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Biggs, Mary L. (17)
Mukamal, Kenneth J. (5)
Ix, Joachim H. (4)
Kuller, Lewis H. (4)
Newman, Anne B. (4)
Siscovick, David S. (4)
de Boer, Ian H. (4)
Carnethon, Mercedes R. (3)
Kizer, Jorge R. (3)
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research-article (18)
1.  Markers of Inflammation in Prevalent and Incident Parkinson’s Disease in the Cardiovascular Health Study 
Ton, Thanh G.N. | Jain, Samay | Biggs, Mary L. | Thacker, Evan L. | Strotmeyer, Elsa S. | Boudreau, Robert | Newman, Anne B. | Longstreth, W.T. | Checkoway, Harvey
Parkinsonism & Related Disorders  2011;18(3):274-278.
Background
Studies demonstrate existence of inflammation in prevalent Parkinson’s disease (PD). We assessed associations of baseline levels of inflammatory markers with prevalent PD at baseline (1989) and incident PD identified over 13 years of follow-up of the Cardiovascular Health Study.
Methods
Blood samples at baseline were measured for fibrinogen, interleukin-6, tumor necrosis factor–α, C-reactive protein, albumin, and white blood cells. The analysis included 60 prevalent and 154 incident PD cases.
Results
Risk of prevalent PD was significantly higher per doubling of IL-6 among women (odds ratio [OR] = 1.5, 95% confidence interval [CI]: 1.0, 2.4) and WBC among men (OR: 2.4, 95% CI: 1.2, 4.9) in multivariate models. Risk of incident PD was not associated with higher levels of any biomarker after adjusting for age, smoking, African American race, and history of diabetes. Inverse associations with incident PD were observed per doubling of C-reactive protein (OR=0.9; 95% CI: 0.8, 1.0) and of fibrinogen among women (OR=0.4; 95% CI: 0.2, 0.8).
Conclusions
Although inflammation exists in PD, it may not represent an etiologic factor. Our findings suggest the need for larger studies that measure inflammatory markers before PD onset.
doi:10.1016/j.parkreldis.2011.11.003
PMCID: PMC3288759  PMID: 22119505
albumins; C-reactive protein; inflammation; interleukin-6; odds ratio; Parkinson’s disease; tumor necrosis factor-α
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2.  Gender Differences in Tea, Coffee, and Cognitive Decline in the Elderly: The Cardiovascular Health Study 
Arab, Lenore | Biggs, Mary L. | O’Meara, Ellen S. | Longstreth, W.T. | Crane, Paul K. | Fitzpatrick, Annette L.
Journal of Alzheimer's disease : JAD  2011;27(3):553-566.
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
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3.  Association of Weight Status with Mortality in Adults with Incident Diabetes 
Carnethon, Mercedes R. | de Chavez, Peter J. | Biggs, Mary L. | Lewis, Cora E. | Pankow, James S. | Bertoni, Alain G. | Golden, Sherita H. | Liu, Kiang | Mukamal, Kenneth J. | Campbell-Jenkins, Brenda | Dyer, Alan R.
JAMA : the journal of the American Medical Association  2012;308(6):581-590.
Context
Type 2 diabetes in normal weight (body mass index [BMI] <25kg/m2) adults is an intriguing representation of the metabolically obese normal weight phenotype with unknown mortality consequences.
Objective
To minimize the influence of diabetes duration and voluntary weight loss on mortality, we tested the association of weight status with mortality in adults with new onset diabetes.
Design
Pooled analysis of five longitudinal cohort studies: Atherosclerosis Risk in Communities Study, 1990–2006; Cardiovascular Health Study, 1992–2008; Coronary Artery Risk Development in Young Adults, 1987–2011; Framingham Offspring Study, 1979–2007; Multi-Ethnic Study of Atherosclerosis, 2002–2011. Participants contributed 27,125 person-years of follow-up.
Setting
2,625 participants with incident diabetes
Participants
Men and women (age>40 years) who developed incident diabetes based on fasting glucose ≥ 126 mg/dL or newly-initiated diabetes medication and who had concurrent measurements of body mass index (BMI). Participants were classified as normal weight if their BMI was 18.5 to 24.99kg/m2 or overweight/obese if BMI≥25 kg/m2.
Main Outcome Measures
Total, cardiovascular, and non-cardiovascular mortality
Results
The proportion of adults who were normal weight at the time of incident diabetes ranged from 9–21% (overall=12%). Over follow-up, 449 participants died, 178 from cardiovascular causes and 253 from non-cardiovascular causes (18 were not classified). The rate of total, cardiovascular and non-cardiovascular mortality was higher in normal weight participants (248.8, 99.8, and 198.1 per 10,000 person-years, respectively) than overweight/obese participants (152.1, 67.8, and 87.9 per 10,000 person-years, respectively). Following adjustment for demographic characteristics and blood pressure, lipids, waist circumference and smoking status, hazard ratios comparing normal weight participants to overweight/obese participants for total, cardiovascular, and non-cardiovascular mortality were 2.08 (95% confidence interval [CI]: 1.52, 2.85), 1.52 (95% CI: 0.89, 2.58) and 2.32 (95% CI: 1.55, 3.48), respectively.
Conclusions
Adults who are normal weight at the time of incident diabetes have higher mortality than adults who are overweight or obese.
doi:10.1001/jama.2012.9282
PMCID: PMC3467944  PMID: 22871870
type 2 diabetes; obesity; cardiovascular disease; longitudinal studies
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4.  Association of Increased Upper Trunk and Decreased Leg Fat With 2-h Glucose in Control and HIV-Infected Persons 
Kosmiski, Lisa A. | Scherzer, Rebecca | Heymsfield, Steven B. | Rimland, David | Simberkoff, Michael S. | Sidney, Stephen | Shlipak, Michael G. | Bacchetti, Peter | Biggs, Mary L. | Grunfeld, Carl
Diabetes Care  2011;34(11):2448-2453.
OBJECTIVE
Changes in body fat distribution and abnormal glucose metabolism are common in HIV-infected patients. We hypothesized that HIV-infected participants would have a higher prevalence of impaired glucose tolerance (IGT) compared with control subjects.
RESEARCH DESIGN AND METHODS
A total of 491 HIV-infected and 187 control participants from the second examination of the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) underwent glucose tolerance testing (GTT). Multivariable regression was used to identify factors associated with GTT parameters.
RESULTS
The prevalence of impaired fasting glucose (IFG) (>110 mg/dL) was similar in HIV-infected and control participants (21 vs. 25%, P = 0.23). In those without IFG, the prevalence of IGT was slightly higher in HIV-infected participants compared with control subjects (13.1 vs. 8.2%, P = 0.14) and in HIV+ participants with lipoatrophy versus without (18.1 vs. 11.5%, P = 0.084). Diabetes detected by GTT was rare (HIV subjects 1.3% and control subjects 0%, P = 0.65). Mean 2-h glucose levels were 7.6 mg/dL higher in the HIV-infected participants (P = 0.012). Increased upper trunk subcutaneous adipose tissue (SAT) and decreased leg SAT were associated with 2-h glucose and IGT in both HIV-infected and control participants. Adjusting for adipose tissue reduced the estimated effects of HIV. Exercise, alcohol use, and current tenofovir use were associated with lower 2-h glucose levels in HIV-infected participants.
CONCLUSIONS
In HIV infection, increased upper trunk SAT and decreased leg SAT are associated with higher 2-h glucose. These body fat characteristics may identify HIV-infected patients with normal fasting glucose but nonetheless at increased risk for diabetes.
doi:10.2337/dc11-0616
PMCID: PMC3198295  PMID: 21926283
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5.  Association of Body Mass Index With Peripheral Arterial Disease in Older Adults 
Ix, Joachim H. | Biggs, Mary L. | Kizer, Jorge R. | Mukamal, Kenneth J. | Djousse, Luc | Zieman, Susan J. | de Boer, Ian H. | Nelson, Tracy L. | Newman, Anne B. | Criqui, Michael H. | Siscovick, David S.
American Journal of Epidemiology  2011;174(9):1036-1043.
The authors hypothesized that the absence of cross-sectional associations of body mass index (BMI; weight (kg)/height (m)2) with peripheral arterial disease (PAD) in prior studies may reflect lower weight among persons who smoke or have poor health status. They conducted an observational study among 5,419 noninstitutionalized residents of 4 US communities aged ≥65 years at baseline (1989–1990 or 1992–1993). Ankle brachial index was measured, and participants reported their history of PAD procedures. Participants were followed longitudinally for adjudicated incident PAD events. At baseline, mean BMI was 26.6 (standard deviation, 4.6), and 776 participants (14%) had prevalent PAD. During 13.2 (median) years of follow-up through June 30, 2007, 276 incident PAD events occurred. In cross-sectional analysis, each 5-unit increase in BMI was inversely associated with PAD (prevalence ratio (PR) = 0.92, 95% confidence interval (CI): 0.85, 1.00). However, among persons in good health who had never smoked, the direction of association was opposite (PR = 1.20, 95% CI: 0.94, 1.52). Similar results were observed between BMI calculated using weight at age 50 years and PAD prevalence (PR = 1.30, 95% CI: 1.11, 1.51) and between BMI at baseline and incident PAD events occurring during follow-up (hazard ratio = 1.32, 95% CI: 1.00, 1.76) among never smokers in good health. Greater BMI is associated with PAD in older persons who remain healthy and have never smoked. Normal weight maintenance may decrease PAD incidence and associated comorbidity in older age.
doi:10.1093/aje/kwr228
PMCID: PMC3243937  PMID: 21920948
ankle brachial index; body mass index; cardiovascular diseases; peripheral arterial disease
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6.  Demographic, medical, and behavioral characteristics associated with over the counter non-steroidal anti-inflammatory drug use in a population based cohort: results from the Multi-Ethnic Study of Atherosclerosis 
Delaney, Joseph A C | Biggs, Mary L. | Kronmal, Richard A | Psaty, Bruce M
Pharmacoepidemiology and drug safety  2010;20(1):83-89.
