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Showing papers by "Ralph B. D'Agostino published in 2007"


Journal ArticleDOI
TL;DR: These findings are consistent with the hypothesized role of visceral fat as a unique, pathogenic fat depot and Measurement of VAT may provide a more complete understanding of metabolic risk associated with variation in fat distribution.
Abstract: Background— Visceral adipose tissue (VAT) compartments may confer increased metabolic risk. The incremental utility of measuring both visceral and subcutaneous abdominal adipose tissue (SAT) in association with metabolic risk factors and underlying heritability has not been well described in a population-based setting. Methods and Results— Participants (n=3001) were drawn from the Framingham Heart Study (48% women; mean age, 50 years), were free of clinical cardiovascular disease, and underwent multidetector computed tomography assessment of SAT and VAT volumes between 2002 and 2005. Metabolic risk factors were examined in relation to increments of SAT and VAT after multivariable adjustment. Heritability was calculated using variance-components analysis. Among both women and men, SAT and VAT were significantly associated with blood pressure, fasting plasma glucose, triglycerides, and high-density lipoprotein cholesterol and with increased odds of hypertension, impaired fasting glucose, diabetes mellitus, ...

2,501 citations


Journal ArticleDOI
TL;DR: The incidence of stent thrombosis did not differ significantly between patients with drug-eluting stents and those with bare-metal stents in randomized clinical trials, although the power to detect small differences in rates was limited.
Abstract: BackgroundDefinitions of stent thrombosis that have been used in clinical trials of drug-eluting stents have been restrictive and have not been used in a uniform manner. MethodsWe applied a hierarchical classification of stent thrombosis set by the Academic Research Consortium (ARC) across randomized trials involving 878 patients treated with sirolimus-eluting stents, 1400 treated with paclitaxel-eluting stents, and 2267 treated with bare-metal stents. We then pooled 4 years of follow-up data. All events were adjudicated by an independent clinical-events committee. ResultsThe cumulative incidence of stent thrombosis according to the original protocol definitions was 1.2% in the sirolimus-stent group versus 0.6% in the bare-metal–stent group (P=0.20; 95% confidence interval [CI], −0.4 to 1.5) and 1.3% in the paclitaxel-stent group versus 0.8% in the bare-metal–stent group (P=0.24; 95% CI, −0.3 to 1.4). The incidence of definite or probable stent thrombosis as defined by the ARC was 1.5% in the sirolimus-st...

1,460 citations


Journal ArticleDOI
21 Mar 2007-JAMA
TL;DR: The reduction of atherosclerotic arterial disease (REACH) registry as discussed by the authors is an international, prospective cohort of 68,236 patients with either established coronary artery disease (CAD, PAD, CVD), or at least three risk factors for atherothrombosis (n = 12,422).
Abstract: ContextFew data document current cardiovascular (CV) event rates in stable patients with atherothrombosis in a community setting. Differential event rates for patients with documented coronary artery disease (CAD), cerebrovascular disease (CVD), or peripheral arterial disease (PAD) or those at risk of these diseases have not been previously evaluated in a single international cohort.ObjectiveTo establish contemporary, international, 1-year CV event rates in outpatients with established arterial disease or with multiple risk factors for atherothrombosis.Design, Setting, and ParticipantsThe Reduction of Atherothrombosis for Continued Health (REACH) Registry is an international, prospective cohort of 68 236 patients with either established atherosclerotic arterial disease (CAD, PAD, CVD; n = 55 814) or at least 3 risk factors for atherothrombosis (n = 12 422), who were enrolled from 5587 physician practices in 44 countries in 2003-2004.Main Outcome MeasuresRates of CV death, myocardial infarction (MI), and stroke.ResultsAs of July 2006, 1-year outcomes were available for 95.22% (n = 64 977) of participants. Cardiovascular death, MI, or stroke rates were 4.24% overall: 4.69% for those with established atherosclerotic arterial disease vs 2.15% for patients with multiple risk factors only. Among patients with established disease, CV death, MI, or stroke rates were 4.52% for patients with CAD, 6.47% for patients with CVD, and 5.35% for patients with PAD. The incidences of the end point of CV death, MI, or stroke or of hospitalization for atherothrombotic event(s) were 15.20% for CAD, 14.53% for CVD, and 21.14% for PAD patients with established disease. These event rates increased with the number of symptomatic arterial disease locations, ranging from 5.31% for patients with risk factors only to 12.58% for patients with 1, 21.14% for patients with 2, and 26.27% for patients with 3 symptomatic arterial disease locations (P<.001 for trend).ConclusionsIn this large, contemporary, international study, outpatients with established atherosclerotic arterial disease, or at risk of atherothrombosis, experienced relatively high annual CV event rates. Multiple disease locations increased the 1-year risk of CV events.

1,156 citations


Journal ArticleDOI
27 Jun 2007-JAMA
TL;DR: The data document the incidence rates of type 1 DM among youth of all racial/ethnic groups, with the highest rates in non-Hispanic white youth, and type 2 DM is still relatively infrequent; however, the highest levels were observed among adolescent minority populations.
Abstract: Context Data on the incidence of diabetes mellitus (DM) among US youth according to racial/ethnic background and DM type are limited. Objective To estimate DM incidence in youth aged younger than 20 years according to race/ethnicity and DM type. Design, setting, and participants A multiethnic, population-based study (The SEARCH for Diabetes in Youth Study) of 2435 youth with newly diagnosed, nonsecondary DM in 2002 and 2003, ascertained at 10 study locations in the United States, covering a population of more than 10 million person-years. Main outcome measure Incidence rates by age group, sex, race/ethnicity, and DM type were calculated per 100,000 person-years at risk. Diabetes mellitus type (type 1/type 2) was based on health care professional assignment and, in a subset, further characterized with glutamic acid decarboxylase (GAD65) autoantibody and fasting C peptide measures. Results The incidence of DM (per 100,000 person-years) was 24.3 (95% confidence interval [CI], 23.3-25.3). Among children younger than 10 years, most had type 1 DM, regardless of race/ethnicity. The highest rates of type 1 DM were observed in non-Hispanic white youth (18.6, 28.1, and 32.9 for age groups 0-4, 5-9, and 10-14 years, respectively). Even among older youth (> or =10 years), type 1 DM was frequent among non-Hispanic white, Hispanic, and African American adolescents. Overall, type 2 DM was still relatively infrequent, but the highest rates (17.0 to 49.4 per 100,000 person-years) were documented among 15- to 19-year-old minority groups. Conclusions Our data document the incidence rates of type 1 DM among youth of all racial/ethnic groups, with the highest rates in non-Hispanic white youth. Overall, type 2 DM is still relatively infrequent; however, the highest rates were observed among adolescent minority populations.

