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1.  Benign Breast Disease, Mammographic Breast Density, and the Risk of Breast Cancer 
Background
Benign breast disease and high breast density are prevalent, strong risk factors for breast cancer. Women with both risk factors may be at very high risk.
Methods
We included 42818 women participating in the Breast Cancer Surveillance Consortium who had no prior diagnosis of breast cancer and had undergone at least one benign breast biopsy and mammogram; 1359 women developed incident breast cancer in 6.1 years of follow-up (78.1% invasive, 21.9% ductal carcinoma in situ). We calculated hazard ratios (HRs) using Cox regression analysis. The referent group was women with nonproliferative changes and average density. All P values are two-sided.
Results
Benign breast disease and breast density were independently associated with breast cancer. The combination of atypical hyperplasia and very high density was uncommon (0.6% of biopsies) but was associated with the highest risk for breast cancer (HR = 5.34; 95% confidence interval [CI] = 3.52 to 8.09, P < .001). Proliferative disease without atypia (25.6% of biopsies) was associated with elevated risk that varied little across levels of density: average (HR = 1.37; 95% CI = 1.11 to 1.69, P = .003), high (HR = 2.02; 95% CI = 1.68 to 2.44, P < .001), or very high (HR = 2.05; 95% CI = 1.54 to 2.72, P < .001). Low breast density (4.5% of biopsies) was associated with low risk (HRs <1) for all benign pathology diagnoses.
Conclusions
Women with high breast density and proliferative benign breast disease are at very high risk for future breast cancer. Women with low breast density are at low risk, regardless of their benign pathologic diagnosis.
doi:10.1093/jnci/djt124
PMCID: PMC3714021  PMID: 23744877
2.  Screening Outcomes in Older US Women Undergoing Multiple Mammograms in Community Practice: Does Interval, Age, or Comorbidity Score Affect Tumor Characteristics or False Positive Rates? 
Background
Uncertainty exists about the appropriate use of screening mammography among older women because comorbid illnesses may diminish the benefit of screening. We examined the risk of adverse tumor characteristics and false positive rates according to screening interval, age, and comorbidity.
Methods
From January 1999 to December 2006, data were collected prospectively on 2993 older women with breast cancer and 137 949 older women without breast cancer who underwent mammography at facilities that participated in a data linkage between the Breast Cancer Surveillance Consortium and Medicare claims. Women were aged 66 to 89 years at study entry to allow for measurement of 1 year of preexisting illnesses. We used logistic regression analyses to calculate the odds of advanced (IIb, III, IV) stage, large (>20 millimeters) tumors, and 10-year cumulative probability of false-positive mammography by screening frequency (1 vs 2 years), age, and comorbidity score. The comorbidity score was derived using the Klabunde approximation of the Charlson score. All statistical tests were two-sided.
Results
Adverse tumor characteristics did not differ statistically significantly by comorbidity, age, or interval. Cumulative probability of a false-positive mammography result was higher among annual screeners than biennial screeners irrespective of comorbidity: 48.0% (95% confidence interval [CI] = 46.1% to 49.9%) of annual screeners aged 66 to 74 years had a false-positive result compared with 29.0% (95% CI = 28.1% to 29.9%) of biennial screeners.
Conclusion
Women aged 66 to 89 years who undergo biennial screening mammography have similar risk of advanced-stage disease and lower cumulative risk of a false-positive recommendation than annual screeners, regardless of comorbidity.
doi:10.1093/jnci/djs645
PMCID: PMC3589257  PMID: 23385442
3.  Weight, mortality, years of healthy life and active life expectancy in older adults 
Journal of the American Geriatrics Society  2007;56(1):10.1111/j.1532-5415.2007.01500.x.
Objective
Two-thirds of older adults are currently classified as overweight or obese. Given that the importance of these weight categories was documented primarily in middle-aged persons, the survival and health status consequences for older adults are controversial. Here, we explore the issue of whether weight categories predict subsequent mortality and morbidity in older adults.
Design, Setting, and Participants
Data came from the Cardiovascular Health Study, a population-based cohort study of 5888 older adults.
Measurements
We estimated the age- and sex-specific probabilities of transition from one health state to another and from one weight category to another. From these probabilities we estimated future life expectancy, years of healthy life, active life expectancy, and the number of years spent in each weight and health category after age 65.
Results
Women who are healthy and of normal weight at age 65 have a life expectancy of 22.1 years. Of that, they spend, on average, 9.6 years as overweight or obese, and 5.3 years in fair or poor health. For both men and women, being underweight at age 65 was associated with worse outcomes than normal weight, while overweight and obesity were rarely worse than normal weight, and were sometimes associated with significantly better outcomes.
Conclusions
Similar to middle-aged populations, older adults are likely to be or to become overweight or obese. However, higher weight is not associated with worse health in this age group. Thus, the number of older adults at a “healthy” weight may be much higher than currently believed.
doi:10.1111/j.1532-5415.2007.01500.x
PMCID: PMC3865852  PMID: 18031486
self-rated health; equilibrium; activities of daily living; years of healthy life; active life expectancy; multi-state life tables; older adults
4.  Outcomes of Screening Mammography by Frequency, Breast Density, and Postmenopausal Hormone Therapy 
JAMA internal medicine  2013;173(9):807-816.
