Genome-wide association study of electrocardiographic and heart rate variability traits: the Framingham Heart Study

BACKGROUND: Heritable electrocardiographic (ECG) and heart rate variability (HRV) measures, reflecting pacemaking, conduction, repolarization and autonomic function in the heart have been associated with risks for cardiac arrhythmias. Whereas several rare monogenic conditions with extreme phenotypes have been noted, few common genetic factors contributing to interindividual variability in ECG and HRV measures have been identified. We report the results of a community-based genomewide association study of six ECG and HRV intermediate traits. METHODS: Genotyping using Affymetrix 100K GeneChip was conducted on 1345 related Framingham Heart Study Original and Offspring cohort participants. We analyzed 1175 Original and Offspring participants with ECG data (mean age 52 years, 52% women) and 548 Offspring participants with HRV data (mean age 48 years, 51% women), in relation to 70,987 SNPs with minor allele frequency ≥ 0.10, call rate ≥ 80%, Hardy-Weinberg p-value ≥ 0.001. We used generalized estimating equations to test association of SNP alleles with multivariable-adjusted residuals for QT, RR, and PR intervals, the ratio of low frequency to high frequency power (LF/HFP), total power (TP) and the standard deviation of normal RR intervals (SDNN). RESULTS: Associations at p < 10-3 were found for 117 (QT), 105 (RR), 111 (PR), 102 (LF/HF), 121 (TP), and 102 (SDNN) SNPs. Several common variants in NOS1AP (4 SNPs with p-values < 10-3; lowest p-value, rs6683968, p = 1 × 10-4) were associated with adjusted QT residuals, consistent with our previously reported finding for NOS1AP in an unrelated sample of FHS Offspring and other cohorts. All results are publicly available at NCBI's dbGaP at. CONCLUSION: In the community-based Framingham Heart Study none of the ECG and HRV results individually attained genomewide significance. However, the presence of bona fide QT-associated SNPs among the top 117 results for QT duration supports the importance of efforts to validate top results from the reported scans. Finding genetic variants associated with ECG and HRV quantitative traits may identify novel genes and pathways implicated in arrhythmogenesis and allow for improved recognition of individuals at high risk for arrhythmias in the general population.National Institutes of Health (K23 N01-HC25195); Doris Duke Charitable Foundation Clinical Scientist Developement Award; Pfizer; National Institutes of Health National Center for Research Resources Shared Instrumentation grant (1S10RR163736-01A1

Properties of Galactic Outflows: Measurements of the Feedback from Star Formation

Properties of starburst-driven outflows in dwarf galaxies are compared to those in more massive galaxies. Over a factor of roughly 10 in galactic rotation speed, supershells are shown to lift warm ionized gas out of the disk at rates up to several times the star formation rate. The amount of mass escaping the galactic potential, in contrast to the disk, does depend on the galactic mass. The temperature of the hottest extended \x emission shows little variation around $\sim 10^{6.7}$ K, and this gas has enough energy to escape from the galaxies with rotation speed less than approximately 130 km/s.Comment: 11 pages + 3 figues. Accepted for publication in the Astrophysical Journa

Analytic solutions of the Rolie Poly model in time-dependent shear

We consider shear flows that comprise of step changes in the shear rate. For these flows, we derive analytic solutions of the Rolie-Poly constitutive equation. Our method involves piecing together solutions for constant rate shear in a variety of flow rate regimes. We obtain solutions for interrupted shear, recoverable strain and non-linear relaxation following cessation of flow. Whenever strong flow is present we neglect reptation, as other mechanisms dominate and for interrupted shear our solution is approximate as we neglect convective constraint release. Our analytic solutions provide new insight in several ways. These include revealing the mechanism of some experimental features of these flows; suggesting a method to extract the polymer contribution to the normal stress in the velocity gradient direction (σyy) from shear stress measurements alone; and a method to isolate the influence of convective constraint release (CCR) from damping function measurements. We also run complementary GLaMM model calculations to verify that insight from our analytic approach translates to this more detailed model

