Showing papers by "Ralph B. D'Agostino published in 2002"

Plasma Homocysteine as a Risk Factor for Dementia and Alzheimer's Disease

Abstract: Background In cross-sectional studies, elevated plasma homocysteine levels have been associated with poor cognition and dementia. Studies of newly diagnosed dementia are required in order to establish whether the elevated homocysteine levels precede the onset of dementia or result from dementia-related nutritional and vitamin deficiencies. Methods A total of 1092 subjects without dementia (667 women and 425 men; mean age, 76 years) from the Framingham Study constituted our study sample. We examined the relation of the plasma total homocysteine level measured at base line and that measured eight years earlier to the risk of newly diagnosed dementia on follow-up. We used multivariable proportional-hazards regression to adjust for age, sex, apolipoprotein E genotype, vascular risk factors other than homocysteine, and plasma levels of folate and vitamins B12 and B6. Results Over a median follow-up period of eight years, dementia developed in 111 subjects, including 83 given a diagnosis of Alzheimer's disease....

Overweight and obesity as determinants of cardiovascular risk: the Framingham experience.

Abstract: Background To our knowledge, no single investigation concerning the long-term effects of overweight status on the risk for hypertension, hypercholesterolemia, diabetes mellitus, and cardiovascular sequelae has been reported. Methods Relations between categories of body mass index (BMI), cardiovascular disease risk factors, and vascular disease end points were examined prospectively in Framingham Heart Study participants aged 35 to 75 years, who were followed up to 44 years. The primary outcome was new cardiovascular disease, which included angina pectoris, myocardial infarction, coronary heart disease, or stroke. Analyses compared overweight (BMI [calculated as weight in kilograms divided by the square of height in meters], 25.0-29.9) and obese persons (BMI ≥30) to a referent group of normal-weight persons (BMI, 18.5-24.9). Results The age-adjusted relative risk (RR) for new hypertension was highly associated with overweight status (men: RR, 1.46; women: RR, 1.75). New hypercholesterolemia and diabetes mellitus were less highly associated with excess adiposity. The age-adjusted RR (confidence interval [CI]) for cardiovascular disease was increased among those who were overweight (men: 1.21 [1.05-1.40]; women: 1.20 [1.03-1.41]) and the obese (men: 1.46 [1.20-1.77]; women: 1.64 [1.37-1.98]). High population attributable risks were related to excess weight (BMI ≥25) for the outcomes hypertension (26% men; 28% women), angina pectoris (26% men; 22% women), and coronary heart disease (23% men; 15% women). Conclusions The overweight category is associated with increased relative and population attributable risk for hypertension and cardiovascular sequelae. Interventions to reduce adiposity and avoid excess weight may have large effects on the development of risk factors and cardiovascular disease at an individual and population level.

Lifetime Risk for Developing Congestive Heart Failure The Framingham Heart Study

Abstract: Background— Congestive heart failure (CHF) is an increasing public health problem. Methods and Results— Among Framingham Heart Study subjects who were free of CHF at baseline, we determined the lifetime risk for developing overt CHF at selected index ages. We followed 3757 men and 4472 women from 1971 to 1996 for 124 262 person-years; 583 subjects developed CHF and 2002 died without prior CHF. At age 40 years, the lifetime risk for CHF was 21.0% (95% CI 18.7% to 23.2%) for men and 20.3% (95% CI 18.2% to 22.5%) for women. Remaining lifetime risk did not change with advancing index age because of rapidly increasing CHF incidence rates. At age 80 years, the lifetime risk was 20.2% (95% CI 16.1% to 24.2%) for men and 19.3% (95% CI 16.5% to 22.2%) for women. Lifetime risk for CHF doubled for subjects with blood pressure ≥160/100 versus <140/90 mm Hg. In a secondary analysis, we only considered those who developed CHF without an antecedent myocardial infarction; at age 40 years, the lifetime risk for CHF was 11...

Residual lifetime risk for developing hypertension in middle-aged women and men: The Framingham Heart Study.

Abstract: ContextThe long-term risk for developing hypertension is best described by the lifetime risk statistic. The lifetime risk for hypertension and trends in this risk over time are unknown.ObjectivesTo estimate the residual lifetime risk for hypertension in older US adults and to evaluate temporal trends in this risk.Design, Setting, and ParticipantsCommunity-based prospective cohort study of 1298 participants from the Framingham Heart Study who were aged 55 to 65 years and free of hypertension at baseline (1976-1998).Main Outcome MeasuresResidual lifetime risk (lifetime cumulative incidence not adjusted for competing causes of mortality) for hypertension, defined as blood pressure of 140/90 mm Hg or greater or use of antihypertensive medications.ResultsThe residual lifetime risks for developing hypertension and stage 1 high blood pressure or higher (≥140/90 mm Hg regardless of treatment) were 90% in both 55- and 65-year-old participants. The lifetime probability of receiving antihypertensive medication was 60%. The risk for hypertension remained unchanged for women, but it was approximately 60% higher for men in the contemporary 1976-1998 period compared with an earlier 1952-1975 period. In contrast, the residual lifetime risk for stage 2 high blood pressure or higher (≥160/100 mm Hg regardless of treatment) was considerably lower in both sexes in the recent period (35%-57% in 1952-1975 vs 35%-44% in 1976-1998), likely due to a marked increase in treatment of individuals with substantially elevated blood pressure.ConclusionThe residual lifetime risk for hypertension for middle-aged and elderly individuals is 90%, indicating a huge public health burden. Although the decline in lifetime risk for stage 2 high blood pressure or higher represents a major achievement, efforts should be directed at the primary prevention of hypertension.