Importance
Controversy exists about the frequency women should undergo screening mammography and whether screening interval should vary according to risk factors beyond age.
Objective
To compare the benefits and harms of screening mammography frequencies according to age, breast density, and postmenopausal hormone therapy (HT) use.
Design
Prospective cohort.
Setting
Data collected January 1994 to December 2008 from mammography facilities in community practice that participate in the Breast Cancer Surveillance Consortium (BCSC) mammography registries.
Participants
Data were collected prospectively on 11 474 women with breast cancer and 922 624 without breast cancer who underwent mammography at facilities that participate in the BCSC.
Main Outcomes and Measures
We used logistic regression to calculate the odds of advanced stage (IIb, III, or IV) and large tumors (>20 mm in diameter) and 10-year cumulative probability of a false-positive mammography result by screening frequency, age, breast density, and HT use. The main predictor was screening mammography interval.
Results
Mammography biennially vs annually for women aged 50 to 74 years does not increase risk of tumors with advanced stage or large size regardless of women’s breast density or HT use. Among women aged 40 to 49 years with extremely dense breasts, biennial mammography vs annual is associated with increased risk of advanced-stage cancer (odds ratio [OR], 1.89; 95% CI, 1.06–3.39) and large tumors (OR, 2.39; 95% CI, 1.37–4.18). Cumulative probability of a false-positive mammography result was high among women undergoing annual mammography with extremely dense breasts who were either aged 40 to 49 years (65.5%) or used estrogen plus progestogen (65.8%) and was lower among women aged 50 to 74 years who underwent biennial or triennial mammography with scattered fibroglandular densities (30.7% and 21.9%, respectively) or fatty breasts (17.4% and 12.1%, respectively).
Conclusions and Relevance
Women aged 50 to 74 years, even those with high breast density or HT use, who undergo biennial screening mammography have similar risk of advanced-stage disease and lower cumulative risk of false-positive results than those who undergo annual mammography. When deciding whether to undergo mammography, women aged 40 to 49 years who have extremely dense breasts should be informed that annual mammography may minimize their risk of advanced-stage disease but the cumulative risk of false-positive results is high.
doi:10.1001/jamainternmed.2013.307
PMCID: PMC3699693  PMID: 23552817
5.  Breast Density, Body Mass Index, and Risk of Tumor Marker-Defined Subtypes of Breast Cancer 
Annals of Epidemiology  2012;22(5):340-348.
Purpose
Breast density and body mass index (BMI) are correlated attributes and are both potentially modifiable risk factors for breast cancer. However, relationships between these factors and risk of molecularly-defined subtypes of breast cancer have not been established.
Methods
We used breast density and BMI data collected by the Breast Cancer Surveillance Consortium from 1,054,466 women aged 40–84 years receiving mammography, including 13,797 women subsequently diagnosed with breast cancer. Cases were classified into three groups based on expression of the estrogen receptor (ER), progesterone receptor (PR), and HER2: 1) ER-positive (ER+, N=10,026), 2) HER2-overexpressing (ER-negative/PR-negative/HER2-positive, N=308), or triple-negative (ER-negative/PR-negative/HER2-negative, N=705). Using Cox regression, we evaluated subtype-specific associations with breast density and BMI.
Results
Breast density was similarly positively associated with risk of all subtypes, especially among women aged 40–64 years. BMI was positively associated with risks of ER+ and triple-negative breast cancer in women aged 50–84 who were not users of hormone therapy.
Conclusions
Breast density is positively associated with breast cancer risk, regardless of disease subtype. Associations with BMI appear to vary more by breast cancer subtype. Additional studies are needed to confirm and further characterize risk factors for HER2-overexpressing and triple-negative breast cancer.
doi:10.1016/j.annepidem.2012.02.002
PMCID: PMC3338877  PMID: 22366170
breast cancer; triple-negative; breast density; body mass index; estrogen receptor; progesterone receptor; HER2
6.  Gender Differences in Tea, Coffee, and Cognitive Decline in the Elderly: The Cardiovascular Health Study 
Although caffeine can enhance cognitive function acutely, long-term effects of consumption of caffeine-containing beverages such as tea and coffee are uncertain. Data on 4,809 participants aged 65 and older from the Cardiovascular Health Study (CHS) were used to examine the relationship of consumption of tea and coffee, assessed by food frequency questionnaire, on change in cognitive function by gender. Cognitive performance was assessed using serial Modified Mini-Mental State (3MS) examinations, which were administered annually up to 9 times. Linear mixed models were used to estimate rates of change in standard 3MS scores and scores modeled using item response theory (IRT). Models were adjusted for age, education, smoking status, clinic site, diabetes, hypertension, stroke, coronary heart disease, depression score, and APOE genotype. Over the median 7.9 years of follow-up, participants who did not consume tea or coffee declined annually by an average of 1.30 points (women) and 1.11 points (men) on standard 3MS scores. In fully adjusted models using either standard or IRT 3MS scores, we found modestly reduced rates of cognitive decline for some, but not all, levels of coffee and tea consumption for women, with no consistent effect for men. Caffeine consumption was also associated with attenuation in cognitive decline in women. Dose-response relationships were not linear. These longitudinal analyses suggest a somewhat attenuated rate of cognitive decline among tea and coffee consumers compared to non-consumers in women but not in men. Whether this association is causal or due to unmeasured confounding requires further study.