907 citations


Journal ArticleDOI
TL;DR: In middle-aged adults, soft drink consumption is associated with a higher prevalence and incidence of multiple metabolic risk factors.
Abstract: Background—Consumption of soft drinks has been linked to obesity in children and adolescents, but it is unclear whether it increases metabolic risk in middle-aged individuals. Methods and Results—We related the incidence of metabolic syndrome and its components to soft drink consumption in participants in the Framingham Heart Study (6039 person-observations, 3470 in women; mean age 52.9 years) who were free of baseline metabolic syndrome. Metabolic syndrome was defined as the presence of 3o f the following: waist circumference 35 inches (women) or 40 inches (men); fasting blood glucose 100 mg/dL; serum triglycerides 150 mg/dL; blood pressure 135/85 mm Hg; and high-density lipoprotein cholesterol 40 mg/dL (men) or 50 mg/dL (women). Multivariable models included adjustments for age, sex, physical activity, smoking, dietary intake of saturated fat, trans fat, fiber, magnesium, total calories, and glycemic index. Cross-sectionally, individuals consuming 1 soft drink per day had a higher prevalence of metabolic syndrome (odds ratio [OR], 1.48; 95% CI, 1.30 to 1.69) than those consuming 1 drink per day. On follow-up (mean of 4 years), new-onset metabolic syndrome developed in 765 (18.7%) of 4095 participants consuming 1 drink per day and in 474 (22.6%) of 2059 persons consuming 1 soft drink per day. Consumption of 1 soft drink per day was associated with increased odds of developing metabolic syndrome (OR, 1.44; 95% CI, 1.20 to 1.74), obesity (OR, 1.31; 95% CI, 1.02 to 1.68), increased waist circumference (OR, 1.30; 95% CI, 1.09 to 1.56), impaired fasting glucose (OR, 1.25; 95% CI, 1.05 to 1.48), higher blood pressure (OR, 1.18; 95% CI, 0.96 to 1.44), hypertriglyceridemia (OR, 1.25; 95% CI, 1.04 to 1.51), and low high-density lipoprotein cholesterol (OR, 1.32; 95% CI 1.06 to 1.64). Conclusions—In middle-aged adults, soft drink consumption is associated with a higher prevalence and incidence of multiple metabolic risk factors. (Circulation. 2007;116:480-488.)

891 citations


Journal ArticleDOI
TL;DR: Parental diabetes, obesity, and metabolic syndrome traits effectively predict type 2 diabetes mellitus risk in a middle-aged white population sample and were used to develop a simple T2DM prediction algorithm to estimate risk of new T2 DM during a 7-year follow-up interval.
Abstract: Background Prediction rules for type 2 diabetes mellitus (T2DM) have been developed, but we lack consensus for the most effective approach. Methods We estimated the 7-year risk of T2DM in middle-aged participants who had an oral glucose tolerance test at baseline. There were 160 cases of new T2DM, and regression models were used to predict new T2DM, starting with characteristics known to the subject (personal model, ie, age, sex, parental history of diabetes, and body mass index [calculated as the weight in kilograms divided by height in meters squared]), adding simple clinical measurements that included metabolic syndrome traits (simple clinical model), and, finally, assessing complex clinical models that included (1) 2-hour post–oral glucose tolerance test glucose, fasting insulin, and C-reactive protein levels; (2) the Gutt insulin sensitivity index; or (3) the homeostasis model insulin resistance and the homeostasis model insulin resistance β-cell sensitivity indexes. Discrimination was assessed with area under the receiver operating characteristic curves (AROCs). Results The personal model variables, except sex, were statistically significant predictors of T2DM (AROC, 0.72). In the simple clinical model, parental history of diabetes and obesity remained significant predictors, along with hypertension, low levels of high-density lipoprotein cholesterol, elevated triglyceride levels, and impaired fasting glucose findings but not a large waist circumference (AROC, 0.85). Complex clinical models showed no further improvement in model discriminations (AROC, 0.850-0.854) and were not superior to the simple clinical model. Conclusion Parental diabetes, obesity, and metabolic syndrome traits effectively predict T2DM risk in a middle-aged white population sample and were used to develop a simple T2DM prediction algorithm to estimate risk of new T2DM during a 7-year follow-up interval.

873 citations


Journal Article
01 Jan 2007-JAMA
TL;DR: In this large, contemporary, international study, outpatients with established atherosclerotic arterial disease, or at risk of atherothrombosis, experienced relatively high annual CV event rates.
Abstract: Context Few data document current cardiovascular (CV) event rates in stable patients with atherothrombosis in a community setting. Differential event rates for patients with documented coronary artery disease (CAD), cerebrovascular disease (CVD), or peripheral arterial disease (PAD) or those at risk of these diseases have not been previously evaluated in a single international cohort. Objective To establish contemporary, international, 1-year CV event rates in outpatients with established arterial disease or with multiple risk factors for atherothrombosis. Design, Setting, and Participants The Reduction of Atherothrombosis for Continued Health (REACH) Registry is an international, prospective cohort of 68 236 patients with either established atherosclerotic arterial disease (CAD, PAD, CVD; n =55 814) or at least 3 risk factors for atherothrombosis (n=12422), who were enrolled from 5587 physician practices in 44 countries in 2003-2004. Main Outcome Measures Rates of CV death, myocardial infarction (Ml), and stroke. Results As of July 2006,1-year outcomes were available for 95.22% (n=64977) of participants. Cardiovascular death, Ml, or stroke rates were 4.24% overall: 4.69% for those with established atherosclerotic arterial disease vs 2.15% for patients with multiple risk factors only. Among patients with established disease, CV death, Ml, or stroke rates were 4.52% for patients with CAD, 6.47% for patients with CVD, and 5.35% for patients with PAD. The incidences of the end point of CV death, Ml, or stroke or of hospitalizationforatherothromboticevent(s) were 15.20% for CAD, 14.53% for CVD, and 21.14% for PAD patients with established disease. These event rates increased with the number of symptomatic arterial disease locations, ranging from 5.31 % for patients with risk factors only to 12.58% for patients with 1, 21.14% for patients with 2, and 26.27% for patients with 3 symptomatic arterial disease locations (P<.001 for trend). Conclusions In this large, contemporary, international study, outpatients with established atherosclerotic arterial disease, or at risk of atherothrombosis, experienced relatively high annual CV event rates. Multiple disease locations increased the 1-year risk of CV events.

