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Transmission/disequilibrium Test (transmission + test)

Distribution by Scientific Domains

Life Sciences	85%
Medical Sciences	14%

Selected Abstracts

Adaptation of the extended transmission/disequilibrium test to distinguish disease associations of multiple loci: the Conditional Extended Transmission/Disequilibrium Test

ANNALS OF HUMAN GENETICS, Issue 3 2000
B. P. C. KOELEMAN
Linkage and association studies in complex diseases are used to identify and fine map disease loci. The process of identifying the aetiological polymorphism, the molecular variant responsible for the linkage and association of the chromosome region with disease, is complicated by the low penetrance of the disease variant, the linkage disequilibrium between physically-linked polymorphic markers flanking the disease variant, and the possibility that more than one polymorphism in the most associated region is aetiological. It is important to be able to detect additional disease determinants in a region containing a cluster of genes, such as the major histocompatibility complex (MHC) region on chromosome 6p21. Some methods have been developed for detection of additional variants, such as the Haplotype Method, Marker Association Segregation Chi-squares (MASC) Method, and the Homozygous Parent Test. Here, the Extended Transmission/Disequilibrium Test is adapted to test for association conditional on a previously associated locus. This test is referred to as the Conditional Extended TDT (CETDT). We discuss the advantages of the CETDT compared to existing methods and, using simulated data, investigate the effect of polymorphism, inheritance, and linkage disequilibrium on the CETDT. [source]

Photoprotection of bacterial-derived melanin against ultraviolet A,induced cell death and its potential application as an active sunscreen

JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 7 2008
J Geng
Abstract Background, The increase in the incidence of non-melanoma skin tumours, photoaging, and immunosuppression demand for more effective sunscreen on ultraviolet A (UVA) irradiation. Objectives, The aim of the study is to evaluate the photoprotective effects of a bacterial-derived melanin against UVA-induced damages in vitro and in vivo. Methods, Human fibroblasts were used to assess the role of the bacterial-derived melanin on cell viability against UVA. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and nuclear morphology were employed to evaluate the photoprotection at the cellular level. Fluorometric assays were performed to detect the formation of reactive oxygen species (ROS) in the cells. Evaluations of the bacterial-derived melanin as a sunscreen were measured by transmission test and persistent pigment darkening on human skin. Results, Bacterial-derived melanin efficiently scavenged ROS in the fibroblasts after UVA irradiation. The cell viability of xeroderma pigmentosum (XP) fibroblast treated with varied doses of melanin increased dramatically in comparison with untreated control and the treated XP fibroblasts became more resistant to UVA-induced apoptosis than normal fibroblasts. Although the relative transmission didn't change too much with different concentration of bacterial-derived melanin, this melanin could keep UVA-irradiated skin from pigment darkening and act as an active sunscreen on skin. Conclusions, The bacterial-derived melanin provided significant protection to fibroblast cell and human skin against the UVA radiation. It has the potential to be developed as an active sunscreen for the patients with photosensitivity skin to sun exposure. [source]

Molecular Characterization and Potential Insect Vector of a Phytoplasma Associated with Garden Beet Witches' Broom in Yazd, Iran

JOURNAL OF PHYTOPATHOLOGY, Issue 4 2007
A. Mirzaie
Abstract In 2002, garden beet witches' broom (GBWB) phytoplasma was detected for the first time in garden beet plants (Beta vulgaris L. ssp. esculenta) in Yazd, Iran. Nested polymerase chain reaction (PCR) and restriction fragment length polymorphic (RFLP) analysis of PCR-amplified phytoplasma 16S rDNA were employed for the detection and identification of the phytoplasma associated with garden beet. A phytoplasma belonging to subgroup 16SrII-E, in the peanut witches' broom group (16SrII), was detected in infected plants. Asymptomatic plant samples and the negative control yielded no amplification. The result of analysis of the nucleotide sequence of a 1428 bp fragment of 16S rDNA gene from GBWB phytoplasma (GenBank accession number DQ302722) was basically consistent with the classification based on RFLP analysis, in which GBWB phytoplasma clustered with phytoplasmas of the 16SrII-E subgroup. A search for a natural phytoplasma vector was conducted in Yazd in 2004, in an area where garden beet crops had been affected since 2002. The associated phytoplasma was detected in one leafhopper species, Orosius albicinctus, commonly present in this region. The leafhopper O. albicinctus was used in transmission tests to determine its vector status for the phytoplasma associated with GBWB. Two of eight plants that had been fed on by O. albicinctus, showed mild symptoms of GBWB including stunting and reddening of midveins. A phytoplasma was detected in the two symptomatic test plants by PCR using universal primers and it was identified by RFLP as the GBWB phytoplasma. This finding suggests O. albicinctus is a vector of the GBWB phytoplasma. [source]