doi:10.3233/JAD-2011-110431
PMCID: PMC3577072  PMID: 21841254
Caffeine; coffee; cognition; tea
7.  Risk Factors for Breast Cancer for Women Age 40 to 49: A Systematic Review and Meta-analysis 
Annals of internal medicine  2012;156(9):635-648.
Background
Identifying risk factors for breast cancer specific to women in their forties could inform screening decisions.
Purpose
To determine what factors increase risk for breast cancer in women age 40–49 years and the magnitudes of risk for each factor.
Data Sources
MEDLINE (January 1996 to November 2011), Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (fourth Quarter 2011), Scopus, and reference lists for published studies; and data from the Breast Cancer Surveillance Consortium (BCSC).
Study Selection
English-language studies and systematic reviews of risk factors for breast cancer in women age 40–49 years. Additional inclusion criteria were applied for each risk factor.
Data Extraction
Data on participants, study design, analysis, follow-up, and outcomes were abstracted. Study quality was rated using established criteria and only studies rated good or fair were included. Results were summarized using meta-analysis when sufficient studies were available, or from the best evidence based on study quality, size, and applicability when meta-analysis was not possible. BCSC data were analyzed with proportional hazards models using partly conditional Cox regression. Reference groups for comparisons were set at U.S. population means.
Data Synthesis
65 studies provided data for estimates. Extremely dense breasts on mammography or first-degree relatives with breast cancer were associated with ≥2-fold increase in breast cancer. Prior breast biopsy, second degree relatives with breast cancer, or heterogeneously dense breasts were associated with 1.5–2.0 increased risk; current oral contraceptive use, nulliparity, and age ≥30 at first birth were associated with 1.0–1.5 increased risk.
Limitations
Studies varied by measures, reference groups, and adjustment for confounders; effects of multiple risk factors were not considered.
Conclusions
Extremely dense breasts and first degree relatives with breast cancer were each associated with ≥2-fold increased breast cancer risk in women age 40–49. Identification of these risk factors may be useful for personalized mammography screening.
Primary Funding Source
National Cancer Institute Activities to Promote Research Collaboration supplement (U01CA086076-10S1). Data collection was supported by the National Cancer Institute funded Breast Cancer Surveillance Consortium (BCSC) cooperative agreement (U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, U01CA70040).
doi:10.1059/0003-4819-156-9-201205010-00006
PMCID: PMC3561467  PMID: 22547473
8.  Mid- and Late-Life Obesity: Risk of Dementia in the Cardiovascular Health Cognition Study 
Archives of neurology  2009;66(3):336-342.
Objectives
To evaluate associations between mid- and late-life obesity and risk of dementia.
Design
Prospective cohort followed 5.4 years from 1992/4 through 1999.
Setting
Community-dwelling sample in four US sites recruited from Medicare eligibility files.
Participants
2,798 adults without dementia, mean age 74.7 years, 59.1% women, participating in the Cardiovascular Health Cognition Study completing a magnetic resonance image, measured for height and weight at baseline (late-life) and self-reporting weight at age 50 (mid-life). Body mass index (BMI) was calculated at both times.
Main Outcome Measures
Dementia, Alzheimer’s disease (AD) and vascular dementia (VaD) classified by a multidisciplinary committee using standardized criteria.
Results
Classification resulted in 480 persons with incident dementia, 245 with AD (no VaD) and 213 with VaD (with or without AD). In evaluations of mid-life obesity, an increased risk of dementia was found for obese (BMI >30) compared to normal (BMI 20-25) persons adjusted for demographics (HR: 1.39, 95% CI: 1.03-1.87) and for caradiovascularl risk factors (HR: 1.36, 95% CI: 0.94-1.95). The risk estimates reversed in assessments of late-life BMI. Underweight persons (BMI < 20) had an increased risk of dementia (HR: 1.62, 95% CI: 1.02-2.64) while being overweight (BMI 25-30) was not associated (HR: 0.92, 95% CI: 0.72-1.18) and being obese reduced the risk of dementia (HR: 0.63, 95% CI: 0.44-0.91) compared to those with normal BMI.