832 citations


Journal ArticleDOI
TL;DR: The comparison of Third Generation Cohort data with measures previously collected from the first two generations will facilitate investigations of genetic and environmental risk factors for subclinical and overt diseases, with a focus on cardiovascular and lung disorders.
Abstract: For nearly 60 years, the Framingham Heart Study has examined the natural history, risk factors, and prognosis of cardiovascular, lung, and other diseases. Recruitment of the Original Cohort began in 1948. Twenty-three years later, 3,548 children of the Original Cohort, along with 1,576 of their spouses, enrolled in the Offspring Cohort. Beginning in 2002, 4,095 adults having at least one parent in the Offspring Cohort enrolled in the Third Generation Cohort, along with 103 parents of Third Generation Cohort participants who were not previously enrolled in the Offspring Cohort. The objective of new recruitment was to complement phenotypic and genotypic information obtained from prior generations, with priority assigned to larger families. From a pool of 6,553 eligible individuals, 1,912 men and 2,183 women consented and attended the first examination (mean age: 40 (standard deviation: 9) years; range: 19-72 years). The examination included clinical and laboratory assessments of vascular risk factors and imaging for subclinical atherosclerosis, as well as assessment of cardiac structure and function. The comparison of Third Generation Cohort data with measures previously collected from the first two generations will facilitate investigations of genetic and environmental risk factors for subclinical and overt diseases, with a focus on cardiovascular and lung disorders.

795 citations


Journal ArticleDOI
TL;DR: Higher serum phosphorus levels are associated with an increased CVD risk in individuals free of CKD and CVD in the community and the need for additional research to elucidate the potential link between phosphorus homeostasis and vascular risk is emphasized.
Abstract: Background Higher levels of serum phosphorus and the calcium-phosphorus product are associated with increased mortality from cardiovascular disease (CVD) in patients with chronic kidney disease (CKD) or prior CVD. However, it is unknown if serum phosphorus levels influence vascular risk in individuals without CKD or CVD. Methods We prospectively evaluated 3368 Framingham Offspring study participants (mean age, 44 years; 51% were women) free of CVD and CKD. We used multivariable Cox models to relate serum phosphorus and calcium levels to CVD incidence. Results On follow-up (mean duration, 16.1 years), there were 524 incident CVD events (159 in women). In multivariable analyses and adjusting for established risk factors and additionally for glomerular filtration rate and for hemoglobin, serum albumin, proteinuria, and C-reactive protein levels, a higher level of serum phosphorus was associated with an increased CVD risk in a continuous fashion (adjusted hazard ratio per increment of milligrams per deciliter, 1.31; 95% confidence interval, 1.05-1.63; P = .02; P value for trend across quartiles = .004). Individuals in the highest serum phosphorus quartile experienced a multivariable-adjusted 1.55-fold CVD risk (95% confidence interval, 1.16%-2.07%; P = .004) compared with those in the lowest quartile. These findings remained robust in time-dependent models that updated CVD risk factors every 4 years and in analyses restricted to individuals without proteinuria and an estimated glomerular filtration rate greater than 90 mL/min per 1.73 m 2 . Serum calcium was not related to CVD risk. Conclusion Higher serum phosphorus levels are associated with an increased CVD risk in individuals free of CKD and CVD in the community. These observations emphasize the need for additional research to elucidate the potential link between phosphorus homeostasis and vascular risk.

766 citations


Journal ArticleDOI
TL;DR: The proportion of CVD attributable to diabetes mellitus has increased over the past 50 years in Framingham, emphasizing the need for increased efforts to prevent DM and to aggressively treat and control CVD risk factors among those with DM.
Abstract: Background— Marked reductions in cardiovascular disease (CVD) morbidity and mortality have occurred in the United States over the last 50 years. We tested the hypothesis that the relative burden of CVD attributable to diabetes mellitus (DM) has increased over the past 5 decades. Methods and Results— Participants aged 45 to 64 years from the Framingham Heart Study, who attended examinations in an “early” time period (1952 to 1974), were compared with those who attended examinations in a later time period (1975 to 1998). The risk of CVD events (n=133 among those with and 1093 among those without DM) attributable to DM in the 2 time periods was assessed with Cox proportional hazards models; population attributable risk of DM as a CVD risk factor was calculated for each time period. The age- and sex-adjusted hazard ratio for DM as a CVD risk factor was 3.0 (95% CI, 2.3 to 3.9) in the earlier time period and 2.5 (95% CI, 1.9 to 3.2) in the later time period. The population attributable risk for DM as a CVD ris...