Elevated Levels of Acute-Phase Proteins and Plasminogen Activator Inhibitor-1 Predict the Development of Type 2 Diabetes: The Insulin Resistance Atherosclerosis Study

Abstract: Elevated serum levels of acute-phase proteins, indicating chronic subclinical inflammation, have been associated with cardiovascular disease as well as the insulin resistance syndrome. Chronic inflammation may also be a risk factor for developing type 2 diabetes. We studied the concentrations of C-reactive protein (CRP), fibrinogen, and plasminogen activator inhibitor-1 (PAI-1) in 1,047 nondiabetic subjects in relation to incident diabetes within 5 years in the Insulin Resistance Atherosclerosis Study. Subjects with diabetes at follow-up (n = 144) had higher baseline levels of fibrinogen (mean +/- SD; 287.8 +/- 58.8 vs. 275.1 +/- 56.0 mg/dl; P = 0.013) as well as of CRP (median [interquartile range]; 2.40 [1.29, 5.87] vs. 1.67 mg/l [0.75, 3.41]; P = 0.0001) and PAI-1 (24 [15, 37.5] vs. 16 ng/ml [9, 27]; P = 0.0001) than nonconverters. The odds ratio (OR) of converting to diabetes was significantly increased with increasing baseline concentrations of the inflammatory markers. In contrast to PAI-1, the association of CRP and fibrinogen with incident diabetes was significantly attenuated after adjustment for body fat (BMI or waist circumference) or insulin sensitivity (S(I)), as assessed by a frequently sampled intravenous glucose tolerance test. In a logistic regression model that included age, sex, ethnicity, clinical center, smoking, BMI, S(I), physical activity, and family history of diabetes, PAI-1 still remained significantly related to incident type 2 diabetes (OR [95% CI] for 1 SD increase: 1.61 [1.20-2.16]; P = 0.002). Chronic inflammation emerges as a new risk factor for the development of type 2 diabetes; PAI-1 predicts type 2 diabetes independent of insulin resistance and other known risk factors for diabetes.

Non‐inferiority trials: design concepts and issues – the encounters of academic consultants in statistics

Abstract: Placebo-controlled trials are the ideal for evaluating medical treatment efficacy. They allow for control of the placebo effect and are most efficient, requiring the smallest numbers of patients to detect a treatment effect. A placebo control is ethically justified if no standard treatment exists, if the standard treatment has not been proven efficacious, there are no risks associated with delaying treatment or escape clauses are included in the protocol. Where possible and justified, they should be the first choice for medical treatment evaluation. Given the large number of proven effective treatments, placebo-controlled trials are often unethical. In these situations active-controlled trials are generally appropriate. The non-inferiority trial is appropriate for evaluation of the efficacy of an experimental treatment versus an active control when it is hypothesized that the experimental treatment may not be superior to a proven effective treatment, but is clinically and statistically not inferior in effectiveness. These trials are not easy to design. An active control must be selected. Good historical placebo-controlled trials documenting the efficacy of the active control must exist. From these historical trials statistical analysis must be performed and clinical judgement applied in order to determine the non-inferiority margin M and to assess assay sensitivity. The latter refers to establishing that the active drug would be superior to the placebo in the setting of the present non-inferiority trial (that is, the constancy assumption). Further, a putative placebo analysis of the new treatment versus the placebo using data from the non-inferiority trial and the historical active versus placebo-controlled trials is needed. Useable placebo-controlled historical trials for the active control are often not available, and determination of assay sensitivity and an appropriate M is difficult and debatable. Serious consideration to expansions of and alternatives to non-inferiority trials are needed.

Fasting and postchallenge glycemia and cardiovascular disease risk: the Framingham Offspring Study.

Abstract: OBJECTIVE —To test the hypothesis that fasting hyperglycemia (FHG) and 2-h postchallenge glycemia (2hPG) independently increase the risk for cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS —During 1991–1995, we examined 3,370 subjects from the Framingham Offspring Study who were free from clinical CVD (coronary heart disease, stroke, or intermittent claudication) or medication-treated diabetes, and we followed them for 4 years for incident CVD events. We used proportional-hazards regression to assess the risk associated with FHG (fasting plasma glucose ≥7.0 mmol/l) and 2hPG, independent of the risk predicted by standard CVD risk factors. RESULTS —Mean subject age was 54 years, 54% were women, and previously undiagnosed diabetes was present in 3.2% by FHG and 4.9% (164) by FHG or a 2hPG ≥11.1 mmol/l. Of these 164 subjects, 55 (33.5%) had 2hPG ≥11.1 without FHG, but these 55 subjects represented only 1.7% of the 3,261 subjects without FHG. During 12,242 person-years of follow-up, there were 118 CVD events. In separate sex- and CVD risk-adjusted models, relative risk (RR) for CVD with fasting plasma glucose ≥7.0 mmol/l was 2.8 (95% CI 1.6–5.0); RR for CVD per 2.1 mmol/l increase in 2hPG was 1.2 (1.1–1.3). When modeled together, the RR for FHG decreased to 1.5 (0.7–3.6), whereas the RR for 2hPG remained significant (1.1, 1.02–1.3). The c -statistic for a model including CVD risk factors alone was 0.744; with addition of FHG, it was 0.746, and with FHG and 2hPG, it was 0.752. CONCLUSIONS —Postchallenge hyperglycemia is an independent risk factor for CVD, but the marginal predictive value of 2hPG beyond knowledge of standard CVD risk factors is small.

