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Michael Knapp - One of the best experts on this subject based on the ideXlab platform.
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the Transmission Disequilibrium Test and parental genotype reconstruction for x chromosomal markers
American Journal of Human Genetics, 2000Co-Authors: Steve Horvath, Nan M Laird, Michael KnappAbstract:Family-based association methods have recently been introduced that allow Testing for linkage in the presence of linkage Disequilibrium between a marker and a disease even if there is only incomplete parental-marker information. No such Tests are currently available for X-linked markers. This report fills this methodological gap by presenting the X-linked sibling Transmission/Disequilibrium Test (XS-TDT) and the X-linked reconstruction-combination Transmission/Disequilibrium Test (XRC-TDT). As do their autosomal counterparts (S-TDT and RC-TDT), these Tests make no assumption about the mode of inheritance of the disease and the ascertainment of the sample. They protect against spurious association due to population stratification. The two Tests were compared by simulations, which show that (1) the X-linked RC-TDT is, in general, considerably more powerful than the X-linked S-TDT and (2) the lack of parental-genotype information can be offset by the typing of a sufficient number of sibling controls. A freely available SAS implementation of these Tests allows the calculation of exact P values.
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using exact p values to compare the power between the reconstruction combined Transmission Disequilibrium Test and the sib Transmission Disequilibrium Test
American Journal of Human Genetics, 1999Co-Authors: Michael KnappAbstract:To the Editor:In a recent letter in the Journal, Laird et al. (1998xThe sib Transmission/Disequilibrium Test is a Mantel-Haenszel Test. Laird, NM, Blacker, D, and Wilcox, M. Am J Hum Genet. 1998; 63: 1915Abstract | Full Text | Full Text PDF | PubMedSee all References1998) pointed out that Spielman and Ewens's (1998xA sibship Test for linkage in the presence of association: the sib Transmission/Disequilibrium Test. Spielman, RS and Ewens, WJ. Am J Hum Genet. 1998; 62: 450–458Abstract | Full Text | Full Text PDF | PubMed | Scopus (511)See all References1998) sib Transmission/Disequilibrium Test (S-TDT) is identical to a Mantel-Haenszel Test of trend. As noted by Laird et al., it is possible by this identity to use commercial software such as StatXact to calculate exact P values for the S-TDT. The superiority of exact P values over asymptotic P values is evident, since it is well known (e.g., see Elston 1998xMethods of linkage analysis—and the assumptions underlying them. Elston, RC. Am J Hum Genet. 1998; 63: 931–934Abstract | Full Text | Full Text PDF | PubMed | Scopus (40)See all References1998) that P values obtained on the basis of theoretical large-sample approximations can be quite unreliable if they are much smaller than .05. An example of the need of small P values is the association scan proposed by Risch and Merikangas (1996xThe future of genetic studies of complex human diseases. Risch, N and Merikangas, K. Science. 1996; 273: 1516–1517Crossref | PubMedSee all References1996), which requires that P values <5×10−8 be observed in order for significance to be declared.It does not seem to be generally known that the calculation of exact P values for the S-TDT does not require sophisticated algorithms at all. To the contrary, it is easily incorporated into any computer program. In essence, the Test statistic of the S-TDT is the total number T of alleles A (i.e., the allele of interest) in affected children in the whole sample. The null distribution of T is the convolution of all null distributions for Ti, where Ti denotes the number of alleles A in family i. The null distribution of Ti, conditional on the observed numbers nai of affected children and nui of unaffected children and on the observed marker-genotype distribution in family i, is easily calculated from a hypergeometric distribution and is concentrated on, at most, 2nai+1 different values. The numerical calculation of the convolution of such distributions concentrated on a small part of the natural numbers is quite feasible, at least for sample sizes typically occurring in practice (see below). The situation is very similar for the reconstruction-combined Transmission/Disequilibrium Test (RC-TDT [Knapp 1999xThe Transmission/Disequilibrium Test and parental-genotype reconstruction: the reconstruction-combined Transmission/Disequilibrium Test. Knapp, M. Am J Hum Genet. 1999; 64: 861–870Abstract | Full Text | Full Text PDF | PubMed | Scopus (122)See all References1999]), which employs reconstruction of missing parental genotypes to enhance the power of the S-TDT. This Test, which does not seem to be identical to any standard statistical procedure and, therefore, requires special software for its application, also allows the calculation of exact P values.I have written an SAS (SAS Institute 1990xSAS Institute. See all References1990) macro that calculates exact P values for the S-TDT and RC-TDT, as well as P values based on z scores (with and without continuity correction). In order to give an impression of the time performance of this program, it was applied to allele M7 of marker D5G23 in Genetic Analysis Workshop 9 data (Hodge 1995xAn oligogenic disease displaying weak marker associations: a summary of contributions to problem 1 of GAW9. Hodge, SE. Genet Epidemiol. 