Conclusions
These results help explain the “obesity paradox” as differences in dementia risk over time are consistent with physical changes in the trajectory toward disability.
doi:10.1001/archneurol.2008.582
PMCID: PMC3513375  PMID: 19273752
9.  Hospitalization for infection and risk of acute ischemic stroke: The Cardiovascular Health Study 
Background and Purpose
Little is known about acute precipitants of ischemic stroke, although evidence suggests infections contribute to risk. We hypothesized that acute hospitalization for infection is associated with short-term risk of stroke.
Methods
The case-crossover design was used to compare hospitalization for infection during case periods (90, 30, or 14 days prior to incident ischemic stroke) and control periods (equivalent time periods exactly 1 or 2 years prior to stroke) in the Cardiovascular Health Study, a population-based cohort of 5888 elderly participants from 4 US sites. Odds ratios and 95% confidence intervals (OR, 95% CI) were calculated using conditional logistic regression. Confirmatory analyses assessed hazard ratios (HR) of stroke from Cox regression models with hospitalization for infection as a time-varying exposure.
Results
During a median follow-up of 12.2 years, 669 incident ischemic strokes were observed in participants without baseline history of stroke. Hospitalization for infection was more likely during case than control time periods; for 90 days prior to stroke, OR=3.4 (95% CI 1.8–6.5). The point estimates of risks were higher when examining shorter intervals: for 30 days, OR= 7.3 (95% CI 1.9–40.9), and 14 days, OR=8.0 (95% CI 1.7–77.3). In survival analyses, risk of stroke was associated with hospitalization for infection in the preceding 90 days, adjusted HR=2.4 (95% CI 1.6–3.4).
Conclusions
Hospitalization for infection is associated with a short-term increased risk of stroke, with higher risks observed for shorter intervals preceding stroke.
doi:10.1161/STROKEAHA.110.608588
PMCID: PMC3125478  PMID: 21546476
Epidemiology; Cerebral Infarction; Infectious Diseases
10.  Comparing Years of Healthy Life, Measured in 16 Ways, for Normal Weight and Overweight Older Adults 
Journal of Obesity  2012;2012:894894.
Introduction. The traditional definitions of overweight and obesity are not age specific, even though the relationship of weight to mortality is different for older adults. Effects of adiposity on aspects of health beside mortality have not been well investigated. Methods. We calculated the number of years of healthy life (YHL) in the 10 years after baseline, for 5,747 older adults. YHL was defined in 16 different ways. We compared Normal and Overweight persons, classified either by body mass index (BMI) or by waist circumference (WC). Findings. YHL for Normal and Overweight persons differed significantly in 25% of the comparisons, of which half favored the Overweight. Measures of physical health favored Normal weight, while measures of mental health and quality of life favored Overweight. Overweight was less favorable when defined by WC than by BMI. Obese persons usually had worse outcomes. Discussion. Overweight older adults averaged as many years of life and years of healthy life as those of Normal weight. There may be no outcome based reason to distinguish Normal from Overweight for older adults. Conclusion. The “Overweight paradox” appears to hold for nonmortality outcomes. New adiposity standards are needed for older adults, possibly different by race and sex.
doi:10.1155/2012/894894
PMCID: PMC3388309  PMID: 22778920
11.  Genetic Ancestry in Lung-Function Predictions 
The New England journal of medicine  2010;363(4):321-330.
BACKGROUND
Self-identified race or ethnic group is used to determine normal reference standards in the prediction of pulmonary function. We conducted a study to determine whether the genetically determined percentage of African ancestry is associated with lung function and whether its use could improve predictions of lung function among persons who identified themselves as African American.
METHODS
We assessed the ancestry of 777 participants self-identified as African American in the Coronary Artery Risk Development in Young Adults (CARDIA) study and evaluated the relation between pulmonary function and ancestry by means of linear regression. We performed similar analyses of data for two independent cohorts of subjects identifying themselves as African American: 813 participants in the Health, Aging, and Body Composition (HABC) study and 579 participants in the Cardiovascular Health Study (CHS). We compared the fit of two types of models to lung-function measurements: models based on the covariates used in standard prediction equations and models incorporating ancestry. We also evaluated the effect of the ancestry-based models on the classification of disease severity in two asthma-study populations.
RESULTS
African ancestry was inversely related to forced expiratory volume in 1 second (FEV1) and forced vital capacity in the CARDIA cohort. These relations were also seen in the HABC and CHS cohorts. In predicting lung function, the ancestry-based model fit the data better than standard models. Ancestry-based models resulted in the reclassification of asthma severity (based on the percentage of the predicted FEV1) in 4 to 5% of participants.
CONCLUSIONS
Current predictive equations, which rely on self-identified race alone, may misestimate lung function among subjects who identify themselves as African American. Incorporating ancestry into normative equations may improve lung-function estimates and more accurately categorize disease severity. (Funded by the National Institutes of Health and others.)
doi:10.1056/NEJMoa0907897
PMCID: PMC2922981  PMID: 20647190
12.  Trajectories of Neighborhood Poverty and Associations With Subclinical Atherosclerosis and Associated Risk Factors 
American Journal of Epidemiology  2010;171(10):1099-1108.