Association of C-Reactive Protein With Carotid Atherosclerosis in Men and Women: The Framingham Heart Study

Abstract: Objective— The objective of this study was to examine the relationship between C-reactive protein (CRP) and carotid atherosclerosis. Background— Levels of CRP, a nonspecific marker of inflammation, predict risk for cardiovascular events. However, the association between CRP and direct measures of atherosclerosis is not well established. Methods and Results— Subjects (n=3173, 52% women, mean age 55) in the offspring cohort of the Framingham Heart Study received a CRP measurement and then underwent carotid ultrasonography 4 years later. Carotid stenosis (≥25%) was present in 24% of men and 14% of women. Age-adjusted odds ratios for carotid stenosis were 1.62 (95%CI 1.12 to 2.36) for men and 3.90 (CI 2.44 to 6.44) for women in the fourth quartile of CRP compared with those in the lowest quartile. After further adjustment for traditional cardiovascular disease risk factors, the odds ratio remained significant for women (2.97, CI 1.72 to 5.25) but not for men. Similarly, after multivariable adjustment, women in the fourth CRP quartile had a higher mean internal carotid intima-media thickness than those in the lowest CRP quartile ( P ≤0.001). There was no association between common carotid intima-media thickness and CRP. Conclusions— There is a graded association between CRP and carotid atherosclerosis in women but not in men. The significance of this difference between sexes merits further investigation.

Factor Analysis of Metabolic Syndrome Using Directly Measured Insulin Sensitivity The Insulin Resistance Atherosclerosis Study

Abstract: Factor analysis, a multivariate correlation technique, has been used to provide insight into the underlying structure of metabolic syndrome, which is characterized by physiological complexity and strong statistical intercorrelation among its key variables. The majority of previous factor analyses, however, have used only surrogate measures of insulin sensitivity. In addition, few have included members of multiple ethnic groups, and only one has presented results separately for subjects with impaired glucose tolerance. The objective of this study was to investigate, using factor analysis, the clustering of physiologic variables using data from 1,087 nondiabetic participants in the Insulin Resistance Atherosclerosis Study (IRAS). This study includes information on the directly measured insulin sensitivity index (SI) from intravenous glucose tolerance testing among African-American, Hispanic, and non-Hispanic white subjects aged 40–69 years at various stages of glucose tolerance. Principal factor analysis identified two factors that explained 28 and 9% of the variance in the dataset, respectively. These factors were interpreted as 1) a “ metabolic” factor, with positive loadings of BMI, waist, fasting and 2-h glucose, and triglyceride and inverse loadings of log(SI+1) and HDL; and 2) a “blood pressure” factor, with positive loadings of systolic and diastolic blood pressure. The results were unchanged when surrogate measures of insulin resistance were used in place of log(SI+1). In addition, the results were similar within strata of sex, glucose tolerance status, and ethnicity. In conclusion, factor analysis identified two underlying factors among a group of metabolic syndrome variables in this dataset. Analyses using surrogate measures of insulin resistance suggested that these variables provide adequate information to explore the underlying intercorrelational structure of metabolic syndrome. Additional clarification of the physiologic characteristics of metabolic syndrome is required as individuals with this condition are increasingly being considered candidates for behavioral and pharmacologic intervention.

Alcohol consumption and hemostatic factors: analysis of the Framingham Offspring cohort.

Abstract: Background— Moderate alcohol consumers have lower rates of cardiovascular disease than abstainers. One proposed mechanism is a beneficial effect on hemostatic parameters, but previous studies have provided conflicting results. Methods and Results— We measured levels of fibrinogen, plasma viscosity, von Willebrand factor, factor VII, plasminogen activator inhibitor antigen-1, and tissue plasminogen activator antigen in a cross-sectional analysis of 3223 adults free of cardiovascular disease enrolled in the Framingham Offspring Study. We assessed their alcohol consumption with a standardized questionnaire. Light-to-moderate alcohol consumption was associated with lower levels of fibrinogen, plasma viscosity, von Willebrand factor, and factor VII. This association was most pronounced for consumers of 3 to 7 drinks weekly for viscosity and 7 to 21 drinks weekly for the other hemostatic measures. Alcohol intake of 7 to 21 drinks weekly or more was associated with impaired fibrinolytic potential, reflected by h...

