Genetic EpidemiologyThis is an RSS file. You can use it to subscribe to this data in your favourite RSS reader, such as GoogleReader, or to display this data on your own website or blog. Subscribe to this data using MyMedWorm.Subscribe to this data using GoogleReader.Subscribe to this data using Bloglines.Subscribe to this data using MyYahoo.

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In remembrance of Richard SpielmanEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
No Abstract (Source: Genetic Epidemiology)
Source: Genetic Epidemiology - November 20, 2009 Category: Epidemiology Authors: Nancy J. Cox Source Type: journals

Practical considerations for imputation of untyped markers in admixed populationsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Imputation of genotypes for markers untyped in a study sample has become a standard approach to increase genome coverage in genome-wide association studies at practically zero cost. Most methods for imputing missing genotypes extend previously described algorithms for inferring haplotype phase. These algorithms generally fall into three classes based on the underlying model for estimating the conditional distribution of haplotype frequencies: a cluster-based model, a multinomial model, or a population genetics-based model. We compared BEAGLE, PLINK, and MACH, representing the three classes of models, respectively, with spe...
Source: Genetic Epidemiology - November 14, 2009 Category: Epidemiology Authors: Daniel Shriner, Adebowale Adeyemo, Guanjie Chen, Charles N. Rotimi Source Type: journals

Fitting ACE structural equation models to case-control family dataEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We describe an ACE model for binary family data; this structural equation model, which has been described previously, combines a general-family extension of the classic ACE twin model with a (possibly covariate-specific) liability-threshold model for binary outcomes. We then introduce our contribution, a likelihood-based approach to fitting the model to singly ascertained case-control family data. The approach, which involves conditioning on the proband's disease status and also setting prevalence equal to a prespecified value that can be estimated from the data, makes it possible to obtain valid estimates of the A, C, and...
Source: Genetic Epidemiology - November 13, 2009 Category: Epidemiology Authors: K. N. Javaras, J. I. Hudson, N. M. Laird Source Type: journals

Sibship analysis of associations between SNP haplotypes and a continuous trait with application to mammographic densityEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In conclusion, our proposed method retains the benefits of the between- and within-pair analysis for pairs of siblings and can be implemented in standard software. Genet. Epidemiol. 2009. © 2009 Wiley-Liss, Inc. (Source: Genetic Epidemiology)
Source: Genetic Epidemiology - November 13, 2009 Category: Epidemiology Authors: J. Stone, L. C. Gurrin, V. M. Hayes, M. C. Southey, J. L. Hopper, G. B. Byrnes Source Type: journals

Comparing apples and oranges: equating the power of case-control and quantitative trait association studiesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Genome-wide association studies have achieved unprecedented success in the identification of novel genes and pathways implicated in complex traits. Typically, studies for disease use a case-control (CC) design and studies for quantitative traits (QT) are population based. The question that we address is what is the equivalence between CC and QT association studies in terms of detection power and sample size? We compare the binary and continuous traits by assuming a threshold model for disease and assuming that the effect size on disease liability has similar feature as on QT. We derive the approximate ratio of the non-cent...
Source: Genetic Epidemiology - November 13, 2009 Category: Epidemiology Authors: Jian Yang, Naomi R. Wray, Peter M. Visscher Source Type: journals

Variance-components methods for linkage and association analysis of ordinal traits in general pedigreesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Many complex human diseases such as alcoholism and cancer are rated on ordinal scales. Well-developed statistical methods for the genetic mapping of quantitative traits may not be appropriate for ordinal traits. We propose a class of variance-component models for the joint linkage and association analysis of ordinal traits. The proposed models accommodate arbitrary pedigrees and allow covariates and gene-environment interactions. We develop efficient likelihood-based inference procedures under the proposed models. The maximum likelihood estimators are approximately unbiased, normally distributed, and statistically efficien...
Source: Genetic Epidemiology - November 13, 2009 Category: Epidemiology Authors: G. Diao, D. Y. Lin Source Type: journals

Detecting rare variants for complex traits using family and unrelated dataEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Large genome-wide association studies (GWAS) have been performed to detect common genetic variants involved in common diseases, but most of the variants found this way account for only a small portion of the trait variance. Furthermore, candidate gene-based resequencing suggests that many rare genetic variants contribute to the trait variance of common diseases. Here we propose two designs, sibpair and unrelated-case designs, to detect rare genetic variants in either a candidate gene-based or genome-wide association analysis. First we show that we can detect and classify together rare risk haplotypes using a relatively sma...
Source: Genetic Epidemiology - October 21, 2009 Category: Epidemiology Authors: Xiaofeng Zhu, Tao Feng, Yali Li, Qing Lu, Robert C. Elston Source Type: journals

