OBJECTIVE We previously described a cross-sectional association between serum uric acid and reduced glomerular filtration rate (GFR) in nonproteinuric patients with type 1 diabetes. Here, we prospectively investigated whether baseline uric acid impacts the risk of early progressive renal function loss (early GFR loss) in these patients. RESEARCH DESIGN AND METHODS Patients with elevated urinary albumin excretion (n = 355) were followed for 4–6 years for changes in urinary albumin excretion and GFR. The changes were estimated by multiple determinations of albumin-to-creatinine ratios (ACRs) and serum cystatin C (GFRcystatin). RESULTS At baseline, the medians (25th–75th percentiles) for uric acid, ACR, and GFRcystatin values were 4.6 mg/dl (3.8–5.4), 26.2 mg/g (15.1–56.0), and 129 ml/min per 1.73 m² (111–145), respectively. During the 6-year follow-up, significant association (P < 0.0002) was observed between serum uric acid and development of early GFR loss, defined as GFRcystatin decline exceeding 3.3% per year. In baseline uric acid concentration categories (in mg/dl: <3.0, 3.0–3.9, 4.0–4.9, 5.0–5.9, and ≥6), the risk of early GFR loss increased linearly (9, 13, 20, 29, and 36%, respectively). This linear increase corresponds to odds ratio 1.4 (95% CI 1.1–1.8) per 1 mg/dl increase of uric acid. The progression and regression of urinary albumin excretion were not associated with uric acid. CONCLUSIONS We found a clear dose-response relation between serum uric acid and risk of early GFR loss in patients with type 1 diabetes. Clinical trials are warranted to determine whether uric acid–lowering drugs can halt renal function decline before it becomes clinically significant.

To investigate the relationship between community drinking water quality and spontaneous abortion, we compared trace element levels in the drinking water of 286 women having a spontaneous abortion through 27 wk gestation with that of 1 391 women having livebirths. Trace element levels were gathered from routine analyses of public tap water supplies from the communities where the women resided during pregnancy. After adjustment for potential confounders, an increase in the frequency of spontaneous abortion was associated with detectable levels of mercury; high levels of arsenic, potassium, and silica; moderately hard water, and surface water. In contrast, a decrease in the frequency of spontaneous abortion was associated with high levels of alkalinity and sulfate, and any detectable level of nitrate. These results require further corroboration because there is a paucity of data investigating this issue.

Is there an association between air pollution exposures and incident infertility? Increased exposure to air pollution is associated with an increased incidence of infertility. Exposures to air pollution have been associated with lower conception and fertility rates. However, the impact of pollution on infertility incidence is unknown. Prospective cohort study using data collected from 116 430 female nurses from September 1989 to December 2003 as part of the Nurses' Health Study II cohort. Infertility was defined by report of attempted conception for ≥12 months without success. Participants were able to report if evaluation was sought and if so, offer multiple clinical indications for infertility. After exclusion, 36 294 members were included in the analysis. Proximity to major roadways and ambient exposures to particulate matter less than 10 microns (PM₁₀), between 2.5 and 10 microns (PM_2.5–10), and less than 2.5 microns (PM_2.5) were determined for residential addresses for the 36 294 members between the years of 1993 and 2003. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using multivariable adjusted Cox proportional hazard models with time-varying covariates. Over 213 416 person-years, there were 2508 incident reports of infertility. Results for overall infertility were inconsistent across exposure types. We observed a small increased risk for those living closer to compared to farther from a major road, multivariable adjusted HR = 1.11 (CI: 1.02–1.20). This was consistent for those reporting primary or secondary infertility. For women living closer to compared to farther from a major road, for primary infertility HR = 1.05 (CI: 0.94–1.17), while for secondary infertility HR = 1.21 (CI: 1.07–1.36). In addition, the HR for every 10 µg/m³ increase in cumulative PM_2.5–10 among women with primary infertility was 1.10 (CI: 0.96–1.27), and similarly was 1.10 (CI: 0.94–1.28) for those with secondary infertility. Within the 2 year window of infertility diagnosis, we do not have the exact date of diagnosis or the exact timing of the start of attempting conception. As infertility status and subtypes of infertility were prospectively collected biennially, we were unable to tightly examine the timing of exposures on incidence of infertility. In terms of exposure quantification, we used ambient air pollution exposures as a proxy for personal exposures, potentially leading to exposure misclassification. However, several studies suggest that ambient measurements are an acceptable surrogate for individual level exposures in most populations. We observed an association between all size fractions of PM exposure, as well as traffic-related air pollution, and incidence of infertility. Of note, the strongest association was observed between cumulative average exposures over the course of follow-up and the risk of infertility, suggesting that chronic exposures may be of greater importance than short-term exposures. The work for this paper was supported by the following: S.M.: Reproductive Scientist Development Program HD000849, and the Building Interdisciplinary Research Careers in Women's Health HD043444, the Boston University CTSI 1UL1TR001430, and a research grant from the Boston University Department of Obstetrics and Gynecology, S.A.M.: R01HD57210 from the National Institute of Child Health and Human Development and the Massachusetts Institute of Technology Center for Environmental Health Sciences Translational Pilot Project Program, R01CA50385 from the National Cancer Institute, J.E.H. and F.L.: 5R01ES017017 from the National Institute for Environmental Health Sciences, 5 P42 ES007381 from the National Institute of Environmental Health at the National Institute of Health. L.V.F.: T32HD060454 in reproductive, perinatal, and pediatric epidemiology from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The Nurses' Health Study II is additionally supported by infrastructure grant UM1CA176726 from the National Cancer Institute, NIH, U.S. Department of Health and Human Services. The authors have no actual or potential competing financial interests to disclose.

