Showing papers by "Ralph B. D'Agostino published in 2001"

Validation of the Framingham coronary heart disease prediction scores: results of a multiple ethnic groups investigation.

Abstract: Context The Framingham Heart Study produced sex-specific coronary heart disease (CHD) prediction functions for assessing risk of developing incident CHD in a white middle-class population. Concern exists regarding whether these functions can be generalized to other populations. Objective To test the validity and transportability of the Framingham CHD prediction functions per a National Heart, Lung, and Blood Institute workshop organized for this purpose. Design, Setting, and Subjects Sex-specific CHD functions were derived from Framingham data for prediction of coronary death and myocardial infarction. These functions were applied to 6 prospectively studied, ethnically diverse cohorts (n = 23 424), including whites, blacks, Native Americans, Japanese American men, and Hispanic men: the Atherosclerosis Risk in Communities Study (1987-1988), Physicians' Health Study (1982), Honolulu Heart Program (1980-1982), Puerto Rico Heart Health Program (1965-1968), Strong Heart Study (1989-1991), and Cardiovascular Health Study (1989-1990). Main Outcome Measures The performance, or ability to accurately predict CHD risk, of the Framingham functions compared with the performance of risk functions developed specifically from the individual cohorts' data. Comparisons included evaluation of the equality of relative risks for standard CHD risk factors, discrimination, and calibration. Results For white men and women and for black men and women the Framingham functions performed reasonably well for prediction of CHD events within 5 years of follow-up. Among Japanese American and Hispanic men and Native American women, the Framingham functions systematically overestimated the risk of 5-year CHD events. After recalibration, taking into account different prevalences of risk factors and underlying rates of developing CHD, the Framingham functions worked well in these populations. Conclusions The sex-specific Framingham CHD prediction functions perform well among whites and blacks in different settings and can be applied to other ethnic groups after recalibration for differing prevalences of risk factors and underlying rates of CHD events.

Plasma Concentration of C-Reactive Protein and Risk of Ischemic Stroke and Transient Ischemic Attack: The Framingham Study

Abstract: Background— The role of C-reactive protein (CRP) as a novel plasma marker of atherothrombotic disease is currently under investigation. Previous studies have mostly related CRP to coronary heart disease, were often restricted to a case-control design, and failed to include pertinent risk factors to evaluate the joint and net effect of CRP on the outcome. We related plasma CRP levels to incidence of first ischemic stroke or transient ischemic attack (TIA) in the Framingham Study original cohort. Methods— There were 591 men and 871 women free of stroke/TIA during their 1980 to 1982 clinic examinations, when their mean age was 69.7 years. CRP levels were measured by using an enzyme immunoassay on previously frozen serum samples. Analyses were based on sex-specific CRP quartiles. Risk ratios (RRs) were derived, and series of trend analyses were performed. Results— During 12 to 14 years of follow-up, 196 ischemic strokes and TIAs occurred. Independent of age, men in the highest CRP quartile had 2 times the ris...

The relation of body fat mass and distribution to markers of chronic inflammation.

Abstract: OBJECTIVE: To study the relation of fibrinogen and C-reactive protein (CRP) to various measures of body fat and body fat distribution and to investigate whether these relations were explained by differences in insulin sensitivity. DESIGN AND SUBJECTS: Cross-sectional analysis of the IRAS (Insulin Resistance Atherosclerosis Study), a large (n=1559) tri-ethnic population (non-Hispanic whites, African-Americans and Mexican-Americans) across different states of glucose tolerance. MEASUREMENTS: Glucose tolerance (oral glucose tolerance test), insulin sensitivity (frequently sampled intravenous glucose tolerance test and minimal model analysis), assessment of body fat mass and distribution (weight, girths, bioelectrical impedance), subclinical atherosclerosis (B-mode ultrasonography of carotid artery intima-media thickness, IMT), CRP (highly sensitive immunoassay), fibrinogen (standard assay). RESULTS: Both CRP and fibrinogen were related to all measures of body fat. Strong correlations (correlation coefficient r≥0.35) were found between CRP and body mass index (BMI), waist circumference and adipose body mass, respectively. The associations were consistent in non-diabetic and type-2 diabetic subjects, were generally stronger in women, and were only moderately attenuated by the prevailing insulin sensitivity (SI). In a multivariate linear regression model waist circumference explained 14.5% of the variability of circulating CRP levels (P=0.0001), BMI 0.4% (P=0.0067), and SI 1.7% (P=0.0001). Common carotid artery IMT was related to CRP and fibrinogen in men, but not in women, and was attenuated after adjusting for BMI or waist. CONCLUSION: Our findings show that measures of body fat are strongly associated with circulating levels of CRP and fibrinogen. These associations were not explained by lower SI in obese subjects. Chronic, subclinical inflammation may be one pathophysiological mechanism explaining the increased risk of atherosclerotic disease associated with adiposity.