Meta-analysis of genome-wide association studies: no efficiency gain in using individual participant dataEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
To identify genetic variants with modest effects on complex human diseases, a growing number of networks or consortia are created for sharing data from multiple genome-wide association studies on the same disease or related disorders. A central question in this enterprise is whether to obtain summary results or individual participant data from relevant studies. We show theoretically and numerically that meta-analysis of summary results is statistically as efficient as joint analysis of individual participant data (provided that both analyses are performed properly under the same modeling assumptions). We illustrate this eq...
Source: Genetic Epidemiology - October 20, 2009 Category: Epidemiology Authors: D. Y. Lin, D. Zeng Source Type: journals

An evaluation of statistical approaches to rare variant analysis in genetic association studiesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Genome-wide association (GWA) studies have proved to be extremely successful in identifying novel common polymorphisms contributing effects to the genetic component underlying complex traits. Nevertheless, one source of, as yet, undiscovered genetic determinants of complex traits are those mediated through the effects of rare variants. With the increasing availability of large-scale re-sequencing data for rare variant discovery, we have developed a novel statistical method for the detection of complex trait associations with these loci, based on searching for accumulations of minor alleles within the same functional unit. ...
Source: Genetic Epidemiology - October 6, 2009 Category: Epidemiology Authors: Andrew P. Morris, Eleftheria Zeggini Source Type: journals

Comparisons of multi-marker association methods to detect association between a candidate region and diseaseEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The joint use of information from multiple markers may be more effective to reveal association between a genomic region and a trait than single marker analysis. In this article, we compare the performance of seven multi-marker methods. These methods include (1) single marker analysis (either the best-scoring single nucleotide polymorphism in a candidate region or a combined test based on Fisher's method); (2) fixed effects regression models where the predictors are either the observed genotypes in the region, principal components that explain a proportion of the genetic variation, or predictors based on Fourier transformat...
Source: Genetic Epidemiology - October 5, 2009 Category: Epidemiology Authors: David H. Ballard, Judy Cho, Hongyu Zhao Source Type: journals

Software for generating liability distributions for pedigrees conditional on their observed disease states and covariatesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
For many multifactorial diseases, aetiology is poorly understood. A major research aim is the identification of disease predictors (environmental, biological, and genetic markers). In order to achieve this, a two-stage approach is proposed. The initial or synthesis stage combines observed pedigree data with previous genetic epidemiological research findings, to produce estimates of pedigree members' disease risk and predictions of their disease liability. A further analysis stage uses the latter as inputs to look for associations with potential disease markers. The incorporation of previous research findings into an analys...
Source: Genetic Epidemiology - September 21, 2009 Category: Epidemiology Authors: Desmond D. Campbell, Pak C. Sham, Jo Knight, Harvey Wickham, Sabine Landau Source Type: journals

A cross-validation procedure for general pedigrees and matched odds ratio fitness metric implemented for the multifactor dimensionality reduction pedigree disequilibrium testEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We report that the CV procedure is valid with the permutation test, MDR-PDT performs similarly with 5- and 10-fold CV, and that the MOR is more powerful than PE as the fitness metric for MDR-PDT. Genet. Epidemiol. 2009. © 2009 Wiley-Liss, Inc. (Source: Genetic Epidemiology)
Source: Genetic Epidemiology - August 20, 2009 Category: Epidemiology Authors: Todd L. Edwards, Eric Torstensen, Scott Dudek, Eden R. Martin, Marylyn D. Ritchie Source Type: journals

Genetic comparison of a Croatian isolate and CEPH European foundersEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Human isolates have been postulated as a good resource for the identification of QTL due to reduced genetic diversity and a more homogeneous environment. Isolates may also have increased linkage disequilibrium (LD) due to small effective population size and, either loss or increase in frequency of alleles that are rare in the general population from which they originate. Here we investigate the difference in allele and genotype frequencies, LD and homozygous tracts between an isolate - several villages from the island of Vis in Croatia - and an outbred population of European origin: the Hapmap CEPH founders. Using the Huma...
Source: Genetic Epidemiology - August 19, 2009 Category: Epidemiology Authors: Pau Navarro, Véronique Vitart, Caroline Hayward, Albert Tenesa, Lina Zgaga, Danica Juricic, Ozren Polasek, Nicholas D. Hastie, Igor Rudan, Harry Campbell, Alan F. Wright, Chris S. Haley, Sara A. Knott Source Type: journals

