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The NHLBI Epidemiology and Biometry Program supports and conducts epidemiological studies of heart and vascular, lung, and blood diseases in defined populations in the United States and other countries. The Program focuses on the development and progression of cardiovascular disease risk factors in children and young adults; development and progression of atherosclerosis measured non-invasively or at autopsy in middle-aged or older adults; and development and progression of overt cardiovascular and pulmonary disease in older adults. Also emphasized are genetic and environmental influences on cardiovascular disease and its risk factors; trends in incidence, prevalence, and mortality from cardiovascular disease, stroke, peripheral vascular disease, congestive heart failure and cardiomyopathy; and relationships between insulin, insulin resistance, and overt diabetes and cardiovascular disease and its risk factors. Other projects investigate incidence of and mortality from cardiovascular, lung, and blood diseases. Research strategies apply family, longitudinal, demographic information and vital statistics to study natural history, etiology, and epidemiology of those diseases.

The program administers several large, long-term, multi-faceted population studies which address a variety of research objectives, many related to the recommendations of the Task Force on Research in Epidemiology and Prevention of Cardiovascular Disease. Since these studies are broad in scope, there is considerable overlap among the priority areas and research objectives. These studies are described below in the order in which they were initiated and are referenced in the summary of research activities under each applicable priority area recommendation.

Framingham Heart Study (1948-2001)

The Framingham Study was designed as a longitudinal investigation of constitutional and environmental factors influencing the development of cardiovascular disease (CVD) in men and women free of these conditions at the outset. Examination and testing of a sample of residents of Framingham, Massachusetts, was initiated in 1948 as a direct operation of the National, Heart, Lung, and Blood Institute (NHLBI). Subsequently, the study of this cohort of men and women has been conducted by direct operation, research contract and research grant. Currently there are approximately 1,100 surviving members of the original 5,209 subjects being studied at the Framingham Study Clinic in Framingham. The Framingham Offspring Study was initiated in 1971 to assess familial and genetic factors as determinants of CHD. By 1975, a sample of 5,124 men and women, consisting of offspring of the original Framingham cohort (and spouses of the offspring) had participated in the study.

The Framingham Study's current objectives are to study the incidence and prevalence of CVD and its risk factors, trends in CVD incidence and its risk factors over time, and familial patterns of CVD and its risk factors. Less prominent but important objectives include the estimation of incidence rates and description of the natural history of cardiovascular disease, including the sequence of clinical signs and symptoms that precede the clinically recognizable syndrome and the consequences and course of clinically manifest disease.

The Coronary Artery Disease Risk Development in Young Adults (CARDIA) (1984-2003)

CARDIA is a study of the distribution and evolution of risk factors for cardiovascular disease (CVD) in 5,115 18-30-year old black and white men and women with a broad range of attained education recruited from four U.S. communities. CARDIA was designed to increase understanding of contributors to changes in CVD risk factors during the critical years of transition from adolescence through young adulthood to middle age. Contracts were originally awarded in 1983 to support the completion of two examinations which began in 1985 and 1987. At the Year 10 examination, 78.5% of the surviving cohort was examined. Measurements of standard risk factors, such as blood pressure, lipids, smoking, and adiposity, have been made at all examinations, to permit analyses of trends in and interrelationships among risk factors. Detailed information on diet, physical fitness, echocardiographically-defined left ventricular mass, blood pressure reactivity, a variety of psychosocial measures, glucose tolerance, and other measures have been collected. DNA has been extracted for genetic analyses, and blood samples stored for future assays. The current objectives of the study are to (1) identify and quantify risk factors for the early development of atherosclerosis in persons aged 33-45, (2) identify and quantify gene-environment interactions that contribute to the development of cardiovascular risk factors and to early atherosclerosis, and (3) determine whether significant race or gender differences exist in the risk factors for early atherosclerosis or in the gene-environment interactions that lead to the development of atherosclerosis.

Atherosclerosis Risk in Communities (ARIC) (1985-2006)

ARIC is a large-scale, long-term program that measures associations of established and suspected coronary heart disease risk factors with both atherosclerosis and new CHD events in men and women age 45-64 at baseline from four diverse communities. The project has two components: community surveillance of morbidity and mortality, and repeated examinations of a representative cohort of men and women in each community. The community surveillance involves abstracting hospital records and death certificates and investigating out-of-hospital deaths. The representative cohorts totaling 16,000 individuals include approximately 4,000 persons from each community. Three of the cohorts reflect the ethnic composition of the communities in which they live; one cohort represents the African-American community exclusively. ARIC provides a measure of the variation in the distribution and determinants of coronary heart disease in the U.S. and, within the limits of ecologic analysis, suggests possible reasons for observed differences.

Cohort participants were examined four times (1987-90, 1990-93, 1993-96, and 1996-99), and contacted annually to update their medical histories. Atherosclerosis is measured by carotid ultrasonography. Arteriosclerosis is measured using retinal photography. Cerebrovascular disease is assessed using MRI in a sample of black and white participants. Risk factors studied include: blood lipids, lipoprotein cholesterols, and apolipoproteins; plasma hemostatic factors; blood chemistries and hematology and indicators of infectious and inflammatory disease; DNA markers of these risk factors; sitting, supine and standing blood pressures; anthropometry; fasting blood glucose and insulin levels; ECG findings; heart rate variability; cigarette and alcohol use; physical activity levels; dietary aspects; and family history.

Cardiovascular Health Study (CHS) (1988-2005)

The Cardiovascular Health Study (CHS) is a population-based, longitudinal study of risk factors for the development and progression of coronary heart disease and stroke in adults over the age of 65 years. This is the most extensive study undertaken by the NHLBI to study cardiovascular disease exclusively in an elderly population. It originated from the recommendations of an NHLBI workshop on the management of coronary heart disease in the elderly. Since atherosclerosis is prevalent in the elderly, the study is focused on factors thought to induce clinically overt disease.

Within a population-based sample of men and women 65 years and older, the objectives of CHS are to: a) quantify associations of conventional and hypothesized risk factors with coronary heart disease (CHD) and stroke; b) assess the associations of non-invasive measures of subclinical disease with the incidence of CHD and stroke; c) quantify the associations of risk factors with subclinical disease; d) characterize the natural history of CHD and stroke, and identify factors associated with clinical course; and e) describe the prevalence and distributions of risk factors, non-invasive measures of subclinical disease, and clinical CHD and stroke.

Strong Heart Study (1988-2000)

The Strong Heart Study was initiated to estimate the morbidity and mortality rates from cardiovascular disease in three geographically diverse groups of American Indians and to estimate the levels of cardiovascular disease risk factors through examinations of 1500 adult men and women 45-74 in each of the three centers. The three centers include the Aberdeen Area Indian Health Service studying the Oglala Sioux; the Cheyenne River Sioux and the Spirit Lake Tribe in North and South Dakota; the University of Oklahoma studying the Apache, Fort Sill Apache, Kiowa, Comanche, Wichita, Delaware and Caddo in Southwestern Oklahoma; and the Medlantic Research Institute studying the Pima and Maricopa near Phoenix, Arizona. After the initial three years the Strong Heart Study was renewed to: 1) extend surveillance of the community for mortality; and 2) reexamine the cohort after an approximate 4 year interval to assess the development of cardiovascular disease and change in CVD risk factors. Echocardiography and pulmonary function testing were added to the examination protocol for the second examination. In 1996 the study was funded to continue the follow-up for morbidity and mortality and to complete a third examination of the study cohort. New measures added to the third exam include measures of carotid atherosclerosis, arterial stiffness, a substudy of asthma, and a family study pilot. Additional efforts in the study of asthma and infectious disease origins of atherosclerosis were added through funding from the Office of Research on Minority Health.

Family Heart Study (1992-2000)

During the study's initial phase, May 1992-May 1996, probands aged 45-69 and their relatives were recruited from the Framingham Heart Study, the Utah Family Tree Study, and the North Carolina and Minnesota sites of the ARIC Study. Two groups of probands were selected, either randomly or by a high family risk of CHD as calculated from family history information from the parent studies. Additional family structure and disease history data were collected on 3,150 probands and 22,909 of their relatives. Clinical examination and follow-up of these random and high CHD risk families were conducted on a total of 1,253 families including 5,975 individuals. The examination components included anthropometry, blood pressure, ECG, carotid ultrasound, pulmonary function, and blood chemistries. Questionnaire data included medical and reproductive histories, diet, physical activity, tobacco and alcohol consumption, education, income and psychosocial factors including hostility, social support and stress. The purpose of the current phase (Phase III), which began in August 1996, is to identify and characterize genes for CHD, atherosclerosis, familial and environmental factors of CHD, and to understand how they interact in the development of clinical outcomes. Candidate gene and genome wide genotyping are being conducted, and these and the initial phase data are analyzed using segregation and linkage methodologies.

National Longitudinal Mortality Study (1994-1999)

The NLMS is a national study of mortality over time among selected Census Bureau samples numbering about 1.4 million persons. The main objectives of the study are to analyze socio-economic, demographic and occupational differentials in mortality within the United States.

The basic procedure involves matching a number of Current Population Surveys (CPS) and other Census files to the National Death Index (NDI) every other year to obtain deaths occurring among these cohorts. Death certificates are then purchased from the states. Causes of death and other data on the death certificate are coded. Mortality rates by age, sex, race, Hispanic origin, occupation, industry, income, education, state of residence and other factors may then be obtained. The follow-up period begins with 1979, the first year covered by the NDI, and ends with 1989. The total number of deaths in the cohorts for these years is estimated to be about 100,000.

Insulin Resistance Atherosclerosis Study (IRAS): Insulin, Insulin Resistance, Hyperglycemia and Cardiovascular Disease (1995-1999)

This initiative was designed to stimulate studies on the relationship of insulin and insulin resistance to cardiovascular disease (CVD) and other recognized CVD risk factors over a range of glucose tolerance from normal to overt diabetes. Specific objectives are to assess the effects of differing levels of insulin and insulin resistance upon: 1) levels of recognized CVD risk factors such as lipids, apoproteins, blood pressure, and coagulation factors; 2) concurrence or "clustering" of CVD risk factor abnormalities including hypertension, dyslipidemia, hyperglycemia, and obesity; 3) prevalence of clinical and subclinical cardiovascular disease; and 4) differences in CVD risk factor distributions between men and women and among racial groups. The 1,626 subjects aged 40-69 include 548 Hispanics and 464 African-Americans; 56 percent of the cohort are women. Diabetics comprise 33 percent of the cohort, persons with impaired glucose tolerance 23 percent, and 44 percent of the participants have normal glucose tolerance. This study is also evaluating the importance of insulin and insulin resistance as independent risk factors for an increase in carotid wall thickness and clinical CVD. Since existing measures of insulin resistance do not to measure exactly the same thing, substudies were conducted to compare insulin resistance measurement techniques and enable the IRAS data to be related to other studies in the literature.

National Health and Nutrition Examination Survey (NHANES IV) (1997-2004)

The National Health and Nutrition Survey (NHANES IV) is a study of a representative sample of about 30,000 of the non-institutionalized population of the United States, obtained through the use of a complex multi-stage survey sampling design. The NHLBI component will obtain information on the prevalence and distribution of common cardiovascular, pulmonary and blood diseases. The core questionnaire will be based on the Health Interview Survey (HIS), and will provide information on disease, risk factors, and components of medical care. Through the use of a mobile exam center, subjects throughout the country will be administered a standardized physical exam including blood pressure, the ankle-arm blood pressure index, venipuncture, and lipids. Sub-populations of the U.S. of particular interest, including minorities and age groups of particular concern such as the very young and the elderly, will be over-sampled. The study will measure national trends of cardiovascular diseases and help determine the extent to which findings in NHLBI population-based epidemiologic studies reflect national data.

