Surfing a genetic association interaction network to identify modulators of antibody response to smallpox vaccine

The variation in antibody response to vaccination likely involves small contributions of numerous genetic variants, such as single-nucleotide polymorphisms (SNPs), which interact in gene networks and pathways. To accumulate the bits of genetic information relevant to the phenotype that are distributed throughout the interaction network, we develop a network eigenvector centrality algorithm (SNPrank) that is sensitive to the weak main effects, gene–gene interactions and small higher-order interactions through hub effects. Analogous to Google PageRank, we interpret the algorithm as the simulation of a random SNP surfer (RSS) that accumulates bits of information in the network through a dynamic probabilistic Markov chain. The transition matrix for the RSS is based on a data-driven genetic association interaction network (GAIN), the nodes of which are SNPs weighted by the main-effect strength and edges weighted by the gene–gene interaction strength. We apply SNPrank to a GAIN analysis of a candidate-gene association study on human immune response to smallpox vaccine. SNPrank implicates a SNP in the retinoid X receptor α (RXRA) gene through a network interaction effect on antibody response. This vitamin A- and D-signaling mediator has been previously implicated in human immune responses, although it would be neglected in a standard analysis because its significance is unremarkable outside the context of its network centrality. This work suggests SNPrank to be a powerful method for identifying network effects in genetic association data and reveals a potential vitamin regulation network association with antibody response

Genome-Wide Detection of Allele Specific Copy Number Variation Associated with Insulin Resistance in African Americans from the HyperGEN Study

African Americans have been understudied in genome wide association studies of diabetes and related traits. In the current study, we examined the joint association of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) with fasting insulin and an index of insulin resistance (HOMA-IR) in the HyperGEN study, a family based study with proband ascertainment for hypertension. This analysis is restricted to 1,040 African Americans without diabetes. We generated allele specific CNV genotypes at 872,243 autosomal loci using Birdsuite, a freely available multi-stage program. Joint tests of association for SNPs and CNVs were performed using linear mixed models adjusting for covariates and familial relationships. Our results highlight SNPs associated with fasting insulin and HOMA-IR (rs6576507 and rs8026527, 3.7*10−7≤P≤1.1*10−5) near ATPase, class V, type 10A (ATP10A), and the L Type voltage dependent calcium channel (CACNA1D, rs1401492, P≤5.2*10−6). ATP10A belongs to a family of aminophospholipid-transporting ATPases and has been associated with type 2 diabetes in mice. CACNA1D has been linked to pancreatic beta cell generation in mice. The two most significant copy variable markers (rs10277702 and rs361367; P<2.0*10−4) were in the beta variable region of the T-cell receptor gene (TCRVB). Human and mouse TCR has been shown to mimic insulin and its receptor and could contribute to insulin resistance. Our findings differ from genome wide association studies of fasting insulin and other diabetes related traits in European populations, highlighting the continued need to investigate unique genetic influences for understudied populations such as African Americans

Recent Advances in the Cylindrical-Wave Approach for Electromagnetic Scattering by Subsurface Targets

"The Cylindrical-Wave Approach (CWA) rigorously solves, in the spectral domain,. the electromagnetic forward scattering by a finite set of buried two-dimensional. perfectly-conducting or dielectric objects. In this technique, the field scattered by. underground objects is represented in terms of a superposition of cylindrical. waves. Use is made of the plane-wave spectrum to take into account the. interaction of such waves with the planar interface between air and soil, and. between different layers eventually present in the ground.. In this work we present the progress we recently made to improve the method. In. particular, we introduced rough perturbations in the interfaces between different. media, in order to model the typical unevenness of real surfaces. Moreover, we. faced the fundamental problem of losses in the ground: this improvement is of. significant importance in remote sensing applications, since real soils have often. complex permittivity and conductivity, and sometimes also a complex. permeability.. The rough deviations on the interface between air and soil have been dealt with. by means of the Small Perturbation Method. Reflection and transmission. coefficients have been evaluated in a first order approximation, and the fields. involved in the scattering problem have been expressed as the sum of a zeroorder. (unperturbed) solution, relevant to the basic case of flat surface, and firstorder. perturbation terms, associated to the surface roughness. Numerical results. for a circular, perfectly-conducting or dielectric, cylinder buried under an. interface with sinusoidal profile, are presented. They have been obtained through. an exact evaluation of the spectral integrals, giving results both in near- and farfield. regions.. As far as the ground losses are concerned, a convergent closed-form. representation of the angular spectrum of a cylindrical wave in a generic lossy. medium is presented. To obtain this spectrum, the canonical Sommerfeld. representation of the first-kind Hankel function of integer order has been used;. its integration path has been modified to ensure the convergence of the integral. for complex values of the wavenumber. Some numerical examples are reported. and the limits of the representation are derived in terms of complex spatial. frequency.

Can Rodent Longevity Studies be Both Short and Powerful?

Many rodent experiments have assessed effects of diets, drugs, genes, and other factors on life span. A challenge with such experiments is their long duration, typically over 3.5 years given rodent life spans, thus requiring significant time costs until answers are obtained. We collected longevity data from 15 rodent studies and artificially truncated them at 2 years to assess the extent to which one will obtain the same answer regarding mortality effects. When truncated, the point estimates were not significantly different in any study, implying that in most cases, truncated studies yield similar estimates. The median ratio of variances of coefficients for truncated to full-length studies was 3.4, implying that truncated studies with roughly 3.4 times as many rodents will often have equivalent or greater power. Cost calculations suggest that shorter studies will be more expensive but perhaps not so much to not be worth the reduced time