Detecting rare functional variants using a wavelet-based test on quantitative and qualitative traits

We conducted a genome-wide association study on the Genetic Analysis Workshop 17 simulated unrelated individuals data using a multilocus score test based on wavelet transformation that we proposed recently. Wavelet transformation is an advanced smoothing technique, whereas the currently popular collapsing methods are the simplest way to smooth multilocus genotypes. The wavelet-based test suppresses noise from the data more effectively, which results in lower type I error rates. We chose a level-dependent threshold for the wavelet-based test to suppress the optimal amount of noise according to the data. We propose several remedies to reduce the inflated type I error rate: using a window of fixed size rather than a gene; using the Bonferroni correction rather than comparing to the maxima of test values for multiple testing corrections; and removing the influence of other factors by using residuals for the association test. A wavelet-based test can detect multiple rare functional variants. Type I error rates can be controlled using the wavelet-based test combined with the mentioned remedies

Patterns of ambulatory care utilization in Taiwan

BACKGROUND: We used the insurance claims of a representative cohort to quantify the patterns of ambulatory care visits, especially the doctor-shopping phenomenon, in Taiwan. METHODS: The ambulatory visit files of the 200,000-person cohort datasets from the National Health Insurance Research Database in 2002 were analyzed. Only a visit with physician consultation would be considered. We computed the visit patterns both by visit count and by patient count. RESULTS: In 2002, there were 182,474 eligible people with 2,443,003 physician consultations. During the year, 87.4% of the cohort had visited physician clinics and 57.5% had visited hospital-based outpatient or emergency departments. On average, a person had 13.4 physician consultations and consulted 3.4 specialties, 5.2 physicians, and 3.9 healthcare facilities in a year. In 2002, 17.3% of the cohort had ever visited different healthcare facilities on the same day; 23.5% had ever visited physicians of the same specialty at different healthcare facilities within 7 days and the percentage of second visits was 3.8% of all visits. Besides, 7.6% of the cohort had visited two or more specialties at the same facility on the same day, and such visits make up 2.5% of all visits. CONCLUSION: The people in Taiwan did visit the physicians and outpatient departments frequently. Many patients not only consulted several physicians of different specialties and at different healthcare facilities during the year, but also switched the physicians and facilities quickly. An effective referral system with efficient data exchange between facilities might be the solution

Genetic variation and evolutionary demography of Fenneropenaeus chinensis populations, as revealed by the analysis of mitochondrial control region sequences

Genetic variation and evolutionary demography of the shrimp Fenneropenaeus chinensis were investigated using sequence data of the complete mitochondrial control region (CR). Fragments of 993 bp of the CR were sequenced for 93 individuals from five localities over most of the species' range in the Yellow Sea and the Bohai Sea. There were 84 variable sites defining 68 haplotypes. Haplotype diversity levels were very high (0.95 ± 0.03-0.99 ± 0.02) in F. chinensis populations, whereas those of nucleotide diversity were moderate to low (0.66 ± 0.36%-0.84 ± 0.46%). Analysis of molecular variance and conventional population statistics (FST ) revealed no significant genetic structure throughout the range of F. chinensis. Mismatch distribution, estimates of population parameters and neutrality tests revealed that the significant fluctuations and shallow coalescence of mtDNA genealogies observed were coincident with estimated demographic parameters and neutrality tests, in implying important past-population size fluctuations or range expansion. Isolation with Migration (IM) coalescence results suggest that F. chinensis, distributed along the coasts of northern China and the Korean Peninsula (about 1000 km apart), diverged recently, the estimated time-split being 12,800 (7,400-18,600) years ago

Plio-Pleistocene sea level and temperature fluctuations in the northwestern Pacific promoted speciation in the globally-distributed flathead mullet Mugil cephalus

<p>Abstract</p> <p>Background</p> <p>The study of speciation in the marine realm is challenging because of the apparent absence of physical barriers to dispersal, which are one of the main drivers of genetic diversity. Although phylogeographic studies using mitochondrial DNA (mtDNA) information often reveal significant genetic heterogeneity within marine species, the evolutionary significance of such diversity is difficult to interpret with these markers. In the northwestern (NW) Pacific, several studies have emphasised the potential importance of sea-level regression during the most recent glaciations as a driver of genetic diversity in marine species. These studies have failed, however, to determine whether the period of isolation was long enough for divergence to attain speciation. Among these marine species, the cosmopolitan estuarine-dependent fish <it>Mugil cephalus </it>represents an interesting case study. Several divergent allopatric mtDNA lineages have been described in this species worldwide, and three occur in sympatry in the NW Pacific.</p> <p>Results</p> <p>Ten nuclear microsatellites were surveyed to estimate the level of genetic isolation of these lineages and determine the role of sea-level fluctuation in the evolution of NW Pacific <it>M. cephalus</it>. Three cryptic species of <it>M. cephalus </it>were identified within this region (NWP1, 2 and 3) using an assignment test on the microsatellite data. Each species corresponds with one of the three mtDNA lineages in the COI phylogenetic tree. NWP3 is the most divergent species, with a distribution range that suggests tropical affinities, while NWP1, with a northward distribution from Taiwan to Russia, is a temperate species. NWP2 is distributed along the warm Kuroshio Current. The divergence of NWP1 from NWP2 dates back to the Pleistocene epoch and probably corresponds to the separation of the Japan and China Seas when sea levels dropped. Despite their subsequent range expansion since this period of glaciation, no gene flow was observed among these three lineages, indicating that speciation has been achieved.</p> <p>Conclusions</p> <p>This study successfully identified three cryptic species in <it>M. cephalus </it>inhabiting the NW Pacific, using a combination of microsatellites and mitochondrial genetic markers. The current genetic architecture of the <it>M. cephalus </it>species complex in the NW Pacific is the result of a complex interaction of contemporary processes and historical events. Sea level and temperature fluctuations during Plio-Pleistocene epochs probably played a major role in creating the marine species diversity of the NW Pacific that is found today.</p