Background
Three types of non-steroidal anti-inflammatory drugs (NSAIDs) can be obtained both over the counter (OTC) and by prescription in the United States. OTC NSAID use is not recorded in prescription claims databases; this might lead to differential misclassification of NSAID exposure status in studies that use computerized pharmacy databases to study NSAID use.
Objective
To evaluate characteristics of OTC versus prescription NSAID users
Methods
This analysis is set within the Multi-Ethnic Study of Atherosclerosis (MESA) study; a prospective cohort study of 6,814 adults from 4 ethnic groups (European descent, Asian, African-American and Hispanic) with a mean age of 62 years. The cohort was restricted to those who initiated NSAID use (aspirin, ibuprofen or naproxen) during follow-up. We compared information about age, sex, ethnicity, body mass index, smoking, diabetes, medication use, education, income, health insurance status and exercisebetween groups.
Results
OTC NSAID use was prevalent at baseline (25% Aspirin, 9% Ibuprofen, 2% Naproxen). Compared to prescribed NSAID use, OTC NSAID use was lower for users of non-European descent for all classes: aspirin (p<0.0001), ibuprofen (p<0.0001) and naproxen (p=0.0094). For aspirin, differences were seen for male gender (Relative Risk (RR):0.92; 95%(Confidence interval) CI:0.86–0.98), use of lipid lowering drugs (RR:0.88; 95% CI: 0.80–0.96), low income (RR:0.89; 95%CI:0.81–0.97), and participants one standard deviation above average in intentional exercise (RR:1.03; 95%CI:1.01–1.05).
Conclusions
OTC NSAID use is prevalent in an older multi-ethnic population and OTC users differ from prescription NSAID users. Caution should be exercised when using prescribed NSAIDs as a proxy for NSAID use.
doi:10.1002/pds.2065
PMCID: PMC3014611  PMID: 21182156
Aspirin; over the counter drug use; ethnicity; Multi-Ethnic Study of Atherosclerosis
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7.  Measures of Adiposity and Future Risk of Ischemic Stroke and Coronary Heart Disease in Older Men and Women 
Kizer, Jorge R. | Biggs, Mary L. | Ix, Joachim H. | Mukamal, Kenneth J. | Zieman, Susan J. | de Boer, Ian H. | Mozaffarian, Dariush | Barzilay, Joshua I. | Strotmeyer, Elsa S. | Luchsinger, Jose A. | Elkind, Mitchell S. V. | Longstreth, W. T. | Kuller, Lewis H. | Siscovick, David S.
American Journal of Epidemiology  2010;173(1):10-25.
The relation between measures of general and central adiposity and individual cardiovascular endpoints remains understudied in older adults. This study investigated the association of measures of body size and composition with incident ischemic stroke or coronary heart disease (1989–2007) in 3,754 community-dwelling US adults aged 65–100 years. Standardized anthropometry and bioelectric impedance measurements were obtained at baseline. Body mass index at age 50 years (BMI50) was calculated on the basis of recalled weight. Although only waist/hip ratio was significantly associated with ischemic stroke in quintile analysis in women, dichotomized body mass index (BMI) (≥30 kg/m2) was the only significant predictor in men. For coronary heart disease, there were significant positive adjusted associations for all adiposity measures, without interaction by sex. This was true for both quintiles and conventional cutpoints for obesity, although BMI-defined overweight (25–29.9 kg/m2) was significant at midlife but not at baseline. Strengths of association for extreme quintiles (quintile 5 vs. quintile 1) were broadly comparable, but the highest effect estimates were for waist/hip ratio (hazard ratio = 1.56, 95% confidence interval: 1.25, 1.94) and BMI50 (hazard ratio = 1.71, 95% confidence interval: 1.37, 2.14), both of which remained significant after adjustment for mediators, BMI, or each other. Whether these differences translate to better risk prediction will require meta-analytical approaches, as will determination of prognostic cutpoints.
doi:10.1093/aje/kwq311
PMCID: PMC3025638  PMID: 21123850
aging; body composition; body size; coronary disease; stroke
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8.  Associations of antiretroviral drug use and HIV-specific risk factors with carotid intima–media thickness 
Delaney, Joseph A.C. | Scherzer, Rebecca | Biggs, Mary L. | Shliplak, Michael G. | Polak, Joseph F. | Currier, Judith S. | Kronmal, Richard A. | Wanke, Christine | Bacchetti, Peter | O'leary, Daniel | Tien, Phyllis C. | Grunfeld, Carl
AIDS (London, England)  2010;24(14):2201-2209.
