Showing papers by "Ralph B. D'Agostino published in 2013"

The Randomized Registry Trial — The Next Disruptive Technology in Clinical Research?

Abstract: The registry-based randomized trial may make less expensive, more efficient clinical studies possible. But before the new study design can be widely used, questions about the quality of the underlying data sets must be addressed.

Low to Moderate Dose Anthracycline-Based Chemotherapy Is Associated With Early Noninvasive Imaging Evidence of Subclinical Cardiovascular Disease

Abstract: Objectives The goal of this study was to determine if low to moderate doses of anthracycline-based chemotherapy (Anth-bC) are associated with subclinical cardiovascular (CV) injury. Background Cancer survivors who receive Anth-bC experience premature CV events. It is unknown whether low to moderate doses of anthracyclines promote early subclinical CV disease manifested by deteriorations in left ventricular ejection fraction (LVEF) or increases in aortic stiffness, or if these doses are associated with changes in quality of life (QOL). Methods In 53 men and women with breast cancer, leukemia, or lymphoma, we assessed left ventricular volumes, LVEF, circumferential strain, aortic pulse wave velocity, late gadolinium enhancement, serum B-type natriuretic peptide, troponin I, and the impact of treatment on QOL before and 1, 3, and 6 months after receipt of Anth-bC. Results Participants averaged 50 ± 2 (range 19 to 80) years in age, 58% were women, 17% were black, and they each received a range of 50 to 375 mg/m 2 of doxorubicin-equivalent chemotherapy. Left ventricular end-systolic volume (48 ± 3 ml to 54 ± 3 ml; p = 0.02), left ventricular strain (–17.7 ± 0.4 to –15.1 ± 0.4; p = 0.0003), pulse wave velocity (6.7 ± 0.5 m/s to 10.1 ± 1 m/s; p = 0.0006), and QOL deterioration (15.4 ± 3.3 to 28.5 ± 3.9; p = 0.008) increased, whereas LVEF (58 ± 1% to 53 ± 1%; p = 0.0002) decreased within 6 months after low to moderate doses of Anth-bC. All findings persisted after accounting for age, gender, race (white/black), doxorubicin-equivalent dose, doxorubicin administration technique, comorbidities associated with CV events, and cancer diagnosis (p = 0.02 to 0.0001 for all). There were no new late gadolinium enhancement findings after 6 months. Conclusions In these study patients, low to moderate doses of Anth-bC were associated with the early development of subclinical abnormalities of cardiac and vascular function that in other populations are associated with the future occurrence of CV events.

Association of Smoking Cessation and Weight Change With Cardiovascular Disease Among Adults With and Without Diabetes

Abstract: Importance Smoking cessation reduces the risks of cardiovascular disease (CVD), but weight gain that follows quitting smoking may weaken the CVD benefit of quitting. Objective To test the hypothesis that weight gain following smoking cessation does not attenuate the benefits of smoking cessation among adults with and without diabetes. Design, Setting, and Participants Prospective community-based cohort study using data from the Framingham Offspring Study collected from 1984 through 2011. At each 4-year examination, self-reported smoking status was assessed and categorized as smoker, recent quitter (≤4 years), long-term quitter (>4 years), and nonsmoker. Pooled Cox proportional hazards models were used to estimate the association between quitting smoking and 6-year CVD events and to test whether 4-year change in weight following smoking cessation modified the association between smoking cessation and CVD events. Main Outcome Measure Incidence over 6 years of total CVD events, comprising coronary heart disease, cerebrovascular events, peripheral artery disease, and congestive heart failure. Results After a mean follow-up of 25 (SD, 9.6) years, 631 CVD events occurred among 3251 participants. Median 4-year weight gain was greater for recent quitters without diabetes (2.7 kg [interquartile range {IQR}, −0.5 to 6.4]) and with diabetes (3.6 kg [IQR, −1.4 to 8.2]) than for long-term quitters (0.9 kg [IQR, −1.4 to 3.2] and 0.0 kg [IQR, −3.2 to 3.2], respectively, P Conclusions and Relevance In this community-based cohort, smoking cessation was associated with a lower risk of CVD events among participants without diabetes, and weight gain that occurred following smoking cessation did not modify this association. This supports a net cardiovascular benefit of smoking cessation, despite subsequent weight gain.

Cardiovascular Disease Risk Assessment: Insights from Framingham.