The authors used data from the Multi-Ethnic Study of Atherosclerosis and latent trajectory class modeling to determine patterns of neighborhood poverty over 20 years (1980–2000 residential history questionnaires were geocoded and linked to US Census data). Using these patterns, the authors examined 1) whether trajectories of neighborhood poverty were associated with differences in the amount of subclinical atherosclerosis (common carotid intimal-media thickness) and 2) associated risk factors (body mass index, hypertension, diabetes, current smoking) at baseline (January 2000–August 2002). The authors found evidence of 5 stable trajectory groups with differing levels of neighborhood poverty (∼6%, 12%, 20%, 30%, and 45%) and 1 group with 29% poverty in 1980 and approximately 11% in 2000. Mostly for women, higher cumulative neighborhood poverty was generally significantly associated with worse cardiovascular outcomes. Trends generally persisted after adjustment for adulthood socioeconomic position and race/ethnicity, although they were no longer statistically significant. Among women who had moved during the 20 years, the long-term measure had stronger associations with outcomes (except smoking) than a single, contemporaneous measure. Results indicate that cumulative 20-year exposure to neighborhood poverty is associated with greater cardiovascular risk for women. In residentially mobile populations, single-point-in-time measures underestimate long-term effects.
doi:10.1093/aje/kwq044
PMCID: PMC2877469  PMID: 20423931
body mass index; carotid artery, internal; diabetes mellitus; hypertension; models, statistical; residential mobility; retrospective studies; smoking
13.  The contribution of a 9p21.3 variant, a KIF6 variant, and C-reactive protein to predicting risk of myocardial infarction in a prospective study 
Background
Genetic risk factors might improve prediction of coronary events. Several variants at chromosome 9p21.3 have been widely reported to be associated with coronary heart disease (CHD) in prospective and case-control studies. A variant of KIF6 (719Arg) has also been reported to be associated with increased risk of CHD in large prospective studies, but not in case-control studies. We asked whether the addition of genetic information (the 9p21.3 or KIF6 variants) or a well-established non-genetic risk factor (C-reactive protein [CRP]) can improve risk prediction by the Framingham Risk Score (FRS) in the Cardiovascular Health Study (CHS)--a prospective observational study of risk factors for cardiovascular disease among > 5,000 participants aged 65 or older.
Methods
Improvement of risk prediction was assessed by change in the area under the receiver-operator characteristic curve (AUC) and by net reclassification improvement (NRI).
Results
Among white participants the FRS was improved by addition of KIF6 719Arg carrier status among men as assessed by the AUC (from 0.581 to 0.596, P = 0.03) but not by NRI (NRI = 0.027, P = 0.32). Adding both CRP and 719Arg carrier status to the FRS improved risk prediction by the AUC (0.608, P = 0.02) and NRI (0.093, P = 0.008) in men, but not women (P ≥ 0.24).
Conclusions
While none of these risk markers individually or in combination improved risk prediction among women, a combination of KIF6 719Arg carrier status and CRP levels modestly improved risk prediction among white men; although this improvement is not significant after multiple-testing correction. These observations should be investigated in other prospective studies.
doi:10.1186/1471-2261-11-10
PMCID: PMC3066109  PMID: 21406102
14.  Association of Coagulation and Inflammation Related Genes and Factor VIIc Levels with Stroke: The Cardiovascular Health Study 
Background
Thrombosis and inflammation are critical in stroke etiology, but associations of coagulation and inflammation gene variants with stroke, and particularly factor VII levels are inconclusive.
Objectives
To test the associations between 736 single nucleotide polymorphisms (SNP) between tagging haplotype patterns of 130 coagulation and inflammation genes, and stroke events in the 5,888 participants ≥ 65 of the observational Cardiovascular Health Study cohort.
Patients
/Methods: With 16 years of follow-up, age and sex-adjusted Cox models were used to estimate associations of SNPs and factor VIIc levels with future stroke.
Results
815 strokes occurred in 5,255 genotyped participants without baseline stroke (748 ischemic strokes, 586 among whites). Among whites, 6 SNPs were associated with stroke with a nominal p <0.01: rs6046 and rs3093261 (F7 gene); rs4918851 and rs3781387 (HABP2 gene); rs3138055 (NFKB1A) and rs4648004 (NFKB1). Two of these SNPs were associated with factor VIIc levels (units = percent activity): rs6046 (β = −18.5, p = 2.38 × 10−83) and rs3093261 (β = 2.99, p = 3.93 × 10−6). Adjusting for age, sex, race, and cardiovascular risk factors, the association of factor VIIc quintiles (Q) with stroke were (HR: 95% CI): Q1 (reference); Q2 (1.4; 1.1, 1.9); Q3 (1.1; 0.8, 1.5); Q4 (1.5; 1.1, 2.0); Q5 (1.6; 1.2, 2.2). Associations between SNPs and stroke were independent of factor VIIc levels.
Conclusions
Variation in factor VII-related genes and factor VIIc levels were associated with risk of incident ischemic stroke in this elderly cohort, suggesting a potential causal role for factor VII in stroke etiology.
doi:10.1111/j.1538-7836.2010.04149.x
PMCID: PMC3030667  PMID: 21114618
Stroke; Genetic Epidemiology; factor VII; hemostasis; inflammation; cardiovascular disease risk
15.  C-reactive Protein Gene Variation and Risk of Community-Acquired Pneumonia 
Respirology (Carlton, Vic.)  2009;15(1):160-164.
Background and Objective
C-reactive protein (CRP) has several potentially antibacterial effects, and variation in the CRP gene is known to influence CRP levels. Whether this variation influences risk of infection, and hence whether CRP has anti-infective activity in humans, is uncertain.
Methods
We evaluated a series of haplotype-tagging single nucleotide polymorphisms among 5374 individuals in the Cardiovascular Health Study (CHS), a cohort of older adults from four communities, who were followed for community-acquired pneumonia for 12-13 years. Secondarily, we evaluated whether these polymorphisms varied among men in the Health Professionals Follow-up Study (HPFS) who self-reported pneumonia on biennial questionnaires.
Results
There were 581 (507 white and 74 black) CHS participants with incident hospitalizations for pneumonia. No SNPs or haplotypes were associated with risk among white CHS participants. Among black participants, the haplotype tagged by A790T was associated with lower risk of incident pneumonia (hazard ratio 0.5; 95% confidence interval, 0.3-0.9) and with higher CRP levels. In HPFS, a separate haplotype was associated with less frequent self-reported pneumonia but not with circulating CRP levels.
Conclusions
Some genetic variants in CRP may be associated with risk of pneumonia, but haplotypes associated with risk are variably associated with baseline CRP levels. If CRP is a relevant component of innate immunity in humans, the inducibility or tissue-specificity of expression may be at least as important as chronic circulating levels.
doi:10.1111/j.1440-1843.2009.01661.x
PMCID: PMC2869386  PMID: 19947988
C-reactive protein; single nucleotide polymorphism; pneumonia; cohort studies; epidemiology
16.  Ginkgo biloba for Preventing Cognitive Decline in Older Adults 
Context
The herbal product Ginkgo biloba is taken frequently with the intention of improving cognitive health in aging. However, evidence from adequately powered clinical trials is lacking regarding its effect on long-term cognitive functioning.
Objective
To determine whether G biloba slows the rates of global or domain-specific cognitive decline in older adults.
Design, Setting, and Participants
The Ginkgo Evaluation of Memory (GEM) study, a randomized, double-blind, placebo-controlled clinical trial of 3069 community-dwelling participants aged 72 to 96 years, conducted in 6 academic medical centers in the United States between 2000 and 2008, with a median follow-up of 6.1 years.
Intervention
Twice-daily dose of 120-mg extract of G biloba (n=1545) or identical-appearing placebo (n=1524).
Main Outcome Measures
Rates of change over time in the Modified Mini-Mental State Examination (3MSE), in the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog), and in neuropsychological domains of memory, attention, visual-spatial construction, language, and executive functions, based on sums of z scores of individual tests.
Results
Annual rates of decline in z scores did not differ between G biloba and placebo groups in any domains, including memory (0.043; 95% confidence interval [CI], 0.034-0.051 vs 0.041; 95% CI, 0.032-0.050), attention (0.043; 95% CI, 0.037-0.050 vs 0.048; 95% CI, 0.041-0.054), visuospatial abilities (0.107; 95% CI, 0.097-0.117 vs 0.118; 95% CI, 0.108-0.128), language (0.045; 95% CI, 0.037-0.054 vs 0.041; 95% CI, 0.033-0.048), and executive functions (0.092; 95% CI, 0.086-0.099 vs 0.089; 95% CI, 0.082-0.096). For the 3MSE and ADAS-Cog, rates of change varied by baseline cognitive status (mild cognitive impairment), but there were no differences in rates of change between treatment groups (for 3MSE, P=.71; for ADAS-Cog, P=.97). There was no significant effect modification of treatment on rate of decline by age, sex, race, education, APOE*E4 allele, or baseline mild cognitive impairment (P>.05).
Conclusion
Compared with placebo, the use of G biloba, 120 mg twice daily, did not result in less cognitive decline in older adults with normal cognition or with mild cognitive impairment.
Trial Registration
clinicaltrials.gov Identifier: NCT00010803
doi:10.1001/jama.2009.1913
PMCID: PMC2832285  PMID: 20040554
17.  Trajectories of Dehydroepiandrosterone Sulfate Predict Mortality in Older Adults: The Cardiovascular Health Study 
Background
Dehydroepiandrosterone sulfate (DHEAS) has been proposed as an antiaging hormone, but its importance is unclear. Assessment of an individual’s ability to maintain a DHEAS set point, through examination of multiple DHEAS levels over time, may provide insight into biologic aging.
Methods
Using Cox proportional hazard models, we examined the relationship between DHEAS trajectory patterns and all-cause death in 950 individuals aged ≥65 years who were enrolled in the Cardiovascular Health Study and had DHEAS levels measured at three to six time points.
Results
Overall, there was a slight decline in DHEAS levels over time (−0.013 μg/mL/y). Three trajectory components were examined: slope, variability, and baseline DHEAS. When examined individually, a steep decline or extreme variability in DHEAS levels was associated with higher mortality (p < .001 for each), whereas baseline DHEAS level was not. In adjusted models including all three components, steep decline (hazard ratio [HR] 1.75, confidence interval [CI] 1.32–2.33) and extreme variability (HR 1.89, CI 1.47–2.43) remained significant predictors of mortality, whereas baseline DHEAS level remained unpredictive of mortality (HR 0.97 per standard deviation, CI 0.88–1.07). The effect of trajectory pattern was more pronounced in men than in women. Individuals with both a steep decline and extreme variability in DHEAS levels had a significantly higher death rate than those with neither pattern (141 vs 48 deaths per 1,000 person-years, p < .001).
Conclusions
Our data show significant heterogeneity in the individual trajectories of DHEAS levels and suggest that these trajectories provide important biologic information about the rate of aging, whereas the DHEAS level itself does not.
doi:10.1093/gerona/glp129
PMCID: PMC2773814  PMID: 19713299
DHEA; DHEAS; Mortality; Aging; Elderly
18.  Biomarkers of inflammation and MRI-defined small vessel disease of the brain: the Cardiovascular Health Study 
Background
To clarify the role of inflammation in the pathogenesis of small vessel disease of the brain, we investigated the association between common variation in the CRP and IL6 genes, plasma CRP and IL6 levels, and presence of MRI-defined white matter lesions (WML) and brain infarcts (BI) in elderly participants of the Cardiovascular Health Study.
Methods and Results
Tag single nucleotide polymorphisms (SNPs) in the CRP and IL6 genes were selected from the SeattleSNPs database. In cross-sectional analyses, logistic regression models adjusting for known CVD risk factors were constructed to assess the associations of plasma CRP and IL6 levels and common CRP and IL6 gene haplotypes with presence of WML or BI in Blacks (N=532) and Whites (N=2,905). Plasma IL6 and CRP levels were associated with presence of WML and BI in both races. In Whites, common haplotypes of the IL6 gene were significantly associated with WML and BI. The common haplotype tagged by the −174G/C promoter polymorphism was associated with an increased risk of WML (OR=1.14; 95% CI: (1.02; 1.28)). The common haplotype tagged by the −572G/C promoter polymorphism was associated with an increased risk of BI (OR=1.57; 95% CI: (1.15; 2.14)). Significant associations were lacking for WML or BI with IL6 gene variation in Blacks, or with CRP gene variation in either race.
Conclusions
This study provides evidence of a genetic basis underlying the relationship between plasma biomarkers of inflammation and small vessel disease of the brain. Further studies to elucidate the specific role of IL6 in disease pathogenesis are warranted.
doi:10.1161/STROKEAHA.107.508135
PMCID: PMC2888487  PMID: 18436879
19.  Gene Variants Associated With Ischemic Stroke 
Background and Purpose
The purpose of this study was to determine whether 74 single nucleotide polymorphisms (SNPs), which had been associated with coronary heart disease, are associated with incident ischemic stroke.
Methods
Based on antecedent studies of coronary heart disease, we prespecified the risk allele for each of the 74 SNPs. We used Cox proportional hazards models that adjusted for traditional risk factors to estimate the associations of these SNPs with incident ischemic stroke during 14 years of follow-up in a population-based study of older adults: the Cardiovascular Health Study (CHS).
Results
In white CHS participants, the prespecified risk alleles of 7 of the 74 SNPs (in HPS1, ITGAE, ABCG2, MYH15, FSTL4, CALM1, and BAT2) were nominally associated with increased risk of stroke (one-sided P<0.05, false discovery rate=0.42). In black participants, the prespecified risk alleles of 5 SNPs (in KRT4, LY6G5B, EDG1, DMXL2, and ABCG2) were nominally associated with stroke (one-sided P<0.05, false discovery rate=0.55). The Val12Met SNP in ABCG2 was associated with stroke in both white (hazard ratio, 1.46; 90% CI, 1.05 to 2.03) and black (hazard ratio, 3.59; 90% CI, 1.11 to 11.6) participants of CHS. Kaplan-Meier estimates of the 10-year cumulative incidence of stroke were greater among Val allele homozygotes than among Met allele carriers in both white (10% versus 6%) and black (12% versus 3%) participants of CHS.
Conclusions
The Val12Met SNP in ABCG2 (encoding a transporter of sterols and xenobiotics) was associated with incident ischemic stroke in white and black participants of CHS.
doi:10.1161/STROKEAHA.108.521328
PMCID: PMC2881155  PMID: 19023099
brain infarction; cerebrovascular accident; epidemiology; genetics; prevention; risk factors
20.  Cross-Sectional and Longitudinal Associations of Neighborhood Cohesion and Stressors with Depressive Symptoms in the Multiethnic Study of Atherosclerosis (MESA) 
Annals of epidemiology  2009;19(1):49-57.
