Ward, Mary H.

Mixture analysis is an emerging statistical tool in epidemiological research that seeks to estimate the health effects associated with mixtures of several exposures. This approach acknowledges that individuals experience many simultaneous exposures and it can estimate the relative importance of components in the mixture. Health effects due to mixtures may vary over space driven by to political, demographic, environmental, or other differences. In such cases, estimating a global mixture effect without accounting for spatial variation would induce bias in effect estimates and potentially lower statistical power. To date, no methods have been developed to estimate spatially varying chemical mixture effects. We developed a Bayesian spatially varying mixture model that estimates spatially varying mixture effects and the importance weights of components in the mixture, while adjusting for covariates. We demonstrate the efficacy of the model through a simulation study that varies the number of mixtures (one and two) and spatial pattern (global, one‐dimensional, radial) and magnitude of mixture effects, showing that the model is able to accurately reproduce the spatial pattern of mixture effects across a diverse set of scenarios. Finally, we apply our model to a multi‐center case‐control study of non‐Hodgkin lymphoma (NHL) in Detroit, Iowa, Los Angeles, and Seattle. We identify significant spatially varying positive and inverse associations with NHL for two mixtures of pesticides in Iowa and do not find strong spatial effects at the other three centers. In conclusion, the Bayesian spatially varying mixture model represents a novel method for modeling spatial variation in mixture effects.

The exposome is an ideal in public health research that posits that individuals experience risk for adverse health outcomes from a wide variety of sources over their lifecourse. There have been increases in data collection in the various components of the exposome, but novel statistical methods are needed that capture multiple dimensions of risk at once. We introduce a Bayesian index low‐rank kriging (LRK) multiple membership model (MMM) to simultaneously estimate the health effects of one or more groups of exposures, the relative importance of exposure components, and cumulative spatial risk over time using residential histories. The model employs an MMM to consider all residential locations for subjects weighted by duration and LRK to increase computational efficiency. We demonstrate the performance of the Bayesian index LRK‐MMM through a simulation study, showing that the model accurately and consistently estimates the health effects of one or several group indices and has high power to identify a region of elevated spatial risk due to unmeasured environmental exposures. Finally, we apply our model to data from a multicenter case‐control study of non‐Hodgkin lymphoma (NHL), finding a significant positive association between one index of pesticides and risk for NHL in Iowa. Additionally, we find an area of significantly elevated spatial risk for NHL in Los Angeles. In conclusion, our Bayesian index LRK‐MMM represents a step forward toward bringing the ideals of the exposome into practice for environmental risk analyzes.

Abstract Background There are several suspected environmental risk factors for non-Hodgkin lymphoma (NHL). The associations between NHL and environmental chemical exposures have typically been evaluated for individual chemicals (i.e., one-by-one). Objectives We determined the association between a mixture of 27 correlated chemicals measured in house dust and NHL risk. Methods We conducted a population-based case–control study of NHL in four National Cancer Institute–Surveillance, Epidemiology, and End Results centers—Detroit, Michigan; Iowa; Los Angeles County, California; and Seattle, Washington—from 1998 to 2000. We used weighted quantile sum (WQS) regression to model the association of a mixture of chemicals and risk of NHL. The WQS index was a sum of weighted quartiles for 5 polychlorinated biphenyls (PCBs), 7 polycyclic aromatic hydrocarbons (PAHs), and 15 pesticides. We estimated chemical mixture weights and effects for study sites combined and for each site individually, and also for histologic subtypes of NHL. Results The WQS index was statistically significantly associated with NHL overall [odds ratio (OR) = 1.30; 95% CI: 1.08, 1.56; p = 0.006; for one quartile increase] and in the study sites of Detroit (OR = 1.71; 95% CI: 1.02, 2.92; p = 0.045), Los Angeles (OR = 1.44; 95% CI: 1.00, 2.08; p = 0.049), and Iowa (OR = 1.76; 95% CI: 1.23, 2.53; p = 0.002). The index was marginally statistically significant in Seattle (OR = 1.39; 95% CI: 0.97, 1.99; p = 0.071). The most highly weighted chemicals for predicting risk overall were PCB congener 180 and propoxur. Highly weighted chemicals varied by study site; PCBs were more highly weighted in Detroit, and pesticides were more highly weighted in Iowa. Conclusions An index of chemical mixtures was significantly associated with NHL. Our results show the importance of evaluating chemical mixtures when studying cancer risk. Citation Czarnota J, Gennings C, Colt JS, De Roos AJ, Cerhan JR, Severson RK, Hartge P, Ward MH, Wheeler DC. 2015. Analysis of environmental chemical mixtures and non-Hodgkin lymphoma risk in the NCI-SEER NHL Study. Environ Health Perspect 123:965–970; http://dx.doi.org/10.1289/ehp.1408630

