Family-based association analysis with ordered categorical phenotypes, covariates and interactions

Genetic association analyses of family-based studies with ordered categorical phenotypes are often conducted using methods either for quantitative or for binary traits, which can lead to suboptimal analyses. Here we present an alternative likelihood-based method of analysis for single nucleotide polymorphism (SNP) genotypes and ordered categorical phenotypes in nuclear families of any size. Our approach, which extends our previous work for binary phenotypes, permits straightforward inclusion of covariate, gene-gene and gene-covariate interaction terms in the likelihood, incorporates a simple model for ascertainment and allows for family-specific effects in the hypothesis test. Additionally, our method produces interpretable parameter estimates and valid confidence intervals. We assess the proposed method using simulated data, and apply it to a polymorphism in the c-reactive protein (CRP) gene typed in families collected to investigate human systemic lupus erythematosus. By including sex interactions in the analysis, we show that the polymorphism is associated with anti-nuclear autoantibody (ANA) production in females, while there appears to be no effect in males.

Linkage disequilibrium assessment via log-linear modeling of SNP haplotype frequencies

Analyses of high-density single-nucleotide polymorphism (SNP) data, such as genetic mapping and linkage disequilibrium (LD) studies, require phase-known haplotypes to allow for the correlation between tightly linked loci. However, current SNP genotyping technology cannot determine phase, which must be inferred statistically. In this paper, we present a new Bayesian Markov chain Monte Carlo (MCMC) algorithm for population haplotype frequency estimation, particulary in the context of LD assessment. The novel feature of the method is the incorporation of a log-linear prior model for population haplotype frequencies. We present simulations to suggest that 1) the log-linear prior model is more appropriate than the standard coalescent process in the presence of recombination (>0.02cM between adjacent loci), and 2) there is substantial inflation in measures of LD obtained by a "two-stage" approach to the analysis by treating the "best" haplotype configuration as correct, without regard to uncertainty in the recombination process. Genet Epidemiol 25:106-114, 2003. (C) 2003 Wiley-Liss, Inc.

DK-1D: a drift-kinetic simulation tool for modelling the shear Alfvén wave and its interaction with collisionless plasma

We present a highly accurate tool for the simulation of shear Alfven waves (SAW) in collisionless plasma. SAW are important in space plasma environments because for small perpendicular scale lengths they can support an electric field parallel to the ambient magnetic field. Electrons can be accelerated by the parallel electric field and these waves have been implicated as the source of vibrant auroral displays. However, the parallel electric field carried by SAW is small in comparison to the perpendicular electric field of the wave, making it difficult to measure directly in the laboratory, or by satellites in the near-Earth plasma environment. In this paper, we present a simulation code that provides a means to study in detail the SAW-particle interaction in both space and laboratory plasma. Using idealised, small-amplitude propagating waves with a single perpendicular wavenumber, the simulation code accurately reproduces the damping rates and parallel electric field amplitudes predicted by linear theory for varying temperatures and perpendicular scale lengths. We present a rigorous kinetic derivation of the parallel electric field strength for small-amplitude SAW and show that commonly-used inertial and kinetic approximations are valid except for where the ratio of thermal to Alfv\'{e}n speed is between 0.7 and 1.0. We also present nonlinear simulations of large-amplitude waves and show that in cases of strong damping, the damping rates and parallel electric field strength deviate from linear predictions when wave energies are greater than only a few percent of the plasma kinetic energy, a situation which is often observed in the magnetosphere. The drift-kinetic code provides reliable, testable predictions of the parallel electric field strength which can be investigated directly in the laboratory, and will help to bridge the gap between studies of SAW in man-made and naturally occuring plasma.