629 citations


Journal ArticleDOI
15 Aug 2007-JAMA
TL;DR: The overall performance of apo B:apo A-I ratio for prediction of CHD was comparable with that of traditional lipid ratios but did not offer incremental utility over total cholesterol:HDL-C.
Abstract: ContextEvidence is conflicting regarding the performance of apolipoproteins vs traditional lipids for predicting coronary heart disease (CHD) risk.ObjectivesTo compare performance of different lipid measures for CHD prediction using discrimination and calibration characteristics and reclassification of risk categories; to assess incremental utility of apolipoproteins over traditional lipids for CHD prediction.Design, Setting, and ParticipantsPopulation-based, prospective cohort from, Framingham, Massachusetts. We evaluated serum total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), non–HDL-C, apolipoprotein (apo) A-I and apo B, and 3 lipid ratios (total cholesterol:HDL-C, LDL-C:HDL-C, and apo B:apo A-I) in 3322 middle-aged white participants who attended the fourth offspring examination cycle (1987-1991) and were without cardiovascular disease. Fifty-three percent of the participants were women.Main Outcome MeasureIncidence of first CHD event (recognized or unrecognized myocardial infarction, angina pectoris, coronary insufficiency, or coronary heart disease death).ResultsAfter a median follow-up of 15.0 years, 291 participants, 198 of whom were men, developed CHD. In multivariate models adjusting for nonlipid risk factors, the apo B:apo A-I ratio predicted CHD (hazard ratio [HR] per SD increment, 1.39; 95% confidence interval [CI], 1.23-1.58 in men and HR, 1.40; 95% CI, 1.16-1.67 in women), but risk ratios were similar for total cholesterol:HDL-C (HR, 1.39; 95% CI, 1.22-1.58 in men and HR, 1.39; 95% CI, 1.17-1.66 in women) and for LDL-C:HDL-C (HR, 1.35; 95% CI, 1.18-1.54 in men and HR, 1.36; 95% CI 1.14-1.63 in women). In both sexes, models using the apo B:apo A-I ratio demonstrated performance characteristics comparable with but not better than that for other lipid ratios. The apo B:apo A-I ratio did not predict CHD risk in a model containing all components of the Framingham risk score including total cholesterol:HDL-C (P = .12 in men; P = .58 in women).ConclusionsIn this large, population-based cohort, the overall performance of apo B:apo A-I ratio for prediction of CHD was comparable with that of traditional lipid ratios but did not offer incremental utility over total cholesterol:HDL-C. These data do not support measurement of apo B or apo A-I in clinical practice when total cholesterol and HDL-C measurements are available.

Journal ArticleDOI
TL;DR: An increase in serum GGT predicts onset of metabolic syndrome, incident CVD, and death suggesting that GGT is a marker of metabolic and cardiovascular risk.
Abstract: Objective— To determine whether serum γ-glutamyl transferase (GGT) predicts cardiovascular disease (CVD) morbidity and mortality, accounting for temporal changes in known CVD risk factors and C-reactive protein (CRP). Methods and Results— In 3451 Framingham Study participants (mean age 44 years, 52% women) we examined the relations of GGT with CVD risk factors, and prospectively determined the risk of new-onset metabolic syndrome, incident CVD, and death. GGT was positively associated with body mass index, blood pressure, LDL cholesterol, triglycerides, and blood glucose in cross-sectional analysis ( P <0.005). On follow-up (mean 19 years), 968 participants developed metabolic syndrome, 535 developed incident CVD, and 362 died. The risk of metabolic syndrome increased with higher GGT (multivariable-adjusted hazard ratio [HR] per SD increment log-GGT, 1.26 [95%CI; 1.18 to 1.35]). Adjusting for established CVD risk factors (as time-dependent covariates updated quadriennially) and baseline CRP, a 1-SD increase in log-GGT conferred a 13% increase in CVD risk ( P =0.007) and 26% increased risk of death ( P <0.001). Individuals in the highest GGT quartile experienced a 67% increase in CVD incidence (multivariable-adjusted HR 1.67, 95%CI; 1.25 to 2.22). Conclusion— An increase in serum GGT predicts onset of metabolic syndrome, incident CVD, and death suggesting that GGT is a marker of metabolic and cardiovascular risk.

Journal ArticleDOI
TL;DR: The propensity score for an individual, defined as the conditional probability of being treated given the individual’s covariates, can be used to balance the covariates in the 2 groups and thus reduce this bias.
Abstract: Propensity scores have been used to reduce bias in observational studies in many fields and are becoming more widely used in cardiovascular research.1 The goal of this statistical primer is to present the definition of propensity scores and to illustrate their use by describing some recent examples found in the cardiovascular disease research literature. Large-scale epidemiological cohort studies such as the Multi-Ethnic Study of Atherosclerosis (MESA)2 are designed to follow a large sample of participants over time without active administration of any interventions. Within MESA, lack of randomization can complicate potential treatment comparisons such as the impact of β-blocker versus angiotensin-converting enzyme inhibitor usage. Nonrandomized comparisons may also arise from within a randomized clinical trial. For instance, the Clopidogrel as Adjunctive Reperfusion Therapy - Thrombolysis in Myocardial Infarction 28 (CLARITY-TIMI 28) trial3 is a randomized study that compares clopidogrel with placebo in 3491 ST-elevation myocardial infarction patients aged 18 to 75 years who have undergone fibrinolysis. In addition to the primary end points, investigators wished to compare the effects of low molecular weight heparin with unfractionated heparin on angiographic and clinical outcomes in participants.4 These treatments were not randomly assigned. In studies such as these, the treatment groups may markedly differ with respect to the observed pretreatment covariates measured on participants. These differences could lead to biased estimates of treatment effects. The propensity score for an individual, defined as the conditional probability of being treated given the individual’s covariates, can be used to balance the covariates in the 2 groups and thus reduce this bias. In a randomized experiment, the randomization of participants to different treatments minimizes the chance of differences on observed or unobserved covariates. However, in nonrandomized studies, systematic differences can exist between treatment groups. To control for this potential bias, information on measured …

Journal ArticleDOI
TL;DR: In a large community-based sample, LDL-P was a more sensitive indicator of low CVD risk than either LDL-C or non-HDL-C, suggesting a potential clinical role for LDL-p as a goal of LDL management.