Risk of Hospitalized Stroke in Men Enrolled in the Honolulu Heart Program and the Framingham Study A Comparison of Incidence and Risk Factor Effects

Abstract: Background and Purpose— Risk of death due to stroke in Japan is more than double the risk in the United States. It remains unknown why some ethnic groups are more prone to stroke than others. Our purpose was to compare the 20-year incidence of hospitalized stroke between Japanese-American men in the Honolulu Heart Program and white men in the Framingham Study. Methods— This was a 20-year follow-up study beginning around 1965, a population-based study on the island of Oahu, Hawaii, and in Framingham, Mass. Participants were 7589 men in Honolulu and 1216 men in Framingham without prevalent coronary heart disease and stroke. Subjects were 45 to 68 years old when follow-up began. Main outcome measures were incident thromboembolic and hemorrhagic stroke. Results— Framingham men had a 40% excess of thromboembolic stroke compared with Honolulu men after adjustment for age and other risk factors (62/1000 versus 45/1000, respectively, P<0.001), whereas incidence of hemorrhagic stroke was nearly identical (14.8/100...

Central Auditory Dysfunction May Precede the Onset of Clinical Dementia in People with Probable Alzheimer's Disease

Abstract: OBJECTIVES: To document the prognostic significance of a central auditory speech-processing deficit for the subsequent onset of probable Alzheimer's disease. DESIGN: Prospective cohort study. SETTING: Framingham Heart Study. PARTICIPANTS: Seven hundred forty dementia-free volunteers from the Framingham Heart Study cohort with symmetric hearing thresholds at biennial examination 15 (1983–1985). MEASUREMENTS: The diagnosis of probable Alzheimer's disease was made prospectively using the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease Related Disorder Association criteria. A central auditory speech-processing deficit was defined as a score of 50% of less correct on the Synthetic Sentence Identification with Ipsilateral Competing Message test in at least one ear with normal word recognition ability in both ears. Cox proportional hazards regression assessed the relationship between a central auditory speech-processing deficit and the age at diagnosis of probable Alzheimer's disease. RESULTS: Forty subjects (5.4%) received a diagnosis of probable Alzheimer's disease during an average of 8.4 years (range 3–12) of follow-up; seven (17.5%) of these had a central auditory speech-processing deficit. The presence of a central auditory speech-processing deficit had an age-adjusted risk ratio for probable Alzheimer's disease of 10.8 (95% CI = 4.6–25.2), and the estimated risk ratio adjusted for age, gender, education level, apolipoprotein allele E4 presence, and hearing level was 23.3 (95% CI = 6.6–82.7). A central auditory speech-processing deficit had a positive predictive value for subsequent probable Alzheimer's disease of 47% but the sensitivity was only 17.5%. CONCLUSION: Central auditory speech-processing deficits may be an early manifestation of probable Alzheimer's disease and may precede the onset of dementia diagnosis by many years. J Am Geriatr Soc 50:482–488, 2002.

C-Reactive Protein Is Associated With Subclinical Epicardial Coronary Calcification in Men and Women The Framingham Heart Study

Abstract: Background— High C-reactive protein (CRP) levels are associated with an increased risk of cardiovascular events, even in apparently healthy individuals. It has not been established whether elevated CRP reflects an increased burden of subclinical coronary atherosclerosis. Methods and Results— We studied a stratified random sample of 321 men and women (mean age 60 years) from the Framingham Heart Study who were free of clinically apparent cardiovascular disease. Subjects underwent electron-beam computed tomography to assess the number of coronary calcifications and the coronary artery calcification (CAC) Agatston score. Spearman correlation coefficients between CRP and CAC score were calculated and adjusted for age, age plus individual risk factors, and age plus the Framingham coronary heart disease risk score. For both sexes, CRP was significantly correlated with the Agatston score (age-adjusted Spearman correlation: 0.25 for men, 0.26 for women; both P<0.01). After adjustment for age and Framingham risk s...

Alcohol Consumption and Risk of Ischemic Stroke: The Framingham Study

Abstract: Background and Purpose— Stroke is a major cause of death in the United States. The association between alcohol consumption and ischemic stroke (IS) remains controversial. Methods— We used data collected on participants in the Framingham Study to assess the association between total alcohol intake and type of alcoholic beverage and development of IS, overall and according to age. Results— A total of 196 men and 245 women developed IS during three 10-year follow-up periods. In the categories of never drinkers, drinkers of 0.1 to 11, 12 to 23, and ≥24 g/d of ethanol (a “typical drink” is ≈12 g of ethanol), and former drinkers of 0.1 to 11 and ≥12 g/d, crude incidence rates of IS were 6.5, 5.9, 4.9, 5.0, 6.7, and 17.8 cases per 1000 person-years, respectively, for men and 5.9, 4.1, 4.1, 4.3, 8.3, and 7.1, respectively, for women. Overall, compared with never drinkers in a multivariate Cox regression, current alcohol consumption was not related significantly to IS in either sex. Former drinking of ≥12 g/d of a...

