Associations between toxicity-weighted concentrations and dementia risk: Results from the Cardiovascular Health Cognition Study.

BACKGROUND: Air pollution is a modifiable risk factor for dementia. Yet, studies on specific sources of air pollution (i.e., toxic chemical emissions from industrial facilities) and dementia risk are scarce. We examined associations between toxicity-weighted concentrations of industrial pollution and dementia outcomes among a large, multi-site cohort of older adults. METHODS: Participants (n = 2770) were ≥ 65 years old (Mean = 75.3, SD = 5.1 years) from the Cardiovascular Health Cognition Study (1992-1999). Toxicity-weighted concentrations were estimated using the Risk Screening Environmental Indicator (RSEI) model which incorporates total reported chemical emissions with toxicity, fate, and transport models. Estimates were aggregated to participants' baseline census tract, averaged across 1988-1992, and log2-transformed. Dementia status was clinically adjudicated in 1998-1999 and categorized by subtype (Alzheimer's, vascular, mixed). We assessed whether RSEI-estimated toxicity-weighted concentrations were associated with 1) odds of prevalent dementia and 2) incident dementia risk by subtype. RESULTS: After adjusting for individual and census-tract level covariates, a doubling in toxicity-weighted concentrations was associated with 9 % higher odds of prevalent dementia (OR = 1.09, 95 % CI: 1.00, 1.19). In discrete-time survival models, each doubling in toxicity-weighted concentrations was associated with a 16 % greater hazard of vascular dementia (HR = 1.16, 95 % CI: 1.01, 1.34) but was not significantly associated with all-cause, Alzheimer's disease, or mixed dementia (p's > 0.05). DISCUSSION: Living in regions with higher toxicity-weighted concentrations was associated with higher odds of prevalent dementia and a higher risk of incident vascular dementia in this large, community-based cohort of older adults. These findings support the need for additional studies to examine whether toxic chemical emissions from industrial and federal facilities may be a modifiable target for dementia prevention.

Association of neighborhood physical activity opportunities with incident cardiovascular disease in the Cardiovascular Health Study.

We determined associations of cumulative exposures to neighborhood physical activity opportunities with risk of incident cardiovascular disease (CVD). We included 3595 participants from the Cardiovascular Health Study recruited between 1989 and 1993 (mean age = 73; 60% women; 11% black). Neighborhood environment measures were calculated using Geographic Information Systems (GIS) and annual information from the National Establishment Time Series database, including the density of (1) walking destinations and (2) physical activity/recreational facilities in a 1- and 5-km radius around the respondent's home. Incident CVD was defined as the development of myocardial infarction, stroke, or cardiovascular death and associations with time to incident CVD were estimated using Cox proportional hazards models. A total of 1986 incident CVD cases occurred over a median follow-up of 11.2 years. After adjusting for baseline and time-varying individual and neighborhood-level confounding, a one standard deviation increase in walking destinations and physical activity/recreational facilities within 5 km of home was associated with a respective 7% (95% confidence interval (CI) = 0.87-0.99) and 12% (95% CI = 0.73-1.0) decreased risk of incident CVD. No significant associations were noted within a 1-km radius. Efforts to improve the availability of physical activity resources in neighborhoods may be an important strategy for lowering CVD.

Relations of Postload and Fasting Glucose With Incident Cardiovascular Disease and Mortality Late in Life: The Cardiovascular Health Study.

BACKGROUND: Older adults have a high prevalence of postload hyperglycemia. Postload glucose has shown more robust associations with cardiovascular disease (CVD) and death than fasting glucose, but data in the oldest old are sparse. METHODS: Fasting and 2-hour postload glucose were measured in community-dwelling older adults, mean age 78, at the 1996-1997 follow-up visit of the Cardiovascular Health Study. We evaluated their associations with atherosclerotic CVD (ASCVD) and mortality using standard Cox regression and competing-risks analyses and assessed improvement in prediction-model discrimination with the c-statistic. RESULTS: Among 2,394 participants without treated diabetes and available data on glycemic measures, there were 579 ASCVD events and 1,698 deaths during median follow-up of 11.2 years. In fully adjusted models, both fasting and 2-hour glucose were associated with ASCVD (HR per SD, 1.13 [1.03-1.25] and 1.17 [1.07-1.28], respectively) and all-cause mortality (HR 1.12 [1.07-1.18] and 1.14 [1.08-1.20]). After mutual adjustment, however, the associations for fasting glucose with both outcomes were abolished, but those for postload glucose were largely unchanged. Consistent findings were observed for ASCVD in competing-risks models. CONCLUSION: In adults surviving to advanced old age, postload glucose was associated with ASCVD and mortality independently of fasting glucose, but fasting glucose was not associated with these outcomes independently of postload glucose. These findings affirm the robust association of postload glucose with ASCVD and death late in life.