Jackson Heart Study (1999-2005)

The Jackson Heart Study (JHS), an Institute-initiated prospective study of the environmental and genetic factors influencing the development of cardiovascular disease (CVD) in African-Americans, is sponsored by the National Heart, Lung, and Blood Institute (NHLBI) and the Office of Research on Minority Health of the National Institutes of Health (ORMH). The Jackson Heart Study initial examination will begin in the fall of 2000, will include 6,500 men and women aged 35-84 and will take three years to complete. The study is a partnership among NHLBI, ORMH and three local institutions: Jackson State University, Tougaloo College and the University of Mississippi Medical Center. The Coordinating Center, located at Jackson State University, will collect and analyze data. The Undergraduate Training Center at Tougaloo College will offer coursework to students in public health and epidemiology and provide practical experience in health research to prepare them for potential careers in these fields. The Exam Center at the University of Mississippi is responsible for recruiting participants and conducting the examinations. By incorporating state-of-the-art physiologic and epidemiologic methods in a stable population-based minority cohort, providing research experience, and building research capabilities at minority institutions, the Jackson Heart Study is uniquely positioned to answer key questions regarding the excess burden of CVD among African-Americans and to address the critical shortage of minority investigators trained in epidemiology and prevention.

Multi-Ethnic Study of Atherosclerosis (MESA) (1999-2009)

MESA (formerly known as the Subclinical Cardiovascular Disease Study) is a 10-year observational study of the characteristics of subclinical cardiovascular disease (disease detected non-invasively before it has produced clinical signs and symptoms) and risk factors that predict progression to clinically overt cardiovascular disease and that predict progression of subclinical disease itself, in a diverse and representative population-based sample of 6,500 men and women aged 45-84. Approximately 40 percent of the cohort will be white, 30 percent African-American, 20 percent Hispanic, and 10 percent Chinese-American. The cohort will be recruited from six Field Centers and characterized with respect to coronary calcification (using electron-beam and helical computed tomography), ventricular mass and function (using cardiac magnetic resonance imaging, flow-mediated endothelial function, carotid intimal-medial wall thickness and presence of echogenic lucencies in the carotid artery (using ultrasonography), lower extremity vascular insufficiency (using ankle-brachial blood pressure indices), electrocardiographic measures, standard coronary risk factors, sociodemographic factors, lifestyle factors, and psychosocial factors. Blood samples will be assayed for putative biochemical risk factors and stored for case-control studies. DNA will be extracted and lymphocytes immortalized for study of candidate genes and possibly genome-wide scanning. Four clinical examinations, 18-24 months apart, are planned. Participants will be followed for identification and characterization of cardiovascular disease events and interventions received.

Iron Overload and Hemochromatosis (2000-2004)

This project will be conducted by the Division of Epidemiology and Clinical Applications, NHLBI, in conjunction with the Division of Blood Diseases and Resources, NHLBI and the Division of Extramural Research, National Human Genome Research Institute (NHGRI). This project will study the prevalence and genetic and environmental determinants and potential clinical, personal, and societal impact of screening for iron overload and hereditary hemochromatosis in a multi-center, multiethnic, primary care-based sample of adult men and women. The study will identify risk factors influencing the phenotypic expression of iron overload and hereditary hemochromatosis, examine interactions between risk factors to determine the relationship between genotype and phenotype, examine the ethical, legal and social issues (ELSI) related to screening, estimate the heritability of iron overload and hemochromatosis, and initiate linkage studies to identify additional main effect and modifier genetic variants. This information will be used to determine the feasibility and potential individual and public health benefits and risks of primary care-based screening and intervention for iron overload and hereditary hemochromatosis. One hundred thousand participants will be recruited from five to seven field centers for screening.

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