Dietary patterns predict the development of overweight in women: The Framingham Nutrition Studies

Abstract: Objective To investigate relationships between dietary patterns and the development of overweight. Design Longitudinal analyses during 12 years of follow-up involved the identification of dietary patterns at baseline using cluster analysis applied to a 145-item semiquantitative food frequency questionnaire. Subjects/setting 737 non-overweight women in the Framingham Offspring/Spouse cohort (mean age, 45 years). Main Outcome Measure Development of overweight (BMI≥25) at follow-up. Statistical Analyses Relative risks were calculated using Proc Genmod and multivariate models comprehensively considered potential confounders. Results Five dietary patterns were identified among the cohort at baseline: Heart Healthy, Light Eating, Wine and Moderate Eating, High Fat, and Empty Calorie. Over 12 years, the crude risk of becoming overweight was 29% overall, ranging from 22% of women in the Wine and Moderate Eating cluster to 41% of women in the Empty Calorie cluster. Compared with women who ate a lower-fat, nutritionally varied Heart Healthy diet, women who ate an Empty Calorie diet that was rich in sweets and fats with fewer servings of nutrient-dense fruits, vegetables, and lean food choices were at higher risk for developing overweight [RR 1.4, 95% CI (0.9, 2.2)] after adjusting for age, smoking status, physical activity, menopausal status, energy intake, intentional dieting, and usual weight pattern. Women who ate an Empty Calorie dietary pattern were also younger and were more likely to smoke. Conclusions Behavioral interventions for weight management and obesity prevention may be enhanced by creatively targeting differences in eating patterns, dietary quality, and other lifestyle behaviors of distinct subgroups of the population. J Am Diet Assoc. 2002;102:1240-1246.

Genomewide Linkage Analysis of Body Mass Index across 28 Years of the Framingham Heart Study

Abstract: We performed a genomewide linkage analysis of six separate measurements of body mass index (BMI) taken over a span of 28 years, from 1971 to 1998, in the Framingham Heart Study. Variance-components linkage analysis was performed on 330 families, using 401 polymorphic markers. The number of individuals with data at each exam ranged from 1,930, in 1971, to 1,401, in 1998. Sex, age, and age squared were included as covariates in the model. There was substantial evidence for linkage on chromosome 6q23-25, in the area of D6S1009, GATA184A08, D6S2436, and D6S305. The six measurements had maximum LOD scores of 4.64, 2.29, 2.41, 1.40, 0.99, and 3.08, respectively, all in the chromosome 6q23-25 region. There was also evidence for linkage of multiple measures on chromosome 11q14 in the area of D11S1998, D11S4464, and D11S912. The six measurements had maximum LOD scores of 0.61, 3.27, 1.30, 0.68, 1.30, and 2.29, respectively, all in the chromosome 11q14 region. Both of these regions have been reported in previous studies. Evidence in the same regions from multiple measurements does not constitute replication; however, it does indicate that linkage studies of BMI are robust with respect to measurement error. It is unclear whether the variation in LOD scores in these regions is due to age effects, varying sample size, or other confounding factors.

Risk stratification of obesity as a coronary risk factor.

Abstract: We examined the extent of coronary heart disease (CHD) risk factor clustering in overweight persons with a body mass index (BMI) of 25 to 29 and an obesity BMI of ≥30 and the influence of this on the hazard of myocardial infarction and coronary mortality. A total of 1,309 men and 739 women aged 30 to 74 years, initially free of cardiovascular disease, comprised the overweight subject group, and 375 men and 356 women comprised the obese subject group at risk. The sample was derived from the original Framingham Study cohort at the 11th biennial examination, and their offspring at initial examination. During 16 years of follow-up of overweight subjects, 188 men and 44 women had CHD events, indicating an age-adjusted rate that was not much different from the slim subjects. In the obese subject group, 72 men and 37 women developed CHD, corresponding to age-adjusted risk ratios 1.48 times that of lean men, and 2.09 times that of lean women. Risk factors were categorized as systolic blood pressure ≥140 mm Hg, total cholesterol ≥240 mg/dl, high-density lipoprotein (HDL) cholesterol 80 beats/min, history of smoking, history of type 2 diabetes, and electrocardiographic left ventricular hypertrophy. Being overweight occurred in isolation of CHD risk factors in 22% of men and in 16.4% of women. Being obese occurred in isolation in only 12.8% of men and 9% of women. Clusters of ≥2 risk factors occurred in 56% of obese men and in 62.4% of obese women, a frequency substantially exceeding that in slim subjects. Compared with obese men without risk factors, those with ≥3 factors had a 2.07 age-adjusted relative risk of developing CHD, and obese women had a 10.9 relative risk (p <0.05). Being overweight and obese promotes clusters of CHD risk factors that greatly influence their impact. Global risk assessment can identify high-risk overweight candidates for CHD who most urgently need correction of associated risk factors, as well as sustained weight reduction.

Coronary artery calcification in type 2 diabetes and insulin resistance: the framingham offspring study.

Abstract: OBJECTIVE —To assess risk for subclinical coronary atherosclerosis using electron beam- computed tomography in subjects with or without insulin resistance and with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT/impaired fasting glucose [IFG]) or type 2 diabetes. RESEARCH DESIGN AND METHODS —We categorized glucose tolerance by type 2 diabetes therapy (diagnosed diabetes) or with an oral glucose tolerance test (OGTT) (IFG, IGT, and OGTT-detected diabetes) and insulin resistance as an elevated fasting insulin level, in subjects attending the fifth examination (1991–1995) of the Framingham Offspring Study. A representative subset of subjects without clinical atherosclerosis was selected for electron beam computed tomography in 1998–1999 from age- and sex-stratified quintiles of the Framingham risk score. The presence of subclinical atherosclerosis was defined as the upper quartile of the Agatston score distribution (score > 170). We assessed risk for subclinical atherosclerosis using multivariable logistic regression. RESULTS —Of 325 subjects aged 31–73 years, 51% were men, 11.2% had IFG/IGT, and 9.9% had diabetes (2.8% with diagnosed diabetes); 14.5% had insulin resistance. Compared with NGT, subjects with IFG/IGT tended to be more likely (adjusted odds ratio 1.5, 95% CI 0.7–3.4) and those with diabetes were significantly more likely (2.7, 1.2–6.1) to have subclinical coronary atherosclerosis. In age- and sex-adjusted models, subjects with insulin resistance were more likely to have subclinical atherosclerosis than those without insulin resistance (2.1, 1.01–4.2), but further risk factor adjustment weakened this association. In adjusted models including insulin resistance, diabetes remained associated with risk for subclinical atherosclerosis (2.8, 1.2–6.7); diagnosed diabetes (6.0, 1.4–25.2) had a larger effect than OGTT-detected diabetes (2.1, 0.8–5.5). CONCLUSIONS —Individuals with diabetes have an elevated burden of subclinical coronary atherosclerosis. Aggressive clinical atherosclerosis prevention is warranted, especially in diagnosed diabetes.

Antecedent blood pressure and risk of cardiovascular disease: the Framingham Heart Study .

Abstract: Background— Casual blood pressure (BP) is a powerful predictor of risk of cardiovascular disease (CVD), but a single BP determination may not accurately reflect the residual impact of antecedent BP levels on vascular risk. It is unclear whether time-averaged past BP measures incrementally improve CVD risk assessment. Methods and Results— We used sex- and age-specific multivariable Cox regression to evaluate the association of current BP (at baseline), recent antecedent BP (average of readings for all available examinations 1 to 10 years before baseline), and remote antecedent BP (average for all available examinations 11 to 20 years before baseline) with the 10-year risk of CVD in 2313 Framingham Study subjects (910 men, 1403 women) free of CVD at baseline. During follow-up, 899 incident initial CVD events were observed (479 in women). In multivariable models incorporating established CVD risk factors, recent and remote antecedent BP predicted CVD risk incrementally over current BP. This effect was consis...

The internal validity of a dietary pattern analysis. The Framingham Nutrition Studies

Abstract: Study objectives: To examine the internal validity of a dietary pattern analysis and its ability to discriminate clusters of people with similar dietary patterns using independently assessed nutrient intakes and heart disease risk factors. Design and participants: Population based study characterising dietary patterns using cluster analysis applied to data from the semiquantitative Framingham food frequency questionnaire collected from 1942 women ages 18–76 years, between 1984–88. Setting: Framingham, Massachusetts. Main results: Of 1942 women included in the cluster analysis, 1828 (94%) were assigned to one of the five dietary pattern clusters: Heart Healthy, Light Eating, Wine and Moderate Eating, High Fat, and Empty Calorie. Dietary patterns differed substantially in terms of individual nutrient intakes, overall dietary risk, heart disease risk factors, and predicted heart disease risk. Women in the Heart Healthy cluster had the most nutrient dense eating pattern, the lowest level of dietary risk, more favourable risk factor levels, and the lowest probability of developing heart disease. Those in the Empty Calorie cluster had a less nutritious dietary pattern, the greatest level of dietary risk, a heavier burden of heart disease risk factors, and a relatively higher probability of developing heart disease. Cluster reproducibility using discriminant analysis showed that 80% of the sample was correctly classified. The cluster technique was highly sensitive and specific (75% to 100%). Conclusions: These findings support the internal validity of a dietary pattern analysis for characterising dietary exposures in epidemiological research. The authors encourage other researchers to explore this technique when investigating relations between nutrition, health, and disease.

Longitudinal Association of Glycemia and Microalbuminuria: The Framingham Offspring Study

Abstract: OBJECTIVE—To assess current and long-term associations of glycemia with microalbuminuria, a marker of generalized endothelial injury. RESEARCH DESIGN AND METHODS—We measured clinical characteristics, fasting plasma glucose, and the urinary albumin-to-creatinine ratio (UACR) in 1,311 men and 1,518 women attending the sixth examination cycle (1995–1998) of the Framingham Offspring Study. After excluding participants with diabetes or cardiovascular disease (CVD) at the baseline examination (1971–1974), we used fasting glucose measured at baseline, examination 6, and at least two additional examinations from 1974 to 1995 in regression models to predict risk for microalbuminuria (UACR ≥30 mg/g) associated with baseline, current, and 24-year time-integrated glycemia. RESULTS—Microalbuminuria was present in 9.5% of men and 13.4% of women. Among men, age-adjusted odds ratios (95% CI) for microalbuminuria associated with each 0.28 mmol/l (5 mg/dl) increase in baseline, current, and time-integrated glucose levels were 1.12 (1.00–1.16), 1.08 (1.05–1.10), and 1.16 (1.11–1.21), respectively. These effects persisted after adjustment for systolic blood pressure and other confounders. Higher glucose levels also predicted incident diabetes and CVD. Mean time-integrated glucose levels were highest among men who developed both CVD and microalbuminuria (SE 6.82 ± 0.16 mmol/l), intermediate among men with either condition (6.03 ± 0.65 mmol/l), and lowest among men with neither condition (5.49 ± 0.02 mmol/l; P CONCLUSIONS—Long-term hyperglycemia and subdiabetic glycemia increase risk for microalbuminuria. Microalbuminuria, type 2 diabetes, and CVD seem to arise together over the course of decades, consistent with the hypothesis that they share a common antecedent.