Purpose
This study examined associations of neighborhood social cohesion, violence and aesthetic quality with depressive symptoms amongst 2619 healthy adults aged 45-84 years enrolled in the Multiethnic Study of Atherosclerosis.
Methods
Neighborhood characteristics were estimated by surveying a separate sample of area residents. Measures of aesthetic environment, social cohesion, and violence were combined into a summary score with increasing scores indicating more favorable environments. Depressive symptoms were measured using the Center for Epidemiologic Studies Depression (CES-D) scale. Marginal maximum likelihood estimation was used to assess associations of neighborhood characteristics with CES-D score at baseline and with the odds of developing incident depression (CES-D score ≥16 or use of antidepressants) over a 4-5 year follow-up among persons with CESD<16 at baseline. Models were adjusted for age, income, education, and race/ethnicity.
Results
Lower levels of social cohesion and aesthetic quality and higher levels of violence were associated with higher mean CES-D scores in men and women (p-value for trend <0.01, adjusted mean difference in CES-D per 1 SD increase in summary score -1.01 (95% CI: -1.85, -0.17) and -1.08 (-1.88, -0.28) in men and women respectively). Associations of neighborhood characteristics with incident depression were in the expected direction for women but confidence intervals were wide (OR of incident depression 0.89 (0.63, 1.26)). No association was seen for men (OR=0.96 (0.74, 1.25)). Conclusions: Neighborhood social cohesion, aesthetic quality and violence are associated with the presence of depressive symptoms in residents.
doi:10.1016/j.annepidem.2008.10.002
PMCID: PMC2763272  PMID: 19064189
mental health; depression; residence characteristics; epidemiology; social environment
21.  Lipoprotein-Associated Phospholipase A2 and Risk of Venous Thrombosis in Older Adults 
American journal of hematology  2008;83(7):524-527.
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme involved in inflammation and platelet function. Inherited deficiency and elevated levels are associated with atherosclerosis. Given potential common etiologies of atherosclerosis and venous thrombosis (VT), we hypothesized that low and high Lp-PLA2 would be associated with VT risk. Lp-PLA2 mass and activity were measured in baseline samples of Cardiovascular Health Study participants (5,888 men and women age ≥65), excluding 354 reporting pre-baseline VT. The study endpoint was VT unrelated to cancer after 11.6 years follow-up. Hazard ratios were estimated using Cox proportional hazard models, adjusting for age, race, sex and body-mass index. With 129 cases of VT, there was no association of Lp-PLA2 activity with risk. Adjusted hazard ratios were 1.19 (CI 0.62, 2.29) and 0.87 (CI 0.43, 1.76) for the lowest and highest decile, respectively, compared to the 10-25th percentile. Corresponding hazard ratios for Lp-PLA2 mass were 1.63 (CI 0.79, 3.34) and 1.33 (CI 0.61, 2.87). Results were robust to several definitions of low or high Lp-PLA2. While the association of Lp-PLA2 levels with arterial disease events implies a role for this enzyme in atherogenesis, our findings suggest that it is not prothrombotic.
doi:10.1002/ajh.21182
PMCID: PMC2596953  PMID: 18383322
Lipoprotein-associated phospholipase A2; risk factor; venous thrombosis; deep vein thrombosis; pulmonary embolus
22.  Association of Gene Variants with Incident Myocardial Infarction in the Cardiovascular Health Study 
Objective
We asked if single nucleotide polymorphisms (SNPs) that had been nominally associated with cardiovascular disease in antecedent studies were also associated with cardiovascular disease in a population–based prospective study of 4,522 individuals aged 65 or older.
Methods
Based on antecedent studies, we prespecified a risk allele and an inheritance model for each of 74 SNPs. We then tested the association of these SNPs with myocardial infarction (MI) in the Cardiovascular Health Study (CHS).
Results
The prespecified risk alleles of 8 SNPs were nominally associated (1-sided P<0.05) with increased risk of MI in white CHS participants. The false discovery rate for these 8 was 0.43, suggesting that about 4 of these 8 are likely to be true positives. The 4 of these 8 SNPs that had the strongest evidence for association with cardiovascular disease prior to testing in CHS (association in 3 antecedent studies) were in KIF6 (CHS HR=1.29; 90%CI 1.1–1.52), VAMP8 (HR=1.2; 90%CI 1.02–1.41), TAS2R50 (HR=1.13; 90%CI 1–1.27), and LPA (HR=1.62; 90%CI 1.09–2.42).
Conclusions
Although most of the SNPs investigated were not associated with MI in CHS, evidence from this investigation combined with previous studies suggests that 4 of these SNPs are likely associated with MI.
doi:10.1161/ATVBAHA.107.153981
PMCID: PMC2636623  PMID: 17975119
coronary disease; myocardial infarction; genetics; polymorphisms

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