Standardized Data Structures in Rare Diseases: CDISC User Guides for Duchenne Muscular Dystrophy and Huntington's Disease.

Interest in drug development for rare diseases has expanded dramatically since the Orphan Drug Act was passed in 1983, with 40% of new drug approvals in 2019 targeting orphan indications. However, limited quantitative understanding of natural history and disease progression hinders progress and increases the risks associated with rare disease drug development. Use of international data standards can assist in data harmonization and enable data exchange, integration into larger datasets, and a quantitative understanding of disease natural history.

Biomarkers of the osteoprotegerin pathway: clinical correlates, subclinical disease, incident cardiovascular disease, and mortality.

Objective: Experimental evidence identified the osteoprotegerin (OPG)/receptor activator of nuclear factor-kappaB (RANK)/RANK ligand (RANKL) pathway as a candidate system modulating vascular remodeling and cardiovascular disease (CVD).

Methods And Results: Serum concentrations of OPG and RANKL were measured in 3250 Framingham Study participants (54% women, 61+/-9 years). During a mean follow-up of 4.

Clinical and echocardiographic correlates of plasma procollagen type III amino-terminal peptide levels in the community.

Background: Left ventricular remodeling is characterized by increased collagen deposition in the extracellular matrix. Levels of plasma procollagen type III amino-terminal peptide (PIIINP), a marker of collagen turnover, are elevated in the setting of recent myocardial infarction, heart failure, and cardiomyopathy. Whether plasma PIIINP levels are a useful indicator of subclinical left ventricular abnormalities in ambulatory individuals has not been studied.

Association of multiple inflammatory markers with carotid intimal medial thickness and stenosis (from the Framingham Heart Study).

Inflammatory markers, particularly C-reactive protein (CRP), predict incident cardiovascular disease and are associated with the presence of subclinical atherosclerosis. The relations between multiple inflammatory markers and direct measures of atherosclerosis are less well established. Participants in the Offspring Cohort of the Framingham Heart Study (n = 2,885, 53% women, mean age 59 years) received routine assessments of common carotid artery intima-media thickness (CCA-IMT), internal carotid artery intima-media thickness (ICA-IMT), and the presence or absence of > or =25% carotid stenosis by ultrasonography.

The Third Generation Cohort of the National Heart, Lung, and Blood Institute's Framingham Heart Study: design, recruitment, and initial examination.

For nearly 60 years, the Framingham Heart Study has examined the natural history, risk factors, and prognosis of cardiovascular, lung, and other diseases. Recruitment of the Original Cohort began in 1948. Twenty-three years later, 3,548 children of the Original Cohort, along with 1,576 of their spouses, enrolled in the Offspring Cohort.

Single-gene mutations and increased left ventricular wall thickness in the community: the Framingham Heart Study.

Background: Mutations in sarcomere protein, PRKAG2, LAMP2, alpha-galactosidase A (GLA), and several mitochondrial genes can cause rare familial cardiomyopathies, but their contribution to increased left ventricular wall thickness (LVWT) in the community is unknown.

Methods And Results: We studied 1862 unrelated participants (52% women; age, 59+/-9 years) from the community-based Framingham Heart Study who had echocardiograms and provided DNA samples but did not have severe hypertension, aortic prosthesis, or significant aortic stenosis. Eight sarcomere protein genes, 3 storage cardiomyopathy-causing genes, and 27 mitochondrial genes were sequenced in unrelated individuals with increased LVWT (maximum LVWT >13 mm).

Cross-sectional correlates of serum heat shock protein 70 in the community.

Background: Recent studies of referral samples suggest that heat shock proteins play a key role in the pathogenesis of high BP and cardiovascular diseases (CVD) including heart failure. It is unclear whether circulating heat shock protein 70 (HSP70) levels are related to CVD risk factors, echocardiographic indexes of left ventricular (LV) remodeling, and prevalent CVD in the population.

Methods: We evaluated the cross-sectional relations of serum HSP70 to established CVD risk factors (including hypertension), markers of oxidative stress (urinary 8-epi-PGF(2alpha)) and inflammation (plasma interleukin-6, C-reactive protein, monocyte chemoattractant protein-1 MCP-1, and soluble intercellular adhesion molecule sICAM-1), echocardiographic LV dimensions and prevalent CVD in 456 Framingham Offspring Study participants (mean age 61 years, 42% women).

Genome scan of systemic biomarkers of vascular inflammation in the Framingham Heart Study: evidence for susceptibility loci on 1q.