Journal ArticleDOI
21 Feb 2007-JAMA
TL;DR: Pulse pressure is an important risk factor for incident AF in a community-based sample and further research is needed to determine whether interventions that reduce pulse pressure will limit the growing incidence of AF.
Abstract: ContextAtrial fibrillation (AF) is responsible for considerable morbidity and mortality, making identification of modifiable risk factors a priority. Increased pulse pressure, a reflection of aortic stiffness, increases cardiac load and may increase AF risk.ObjectiveTo examine relations between pulse pressure and incident AF.Design, Setting, and ParticipantsProspective, community-based observational cohort in Framingham, Mass, including 5331 Framingham Heart Study participants aged 35 years and older and initially free from AF (median age, 57 years; 55% women).Main Outcome MeasuresIncident AF.ResultsAF developed in 698 participants (13.1%) a median of 12 years after pulse pressure assessment. Cumulative 20-year AF incidence rates were 5.6% for pulse pressure of 40 mm Hg or less (25th percentile) and 23.3% for pulse pressure greater than 61 mm Hg (75th percentile). In models adjusted for age, sex, baseline and time-dependent change in mean arterial pressure, and clinical risk factors for AF (body mass index, smoking, valvular disease, diabetes, electrocardiographic left ventricular hypertrophy, hypertension treatment, and prevalent myocardial infarction or heart failure), pulse pressure was associated with increased risk for AF (adjusted hazard ratio [HR], 1.26 per 20-mm Hg increment; 95% confidence interval [CI], 1.12-1.43; P<.001). In contrast, mean arterial pressure was unrelated to incident AF (adjusted HR, 0.96 per 10-mm Hg increment; 95% CI, 0.88-1.05; P = .39). Systolic pressure was related to AF (HR, 1.14 per 20-mm Hg increment; 95% CI, 1.04-1.25; P = .006); however, if diastolic pressure was added, model fit improved and the diastolic relation was inverse (adjusted HR, 0.87 per 10-mm Hg increment; 95% CI, 0.78-0.96; P = .01), consistent with a pulse pressure effect. Among patients with interpretable echocardiographic images, the association between pulse pressure and AF persisted in models that adjusted for baseline left atrial dimension, left ventricular mass, and left ventricular fractional shortening (adjusted HR, 1.23; 95% CI, 1.09-1.39; P = .001).ConclusionPulse pressure is an important risk factor for incident AF in a community-based sample. Further research is needed to determine whether interventions that reduce pulse pressure will limit the growing incidence of AF.

Journal ArticleDOI
17 Jan 2007-JAMA
TL;DR: Observational, nonrandomized studies have a role when RCTs are not available, and, even when they are available, to quantify effectiveness and other real world experiences and to adjust for pretreatment imbalances.
Abstract: THE RANDOMIZED CLINICAL TRIAL (RCT) IS THE ideal method for measuring treatment effects. Participants in clinical trials are randomly assigned to a treatment or control group. Randomization reduces biases by making treatment and control groups “equal with respect to all features,” except the treatment assignment. When randomization is performed correctly, differences in efficacy found by statistical comparisons can be attributed to the difference between the treatment and control. However, the RCT does not necessarily provide the final answer to treatment effectiveness, as there are many restrictions that limit generalizability. For example, RCTs are often restricted to patients with limited disease, comorbidity, and concomitant medications. Thus, RCTs generally demonstrate efficacy rather than effectiveness, where efficacy is the treatment effect under the restricted conditions of the RCT and effectiveness is the treatment effect under the conditions of usual practice. Observational, nonrandomized studies have a role when RCTs are not available, and, even when RCTs are available, to quantify effectiveness and other real world experiences. A contemporary example of this is the evaluation of drugeluting stents, for which RCTs have demonstrated shortterm efficacy for relatively healthy patients and observational studies are beginning to address long-term effectiveness and safety problems and use of clopidogrel in a broader array of patients. There are many approaches for making statistical inferences from observational data. Some approaches focus on study design, others on statistical techniques. However, even with the best of designs, observational studies, unlike the RCTs, do not automatically control for selection biases. Therefore, statistical methods involving matching, stratification, and/or covariance adjustment are needed. Lack of randomization in observational studies may result in large differences on the observed (and unobserved) participant characteristics between the treatment and control groups. These differences can lead to biased estimates of treatment effects. The goal of the statistical techniques that focus on observational data is to create an analysis that resembles what would occur had the treatment been randomly assigned. In RCTs, the balance is achieved on participant characteristics that occur before the treatment is administered. The success of randomization in creating balance can be assessed before any outcome measurements are taken. Therefore, in observational studies, the first goal of a statistical technique is to create balance between treatments on characteristics that are assessed before the actual treatment is administered. Once this balance has been achieved, outcome measurements can be ascertained and compared between groups. In practice, this goal is often difficult to achieve because the data available for observational studies usually contain measured patient characteristics that are obtained before, during, and after treatment administration, and it is often difficult to determine exactly which patient characteristics are pretreatment or not. Furthermore, there frequently are unmeasured characteristics that are not available, inadequately measured, or unknown. Thus, the statistical methods in observational studies need first to be judged based on their performance in creating a balance on background characteristics between treated and control groups and the impact of outcome data should play no role in this assessment. To adjust for pretreatment imbalances, 2 statistical approaches often used are analysis of covariance methods and propensity score methods. These 2 methods complement each other and generally should be used together rather than choosing between one or the other. Analysis of covariance refers here to standard statistical analyses that produce estimates of treatment effects adjusted for background characteristics (covariates), which are included explicitly in a statistical (regression) model. With observational studies, this technique can produce biased estimates of treatment effects if there is extreme imbalance of the background characteristics and/or the treatment effect