Background
Previous research has demonstrated an increase in carotid intima–media thickness (cIMT) in HIV-infected individuals compared to controls. However, the reason for this increased level of subclinical vascular disease is unknown.
Objective
To identify HIV-related risk factors for increased cIMT.
Methods
We evaluated the relationship between HIV-related characteristics (including markers of HIV disease severity and use of antiretroviral therapy) and cIMT measurements in the internal/bulb and common carotid regions among 538 HIV-infected participants from the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). We used Bayesian model averaging to estimate the posterior probability of candidate HIV and non-HIV-related risk factors being true predictors of increased cIMT. Variables with a posterior probability of more than 50% were used to develop a selected regression model for each of the anatomic regions.
Results
For common cIMT, the Bayesian model selection process identified age, African-American race, and systolic and diastolic blood pressure with probability more than 95%, HDL cholesterol with probability 85% and Hispanic ethnicity with probability 51%. Among the HIV-related factors included in the analysis, only tenofovir use was selected (51% probability). In the selected model, duration of tenofovir use was associated with lower common cIMT (−0.0094 mm/year of use; 95% confidence interval: −0.0177 to −0.0010). For internal cIMT, no HIV-related risk factors were above the 50% posterior probability threshold.
Conclusion
We observed an inverse association between duration of tenofovir use and common carotid cIMT. Whether this association is causal or due to confounding by indication needs further investigation.
doi:10.1097/QAD.0b013e32833d2132
PMCID: PMC3224487  PMID: 20671544
atherosclerosis; carotid intima–media thickness; HIV; tenofovir
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9.  Diabetes and Coronary Heart Disease as Risk Factors for Mortality in Older Adults 
Carnethon, Mercedes R. | Biggs, Mary L. | Barzilay, Joshua | Kuller, Lewis H. | Mozaffarian, Dariush | Mukamal, Kenneth | Smith, Nicholas L. | Siscovick, David
The American journal of medicine  2010;123(6):556.e1-556.e9.
Background
Type 2 diabetes has been described a coronary heart disease (CHD) “risk equivalent”. We tested whether cardiovascular and all-cause mortality rates were similar between participants with prevalent CHD versus diabetes in an older adult population in whom both glucose disorders and pre-existing atherosclerosis are common.
Methods
The Cardiovascular Health Study is a longitudinal study of men and women (n= 5784) aged ≥65 years at baseline who were followed from baseline (1989/92-93) through 2005 for mortality. Diabetes was defined by fasting plasma glucose ≥7.0 mmol/L or use of diabetes control medications. Prevalent CHD was determined by confirmed history of myocardial infarction (MI), angina, or coronary revascularization.
Results
Following multivariable adjustment for other cardiovascular disease risk factors and subclinical atherosclerosis, CHD mortality risk was similar between participants with CHD alone vs. diabetes alone (hazard ratio [HR]=1.04, 95% CI, 0.83-1.30). The proportion of mortality attributable to prevalent diabetes (Population Attributable Risk Percent =8.4%) and prevalent CHD (6.7%) was similar in women, but the proportion of mortality attributable to CHD (16.5%) as compared with diabetes (6.4%) was markedly higher in men. Patterns were similar for cardiovascular disease mortality. By contrast, the adjusted relative hazard of total mortality was lower among participants with CHD alone (HR =0.85, 95% CI, 0.75-0.96) as compared with those who had diabetes alone.
Conclusions
Among older adults, diabetes alone confers a similar risk for cardiovascular mortality as established clinical CHD. The public health burden of both diabetes and CHD is substantial, particularly among women.
doi:10.1016/j.amjmed.2009.11.023
PMCID: PMC3145803  PMID: 20569763
type 2 diabetes; cardiovascular disease; longitudinal studies; older adults
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10.  Ginkgo biloba and risk of cancer: Secondary Analysis of the Ginkgo Evaluation of Memory (GEM) Study 
Biggs, Mary L. | Sorkin, Barbara C. | Nahin, Richard L. | Kuller, Lewis H. | Fitzpatrick, Annette L.
Pharmacoepidemiology and drug safety  2010;19(7):694-698.
Purpose
Evidence from in vitro and in vivo studies suggests that Ginkgo biloba has cancer chemopreventive properties, but epidemiological evidence is sparse. We analyzed cancer as a secondary endpoint in the Ginkgo Evaluation of Memory (GEM) Study, the largest randomized, double-blind, placebo-controlled clinical trial of Ginkgo supplementation to date.