Flow in linearly sheared two dimensional foams: from bubble to bulk scale

We probe the flow of two dimensional foams, consisting of a monolayer of bubbles sandwiched between a liquid bath and glass plate, as a function of driving rate, packing fraction and degree of disorder. First, we find that bidisperse, disordered foams exhibit strongly rate dependent and inhomogeneous (shear banded) velocity profiles, while monodisperse, ordered foams are also shear banded, but essentially rate independent. Second, we introduce a simple model based on balancing the averaged drag forces between the bubbles and the top plate and the averaged bubble-bubble drag forces. This model captures the observed rate dependent flows, and the rate independent flows. Third, we perform independent rheological measurements, both for ordered and disordered systems, and find these to be fully consistent with the scaling forms of the drag forces assumed in the simple model, and we see that disorder modifies the scaling. Fourth, we vary the packing fraction $\phi$ of the foam over a substantial range, and find that the flow profiles become increasingly shear banded when the foam is made wetter. Surprisingly, our model describes flow profiles and rate dependence over the whole range of packing fractions with the same power law exponents -- only a dimensionless number $k$ which measures the ratio of the pre-factors of the viscous drag laws is seen to vary with packing fraction. We find that $k \sim (\phi-\phi_c)^{-1}$, where $\phi_c \approx 0.84$, corresponding to the 2d jamming density, and suggest that this scaling follows from the geometry of the deformed facets between bubbles in contact. Overall, our work suggests a route to rationalize aspects of the ubiquitous Herschel-Bulkley (power law) rheology observed in a wide range of disordered materials.Comment: 16 pages, 14 figures, submitted to Phys. Rev. E. High quality version available at: http://www.physics.leidenuniv.nl/sections/cm/gr

Addition of Inflammatory Biomarkers Did Not Improve Diabetes Prediction in the Community: The Framingham Heart Study

Background: Prior studies have reported conflicting findings with regard to the association of biomarkers in the prediction of incident type 2 diabetes. We evaluated 12 biomarkers as possible diabetes predictors in the Framingham Heart Study. Methods and results: Biomarkers representing inflammation (C-reactive protein, interleukin-6, monocyte chemoattractant protein-1, tumor necrosis factor receptor 2, osteoprotegerin, and fibrinogen), endothelial dysfunction (intercellular adhesion molecule-1), vascular damage (CD40-ligand, P-selectin, and lipoprotein-associated phospholipase A2 mass and activity), and oxidative stress (urinary isoprostanes) were measured in participants without diabetes attending the Offspring seventh (n=2499) or multiethnic Omni second (n=189) examination (1998–2001). Biomarkers were loge transformed and standardized. Multivariable logistic regression tested each biomarker in association with incident diabetes at a follow-up examination (the Offspring eighth and Omni third examination; mean 6.6 years later), with adjustment for age, sex, cohort, body mass index, fasting glucose, systolic blood pressure, high-density lipoprotein cholesterol, triglycerides, and smoking. C statistics were evaluated with and without inflammatory markers. In 2638 participants (56% women, mean age 59 years), 162 (6.1%) developed type 2 diabetes. All biomarkers, excluding osteoprotegerin, were associated with the outcome with adjustment for age, sex, and cohort; however, none remained significant after multivariable adjustment (all P>0.05). The c statistic from the model including only clinical covariates (0.89) did not statistically significantly improve after addition of biomarkers (all P>0.10). Conclusions: Biomarkers representing different inflammatory pathways are associated with incident diabetes but do not remain statistically significant after adjustment for established clinical covariates. Inflammatory biomarkers might not be an effective resource to predict type 2 diabetes in community-based samples

A Single Visualization Technique for Displaying Multiple Metabolite-Phenotype Associations.

To assist with management and interpretation of human metabolomics data, which are rapidly increasing in quantity and complexity, we need better visualization tools. Using a dataset of several hundred metabolite measures profiled in a cohort of ~1500 individuals sampled from a population-based community study, we performed association analyses with eight demographic and clinical traits and outcomes. We compared frequently used existing graphical approaches with a novel 'rain plot' approach to display the results of these analyses. The 'rain plot' combines features of a raindrop plot and a conventional heatmap to convey results of multiple association analyses. A rain plot can simultaneously indicate effect size, directionality, and statistical significance of associations between metabolites and several traits. This approach enables visual comparison features of all metabolites examined with a given trait. The rain plot extends prior approaches and offers complementary information for data interpretation. Additional work is needed in data visualizations for metabolomics to assist investigators in the process of understanding and convey large-scale analysis results effectively, feasibly, and practically

Heterogeneity in Residential Yard Care: Evidence from Boston, Miami, and Phoenix

The management of residential landscapes occurs within a complex socio-ecological system linking household decision-making with ecological properties, multi-scalar human drivers, and the legacy effects of past management. Conventional wisdom suggests that resource-intensive turf grass yards are the most common landscaping outcome, resulting in a presumed homogeneous set of residential landscaping practices throughout North America. We examine this homogenization thesis through an interview-based, cross-site study of residential landscape management in Boston, Phoenix, and Miami. Counter to the homogeneity thesis, we find that yard management practices often exhibit heterogeneity, for example, in groundcover choice or use of chemical inputs. The degree of heterogeneity in management practices varies according to the scale of analysis, and is the outcome of a range of constraints and opportunities to which households respond differently depending on their existing yard and landscaping preferences. This study highlights the importance of multi-scalar and cross-site analyses of decision-making in socio-ecological systems, and presents opportunities for longitudinal and cross-site research to examine the extent to which homogeneity is actually present in the management of residential landscapes over time and in diverse places