women enrolled between 2003 and 2009. Lifetime history of NSAID use was estimated from self-reported data in pill-years, with 1 pill per week for a year equivalent to 1 pill-year. Cox regression models were used to estimate hazard ratios (HRs) of breast cancer in relation to pill-years of use for different NSAIDs, with adjustment for potential confounders. RESULTS: In the full cohort, although there was some evidence that use of non-aspirin, non-COXib NSAIDs was associated with lower breast cancer risk, there was little evidence of overall association for most categories of NSAID use. Among postmenopausal women NSAID use was not associated with reduced risk of breast cancer. However, among premenopausal women there was significantly reduced risk for any NSAID (HR4vs1=0.66, 95% CI: 0.50-0.87) and specifically for aspirin (HR4vs1=0.57, 95% CI: 0.33-0.98), with small, but non-significant reductions in risk for other drug classes. CONCLUSION: Women with a sister with breast cancer are themselves at increased risk and might benefit the most from chemoprevention. Although there was little evidence of protective effect from NSAIDs in the overall cohort of women or among the subset who are postmenopausal, there is intriguing evidence that NSAID use, particularly aspirin, may reduce risk among premenopausal women.

Using risk-based sampling to enrich cohorts for endpoints, genes, and exposures.

Targeting the first-degree relatives of people with a particular complex disease can offer a powerful approach to building a risk-based cohort for prospective studies of etiologic factors. Such a cohort provides both a sizable increase in the rate of accrual of newly incident cases, enriching for risk factors that are known or even unknown, and a high level of motivation among participants. A nationwide study of breast cancer in the United States and Puerto Rico, the Sister Study, made up of women who are each the sister of a woman with breast cancer, exemplifies this approach. In this paper, the authors provide power calculations to aid in the design of such studies and quantify their benefits for detecting both genetic variants related to risk and interactive effects of genetic and environmental factors. While the risk-based cohort can have markedly increased prevalences of rare causative alleles, most of the power advantages for this design is due to the increased rate of accrual of newly incident cases rather than the increase in any one individual allele.

Causes of Mortality and Risk Factors for Injury Mortality among Children in the Agricultural Health Study.

Farm children face unique health risks due to sharing their residential environment with hazardous machinery and materials. Causes of mortality among farm children have not been comprehensively described. OBJECTIVE: In the Agricultural Health Study (AHS) cohort, we examined causes of mortality among 21,360 children in Iowa and North Carolina between 1975 and 1998. METHODS: We matched identifying information for children provided by mothers on self-administered questionnaires to state death registries (1975-1998). Data on farm and family characteristics were provided by parents via enrollment questionnaires (1993-1997). Standardized mortality ratios (SMRs) were calculated, using state mortality data to generate expected deaths. We used logistic regression to examine parent, child and farm characteristics associated with injury mortality. RESULTS: There were 162 deaths in Iowa (SMR=0.69; 95% confidence interval (CI)=0.60, 0.81) and 26 deaths in North Carolina (SMR=0.42; 95%CI=0.28, 0.61) in children aged 0-19 years. This deficit was largely due to deaths in the first year of life. Although deaths from overall unintentional injury were not increased, excess agricultural machinery mortality was observed in Iowa (SMR=9.25; 95% CI=5.12, 16.70). In case-control comparisons, maternal age less than 25 years at child's birth (OR=2.17; 95%CI=1.05, 4.49) and having more than 2 children in the family (OR=2.79; 95%CI=1.47, 5.30) were associated with increased child injury mortality. For children under 14 years, participation in farm work was associated with increased risk of agricultural machine-related mortality (OR=3.92; 95% CI=1.04, 14.78). CONCLUSIONS: Parent and child characteristics associated with child injury mortality could be used to target farm safety interventions.

Incidence of leukemia, lymphoma, and multiple myeloma in Czech uranium miners: a case-cohort study.