Sleep Disturbances and Glucose Metabolism in Older Adults: The Cardiovascular Health Study.

OBJECTIVE: We examined the associations of symptoms of sleep-disordered breathing (SDB), which was defined as loud snoring, stopping breathing for a while during sleep, and daytime sleepiness, and insomnia with glucose metabolism and incident type 2 diabetes in older adults. RESEARCH DESIGN AND METHODS: Between 1989 and 1993, the Cardiovascular Health Study recruited 5,888 participants ≥65 years of age from four U.S. communities. Participants reported SDB and insomnia symptoms yearly through 1989-1994. In 1989-1990, participants underwent an oral glucose tolerance test, from which insulin secretion and insulin sensitivity were estimated. Fasting glucose levels were measured in 1989-1990 and again in 1992-1993, 1994-1995, 1996-1997, and 1998-1999, and medication use was ascertained yearly. We determined the cross-sectional associations of sleep symptoms with fasting glucose levels, 2-h glucose levels, insulin sensitivity, and insulin secretion using generalized estimated equations and linear regression models. We determined the associations of updated and averaged sleep symptoms with incident diabetes in Cox proportional hazards models. We adjusted for sociodemographics, lifestyle factors, and medical history. RESULTS: Observed apnea, snoring, and daytime sleepiness were associated with higher fasting glucose levels, higher 2-h glucose levels, lower insulin sensitivity, and higher insulin secretion. The risk of the development of type 2 diabetes was positively associated with observed apnea (hazard ratio [HR] 1.84 [95% CI 1.19-2.86]), snoring (HR 1.27 [95% CI 0.95-1.71]), and daytime sleepiness (HR 1.54 [95% CI 1.13-2.12]). In contrast, we did not find consistent associations between insomnia symptoms and glucose metabolism or incident type 2 diabetes. CONCLUSIONS: Easily collected symptoms of SDB are strongly associated with insulin resistance and the incidence of type 2 diabetes in older adults. Monitoring glucose metabolism in such patients may prove useful in identifying candidates for lifestyle or pharmacological therapy. Further studies are needed to determine whether insomnia symptoms affect the risk of diabetes in younger adults.

Validation of secondary data sources to identify Parkinson disease against clinical diagnostic criteria.

Parkinson disease (PD) is the second most common neurodegenerative disorder. Its diagnosis relies solely on a clinical examination and is not straightforward because no diagnostic test exists. Large, population-based, prospective cohort studies designed to examine other outcomes that are more common than PD might provide cost-efficient alternatives for studying the disease. However, most cohort studies have not implemented rigorous systematic screening for PD. A majority of epidemiologic studies that utilize population-based prospective designs rely on secondary data sources to identify PD cases. Direct validation of these secondary sources against clinical diagnostic criteria is lacking. The Framingham Heart Study has prospectively screened and evaluated participants for PD based on clinical diagnostic criteria. We assessed the predictive value of secondary sources for PD identification relative to clinical diagnostic criteria in the Framingham Heart Study (2001-2012). We found positive predictive values of 1.0 (95% confidence interval: 0.868, 1.0), 1.0 (95% confidence interval: 0.839, 1.0), and 0.50 (95% confidence interval: 0.307, 0.694) for PD identified from self-report, use of antiparkinsonian medications, and Medicare claims, respectively. The negative predictive values were all higher than 0.99. Our results highlight the limitations of using only Medicare claims data and suggest that population-based cohorts may be utilized for the study of PD determined via self-report or medication inventories while preserving a high degree of confidence in the validity of PD case identification.

Enhancing case ascertainment of Parkinson's disease using Medicare claims data in a population-based cohort: the Cardiovascular Health Study.