Metabolic Abnormalities and Cardiovascular Disease Risk Factors in Adults with Human Immunodeficiency Virus Infection and Lipodystrophy

Abstract: We evaluated metabolic and clinical features of 71 HIV-infected patients with lipodystrophy by comparing them with 213 healthy control subjects, matched for age and body mass index, from the Framingham Offspring Study. Thirty HIV-infected patients without fat redistribution were compared separately with 90 matched control subjects from the Framingham Offspring Study. Fasting glucose, insulin, and lipid levels; glucose and insulin response to standard oral glucose challenge; and anthropometric measurements were determined. HIV-infected patients with lipodystrophy demonstrated significantly increased waist-to-hip ratios, fasting insulin levels, and diastolic blood pressure compared with controls. Patients with lipodystrophy were more likely to have impaired glucose tolerance, diabetes, hypertriglyceridemia, and reduced levels of high-density lipoprotein (HDL) cholesterol than were controls. With the exception of HDL cholesterol level, these risk factors for cardiovascular disease (CVD) were markedly attenuated in patients without lipodystrophy and were not significantly different in comparison with controls. These data demonstrate a metabolic syndrome characterized by profound insulin resistance and hyperlipidemia. CVD risk factors are markedly elevated in HIV-infected patients with fat redistribution.

Fasting Plasma Homocysteine Levels in the Insulin Resistance Syndrome: The Framingham Offspring Study

Abstract: OBJECTIVE —Insulin resistance, associated metabolic abnormalities, and elevated homocysteine levels are risk factors for cardiovascular disease (CVD). We examined relationships between homocysteine levels and features of insulin resistance syndrome (IRS). RESEARCH DESIGN AND METHODS —We measured clinical characteristics, plasma levels of fasting homocysteine, folate, B vitamins, creatinine, and fasting and 2-h insulin and glucose levels after a 75-g oral glucose tolerance test in 2,214 subjects without CVD at the fifth examination (1991–1995) of the Framingham Offspring Study. After excluding 203 subjects with diabetes, the remaining 2,011 subjects were categorized as having none, one, two, or all three of the phenotypes of IRS: impaired glucose tolerance, hypertension, and/or a central metabolic syndrome (two or more traits: obesity, dyslipidemia, or hyperinsulinemia). In addition, in 1,592 subjects attending the sixth examination (1995–1998), we measured the urine albumin/creatinine ratio (UACR). Age-, sex-, creatinine-, vitamin-, and UACR-adjusted mean homocysteine levels or proportions with homocysteine >14 μmol/l in each phenotypic category and differences between categories were assessed with regression models. RESULTS —The mean age of the subjects was 54 years (range 28–82); 55% were women, 12.3% had hyperinsulinemia, and 15.9% had two or more of the IRS phenotypes. Adjusted mean homocysteine levels were higher comparing those with hyperinsulinemia (9.8 μmol/l) and those without (9.4 μmol/l, P = 0.04) and were higher among subjects with two or more IRS phenotypes (9.9 μmol/l) compared with those with 1 or no phenotype (9.3 μmol/l, P = 0.003). Mean UACR levels were also higher among subjects with two or more IRS phenotypes (7.2 mg/g) compared with those with 1 or no phenotype (5.5 mg/g, P = 0.007). CONCLUSIONS —Hyperhomocysteinemia and abnormal urinary albumin excretion are both associated with hyperinsulinemia and may partially account for increased risk of CVD associated with insulin resistance. Because hyperhomocysteinemia and microalbuminuria also reflect endothelial injury, these observations also support the hypothesis that endothelial dysfunction is associated with expression of the IRS.

Serial positron emission tomography scans following radiation therapy of patients with head and neck cancer.

Abstract: Background A single institution study was undertaken to evaluate the role of positron emission tomography (PET) scans with fluorodeoxyglucose (FDG) prior to radiation and following radiation. Methods Forty-five patients with head and neck cancers were evaluated with FDG-PET scans as well as either CT or MRI prior to treatment with definitive radiation (RT). These same scans were obtained following completion of RT at 1 month (36 patients), 4 months (28 patients), 12 months (19 patients), and 24 months (15 patients). Standard uptake values (SUV) normalized for blood glucose and lean body mass were calculated on the initial and 1-month post-treatment PET scans. Results Fifteen patients are alive without evidence of disease at 24 to 52 months following RT. Initial SUVs were calculated on the primary tumor site and ranged from 2.5 to 28.5. These values did not have any correlation with local control when examined for the entire group, primary site, or T stage. One-month post-RT SUV ranged from 1.8 to 6.24. Of the 36 1-month post-RT PET scans, six were interpreted as positive for residual disease and were confirmed by biopsy. Four of the five scans, which were interpreted as equivocal, were positive on biopsy. Seven of the 25 scans, which were interpreted as negative for tumor, were positive on biopsy. Four-month scans were more accurate for disease with disease noted in 0 of 18 negative scans, 6 of 7 positive scans, and 2 of 3 equivocal scans. Conclusions PET is useful for initial imaging of head and neck cancers. SUV does not appear to be useful for predicting outcome following treatment with RT. One-month post-RT scans were inaccurate for predicting the presence of cancer. Four-month post-RT scans were a better predictor for the presence of cancer. © 2001 John Wiley & Sons, Inc. Head Neck 23: 942–946, 2001.

