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Showing papers by "Ralph B. D'Agostino published in 2003"


Journal ArticleDOI
TL;DR: Individuals with AF or CHF who subsequently develop the other condition have a poor prognosis, and additional studies addressing the pathogenesis, prevention, and optimal management of the joint occurrence of AF and CHF appear warranted.
Abstract: Background— Atrial fibrillation (AF) and congestive heart failure (CHF) frequently occur together, but there is limited information regarding their temporal relations and the combined influence of these conditions on mortality. Methods and Results— We studied participants in the Framingham Study with new-onset AF or CHF. Multivariable Cox proportional hazards models with time-dependent variables were used to evaluate whether mortality after AF or CHF was affected by the occurrence and timing of the other condition. Hazard ratios (HRs) were adjusted for time period and cardiovascular risk factors. During the study period, 1470 participants developed AF, CHF, or both. Among 382 individuals with both conditions, 38% had AF first, 41% had CHF first, and 21% had both diagnosed on the same day. The incidence of CHF among AF subjects was 33 per 1000 person-years, and the incidence of AF among CHF subjects was 54 per 1000 person-years. In AF subjects, the subsequent development of CHF was associated with increase...

1,747 citations


Journal ArticleDOI
27 Aug 2003-JAMA
TL;DR: In this paper, a risk score for stroke was derived that included the following risk predictors: advancing age, female sex, increasing systolic blood pressure, prior stroke or transient ischemic attack, and diabetes.
Abstract: ContextPrior risk stratification schemes for atrial fibrillation (AF) have been based on randomized trial cohorts or Medicare administrative databases, have included patients with established AF, and have focused on stroke as the principal outcome.ObjectiveTo derive risk scores for stroke alone and stroke or death in community-based individuals with new-onset AF.Design, Setting, and ParticipantsProspective, community-based, observational cohort in Framingham, Mass. We identified 868 participants with new-onset AF, 705 of whom were not treated with warfarin at baseline. Risk scores for stroke (ischemic or hemorrhagic) and stroke or death were developed with censoring when warfarin initiation occurred during follow-up. Event rates were examined in low-risk individuals, as defined by the risk score and 4 previously published risk schemes.Main Outcome MeasuresStroke and the combination of stroke or death.ResultsDuring a mean follow-up of 4.0 years free of warfarin use, stroke alone occurred in 83 participants and stroke or death occurred in 382 participants. A risk score for stroke was derived that included the following risk predictors: advancing age, female sex, increasing systolic blood pressure, prior stroke or transient ischemic attack, and diabetes. With the risk score, 14.3% of the cohort had a predicted 5-year stroke rate ≤7.5% (average annual rate ≤1.5%), and 30.6% of the cohort had a predicted 5-year stroke rate ≤10% (average annual rate ≤2%). Actual stroke rates in these low-risk groups were 1.1 and 1.5 per 100 person-years, respectively. Previous risk schemes classified 6.4% to 17.3% of subjects as low risk, with actual stroke rates of 0.9 to 2.3 per 100 person-years. A risk score for stroke or death is also presented.ConclusionThese risk scores can be used to estimate the absolute risk of an adverse event in individuals with AF, which may be helpful in counseling patients and making treatment decisions.

705 citations


Journal ArticleDOI
TL;DR: In this paper, the authors support a key role for cytokines in left ventricular remodeling in congestive heart failure (CHF) patients and show that elevated plasma cytokine levels are associated with increased mortality.
Abstract: Background— Experimental studies support a key role for cytokines in left ventricular remodeling. In congestive heart failure (CHF) patients, elevated plasma cytokine levels are associated with wor...

687 citations


Journal ArticleDOI
TL;DR: In this elderly cohort, more women experienced initial strokes and were more disabled at 6 months post-stroke than men, however, older age at stroke onset, not gender or stroke subtype, was associated with greater disability.
Abstract: The magnitude of disability among elderly stroke survivors is substantial. There have been few community-based estimates of the contribution gender and older age make to stroke-related disability and outcome. Using the original Framingham Study cohort, we documented gender-specific neurological deficits and disability differences in stroke survivors at six months post-stroke. Logistic regression analyses were performed to estimate odds ratios, comparing men and women, and adjusting for age, and age and stroke subtype. Age and gender-matched controls were then compared to distinguish stroke-related disability from disability associated with general aging. Results showed that almost half (43%) of all elderly stroke survivors in the cohort had moderate to severe neurological deficits. In the crude analyses, women were more dependent in ADLs (33.9% vs 15.6%), less likely to walk unassisted (40.3% vs 17.8%), and living in nursing homes (34.9 % vs 13.3%). After adjusting for age and stroke subtype, it was older age that accounted for the severity of disability. When compared to age and gender-matched controls, stroke cases were significantly more disabled in all domains studied. In this elderly cohort, more women experienced initial strokes and were more disabled at 6 months post-stroke than men. However, older age at stroke onset, not gender or stroke subtype, was associated with greater disability. Health care providers need to understand that strokes occur later in life for women and that because of age, women are at greater risk for disability and institutionalization.