Discovering joint associations between disease and gene pairs with a novel similarity test

Genes in a functional pathway can have complex interactions. A gene might activate or suppress another gene, so it is of interest to test joint associations of gene pairs. To simultaneously detect the joint association between disease and two genes (or two chromosomal regions), we propose a new test with the use of genomic similarities. Our test is designed to detect epistasis in the absence of main effects, main effects in the absence of epistasis, or the presence of both main effects and epistasis. Results: The simulation results show that our similarity test with the matching measure is more powerful than the Pearson's chi(2) test when the disease mutants were introduced at common haplotypes, but is less powerful when the disease mutants were introduced at rare haplotypes. Our similarity tests with the counting measures are more sensitive to marker informativity and linkage disequilibrium patterns, and thus are often inferior to the similarity test with the matching measure and the Pearson 's chi(2) test. Conclusions: In detecting joint associations between disease and gene pairs, our similarity test is a complementary method to the Pearson's chi(2) test

Using an Uncertainty-Coding Matrix in Bayesian Regression Models for Haplotype-Specific Risk Detection in Family Association Studies

Haplotype association studies based on family genotype data can provide more biological information than single marker association studies. Difficulties arise, however, in the inference of haplotype phase determination and in haplotype transmission/non-transmission status. Incorporation of the uncertainty associated with haplotype inference into regression models requires special care. This task can get even more complicated when the genetic region contains a large number of haplotypes. To avoid the curse of dimensionality, we employ a clustering algorithm based on the evolutionary relationship among haplotypes and retain for regression analysis only the ancestral core haplotypes identified by it. To integrate the three sources of variation, phase ambiguity, transmission status and ancestral uncertainty, we propose an uncertainty-coding matrix which combines these three types of variability simultaneously. Next we evaluate haplotype risk with the use of such a matrix in a Bayesian conditional logistic regression model. Simulation studies and one application, a schizophrenia multiplex family study, are presented and the results are compared with those from other family based analysis tools such as FBAT. Our proposed method (Bayesian regression using uncertainty-coding matrix, BRUCM) is shown to perform better and the implementation in R is freely available

Haplotype-based quantitative trait mapping using a clustering algorithm

BACKGROUND: With the availability of large-scale, high-density single-nucleotide polymorphism (SNP) markers, substantial effort has been made in identifying disease-causing genes using linkage disequilibrium (LD) mapping by haplotype analysis of unrelated individuals. In addition to complex diseases, many continuously distributed quantitative traits are of primary clinical and health significance. However the development of association mapping methods using unrelated individuals for quantitative traits has received relatively less attention. RESULTS: We recently developed an association mapping method for complex diseases by mining the sharing of haplotype segments (i.e., phased genotype pairs) in affected individuals that are rarely present in normal individuals. In this paper, we extend our previous work to address the problem of quantitative trait mapping from unrelated individuals. The method is non-parametric in nature, and statistical significance can be obtained by a permutation test. It can also be incorporated into the one-way ANCOVA (analysis of covariance) framework so that other factors and covariates can be easily incorporated. The effectiveness of the approach is demonstrated by extensive experimental studies using both simulated and real data sets. The results show that our haplotype-based approach is more robust than two statistical methods based on single markers: a single SNP association test (SSA) and the Mann-Whitney U-test (MWU). The algorithm has been incorporated into our existing software package called HapMiner, which is available from our website at . CONCLUSION: For QTL (quantitative trait loci) fine mapping, to identify QTNs (quantitative trait nucleotides) with realistic effects (the contribution of each QTN less than 10% of total variance of the trait), large samples sizes (≥ 500) are needed for all the methods. The overall performance of HapMiner is better than that of the other two methods. Its effectiveness further depends on other factors such as recombination rates and the density of typed SNPs. Haplotype-based methods might provide higher power than methods based on a single SNP when using tag SNPs selected from a small number of samples or some other sources (such as HapMap data). Rank-based statistics usually have much lower power, as shown in our study

Significance testing in ridge regression for genetic data.

Published versio

Consistency of Financial Interest Disclosures in the Biomedical Literature: The Case of Coronary Stents

Background Disclosure of authors' financial interests has been proposed as a strategy for protecting the integrity of the biomedical literature. We examined whether authors' financial interests were disclosed consistently in articles on coronary stents published in 2006. Methodology/Principal Findings We searched PubMed for English-language articles published in 2006 that provided evidence or guidance regarding the use of coronary artery stents. We recorded article characteristics, including information about authors' financial disclosures. The main outcome measures were the prevalence, nature, and consistency of financial disclosures. There were 746 articles, 2985 authors, and 135 journals in the database. Eighty-three percent of the articles did not contain disclosure statements for any author (including declarations of no interests). Only 6% of authors had an article with a disclosure statement. In comparisons between articles by the same author, the types of disagreement were as follows: no disclosure statements vs declarations of no interests (64%); specific disclosures vs no disclosure statements (34%); and specific disclosures vs declarations of no interests (2%). Among the 75 authors who disclosed at least 1 relationship with an organization, there were 2 cases (3%) in which the organization was disclosed in every article the author wrote. Conclusions/Significance In the rare instances when financial interests were disclosed, they were not disclosed consistently, suggesting that there are problems with transparency in an area of the literature that has important implications for patient care. Our findings suggest that the inconsistencies we observed are due to both the policies of journals and the behavior of some authors

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO