Association of Multiorgan Computed Tomographic Phenomap With Adverse Cardiovascular Health Outcomes: The Framingham Heart Study.

Importance: Increased ability to quantify anatomical phenotypes across multiple organs provides the opportunity to assess their cumulative ability to identify individuals at greatest susceptibility for adverse outcomes. Objective: To apply unsupervised machine learning to define the distribution and prognostic importance of computed tomography-based multiorgan phenotypes associated with adverse health outcomes. Design, Setting, and Participants: This asymptomatic community-based cohort study included 2924 Framingham Heart Study participants between July 2002 and April 2005 undergoing computed tomographic imaging of the chest and abdomen. Participants are from the offspring and third-generation cohorts. Exposures: Eleven computed tomography-based measures of valvular/vascular calcification, adiposity, and muscle attenuation. Main Outcomes and Measures: All-cause mortality and cardiovascular disease (myocardial infarction, stroke, or cardiovascular death). Results: The median age of the participants was 50 years (interquartile range, 43-60 years), and 1422 (48.6%) were men. Principal component analysis identified 3 major anatomic axes: (1) global calcification (defined by aortic, thoracic, coronary, and valvular calcification); (2) adiposity (defined by pericardial, visceral, hepatic, and intrathoracic fat); and (3) muscle attenuation that explained 65.7% of the population variation. Principal components showed different evolution with age (continuous increase in global calcification, decrease in muscle attenuation, and U-shaped association with adiposity) but similar patterns in men and women. Using unsupervised clustering approaches in the offspring cohort (n = 1150), we identified a cohort (n = 232; 20.2%) with an unfavorable multiorgan phenotype across all 3 anatomic axes as compared with a favorable multiorgan phenotype. Membership in the unfavorable phenotypic cluster was associated with a greater prevalence of cardiovascular disease risk factors and with increased all-cause mortality (hazard ratio, 2.61; 95% CI, 1.74-3.92; P < .001), independent of coronary artery calcium score, visceral adipose tissue, and 10-year global cardiovascular disease Framingham risk, and it provided improvement in metrics of discrimination and reclassification. Conclusions and Relevance: This proof-of-concept analysis demonstrates that unsupervised machine learning, in an asymptomatic community cohort, identifies an unfavorable multiorgan phenotype associated with adverse health outcomes, especially in elderly American adults. Future investigations in larger populations are required not only to validate the present results, but also to harness clinical, biochemical, imaging, and genetic markers to increase our understanding of healthy cardiovascular aging.

Bivariate heritability of total and regional brain volumes: the Framingham Study.

Heritability and genetic and environmental correlations of total and regional brain volumes were estimated from a large, generally healthy, community-based sample, to determine if there are common elements to the genetic influence of brain volumes and white matter hyperintensity (WMH) volume. There were 1538 Framingham Heart Study participants with brain volume measures from quantitative magnetic resonance imaging who were free of stroke and other neurologic disorders that might influence brain volumes and who were members of families with at least 2 Framingham Heart Study participants. Heritability was estimated using variance component methodology and adjusting for the components of the Framingham stroke risk profile. Genetic and environmental correlations between traits were obtained from bivariate analysis. Heritability estimates ranging from 0.46 to 0.60 were observed for total brain, WMH, hippocampal, temporal lobe, and lateral ventricular volumes. Moderate, yet significant, heritability was observed for the other measures. Bivariate analyses demonstrated that relationships between brain volume measures, except for WMH, reflected both moderate to strong shared genetic and shared environmental influences. This study confirms strong genetic effects on brain and WMH volumes. These data extend current knowledge by showing that these 2 different types of magnetic resonance imaging measures do not share underlying genetic or environmental influences.