Shades of gray: a comparison of linkage disequilibrium between Hutterites and EuropeansEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Founder or isolated populations have advantages for genetic studies due to decreased genetic and environmental heterogeneity. However, whereas longer-range linkage disequilibrium (LD) in these populations is expected to facilitate gene localization, extensive LD may actually limit the ability for gene discovery. The North American Hutterite population is one of the best characterized young founder populations and members of this isolate have been the subjects of our studies of complex traits, including fertility, asthma and cardiovascular disease, for >20 years. Here, we directly assess the patterns and extent of global LD...
Source: Genetic Epidemiology - August 19, 2009 Category: Epidemiology Authors: Emma E. Thompson, Ying Sun, Dan Nicolae, Carole Ober Source Type: journals

Extent and distribution of linkage disequilibrium in the Old Order AmishEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Knowledge of the extent and distribution of linkage disequilibrium (LD) is critical to the design and interpretation of gene mapping studies. Because the demographic history of each population varies and is often not accurately known, it is necessary to empirically evaluate LD on a population-specific basis. Here we present the first genome-wide survey of LD in the Old Order Amish (OOA) of Lancaster County Pennsylvania, a closed population derived from a modest number of founders. Specifically, we present a comparison of LD between OOA individuals and US Utah participants in the International HapMap project (abbreviated CE...
Source: Genetic Epidemiology - August 19, 2009 Category: Epidemiology Authors: Cristopher V. Van Hout, Albert M. Levin, Evadnie Rampersaud, Haiqing Shen, Jeffrey R. O'Connell, Braxton D. Mitchell, Alan R. Shuldiner, Julie A. Douglas Source Type: journals

Association tests using kernel-based measures of multi-locus genotype similarity between individualsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We present simulation results comparing our statistic to the U-statistic-based method by Schaid et al. ([2005] Am. J. Hum. Genet. 76:780-793) and another statistic by Wessel and Schork ([2006] Am. J. Hum. Genet. 79:792-806). We consider a variety of different disease models and assumptions about how many SNPs within the gene are actually associated with disease. Our results indicate that our statistic has higher power than other statistics under most realistic conditions. Genet. Epidemiol. 2009. © 2009 Wiley-Liss, Inc. (Source: Genetic Epidemiology)
Source: Genetic Epidemiology - August 19, 2009 Category: Epidemiology Authors: Indranil Mukhopadhyay, Eleanor Feingold, Daniel E. Weeks, Anbupalam Thalamuthu Source Type: journals

Detection of parent-of-origin effects using general pedigree dataEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study, we extend PAT to accommodate general pedigree data by proposing the pedigree PAT (PPAT) statistic, which uses all informative family trios from pedigrees. To fully utilize pedigrees with some missing genotypes, we further develop the Monte Carlo (MC) PPAT (MCPPAT) statistic based on MC sampling and estimation. Extensive simulations were carried out to evaluate the performance of the proposed methods. Under the assumption that the pedigrees and their associated affection patterns are randomly drawn from a population of pedigrees with at least one affected offspring, we demonstrated that MCPPAT is a valid test...
Source: Genetic Epidemiology - August 12, 2009 Category: Epidemiology Authors: Ji-Yuan Zhou, Jie Ding, Wing K. Fung, Shili Lin Source Type: journals

Correcting "winner's curse" in odds ratios from genomewide association findings for major complex human diseasesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Genome-wide association studies (GWAS) provide an important approach for identifying common genetic variants that predispose to human disease. However, odds ratio (OR) estimates for the reported findings from GWAS discovery data are typically affected by a bias away from the null sometimes referred to the "winner's curse". Also standard confidence intervals (CIs) may have far from the desired coverage rates. We applied a bias reduction method to GWAS findings from several major complex human diseases, including breast cancer, colorectal cancer, lung cancer, prostate cancer, type I diabetes, and type II diabetes. We found t...
Source: Genetic Epidemiology - July 28, 2009 Category: Epidemiology Authors: Hua Zhong, Ross L. Prentice Source Type: journals

Were genome-wide linkage studies a waste of time? Exploiting candidate regions within genome-wide association studiesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
A central issue in genome-wide association (GWA) studies is assessing statistical significance while adjusting for multiple hypothesis testing. An equally important question is the statistical efficiency of the GWA design as compared to the traditional sequential approach in which genome-wide linkage analysis is followed by region-wise association mapping. Nevertheless, GWA is becoming more popular due in part to cost efficiency: commercially available 1M chips are nearly as inexpensive as a custom-designed 10 K chip. It is becoming apparent, however, that most of the on-going GWA studies with 2,000-5,000 samples are in fa...
Source: Genetic Epidemiology - July 22, 2009 Category: Epidemiology Authors: Yun J. Yoo, Shelley B. Bull, Andrew D. Paterson, Daryl Waggott, The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group, Lei Sun Source Type: journals

Visualizing disease associations: graphic analysis of frequency distributions as a function of age using moving average plots (MAP) with application to Alzheimer's and Parkinson's diseaseEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Age-related variation in marker frequency can be a confounder in association studies, leading to both false-positive and false-negative findings and subsequently to inconsistent reproducibility. We have developed a simple method, based on a novel extension of moving average plots (MAP), which allows investigators to inspect the frequency data for hidden age-related variations. MAP uses the standard case-control association data and generates a birds-eye view of the frequency distributions across the age spectrum; a picture in which one can see if, how, and when the marker frequencies in cases differ from that in controls. ...
Source: Genetic Epidemiology - July 6, 2009 Category: Epidemiology Authors: Haydeh Payami, Denise M. Kay, Cyrus P. Zabetian, Gerard D. Schellenberg, Stewart A. Factor, Colin C. McCulloch Source Type: journals

Methods for detecting interactions between genetic polymorphisms and prenatal environment exposure with a mother-child designEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Prenatal exposures such as polycyclic aromatic hydrocarbons and early postnatal environmental exposures are of particular concern because of the heightened susceptibility of the fetus and infant to diverse environmental pollutants. Marked inter-individual variation in response to the same level of exposure was observed in both mothers and their newborns, indicating that susceptibility might be due to genetic factors. With the mother-child pair design, existing methods developed for parent-child trio data or random sample data are either not applicable or not designed to optimally use the information. To take full advantage...
Source: Genetic Epidemiology - July 5, 2009 Category: Epidemiology Authors: Shuang Wang, Tian Zheng, Stephen Chanock, Wieslaw Jedrychowski, Frederica P. Perera Source Type: journals

Assessment of SNP streak statistics using gene drop simulation with linkage disequilibriumEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We describe methods and programs for simulating the genotypes of individuals in a pedigree at large numbers of linked loci when the alleles of the founders are under linkage disequilibrium. Both simulation and estimation of linkage disequilibrium models are shown to be feasible on a genome wide scale. The methods are applied to evaluate the statistical significance of streaks of loci at which sets of related individuals share a common allele. The effects of properly allowing for linkage disequilibrium are shown to be important as they explain many of the large observations. This is illustrated by reanalysis of a previously...
Source: Genetic Epidemiology - July 5, 2009 Category: Epidemiology Authors: Alun Thomas Source Type: journals

Single-marker and two-marker association tests for unphased case-control genotype data, with a power comparisonEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In case-control single nucleotide polymorphism (SNP) data, the allele frequency, Hardy Weinberg Disequilibrium, and linkage disequilibrium (LD) contrast tests are three distinct sources of information about genetic association. While all three tests are typically developed in a retrospective context, we show that prospective logistic regression models may be developed that correspond conceptually to the retrospective tests. This approach provides a flexible framework for conducting a systematic series of association analyses using unphased genotype data and any number of covariates. For a single stage study, two single-mar...
Source: Genetic Epidemiology - June 25, 2009 Category: Epidemiology Authors: Sulgi Kim, Nathan J. Morris, Sungho Won, Robert C. Elston Source Type: journals

Prostate cancer segregation analyses using 4390 families from UK and Australian population-based studiesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Familial aggregation of prostate cancer is likely to be due to multiple susceptibility loci, perhaps acting in conjunction with shared lifestyle risk factors. Models that assume a single mode of inheritance may be unrealistic. We analyzed genetic models of susceptibility to prostate cancer using segregation analysis of occurrence in families ascertained through population-based series totaling 4390 incident cases. We investigated major gene models (dominant, recessive, general, X-linked), polygenic models, and mixed models of susceptibility using the pedigree analysis software MENDEL. The hypergeometric model was used to a...
Source: Genetic Epidemiology - June 5, 2009 Category: Epidemiology Authors: Robert J. MacInnis, Antonis C. Antoniou, Rosalind A. Eeles, Gianluca Severi, Michelle Guy, Lesley McGuffog, Amanda L. Hall, Lynne T. O'Brien, Rosemary A. Wilkinson, David P. Dearnaley, Audrey T. Ardern-Jones, Alan Horwich, Vincent S. Khoo, Christopher C. Source Type: journals

Bayesian mixture modeling of gene-environment and gene-gene interactionsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We describe a hierarchical mixture model that allows all interactions to be investigated simultaneously, but assumes the effects come from a mixture prior with two components, one that reflects small null effects and the second for epidemiologically significant effects. Effects from the former are effectively set to zero, hence increasing the power for the detection of real signals. The prior framework is very flexible, which allows substantive information to be incorporated into the analysis. We illustrate the methods first using simulation, and then on data from a case-control study of lung cancer in Central and Eastern ...
Source: Genetic Epidemiology - June 2, 2009 Category: Epidemiology Authors: Jon Wakefield, Frank De Vocht,, Rayjean J. Hung Source Type: journals

A novel method for haplotype clustering and visualizationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In population genetics, it is common to represent the haplotype diversity at a genomic region between multiple populations using well-constructed visual representations. This typically requires the chromosomes from these populations to be grouped according to some definition of haplotypic similarity. Here, we introduce a novel algorithm for clustering haplotypes with the specific aim of addressing haplotype diversity within or between populations. The algorithm allows for missing data in the haplotypes and appropriately downweighs single nucleotide polymorphisms with higher extent of missingness. By identifying the canonic...
Source: Genetic Epidemiology - May 30, 2009 Category: Epidemiology Authors: Yik Y. Teo, Kerrin S. Small Source Type: journals

Discovering genetic ancestry using spectral graph theoryEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
As one approach to uncovering the genetic underpinnings of complex disease, individuals are measured at a large number of genetic variants (usually SNPs) across the genome and these SNP genotypes are assessed for association with disease status. We propose a new statistical method called Spectral-GEM for the analysis of genome-wide association studies; the goal of Spectral-GEM is to quantify the ancestry of the sample from such genotypic data. Ignoring structure due to differential ancestry can lead to an excess of spurious findings and reduce power. Ancestry is commonly estimated using the eigenvectors derived from princi...
Source: Genetic Epidemiology - May 21, 2009 Category: Epidemiology Authors: Ann B. Lee, Diana Luca, Lambertus Klei, Bernie Devlin, Kathryn Roeder Source Type: journals

Parametric model-based statistics for possible genotyping errors and sample stratification in sibling-pair SNP dataEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The detection of genotyping errors, based on apparent Mendelian incompatibilities in a sample of sib-pairs, is a complicated problem. In the case of a single marker and unknown parental genotypes, all combinations of sib-pair genotypes are self-consistent. Moreover, the observed deviation from equilibrium genotype frequencies may result from genotyping errors as well as from the sample's stratification. This in turn, may profoundly affect the results of association and linkage analyses, and therefore an estimation of these factors should be done beforehand. Here we present several parametric models, and using likelihood ra...
Source: Genetic Epidemiology - May 19, 2009 Category: Epidemiology Authors: Michael Korostishevsky, Ida Malkin, Tim Spector, Gregory Livshits Source Type: journals

Avoiding the high Bonferroni penalty in genome-wide association studiesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study, we compare recently developed Meff methods and validate them by the permutation test with 10,000 random shuffles using two real GWAS data sets: an Illumina 1M BeadChip and an Affymetrix GeneChip® Human Mapping 500K Array Set. Our results show that the simpleM method produces the best approximation of the permutation threshold, and it does so in the shortest amount of time. We also show that Meff is indeed valid on a genome-wide scale in these data sets based on statistical theory and significance tests. The significance thresholds derived can provide practical guidelines for other studies using similar popu...
Source: Genetic Epidemiology - May 15, 2009 Category: Epidemiology Authors: Xiaoyi Gao, Lewis C. Becker, Diane M. Becker, Joshua D. Starmer, Michael A. Province Source Type: journals

Shrinkage estimation for robust and efficient screening of single-SNP association from case-control genome-wide association studiesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Population-based case-control design has become one of the most popular approaches for conducting genome-wide association scans for rare diseases like cancer. In this article, we propose a novel method for improving the power of the widely used single-single-nucleotide polymorphism (SNP) two-degrees-of-freedom (2 d.f.) association test for case-control studies by exploiting the common assumption of Hardy-Weinberg Equilibrium (HWE) for the underlying population. A key feature of the method is that it can relax the assumed model constraints via a completely data-adaptive shrinkage estimation approach so that the number of fa...
Source: Genetic Epidemiology - May 11, 2009 Category: Epidemiology Authors: Sheng Luo, Bhramar Mukherjee, Jinbo Chen, Nilanjan Chatterjee Source Type: journals

Case-only genome-wide interaction study of disease risk, prognosis and treatmentEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Case-control genome-wide association (GWA) studies have facilitated the identification of susceptibility loci for many complex diseases; however, these studies are often not adequately powered to detect gene-environment (G×E) and gene-gene (G×G) interactions. Case-only studies are more efficient than case-control studies for detecting interactions and require no data on control subjects. In this article, we discuss the concept and utility of the case-only genome-wide interaction (COGWI) study, in which common genetic variants, measured genome-wide, are screened for association with environmental exposures or genetic vari...
Source: Genetic Epidemiology - May 11, 2009 Category: Epidemiology Authors: Brandon L. Pierce, Habibul Ahsan Source Type: journals

Association test of multiallelic gene copy numbers in family triosEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We present theoretical derivation of the statistics and results of simulation studies that show robustness of our approach and power under several genetic models. Genet. Epidemiol. 2009. © 2009 Wiley-Liss, Inc. (Source: Genetic Epidemiology)
Source: Genetic Epidemiology - April 29, 2009 Category: Epidemiology Authors: Sadeep Shrestha, Brahim Aissani, Hemant K. Tiwari, Howard W. Wiener Source Type: journals

On the use of phylogeny-based tests to detect association between quantitative traits and haplotypesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This study focuses on ALTree-q association test which is based on one-way analyses of variance (ANOVA) performed at the different levels of the tree. The statistical properties (type-one error and power rates) were estimated through simulations under different genetic models and were compared to another phylogeny-based test, TreeScan, (Templeton, 2005) and to a haplotypic omnibus test consisting in a one-way ANOVA between all haplotypes. For dominant and additive models ALTree-q is usually the most powerful test whereas TreeScan performs better under a recessive model. However, power depends strongly on the recurrence rate...
Source: Genetic Epidemiology - April 27, 2009 Category: Epidemiology Authors: Claire Bardel, Vincent Danjean, Pierre Morange, Emmanuelle Génin, Pierre Darlu Source Type: journals

Genome-wide association scans for secondary traits using case-control samplesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Genome-wide association studies (GWAS) require considerable investment, so researchers often study multiple traits collected on the same set of subjects to maximize return. However, many GWAS have adopted a case-control design; improperly accounting for case-control ascertainment can lead to biased estimates of association between markers and secondary traits. We show that under the null hypothesis of no marker-secondary trait association, naïve analyses that ignore ascertainment or stratify on case-control status have proper Type I error rates except when both the marker and secondary trait are independently associated w...
Source: Genetic Epidemiology - April 18, 2009 Category: Epidemiology Authors: Genevieve M. Monsees, Rulla M. Tamimi, Peter Kraft Source Type: journals

Gene-environment interaction tests for dichotomous traits in trios and sibshipsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
When testing for genetic effects, failure to account for a gene-environment interaction can mask the true association effects of a genetic marker with disease. Family-based association tests are popular because they are completely robust to population substructure and model misspecification. However, when testing for an interaction, failure to model the main genetic effect correctly can lead to spurious results. Here we propose a family-based test for interaction that is robust to model misspecification, but still sensitive to an interaction effect, and can handle continuous covariates and missing parents. We extend the FB...
Source: Genetic Epidemiology - April 13, 2009 Category: Epidemiology Authors: Thomas J. Hoffmann, Christoph Lange, Stijn Vansteelandt, Nan M. Laird Source Type: journals

A novel haplotype-sharing approach for genome-wide case-control association studies implicates the calpastatin gene in Parkinson's diseaseEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The large number of markers considered in a genome-wide association study (GWAS) has resulted in a simplification of analyses conducted. Most studies are analyzed one marker at a time using simple tests like the trend test. Methods that account for the special features of genetic association studies, yet remain computationally feasible for genome-wide analysis, are desirable as they may lead to increased power to detect associations. Haplotype sharing attempts to translate between population genetics and genetic epidemiology. Near a recent mutation that increases disease risk, haplotypes of case participants should be more...
Source: Genetic Epidemiology - April 13, 2009 Category: Epidemiology Authors: Andrew S. Allen, Glen A. Satten Source Type: journals

A note on permutation tests for genetic association analysis of quantitative traits when variances are heterogeneousEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The genetic dissection of quantitative traits, or endophenotypes, usually involves genetic linkage or association analysis in pedigrees and subsequent fine mapping association analysis in the population. The ascertainment procedure for quantitative traits often results in unequal variance of observations. For example, some phenotypes may be clinically measured whilst others are from self-reports, or phenotypes may be the average of multiple measures but with the number of measurements varying. The resulting heterogeneity of variance poses no real problem for analysis, as long as it is properly modelled and thereby taken in...
Source: Genetic Epidemiology - April 13, 2009 Category: Epidemiology Authors: Danielle Posthuma, Dirk-Jan de Koning, Conor Dolan, Michael E. Goddard, Peter M. Visscher Source Type: journals