Methods
A total of 3,069 GEM participants 75+ years of age were randomized to twice-daily doses of either 120mg Ginkgo extract (EGb 761) or placebo and followed for a median 6.1 years. We identified hospitalizations for invasive cancer by reviewing hospital admission and discharge records for all reported hospitalizations over follow-up. Using an intention-to-treat approach, we compared the risk of cancer hospitalization between participants assigned to treatment and those assigned to placebo.
Results
During the intervention, there were 148 cancer hospitalizations in the placebo group and 162 in the EGb 761 group (Hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.87–1.36; p=0.46). Among the site-specific cancers analyzed, we observed an increased risk of breast (HR, 2.15; 95% CI, 0.97–4.80; p=0.06) and colorectal (HR, 1.62; 95% CI, 0.92–2.87; p=0.10) cancer, and a reduced risk of prostate cancer (HR, 0.71; 95% CI, 0.43–1.17; p=0.18).
Conclusions
Overall, these results do not support the hypothesis that regular use of Ginkgo biloba reduces the risk of cancer.
doi:10.1002/pds.1979
PMCID: PMC2917376  PMID: 20582906
Ginkgo biloba; randomized controlled trial; breast cancer; prostate cancer; complimentary and alternative medicine
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11.  Association Between Adiposity in Midlife and Older Age and Risk of Diabetes in Older Adults 
Biggs, Mary L. | Mukamal, Kenneth J. | Luchsinger, Jose A. | Ix, Joachim H. | Carnethon, Mercedes R. | Newman, Anne B. | de Boer, Ian H. | Strotmeyer, Elsa S. | Mozaffarian, Dariush | Siscovick, David S.
JAMA : the journal of the American Medical Association  2010;303(24):2504-2512.
Context
Adiposity is a well-recognized risk factor for type 2 diabetes among young and middle-aged adults, but the relationship between body composition and type 2 diabetes is not well described among older adults.
Objective
To examine the relationship between adiposity, changes in adiposity, and risk of incident type 2 diabetes in adults 65 years of age and older.
Design, Setting, and Participants
Prospective cohort study (1989-2007) of 4193 men and women 65 years of age and older in the Cardiovascular Health Study. Measures of adiposity were derived from anthropometry and bioelectrical impedance data at baseline and anthropometry repeated 3 years later.
Main Outcome Measure
Incident diabetes was ascertained based on use of antidiabetic medication or a fasting glucose level of 126 mg/dL or greater.
Results
Over median follow-up of 12.4 years (range, 0.9-17.8 years), 339 cases of incident diabetes were ascertained (7.1/1000 person-years). The adjusted hazard ratio (HR) (95% confidence interval [CI]) of type 2 diabetes for participants in the highest quintile of baseline measures compared with those in the lowest was 4.3 (95% CI, 2.9-6.5) for body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]), 3.0 (95% CI, 2.0-4.3) for BMI at 50 years of age, 4.2 (95% CI, 2.8-6.4) for weight, 4.0 (95% CI, 2.6-6.0) for fat mass, 4.2 (95% CI, 2.8-6.2) for waist circumference, 2.4 (95% CI, 1.6-3.5) for waist-hip ratio, and 3.8 (95% CI, 2.6-5.5) for waist-height ratio. However, when stratified by age, participants 75 years of age and older had HRs approximately half as large as those 65 to 74 years of age. Compared with weight-stable participants (±2 kg), those who gained the most weight from 50 years of age to baseline (≥9 kg), and from baseline to the third follow-up visit (≥6 kg), had HRs for type 2 diabetes of 2.8 (95% CI, 1.9-4.3) and 2.0 (95% CI, 1.1-3.7), respectively. Participants with a greater than 10-cm increase in waist size from baseline to the third follow-up visit had an HR of type 2 diabetes of 1.7 (95% CI, 1.1-2.8) compared with those who gained or lost 2 cm or less.
Conclusion
Among older adults, overall and central adiposity, and weight gain during middle age and after the age of 65 years are associated with risk of diabetes.
doi:10.1001/jama.2010.843
PMCID: PMC3047456  PMID: 20571017
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12.  Differential White Blood Cell Count and Type 2 Diabetes: Systematic Review and Meta-Analysis of Cross-Sectional and Prospective Studies 
Gkrania-Klotsas, Effrossyni | Ye, Zheng | Cooper, Andrew J. | Sharp, Stephen J. | Luben, Robert | Biggs, Mary L. | Chen, Liang-Kung | Gokulakrishnan, Kuppan | Hanefeld, Markolf | Ingelsson, Erik | Lai, Wen-An | Lin, Shih-Yi | Lind, Lars | Lohsoonthorn, Vitool | Mohan, Viswanathan | Muscari, Antonio | Nilsson, Goran | Ohrvik, John | Chao Qiang, Jiang | Jenny, Nancy Swords | Tamakoshi, Koji | Temelkova-Kurktschiev, Theodora | Wang, Ya-Yu | Yajnik, Chittaranjan Sakerlal | Zoli, Marco | Khaw, Kay-Tee | Forouhi, Nita G. | Wareham, Nicholas J. | Langenberg, Claudia | Fadini, Gian Paolo
PLoS ONE  2010;5(10):e13405.
Objective
Biological evidence suggests that inflammation might induce type 2 diabetes (T2D), and epidemiological studies have shown an association between higher white blood cell count (WBC) and T2D. However, the association has not been systematically investigated.
Research Design and Methods
Studies were identified through computer-based and manual searches. Previously unreported studies were sought through correspondence. 20 studies were identified (8,647 T2D cases and 85,040 non-cases). Estimates of the association of WBC with T2D were combined using random effects meta-analysis; sources of heterogeneity as well as presence of publication bias were explored.
Results
The combined relative risk (RR) comparing the top to bottom tertile of the WBC count was 1.61 (95% CI: 1.45; 1.79, p = 1.5*10−18). Substantial heterogeneity was present (I2 = 83%). For granulocytes the RR was 1.38 (95% CI: 1.17; 1.64, p = 1.5*10−4), for lymphocytes 1.26 (95% CI: 1.02; 1.56, p = 0.029), and for monocytes 0.93 (95% CI: 0.68; 1.28, p = 0.67) comparing top to bottom tertile. In cross-sectional studies, RR was 1.74 (95% CI: 1.49; 2.02, p = 7.7*10−13), while in cohort studies it was 1.48 (95% CI: 1.22; 1.79, p = 7.7*10−5). We assessed the impact of confounding in EPIC-Norfolk study and found that the age and sex adjusted HR of 2.19 (95% CI: 1.74; 2.75) was attenuated to 1.82 (95% CI: 1.45; 2.29) after further accounting for smoking, T2D family history, physical activity, education, BMI and waist circumference.
Conclusions
A raised WBC is associated with higher risk of T2D. The presence of publication bias and failure to control for all potential confounders in all studies means the observed association is likely an overestimate.
doi:10.1371/journal.pone.0013405
PMCID: PMC2956635  PMID: 20976133
Related Articles
13.  C-reactive protein, interleukin-6, and prostate cancer risk in men aged 65 years and older 
Pierce, Brandon L. | Biggs, Mary L. | DeCambre, Marvalyn | Reiner, Alexander P. | Li, Christopher | Fitzpatrick, Annette | Carlson, Christopher S. | Stanford, Janet L. | Austin, Melissa A.
Cancer causes & control : CCC  2009;20(7):1193-1203.
Inflammation is believed to play a role in prostate cancer (PCa) etiology, but it is unclear whether inflammatory markers C-reactive protein (CRP) and interleukin-6 (IL-6) associate with PCa risk in older men. Using Cox regression, we assessed the relationship between baseline concentrations of CRP and IL-6 and subsequent PCa risk in the Cardiovascular Health Study, a population-based cohort study of mostly European American men ages >64 years (n=2234; mean follow-up = 8.7 years; 215 incident PCa cases). We also tested associations between CRP and IL-6 tagSNPs and PCa risk, focusing on SNPs known to associate with circulating CRP and/or IL-6. Results: Neither CRP nor IL-6 blood concentrations were associated with PCa risk. The C allele of IL-6 SNP rs1800795 (-174), a known functional variant, was associated with increased risk in a dominant model (HR=1.44; 95% CI=1.03-2.01; p=0.03) but was not statistically significant after accounting for multiple tests (permutation p=0.21). Our results suggest that circulating CRP and IL-6 do not influence PCa risk. SNPs at the CRP locus are not associated with PCa risk in this cohort, while the association between rs1800795 and PCa risk warrants further investigation.
doi:10.1007/s10552-009-9320-4
PMCID: PMC2846958  PMID: 19267250
Prostate cancer; inflammation; C-reactive protein (CRP); interleukin-6 (IL-6); IL-6 rs1800795 (-174)
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14.  PHYSICAL ACTIVITY IN ADOLESCENCE AND TESTICULAR GERM CELL CANCER RISK 
Littman, Alyson J | Doody, David R | Biggs, Mary L | Weiss, Noel S | Starr, Jacqueline R | Schwartz, Stephen M
Cancer causes & control : CCC  2009;20(8):1281-1290.
Objective
Several, but not all, studies have observed increased risks of testicular germ cell cancer (TGCC) associated with bicycling and other recreational activities. To further examine whether physical activity (PA) in adolescence is associated with TGCC risk, the authors conducted a case-control study in western Washington State.
Methods
Cases (n=391) were men diagnosed with TGCC who were identified through a population-based cancer registry. Controls (n=1023) were men identified from the general population in western Washington State by using random digit telephone dialing. Participants were queried about various specific PA in grades 7–12 including bicycling, horseback riding, competitive sports, physical education class, as well as moderate, vigorous, and sedentary activities in general.
Results
In multivariate analyses, bicycling, vigorous-intensity activities, and sedentary activities were not associated with TGCC risk, while horseback riding and wrestling were associated with decreased risks, and moderate-intensity activities, soccer, basketball and intermediate duration of competitive activities were associated with increased risks.
Conclusions
The lack of internal consistency of the findings within the current study and of findings among prior studies, suggests that PA contributes little, if any, to the risk of TGCC.
doi:10.1007/s10552-009-9347-6
PMCID: PMC2890221  PMID: 19399630
testicular cancer; physical activity; case-control study; adolescent
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15.  Polymorphisms in the Mitochondrial DNA Control Region and Frailty in Older Adults 
Moore, Ann Z. | Biggs, Mary L. | Matteini, Amy | O'Connor, Ashley | McGuire, Sarah | Beamer, Brock A. | Fallin, M. Danielle | Fried, Linda P. | Walston, Jeremy | Chakravarti, Aravinda | Arking, Dan E. | Schrijver, Iris
PLoS ONE  2010;5(6):e11069.
Background
Mitochondria contribute to the dynamics of cellular metabolism, the production of reactive oxygen species, and apoptotic pathways. Consequently, mitochondrial function has been hypothesized to influence functional decline and vulnerability to disease in later life. Mitochondrial genetic variation may contribute to altered susceptibility to the frailty syndrome in older adults.
Methodology/Principal Findings
To assess potential mitochondrial genetic contributions to the likelihood of frailty, mitochondrial DNA (mtDNA) variation was compared in frail and non-frail older adults. Associations of selected SNPs with a muscle strength phenotype were also explored. Participants were selected from the Cardiovascular Health Study (CHS), a population-based observational study (1989–1990, 1992–1993). At baseline, frailty was identified as the presence of three or more of five indicators (weakness, slowness, shrinking, low physical activity, and exhaustion). mtDNA variation was assessed in a pilot study, including 315 individuals selected as extremes of the frailty phenotype, using an oligonucleotide sequencing microarray based on the Revised Cambridge Reference Sequence. Three mtDNA SNPs were statistically significantly associated with frailty across all pilot participants or in sex-stratified comparisons: mt146, mt204, and mt228. In addition to pilot participants, 4,459 additional men and women with frailty classifications, and an overlapping subset of 4,453 individuals with grip strength measurements, were included in the study population genotyped at mt204 and mt228. In the study population, the mt204 C allele was associated with greater likelihood of frailty (adjusted odds ratio = 2.04, 95% CI = 1.07–3.60, p = 0.020) and lower grip strength (adjusted coefficient = −2.04, 95% CI = −3.33– −0.74, p = 0.002).
Conclusions
This study supports a role for mitochondrial genetic variation in the frailty syndrome and later life muscle strength, demonstrating the importance of the mitochondrial genome in complex geriatric phenotypes.
doi:10.1371/journal.pone.0011069
PMCID: PMC2883558  PMID: 20548781
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16.  Association of Marijuana Use and the Incidence of Testicular Germ Cell Tumors 
Daling, Janet R. | Doody, David R. | Sun, Xiaofei | Trabert, Britton L. | Weiss, Noel S. | Chen, Chu | Biggs, Mary L. | Starr, Jacqueline R. | Dey, Sudhansu K. | Schwartz, Stephen M.
Cancer  2009;115(6):1215-1223.
Background
The incidence of testicular germ cell tumors (TGCT) has been increasing the past 4–6 decades, but exposures accounting for this rise have not been identified. Marijuana use has also grown over this time period, and chronic marijuana use produces adverse effects on the human endocrine and reproductive systems. We tested the hypothesis that marijuana use is a risk factor for TGCT.
Methods
A population-based case-control study of 369 men age 18–44 years diagnosed with a TGCT from January 1999– January 2006 was conducted in King, Pierce and Snohomish Counties in Washington State. Their responses to questions on lifetime marijuana use were compared to those of 979 age-matched controls residing in the same three counties during the case diagnosis period.