Nitrate and nitrite are precursors in the endogenous formation of N‐nitroso compounds (NOC), potential human carcinogens. We evaluated the association of nitrate and nitrite ingestion with postmenopausal ovarian cancer risk in the Iowa Women's Health Study. Among 28,555 postmenopausal women, we identified 315 incident epithelial ovarian cancers from 1986 to 2010. Dietary nitrate and nitrite intakes were assessed at baseline using food frequency questionnaire data. Drinking water source at home was obtained in a 1989 follow‐up survey. Nitrate‐nitrogen (NO3‐N) and total trihalomethane (TTHM) levels for Iowa public water utilities were linked to residences and average levels were computed based on each woman's duration at the residence. We computed multivariable‐adjusted hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards regression. We tested interactions of nitrate with TTHMs and dietary factors known to influence NOC formation. Ovarian cancer risk was 2.03 times higher (CI = 1.22–3.38, ptrend = 0.003) in the highest quartile (≥2.98 mg/L) compared with the lowest quartile (≤0.47 mg/L; reference) of NO3‐N in public water, regardless of TTHM levels. Risk among private well users was also elevated (HR = 1.53, CI = 0.93–2.54) compared with the same reference group. Associations were stronger when vitamin C intake was <median (pinteraction = 0.01 and 0.33 for private well and public supplies, respectively). Dietary nitrate was inversely associated with ovarian cancer risk (ptrend = 0.02); whereas, dietary nitrite from processed meats was positively associated with the risk (ptrend = 0.04). Our findings indicate that high nitrate levels in public drinking water and private well use may increase ovarian cancer risk among postmenopausal women.

Abstract Background: Nitrate and nitrite are precursors of N-nitroso compounds, known animal and human carcinogens. Nitrate and nitrite are common in foods, such as vegetables and processed meats, and nitrate is a contaminant of drinking water. We previously reported an increased ovarian cancer risk associated with higher nitrate intake in public water supplies in the Iowa Women's Health Study. Here, we report results based on an additional 12 years of follow-up and we present results for dietary nitrate and nitrite intake. Methods: Among 28,555 postmenopausal women aged 55–69 y at baseline, we identified 315 incident epithelial ovarian cancers between 1986 and 2010. Dietary nitrate and nitrite intakes were assessed using a food frequency questionnaire at baseline. Information on drinking water source was obtained in 1989. Nitrate-nitrogen (NO3-N) levels in public water supplies (average level 1955-1988) and water sources (finished surface or ground water) were from a database of monitoring data for Iowa water utilities. Cox proportional hazards regression generated hazard ratios (HR) and 95% confidence intervals (CI). Because disinfection by-products (DBP) are higher in surface water and have been associated with increased risk for certain cancers, we determined whether the association between nitrate intake from drinking water and ovarian cancer risk differed by water source. Results: Neither total dietary nitrate nor nitrite intake was associated with ovarian cancer risk after adjusting for age, energy intake, family history of ovarian cancer, number of live births, and history of unilateral oophorectomy. Nitrate and nitrite intakes from animal or plant sources, or processed meats were not associated with ovarian cancer risk. Among women who drank public water, we observed an increased risk for ovarian cancer with higher average levels of NO3-N (ptrend=0.004). Compared with women in the lowest quartile of NO3-N levels (&lt;0.36 mg/L), risk was 1.81 (95% CI=1.08-3.05) and 2.02 (95% CI=1.21-3.36) times higher in the third (1.0-2.5 mg/L) and fourth (&gt;2.5 mg/L) quartiles, respectively. Ovarian cancer risk among private well water drinkers was elevated (HR=1.52, 95% CI=0.91-2.53) but not statistically significantly different from the referent group. When stratified by water source, the positive association between NO3-N levels in public water and ovarian cancer risk was confined to women who drank water from surface sources (ptrend=0.007; pinteraction=0.04). Conclusions: Dietary nitrate or nitrite intake was not associated with ovarian cancer risk. Our findings for nitrate intake from public water supplies suggest that nitrate intake from drinking water may increase ovarian cancer risk, particularly in the likely presence of other contaminants found in surface water. Further evaluation of DBP and other water contaminant levels on ovarian cancer risk in this population is warranted. Citation Format: Maki Inoue-Choi, Kristin E. Anderson, James R. Cerhan, Peter J. Weyer, Mary H. Ward. Dietary intake of nitrate and nitrite, nitrate in drinking water, and ovarian cancer risk among postmenopausal women in Iowa. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 149. doi:10.1158/1538-7445.AM2013-149