Cardiovascular Risk Assessment Based on US Cohort Studies Findings From a National Heart, Lung, and Blood Institute Workshop

Abstract: This report was derived from a workshop on cardiovascular risk assessment sponsored by the National Heart, Lung, and Blood Institute, which addressed whether risk equations developed in the Framingham Heart Study (FHS) for predicting new-onset coronary heart disease (CHD) apply to diverse population groups. Preparation for the workshop included a reanalysis and comparison of prospective studies in several different populations in which risk factors were related to cardiovascular outcomes. Some studies included fatal and nonfatal CHD end points, whereas others contained only CHD mortality. Extensive collaboration provided as much uniformity as possible with respect to both risk factors and CHD end points. The FHS has led in defining the quantitative impact of risk factors.1 Many potential risk factors were measured and related to cardiovascular outcomes. Several risk factors proved to be strong, largely independent predictors of cardiovascular disease (CVD). These factors—advancing age, cigarette smoking, blood pressure (particularly systolic), cholesterol in total serum and HDL, and diabetes—served as the basis for the development of risk prediction equations.1 If FHS risk estimates are to be widely used, they must apply widely in the US population. To document their transportability, they must be compared with prospective studies in other populations. Although the FHS is the longest running prospective study, there are other major studies. The cardiovascular end points of these other studies have varied. Some include cardiovascular morbidity and mortality; others have only cardiovascular mortality. Among the end points, CHD is the most extensively reported; for this reason, CHD was the primary focus of the workshop. ### Multivariate Relative Risk Comparisons In preparation for the workshop, multivariate regression coefficients for each risk factor were compared in different populations with those of the FHS. Adjusted relative risk estimates make it possible to determine whether each independent risk factor confers a similar or different relative risk among different …

Increased PAI-1 and tPA Antigen Levels Are Reduced with Metformin Therapy in HIV-Infected Patients with Fat Redistribution and Insulin Resistance

Abstract: Cardiovascular disease (CVD) risk associated with fat redistribution seen among HIV-infected individuals remains unknown, but may be increased due to hyperlipidemia, hyperinsulinemia, increased visceral adiposity, and a prothrombotic state associated with these metabolic abnormalities. In this study we characterized plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (tPA) antigen levels, markers of fibrinolysis and increased CVD risk, in HIV lipodystrophic patients compared to controls. Furthermore, we investigated the effect of treatment with metformin on PAI-1 and tPA antigen levels in patients with HIV-associated fat redistribution. Eighty-six patients (age 43 +/- 1 yr, BMI 26.1 +/- 0.5 kg/m(2)) with HIV and fat redistribution were compared to 258 age- and BMI-matched subjects from the Framingham Offspring study. In addition, 25 HIV-infected patients with fat redistribution and fasting insulin >15 microU/mL [104 pmol/L] or impaired glucose tolerance, but without diabetes mellitus were enrolled in a placebo-controlled treatment study of metformin 500 mg twice daily. PAI-1 and tPA antigen levels were significantly increased in patients with HIV related fat redistribution compared to Framingham control subjects (46.1 +/- 4 vs 18.9 +/- 0.9 microg/L PAI-1, 16.6 +/- 0.8 vs. 8.0 +/- 0.3 microg/L tPA, P = 0.0001). Among patients with HIV infection, a multivariate regression analysis including age, sex, waist-to-hip ratio, BMI, smoking status, protease inhibitor use and insulin area under the curve (AUC), found gender and insulin AUC were significant predictors of tPA antigen. Twelve weeks of metformin treatment resulted in decreased tPA antigen levels (-1.9 +/- 1.4 vs +1.4 +/- 1.0 microg/L in the placebo-treated group P = 0.02). Similarly, metformin resulted in improvement in PAI-1 levels (-8.7 +/- 2.3 vs +1.7 +/- 2.9 microg/L, P = 0.03). Change in insulin AUC correlated significantly with change in tPA antigen (r = 0.43, P = 0.03). PAI-1 and tPA antigen, markers of impaired fibrinolysis and increased CVD risk, are increased in association with hyperinsulinemia in patients with HIV and fat redistribution. Metformin reduces PAI-1 and tPA antigen concentrations in these patients and may ultimately improve associated CVD risk.

Predicting mortality in nursing home residents with lower respiratory tract infection: The Missouri LRI Study.