Chromosome 8q24 risk variants in hereditary and non-hereditary prostate cancer patients,

THE PROSTATE, Issue 5 2008
Jielin Sun
Abstract Background Multiple variants in three regions at 8q24 are consistently found to be associated with prostate cancer (PCa) risk in population-based association studies. The role that these variants may play in familial prostate cancer risk has not been extensively investigated. Methods We evaluated 12 SNPs at three 8q24 regions using population-based association and family-based linkage and association methods in hereditary PCa (HPC) probands and their families, non-HPC patients, and unaffected screened controls, all recruited at Johns Hopkins Hospital. Results For multiple variants in Region 1 (e.g., rs1447295) and Region 2 (e.g., rs16901979), we found statistically significantly higher frequencies of previously identified risk alleles and genotypes in HPC probands than in unaffected controls. Furthermore, in Region 2 the risk alleles were statistically significantly more frequent in HPC probands than in non-HPC patients. Family-based transmission tests found risk alleles of SNPs in Region 2, but not in Regions 1 and 3, were significantly over-transmitted to affected men in these families. We found little evidence supporting PCa linkage at 8q24 in 168 HPC families, in part explained by the observation of multiple, different risk allele-containing haplotypes segregating in the vast majority of these families. Conclusions Our study further supports the presence of PCa susceptibility loci at 8q24, particular at Region 2, and also provides evidence that these SNPs play an important role in familial prostate cancer. Large family-based studies are needed to confirm our novel findings. Prostate 68: 489,497, 2008. © 2008 Wiley-Liss, Inc. [source]

Quantitative trait association in parent offspring trios: Extension of case/pseudocontrol method and comparison of prospective and retrospective approaches

GENETIC EPIDEMIOLOGY, Issue 8 2007
Eleanor Wheeler
Abstract The case/pseudocontrol method provides a convenient framework for family-based association analysis of case-parent trios, incorporating several previously proposed methods such as the transmission/disequilibrium test and log-linear modelling of parent-of-origin effects. The method allows genotype and haplotype analysis at an arbitrary number of linked and unlinked multiallelic loci, as well as modelling of more complex effects such as epistasis, parent-of-origin effects, maternal genotype and mother-child interaction effects, and gene-environment interactions. Here we extend the method for analysis of quantitative as opposed to dichotomous (e.g. disease) traits. The resulting method can be thought of as a retrospective approach, modelling genotype given trait value, in contrast to prospective approaches that model trait given genotype. Through simulations and analytical derivations, we examine the power and properties of our proposed approach, and compare it to several previously proposed single-locus methods for quantitative trait association analysis. We investigate the performance of the different methods when extended to allow analysis of haplotype, maternal genotype and parent-of-origin effects. With randomly ascertained families, with or without population stratification, the prospective approach (modeling trait value given genotype) is found to be generally most effective, although the retrospective approach has some advantages with regard to estimation and interpretability of parameter estimates when applied to selected samples. Genet. Epidemiol. 2007. © 2007 Wiley-Liss, Inc. [source]

Informative-Transmission Disequilibrium Test (i-TDT): combined linkage and association mapping that includes unaffected offspring as well as affected offspring

GENETIC EPIDEMIOLOGY, Issue 2 2007
Chao-Yu Guo
Abstract To date, there is no test valid for the composite null hypothesis of no linkage or no association that utilizes transmission information from heterozygous parents to their unaffected offspring as well as the affected offspring from ascertained nuclear families. Since the unaffected siblings also provide information about linkage and association, we introduce a new strategy called the informative-transmission disequilibrium test (i-TDT), which uses transmission information from heterozygous parents to all of the affected and unaffected offspring in ascertained nuclear families and provides a valid chi-square test for both linkage and association. The i-TDT can be used in various study designs and can accommodate all types of independent nuclear families with at least one affected offspring. We show that the transmission/disequilibrium test (TDT) (Spielman et al. [1993] Am. J. Hum. Genet. 52:506,516) is a special case of the i-TDT, if the study sample contains only case-parent trios. If the sample contains only affected and unaffected offspring without parental genotypes, the i-TDT is equivalent to the sibship disequilibrium test (SDT) (Horvath and Laird [1998] Am. J. Hum. Genet. 63:1886,1897. In addition, the test statistic of i-TDT is simple, explicit and can be implemented easily without intensive computing. Through computer simulations, we demonstrate that power of the i-TDT can be higher in many circumstances compared to a method that uses affected offspring only. Applying the i-TDT to the Framingham Heart Study data, we found that the apolipoprotein E (APOE) gene is significantly linked and associated with cross-sectional measures and longitudinal changes in total cholesterol. Genet. Epidemiol. © 2006 Wiley-Liss, Inc. [source]

