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

Synthesis and characterization of TiL2 complexes with tridentate (ONO) (S)-NOBIN Schiff-base ligands

Tridentate (ONO) C[subscript 1]-symmetric Schiff base ligands were synthesized by the condensation of (S)-2-amino-2'-hydroxy-1,1'-binaphthyalene with 4-hydroxy-3-phenanthrenecarboxaldehyde or 1-hydroxybenz[a]anthracene-2-carboxaldehyde. C[subscript 2]-symmetric titanium(IV) Schiff base complexes, TiL[subscript 2], were synthesized and characterized with these ligands. The complex with the benz[a]anthryl unit crystallizes in a facial coordination mode, OC-6-1'3'-C, whereas complex with phenanthryl unit crystallizes in a meridional mode, OC-6-22'-A. A comparison between the complexes and the ligands were done in solution using circular dichroism spectroscopy. Preliminary catalytic studies showed that these complexes can catalyze asymmetric carbonyl-ene addition reactions of 2-methoxypropene with aromatic aldehydes with moderate selectivity. The ligands and complexes were characterized by NMR, HRMS, single crystal X-ray diffraction and CD spectroscopy

Modeling Spatial Patterns of Traffic-Related Air Pollutants in Complex Urban Terrain

Background: The relationship between traffic emissions and mobile-source air pollutant concentrations is highly variable over space and time and therefore difficult to model accurately, especially in urban settings with complex terrain. Regression-based approaches using continuous real-time mobile measurements may be able to characterize spatiotemporal variability in traffic-related pollutant concentrations but require methods to incorporate temporally varying meteorology and source strength in a physically interpretable fashion. Objective: We developed a statistical model to assess the joint impact of both meteorology and traffic on measured concentrations of mobile-source air pollutants over space and time. Methods: In this study, traffic-related air pollutants were continuously measured in the Williamsburg neighborhood of Brooklyn, New York (USA), which is affected by traffic on a large bridge and major highway. One-minute average concentrations of ultrafine particulate matter (UFP), fine particulate matter [$\leq 2.5 \mu m$ in aerodynamic diameter $(PM_{2.5})$], and particle-bound polycyclic aromatic hydrocarbons were measured using a mobile-monitoring protocol. Regression modeling approaches to quantify the influence of meteorology, traffic volume, and proximity to major roadways on pollutant concentrations were used. These models incorporated techniques to capture spatial variability, long- and short-term temporal trends, and multiple sources. Results: We observed spatial heterogeneity of both UFP and $PM_{2.5}$ concentrations. A variety of statistical methods consistently found a 15–20% decrease in UFP concentrations within the first 100 m from each of the two major roadways. For $PM_{2.5}$, temporal variability dominated spatial variability, but we observed a consistent linear decrease in concentrations from the roadways. Conclusions: The combination of mobile monitoring and regression analysis was able to quantify local source contributions relative to background while accounting for physically interpretable parameters. Our results provide insight into urban exposure gradients

Quantifying nearness in visual spaces

Preprint versionCybernetic vision systems can be deployed in problem domains where the goal is to achieve results similar to those produced by humans. Fundamentally, these problems consist of evaluation of image content between sets of images. This article contrasts two theoretical frameworks for image comparison, namely, the semantic similarity approach used in the earth mover's distance (EMD) and the integrated region matching (IRM) similarity measure, with the tolerance nearness measure (tNM) based on near set theory. The contribution of this article is a comparison of the image similarity measures EMD, IRM, and tNM, as well as a signature-based approach to calculating the tolerance nearness measure."This research has been supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) grant 194376, the University of Winnipeg Research Start-Up Grant, and the University of Winnipeg Major Research Grant."https://www.tandfonline.com/doi/abs/10.1080/01969722.2012.73279

A Randomized, Controlled, Phase 2 Study of Maralixibat in the Treatment of Itching Associated With Primary Biliary Cholangitis.

Primary biliary cholangitis (PBC) is typically associated with elevated serum bile acid levels and pruritus, but pruritus is often refractory to treatment with existing therapies. This phase 2 study assessed the efficacy and safety of maralixibat, a selective, ileal, apical, sodium-dependent, bile acid transporter inhibitor, in adults with PBC and pruritus. Adults with PBC and pruritus who had received ursodeoxycholic acid (UDCA) for ≥6 months or were intolerant to UDCA were randomized 2:1 to maralixibat (10 or 20 mg/day) or placebo for 13 weeks in combination with UDCA (when tolerated). The primary outcome was change in Adult Itch Reported Outcome (ItchRO™) average weekly sum score (0, no itching; 70, maximum itching) from baseline to week 13/early termination (ET). The study enrolled 66 patients (maralixibat [both doses combined], n = 42; placebo, n = 24). Mean ItchRO™ weekly sum scores decreased from baseline to week 13/ET with maralixibat (-26.5; 95% confidence interval [CI], -31.8, -21.2) and placebo (-23.4; 95% CI, -30.3, -16.4). The difference between groups was not significant (P = 0.48). In the maralixibat and placebo groups, adverse events (AEs) were reported in 97.6% and 70.8% of patients, respectively. Gastrointestinal disorders were the most frequently reported AEs (maralixibat, 78.6%; placebo, 50.0%). Conclusion: Reductions in pruritus did not differ significantly between maralixibat and placebo. However, a large placebo effect may have confounded assessment of pruritus. Lessons learned from this rigorously designed and executed trial are indispensable for understanding how to approach trials assessing pruritus as the primary endpoint and the therapeutic window of bile acid uptake inhibition as a therapeutic strategy in PBC