Abstract: ContextLower respiratory tract infection (LRI) is a leading cause of mortality and hospitalization in nursing home residents. Treatment decisions may be aided by a clinical prediction rule that identifies residents at low and high risk of mortality.ObjectiveTo identify patient characteristics predictive of 30-day mortality in nursing home residents with an LRI.Design, Setting, and PatientsProspective cohort study of 1406 episodes of LRI in 1044 residents of 36 nursing homes in central Missouri and the St Louis, Mo, area between August 15, 1995, and September 30, 1998.Main Outcome MeasureThirty-day all-cause mortality.ResultsThirty-day mortality was 14.7% (n = 207). In a logistic analysis, using generalized estimating equations to adjust for clustering, we developed an 8-variable model to predict 30-day mortality, including serum urea nitrogen, white blood cell count, body mass index, pulse rate, activities of daily living status, absolute lymphocyte count of less than 800/µL (0.8 × 109/L), male sex, and deterioration in mood over 90 days. In validation testing, the model exhibited reasonable discrimination (c = .76) and calibration (nonsignificant Hosmer-Lemeshow goodness-of-fit statistic, P = .54). A point score based on this model's variables fit to the entire data set closely matched observed mortality. Fifty-two percent of residents had low (score of 0-4) or relatively low (score of 5-6) predicted 30-day mortality, with 2.2% and 6.2% actual mortality, respectively.ConclusionsOur model distinguishes nursing home residents at relatively low risk for mortality due to LRI. If independently validated, our findings could help physicians identify nursing home residents in need of different therapeutic approaches for LRI.

Validation of a dietary pattern approach for evaluating nutritional risk: the Framingham Nutrition Studies.

Abstract: Objective To validate the use of cluster analysis for characterizing population dietary patterns. Design Cluster analysis was applied to a food frequency questionnaire to define dietary patterns. Independent estimates of nutrient intake were derived from 3-day food records. Heart disease risk factors were assessed using standardized protocols in a clinic setting. Setting Adult women (n= 1,828) participating in the Framingham Offspring-Spouse study. Statistical analyses Age-adjusted mean nutrient intakes were determined for each cluster. Analysis of covariance was used to evaluate pairwise differences in intake across clusters. Compliance with published recommendations was determined for selected heart disease risk factors. Differences in age-adjusted compliance across clusters were evaluated using logistic regression. Results Cluster analysis identified 5 distinct dietary patterns characterized by unique food behaviors and significantly different nutrient intake profiles. Patterns rich in fruits, vegetables, grains, low-fat dairy, and lean protein foods resulted in higher nutrient density. Patterns rich in fatty foods, added fats, desserts, and sweets were less nutrient-dense. Women who consumed an Empty Calorie pattern were less likely to achieve compliance with clinical risk factor guidelines in contrast to most other groups of women. Conclusions Cluster analysis is a valid tool for evaluating nutrition risk by considering overall patterns and food behaviors. This is important because dietary patterns appear to be linked with other health-related behaviors that confer risk for chronic disease. Therefore, insight into dietary behaviors of distinct clusters within a population can help to design intervention strategies for prevention and management of chronic health conditions including obesity and cardiovascular disease. J Am Diet Assoc. 2001;101:187-194.

Hemostatic state and atrial fibrillation (the Framingham Offspring Study).

Abstract: Atrial fibrillation (AF) is strongly associated with thromboembolic complications, although the mechanism for the increased risk has not been fully explained. To determine whether AF might be associated with a hypercoagulable state, we studied hemostatic factors in subjects with or without AF in the Framingham Heart Study. In 3,577 subjects, we measured fibrinogen, von Willebrand factor antigen, tissue plasminogen activator (tPA) antigen, and plasminogen activator inhibitor-1 antigen. Forty-seven subjects had AF at the index clinic examination and 15 had AF on a prior examination, but not on the current examination. Before matching, the 47 subjects with prevalent AF had higher levels of fibrinogen, von Willebrand factor, and tPA antigen than those without AF, all p ≤0.03. Compared with 167 referent subjects matched for age, sex, and other risk factors, those with AF had higher tPA antigen levels than those without AF, 11.8 ± 4.0 ng/ml versus 10.5 ± 3.9 ng/ml (p = 0.04). However, when further stratified according to their cardiovascular disease status, the differences in hemostatic factors were no longer significant. We conclude that the prothrombotic profile associated with AF was explained by the risk factors of the subjects and the presence of cardiovascular disease. Nonetheless, the hemostatic changes may contribute toward the propensity for thromboembolic complications in AF. Further prospective studies are needed to evaluate whether measurement of these and other hemostatic factors will identify patients with AF who are at increased risk for thromboembolic complications, and who may therefore benefit from more intensive therapy.

Prolonged Antimicrobial Activity of a Catheter Containing Chlorhexidine-Silver Sulfadiazine Extends Protection against Catheter Infections In Vivo

Abstract: The present study evaluated in vitro and in vivo a new chlorhexidine (C)-silver sulfadiazine (S) vascular catheter (the CS2 catheter) characterized by a higher C content and by the extended release of the surface-bound antimicrobials. The CS2 catheter was compared with a first-generation, commercially available CS catheter (the CS1 catheter). The CS2 catheter produced slightly smaller zones of inhibition (mean difference, 0.9 mm [P < 0.001]) at 24 h against Staphylococcus aureus and five other microorganisms by several different methodologies. However, in a rabbit model, both CS catheters were similarly efficacious in preventing a catheter infection when the rabbits were inoculated with 10(4) to 10(7) CFU of S. aureus at the time of catheter insertion. The CS2 catheter retained its antimicrobial activity significantly longer in vitro and in vivo (half-lives exceeded 34 and 7 days, respectively) and was also significantly more efficacious in preventing a catheter infection when 10(6) CFU of S. aureus was inoculated 2 days after catheter implantation (P < 0.001). These results suggest that prolonged anti-infective activity on the external catheter surface provides improved efficacy in the prevention of infection.