669 citations


Journal ArticleDOI
TL;DR: The adverse effects of obesity and hypertension in men are independent and cumulative with respect to cognitive deficit, and the best performance was observed in nonobese, normotensive men.
Abstract: OBJECTIVE: To determine the independent effects of obesity and hypertension on cognitive functioning. METHODS: Using a prospective design, male (n=551) and female (n=872) participants of the Framingham Heart Study were classified by presence or absence of obesity and hypertension based on data collected over an 18-y surveillance period. All subjects were free from dementia, stroke, and clinically diagnosed cardiovascular disease up to the time of cognitive testing. Statistical models were adjusted for age, education, occupation, cigarette smoking, alcohol consumption, total cholesterol, and a diagnosis of type II diabetes. Body mass index status (nonobese or obese) and blood pressure status (normotensive or hypertensive) were then related to cognitive performance (learning, memory, executive functioning, and abstract reasoning) on tests administered 4–6 y later. RESULTS: Adverse effects of obesity and hypertension on cognitive performance were observed for men only. Obese and hypertensive men performed more poorly than men classified as either obese or hypertensive, and the best performance was observed in nonobese, normotensive men. CONCLUSIONS: The adverse effects of obesity and hypertension in men are independent and cumulative with respect to cognitive deficit.

661 citations


Journal ArticleDOI
01 Aug 2003-Diabetes
TL;DR: The metabolic syndrome typically affects 20-30% of middle-aged adults in the U.S. and by any criteria, subjects with the metabolic syndrome are more insulin resistant and at increased predicted risk for CHD versus those without the syndrome.
Abstract: The metabolic syndrome may be a common phenotype increasing risk for type 2 diabetes and cardiovascular disease. We assessed the prevalence and characteristics of the metabolic syndrome among population-based samples of 3,224 white subjects attending Framingham Offspring Study (FOS) exam 5 (1991-1995) and 1,081 non-Hispanic white and 1,656 Mexican-American subjects attending the San Antonio Heart Study (SAHS) phase II follow-up exam (1992-1996). Subjects were approximately 50% women, aged 30-79 years, without diabetes, and classified with the metabolic syndrome according to criteria for obesity, dyslipidemia, hyperglycemia, and hypertension proposed by the Third Report of the National Cholesterol Education Program's Adult Treatment Panel (ATP III) or the World Health Organization (WHO). We used regression models to estimate rates across ethnic groups and to assess the association of the metabolic syndrome with insulin resistance and predicted 10-year coronary heart disease (CHD) risk. Among FOS white subjects, the age- and sex-adjusted prevalence of the metabolic syndrome was 24% by both ATP III and WHO criteria; among SAHS non-Hispanic white subjects, 23 and 21%, respectively; and among SAHS Mexican-American subjects, 31 and 30%. Rates were highest among Mexican-American women (ATP III, 33%) and lowest among white women (21%). Subjects with the metabolic syndrome by ATP III criteria had higher age-, sex-, and ethnicity-adjusted levels of fasting insulin (11.3 micro U/ml), homeostasis model assessment of insulin resistance (2.7), and predicted CHD risk (11.8%) than those without the syndrome (5.9 micro U/ml, 1.3, and 6.4%, respectively; all P = 0.0001); differences were similar using WHO criteria. We conclude that the metabolic syndrome typically affects 20-30% of middle-aged adults in the U.S. By any criteria, subjects with the metabolic syndrome are more insulin resistant and at increased predicted risk for CHD versus those without the metabolic syndrome.

496 citations


Journal ArticleDOI
TL;DR: The calibrated Framingham function may help to more accurately estimate the overall risk of CHD in the Spanish population for primary prevention purposes.
Abstract: Introduction and objectives. The Framingham coronary heart disease (CHD) functions overestimate the risk of CHD in countries with a low incidence. Consequently, these functions should be calibrated for the purpose of primary prevention. Calibrated Framingham function charts of overall CHD risk for the Spanish population are presented. Patients and methods. The Framingham functions were calibrated by substituting the prevalence of CHD risk factors and incidence found in Framingham with the same values for Spain. The Framingham function that included high-density lipoprotein (HDL) cholesterol was used. The 10-year probability of developing a CHD event was estimated for several combinations of risk factors and HDL levels ranging from 35 to 59 mg/dl. Color-coded charts were prepared that show the exact probability of CHD corresponding to each combination of risk factors, shown in separate cells on the chart. Results. The event rate and prevalence of CHD risk factors differed considerably between Girona and Framingham. HDL 60 mg/dL reduced it by 50%. The proportion of cells in which the 10-year probability of developing a CHD event was > 9% was 2.3 times higher and that of cells with a probability > 19% was 13 times lower in the chart calibrated for Spain than in the original Framingham charts. Conclusions. The calibrated Framingham function may help to more accurately estimate the overall risk of CHD in the Spanish population for primary prevention purposes. The calibrated function should be validated, and the development of functions for the Spanish population should be promoted.

451 citations


Journal ArticleDOI
TL;DR: The independent association of MAC with incident CVD and CVD death underscores that cardiac calcification is a marker of increased CVD risk.
Abstract: Background— Mitral annular calcification (MAC) has been associated with stroke in longitudinal, community-based cohorts and cardiovascular disease (CVD) outcomes in many small retrospective studies. Prospective data are limited on the relation of MAC with CVD morbidity and mortality. Methods and Results— We examined the association between MAC assessed by M-mode echocardiography and the incidence of CVD, CVD death, and all-cause death over 16 years of follow-up in the Framingham Heart Study subjects who attended a routine examination between 1979 and 1981. Cox proportional hazards models were used to estimate hazard ratios (HRs) associated with the presence of MAC for each outcome. Of 1197(445 male, 752 female) subjects who had adequate echocardiographic assessment, 14% had MAC. There were 307 incident CVD events and 621 deaths. In multivariable adjusted analyses, MAC was associated with an increased risk of incident CVD (HR, 1.5; 95% CI, 1.1, 2.0), CVD death (HR, 1.6; 95% CI, 1.1, 2.3), and all-cause death (HR, 1.3; 95% CI, 1.04, 1.6). For each 1-mm increase in MAC, the risk of incident CVD, CVD death, and all-cause death increased by ≈10%. Conclusions— The independent association of MAC with incident CVD and CVD death underscores that cardiac calcification is a marker of increased CVD risk.

388 citations


Journal ArticleDOI
TL;DR: Greater levels or production of the catabolic cytokines TNF-alpha and interleukin 6 are associated with increased mortality in community-dwelling elderly adults, whereas IGF-1 levels had the opposite effect.

383 citations


Journal ArticleDOI
TL;DR: The Framingham function became an effective method of estimating the risk in this region with low coronary heart disease incidence and more than doubled the actual risk of coronary disease observed in north east Spain.
Abstract: Aim: To determine whether the Framingham function accurately predicts the 10 year risk of coronary disease and to adapt this predictive method to the characteristics of a Spanish population. Method and Results: A Framingham function for predicting 10 year coronary deaths and non-fatal myocardial infarction was applied to the population of the province of Gerona, Spain, where the cumulated incidence rate of myocardial infarction has been determined since 1988 by a specific registry. The prevalence of cardiovascular risk factors in this region of Spain was established in 1995 by a cross sectional study on a representative sample of 1748 people. The number of cases estimated by the Framingham function for 10 year coronary deaths and non-fatal myocardial infarction was compared with that observed. The Framingham function estimated 2425 coronary heart disease cases in women and 1181 were observed. In men, 9919 were estimated and 3706 were observed. Recalibrating the Framingham equations to the event rate and the prevalence of the risk factors in Gerona led to estimates very close to the number of cases observed in Gerona men and women. Conclusions: The Framingham function estimates more than doubled the actual risk of coronary disease observed in north east Spain. After calibration, the Framingham function became an effective method of estimating the risk in this region with low coronary heart disease incidence.

355 citations


Book ChapterDOI
TL;DR: This chapter focuses on the evaluation of the performance of an HRAF with regard to its ability to predict the outcome variable and considers a time to event survival model with censored observations, such as the Cox regression model.
Abstract: Publisher Summary Prediction functions or Health Risk Appraisal Functions (HRAF) are mathematical models of the probability of an event. This chapter focuses on the evaluation of the performance of an HRAF with regard to its ability to predict the outcome variable. It considers a time to event survival model with censored observations, such as the Cox regression model. The performance of a model with regard to its discrimination and calibration is evaluated. Discrimination refers to a model's ability to correctly distinguish the two classes of outcomes. A model with good discrimination ability produces higher predicted probabilities to subjects who had events than subjects who did not have events. Perfect discrimination would result in two non-overlapping sets of predicted probabilities from the model: one set for the positive outcomes and the other for the negative outcomes. Calibration describes how closely the predicted probabilities agree numerically with the actual outcomes. A model is well calibrated when the predicted and observed values agree for any reasonable grouping of the observation, ordered by increasing predicted values. Calibration measures are often statistics that partition a data set into groups and assess how the average predicted probability compares with the outcome prevalence in each group.

Journal ArticleDOI
TL;DR: Higher intakes of whole grains were associated with increases in insulin sensitivity, and the addition of fiber and magnesium resulted in a nonsignificant association that is consistent with the hypothesis that these constituents account for some of the effect of whole grain-containing foods on S(I).

Journal ArticleDOI
TL;DR: In this article, the authors showed that FKN-dependent cell-cell adhesion under conditions of physiologic shear is severely reduced in cells expressing CX3CR1-M280.
Abstract: The chemokine receptor CX3CR1 is a proinflammatory leukocyte receptor specific for the chemokine fractalkine (FKN or CX3CL1). In two retrospective studies, CX3CR1 has been implicated in the pathogenesis of atherosclerotic cardiovascular disease (CVD) based on statistical association of a common receptor variant named CX3CR1-M280 with lower prevalence of atherosclerosis, coronary endothelial dysfunction, and acute coronary syndromes. However, the general significance of CX3CR1-M280 and its putative mechanism of action have not previously been defined. Here we show that FKN-dependent cell-cell adhesion under conditions of physiologic shear is severely reduced in cells expressing CX3CR1-M280. This was associated with marked reduction in the kinetics of FKN binding as well as reduced FKN-induced chemotaxis of primary leukocytes from donors homozygous for CX3CR1-M280. We also show that CX3CR1-M280 is independently associated with a lower risk of CVD (adjusted odds ratio, 0.60, P = 0.008) in the Offspring Cohort of the Framingham Heart Study, a long-term prospective study of the risks and natural history of this disease. These data provide mechanism-based and consistent epidemiologic evidence that CX3CR1 may be involved in the pathogenesis of CVD in humans, possibly by supporting leukocyte entry into the coronary artery wall. Moreover, they suggest that CX3CR1-M280 is a genetic risk factor for CVD.

Journal ArticleDOI
TL;DR: This community-based study followed 717 elderly people without known myocardial infarction or heart failure for 5 to 9 years to hypothesized that a low serum IGF-I level may be associated with an increased risk for congestive heart failure.
Abstract: In this prospective, community-based study, serum insulin-like growth factor I level was inversely related to the risk for congestive heart failure in elderly people without a previous myocardial i...

Journal ArticleDOI
TL;DR: In this paper, the authors examined the impact of baseline and lifetime plasma total cholesterol levels averaged across many years on the risk for Alzheimer disease in a large, population-based cohort.
Abstract: Background Previous studies examining the association of plasma cholesterol levels with the risk for development of Alzheimer disease (AD) have been inconclusive. We examined the impact of baseline and lifetime plasma total cholesterol levels averaged across many years on the risk for AD in a large, population-based cohort. Methods Five thousand two hundred nine subjects from the Framingham Study original cohort underwent biennial evaluation for cardiovascular risk factors since 1950, with estimations of serum total cholesterol levels at 19 of these 25 biennial examinations. The study sample consisted of 1026 subjects from this cohort who were alive and free of stroke and dementia at examination cycle 20 (1988-1989) and had undergone apolipoprotein E (APOE) genotyping. The main outcome measure was incident AD diagnosed using standard criteria, according to average total cholesterol levels across biennial examination cycles 1 to 15 and baseline total cholesterol level measured at the 20th biennial examination cycle. Results Alzheimer disease developed in 77 subjects from 1992 to 2000. After adjustment for age, sex,APOEgenotype, smoking, body mass index (calculated as weight in kilograms divided by the square of height in meters), coronary heart disease, and diabetes, we found no significant association between the risk for incident AD and average cholesterol level at biennial examination cycles 1 to 15 (hazard ratio per 10-mg/dL [0.3-mmol/L] rise, 0.95; 95% confidence interval, 0.87-1.04) or baseline total cholesterol level at examination 20 (hazard ratio, 0.97; 95% confidence interval, 0.90-1.05). Conclusion In this large, population-based cohort, baseline and long-term average serum total cholesterol levels were not associated with the risk for incident AD.