Using a case-control design, the authors studied female residents of five Massachusetts towns between 1983 and 1986. The objective was to measure the associations between breast cancer occurrence and exposure to active and passive cigarette smoke. Until recently, exposure to tobacco smoke has not been thought to cause breast cancer. Novel perspectives on measuring the association of tobacco smoke with the occurrence of breast cancer and studies of genetically susceptible populations argue for further investigation. In this study, the authors found that ever-active smokers had an odds ratio of 2.0 (95 percent confidence interval (CI) 1.1–3.6) when compared with never-active, never-passive smokers. Women who smoked only before their first pregnancy (odds ratio = 5.6, 95 percent CI 1.5–21) and women who quit smoking 5–15 years before their index year (odds ratio = 3.9, 95 percent CI 1.4–10) were at the highest risk. Passive-only smokers had an odds ratio of 2.0 (95 percent CI 1.1–3.7) when compared with never-active, never-passive smokers. Among those women who were exposed to passive smoke before age 12 years, the odds ratios were 4.5 (95 percent CI 1.2–16) for passive-only smokers and 7.5 (95 percent CI 1.6–36) for ever-active smokers. Women who were first exposed to passive smoke after age 12 years had lower, although still elevated, odds ratios. The pattern of associations between exposure to cigarette smoke and the occurrence of breast cancer comports with a model of breast carcinogenesis. Am J Epidemiol 1999;149:5–12.

Mapping spatial distributions of disease occurrence and risk can serve as a useful tool for identifying exposures of public health concern. Disease registry data are often mapped by town or county of diagnosis and contain limited data on covariates. These maps often possess poor spatial resolution, the potential for spatial confounding, and the inability to consider latency. Population-based case-control studies can provide detailed information on residential history and covariates. Generalized additive models (GAMs) provide a useful framework for mapping point-based epidemiologic data. Smoothing on location while controlling for covariates produces adjusted maps. We generate maps of odds ratios using the entire study area as a reference. We smooth using a locally weighted regression smoother (loess), a method that combines the advantages of nearest neighbor and kernel methods. We choose an optimal degree of smoothing by minimizing Akaike's Information Criterion. We use a deviance-based test to assess the overall importance of location in the model and pointwise permutation tests to locate regions of significantly increased or decreased risk. The method is illustrated with synthetic data and data from a population-based case-control study, using S-Plus and ArcView software. Our goal is to develop practical methods for mapping population-based case-control and cohort studies. The method described here performs well for our synthetic data, reproducing important features of the data and adequately controlling the covariate. When applied to the population-based case-control data set, the method suggests spatial confounding and identifies statistically significant areas of increased and decreased odds ratios.

The relationship between community drinking water quality and the occurrence of late adverse pregnancy outcomes was investigated by conducting a case-control study among women who delivered infants during August 1977 through March 1980 at Brigham and Women's Hospital in Massachusetts. The water quality indices were compared among 1 039 congenital anomaly cases, 77 stillbirth cases, 55 neonatal death cases, and 1 177 controls. Trace element levels were gathered from routine analyses of public water supplies from the communities in which the women resided during pregnancy. It was observed that, after adjustment for confounding, the frequency of stillbirths was increased for women exposed to chlorinated surface water (OR 2.6 95% CI 0.9–7.5) and for women exposed to detectable lead levels (OR 2.1; 95% CI 0.6–7.2); the frequency of cardiovascular defects was increased relative to detectable lead levels (OR 2.2, 95% CI 0.9–5.7); and the frequency of central nervous system defects was increased relative to the highest tertile of potassium (OR 6.3, 95% CI 1.1–37.3). The frequency of ear, face, and neck anomalies was increased in relation to detectable silver levels (OR 3.3, 95% CI 0.9–12.2), but the frequency decreased relative to high potassium levels (OR 0.2, 95% CI 0.1–0.7). The frequency of neonatal deaths was decreased relative to detectable fluoride levels (OR 0.4, 95% CI 0.2–1.0), and the frequency of musculoskeletal defects was decreased relative to detectable chromium levels (OR 0.4, 95% CI 0.2–1.0). The majority of these associations were not stable statistically. Further research is needed to corroborate these findings.