Elevated midlife blood pressure increases stroke risk in elderly persons: the Framingham Study.

Abstract: Background Stroke risk predictions are traditionally based on current blood pressure (BP). The potential impact of a subject's past BP experience (antecedent BP) is unknown. We assessed the incremental impact of antecedent BP on the risk of ischemic stroke. Methods A total of 5197 stroke-free subjects (2330 men) in the community-based Framingham Study cohort were enrolled from September 29, 1948, to April 25, 1953, and followed up to December 31, 1998. We determined the 10-year risk of completed initial ischemic stroke for 60-, 70-, and 80-year-old subjects as a function of their current BP (at baseline), recent antecedent BP (average of readings at biennial examinations 1-9 years before baseline), and remote antecedent BP (average at biennial examinations 10-19 years earlier), with adjustment for smoking and diabetes mellitus. Models incorporating antecedent BP were also adjusted for baseline BP. The effect of each BP component (systolic BP, diastolic BP, and pulse pressure) was assessed separately. Results Four hundred ninety-one ischemic strokes (209 in men) were observed in eligible subjects. The antecedent BP influenced the 10-year stroke risk at the age of 60 years (relative risk per SD increment of recent antecedent systolic BP: women, 1.68 [95% confidence interval, 1.25-2.25]; and men, 1.92 [95% confidence interval, 1.39-2.66]) and at the age of 70 years (relative risk per SD increment of recent antecedent systolic BP: women, 1.66 [95% confidence interval, 1.28-2.14]; and men, 1.30 [95% confidence interval, 0.97-1.75]). This effect was evident for recent and remote antecedent BP, consistent in hypertensive and nonhypertensive subjects, and demonstrable for all BP components. Conclusions Antecedent BP contributes to the future risk of ischemic stroke. Optimal prevention of late-life stroke will likely require control of midlife BP.

Postmenopausal estrogen use, type of menopause, and lens opacities: the Framingham studies.

Abstract: Background Previous studies of estrogen replacement therapy and lens opacities have not reported consistent findings. Objective To investigate whether postmenopausal estrogen use is associated with the occurrence of age-related lens opacities (nuclear, cortical, and posterior subcapsular). Methods Surviving members of the original cohort of the Framingham Heart Study who also participated in the Framingham Eye Study (1986-1989) were examined for the absence or presence of lens opacities. Data from the Framingham Heart Study, including information on menopausal status (collected biennially from approximately 1948) and use of estrogen replacement therapy (collected biennially from approximately 1960) were used to examine associations between lens opacities and duration of postmenopausal estrogen use, type of menopause, and age at menopause. Five hundred twenty-nine women, aged 66 to 93 years, were included. Multivariable-adjusted odds ratios of specific types of lens opacities were calculated for (1) duration of estrogen use (never and 1-2, 3-9, and ≥10 years), (2) surgical vs natural menopause, and (3) age at menopause. Results Longer duration of postmenopausal estrogen therapy was inversely associated with the presence of nuclear lens opacities in an adjusted model. Women who had taken estrogen for 10 years or longer had a 60% reduction in risk compared with nonusers (odds ratio, 0.4; 95% confidence interval, 0.2-1.01). Longer duration of estrogen use was associated with fewer posterior subcapsular opacities at a borderline level of significance. No association was noted for cortical opacities. The risk of posterior subcapsular opacities was significantly increased for women who had undergone surgical menopause compared with women with natural menopause (odds ratio, 2.2; 95% confidence interval, 1.1-4.3). No association was noted for lens opacities and age at menopause. Conclusion Data from our study and other studies suggest that a reduction in the risk of lens opacities may be an additional benefit of postmenopausal estrogen use.

Carotid MR angiography: phase II study of safety and efficacy for MS-325.

Abstract: PURPOSE: To evaluate the safety and efficacy of MS-325 in patients suspected of having carotid arterial disease. MATERIALS AND METHODS: Fifty carotid arteries in 26 patients were imaged with three-dimensional spoiled gradient-recalled-echo magnetic resonance (MR) angiography at 5 and 50 minutes after injection of MS-325. MS-325 was administered intravenously as a single dose of 0.01, 0.03, or 0.05 mmol per kilogram of body weight as determined with a dose randomization scheme for four, nine, and 13 patients, respectively. Safety, including clinical laboratory changes and electrocardiographic monitoring, was assessed until approximately 3 days after injection. Conventional contrast agent–enhanced angiography was used as the standard of reference. Independent readers blinded to the dose interpreted the MR angiographic and conventional images. Images were assessed for location and extent of carotid arterial stenosis. RESULTS: There were no severe or serious adverse events. For the determination of clinically...