Journal ArticleDOI
TL;DR: An increased proinflammatory state is shown in prediabetic individuals who are predominantly insulin resistant but not in those with a primary defect in &bgr;-cell function, and this risk seems to be restricted to subjects with high insulin resistance.
Abstract: Background— Elevated levels of proinflammatory proteins are predictive of both cardiovascular (CV) disease and type 2 diabetes. Previously, atherogenic changes in traditional CV risk factors in the prediabetic state were mainly seen in insulin-resistant subjects rather than in those with a predominant defect in insulin secretion. Methods and Results— We studied in prediabetic individuals from the Insulin Resistance Atherosclerosis Study (IRAS) the relation of C-reactive protein (CRP), plasminogen activator inhibitor (PAI)-1, and fibrinogen to defects in insulin sensitivity (SI) and first-phase insulin secretion, respectively, as assessed using a frequently sampled intravenous glucose tolerance test. One hundred forty-eight of 906 (16.3%) nondiabetic individuals developed diabetes after a mean follow-up of 5.2 years. Prediabetic individuals who were insulin resistant had higher levels of PAI-1 (mean [95% CI], 25.83 ng/mL [22.42 to 29.77] versus 16.31 ng/mL [12.56 to 21.18]; P=0.003) and CRP (mean [95% CI],...

Journal ArticleDOI
01 Feb 2003-Diabetes
TL;DR: Substantial differences are found between published IR indexes in the prediction of diabetes, with ISI(0,120) consistently showing the strongest prediction.
Abstract: To determine and formally compare the ability of simple indexes of insulin resistance (IR) to predict type 2 diabetes, we used combined prospective data from the San Antonio Heart Study, the Mexico City Diabetes Study, and the Insulin Resistance Atherosclerosis Study, which include well-characterized cohorts of non-Hispanic white, African-American, Hispanic American, and Mexican subjects with 5-8 years of follow-up. Poisson regression was used to assess the ability of each candidate index to predict incident diabetes at the follow-up examination (343 of 3,574 subjects developed diabetes). The areas under the receiver operator characteristic (AROC) curves for each index were calculated and statistically compared. In pooled analysis, Gutt et al.'s insulin sensitivity index at 0 and 120 min (ISI(0,120)) displayed the largest AROC (78.5%). This index was significantly more predictive (P < 0.0001) than a large group of indexes (including those by Belfiore, Avignon, Katz, and Stumvoll) that had AROC curves between 66 and 74%. These findings were essentially similar both after adjustment for covariates and when analyses were conducted separately by glucose tolerance status and ethnicity/study subgroups. In conclusion, we found substantial differences between published IR indexes in the prediction of diabetes, with ISI(0,120) consistently showing the strongest prediction. This index may reflect other aspects of diabetes pathogenesis in addition to IR, which might explain its strong predictive abilities despite its moderate correlation with direct measures of IR.

Journal ArticleDOI
12 Mar 2003-JAMA
TL;DR: An increased plasma homocysteine level independently predicts risk of the development of CHF in adults without prior myocardial infarction.
Abstract: ContextElevated plasma homocysteine levels are associated with increased risk of vascular disease. It is unclear whether elevated homocysteine levels are a risk factor for congestive heart failure (CHF).ObjectiveTo study prospectively the association between nonfasting plasma homocysteine and incidence of CHF.Design, Setting, and ParticipantsCommunity-based prospective cohort study of 2491 adults (mean age 72 years, 1547 women) who participated in the Framingham Heart Study during the 1979-1982 and 1986-1990 examinations and were free of CHF or prior myocardial infarction (recognized or unrecognized) at baseline.Main Outcome MeasureIncidence of a first episode of CHF during an 8-year follow-up period.ResultsDuring follow-up, 156 subjects (88 women) developed CHF. In multivariable analyses controlling for established risk factors for CHF including the occurrence of myocardial infarction (recognized or unrecognized) during follow-up, plasma homocysteine levels higher than the sex-specific median value were associated with an adjusted hazards ratio for heart failure of 1.93 in women (95% confidence interval, 1.19-3.14) and 1.84 in men (95% confidence interval, 1.06-3.17). The relation of plasma homocysteine levels to CHF risk was more continuous in women than in men. In analyses restricted to participants without any manifestation of coronary heart disease at baseline, the association of plasma homocysteine levels with risk of CHF was maintained in men and women.ConclusionsAn increased plasma homocysteine level independently predicts risk of the development of CHF in adults without prior myocardial infarction. Additional investigations are warranted to confirm these findings.