PURPOSE: We sought to improve a previous algorithm to ascertain Parkinson's disease (PD) in the Cardiovascular Health Study by incorporating additional data from Medicare outpatient claims. We compared our results to the previous algorithm in terms of baseline prevalence and incidence of PD, as well as associations with baseline smoking characteristics. METHODS: Our original case ascertainment used self-reported diagnosis, antiparkinsonian medication, and hospitalization discharge International Classification of Diseases-Ninth version code. In this study, we incorporated additional data from fee-for-service Medicare claims, extended follow-up time, review of hospitalization records, and adjudicated cause of death. Two movement disorders specialists adjudicated final PD status. We used logistic regression models and controlled for age, sex, African American race, and education. RESULTS: We identified 75 additional cases but reclassified 80 previously identified cases as not having PD. We observed significant inverse association with smoking status (odds ratio = 0.42; 95% confidence interval (CI) = 0.22, 0.79), and inverse linear trends with pack-years (p = 0.005), and cigarettes per day (p = 0.019) with incident PD. All estimates were stronger than those from the previous algorithm. CONCLUSIONS: Our enhanced method did not alter prevalence and incidence estimates compared with our previous algorithm. However, our enhanced method provided stronger estimates of association, potentially due to reduced level of disease misclassification.

Effect of inter-reader variability on outcomes in studies using carotid intima media thickness quantified by carotid ultrasonography.

Systematic differences between readers or equipment in imaging studies are not uncommon; failure to account for such differences when using Carotid Ultrasonography may introduce bias into associations between carotid intima media thickness (cIMT) and outcomes. We demonstrate the impact of this source of systematic measurement error (SME) using data on 5,521 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) and 661 participants from the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). Participants were between 37 and 78 years old. Two outcomes were considered: (1) the effect of HIV infection on cIMT (between study) and (2) the association of cIMT with cardiovascular events (within study). All estimates were adjusted for demographics (age, gender, and ethnicity) and for traditional cardiovascular disease risk factors (smoking, blood pressure, diabetes and cholesterol). When comparing the FRAM and MESA cohorts to estimate the association of HIV infection on common cIMT, accounting for machine and reader variability (between study variability) reduced the difference associated with HIV infection from +0.080 mm (95% Confidence Interval (CI):0.065-0.095) to +0.037 mm (95% CI:0.003 to 0.072) while internal cIMT declined from +0.254 mm (95% CI:0.205-0.303) to +0.192 mm (95% CI:0.076-0.308). Attenuation of the association between cIMT and cardiovascular endpoints occurred when within study reader variability was not accounted for. The effect of SME due to use of multiple readers or machines is most important when comparisons are made between two different study populations. Within-cohort measurement error dilutes the association with events.

Subfertility and the risk of testicular germ cell tumors (United States).

OBJECTIVES: Previous studies have reported an association between subfertility and the risk of testicular germ cell tumors. We examined fertility, measured by number of children fathered and prior diagnosis of infertility, as a risk factor for testicular cancer, while accounting for the influence of occult cancer and cryptorchidism. METHODS: Tumor registry data were used to identify 329 cases of testicular cancer in white men aged 20 to 69 years, diagnosed in western Washington State from 1977 to 1983; 672 cancer-free controls were identified by random-digit dialing. Telephone interviews ascertained reproductive histories and basic demographic information. Logistic regression was used to estimate the relative risk of testicular cancer associated with fertility. RESULTS: Testicular cancer risk was decreased among men who had previously fathered a child (age-adjusted odds ratio (OR) 0.76, 95% confidence interval (CI): 0.54-1.06). Inverse associations were seen for seminomas and non-seminomas, and only slight attenuations in the ORs were observed when men with a history of cryptorchidism were excluded. Prior diagnosis of infertility was associated with an increased risk of testicular cancer (OR 2.40, 95% CI: 1.00-5.77). CONCLUSIONS: These results are consistent with an increased risk of testicular cancer among men with reduced fertility that goes beyond the effects of cryptorchidism.

Differences in testis cancer survival by race and ethnicity: a population-based study, 1973-1999 (United States).

OBJECTIVE: We examined the relationship between race/ethnicity and testis cancer survival in a population-based setting. METHODS: We analyzed 16,086 cases of primary testis cancer diagnosed during 1973-1999 and reported to 12 cancer registries participating in the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. We compared testis cancer-specific survival between patients from different racial/ethnic groups by use of the hazard ratio (HR) and 95% confidence intervals (CI) calculated from Cox proportional hazards models, adjusting for stage, histology, and period of diagnosis. RESULTS: Relative to non-Hispanic whites, a greater proportion of African American, Native American, Hawaiian, and Hispanic patients were diagnosed at late stages. There were 886 deaths among 16,086 testis cancer patients and overall 5-year survival was 95%. After adjustment for stage, histology, and period of diagnosis, the risk of dying from testis cancer was increased among African Americans (HR = 2.3; CI: 1.6-3.2), Native Americans (HR = 2.1; CI: 1.1-3.9), Filipinos (HR = 3.6; CI: 1.3-9.5), Hawaiians (HR = 2.4; CI: 1.4-4.1), and Hispanics (HR = 1.4; CI: 1.1-1.8), compared to non-Hispanic whites. CONCLUSION: These findings are consistent with previous reports of race/ethnic disparities in stage at diagnosis and survival in testis cancer patients as well as other cancer patients. Further research is needed to understand the reasons underlying these disparities.