Introductory Applied Biostatistics

Abstract: 1. INTRODUCTION. 2. MOTIVATION. Introduction. Vocabulary. Population Parameters. Sampling and Sample Statistics. Statistical Inference. 3. SUMMARIZING DATA. Introduction. Background. Descriptive Statistics and Graphical Methods. Key Formulas. Statistical Computing. Problems. 4. PROBABILITY. Introduction. Background. First Principles. Combinations and Permutations. The Binomial Distribution. The Normal Distribution. Key Formulas. Applications Using SAS. Problems. 5. SAMPLING DISTRIBUTIONS. Introduction. Background. The Central Limit Theorem. Key Formulas. Applications Using SAS. Problems. 6. STATISTICAL INFERENCE: PROCEDURES FOR . Introduction. Estimating . Testing Hypotheses Concerning . Key Formulas. Statistical Computing. Problems. 7. STATISTICAL INFERENCE: PROCEDURES FOR ( 1- 2) Introduction. Statistical Inference Concerning ( 1- 2). Power and Samples Size Determination. Key Formulas. Statistical Computing. Problems. 8. CATEGORICAL DATA. Introduction. Statistical Inference Concerning p. Cross-tabulation Tables. Diagnostic Tests: Sensitivity and Specificity. Statistical Inference Concerning (p1-p2). Chi-Square Tests. Precision, Power and Sample Size Determination. Key Formulas. Statistical Computing. Problems. 9. COMPARING RISKS IN TWO POPULATIONS. Introduction. Effect Measures. Confidence Intervals for Effect Measures. The Chi-Square Test of Homogeneity. Fisher"s Exact Test. Cox-Mantel-Haenzel Method. Precision, Power and Sample Size Determination. Key Formulas. Statistical Computing. Problems. 10. ANALYSIS OF VARIANCE. Introduction. Background Logic. Notation and Examples. Fixed vs. Random Effects Models. Evaluating Treatment Effects. Multiple Comparisons. Repeated Measures Analysis of Variance. Key Formulas. Statistical Computing. Problems. 11. CORRELATION AND REGRESSION. Introduction. Correlation Analysis. Simple Linear Regression. Multiple Regression Analysis. Logistic Regression Analysis. Key Formulas. Statistical Computing. Problems. 12. LOGISTIC REGRESSION ANALYSIS. Introduction. The Logistic Model. Statistical Inference for Simple Logistic Regression. Multiple Logistic Regression. ROC Area. Key Formulas. Statistical Computing. Problems. 13. NONPARAMETRIC TESTS. Introduction. The Sign Test (Two Dependent Samples Test). The Wilcoxon Signed-Rank Test (Two Dependent Samples). The Wilcoxon Rank Sum Test (Two Independent Samples). The Kruskal-Wallis Test (k Independent Samples). Spearman Correlation (Correlation between Variables). Key Formulas. Statistical Computing. Problems. 14. INTRODUCTION TO SURVIVAL ANALYSIS. Introduction. Incomplete Follow-Up. Time to Event. Survival Analysis Techniques. Appendix A: Introduction to Statistical Computing Using SAS. Introduction to SAS. The Data Step. Appendix B. Statistical Tables. Statistical Tables. SAS Programs used to generate table entries.

Platelet Glycoprotein IIIa PlA Polymorphism, Fibrinogen, and Platelet Aggregability The Framingham Heart Study

Abstract: Background— Recent data suggest that the PlA2 allele of the platelet glycoprotein IIIa receptor may be a genetic risk factor for cardiovascular disease. We previously reported that the PlA2 allele was associated with increased platelet aggregability, as indicated by lower epinephrine threshold concentrations. Paradoxically, however, it has been reported that PlA2-positive platelets have reduced fibrinogen binding. Because fibrinogen mediates platelet aggregability, we hypothesized that plasma fibrinogen levels may interact with PlA genotype in modulating platelet aggregability. Methods and Results— Glycoprotein IIIa PlA genotype, fibrinogen level, and platelet aggregability were ascertained in 1340 subjects enrolled into the Framingham Offspring Study. Platelet aggregability was evaluated by the Born method. Higher fibrinogen levels were associated with increased epinephrine-induced aggregation (P=0.002) and a trend for ADP-induced aggregation (P=0.07). The fibrinogen effect was genotype specific, however...

