A genome-wide association study for blood lipid phenotypes in the Framingham Heart Study

BACKGROUND:Blood lipid levels including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) are highly heritable. Genome-wide association is a promising approach to map genetic loci related to these heritable phenotypes.METHODS:In 1087 Framingham Heart Study Offspring cohort participants (mean age 47 years, 52% women), we conducted genome-wide analyses (Affymetrix 100K GeneChip) for fasting blood lipid traits. Total cholesterol, HDL-C, and TG were measured by standard enzymatic methods and LDL-C was calculated using the Friedewald formula. The long-term averages of up to seven measurements of LDL-C, HDL-C, and TG over a ~30 year span were the primary phenotypes. We used generalized estimating equations (GEE), family-based association tests (FBAT) and variance components linkage to investigate the relationships between SNPs (on autosomes, with minor allele frequency [greater than or equal to]10%, genotypic call rate [greater than or equal to]80%, and Hardy-Weinberg equilibrium p [greater than or equal to] 0.001) and multivariable-adjusted residuals. We pursued a three-stage replication strategy of the GEE association results with 287 SNPs (P < 0.001 in Stage I) tested in Stage II (n ~1450 individuals) and 40 SNPs (P < 0.001 in joint analysis of Stages I and II) tested in Stage III (n~6650 individuals).RESULTS:Long-term averages of LDL-C, HDL-C, and TG were highly heritable (h2 = 0.66, 0.69, 0.58, respectively; each P < 0.0001). Of 70,987 tests for each of the phenotypes, two SNPs had p < 10-5 in GEE results for LDL-C, four for HDL-C, and one for TG. For each multivariable-adjusted phenotype, the number of SNPs with association p < 10-4 ranged from 13 to 18 and with p < 10-3, from 94 to 149. Some results confirmed previously reported associations with candidate genes including variation in the lipoprotein lipase gene (LPL) and HDL-C and TG (rs7007797; P = 0.0005 for HDL-C and 0.002 for TG). The full set of GEE, FBAT and linkage results are posted at the database of Genotype and Phenotype (dbGaP). After three stages of replication, there was no convincing statistical evidence for association (i.e., combined P < 10-5 across all three stages) between any of the tested SNPs and lipid phenotypes.CONCLUSION:Using a 100K genome-wide scan, we have generated a set of putative associations for common sequence variants and lipid phenotypes. Validation of selected hypotheses in additional samples did not identify any new loci underlying variability in blood lipids. Lack of replication may be due to inadequate statistical power to detect modest quantitative trait locus effects (i.e., < 1% of trait variance explained) or reduced genomic coverage of the 100K array. GWAS in FHS using a denser genome-wide genotyping platform and a better-powered replication strategy may identify novel loci underlying blood lipids.

Stochastic Refinement of the Visual Hull to Satisfy Photometric and Silhouette Consistency Constraints

An iterative method for reconstructing a 3D polygonal mesh and color texture map from multiple views of an object is presented. In each iteration, the method first estimates a texture map given the current shape estimate. The texture map and its associated residual error image are obtained via maximum a posteriori estimation and reprojection of the multiple views into texture space. Next, the surface shape is adjusted to minimize residual error in texture space. The surface is deformed towards a photometrically-consistent solution via a series of 1D epipolar searches at randomly selected surface points. The texture space formulation has improved computational complexity over standard image-based error approaches, and allows computation of the reprojection error and uncertainty for any point on the surface. Moreover, shape adjustments can be constrained such that the recovered model's silhouette matches those of the input images. Experiments with real world imagery demonstrate the validity of the approach.

Head Tracking via Robust Registration in Texture Map Images

A novel method for 3D head tracking in the presence of large head rotations and facial expression changes is described. Tracking is formulated in terms of color image registration in the texture map of a 3D surface model. Model appearance is recursively updated via image mosaicking in the texture map as the head orientation varies. The resulting dynamic texture map provides a stabilized view of the face that can be used as input to many existing 2D techniques for face recognition, facial expressions analysis, lip reading, and eye tracking. Parameters are estimated via a robust minimization procedure; this provides robustness to occlusions, wrinkles, shadows, and specular highlights. The system was tested on a variety of sequences taken with low quality, uncalibrated video cameras. Experimental results are reported.

Multi-Area Visuotopic Map Complexes in Macaque Striate and Extra-striate Cortex

We propose that a simple, closed-form mathematical expression--the Wedge-Dipole mapping--provides a concise approximation to the full-field, two-dimensional topographic structure of macaque V1, V2, and V3. A single map function, which we term a map complex, acts as a simultaneous descriptor of all three areas. Quantitative estimation of the Wedge-Dipole parameters is provided via 2DG data of central-field V1 topography and a publicly available data set of full-field macaque V1 and V2 topography. Good quantitative agreement is obtained between the data and the model presented here. The increasing importance of fMRI-based brain imaging motivates the development of more sophisticated two-dimensional models of cortical visuotopy, in contrast to the one-dimensional approximations that have been in common use. One reason is that topography has traditionally supplied an important aspect of "ground truth", or validation, for brain imaging, suggesting that further development of high-resolution fMRI will be facilitated by this data analysis. In addition, several important insights into the nature of cortical topography follows from this work. The presence of anisotropy in cortical magnification factor is shown to follow mathematically from the shared boundary conditions at the V1-V2 and V2-V3 borders, and therefore may not causally follow from the existence of columnar systems in these areas, as is widely assumed. An application of the Wedge-Dipole model to localizing aspects of visual processing to specific cortical areas--extending previous work in correlating V1 cortical magnification factor to retinal anatomy or visual psychophysics data--is briefly discussed.

Adaptive Resonance Associative Map: A Hierarchical ART System for Fast Stable Associative Learning

This paper introduces a new class of predictive ART architectures, called Adaptive Resonance Associative Map (ARAM) which performs rapid, yet stable heteroassociative learning in real time environment. ARAM can be visualized as two ART modules sharing a single recognition code layer. The unit for recruiting a recognition code is a pattern pair. Code stabilization is ensured by restricting coding to states where resonances are reached in both modules. Simulation results have shown that ARAM is capable of self-stabilizing association of arbitrary pattern pairs of arbitrary complexity appearing in arbitrary sequence by fast learning in real time environment. Due to the symmetrical network structure, associative recall can be performed in both directions.