Journal ArticleDOI
TL;DR: Using a 100K genome-wide scan, a set of putative associations for common sequence variants and lipid phenotypes are generated using a three-stage replication strategy of the GEE association results with no convincing statistical evidence for association between any of the tested SNPs and lipid phenotype.
Abstract: Blood lipid levels including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) are highly heritable. Genome-wide association is a promising approach to map genetic loci related to these heritable phenotypes. In 1087 Framingham Heart Study Offspring cohort participants (mean age 47 years, 52% women), we conducted genome-wide analyses (Affymetrix 100K GeneChip) for fasting blood lipid traits. Total cholesterol, HDL-C, and TG were measured by standard enzymatic methods and LDL-C was calculated using the Friedewald formula. The long-term averages of up to seven measurements of LDL-C, HDL-C, and TG over a ~30 year span were the primary phenotypes. We used generalized estimating equations (GEE), family-based association tests (FBAT) and variance components linkage to investigate the relationships between SNPs (on autosomes, with minor allele frequency ≥10%, genotypic call rate ≥80%, and Hardy-Weinberg equilibrium p ≥ 0.001) and multivariable-adjusted residuals. We pursued a three-stage replication strategy of the GEE association results with 287 SNPs (P < 0.001 in Stage I) tested in Stage II (n ~1450 individuals) and 40 SNPs (P < 0.001 in joint analysis of Stages I and II) tested in Stage III (n~6650 individuals). Long-term averages of LDL-C, HDL-C, and TG were highly heritable (h2 = 0.66, 0.69, 0.58, respectively; each P < 0.0001). Of 70,987 tests for each of the phenotypes, two SNPs had p < 10-5 in GEE results for LDL-C, four for HDL-C, and one for TG. For each multivariable-adjusted phenotype, the number of SNPs with association p < 10-4 ranged from 13 to 18 and with p < 10-3, from 94 to 149. Some results confirmed previously reported associations with candidate genes including variation in the lipoprotein lipase gene (LPL) and HDL-C and TG (rs7007797; P = 0.0005 for HDL-C and 0.002 for TG). The full set of GEE, FBAT and linkage results are posted at the database of Genotype and Phenotype (dbGaP). After three stages of replication, there was no convincing statistical evidence for association (i.e., combined P < 10-5 across all three stages) between any of the tested SNPs and lipid phenotypes. Using a 100K genome-wide scan, we have generated a set of putative associations for common sequence variants and lipid phenotypes. Validation of selected hypotheses in additional samples did not identify any new loci underlying variability in blood lipids. Lack of replication may be due to inadequate statistical power to detect modest quantitative trait locus effects (i.e., <1% of trait variance explained) or reduced genomic coverage of the 100K array. GWAS in FHS using a denser genome-wide genotyping platform and a better-powered replication strategy may identify novel loci underlying blood lipids.

Journal ArticleDOI
TL;DR: The Framingham function adapted to local population characteristics accurately and reliably predicted the 5-year CHD risk for patients aged 35–74 years, in contrast with the original function, which consistently overestimated the actual risk.
Abstract: Background: To assess the reliability and accuracy of the Framingham coronary heart disease (CHD) risk function adapted by the Registre Gironi del Cor (REGICOR) investigators in Spain. Methods: A 5-year follow-up study was completed in 5732 participants aged 35–74 years. The adaptation consisted of using in the function the average population risk factor prevalence and the cumulative incidence observed in Spain instead of those from Framingham in a Cox proportional hazards model. Reliability and accuracy in estimating the observed cumulative incidence were tested with the area under the curve comparison and goodness-of-fit test, respectively. Results: The Kaplan–Meier CHD cumulative incidence during the follow-up was 4.0% in men and 1.7% in women. The original Framingham function and the REGICOR adapted estimates were 10.4% and 4.8%, and 3.6% and 2.0%, respectively. The REGICOR-adapted function’s estimate did not differ from the observed cumulated incidence (goodness of fit in men, p = 0.078, in women, p = 0.256), whereas all the original Framingham function estimates differed significantly (p Conclusion: The Framingham function adapted to local population characteristics accurately and reliably predicted the 5-year CHD risk for patients aged 35–74 years, in contrast with the original function, which consistently overestimated the actual risk.

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TL;DR: A quantitative calculator to estimate the 5-year risk of developing POAG, based on the pooled OHTS-EGPS predictive model, has high precision and will be useful for clinicians and patients in deciding the frequency of tests and examinations during follow-up and advisability of initiating preventive treatment.

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TL;DR: The observation that high vitamin K status was associated with lower concentrations of inflammatory markers suggests that a possible protective role for vitamin K in inflammation merits further investigation.
Abstract: In vitro data suggest protective roles for vitamins K and D in inflammation. To examine associations between vitamins K and D and inflammation in vivo, the authors used multiple linear regression analyses, adjusted for age, sex, body mass index, triglyceride concentrations, use of aspirin, use of lipid-lowering medication, season, menopausal status, and hormone replacement therapy. Participants were from the Framingham Offspring Study (1997-2001; n = 1,381; mean age = 59 years; 52% women). Vitamin K status, measured by plasma phylloquinone concentration and phylloquinone intake, was inversely associated with circulating inflammatory markers as a group and with several individual inflammatory biomarkers (p < 0.01). Percentage of undercarboxylated osteocalcin, a functional measure of vitamin K status, was not associated with overall inflammation but was associated with C-reactive protein (p < 0.01). Although plasma 25-hydroxyvitamin D was inversely associated with urinary isoprostane concentration, an indicator of oxidative stress (p < 0.01), overall associations between vitamin D status and inflammation were inconsistent. The observation that high vitamin K status was associated with lower concentrations of inflammatory markers suggests that a possible protective role for vitamin K in inflammation merits further investigation.

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TL;DR: The data suggest that modulation of prostate cancer development by polyunsaturated fatty acids is mediated in part through Bad-dependent apoptosis, highlighting the importance of gene-diet interactions in prostate cancer.
Abstract: Although a causal role of genetic alterations in human cancer is well established, it is still unclear whether dietary fat can modulate cancer risk in a predisposed population. Epidemiological studies suggest that diets rich in omega-3 polyunsaturated fatty acids reduce cancer incidence. To determine the influence of fatty acids on prostate cancer risk in animals with a defined genetic lesion, we used prostate-specific Pten-knockout mice, an immune-competent, orthotopic prostate cancer model, and diets with defined polyunsaturated fatty acid levels. We found that omega-3 fatty acids reduced prostate tumor growth, slowed histopathological progression, and increased survival, whereas omega-6 fatty acids had opposite effects. Introducing an omega-3 desaturase, which converts omega-6 to omega-3 fatty acids, into the Pten-knockout mice reduced tumor growth similarly to the omega-3 diet. Tumors from mice on the omega-3 diet had lower proportions of phosphorylated Bad and higher apoptotic indexes compared with those from mice on omega-6 diet. Knockdown of Bad eliminated omega-3-induced cell death, and introduction of exogenous Bad restored the sensitivity to omega-3 fatty acids. Our data suggest that modulation of prostate cancer development by polyunsaturated fatty acids is mediated in part through Bad-dependent apoptosis. This study highlights the importance of gene-diet interactions in prostate cancer.