Applicability of Cholesterol-Lowering Primary Prevention Trials to a General Population: The Framingham Heart Study

Abstract: Background Four large trials have shown cholesterol-reduction therapy to be effective for primary prevention of coronary heart disease (CHD). Methods To determine the generalizability of these trials to a community-based sample, we compared the total cholesterol and high-density lipoprotein cholesterol (HDL-C) distributions of patients in the 4 trials with those of Framingham Heart Study subjects. Lipid profiles that have not been studied were identified. Twelve-year rates of incident CHD were compared between subjects who met eligibility criteria and those who did not. Results The Framingham sample included 2498 men and 2870 women aged 30 to 74 years. Among Framingham men, 23.4% to 42.0% met eligibility criteria for each of the 4 trials based on their lipid levels; 60.2% met eligibility criteria for at least 1 trial. For the 1 trial that included women, 20.2% of Framingham women met eligibility criteria. In general, subjects with desirable total cholesterol levels and lower HDL-C levels and subjects with average total cholesterol levels and average to higher HDL-C levels have not been included in these trials. Among subjects who developed incident CHD during follow-up, 25.1% of men and 66.2% of women would not have been eligible for any trial. Most ineligible subjects who developed CHD had isolated hypertriglyceridemia (>2.25 mmol/L [>200 mg/dL]). Conclusions In our sample, 40% of men and 80% of women had lipid profiles that have not been studied in large trials to date. We observed a large number of CHD events in "ineligible" subjects in whom hypertriglyceridemia was common. Further studies are needed to define the role of lipid-lowering therapy vs other strategies for primary prevention in the general population.

Insulin secretion, obesity, and potential behavioral influences: results from the Insulin Resistance Atherosclerosis Study (IRAS).

Abstract: Background This work was conducted to evaluate associations of insulin secretion with overall and central obesity, dietary fats, physical activity, and alcohol. Methods A frequently sampled intravenous glucose tolerance test (FSIGT) was used to assess acute insulin response to glucose (AIR) and insulin sensitivity (SI) among adult participants (n=675 with normal, NGT; n=332 with impaired glucose tolerance, IGT) in the Insulin Resistance Atherosclerosis Study (IRAS). Disposition index (DI) was calculated as the sum of the log-transformed AIR and SI to reflect pancreatic compensation for insulin resistance. Obesity was measured as body mass index (kg/m2, BMI) and central fat distribution by waist circumference (cm). Dietary fat intake (total, saturated, polyunsaturated, oleic acid), physical activity, and alcohol intake were assessed by standardized interview. Results In unadjusted analyses, BMI and waist were each positively correlated with AIR among NGTs (r=0.26 and 0.23, respectively; p<0.0001) but correlations were weaker among the IGTs (r=0.10, NS; r=0.13, p<0.05 for BMI and waist, respectively). BMI and waist were inversely correlated with DI among NGTs (r=−0.13 and −0.20, respectively; p<0.0001) and among IGTs (r=−0.20 and −0.19, respectively, p<0.0001). Dietary fat variables were positively related, and alcohol was inversely related, to AIR among NGTs (p<0.01) but not among IGTs. With all factors considered simultaneously in a pooled analysis of IGTs and NGTs, waist, but not BMI, was positively associated with AIR (p<0.001) and inversely associated with DI (p<0.01). None of the behavioral variables were independently related to either outcome. Conclusion Among non-diabetic patients, central obesity appears to be related to higher insulin secretion, but to lower capacity of the pancreas to respond to the ambient insulin resistance. Copyright © 2001 John Wiley & Sons, Ltd.

Clinical and microbial evaluation of a histatin-containing mouthrinse in humans with experimental gingivitis.

Abstract: Objective: P-113, a 12 amino acid histatin-based peptide, was evaluated in a mouthrinse formulation for safety, prevention of the development of experimental gingivitis, and for its effects on periodontal flora. Method: 159 periodontally healthy subjects abstained from oral hygiene procedures and self-administered either 0.005%, 0.01%, 0.05% P-113 or placebo mouthrinse formulations twice daily over a four week treatment period. During this time, the safety, anti-plaque, and anti-gingivitis effects of P-113 were evaluated. Results: There was a significant reduction in plaque (p=0.046) and a reduction in gingivitis (p=0.086) for subjects using 0.01% P-113 mouthrinse. Significantly more subjects in the 0.01% and 0.05% treatment groups showed a small increase in plaque index of <0.25 as compared to the placebo group (p<0.05). Similar trends were noted for changes in the % of sites with bleeding on probing in the 0.01% P-113 group. There were no treatment-related adverse events, and there were no adverse shifts in supragingival microflora during the study. Conclusion: These data suggest that P-113 mouthrinse is safe and reduces plaque, gingivitis and gingival bleeding in the human experimental gingivitis model.

Quantitative analysis from CT is prognostic for local control of supraglottic carcinoma.

Abstract: Background The purpose of this study was to determine whether pretreatment imaging with CT was prognostic for control of the primary site in patients with squamous cell carcinoma of the supraglottic larynx. Methods Pretreatment CT studies were obtained on 28 patients treated definitively with radiation therapy for supraglottic larynx cancer between 1991 and 1997. Follow-up ranged from 20–58 months. Results Local control was achieved in 61% of patients. Tumor volumes ranged from 0–68.6 cm3, with a median of 3.1 cm3. Local control rates for tumors with volumes greater than or less than 8 cm3 were 20% and 70%, respectively (p = .0077). Mean tumor volumes for patients with and without recurrences were 10 cm3 and 3.4 cm3, respectively. Conclusions This study demonstrates that quantitative analysis from CT imaging is prognostic for control of the primary site when radiation therapy is given for treatment of supraglottic cancer. © 2001 John Wiley & Sons, Inc. Head Neck 23: 1031– 1036, 2001.