Abstract: Cardiovascular disease (CVD) is among the leading causes of death and disability worldwide. Since its beginning, the Framingham study has been a leader in identifying CVD risk factors. Clinical trials have demonstrated that when the modifiable risk factors are treated and corrected, the chances of CVD occurring can be reduced. The Framingham study also recognized that CVD risk factors are multifactorial and interact over time to produce CVD. In response, Framingham investigators developed the Framingham Risk Functions (also called Framingham Risk Scores) to evaluate the chance or likelihood of developing CVD in individuals. These functions are multivariate functions (algorithms) that combine the information in CVD risk factors such as sex, age, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, smoking behavior, and diabetes status to produce an estimate (or risk) of developing CVD or a component of CVD (such as coronary heart disease, stroke, peripheral vascular disease, or heart failure) over a fixed time, for example, the next 10 years. These estimates of CVD risk are often major inputs in recommending drug treatments such as cholesterol-lowering drugs.

Behavioral stress accelerates prostate cancer development in mice

Abstract: Prostate cancer patients have increased levels of stress and anxiety. Conversely, men who take beta blockers, which interfere with signaling from the stress hormones adrenaline and noradrenaline, have a lower incidence of prostate cancer; however, the mechanisms underlying stress–prostate cancer interactions are unknown. Here, we report that stress promotes prostate carcinogenesis in mice in an adrenaline-dependent manner. Behavioral stress inhibited apoptosis and delayed prostate tumor involution both in phosphatase and tensin homolog–deficient (PTEN-deficient) prostate cancer xenografts treated with PI3K inhibitor and in prostate tumors of mice with prostate-restricted expression of c-MYC (Hi-Myc mice) subjected to androgen ablation therapy with bicalutamide. Additionally, stress accelerated prostate cancer development in Hi-Myc mice. The effects of stress were prevented by treatment with the selective β2-adrenergic receptor (ADRB2) antagonist ICI118,551 or by inducible expression of PKA inhibitor (PKI) or of BCL2-associated death promoter (BAD) with a mutated PKA phosphorylation site (BAD S112A ) in xenograft tumors. Effects of stress were also blocked in Hi-Myc mice expressing phosphorylation-deficient BAD (BAD 3SA ). These results demonstrate interactions between prostate tumors and the psychosocial environment mediated by activation of an adrenaline/ADRB2/ PKA/BAD antiapoptotic signaling pathway. Our findings could be used to identify prostate cancer patients who could benefit from stress reduction or from pharmacological inhibition of stress-induced signaling.

Traditional multiplicity adjustment methods in clinical trials

Abstract: This tutorial discusses important statistical problems arising in clinical trials with multiple clinical objectives based on different clinical variables, evaluation of several doses or regiments of a new treatment, analysis of multiple patient subgroups, etc. Simultaneous assessment of several objectives in a single trial gives rise to multiplicity. If unaddressed, problems of multiplicity can undermine integrity of statistical inferences. The tutorial reviews key concepts in multiple hypothesis testing and introduces main classes of methods for addressing multiplicity in a clinical trial setting. General guidelines for the development of relevant and efficient multiple testing procedures are presented on the basis of application-specific clinical and statistical information. Case studies with common multiplicity problems are used to motivate and illustrate the statistical methods presented in the tutorial, and software implementation of the multiplicity adjustment methods is discussed. Copyright © 2013 John Wiley & Sons, Ltd.

Impact of enzyme replacement therapy on survival in adults with Pompe disease: results from a prospective international observational study.

Abstract: Pompe disease is a rare metabolic myopathy for which disease-specific enzyme replacement therapy (ERT) has been available since 2006. ERT has shown efficacy concerning muscle strength and pulmonary function in adult patients. However, no data on the effect of ERT on the survival of adult patients are currently available. The aim of this study was to assess the effect of ERT on survival in adult patients with Pompe disease. Data were collected as part of an international observational study conducted between 2002 and 2011, in which patients were followed on an annual basis. Time-dependent Cox’s proportional hazards models were used for univariable and multivariable analyses. Overall, 283 adult patients with a median age of 48 years (range, 19 to 81 years) were included in the study. Seventy-two percent of patients started ERT at some time during follow-up, and 28% never received ERT. During follow-up (median, 6 years; range, 0.04 to 9 years), 46 patients died, 28 (61%) of whom had never received ERT. After adjustment for age, sex, country of residence, and disease severity (based on wheelchair and ventilator use), ERT was positively associated with survival (hazard ratio, 0.41; 95% CI, 0.19 to 0.87). This prospective study was the first to demonstrate the positive effect of ERT on survival in adults with Pompe disease. Given the relatively recent registration of ERT for Pompe disease, these findings further support its beneficial impact in adult patients.

