Stratified randomization controls better for batch effects in 450K methylation analysis: a cautionary tale

Background: Batch effects in DNA methylation microarray experiments can lead to spurious results if not properly handled during the plating of samples. Methods: Two pilot studies examining the association of DNA methylation patterns across the genome with obesity in Samoan men were investigated for chip- and row-specific batch effects. For each study, the DNA of 46 obese men and 46 lean men were assayed using Illumina's Infinium HumanMethylation450 BeadChip. In the first study (Sample One), samples from obese and lean subjects were examined on separate chips. In the second study (Sample Two), the samples were balanced on the chips by lean/obese status, age group, and census region. We used methylumi, watermelon, and limma R packages, as well as ComBat, to analyze the data. Principal component analysis and linear regression were respectively employed to identify the top principal components and to test for their association with the batches and lean/obese status. To identify differentially methylated positions (DMPs) between obese and lean males at each locus, we used a moderated t-test.Results: Chip effects were effectively removed from Sample Two but not Sample One. In addition, dramatic differences were observed between the two sets of DMP results. After removing'' batch effects with ComBat, Sample One had 94,191 probes differentially methylated at a q-value threshold of 0.05 while Sample Two had zero differentially methylated probes. The disparate results from Sample One and Sample Two likely arise due to the confounding of lean/obese status with chip and row batch effects.Conclusion: Even the best possible statistical adjustments for batch effects may not completely remove them. Proper study design is vital for guarding against spurious findings due to such effects

Endophenotypes for Age-Related Macular Degeneration: Extending Our Reach into the Preclinical Stages of Disease.

The key to reducing the individual and societal burden of age-related macular degeneration (AMD)-related vision loss, is to be able to initiate therapies that slow or halt the progression at a point that will yield the maximum benefit while minimizing personal risk and cost. There is a critical need to find clinical markers that, when combined with the specificity of genetic testing, will identify individuals at the earliest stages of AMD who would benefit from preventive therapies. These clinical markers are endophenotypes for AMD, present in those who are likely to develop AMD, as well as in those who have clinical evidence of AMD. Clinical characteristics associated with AMD may also be possible endophenotypes if they can be detected before or at the earliest stages of the condition, but we and others have shown that this may not always be valid. Several studies have suggested that dynamic changes in rhodopsin regeneration (dark adaptation kinetics and/or critical flicker fusion frequencies) may be more subtle indicators of AMD-associated early retinal dysfunction. One can test for the relevance of these measures using genetic risk profiles based on known genetic risk variants. These functional measures may improve the sensitivity and specificity of predictive models for AMD and may also serve to delineate clinical subtypes of AMD that may differ with respect to prognosis and treatment

Self-Similarity in Random Collision Processes

Kinetics of collision processes with linear mixing rules are investigated analytically. The velocity distribution becomes self-similar in the long time limit and the similarity functions have algebraic or stretched exponential tails. The characteristic exponents are roots of transcendental equations and vary continuously with the mixing parameters. In the presence of conservation laws, the velocity distributions become universal.Comment: 4 pages, 4 figure

Linkage analysis of adult height with parent-of-origin effects in the Framingham Heart Study

Current linkage analysis methods for quantitative traits do not usually incorporate imprinting effects. Here, we carried out genome-wide linkage analysis for loci influencing adult height in the Framingham Heart Study subjects using variance components while allowing for imprinting effects. We used a sex-averaged map for the 22 autosomes, while chromosomes 6, 14, 18, and 19 were also analyzed using sex-specific maps. We compared results from these four analyses: 1) non-imprinted with sex-averaged maps, 2) imprinted with sex-averaged maps, 3) non-imprinted with sex-specific maps, and 4) imprinted with sex-specific maps. We found four regions on three chromosomes (14q32, 18p11-q21, 18q21-22, and 19q13) with LOD scores above 2.0, with a maximum LOD score of 3.12, allowing for imprinting and sex-specific maps, at D18S1364 on 18q21. While we obtained significant evidence of imprinting effects in both the 18p11-q21 and 19q13 regions when using sex-averaged maps, there were no significant differences between the imprinted and non-imprinted LOD scores when we used sex-specific maps. Our results illustrate the importance of allowing for gender-specific effects in linkage analyses, whether these are in the form of gender-specific recombination frequencies, or in the form of imprinting effects