OBJECTIVE: Uranium miners are chronically exposed to low levels of radon and its progeny. We investigated whether radon exposure is associated with increased incidence of leukemia, lymphoma, or multiple myeloma in this population. DESIGN: We conducted a retrospective case-cohort study in 23,043 uranium miners and identified a total of 177 incident cases of leukemia, lymphoma, and myeloma. Detailed information on occupational radon exposure was obtained for the cases and a randomly selected subcohort of 2,393 subjects. We used the proportional hazards model with power relative risk (RR) function to estimate and test the effects of cumulative radon exposures on incidence rates. RESULTS: Incidence of all leukemia combined and chronic lymphocytic leukemia (CLL) alone was positively associated with cumulative radon exposure. The RR comparing high radon exposure [110 working level months (WLM) ; 80th percentile] to low radon exposure (3 WLM ; 20th percentile) was 1.75 [95% confidence interval (CI) , 1.10-2.78 ; p = 0.014] for all leukemia combined and 1.98 (95% CI, 1.10-3.59 ; p = 0.016) for CLL. Myeloid leukemia and Hodgkin lymphoma were also associated with radon, but RRs were not statistically significant. There was no apparent association of radon with either non-Hodgkin lymphoma or multiple myeloma. Exposure to radon and its progeny was associated with an increased risk of developing leukemia in underground uranium miners. CLL, not previously believed to be radiogenic, was linked to radon exposure.

Indoor radon and lung cancer risk in connecticut and utah.

Radon is a well-established cause of lung cancer in miners. Residents of homes with high levels of radon are potentially also at risk. Although most individual studies of indoor radon have failed to demonstrate significant risks, results have generally been consistent with estimates from studies of miners. We studied 1474 incident lung cancer cases aged 40-79 yr in Connecticut, Utah, and southern Idaho. Population controls (n = 1811) were identified by random telephone screening and from lists of Medicare recipients, and were selected to be similar to cases on age, gender, and smoking 10 yr before diagnosis/interview using randomized recruitment. Complete residential histories and information on known lung cancer risk factors were obtained by in-person and telephone interviews. Radon was measured on multiple levels of past and current homes using 12-mo alpha-track etch detectors. Missing data were imputed using mean radon concentrations for informative subgroups of controls. Average radon exposures were lower than anticipated, with median values of 23 Bq/m3 in Connecticut and 45 Bq/m3 in Utah/southern Idaho. Overall, there was little association between time-weighted average radon exposures 5 to 25 yr prior to diagnosis/interview and lung cancer risk. The excess relative risk (ERR) associated with a 100-Bq/m3 increase in radon level was 0.002 (95% CI -0.21, 0.21) in the overall population, 0.134 (95% CI -0.23, 0.50) in Connecticut, and -0.112 (95% CI -0.34, 0.11) in Utah/Idaho. ERRs were higher for some subgroups less prone to misclassification, but there was no group with a statistically significant linear increase in risk. While results were consistent with the estimates from studies of miners, this study provides no evidence of an increased risk for lung cancer at the exposure levels observed.

Causes of mortality and risk factors for injury mortality among children in the agricultural health study.

UNLABELLED: Farm children face unique health risks due to sharing their residential environment with hazardous machinery and materials. Causes of mortality among farm children have not been comprehensively described. OBJECTIVE: In the Agricultural Health Study (AHS) cohort, we examined causes of mortality among 21,360 children in Iowa and North Carolina between 1975 and 1998. METHODS: We matched identifying information for children provided by mothers on self-administered questionnaires to state death registries (1975-1998). Data on farm and family characteristics were provided by parents via enrollment questionnaires (1993-1997). Standardized mortality ratios (SMRs) were calculated, using state mortality data to generate expected deaths. We used logistic regression to examine parent, child and farm characteristics associated with injury mortality. RESULTS: There were 162 deaths in Iowa (SMR = 0.69; 95% confidence interval (CI) = 0.60, 0.81) and 26 deaths in North Carolina (SMR = 0.42; 95% CI = 0.28, 0.61) in children aged 0-19 years. This deficit was largely due to deaths in the first year of life. Although deaths from overall unintentional injury were not increased, excess agricultural machinery mortality was observed in Iowa (SMR = 9.25; 95% CI = 5.12, 16.70). In case-control comparisons, maternal age less than 25 years at child's birth (OR = 2.17; 95% CI = 1.05, 4.49) and having more than 2 children in the family (OR = 2.79; 95% CI = 1.47, 5.30) were associated with increased child injury mortality. For children under 14 years, participation in farm work was associated with increased risk of agricultural machine-related mortality (OR = 3.92; 95% CI = 1.04, 14.78). CONCLUSIONS: Parent and child characteristics associated with child injury mortality could be used to target farm safety interventions.

Occupation, hobbies, and acute leukemia in adults.