C-reactive protein is more strongly related to post-glucose load glucose than to fasting glucose in non-diabetic subjects; the Insulin Resistance Atherosclerosis Study.

Abstract: Aims It has been suggested that cardiovascular disease may be more strongly related to post-challenge glycaemia than to fasting glucose concentrations. We hypothesized that subclinical inflammation, as indicated by elevated serum levels of C-reactive protein (CRP), may partially explain the association of cardiovascular disease with post-challenge glycaemia. Methods We studied the relationship of CRP (measured with a highly sensitive immunoassay) with fasting glucose and 2-h glucose concentrations during an oral glucose tolerance test in non-diabetic subjects from the Insulin Resistance Atherosclerosis Study. Results Spearman correlation analyses and multiple linear regression analyses showed a significant association of both fasting glucose and 2-h glucose concentrations with CRP levels, after adjusting for demographic covariates (age, sex, ethnicity, clinical centre; Spearman correlation coefficients: r = 0.18 for fasting glucose, r = 0.27 for 2-h glucose, both P < 0.0001). However, after additional adjustment for body mass index and waist–hip ratio only 2-h glucose (and not fasting glucose) was significantly related to CRP (r = 0.03 for fasting glucose, P = NS; r = 0.14 for 2-h glucose, P < 0.0001). Adding insulin sensitivity to the multivariate models further weakened the relationship of CRP to 2-h glucose (r = 0.07, P < 0.05). CRP mean values increased by 2-h glucose category (normal vs. impaired glucose tolerance vs. isolated post-challenge hyperglycaemia). Conclusions Chronic, subclinical inflammation, as indicated by elevated circulating CRP levels, is more strongly associated with post-challenge glycaemia than with fasting glucose levels in non-diabetic subjects. This association is partially independent of body fat and insulin resistance. Diabet. Med. 19, 939–943 (2002)

Increased proinsulin levels and decreased acute insulin response independently predict the incidence of type 2 diabetes in the insulin resistance atherosclerosis study.

Abstract: Previous studies have indicated that β-cell dysfunction predicts the development of diabetes, although it is unknown whether the use of combinations of insulin secretory measures further improves prediction. The Insulin Resistance Atherosclerosis Study is a prospective, multicenter, epidemiological study of the relationship between insulin sensitivity and the risk of diabetes and cardiovascular disease. At baseline, fasting concentrations of insulin, intact proinsulin (PI), and split PI were measured, and acute insulin response (AIR) was determined during a frequently sampled intravenous glucose tolerance test (FSIGTT). Subjects who were nondiabetic at baseline ( n = 903) were reexamined after 5 years of follow-up; 148 had developed diabetes. In separate logistic regression models adjusted for age, sex, clinic, and ethnicity, 1 SD differences in measures of β-cell dysfunction were associated with diabetes incidence (AIR: odds ratio [OR] 0.37, 95% CI 0.27–0.52; intact PI: OR 1.90, 95% CI 1.57–2.30; split PI: OR 1.94, 95% CI 1.63–2.31). After additional adjustment for BMI, impaired glucose tolerance, and insulin sensitivity, these measures continued to be significantly associated with risk of diabetes (all P < 0.0001). Furthermore, in models that included both PI and AIR, each was an independent predictor, and individuals who had combined low AIR and high PI experienced the highest diabetes risk. In conclusion, both low AIR and high PI independently predicted diabetes in a well-characterized multiethnic population. Although fasting PI is simpler to assess, determining AIR from an FSIGTT may further improve prediction. If pharmacological agents to prevent diabetes are proved to be efficacious in ongoing clinical trials, then it may be beneficial to perform FSIGTTs to identify better (for intensive intervention) prediabetic subjects who would ultimately require lifelong pharmacological therapy.

Association between increased homocysteine levels and impaired fibrinolytic potential: potential mechanism for cardiovascular risk.

Abstract: Background: Elevated homocysteine levels increase cardiovascular risk although the mechanism is not well understood. Since thrombosis plays an important role in plaque development and acute coronary syn-dromes, hyperhomocysteinemia may increase risk by increasing the thrombotic potential. Methods and Results: Hemostatic risk factors were measured in 3216 individuals (1451 men and 1765 women) free of cardiovascular disease who participated in cycle 5 of the Framingham Offspring Study. An increase in homocysteine level was associated with a rise in plasminogen activator inhibitor (PAI-1), tissue plasminogen activator (TPA) antigen, von Willebrand factor and fibrinogen level. After regression analyses adjusting for covariates, there remained significant associations between homocysteine and PAI-1 and TPA antigen. Conclusion: Increasing homocysteine levels are associated with impaired fibrinolytic potential, as indicated by increased PAI-1 and TPA antigen levels. These data suggest that folic acid and other homocysteine lowering therapies may decrease cardiac events through a reduction in thrombotic tendency.