Journal ArticleDOI
TL;DR: The association of the genotype with PAI-1 levels was seen consistently among all 3 ethnic groups and was unaffected by metabolic covariates, including insulin resistance.
Abstract: Background— The 4G/5G polymorphism of the plasminogen activator inhibitor-1 (PAI-1) gene has been related to cardiovascular disease. Methods and Results— Insulin resistance was measured with a frequently sampled intravenous glucose tolerance test in the Insulin Resistance Atherosclerosis Study (IRAS), and PAI-1 4G/5G promoter genotype was established by allele-specific polymerase chain reaction amplification of genomic DNA. There were 287 subjects with the 4G/4G genotype (18.4%), 691 heterozygote subjects (44.2%), and 586 carriers of the 5G/5G genotype (37.5%). The genotype distribution was different across the 3 ethnic groups (P=0.001). PAI-1 levels were lower in blacks than in non-Hispanic whites and Hispanics and lower in non-Hispanic whites than in Hispanics (all P=0.0001). Subjects homozygous for the 4G allele had the highest plasma PAI-1, heterozygote subjects were intermediate, and 5G homozygotes had the lowest levels of PAI-1. These patterns remained unaffected by adjustments for age, gender, clin...

Journal ArticleDOI
TL;DR: Elevated apoB is more strongly associated than LDLC with other risk factors, including measures in the National Cholesterol Education Program guidelines for lipid treatment and other more recently established risk factors.
Abstract: Background— Risk factors for vascular disease include obesity, dyslipidemia, hypertension, dysglycemia, insulin resistance, inflammation, thrombosis, and subclinical atherosclerosis. This study com...

Journal ArticleDOI
TL;DR: Although CHD risk is increased in HIV-infected patients with fat redistribution, the pattern of fat distribution and sex are potential important components in determining the risk in this population.
Abstract: A metabolic syndrome has been described among human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy; the syndrome is characterized by fat redistribution, insulin resistance, and dyslipidemia. We compared the 10-year coronary heart disease (CHD) risk estimates for 91 HIV-infected men and women with fat redistribution with the risk estimates for 273 age-, sex-, and body mass index (BMI)-matched subjects enrolled in the Framingham Offspring Study. Thirty HIV-infected patients without fat redistribution were also compared with 90 age- and BMI-matched control subjects. The 10-year CHD risk estimate was significantly elevated among HIV-infected patients with fat redistribution, particularly among men; however, when they were matched with control subjects by waist-to-hip ratio, the 10-year CHD risk estimate did not significantly differ between groups. HIV-infected patients without fat redistribution did not have a greater CHD risk estimate than did control subjects. In addition, the CHD risk estimate was greatest in HIV-infected patients who had primary lipoatrophy, compared with those who had either lipohypertrophy or mixed fat redistribution. Therefore, although CHD risk is increased in HIV-infected patients with fat redistribution, the pattern of fat distribution and sex are potential important components in determining the risk in this population.

Journal ArticleDOI
TL;DR: Lifetime risk of CHD increases sharply with higher total cholesterol levels for men and women at all ages, and data support an important role for cholesterol screening in younger patients, and they may help target high-risk patients for lifestyle modification or drug therapy.
Abstract: Background We sought to assess how cholesterol levels at different ages modify the remaining lifetime risk of coronary heart disease (CHD). Methods We included all Framingham Heart Study participants examined from 1971 through 1996 who did not have CHD and were not receiving lipid-lowering therapy. At index ages of 40, 50, 60, 70, and 80 years, participants were stratified by total cholesterol level and by cholesterol subfractions. Lifetime risk of CHD was calculated with death free of CHD as a competing event. Results Among 3269 men and 4019 women, 1120 developed CHD and 1365 died free of CHD during follow-up. At each index age, lifetime risk of CHD increased with higher cholesterol levels, and time to event decreased. At age 40 years, the lifetime risks of CHD through age 80 years for men with total cholesterol levels less than 200 mg/dL ( Conclusions Lifetime risk of CHD increases sharply with higher total cholesterol levels for men and women at all ages. These data support an important role for cholesterol screening in younger patients, and they may help target high-risk patients for lifestyle modification or drug therapy.