Reduced Heart Rate Variability Among Youth With Type 1 Diabetes The SEARCH CVD study

Abstract: OBJECTIVE This study compared heart rate variability (HRV) parameters in youth with and without type 1 diabetes and explored potential contributors of altered HRV. RESEARCH DESIGN AND METHODS HRV parameters were measured among 354 youth with type 1 diabetes (mean age 18.8 years, diabetes duration 9.8 years, and mean A1C 8.9%) and 176 youth without diabetes (mean age 19.2 years) participating in the SEARCH CVD study. Multiple linear regression was used to assess the relationship between diabetes status and HRV parameters, adjusting for covariates. RESULTS Compared with control subjects, youth with type 1 diabetes had reduced overall HRV (10.09 ms lower SD of NN intervals [SDNN]) and markers of parasympathetic loss (13.5 ms reduced root mean square successive difference of NN intervals [RMSSD] and 5.2 normalized units (n.u.) reduced high frequency [HF] power) with sympathetic override (5.2 n.u. increased low frequency [LF] power), independent of demographic, anthropometric, and traditional cardiovascular risk factors. Older age, female sex, higher LDL cholesterol and triglyceride levels, and presence of microalbuminuria were independently associated with lower HRV but did not account for the observed differences between youth with and without diabetes. Youth with type 1 diabetes and A1C levels ≥7.5% had significantly worse HRV parameters than control subjects; however, in youth with optimal glycemic control (A1C <7.5%), HRV parameters did not differ significantly from control subjects. CONCLUSIONS Youth with type 1 diabetes have signs of early cardiac autonomic neuropathy: reduced overall HRV and parasympathetic loss with sympathetic override. The main driver of these subclinical abnormalities appears to be hyperglycemia.

Key multiplicity issues in clinical drug development.

Abstract: Much progress has been made over the past decade with the development of novel methods for addressing increasingly more complex multiplicity problems arising in confirmatory Phase III clinical trials. This includes traditional problems with a single source of multiplicity, for example, analysis of multiple endpoints or dose–placebo contrasts. In addition, more advanced problems with several sources of multiplicity have attracted attention in clinical drug development. These problems include two or more families of objectives such as multiple endpoints evaluated at multiple dose levels or in multiple patient populations. This paper provides a review of concepts that play a central role in defining and solving multiplicity problems (error rate definitions) and introduces main classes of multiple testing procedures widely used in clinical trials (nonparametric, semiparametric, and parametric procedures). The paper also presents recent advances in multiplicity research, including gatekeeping procedures for clinical trials with multiple sets of objectives. The concepts and methods introduced in the paper are illustrated using several case studies on the basis of real clinical trials. Software implementation of commonly used multiple testing and gatekeeping procedures is discussed. Copyright © 2012 John Wiley & Sons, Ltd.

Relationship of lycopene intake and consumption of tomato products to incident CVD.

Abstract: Evidence for cardioprotective effects of lycopene is inconsistent. Studies of circulating lycopene generally report inverse associations with cardiovascular disease (CVD) risk, but studies based on lycopene intake do not. The failure of the dietary studies to support the findings based on biomarkers may be due in part to misclassification of lycopene intakes. To address this potential misclassification, we used repeated measures of intake obtained over 10 years to characterize the relation between lycopene intake and incidence of CVD (n=314), coronary heart disease (CHD, n=171) and stroke (n=99) in the Framingham Offspring Study. Hazards ratios (HR) for incident outcomes were derived from Cox proportional hazards regression models using logarithmically transformed lycopene intake adjusted for CVD risk factors and correlates of lycopene intake. HRs were interpreted as the increased risk for a 2.7-fold difference in lycopene intake, a difference approximately equal to its inter-quartile range. Using an average of three intake measures with a 9 year follow-up, lycopene intake was inversely associated with CVD incidence (hazards ratio (HR): 0.83, 95% confidence interval (CI): 0.70-0.98). Using an average of two intake measures and 11 years of follow-up, lycopene intake was inversely associated with CHD incidence (HR: 0.74, 95% CI: 0.58-0.94). Lycopene intake was unrelated to stroke incidence. Our study of lycopene intake and CVD provides supporting evidence for an inverse association between lycopene and CVD risk but additional research is needed to determine if lycopene or other components of tomatoes, the major dietary source of lycopene, are responsible for the observed association.

Age Trends in Estradiol and Estrone Levels Measured Using Liquid Chromatography Tandem Mass Spectrometry in Community-Dwelling Men of the Framingham Heart Study