Alcohol consumption and risk of lung cancer: the Framingham Study.

Abstract: BACKGROUND Reports on the association between alcohol consumption and the risk of lung cancer have been inconsistent. The purpose of this study was to assess this association in a cohort study. METHODS This study included 4265 participants in the original population-based Framingham Study cohort and 4973 subjects in the offspring cohort. Alcohol consumption data were collected periodically for both cohorts. We used the risk sets method to match control subjects to each case patient based on age, sex, smoking variables, and year of birth. We used a conditional logistic regression model to estimate the relative risk of lung cancer according to alcohol consumption. RESULTS Alcohol consumption was generally light to moderate (i.e., <12 g/day) in both cohorts. During mean follow-ups of 32.8 years in the original and 16.2 years in the offspring cohorts, 269 cases of lung cancer occurred. In categories of total alcohol consumption of 0, 0.1-12, 12.1-24, and greater than 24 g/day, the crude incidence rates of lung cancer were 7.4, 13.6, 16.4, and 25.2 cases per 10 000 person-years, respectively, in the original cohort and 6.6, 4.3, 7.9, and 12.3 cases per 10 000 person-years, respectively, in the offspring cohort. However, after adjustment for age, sex, pack-years of smoking, smoking status, and year of birth in a multivariable conditional logistic regression model, relative risks for lung cancer from the lowest to the highest category of alcohol consumption were 1.0 (referent), 1.0 (95% confidence interval [CI] = 0.5 to 2.1), 1.0 (95% CI = 0.5 to 2.3), and 1.1 (95% CI = 0.5 to 2.3), respectively, in the original cohort and 1.0, 1.4 (95% CI = 0.5 to 3.6), 1.1 (95% CI = 0.3 to 3.6), and 2.0 (95% CI = 0.7 to 5.7), respectively, in the offspring cohort. CONCLUSION Alcohol consumption among subjects in the Framingham Study, most of whom were light to moderate drinkers, was not statistically significantly associated with the risk of lung cancer.

Discrimination Index, the Area Under the ROC Curve

Abstract: The accuracy of fit of a mathematical predictive model is the degree to which the predicted values coincide with the observed outcome. When the outcome variable is dichotomous and predictions are stated as probabilities that an event will occur, models can be checked for good discrimination and calibration. In case of the multiple logistic regression model for binary outcomes (event, non-event), the area under the ROC (Receiver Operating Characteristic) curve is the most used measure of model discrimination. The area under the ROC curve is identical to the Mann-Whitney statistic. We consider shift models for the distributions of predicted probabilities for event and non-event. From the interval estimates of the shift parameter, we calculate the confidence intervals for the area under the ROC curve. Also, we present the development of a general description of an overall discrimination index C (overall C) which we can extend to a survival time model such as the the Cox regression model. The general theory of rank correlation is applied in developing the overall C. The overall C is a linear combination of three independent components: event vs. non-event, event vs. event and event vs. censored. By showing that these three components are asymptotically normally distributed, the overall C is shown to be asymptotically normally distributed. The expected value and the variance of the overall C are presented.

Clinical and microbial evaluation of a histatin‐containing mouthrinse in humans with experimental gingivitis: a phase‐2 multi‐center study

Abstract: But: Le P-113, un peptide contenant de l'histatine a ete evalue dans un bain de bouche pour sa securite et son efficacite dans une etude multicentrique phase 2. Methode. 294 sujets sains ont arrete toute hygiene buccale et se sont rince avec soit 15 ml de P-113 0.01%, 15 ml de P-113 0.03% ou 15 ml d'une solution placebo 2× par jour durant une periode de 4 semaines. Pendant ce temps, les effets anti-plaque et anti-gingivite, la securite ont ete evalues. Resultats: Il y avait une reduction significative entre l'examen de depart et le jour 22 dans le saignement au sondage dans le groupe P-113 0.01% (p=0.049). Aucune tendance significative dans la reduction des autres parametres n'a ete observee dans cette population (p≥0.159). Un sous-groupe de sujets qui developpaient des niveaux significatifs de maladie durant ces 4 semaines a ete identifie sur base de leur indice gingival initial ≥0.75. Des decouvertes significatives ont ete observees pour le saignement au sondage, l'indice gingival et l'indice de plaque dentaire dans cette population (p<0.05). Il n'y a eu aucun signe negatif du au traitement ni aucune variation negative dans la flore sus-gingivale durant l'etude. Des quantites significatives du peptide ont ete retenues dans la cavite buccale apres rincage. Conclusion: Ces donnes suggerent que le rincage au P-113 est sur et reduit le developement du saignement gingival, la gingivite et la plaque dentaire dans le modele de la gingivite experimentale humaine.