Method for using complete and incomplete trios to identify genes related to a quantitative trait,

GENETIC EPIDEMIOLOGY, Issue 1 2004
Emily O. Kistner
Abstract A number of tests for linkage and association with qualitative traits have been developed, with the most well-known being the transmission/disequilibrium test (TDT). For quantitative traits, varying extensions of the TDT have been suggested. The quantitative trait approach we propose is based on extending the log-linear model for case-parent trio data (Weinberg et al. [1998] Am. J. Hum. Genet. 62:969,978). Like the log-linear approach for qualitative traits, our proposed polytomous logistic approach for quantitative traits allows for population admixture by conditioning on parental genotypes. Compared to other methods, simulations demonstrate good power and robustness of the proposed test under various scenarios of the genotype effect, distribution of the quantitative trait, and population stratification. In addition, missing parental genotype data can be accommodated through an expectation-maximization (EM) algorithm approach. The EM approach allows recovery of most of the lost power due to incomplete trios. Published 2004 Wiley-Liss, Inc. [source]

Properties of case/pseudocontrol analysis for genetic association studies: Effects of recombination, ascertainment, and multiple affected offspring

GENETIC EPIDEMIOLOGY, Issue 3 2004
Heather J. Cordell
Abstract The case/pseudocontrol approach is a general framework for family-based association analysis, incorporating several previously proposed methods such as the transmission/disequilibrium test and log-linear modelling of parent-of-origin effects. In this report, I examine the properties of methods based on a case/pseudocontrol approach when applied to a linked marker rather than (or in addition to) the true disease locus or loci, and when applied to sibships that have been ascertained on, or that may simply contain, multiple affected sibs. Through simulations and analytical calculations, I show that the expected values of the observed relative risk parameters (estimating quantities such as effects due to a child's own genotype, maternal genotype, and parent-of-origin) depend crucially on the ascertainment scheme used, as well as on whether there is non-negligible recombination between the true disease locus and the locus under study. In the presence of either recombination or ascertainment on multiple affected offspring, methods based on conditioning on parental genotypes are shown to give unbiased genotype relative risk estimates at the true disease locus (or loci) but biased estimates of population genotype relative risks at a linked marker, suggesting that the resulting estimates may be misleading when used to predict the power of future studies. Methods that allow for exchangeability of parental genotypes are shown (in the presence of either recombination or ascertainment on multiple affected offspring) to produce false-positive evidence of maternal genotype effects when there are true parent-of-origin or mother-child interaction effects, even when analyzing the true locus. These results suggest that care should be taken in both the interpretation and application of parameter estimates obtained from family-based genetic association studies. © 2004 Wiley-Liss, Inc. [source]

A Bayesian approach to the transmission/disequilibrium test for binary traits

GENETIC EPIDEMIOLOGY, Issue 1 2002
Varghese George
Abstract The transmission/disequilibrium test (TDT) for binary traits is a powerful method for detecting linkage between a marker locus and a trait locus in the presence of allelic association. The TDT uses information on the parent-to-offspring transmission status of the associated allele at the marker locus to assess linkage or association in the presence of the other, using one affected offspring from each set of parents. For testing for linkage in the presence of association, more than one offspring per family can be used. However, without incorporating the correlation structure among offspring, it is not possible to correctly assess the association in the presence of linkage. In this presentation, we propose a Bayesian TDT method as a complementary alternative to the classical approach. In the hypothesis testing setup, given two competing hypotheses, the Bayes factor can be used to weigh the evidence in favor of one of them, thus allowing us to decide between the two hypotheses using established criteria. We compare the proposed Bayesian TDT with a competing frequentist-testing method with respect to power and type I error validity. If we know the mode of inheritance of the disease, then the joint and marginal posterior distributions for the recombination fraction (,) and disequilibrium coefficient (,) can be obtained via standard MCMC methods, which lead naturally to Bayesian credible intervals for both parameters. Genet. Epidemiol. 22:41,51, 2002. © 2002 Wiley-Liss, Inc. [source]