Coronary artery calcium quantification with retrospectively gated helical CT: protocols and techniques.

Abstract: Current generation Helical Computed Tomography, when coupled with cardiac gating can be used to measure coronary vascular calcium. In this article we review the development of retrospectively gated helical computed tomography on a single slice HCT system and its relation to electron beam CT. The impact of heart rate on selection of helical pitch for the creation of a diastolic image set is detailed, as well as, scanning and post-processing techniques are discussed. The development and initial experience of cardiac gating with multidetector CT systems is presented.

Nasal carriage of Staphylococcus aureus among patients receiving allergen-injection immunotherapy: associated factors and quantitative nasal cultures.

Abstract: OBJECTIVE: To compare the prevalence of nasal Staphylococcus aureus carriage among outpatients receiving allergen-injection immunotherapy with the prevalence among healthy controls and to determine predictors of nasal S aureus carriage. DESIGN: Survey. SETTING: Allergy clinic of a university hospital. PARTICIPANTS: A volunteer sample consisting of 45 outpatients undergoing desensitization therapy and 84 first- and second-year medical students. RESULTS: The nasal S aureus carriage rate was significantly higher among patients (46.7%) than among students (26.2%; P=.019). In a multivariate model adjusted for age and gender, the presence of atopic dermatitis or eczema was the only independent predictor of nasal S aureus carriage (odds ratio [OR], 4.4; 95% confidence interval [CI 95 ], 1.2-16.0; P=.02). The only other participant characteristic associated with nasal S aureus carriage was immunotherapy with allergen injections (OR, 1.98; CI 95 , 0.7-6.0), but this association did not reach statistical significance (P=.23). The probability of nasal S aureus carriage was 88.9% for patients receiving allergen injections and having atopic dermatitis or eczema, and 36.1% for patients receiving allergen injections without atopic dermatitis or eczema. CONCLUSIONS: Patients undergoing desensitization have a higher nasal carriage rate of S aureus. However, factors other than the regular use of needles, and in particular abnormalities related to the atopic constitution of these patients, may predispose this population for S aureus carriage.

Predictive performance of missing data methods for logistic regression, classification trees and neural networks

Abstract: Although the effect of missing data on regression estimates has received considerable attention, their effect on predictive performance has been neglected. We studied the performance of three missing data strategies—omission of records with missing values, replacement with a mean and imputation based on regression—on the predictive performance of logistic regression (LR), classification tree (CT) and neural network (NN) models in the presence of data missing completely at random (MCAR). Models were constructed using datasets of size 500 simulated from a joint distribution of binary and continuous predictors including nonlinearities, collinearity and interactions between variables. Though omission produced models that fit better on the data from which the models were developed, imputation was superior on average to omission for all models when evaluating the receiver operating characteristic (ROC) curve area, mean squared error (MSE), pooled variance across outcome categories and calibration X 2 on an inde...

Stroke Risk Profile Predicts Brain Volume and Cognitive Function in Stroke-free Subjects: The Framingham Study

Abstract: 30 Background: The contribution of stroke risk factors to the pervasive brain atrophy and cognitive impairment seen with aging is controversial. This is partly due to a paucity of longitudinal data in stroke-free subjects. We hypothesize, that even in subjects who remain free of clinical stroke, exposure to stroke risk factors may adversely impact brain volume. Objective: To prospectively examine the association of Framingham Stroke Risk Profile (FSRP) scores at baseline with MRI brain volume on follow-up, and to further evaluate the association of brain volume with cognitive function, in a population-based cohort of stroke- and dementia-free subjects. Methods: Framingham Offspring Study subjects were evaluated for stroke risk factors at exam 5 (1991–1995). A sex-specific, composite FSRP score was calculated for each subject, as validated in prior studies. 909 subjects (age range 42–82, mean age: 61 years, 427 men), who remained free of clinical dementia and stroke, underwent quantitative MRI imaging and neuropsychological evaluation, 4 to 9 years later (1999–2000). Using linear regression models adjusted for age and sex, we examined the association between the FSRP score and Total Cerebral Brain Volume- TCBV (expressed as a ratio of total cranial volume). We also evaluated the association of TCBV with age- and education- adjusted scores on a battery of neuropsychological tests administered at the time of imaging. Results: There was a strong inverse association between TCBV and the FSRP score (p=0.002). TCBV also showed a significant positive association with performance on tests of manual dexterity (e.g. finger tapping; p 0.05). Conclusion: An adverse stroke risk profile predicted lower MRI brain volume, which in turn was associated with poorer performance on specific neuropsychological tests suggestive of vascular cognitive impairment. Pathogenetic mechanisms for these associations in stroke-free subjects could include various vascular causes for accelerated brain aging and merit further study.