1995; 12: 545–554Crossref | PubMed | Scopus (13)See all References1995). When all parental genotypes in these families are assumed to be unknown, 107 families remain that can be analyzed with the S-TDT and the RC-TDT. The program required less than 3 CPU-seconds for this analysis, on a low-end IBM RS6000 workstation. If each family is multiplied 10-fold (i.e., resulting in a data set of 1,070 families, which is more than the sample sizes usually occurring in practice), the SAS macro required 24 CPU-seconds.The implementation of the RC-TDT in this macro differs, in two points, from the description given by Knapp (1999xThe Transmission/Disequilibrium Test and parental-genotype reconstruction: the reconstruction-combined Transmission/Disequilibrium Test. Knapp, M. Am J Hum Genet. 1999; 64: 861–870Abstract | Full Text | Full Text PDF | PubMed | Scopus (122)See all References1999) and from the program formerly used to compare the power of the RC-TDT versus that of the S-TDT. Both changes are related to families with marker information available for a single parent: 1.Families in which all children possess the same genotype neither allow parental-genotype reconstruction nor are suitable for S-TDT analysis. Therefore, these families were discarded from the analysis by Knapp (1999xThe Transmission/Disequilibrium Test and parental-genotype reconstruction: the reconstruction-combined Transmission/Disequilibrium Test. Knapp, M. Am J Hum Genet. 1999; 64: 861–870Abstract | Full Text | Full Text PDF | PubMed | Scopus (122)See all References1999). If only a single parental marker genotype is missing and the genotype of the typed parent is AB, however, Curtis and Sham (1995xA note on the application of the Transmission Disequilibrium Test when a parent is missing. Curtis, D and Sham, PC. Am J Hum Genet. 1995; 56: 811–812PubMedSee all References1995) have shown that affected offsprings with an allele not present in the available parent (e.g., C) can be used for TDT analysis. The modified RC-TDT therefore includes such families. Here, the distribution of the number of alleles A is concentrated on the points 0 and nai, since it is required that all children in the family have the same marker genotype. (If more than one allele that is not present in the typed parent occurs in the genotype of the sibship, the missing parental genotype can be reconstructed; and, if both alleles A and B occur in the children, the family is suitable for analysis by S-TDT.)2.Knapp (1999xThe Transmission/Disequilibrium Test and parental-genotype reconstruction: the reconstruction-combined Transmission/Disequilibrium Test. Knapp, M. Am J Hum Genet. 1999; 64: 861–870Abstract | Full Text | Full Text PDF | PubMed | Scopus (122)See all References1999, p. 864) has discussed the distinction between exact reconstruction of the missing parental genotype and the condition given in his table 2, for a BC×AB mating (with the BC parent being typed). Inadvertently, the program used to obtain the power estimates shown in Knapp's (1999xThe Transmission/Disequilibrium Test and parental-genotype reconstruction: the reconstruction-combined Transmission/Disequilibrium Test. Knapp, M. Am J Hum Genet. 1999; 64: 861–870Abstract | Full Text | Full Text PDF | PubMed | Scopus (122)See all References1999) table 5 considered a family to be reconstructable only in the case of exact reconstruction but used the null expectation and null variance as given in Knapp's table 2. Both of these values are too large for families that allow for exact reconstruction. Therefore, this bug systematically underestimates the power of the RC-TDT.Both to compare the power of the S-TDT with the power of the RC-TDT, when rejection of the null hypothesis is based on exact P values for both Tests, and to assess the effect of the two changes for the RC-TDT that have been described above, the same simulated samples that had been presented by Knapp (1999xThe Transmission/Disequilibrium Test and parental-genotype reconstruction: the reconstruction-combined Transmission/Disequilibrium Test. Knapp, M. Am J Hum Genet. 1999; 64: 861–870Abstract | Full Text | Full Text PDF | PubMed | Scopus (122)See all References1999) were reanalyzed. When the results shown in table 1table 1 are compared with the power estimates given in Knapp's (1999xThe Transmission/Disequilibrium Test and parental-genotype reconstruction: the reconstruction-combined Transmission/Disequilibrium Test. Knapp, M. Am J Hum Genet. 1999; 64: 861–870Abstract | Full Text | Full Text PDF | PubMed | Scopus (122)See all References1999) table 5, it can be seen that P values based on z scores with continuity correction tend to be conservative. The most pronounced increase in power for families with only one missing parental genotype is observed for two sibs, in which the first of the RC-TDT changes described above could be expected to have the largest effect. (An SAS macro that calculates the S-TDT and RC-TDT Test statistics and their respective exact P values can be obtained, by request via e-mail, from the author.)Table 1Simulated Power of Exact S-TDT and Exact RC-TDT, for Sibships with at Least One Affected Sib (α=.001, R=500 Replicated Samples)Power300 Families, Each with Two Sibs150 Families, Each with Four Sibs100 Families, Each with Six SibsRC-TDTRC-TDTModelS-TDTRC-TDT: Paternal MissingaaS-TDTBoth MissingbbPaternal MissingaaS-TDTBoth MissingbbPaternal MissingaaD1.63.83.59.64.67.52.59.61D2.65.85.86.88.91.86.90.90D3.65.92.97.98.98.98.98.98A1.64.79.53.57.60.40.45.48A2.61.80.66.72.75.64.71.73A3.63.83.80.85.88.82.85.86R1.57.60.52.56.60.40.44.48R2.61.66.67.70.71.64.66.69R3.59.70.81.82.84.81.81.81aOnly the paternal genotype is missing in all families.bBoth parental genotypes are missing in all families.