Kinetics of High Pressure Argon-helium Pulsed Gas Discharge

Simulations of a pulsed direct current discharge are performed for a 7% argon in helium mixture at a pressure of 270 Torr using both zero- and one-dimensional models. Kinetics of species relevant to the operation of an optically pumped rare-gas laser are analyzed throughout the pulse duration to identify key reaction pathways. Time dependent densities, electron temperatures, current densities, and reduced electric fields in the positive column are analyzed over a single 20 μs pulse, showing temporal agreement between the two models. Through the use of a robust reaction rate package, radiation trapping is determined to play a key role in reducing Ar(1s5) metastable loss rates through the reaction sequence Ar(1s5)+e− → Ar(1s4)+e− followed by Ar(1s4) → Ar + ℏω⁠. Collisions with He are observed to be responsible for Ar(2p9) mixing, with nearly equal rates to Ar(2p10) and Ar(2p8) ⁠. Additionally, dissociative recombination of Ar2+ is determined to be the dominant electron loss mechanism for the simulated discharge conditions and cavity size

Suggestive Linkage Detected for Blood Pressure Related Traits on 2q and 22q in the Population on the Samoan Islands

Background High blood pressure or hypertension is a major risk factor involved in the development of cardiovascular diseases. We conducted genome-wide variance component linkage analyses to search for loci influencing five blood pressure related traits including the quantitative traits systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP), the dichotomous trait hypertension (HT) and the bivariate quantitative trait SBP-DBP in families residing in American Samoa and Samoa, as well as in the combined sample from the two polities. We adjusted the traits for a number of environmental covariates such as smoking, alcohol consumption, physical activity and material life style. Results We found suggestive univariate linkage for SBP on chromosome 2q35-q37 (LOD 2.4) and for PP on chromosome 22q13 (LOD 2.2), two chromosomal regions that recently have been associated with SBP and PP, respectively. Conclusion We have detected additional evidence for a recently reported locus associated with SBP on chromosome 2q and a susceptibility locus for PP on chromosome 22q. However, differences observed between the results from our three partly overlapping genetically homogenous study samples from the Samoan islands suggest that additional studies should be performed in order to verify these results

Effect of Ar(3p\u3csup\u3e5\u3c/sup\u3e4p; 2p)+M -\u3e Ar(3p\u3csup\u3e5\u3c/sup\u3e4s; 1s)+M branching ratio on optically pumped rare gas laser performance

Optically pumped rare gas laser performance is analyzed as a function of the Ar(3p54p; 2p) + M → Ar(3p54s; 1s) + M branching ratios. Due to the uncertainty in the branching ratios, a sensitivity study is performed to determine the effect on output and absorbed pump laser intensities. The analysis is performed using a radio frequency dielectric barrier discharge as the source of metastable production for a variety of Argon in Helium mixtures over pressures ranging from 200 to 500 Torr. Peak output laser intensities show a factor of 7 increase as the branching ratio is increased from 0.25 to 1.00. The collection of Ar* in Ar(1s4) is inversely proportional to the branching ratio and decreases output laser intensity by reducing the density of species directly involved with lasing

Cooperative Behavior of Kinetically Constrained Lattice Gas Models of Glassy Dynamics

Kinetically constrained lattice models of glasses introduced by Kob and Andersen (KA) are analyzed. It is proved that only two behaviors are possible on hypercubic lattices: either ergodicity at all densities or trivial non-ergodicity, depending on the constraint parameter and the dimensionality. But in the ergodic cases, the dynamics is shown to be intrinsically cooperative at high densities giving rise to glassy dynamics as observed in simulations. The cooperativity is characterized by two length scales whose behavior controls finite-size effects: these are essential for interpreting simulations. In contrast to hypercubic lattices, on Bethe lattices KA models undergo a dynamical (jamming) phase transition at a critical density: this is characterized by diverging time and length scales and a discontinuous jump in the long-time limit of the density autocorrelation function. By analyzing generalized Bethe lattices (with loops) that interpolate between hypercubic lattices and standard Bethe lattices, the crossover between the dynamical transition that exists on these lattices and its absence in the hypercubic lattice limit is explored. Contact with earlier results are made via analysis of the related Fredrickson-Andersen models, followed by brief discussions of universality, of other approaches to glass transitions, and of some issues relevant for experiments.Comment: 59 page