A modified forward multiple regression in high-density genome-wide association studies for complex traitsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Genome-wide association studies (GWAS) have been widely used to identify genetic effects on complex diseases or traits. Most currently used methods are based on separate single-nucleotide polymorphism (SNP) analyses. Because this approach requires correction for multiple testing to avoid excessive false-positive results, it suffers from reduced power to detect weak genetic effects under limited sample size. To increase the power to detect multiple weak genetic factors and reduce false-positive results caused by multiple tests and dependence among test statistics, a modified forward multiple regression (MFMR) approach is pr...
Source: Genetic Epidemiology - April 13, 2009 Category: Epidemiology Authors: Xiangjun Gu, Ralph F. Frankowski, Gary L. Rosner, Mary Relling, Bo Peng, Christopher I. Amos Source Type: journals

On testing for genetic association in case-control studies when population allele frequencies are knownEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study we consider frequentist and Bayesian statistical methods for testing for SNP genotype association when population MAFs are known and when both cases and controls are available. We demonstrate that for rare diseases the most powerful frequentist design is, somewhat counterintuitively, to actively discard the controls even though they contain information on the association. In contrast we develop a Bayesian test which uses all available information (cases and controls) and appears to exhibit uniformaly greater power than all frequentist methods we considered. Genet. Epidemiol. 2009. © 2009 Wiley Liss, Inc. (So...
Source: Genetic Epidemiology - April 13, 2009 Category: Epidemiology Authors: A. Antonyuk, C. Holmes Source Type: journals

A propensity score approach to correction for bias due to population stratification using genetic and non-genetic factorsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Confounding due to population stratification (PS) arises when differences in both allele and disease frequencies exist in a population of mixed racial/ethnic subpopulations. Genomic control, structured association, principal components analysis (PCA), and multidimensional scaling (MDS) approaches have been proposed to address this bias using genetic markers. However, confounding due to PS can also be due to non-genetic factors. Propensity scores are widely used to address confounding in observational studies but have not been adapted to deal with PS in genetic association studies. We propose a genomic propensity score (GPS...
Source: Genetic Epidemiology - April 11, 2009 Category: Epidemiology Authors: Huaqing Zhao, Timothy R. Rebbeck, Nandita Mitra Source Type: journals

Pathway analysis by adaptive combination of P-valuesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
It is increasingly recognized that pathway analyses - a joint test of association between the outcome and a group of single nucleotide polymorphisms (SNPs) within a biological pathway - could potentially complement single-SNP analysis and provide additional insights for the genetic architecture of complex diseases. Building upon existing P-value combining methods, we propose a class of highly flexible pathway analysis approaches based on an adaptive rank truncated product statistic that can effectively combine evidence of associations over different SNPs and genes within a pathway. The statistical significance of the pathw...
Source: Genetic Epidemiology - March 30, 2009 Category: Epidemiology Authors: Kai Yu, Qizhai Li, Andrew W. Bergen, Ruth M. Pfeiffer, Philip S. Rosenberg, Neil Caporaso, Peter Kraft, Nilanjan Chatterjee Source Type: journals

Case-control association testing in the presence of unknown relationshipsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Genome-wide association studies result in inflated false-positive results when unrecognized cryptic relatedness exists. A number of methods have been proposed for testing association between markers and disease with a correction for known pedigree-based relationships. However, in most case-control studies, relationships are generally unknown, yet the design is predicated on the assumption of at least ancestral relatedness among cases. Here, we focus on adjusting cryptic relatedness when the genealogy of the sample is unknown, particularly in the context of samples from isolated populations where cryptic relatedness may be ...
Source: Genetic Epidemiology - March 30, 2009 Category: Epidemiology Authors: Yoonha Choi, Ellen M. Wijsman, Bruce S. Weir Source Type: journals

A comparison of analytical methods for genetic association studiesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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Source: Genetic Epidemiology - March 22, 2009 Category: Epidemiology Authors: Alison A. Motsinger-Reif, David M. Reif, Theresa J. Fanelli, Marylyn D. Ritchie Source Type: journals

Mapping quantitative traits in unselected families: algorithms and examplesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Linkage analysis has been widely used to identify from family data genetic variants influencing quantitative traits. Common approaches have both strengths and limitations. Likelihood ratio tests typically computed in variance component analysis can accommodate large families but are highly sensitive to departure from normality assumptions. Regression-based approaches are more robust but their use has primarily been restricted to nuclear families. In this paper, we develop methods for mapping quantitative traits in moderately large pedigrees. Our methods are based on the score statistic, which in contrast to the likelihood ...
Source: Genetic Epidemiology - March 12, 2009 Category: Epidemiology Authors: Josée Dupuis, Jianxin Shi, Alisa K. Manning, Emelia J. Benjamin, James B. Meigs, L. Adrienne Cupples, David Siegmund Source Type: journals