Abstract Background: Ingested nitrate can form N-nitroso compounds endogenously, which may lead to DNA adducts and activating mutations in oncogenes. However, previous studies have reported null or inverse associations between dietary nitrate intake and cancer risk, while nitrate intake from drinking water has shown null or positive associations with cancer risk. These associations may be confounded by protective effects of dietary folate, which provides methyl groups for nucleotide synthesis, and thus plays a vital role in the DNA repair system. In a small case-control study, an increased risk of breast cancer was observed among individuals with high dietary nitrate relative to folate intake. We therefore evaluated interaction of total folate with nitrate intake from diet and drinking water on breast cancer risk in the Iowa Women's Health Study (IWHS). Methods: The IWHS is a prospective cohort study of cancer among 41,836 women in Iowa, initiated in 1986. Dietary intake was assessed at study baseline using a food frequency questionnaire (FFQ). Nitrate intake from foods and total folate intake from foods and dietary supplements were computed using consumption frequencies collected by the FFQ. Nitrate intake from drinking water was assessed using a historical analytical database on Iowa municipal water supplies in 15,151 women using municipal water supply. We evaluated the interaction of nitrate and total folate intake with breast cancer risk using Cox proportional hazard regression modeling, adjusting for potential confounders (age, body mass index, waist-hip-ratio, education, smoking, family history of breast cancer, age at menopause, age at first live birth, estrogen use, total energy intake, and intake of vitamin C and E and flavonoids). Results: After baseline exclusions (history of cancer at baseline, previous mastectomy or partial breast resection, implausible energy intake, or ≥30 missing responses on the FFQ), there were 34,388 postmenopausal women in the analytic cohort. Through 2008, 2,875 incident breast cancer cases were identified. Nitrate intake from diet or drinking water was not associated with breast cancer risk. After stratification by total folate intake, high dietary nitrate intake (&gt;106.1 mg/day) was associated with a marginally decreased risk of breast cancer compared to those with low nitrate intake (≤106.1 mg/day) (HR=0.90, 95% confidence interval=0.81–1.00) only among women with folate intake &lt;400 μg/day (p for interaction = 0.65). There was no interaction of nitrate intake from drinking water and total folate intake on breast cancer risk. Conclusions: Our findings do not support the previously reported increased risk of breast cancer risk among individuals with high dietary nitrate and low folate intake. The inverse association between nitrate intake and breast cancer risk observed among women with low folate intake in the present study may be attributed to residual confounding due to high correlation among intakes of nitrate, folate and antioxidants. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A86.

Abstract Subclinical variation in immune response may be a risk factor for non-Hodgkin lymphoma (NHL). Endotoxin is a substance located in the cell wall of gram-negative bacteria that elicits a strong innate and inflammatory immune response. It is present in large amounts in animal and human fecal material, other organic material, and cigarette smoke. We hypothesized that higher endotoxin exposure might be a risk factor for NHL because of its effect on B-cell activation. Using a population based, multi-center (Detroit, Iowa, Los Angeles and Seattle) case-control study, we evaluated the association between endotoxin levels in carpet dust and NHL risk. During an in-person interview, we collected used vacuum cleaner bags from participants who had used their vacuum within the past year and had owned at least half of their carpets or rugs for 5 years or more. Dust samples were analyzed using the kinetic chromogenic Limulus amebocyte lysate assay in the Pulmonary Toxicology Facility, University of Iowa. Endotoxin measurements from 629 cases and 467 controls were log-transformed and evaluated as both continuous and categorical variables. In order to examine a possible threshold effect, endotoxin levels among controls were categorized into tertiles, with the highest tertile further split into two equal groups based on a preliminary model search. Multivariable logistic regression was used to estimate the effect of endotoxin on NHL risk adjusted for sex, age, race, education, study center, and last change of vacuum bag. The highest category of household endotoxin level in dust was associated with a 35% significantly decreased risk of NHL relative to the lowest category (95% confidence interval [CI] = 0.44, 0.96). The effect was stronger for the diffuse large B-cell lymphoma (DLBCL) subtype (Odds Ratio [OR]= 0.49; 95% CI= 0.26,0.91). In conclusion, contrary to our initial hypothesis, our results suggest an inverse association between high levels of household endotoxin and NHL risk. Further studies are needed to validate this finding, ideally with endotoxin measurements prior to diagnosis. Possible mechanisms of action will be discussed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5736.

AbstractUnderstanding patterns of etiologic commonality and heterogeneity for non-Hodgkin lymphomas may illuminate lymphomagenesis. We present the first systematic comparison of risks by lymphoma subtype for a broad range of putative risk factors in a population-based case-control study, including diffuse large B-cell (DLBCL; N = 416), follicular (N = 318), and marginal zone lymphomas (N = 106), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; N = 133). We required at least 2 of 3 analyses to support differences in risk: (1) polytomous logistic regression, (2) homogeneity tests, or (3) dichotomous logistic regression, analyzing all 7 possible pairwise comparisons among the subtypes, corresponding to various groupings by clinical behavior, genetic features, and differentiation. Late birth order and high body mass index (≥ 35) kg/m2) increased risk for DLBCL alone. Autoimmune conditions increased risk for marginal zone lymphoma alone. The tumor necrosis factor G-308A polymorphism (rs1800629) increased risks for both DLBCL and marginal zone lymphoma. Exposure to certain dietary heterocyclic amines from meat consumption increased risk for CLL/SLL alone. We observed no significant risk factors for follicular lymphoma alone. These data clearly support both etiologic commonality and heterogeneity for lymphoma subtypes, suggesting that immune dysfunction is of greater etiologic importance for DLBCL and marginal zone lymphoma than for CLL/SLL and follicular lymphoma.