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TL;DR: The study suggests that marital communication, conflict, and strain are associated with adverse health outcomes and further research into the influence of marital stress on health is merited.
Abstract: Objective To determine if marriage and marital strain are related to the 10-year coronary heart disease (CHD) incidence or total mortality. Research has demonstrated associations between marital strain and prognosis of heart disease, but little research has addressed the association between specific aspects of marital strain and incident CHD. Methods From 1984 to 1987, 3682 participants (mean age 48.5 +/- 10.1 (standard deviation) years; 52% women) of the Framingham Offspring Study were examined; measures of marital status, marital strain, and risk factors for CHD were collected at the baseline examination. The present study describes the 10-year follow-up for incident CHD and total mortality. Results After adjusting for age, systolic blood pressure, body mass index, cigarette smoking, diabetes, and total cholesterol/high density cholesterol, the married men compared with unmarried men were almost half as likely to die during follow-up (hazard ratio (HR) = 0.54; 95% confidence interval (CI): 0.34-0.83). Women who "self-silenced" during conflict with their spouse, compared with women who did not, had four times the risk of dying (HR = 4.01; 95% CI: 1.75-9.20). Men with wives who were upset by work were 2.7 times more likely to develop CHD (HR = 2.71; 95% CI: 1.22-6.03). Marital happiness, satisfaction, and disagreements were not related to the development of CHD or death in men or women. Conclusions Our study suggests that marital communication, conflict, and strain are associated with adverse health outcomes. Further research into the influence of marital stress on health is merited.

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TL;DR: Using single nucleotide polymorphisms from a 100K genome-wide scan, this work examines the associations of common polymorphisms with phenotypic variation in this community-based cohort and provides a full-disclosure, web-based resource of results for future replication studies.
Abstract: Background The Framingham Heart Study (FHS), founded in 1948 to examine the epidemiology of cardiovascular disease, is among the most comprehensively characterized multi-generational studies in the world. Many collected phenotypes have substantial genetic contributors; yet most genetic determinants remain to be identified. Using single nucleotide polymorphisms (SNPs) from a 100K genome-wide scan, we examine the associations of common polymorphisms with phenotypic variation in this community-based cohort and provide a full-disclosure, web-based resource of results for future replication studies.

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TL;DR: In this paper, the authors found that metabolic syndrome increased risk for type 2 diabetes and cardiovascular disease (CVD) and may be associated with insulin resistance, and tested the hypothesis that the metabolic syndrome confers risk with or without concomitant insulin resistance.
Abstract: OBJECTIVE: Metabolic syndrome increases the risk for type 2 diabetes and cardiovascular disease (CVD) and may be associated with insulin resistance. RESEARCH DESIGN AND METHODS: We tested the hypothesis that the metabolic syndrome confers risk with or without concomitant insulin resistance among 2,803 Framingham Offspring Study subjects followed up to 11 years for new diabetes (135 cases) or CVD (240 cases). We classified subjects by presence of metabolic syndrome (using the National Cholesterol Education Program's [NCEPs] Third Adult Treatment Panel [ATP III], International Diabetes Federation [IDF], or European Group for the Study of Insulin Resistance [EGIR] criteria) and insulin resistance (homeostasis model assessment of insulin resistance > or = 75th percentile) and used separate risk factor-adjusted proportional hazards models to estimate relative risks (RRs) for diabetes or CVD using as referents those without insulin resistance, metabolic syndrome, or without both. RESULTS: Fifty-six percent of individuals with ATP III, 52% with IDF, and 100% with EGIR definitions of metabolic syndrome had insulin resistance. Insulin resistance increased risk for diabetes (RR 2.6 [95% CI 1.7-4.0]) and CVD (1.8 [1.4-2.3]) as did metabolic syndrome for diabetes (ATP III, 3.5 [2.2-5.6]; IDF, 4.6 [2.7-7.7]; and EGIR, 3.3 [2.1-5.1]) and CVD (ATP III, 1.8 [1.4-2.3]; IDF, 1.7 [1.3-2.3]; and EGIR, 2.1 [1.6-2.7]). Relative to those without either metabolic syndrome or insulin resistance, metabolic syndrome and insulin resistance increased risk for diabetes (ATP III, 6.0 [3.3-10.8] and IDF, 6.9 [3.7-13.0]) and CVD (ATP III, 2.3 [1.7-3.1] and IDF, 2.2 [1.6-3.0]). Any instance of metabolic syndrome without insulin resistance increased risk for diabetes approximately threefold (P < 0.001); IDF metabolic syndrome without insulin resistance (RR 1.6, P = 0.01), but not ATP III metabolic syndrome without insulin resistance (RR 1.3, P = 0.2), increased risk for CVD. CONCLUSIONS: Metabolic syndrome increased risk for diabetes regardless of insulin resistance. Metabolic syndrome by ATP III criteria may require insulin resistance to increase risk for CVD. The simultaneous presence of metabolic syndrome and insulin resistance identifies an especially high-risk individual.