Journal ArticleDOI
01 Nov 2003-Diabetes
TL;DR: Although both the WHO and NCEP MetS criteria identify nondiabetic individuals with low insulin sensitivity, the associations were notably stronger using the WHO definition, although the definitions are generally less useful for identifying those with low AIR or DI.
Abstract: Recently, the metabolic syndrome (MetS) has attracted much attention as a risk cluster for cardiovascular disease. Although it is believed that individuals with the MetS have insulin resistance (IR), there are few data using direct measures of IR such as glucose clamps or frequently sampled intravenous glucose tolerance tests (FSIGTTs). We examined associations of MetS with FSIGTT-derived measures of insulin sensitivity and secretion among nondiabetic subjects in the Insulin Resistance Atherosclerosis Study. Two sets of MetS criteria were evaluated: those from the 1999 World Health Organization (WHO) and the 2001 National Cholesterol Education Program (NCEP). Both WHO and NCEP MetS definitions were significantly associated with risk of being in the lowest quartile of directly measured insulin sensitivity (P < 0.0001 for all subjects as well as within ethnic subgroups). However, the associations with WHO-MetS were stronger for all subjects combined (WHO: odds ratio [OR] = 10.2; 95% CI 7.5-13.9; NCEP: OR = 4.6; 3.4-6.2) and in separate analyses of non-Hispanic whites, blacks, and Hispanics. WHO and NCEP MetS definitions were also significantly associated with risk of being in the lowest quartile of insulin sensitivity-adjusted acute insulin response (AIR) and disposition index (DI; all P < 0.01), although the associations were generally weaker than those for insulin sensitivity and there was no difference between the two definitions in all subjects combined (low AIR, WHO: OR = 1.7, 1.2-2.4; NCEP: OR = 1.7, 1.2-2.5). There were, however, a number of ethnic differences, including a stronger association of NCEP-MetS with low AIR among blacks. WHO-MetS was significantly more sensitive than NCEP-MetS in detecting low insulin sensitivity (65.4 vs. 45.6%, respectively; P < 0.0001), with no significant differences in specificity between the definitions (84.4 vs. 84.6%; P = 0.91), although WHO-MetS had a larger area under the receiver operating characteristic curve (75% vs. 65%; P < 0.0001). In conclusion, although both the WHO and NCEP MetS criteria identify nondiabetic individuals with low insulin sensitivity, the associations were notably stronger using the WHO definition. The definitions are generally less useful for identifying those with low AIR or DI, although NCEP-MetS seems to differentiate black subjects with insulin secretion defects.

Journal ArticleDOI
TL;DR: A simulation study that compared the external validity of standard logistic regression with piecewise-linear and quadratic terms (LR2), classification trees, and neural networks (NNETs) highlights the necessity of external validation to test the transportability of predictive models.

Journal ArticleDOI
TL;DR: It is found that there is no major relation of baseline plasma homocysteine levels to hypertension incidence or longitudinal blood pressure progression in a large, community-based cohort of nonhypertensive individuals after adjustment for age, sex, and other important covariates.
Abstract: Plasma homocysteine is cross-sectionally associated with blood pressure in large, community-based studies. It is unknown whether elevated plasma homocysteine predicts hypertension incidence. We inv ...

Journal ArticleDOI
TL;DR: Early-onset parental CHD, in particular, identifies offspring with a strong familial predisposition to atherosclerosis, which is more prevalent in individuals with a family history of CHD.
Abstract: Background— A family history of coronary heart disease (CHD) is an independent risk factor for cardiovascular events. However, the mechanisms underlying this susceptibility have not been fully elucidated. We hypothesized that an important mediator of the familial predisposition to CHD is subclinical atherosclerosis, which is detectable by noninvasive imaging. Methods and Results— We studied 1662 subjects (mean age 57, 51% women) in the Framingham Offspring Study who underwent carotid ultrasonography and had both biological parents in the original (parental) cohort. Parental CHD events were validated prospectively by a physician endpoint committee. The associations of carotid intima-media thickness (IMT) with premature parental CHD (occurring before age 60) and any parental CHD (no age restriction) were examined in age- and multivariable-adjusted analyses. Age-adjusted mean internal carotid IMT was higher in subjects who had at least one parent with premature CHD than in those without a validated parental ...