Abstract: THE estrogens have been linked to the pathophysiology of gynecomastia, osteoporosis, inflammation, and cardiovascular disease (CVD), but the precise biologic role of the circulating estrone and estradiol in men remains poorly understood (1,2). The function of estrone, which is at least as abundant in the circulation as estradiol but is less potent than estradiol in some bioassays (3), has been even less well studied as compared with estradiol. In men, circulating estradiol is derived partly from direct testicular secretion and partly from peripheral aromatization of testosterone, whereas circulating estrone is derived predominantly from peripheral conversion of delta 4-androstenedione (3–10). A decline in testosterone and androstenedione levels with aging would, therefore, be expected to result in lower estradiol and estrone levels, respectively, in older men as compared with younger men. However, the data on age-related changes in estradiol levels are conflicting. Although some studies have reported lower estradiol levels in older men than in young men (11–15), others have noted stable (16,17) or even rising estradiol levels with age (18). Very few studies have investigated the age trends in estrone levels (14,15). Additionally, few studies have interpreted age trends in estrone and estradiol levels in the context of age-related changes in lifestyle and health-related factors. The estradiol levels were measured in most studies using direct immunoassays, whose accuracy in the low range prevalent in men has been questioned (19–21). Using cross-sectional data from the Framingham Heart Study (FHS), we examined the age distribution of estradiol and estrone concentrations and the relationship of these hormones to body mass index (BMI), total testosterone, sex hormone–binding globulin (SHBG), diabetes mellitus, C-reactive protein, and lifestyle factors such as smoking and alcohol consumption in a sample of community-dwelling men. We also determined how comorbid conditions, lifestyle factors, inflammation, testosterone, and SHBG levels influence the age trends in estrone and estradiol levels. We adjusted the analyses for SHBG, the major binding protein for circulating estradiol that has been associated with metabolic disorders, which may indirectly affect estrogen levels. We measured estrone and estradiol levels using liquid chromatography tandem mass spectrometry (LC-MS/MS), widely accepted as the method with the highest accuracy and sensitivity (19–21).

Reduced Heart Rate Variability Is Associated With Increased Arterial Stiffness in Youth With Type 1 Diabetes The SEARCH CVD study

Abstract: OBJECTIVE Reduced heart rate variability (HRV) and increased arterial stiffness (AS) are both present in youth with type 1 diabetes. However, it is unclear whether they are associated and whether their association is independent of cardiovascular disease (CVD) risk factors. RESEARCH DESIGN AND METHODS The SEARCH Cardiovascular Disease (SEARCH CVD) study explored the cross-sectional relationships between HRV and several measures of AS in youth with ( n = 344) and without ( n = 171) type 1 diabetes. The SphygmoCor device (AtCor Medical, Sydney, Australia) was used to measure HRV using SD of normal R-R interval (SDNN), as well as AS, using pulse wave velocity in the carotid to femoral segment (PWV-trunk) and augmentation index adjusted to a heart rate of 75 bpm (AIx75). Brachial distensibility (BrachD), another index of AS, was measured with a DynaPulse instrument (Pulse Metric, San Diego, CA). Multiple linear regression analyses explored the associations between HRV and each of the three AS measures, after adjusting for demographic characteristics and traditional CVD risk factors (blood pressure, lipids, obesity, microalbuminuria, and smoking) separately, for youth with and without type 1 diabetes. RESULTS Among youth with type 1 diabetes, lower SDNN was associated with peripheral AS (lower BrachD, P = 0.01; r 2 = 0.30) and central AS (higher PVW-trunk, P < 0.0001; r 2 = 0.37; and higher AIx75, P = 0.007; r 2 = 0.08). These associations were attenuated with adjustment for CVD risk factors, but remained statistically significant for BrachD and PWV-trunk. While a similar association between HRV and BrachD was present in control youth, lower HRV was not associated with increased central AS or with AIx75. CONCLUSIONS Longitudinal studies are needed to understand the pathways responsible for these associations.

Evaluating the Effectiveness of a Lay Health Promoter-Led, Community-Based Participatory Pesticide Safety Intervention With Farmworker Families:

Abstract: Pesticide safety training is mandated for migrant and seasonal farmworkers. However, none is required for family members, who implement home sanitation to protect against pesticide exposure and need to control pests in substandard housing. Controlled studies have demonstrated the efficacy of pesticide education programs for farmworker families, but no carefully evaluated demonstration projects have shown effectiveness in public health settings. This project evaluates a lay health promoter program to improve pesticide-related knowledge and practices. Promotoras from six agencies recruited families with children to deliver a six-lesson, in-home, culturally and educationally appropriate curriculum. Independently conducted pre- and posttests evaluated changes in knowledge and practices. Adults in 610 families completed the study. Most were from Mexico, with low levels of formal education. Significant improvements in knowledge were observed for all six lessons. Significant improvements were observed in practic...

Neck circumference and the development of cardiovascular disease risk factors in the Framingham Heart Study.