STrengthening the REporting of Genetic Association Studies (STREGA) - an extension of the STROBE statementEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information in the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association studies (STREGA) initiative builds on the STrengthening the Reporting of OBservational Studies in Epidemiology (STROBE) Statement and provides additions to 12 of the 22 items on the STROBE checklist. The...
Source: Genetic Epidemiology - March 10, 2009 Category: Epidemiology Authors: Julian Little, Julian P. T. Higgins, John P. A. Ioannidis, David Moher, France Gagnon, Erik von Elm, Muin J. Khoury, Barbara Cohen, George Davey-Smith, Jeremy Grimshaw, Paul Scheet, Marta Gwinn, Robin E. Williamson, Guang Yong Zou, Kim Hutchings, Candice Source Type: journals

Identification of gene-gene interactions in the presence of missing data using the multifactor dimensionality reduction methodEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Gene-gene interaction is believed to play an important role in understanding complex traits. Multifactor dimensionality reduction (MDR) was proposed by Ritchie et al. [2001. Am J Hum Genet 69:138-147] to identify multiple loci that simultaneously affect disease susceptibility. Although the MDR method has been widely used to detect gene-gene interactions, few studies have been reported on MDR analysis when there are missing data. Currently, there are four approaches available in MDR analysis to handle missing data. The first approach uses only complete observations that have no missing data, which can cause a severe loss of...
Source: Genetic Epidemiology - February 26, 2009 Category: Epidemiology Authors: Junghyun Namkung, Robert C. Elston, Jun-Mo Yang, Taesung Park Source Type: journals

Adapting the logical basis of tests for Hardy-Weinberg Equilibrium to the real needs of association studies in human and medical geneticsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We present a logically unflawed solution to the problem of establishing (approximate) compatibility of an observed genotype distribution with HWE. The test is available in one- and two-sided versions. For both versions, we provide tools for exact power calculation. We demonstrate the merits of the new approach through comparison with the traditional [chi]2 goodness-of-fit test in 2×60 genotype distributions from 43 published genetic studies of complex diseases where departure from HWE was noted in either the case or control sample. In addition, we show that the new test is useful for the analysis of genome-wide associatio...
Source: Genetic Epidemiology - February 22, 2009 Category: Epidemiology Authors: Katrina A. B. Goddard, Andreas Ziegler, Stefan Wellek Source Type: journals

Testing for genetic association in the presence of population stratification in genome-wide association studiesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Genome-wide case-control association study is gaining popularity, thanks to the rapid development of modern genotyping technology. In such studies, population stratification is a potential concern especially when the number of study subjects is large as it can lead to seriously inflated false-positive rates. Current methods addressing this issue are still not completely immune to excess false positives. A simple method that corrects for population stratification is proposed. This method modifies a test statistic such as the Armitage trend test by using an additive constant that measures the variation of the effect size con...
Source: Genetic Epidemiology - February 20, 2009 Category: Epidemiology Authors: Kai Wang Source Type: journals

Using genome-wide pathway analysis to unravel the etiology of complex diseasesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study, we evaluated alternative methods to study GWAS data. Instead of focusing on the single nucleotide polymorphisms (SNPs) with the highest statistical significance, we took advantage of prior biological information and tried to detect overrepresented pathways in the GWAS data. We evaluated whether pathway classification analysis can help prioritize the biological pathways most likely to be involved in the disease etiology. In this study, we present the various benefits and limitations of pathway-classification tools in analyzing GWAS data. We show multiple differences in outcome between pathway tools analyzing ...
Source: Genetic Epidemiology - February 20, 2009 Category: Epidemiology Authors: Clara C. Elbers, Kristel R. van Eijk, Lude Franke, Flip Mulder, Yvonne T. van der Schouw, Cisca Wijmenga, N. Charlotte Onland-Moret Source Type: journals

A new measure of the effective number of tests, a practical tool for comparing families of non-independent significance testsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
p-Values from tests of significance can be combined using the [Scaron]idák correction (or the closely related Bonferroni correction) or Fisher's method, but both these methods require that the p-values combined be independent when all null hypotheses tested are true. In this paper adjustments to these methods are proposed, using a new eigenvalue-based measure of the effective number of independent tests to which the actual tests performed are equivalent, and are compared with adjustments proposed by previous authors. The adjusted methods are evaluated using a sample of 726 Alzheimer's disease (AD) cases and 707 group-matc...
Source: Genetic Epidemiology - February 15, 2009 Category: Epidemiology Authors: Nicholas W. Galwey Source Type: journals