Occupational and industrial exposures have been implicated in the etiology of leukemia, yet uncertainty remains regarding potential high risk occupations. We examined the associations between self-reported occupations and hobbies and acute leukemia risk using data from 811 cases and 637 controls participating in a case-control study in the U.S. and Canada. We found that several occupations may increase the risk of acute leukemia, particularly occupations related to petroleum products, rubber, nuclear energy, munitions, plastics, and electronics manufacturing. Differences were noted according to histological type. Other occupations and hobbies were not clearly associated with risk.

Cancer risk and parental pesticide application in children of Agricultural Health Study participants.

Parental exposure to pesticides may contribute to childhood cancer risk. Through the Agricultural Health Study, a prospective study of pesticide applicators in Iowa and North Carolina, we examined childhood cancer risk and associations with parental pesticide application. Identifying information for 17,357 children of Iowa pesticide applicators was provided by parents via questionnaires (1993-1997) and matched against the Iowa Cancer Registry. Fifty incident childhood cancers were identified (1975-1998). Risk of all childhood cancers combined was increased [standardized incidence ratio (SIR) = 1.36; 95% confidence interval (CI), 1.03-1.79]. Risk of all lymphomas combined was also increased (SIR = 2.18; 95% CI, 1.13-4.19), as was risk of Hodgkin's lymphoma (SIR = 2.56; 95% CI, 1.06-6.14). We used logistic regression to explore associations between self-reported parental pesticide application practices and childhood cancer risk. No association was detected between frequency of parental pesticide application and childhood cancer risk. An increased risk of cancer was detected among children whose fathers did not use chemically resistant gloves [odds ratio (OR) = 1.98; 95% CI, 1.05-3.76] compared with children whose fathers used gloves. Of 16 specific pesticides used by fathers prenatally, ORs were increased for aldrin (OR = 2.66), dichlorvos (OR = 2.06), and ethyl dipropylthiocarbamate (OR = 1.91). However, these results were based on small numbers and not supported by prior biologic evidence. Identification of excess lymphoma risk suggests that farm exposures including pesticides may play a role in the etiology of childhood lymphoma.

DDT metabolite and androgens in African-American farmers.

BACKGROUND: The ubiquitous dichlorodiphenyltrichloroethane (DDT) metabolite 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) is an androgen receptor antagonist. Data on potential antiandrogenic activity of DDE in humans are limited. METHODS: The relations between concentrations of plasma DDE and several serum androgens (total testosterone, bioavailable testosterone, 5alpha-dihydrotestosterone, and free androgen index) were examined in 137 North Carolina black male farmers, using multiple linear regression. RESULTS: Participants ranged in age from 30 to 88 years (mean = 62 years). Most had farmed for about 30 years and 27% reported having used DDT. The median DDE level was 7.7 microg per liter (1213 microg per kg lipid), slightly higher than in other recent studies. Overall, concentrations of DDE and androgens were unrelated. Total testosterone decreased 2% (95% confidence limits [CL] = -9%, 5%) per increase in interquartile distance of lipid-adjusted DDE. The percentage change in other hormones was similarly negligible. However, among those whose DDE level was in the top tenth percentile, compared with all others, total testosterone and free androgen index were lower by 23% (CL= -40%, 1%) and 22% (CL =-41%, 4%) respectively. Plasma androgen levels decreased with age, a relation that has previously been studied only in whites. CONCLUSIONS: Studies of more highly exposed populations may be needed to evaluate effects, if any, of DDE.

Pesticide use and pesticide-related symptoms among black farmers in the Agricultural Health Study.

BACKGROUND: Health effects of pesticides have not been well studied in black farmers. We describe agricultural practices and pesticide-related symptoms in North Carolina black and white farmers participating in the Agricultural Health Study. METHODS: Self-administered questionnaires were completed by 891 black and 11,909 white farmers licensed to apply restricted pesticides. Regression models were used to compare characteristics by race. RESULTS: Black farmers reported lower lifetime pesticide use, less use of each class of pesticides (e.g., herbicides, insecticides), less use of high exposure application methods, and fewer pesticide-related symptoms such as headaches or dizziness, skin irritation, chest discomfort and feeling nervous or depressed than did white farmers. CONCLUSIONS: Differences between black and white farmers may be explained by farm characteristics or economics. Despite lower use of pesticides, black farmers may have other work practices that affect exposure and risk.