Abstract: Upper-body subcutaneous adipose tissue, estimated by neck circumference (NC), is a unique fat depot that may confer additional risk for metabolic risk factors over generalized and central adiposity (1). Using a prospective study design, we now evaluate whether NC improves the prediction of incident cardiovascular disease risk factors over BMI and waist circumference (2). Framingham Heart Study participants ( n = 2,732; 54% women; mean age, 57 years) were followed for ∼10 years (1995–2008) for the development of type 2 diabetes (fasting plasma glucose ≥126 mg/dL or treatment), hypertension, low HDL cholesterol (<40 mg/dL, men; <50 mg/dL, women), and high triglycerides (≥150 mg/dL or lipid treatment). NC, BMI, and waist circumference were standardized within each sex to a mean of zero and an SD of one. Logistic regression models, adjusted for age, sex, and smoking, were used to test the association between 1 SD increment of NC with each outcome. …

Cardiovascular Risk Factors Are Associated With Increased Arterial Stiffness in Youth With Type 1 Diabetes: The SEARCH CVD study

Abstract: OBJECTIVE To evaluate if presence of cardiovascular (CV) risk factors and their clustering as metabolic syndrome (MetS) is associated with increased arterial stiffness and accelerated progression over time among youth with type 1 diabetes. RESEARCH DESIGN AND METHODS Longitudinal study of 298 youth with type 1 diabetes (age 14.5 years; 46.3% female; duration 4.8 years), with two research visits conducted 5 years apart. CV factors included: waist circumference, blood pressure (BP), fasting lipids (HDL cholesterol, LDL cholesterol [LDL-c], triglycerides), albumin/creatinine ratio, and HbA 1c . MetS was based on Adult Treatment Panel III criteria modified for youth. Pulse wave velocity (PWV) in the carotid–femoral segment was measured by tonometry. Mixed models were used to assess the rate of progression in PWV and the association between CV factors and PWV over time. RESULTS PWV increased significantly over time (0.145 m/s/year; P P = 0.0035), large waist ( P P = 0.0003) at baseline were each associated with worse PWV over time. These baseline factors, however, did not significantly influence the rate of progression. Increases in waist circumference ( P P = 0.0156), and declining glucose control (HbA 1c ; P = 0.0419) were independently associated with higher PWV over time. CONCLUSIONS Presence, clustering, and worsening of CV risk factors are associated with increased arterial stiffness over time in youth with type 1 diabetes. Whether improvement in CV risk factors early in life will slow the progression of arterial stiffness and reduce the burden of CV disease in this population requires further study.

Feasibility of Using a Community-Supported Agriculture Program to Improve Fruit and Vegetable Inventories and Consumption in an Underresourced Urban Community

Abstract: Introduction Direct-to-consumer marketing efforts, such as community-supported agriculture (CSA), have been proposed as a solution for disparities in fruit and vegetable consumption. Evaluations of such efforts have been limited. The objective of this study was to test the feasibility of a CSA intervention to increase household inventory of fruits and vegetables and fruit and vegetable consumption of residents of an underresourced community. Methods For this randomized, controlled feasibility study, we recruited 50 low-income women with children. Intervention (n=25) participants were offered 5 educational sessions and a box of fresh produce for 16 weeks; control participants were not offered the sessions nor were they included in the produce delivery. We collected data on participants' home inventory of fruits and vegetables and on their consumption of fruits and vegetables at baseline (May 2012) and postintervention (August and September 2012). Results Of 55 potential participants, 50 were enrolled and 44 were reached for follow-up. We observed a significant increase in the number of foods in the household inventory of fruits and vegetables in the intervention group compared with the control group. The intervention group reported greater increases in fruit and vegetable consumption; however, these did not reach significance. Intervention participants picked up produce 9.2 (standard deviation=4.58) of 16 weeks; challenges included transportation and work schedules. Most participants (20 of 21) expressed interest in continued participation; all stated a willingness to pay $10 per week, and some were willing to pay as much as $25 per week. Conclusion CSA is a feasible approach for providing fresh fruits and vegetables to an underresourced community. Future studies should evaluate the impact of such a program in a larger sample and should take additional steps to facilitate participation.

Sex-specific differences in the predictive value of cholesterol homeostasis markers and 10-year cardiovascular disease event rate in Framingham Offspring Study participants.

Abstract: BackgroundAvailable data are inconsistent regarding factors influencing plasma cholesterol homeostasis marker concentrations and their value in predicting subsequent cardiovascular disease (CVD) ev...

Effect of type 1 diabetes on carotid structure and function in adolescents and young adults: the SEARCH CVD study.