Robust Quantitative Trait Association Tests in the Parent-Offspring Triad Design: Conditional Likelihood-Based Approaches

ANNALS OF HUMAN GENETICS, Issue 2 2009
J.-Y. Wang
Summary Association studies, based on either population data or familial data, have been widely applied to mapping of genes underlying complex diseases. In family-based association studies, using case-parent triad families, the popularly used transmission/disequilibrium test (TDT) was proposed for avoidance of spurious association results caused by other confounders such as population stratification. Originally, the TDT was developed for analysis of binary disease data. Extending it to allow for quantitative trait analysis of complex diseases and for robust analysis of binary diseases against the uncertainty of mode of inheritance has been thoroughly discussed. Nevertheless, studies on robust analysis of quantitative traits for complex diseases received relatively less attention. In this paper, we use parent-offspring triad families to demonstrate the feasibility of establishment of the robust candidate-gene association tests for quantitative traits. We first introduce the score statistics from the conditional likelihoods based on parent-offspring triad data under various genetic models. By applying two existing robust procedures we then construct the robust association tests for analysis of quantitative traits. Simulations are conducted to evaluate empirical type I error rates and powers of the proposed robust tests. The results show that these robust association tests do exhibit robustness against the effect of misspecification of the underlying genetic model on testing powers. [source]

Two-sample Comparison Based on Prediction Error, with Applications to Candidate Gene Association Studies

ANNALS OF HUMAN GENETICS, Issue 1 2007
K. Yu
Summary To take advantage of the increasingly available high-density SNP maps across the genome, various tests that compare multilocus genotypes or estimated haplotypes between cases and controls have been developed for candidate gene association studies. Here we view this two-sample testing problem from the perspective of supervised machine learning and propose a new association test. The approach adopts the flexible and easy-to-understand classification tree model as the learning machine, and uses the estimated prediction error of the resulting prediction rule as the test statistic. This procedure not only provides an association test but also generates a prediction rule that can be useful in understanding the mechanisms underlying complex disease. Under the set-up of a haplotype-based transmission/disequilibrium test (TDT) type of analysis, we find through simulation studies that the proposed procedure has the correct type I error rates and is robust to population stratification. The power of the proposed procedure is sensitive to the chosen prediction error estimator. Among commonly used prediction error estimators, the .632+ estimator results in a test that has the best overall performance. We also find that the test using the .632+ estimator is more powerful than the standard single-point TDT analysis, the Pearson's goodness-of-fit test based on estimated haplotype frequencies, and two haplotype-based global tests implemented in the genetic analysis package FBAT. To illustrate the application of the proposed method in population-based association studies, we use the procedure to study the association between non-Hodgkin lymphoma and the IL10 gene. [source]

Adaptation of the extended transmission/disequilibrium test to distinguish disease associations of multiple loci: the Conditional Extended Transmission/Disequilibrium Test

Global transmission/disequilibrium tests based on haplotype sharing in multiple candidate genes

GENETIC EPIDEMIOLOGY, Issue 4 2005
Kai Yu
Abstract It is well recognized that multiple genes are likely contributing to the susceptibility of most common complex diseases. Studying one gene at a time might reduce our chance to identify disease susceptibility genes with relatively small effect sizes. Therefore, it is crucial to develop statistical methods that can assess the effect of multiple genes collectively. Motivated by the increasingly available high-density markers across the whole human genome, we propose a class of TDT-type methods that can jointly analyze haplotypes from multiple candidate genes (linked or unlinked). Our approach first uses a linear signed rank statistic to compare at an individual gene level the structural similarity among transmitted haplotypes against that among non-transmitted haplotypes. The results of the ranked comparisons from all considered genes are subsequently combined into global statistics, which can simultaneously test the association of the set of genes with the disease. Using simulation studies, we find that the proposed tests yield correct type I error rates in stratified populations. Compared with the gene-by-gene test, the new global tests appear to be more powerful in situations where all candidate genes are associated with the disease. Genet. Epidemiol. 2005. © 2005 Wiley-Liss, Inc. [source]