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TL;DR: The results suggest that genes associated with clinical neurological disease also have detectable effects on subclinical phenotypes, and illustrate the use of an unbiased approach to discover novel pathways that may be involved in brain aging.
Abstract: Brain magnetic resonance imaging (MRI) and cognitive tests can identify heritable endophenotypes associated with an increased risk of developing stroke, dementia and Alzheimer's disease (AD). We conducted a genome-wide association (GWA) and linkage analysis exploring the genetic basis of these endophenotypes in a community-based sample. A total of 705 stroke- and dementia-free Framingham participants (age 62 +9 yrs, 50% male) who underwent volumetric brain MRI and cognitive testing (1999–2002) were genotyped. We used linear models adjusting for first degree relationships via generalized estimating equations (GEE) and family based association tests (FBAT) in additive models to relate qualifying single nucleotide polymorphisms (SNPs, 70,987 autosomal on Affymetrix 100K Human Gene Chip with minor allele frequency ≥ 0.10, genotypic call rate ≥ 0.80, and Hardy-Weinberg equilibrium p-value ≥ 0.001) to multivariable-adjusted residuals of 9 MRI measures including total cerebral brain (TCBV), lobar, ventricular and white matter hyperintensity (WMH) volumes, and 6 cognitive factors/tests assessing verbal and visuospatial memory, visual scanning and motor speed, reading, abstract reasoning and naming. We determined multipoint identity-by-descent utilizing 10,592 informative SNPs and 613 short tandem repeats and used variance component analyses to compute LOD scores. The strongest gene-phenotype association in FBAT analyses was between SORL1 (rs1131497; p = 3.2 × 10-6) and abstract reasoning, and in GEE analyses between CDH4 (rs1970546; p = 3.7 × 10-8) and TCBV. SORL1 plays a role in amyloid precursor protein processing and has been associated with the risk of AD. Among the 50 strongest associations (25 each by GEE and FBAT) were other biologically interesting genes. Polymorphisms within 28 of 163 candidate genes for stroke, AD and memory impairment were associated with the endophenotypes studied at p < 0.001. We confirmed our previously reported linkage of WMH on chromosome 4 and describe linkage of reading performance to a marker on chromosome 18 (GATA11A06), previously linked to dyslexia (LOD scores = 2.2 and 5.1). Our results suggest that genes associated with clinical neurological disease also have detectable effects on subclinical phenotypes. These hypothesis generating data illustrate the use of an unbiased approach to discover novel pathways that may be involved in brain aging, and could be used to replicate observations made in other studies.

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TL;DR: Longevity and aging traits are associated with SNPs on the Affymetrix 100K SNP GeneChip and none of the associations achieved genome-wide significance.
Abstract: Family studies and heritability estimates provide evidence for a genetic contribution to variation in the human life span. We conducted a genome wide association study (Affymetrix 100K SNP GeneChip) for longevity-related traits in a community-based sample. We report on 5 longevity and aging traits in up to 1345 Framingham Study participants from 330 families. Multivariable-adjusted residuals were computed using appropriate models (Cox proportional hazards, logistic, or linear regression) and the residuals from these models were used to test for association with qualifying SNPs (70, 987 autosomal SNPs with genotypic call rate ≥80%, minor allele frequency ≥10%, Hardy-Weinberg test p ≥ 0.001). In family-based association test (FBAT) models, 8 SNPs in two regions approximately 500 kb apart on chromosome 1 (physical positions 73,091,610 and 73, 527,652) were associated with age at death (p-value < 10-5). The two sets of SNPs were in high linkage disequilibrium (minimum r2 = 0.58). The top 30 SNPs for generalized estimating equation (GEE) tests of association with age at death included rs10507486 (p = 0.0001) and rs4943794 (p = 0.0002), SNPs intronic to FOXO1A, a gene implicated in lifespan extension in animal models. FBAT models identified 7 SNPs and GEE models identified 9 SNPs associated with both age at death and morbidity-free survival at age 65 including rs2374983 near PON1. In the analysis of selected candidate genes, SNP associations (FBAT or GEE p-value < 0.01) were identified for age at death in or near the following genes: FOXO1A, GAPDH, KL, LEPR, PON1, PSEN1, SOD2, and WRN. Top ranked SNP associations in the GEE model for age at natural menopause included rs6910534 (p = 0.00003) near FOXO3a and rs3751591 (p = 0.00006) in CYP19A1. Results of all longevity phenotype-genotype associations for all autosomal SNPs are web posted at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 . Longevity and aging traits are associated with SNPs on the Affymetrix 100K GeneChip. None of the associations achieved genome-wide significance. These data generate hypotheses and serve as a resource for replication as more genes and biologic pathways are proposed as contributing to longevity and healthy aging.

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TL;DR: A community-based genome-wide association study of major CVD outcomes finds genetic variants associated with CVD may point to novel disease pathways and identify potential targeted preventive therapies.
Abstract: National Institute of Health and the National Heart, Lung, and Blood Institute (N01-HC 25195); National Health Institutes National Center for Research Resources Shared Instrumentation grant (ISI0RR163736-01A1)

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TL;DR: Overall, incidence rates of overweight increased 2-fold and that of obesity more than 3-fold over 5 decades, findings that remained robust upon additional adjustment for baseline BMI in each decade.

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TL;DR: Higher circulating plasminogen activator inhibitor-1 and aldosterone levels are associated with the development of MetS and with longitudinal change of its components, suggesting that these biomarkers and related pathways play a key role in mediating metabolic risk.
Abstract: Background— The metabolic syndrome (MetS) is associated with increased cardiovascular risk. We evaluated the relative contributions of circulating biomarkers representing distinct biological pathwa...

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TL;DR: This initiative will characterize more precisely and in greater detail the shape and strength of the age- and sex-specific associations of several lipid and inflammatory markers with incident coronary heart disease outcomes (and, secondarily, with other incident cardiovascular outcomes) under a wide range of circumstances.
Abstract: Many long-term prospective studies have reported on associations of cardiovascular diseases with circulating lipid markers and/or inflammatory markers. Studies have not, however, generally been designed to provide reliable estimates under different circumstances and to correct for within-person variability. The Emerging Risk Factors Collaboration has established a central database on over 1.1 million participants from 104 prospective population-based studies, in which subsets have information on lipid and inflammatory markers, other characteristics, as well as major cardiovascular morbidity and cause-specific mortality. Information on repeat measurements on relevant characteristics has been collected in approximately 340,000 participants to enable estimation of and correction for within-person variability. Re-analysis of individual data will yield up to approximately 69,000 incident fatal or nonfatal first ever major cardiovascular outcomes recorded during about 11.7 million person years at risk. The primary analyses will involve age-specific regression models in people without known baseline cardiovascular disease in relation to fatal or nonfatal first ever coronary heart disease outcomes. This initiative will characterize more precisely and in greater detail than has previously been possible the shape and strength of the age- and sex-specific associations of several lipid and inflammatory markers with incident coronary heart disease outcomes (and, secondarily, with other incident cardiovascular outcomes) under a wide range of circumstances. It will, therefore, help to determine to what extent such associations are independent from possible confounding factors and to what extent such markers (separately and in combination) provide incremental predictive value.