Abstract: OBJECTIVE Type 1 diabetes mellitus causes increased carotid intima-media thickness (IMT) in adults. We evaluated IMT in young subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS Participants with type 1 diabetes ( N = 402) were matched to controls ( N = 206) by age, sex, and race or ethnicity. Anthropometric and laboratory values, blood pressure, and IMT were measured. ANCOVA was used to assess differences controlling for demographic risk factors, cardiovascular risk factors, and HbA 1c . RESULTS Subjects were 18.9 ± 3.3 years old (50% male, 82.7% non-Hispanic white). Youth with type 1 diabetes had thicker bulb IMT, which remained significantly different after adjustment for demographics and cardiovascular risk factors. Age, sex, adiposity, and systolic blood pressure were consistent significant determinants of IMT. Adjustment for HbA 1c eliminated the difference, suggesting the difference was attributable to poor glycemic control. CONCLUSIONS Carotid IMT may be increased in youth with type 1 diabetes at high risk for cardiovascular disease. Better control of diabetes may be essential in preventing progression of atherosclerosis.

Early-Adulthood Cardiovascular Disease Risk Factor Profiles Among Individuals With and Without Diabetes in the Framingham Heart Study

Abstract: OBJECTIVE Many studies of diabetes have examined risk factors at the time of diabetes diagnosis instead of considering the lifetime burden of adverse risk factor levels. We examined the 30-year cardiovascular disease (CVD) risk factor burden that participants have up to the time of diabetes diagnosis. RESEARCH DESIGN AND METHODS Among participants free of CVD, incident diabetes cases (fasting plasma glucose ≥126 mg/dL or treatment) occurring at examinations 2 through 8 (1979–2008) of the Framingham Heart Study Offspring cohort were age- and sex-matched 1:2 to controls. CVD risk factors (hypertension, high LDL cholesterol, low HDL cholesterol, high triglycerides, obesity) were measured at the time of diabetes diagnosis and at time points 10, 20, and 30 years prior. Conditional logistic regression was used to compare risk factor levels at each time point between diabetes cases and controls. RESULTS We identified 525 participants with new-onset diabetes who were matched to 1,049 controls (mean age, 60 years; 40% women). Compared with those without diabetes, individuals who eventually developed diabetes had higher levels of hypertension (odds ratio [OR], 2.2; P = 0.003), high LDL (OR, 1.5; P = 0.04), low HDL (OR, 2.1; P = 0.0001), high triglycerides (OR, 1.7; P = 0.04), and obesity (OR, 3.3; P < 0.0001) at time points 30 years before diabetes diagnosis. After further adjustment for BMI, the ORs for hypertension (OR, 1.9; P = 0.02) and low HDL (OR, 1.7; P = 0.01) remained statistically significant. CONCLUSIONS CVD risk factors are increased up to 30 years before diagnosis of diabetes. These findings highlight the importance of a life course approach to CVD risk factor identification among individuals at risk for diabetes.

Understanding increments in model performance metrics

Abstract: The area under the receiver operating characteristic curve (AUC) is the most commonly reported measure of discrimination for prediction models with binary outcomes. However, recently it has been criticized for its inability to increase when important risk factors are added to a baseline model with good discrimination. This has led to the claim that the reliance on the AUC as a measure of discrimination may miss important improvements in clinical performance of risk prediction rules derived from a baseline model. In this paper we investigate this claim by relating the AUC to measures of clinical performance based on sensitivity and specificity under the assumption of multivariate normality. The behavior of the AUC is contrasted with that of discrimination slope. We show that unless rules with very good specificity are desired, the change in the AUC does an adequate job as a predictor of the change in measures of clinical performance. However, stronger or more numerous predictors are needed to achieve the same increment in the AUC for baseline models with good versus poor discrimination. When excellent specificity is desired, our results suggest that the discrimination slope might be a better measure of model improvement than AUC. The theoretical results are illustrated using a Framingham Heart Study example of a model for predicting the 10-year incidence of atrial fibrillation.

Patterns of weight change and progression to overweight and obesity differ in men and women: implications for research and interventions.

Abstract: OBJECTIVE To evaluate long-term patterns of weight change and progression to overweight and obesity during adulthood. DESIGN Prospective study. Changes in mean BMI, waist circumference (WC) and weight were assessed over a mean 26-year follow-up (1971–1975 to 1998–2001). Mean BMI (95% CI) and mean WC (95% CI) of men and women in BMI and age groups were computed. Mean weight change in BMI and age categories was compared using analysis of covariance. SETTING Framingham Heart Study Offspring/Spouse Nutrition Study. SUBJECTS Men and women (n 2394) aged 20–63 years. RESULTS During follow-up, increases in BMI (men: 2?2 kg/m2; women: 3?7 kg/m2) and WC (men: 5?7 cm; women: 15?1 cm) were larger in women than men. BMI gains were greatest in younger adults (20–39 years) and smallest in obese older adults (50–69 years). The prevalence of obesity doubled in men (to 33?2%) and tripled in women (to 26?6 %). Among normal-weight individuals, abdominal obesity developed in women only. The prevalence of abdominal obesity increased 1?8-fold in men (to 53?0%) and 2?4-fold in women (to 71?2 %). Weight gain was greatest in the youngest adults (20–29 years), particularly women. Gains continued into the fifth decade among men and then declined in the sixth decade; in women gains continued into the sixth decade. CONCLUSIONS Patterns of weight change and progression to obesity during adulthood differ in men and women. Preventive intervention strategies for overweight and obesity need to consider age- and sex-specific patterns of changes in anthropometric measures.

A Proposal for Integrated Efficacy-to-Effectiveness (E2E) Clinical Trials

Abstract: We propose an “efficacy-to-effectiveness” (E2E) clinical trial design, in which an effectiveness trial would commence seamlessly upon completion of the efficacy trial. Efficacy trials use inclusion/exclusion criteria to produce relatively homogeneous samples of participants with the target condition, conducted in settings that foster adherence to rigorous clinical protocols. Effectiveness trials use inclusion/exclusion criteria that generate heterogeneous samples that are more similar to the general patient spectrum, conducted in more varied settings, with protocols that approximate typical clinical care. In E2E trials, results from the efficacy trial component would be used to design the effectiveness trial component, to confirm and/or discern associations between clinical characteristics and treatment effects in typical care, and potentially to test new hypotheses. An E2E approach may improve the evidentiary basis for selecting treatments, expand understanding of the effectiveness of treatments in subgroups with particular clinical features, and foster incorporation of effectiveness information into regulatory processes.

Circulating Estrone Levels Are Associated Prospectively With Diabetes Risk in Men of the Framingham Heart Study

Abstract: OBJECTIVE In postmenopausal women and preclinical murine models, estrogen administration reduces diabetes risk; however, the relationship of estradiol and estrone to diabetes in men is poorly understood. We determined the relationship between circulating estradiol and estrone levels and diabetes risk in community-dwelling men of the Framingham Heart Study (FHS). METHODS Cross-sectional relationships of estradiol and estrone levels with diabetes were assessed at examination 7 (1998–2001) in FHS generation 2 men ( n = 1,458); prospective associations between hormone levels at examination 7 and incident diabetes were assessed 6.8 years later at examination 8. Type 2 diabetes mellitus was defined as fasting glucose >125 mg/dL, medication use, or both. Estradiol, estrone, and testosterone levels were measured with liquid chromatography tandem mass spectrometry, and free estradiol and estrone were calculated. RESULTS In cross-sectional models, men with elevated estrone and estradiol had 40% and 62% increased likelihoods of existing diabetes per cross-sectional doubling of estrone and estradiol levels, respectively. Free estrone (cross-sectional odds ratio 1.28 [95% CI 1.02–1.62], P = 0.04) was associated with impaired fasting glucose at examination 7. There was an increase in risk of existing diabetes with increasing quartiles of total and free estrone and estradiol and an increase in risk of incident diabetes with increasing quartiles of estrone levels. In multivariate longitudinal analyses, a twofold increase in total or free estrone levels at examination 7 was associated with 77 and 93% increases, respectively, in odds of incident diabetes at examination 8. CONCLUSIONS Although both estradiol and estrone exhibit cross-sectional associations with diabetes in men, in longitudinal analyses estrone is a more sensitive marker of diabetes risk than estradiol.

Impact of Glycemic Control on Heart Rate Variability in Youth with Type 1 Diabetes: The SEARCH CVD Study

Abstract: Aim: This study explored the role of glycemic control on cardiac autonomic function, measured by heart rate variability (HRV), in youth with type 1 diabetes. Patients and Methods: A retrospective cohort of 345 youth with type 1 diabetes (mean age, 18.5 years; duration, 10 years) participating in the SEARCH for Diabetes in Youth study were enrolled in the ancillary SEARCH Cardiovascular Disease (CVD) study. Anthropometric, metabolic, and HRV parameters were collected at the current research visit. Glycemic control over time was assessed by the mean glycated hemoglobin (A1c) levels collected over the past 6 years. Multiple linear regression analysis assessed the association between A1c over time and HRV parameters, independent of demographic and CVD risk factors. Participants were categorized into four glycemic control categories based on their mean A1c over time: Group 1, optimal (mean A1c, ≤7.4%); Group 2 (mean A1c, 7.5–8.4%); Group 3 (mean A1c, 8.5–9.4%), and Group 4, poor (mean A1c, ≥9.5%), and a linear trend was explored across these categories. Results: For every 1% increase in the average A1c over 6 years there was a 5% decrease in the SD of the normal RR interval (SDNN) (P=0.02) and 7% decrease in the root mean square successive difference of the RR interval (RMSSD) (P=0.02), independent of demographic and traditional CVD risk factors. A dose–response relationship between worsening glucose control categories and measures of overall reduced HRV was found. Conclusions: Chronic hyperglycemia is the main determinant of early cardiac autonomic dysfunction, manifested as reduced overall HRV and parasympathetic loss, among youth with type 1 diabetes.