Vascular inflammation plays a central role in atherosclerosis and inflammatory biomarkers predict risk of cardiovascular disease (CVD). Thus, finding genes that influence systemic levels of inflammatory biomarkers may provide insights into genetic determinants of vascular inflammation and CVD. We conducted variance-component linkage analyses of blood levels of four biomarkers of vascular inflammation [C-reactive protein (CRP), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), soluble intercellular adhesion molecule-1 (sICAM-1)] in 304 extended families from the Framingham Heart Study, using data from a 10cM genome scan.

Clinical and genetic correlates of serum aldosterone in the community: the Framingham Heart Study.

Background: We investigated the environmental and genetic sources of interindividual variability in serum aldosterone level in a large, community-based sample.

Methods: We examined the relation of serum aldosterone to vascular risk factors, urine sodium, and candidate single nucleotide polymorphisms in 2891 Framingham Offspring Study participants (53.2% women, mean age 59 years) using multivariable linear regression.

QT interval is a heritable quantitative trait with evidence of linkage to chromosome 3 in a genome-wide linkage analysis: The Framingham Heart Study.

Objectives: To identify genomic regions linked to QT interval duration in an unselected population.

Background: QT interval prolongation is associated with increased risk of sudden cardiac death and coronary heart disease and may result from acquired conditions or inherited ion channel defects. The influence of genetic variants on QT interval length in apparently healthy individuals is uncertain.

Heritability and correlates of intercellular adhesion molecule-1 in the Framingham Offspring Study.

Objectives: We sought to determine the clinical factors and heritability associated with inflammation measured as circulating levels of soluble-intercellular adhesion molecule-1 (sICAM-1) in a community-based cohort.

Background: Several prospective studies indicate that circulating sICAM-1 is predictive of future cardiovascular events. However, in some studies this predictive value is lost after multivariable adjustment for traditional cardiovascular disease (CVD) risk factors.

Genome-wide scan for pulse pressure in the National Heart, Lung and Blood Institute's Framingham Heart Study.

The objective of this study was to assess heritability and identify chromosomal regions showing evidence of linkage to pulse pressure (PP), a simple indicator of proximal conduit vessel stiffness. Blood pressure data were analyzed for 8478 members of the National Heart, Lung and Blood Institute's (NHLBI) Framingham Heart Study. Long-term PP was defined using 2-stage analysis.

Haptoglobin phenotype and prevalent coronary heart disease in the Framingham offspring cohort.

Background: The haptoglobin (Hp) locus is polymorphic with two major alleles denoted 1 and 2. Several recent prospective longitudinal studies have demonstrated conflicting results regarding whether there is an increase or decrease in the relative risk of coronary heart disease (CHD) conferred on individuals homozygous for the haptoglobin 1 allele (Hp 1-1).

Methods: We sought to examine the relationship between Hp type and prevalent coronary heart disease in a cross-sectional study from a large community-based cohort, the Framingham Heart Offspring Study (n = 3273).

Absence of association between polymorphisms in the hemostatic factor pathway genes and carotid intimal medial thickness: the Framingham Heart Study.

Background And Purpose: Fibrinogen, plasminogen activator inhibitor-1, and other key proteins in the coagulation cascade have been implicated in the origin of cardiovascular disease. Polymorphisms in genes encoding these proteins have been associated with variability in plasma levels of these proteins. Carotid intimal medial thickness (IMT) is a heritable, quantitative measure of atherosclerosis that is predictive of subsequent myocardial infarction and stroke.

Heritability and genetic linkage of plasma natriuretic peptide levels.

Background: Natriuretic peptides play a critical role in the maintenance of salt and water homeostasis and regulation of vascular tone. Thus, interindividual variation in plasma natriuretic peptide levels may contribute to variation in susceptibility to volume overload and hypertension. It is unknown to what extent genetic factors contribute to variation in plasma natriuretic peptide levels.

Obesity and systemic oxidative stress: clinical correlates of oxidative stress in the Framingham Study.

Objective: To determine the clinical conditions associated with systemic oxidative stress in a community-based cohort. Information regarding cardiovascular risk factors associated with systemic oxidative stress has largely been derived from highly selected samples with advanced stages of vascular disease. Thus, it has been difficult to evaluate the relative contribution of each cardiovascular risk factor to systemic oxidative stress and to determine whether such risk factors act independently and are applicable to the general population.

Genome scan linkage results for heart rate variability (the Framingham Heart Study).

There is a substantial heritable component to the beat-to-beat variation in heart rate. However, the molecular mechanisms underlying the control of heart rate variability (HRV) remain unknown. The present study sought to identify chromosomal regions linked to HRV phenotypes.