Journal ArticleDOI
TL;DR: Examining some practical clinical decision‐making scenarios for the selection and analysis of efficacy outcome measures in clinical trials with inherent multiplicity components finds that some are more difficult than others.
Abstract: The ideal approach for the design and analysis of clinical trials is to select a single primary endpoint that provides a complete characterization of the disease under study and permits an efficient evaluation of the effect of a test drug. However, this is often not possible for a number of diseases or clinical trials. This paper examines some practical clinical decision-making scenarios for the selection and analysis of efficacy outcome measures in clinical trials with inherent multiplicity components.

Journal Article
TL;DR: Relatively small changes in SBP associated with use of common arthritis medications can have a significant effect on the cardiovascular risk profile, and it is important that clinicians who treat patients with OA/RA accurately weigh the potential risks of these medications against their benefits.
Abstract: OBJECTIVE: To estimate the potential effect on cardiovascular event occurrence and treatment costs associated with increases in systolic blood pressure (SBP) among patients with osteoarthritis (OA) and rheumatoid arthritis (RA). METHODS: We used cardiovascular risk prediction models from the Framingham Heart Study and data on risk factors from the Third National Health and Nutrition Examination Survey (NHANES III) to estimate occurrences of ischemic heart disease and stroke over one year among US adults with OA/RA. Separate analyses were conducted for treated hypertensive patients, and untreated hypertensive and normotensive patients, respectively. Published estimates were used to assign costs to these events and to follow care. The effect of incremental increases in SBP on events and costs was then assessed. Monte Carlo simulation was undertaken to assess the range of event occurrence and costs associated with alternative assumptions regarding the distribution of increased SBP in the at-risk population. RESULTS: Of the estimated 30 million adults in the US aged > or = 35 years with OA and RA, roughly 11.8 million (39%) receive pharmacologic treatment for hypertension. Increases in SBP of 1-5 mm Hg were associated with 7,100-35,700 additional ischemic heart disease and stroke events over one year, with corresponding costs (year 2000 USD) of 114-569 million year 2000 USD. A 20 mm Hg increase in SBP experienced by 15% of the at-risk population (equivalent to a population-average 3 mm Hg increase) is associated with about 21,700 additional events (95% CI 19,120, 24,221) and 346 million year 2000 USD (95% CI 305 year 2000 USD, 387 million) in associated costs. CONCLUSION: Relatively small changes in SBP associated with use of common arthritis medications can have a significant effect on the cardiovascular risk profile. It is important that clinicians who treat patients with OA/RA accurately weigh the potential risks of these medications against their benefits.

Journal ArticleDOI
TL;DR: A meta-analysis of insomnia medication trials for 1966 through 2000 conducted for the purpose of estimating the magnitude of sleep EAP argues for the retention of a placebo control in future insomnia clinical trials.

Journal ArticleDOI
TL;DR: The robustness and power of various versions of parametric analysis of covariance applied to small samples of ordinal scaled data are investigated through computer simulation and the hierarchical approach which first tests for homogeneity of regression slopes and then fits separate slopes if there is significant non-homogeneity produced significance levels that exceeded the nominal levels.
Abstract: In clinical trials comparing two treatments, ordinal scales of three, four or five points are often used to assess severity, both prior to and after treatment. Analysis of covariance is an attractive technique, however, the data clearly violate the normality assumption and in the presence of small samples, and large sample theory may not apply. The robustness and power of various versions of parametric analysis of covariance applied to small samples of ordinal scaled data are investigated through computer simulation. Subjects are randomized to one of two competing treatments and the pre-treatment, or baseline, assessment is used as the covariate. We compare two parametric analysis of covariance tests that vary according to the treatment of the homogeneity of regressions slopes and the two independent samples t-test on difference scores. Under the null hypothesis of no difference in adjusted treatment means, we estimated actual significance levels by comparing observed test statistics to appropriate critical values from the F- and t-distributions for nominal significance levels of 0.10, 0.05, 0.02 and 0.01. We estimated power by similar comparisons under various alternative hypotheses. The model which assumes homogeneous slopes and the t-test on difference scores were robust in the presence of three, four and five point ordinal scales. The hierarchical approach which first tests for homogeneity of regression slopes and then fits separate slopes if there is significant non-homogeneity produced significance levels that exceeded the nominal levels especially when the sample sizes were small. The model which assumes homogeneous regression slopes produced the highest power among competing tests for all of the configurations investigated. The t-test on difference scores also produced good power in the presence of small samples.