Genome-wide association of echocardiographic dimensions, brachial artery endothelial function and treadmill exercise responses in the Framingham Heart Study

<p>Abstract</p> <p>Background</p> <p>Echocardiographic left ventricular (LV) measurements, exercise responses to standardized treadmill test (ETT) and brachial artery (BA) vascular function are heritable traits that are associated with cardiovascular disease risk. We conducted a genome-wide association study (GWAS) in the community-based Framingham Heart Study.</p> <p>Methods</p> <p>We estimated multivariable-adjusted residuals for quantitative echocardiography, ETT and BA function traits. Echocardiography residuals were averaged across 4 examinations and included LV mass, diastolic and systolic dimensions, wall thickness, fractional shortening, left atrial and aortic root size. ETT measures (single exam) included systolic blood pressure and heart rate responses during exercise stage 2, and at 3 minutes post-exercise. BA measures (single exam) included vessel diameter, flow-mediated dilation (FMD), and baseline and hyperemic flow responses. Generalized estimating equations (GEE), family-based association tests (FBAT) and variance-components linkage were used to relate multivariable-adjusted trait residuals to 70,987 SNPs (Human 100K GeneChip, Affymetrix) restricted to autosomal SNPs with minor allele frequency ≥0.10, genotype call rate ≥0.80, and Hardy-Weinberg equilibrium p ≥ 0.001.</p> <p>Results</p> <p>We summarize results from 17 traits in up to 1238 related middle-aged to elderly men and women. Results of all association and linkage analyses are web-posted at <url>http://ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007</url>. We confirmed modest-to-strong heritabilities (estimates 0.30–0.52) for several Echo, ETT and BA function traits. Overall, p < 10^-5in either GEE or FBAT models were observed for 21 SNPs (nine for echocardiography, eleven for ETT and one for BA function). The top SNPs associated were (GEE results): LV diastolic dimension, rs1379659 (<it>SLIT2</it>, p = 1.17*10^-7); LV systolic dimension, rs10504543 (<it>KCNB2</it>, p = 5.18*10^-6); LV mass, rs10498091 (p = 5.68*10^-6); Left atrial size, rs1935881 (<it>FAM5C</it>, p = 6.56*10^-6); exercise heart rate, rs6847149 (<it>NOLA1</it>, p = 2.74*10^-6); exercise systolic blood pressure, rs2553268 (<it>WRN</it>, p = 6.3*10^-6); BA baseline flow, rs3814219 (<it>OBFC1</it>, 9.48*10^-7), and FMD, rs4148686 (<it>CFTR</it>, p = 1.13*10^-5). Several SNPs are reasonable biological candidates, with some being related to multiple traits suggesting pleiotropy. The peak LOD score was for LV mass (4.38; chromosome 5); the 1.5 LOD support interval included <it>NRG2</it>.</p> <p>Conclusion</p> <p>In hypothesis-generating GWAS of echocardiography, ETT and BA vascular function in a moderate-sized community-based sample, we identified several SNPs that are candidates for replication attempts and we provide a web-based GWAS resource for the research community.</p

Phenotype-genotype association grid: a convenient method for summarizing multiple association analyses

BACKGROUND: High-throughput genotyping generates vast amounts of data for analysis; results can be difficult to summarize succinctly. A single project may involve genotyping many genes with multiple variants per gene and analyzing each variant in relation to numerous phenotypes, using several genetic models and population subgroups. Hundreds of statistical tests may be performed for a single SNP, thereby complicating interpretation of results and inhibiting identification of patterns of association. RESULTS: To facilitate visual display and summary of large numbers of association tests of genetic loci with multiple phenotypes, we developed a Phenotype-Genotype Association (PGA) grid display. A database-backed web server was used to create PGA grids from phenotypic and genotypic data (sample sizes, means and standard errors, P-value for association). HTML pages were generated using Tcl scripts on an AOLserver platform, using an Oracle database, and the ArsDigita Community System web toolkit. The grids are interactive and permit display of summary data for individual cells by a mouse click (i.e. least squares means for a given SNP and phenotype, specified genetic model and study sample). PGA grids can be used to visually summarize results of individual SNP associations, gene-environment associations, or haplotype associations. CONCLUSION: The PGA grid, which permits interactive exploration of large numbers of association test results, can serve as an easily adapted common and useful display format for large-scale genetic studies. Doing so would reduce the problem of publication bias, and would simplify the task of summarizing large-scale association studies