P53 alterations in bladder tumors from arsenic and tobacco exposed patients.

Previous studies demonstrated that tobacco and arsenic exposure are risk factors for bladder cancer. A case-case study was conducted to compare p53 mutations in 147 bladder tumors from South American patients by tobacco and arsenic exposure. Information on residential history and lifestyle factors was collected. The prevalence of p53 mutations and protein expression was examined in relation to tumor stage, grade, patient age, gender, tobacco and arsenic exposure. Smokers were grouped as ever/never smokers and by pack years of exposure (0, 1-20, >20). Patients were also grouped into four arsenic exposure categories based on the average of the five highest years arsenic concentration in their drinking water: group 1, non-detectable to <10 microg/l (n = 50); group 2, 10-99 microg/l (n = 31); group 3, 100-299 microg/l (n = 35); group 4, >300 microg/l (n = 30). The proportion of tumor samples with p53 mutations and P53 immunopositivity increased strongly with both stage and grade, but not with arsenic exposure or smoking. The prevalence of tumors containing mutational transitions increased markedly with tumor stage (from 14 to 52%, P(trend) = 0.005) and grade (from 11 to 48%, P(trend) = 0.004) and was higher in smokers than in non-smokers (34 versus 18%, respectively, P = 0.10). An increasing trend was observed with pack years of smoking (P = 0.09). The majority of mutations in tumors from both smokers and non-smokers were G-->A transitions, however, in smokers a preference for G-->A transitions at CpG sites was observed (P = 0.07, two-tailed) and a positive trend was observed with pack years of exposure (P = 0.04). A hotspot was found at codon 273 in 12% of the tumors from smokers but was not observed in never smokers (P = 0.05) and a positive trend was observed with pack years of tobacco exposure (P = 0.001). Neither stage nor grade demonstrated a preference for CpG site mutation, suggesting that these changes may be early exposure-related events in carcinogenesis and are not related to tumor progression. Arsenic exposure was not associated with an increased prevalence of p53 mutation or P53 immunopositivity and there was no evidence of interaction between arsenic and smoking with these outcome variables.

Maternal, delivery, and perinatal characteristics associated with cryptorchidism: a population-based case-control study among births in Washington State.

BACKGROUND: The etiology of cryptorchidism is largely unknown. To identify maternal, perinatal, and delivery characteristics associated with cryptorchidism at birth, we conducted a population-based case-control study using Washington State birth certificates linked to birth hospitalization records. METHODS: We identified 2,395 cases of cryptorchidism among male infants born in Washington State during 1986-1996, and, for comparison, we randomly selected four controls per case (N = 9,580), frequency-matched by year of birth. RESULTS: Infant characteristics associated with cryptorchidism included low birth weight (OR = 1.5; 95% CI = 1.3-1.8), small size for gestational age (OR = 1.9; 95% CI = 1.6-2.2), and breech presentation (OR = 1.7; 95% CI = 1.4-2.1). In addition to cryptorchidism, cases were more likely to have another type of congenital malformation (OR = 3.7; 95% CI = 3.2-4.2), particularly digestive (OR = 6.8; 95% CI = 3.7-12.7) or genitourinary (OR = 4.1; 95% CI = 3.0-5.6). Maternal and pregnancy characteristics associated with cryptorchidism included nulliparity (OR = 1.2; 95% CI = 1.1-1.3), maternal smoking during pregnancy (OR = 1.2; 95% CI = 1.1-1.4), and the following pregnancy complications: oligohydramnios (OR = 1.8; 95% CI = 1.3-2.6), placental abnormality (OR = 1.3; 95% CI = 1.0-1.8), and pregnancy-induced hypertension (OR = 1.6; 95% CI = 1.4-1.9). Odds ratios were similar when the analysis was restricted to term infants. CONCLUSIONS: These findings suggest that factors affecting fetal growth and development may increase the risk of cryptorchidism.