Results
Men with a TGCT were more likely to be current marijuana smokers at reference date compared to controls, OR (odds ratio) =1.7, 95% CI (Confidence Interval) =1.1–2.5. When we conducted analyses according to histologic type, most of the association between current marijuana use and TGCT was in nonseminomas-mixed histology tumors, OR current use=2.3, 95% CI=1.3–4.0. Age at first use among current users appeared to modify risk (age<18 OR=2.8 vs. age≥18 OR=1.3) as did frequency of use (daily or weekly OR=3.0 vs.
Conclusions
We observed an association between marijuana use and occurrence of nonseminoma germ cell tumors of the testis. Additional studies of TGCTs are needed to test this hypothesis, including molecular analyses of cannabinoid receptors and endocannabinoid signaling that may provide clues to biologic mechanisms.
doi:10.1002/cncr.24159
PMCID: PMC2759698  PMID: 19204904
Marijuana Use; testicular tumors
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Biggs, Mary L. | Davis, Mark D. | Eaton, David L. | Weiss, Noel S. | Barr, Dana B. | Doody, David R. | Fish, Sherianne | Needham, Larry L. | Chen, Chu | Schwartz, Stephen M.
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology  2008;17(8):2012-2018.
Testicular germ cell carcinoma (TGCC) is the most common malignancy among men aged 20–34. Although the pathogenesis of TGCC is poorly understood, sub-optimal androgen levels or impaired androgen signaling may play a role. Some persistent organochlorine pesticides commonly found in human tissue possess anti-androgenic properties. We examined whether the risk of TGCC is associated with serum levels of 11 organochlorine pesticides, including p,p’-DDE, and whether the p,p-DDE-TGCC association is modified by CAG or GGN repeat polymorphisms in the androgen receptor (AR) gene. We conducted a population-based case-control study among 18–44 year-old male residents of three Washington State counties. Cases (n=246) were diagnosed during 1999–2003 with a first, primary TGCC. Controls (n=630) were men of similar age with no history of TGCC from the same population identified through random-digit telephone dialing. Questionnaires elicited information on demographic, medical, and lifestyle factors. A blood specimen provided serum for gas chromatography-high resolution mass spectrometry analysis of organochlorine pesticide residues, and DNA for genotyping. We observed no clear patterns between TGCC risk and concentrations of any of the organochlorines measured, nor did we observe that the risk associated with p,p’-DDE was modified by AR CAG (<23 vs.23+ repeats) or GGN (<17 vs.17+ repeats) genotype. This study does not provide support for the hypothesis that adult exposure to organochlorine pesticides is associated with risk of TGCC. Due to uncertainty regarding how well organochlorine levels measured in adulthood reflect exposures during early life, further research is needed using exposure measurements collected in utero or during infancy.
doi:10.1158/1055-9965.EPI-08-0032
PMCID: PMC2766345  PMID: 18708392
testicular cancer; organochlorines; DDE; pesticides; androgen receptor
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Zieman, Susan J. | Kamineni, Aruna | Ix, Joachim H. | Barzilay, Joshua | Djoussé, Luc | Kizer, Jorge R. | Biggs, Mary L. | de Boer, Ian H. | Chonchol, Michel | Gottdiener, John S. | Selvin, Elizabeth | Newman, Anne B. | Kuller, Lewis H. | Siscovick, David S. | Mukamal, Kenneth J. | Hamel, Frederick G.
PLoS ONE  2012;7(10):e47941.
Objective
Arterial and ventricular stiffening are characteristics of diabetes and aging which confer significant morbidity and mortality; advanced glycation endproducts (AGE) are implicated in this stiffening pathophysiology. We examined the association between HbA1c, an AGE, with arterial and ventricular stiffness measures in older individuals without diabetes.
Research Design & Methods
Baseline HbA1c was measured in 830 participants free of diabetes defined by fasting glucose or medication use in the Cardiovascular Health Study, a population-based cohort study of adults aged ≥65 years. We performed cross-sectional analyses using baseline exam data including echocardiography, ankle and brachial blood pressure measurement, and carotid ultrasonography. We examined the adjusted associations between HbA1c and multiple arterial and ventricular stiffness measures by linear regression models and compared these results to the association of fasting glucose (FG) with like measures.
Results
HbA1c was correlated with fasting and 2-hour postload glucose levels (r = 0.21; p<0.001 for both) and positively associated with greater body-mass index and black race. In adjusted models, HbA1c was not associated with any measure of arterial or ventricular stiffness, including pulse pressure (PP), carotid intima-media thickness, ankle-brachial index, end-arterial elastance, or left ventricular mass (LVM). FG levels were positively associated with systolic, diastolic and PP and LVM.
Conclusions
In this sample of older adults without diabetes, HbA1c was not associated with arterial or ventricular stiffness measures, whereas FG levels were. The role of AGE in arterial and ventricular stiffness in older adults may be better assessed using alternate AGE markers.
doi:10.1371/journal.pone.0047941
PMCID: PMC3484154  PMID: 23118911
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