Neck circumference, carotid wall intima-media thickness, and incident stroke.

Abstract: Locally acting fat depots may contribute to obesity complications, in particular vascular disease, through direct paracrine effects (1,2). The carotid arteries are encased in fat, and total upper-body subcutaneous fat is estimated by neck circumference (NC). NC has been independently correlated with cardiometabolic risk factors above and beyond that of other adiposity measures (3,4). Carotid wall intima-media thickness (IMT) is a surrogate marker of subclinical atherosclerosis and has been associated with cardiovascular and stroke outcomes (5). The aim of this study was to evaluate the association of NC and carotid wall IMT above and beyond traditional cardiovascular risk factors and generalized adiposity. Framingham Heart Study offspring participants who underwent carotid ultrasonography and NC measurements were included ( n = 3,274; mean age 59 years; 52% women); NC, internal carotid artery (ICA) IMT, and common carotid artery (CCA) IMT were determined as previously described (4,5). Linear regression models evaluated the association between adiposity exposures and IMT. NC, BMI, and …

Nutritional Factors and Preservation of C-Peptide in Youth With Recently Diagnosed Type 1 Diabetes: SEARCH Nutrition Ancillary Study

Abstract: OBJECTIVE To test the novel hypothesis that nutritional factors previously associated with type 1 diabetes etiology or with insulin secretion are prospectively associated with fasting C-peptide (FCP) concentration among youth recently diagnosed with type 1 diabetes. RESEARCH DESIGN AND METHODS Included were 1,316 youth with autoantibody-positive type 1 diabetes who participated in the SEARCH for Diabetes in Youth study (baseline disease duration, 9.9 months; SD, 6.3). Nutritional exposures included breastfeeding and age at introduction of complementary foods, baseline plasma long-chain omega-3 fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), vitamin D, vitamin E, and, from a baseline food frequency questionnaire, estimated intake of the branched-chain amino acid leucine and total carbohydrate. Multiple linear regression models were conducted to relate each nutritional factor to baseline FCP adjusted for demographics, disease-related factors, and other confounders. Prospective analyses included the subset of participants with preserved β-cell function at baseline (baseline FCP ≥0.23 ng/mL) with additional adjustment for baseline FCP and time (mean follow-up, 24.3 months; SD, 8.2; n = 656). FCP concentration was analyzed as log(FCP). RESULTS In adjusted prospective analyses, baseline EPA ( P = 0.02), EPA plus DHA ( P = 0.03), and leucine ( P = 0.03) were each associated positively and significantly with FCP at follow-up. Vitamin D was unexpectedly inversely associated with FCP ( P = 0.002). CONCLUSIONS Increased intake of branched-chain amino acids and long-chain omega-3 fatty acids may support preservation of β-cell function. This represents a new direction for research to improve prognosis for type 1 diabetes.

Vitamin D in youth with Type 1 diabetes: prevalence of insufficiency and association with insulin resistance in the SEARCH Nutrition Ancillary Study

Abstract: Aims To determine the prevalence of plasma vitamin D (25-dihydroxyvitamin D) insufficiency in individuals with Type 1 diabetes and to determine the cross-sectional and longitudinal associations of plasma vitamin D with insulin resistance. Methods Participants from the SEARCH for Diabetes in Youth Study [n = 1426; mean age 11.2 years (sd 3.9)] had physician-diagnosed Type 1 diabetes [diabetes duration mean 10.2 months (sd 6.5)] with data available at baseline and follow-up (approximately 12 and 24 months after baseline). Insulin resistance was estimated using a validated equation. Cross-sectional and longitudinal multivariate logistic regression models were used to determine the association of plasma vitamin D with insulin resistance, adjusting for potential confounders. Results Forty-nine per cent of individuals had plasma vitamin D < 50 nmol/l and 26% were insulin resistant. In cross-sectional multivariate analyses, participants who had higher plasma vitamin D (65 nmol/l) had lower odds of prevalent insulin resistance than participants with lower plasma vitamin D (25 nmol/l) (odds ratio 0.70, 95% CI 0.57–0.85). This association was attenuated after additional adjustment for BMI z-score, which could be a confounder or a mediator (odds ratio 0.81, 95% CI 0.64–1.03). In longitudinal multivariate analyses, individuals with higher plasma vitamin D at baseline had lower odds of incident insulin resistance, but this was not significant (odds ratio 0.85, 95% CI 0.63–1.14). Conclusions Vitamin D insufficiency is common in individuals with Type 1 diabetes and may increase risk for insulin resistance. Additional prospective studies are needed to determine the association between plasma vitamin D and insulin resistance, and to further examine the role of adiposity on this association.