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a note on power approximations for the Transmission Disequilibrium Test
American Journal of Human Genetics, 1999Co-Authors: Michael KnappAbstract:The Transmission/Disequilibrium Test (TDT) is a popular method for detection of the genetic basis of a disease. Investigators planning such studies require computation of sample size and power, allowing for a general genetic model. Here, a rigorous method is presented for obtaining the power approximations of the TDT for samples consisting of families with either a single affected child or affected sib pairs. Power calculations based on simulation show that these approximations are quite precise. By this method, it is also shown that a previously published power approximation of the TDT is erroneous.
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the Transmission Disequilibrium Test and parental genotype reconstruction the reconstruction combined Transmission Disequilibrium Test
American Journal of Human Genetics, 1999Co-Authors: Michael KnappAbstract:Spielman and Ewens recently proposed a method for Testing a marker for linkage with a disease, which combines data from families with and without information on parental genotypes. For some families without parental-genotype information, it may be possible to reconstruct missing parental genotypes from the genotypes of their offspring. The treatment of such a reconstructed family as if parental genotypes have been typed, however, can introduce bias. In the present study, a new method is presented that employs parental-genotype reconstruction and corrects for the biases resulting from reconstruction. The results of an application of this method to a real data set and of a simulation study suggest that this approach may increase the power to detect linkage.
Derek Gordon - One of the best experts on this subject based on the ideXlab platform.
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TDT-HET: A new Transmission Disequilibrium Test that incorporates locus heterogeneity into the analysis of family-based association data
BMC bioinformatics, 2012Co-Authors: Douglas Londono, Steven Buyske, Stephen J. Finch, Swarkar Sharma, Carol A. Wise, Derek GordonAbstract:Locus heterogeneity is one of the most documented phenomena in genetics. To date, relatively little work had been done on the development of methods to address locus heterogeneity in genetic association analysis. Motivated by Zhou and Pan's work, we present a mixture model of linked and unlinked trios and develop a statistical method to estimate the probability that a heterozygous parent transmits the disease allele at a di-allelic locus, and the probability that any trio is in the linked group. The purpose here is the development of a Test that extends the classic Transmission Disequilibrium Test (TDT) to one that accounts for locus heterogeneity. Our simulations suggest that, for sufficiently large sample size (1000 trios) our method has good power to detect association even the proportion of unlinked trios is high (75%). While the median difference (TDT-HET empirical power - TDT empirical power) is approximately 0 for all MOI, there are parameter settings for which the power difference can be substantial. Our multi-locus simulations suggest that our method has good power to detect association as long as the markers are reasonably well-correlated and the genotype relative risk are larger. Results of both single-locus and multi-locus simulations suggest our method maintains the correct type I error rate. Finally, the TDT-HET statistic shows highly significant p-values for most of the idiopathic scoliosis candidate loci, and for some loci, the estimated proportion of unlinked trios approaches or exceeds 50%, suggesting the presence of locus heterogeneity. We have developed an extension of the TDT statistic (TDT-HET) that allows for locus heterogeneity among coded trios. Benefits of our method include: estimates of parameters in the presence of heterogeneity, and reasonable power even when the proportion of linked trios is small. Also, we have extended multi-locus methods to TDT-HET and have demonstrated that the empirical power may be high to detect linkage. Last, given that we obtain PPBs, we conjecture that the TDT-HET may be a useful method for correctly identifying linked trios. We anticipate that researchers will find this property increasingly useful as they apply next-generation sequencing data in family based studies.
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when a case is not a case effects of phenotype misclassification on power and sample size requirements for the Transmission Disequilibrium Test with affected child trios
Human Heredity, 2009Co-Authors: Steven Buyske, Tara C Matise, Guang Yang, Derek GordonAbstract:Phenotype misclassification in genetic studies can decrease the power to detect association between a disease locus and a marker locus. To date, studies of misclassification have focused primarily on case-control designs. The purpose of this work is to quantify the effects of phenotype misclassification on the Transmission Disequilibrium Test (TDT) applied to affected child trios, where both parents are genotyped. We compute the non-centrality parameter of the distribution corresponding to the TDT statistic when there is linkage and association of a marker locus with a disease locus and there is phenotype misclassification. We verify our analytic calculations with simulations and provide an example sample size calculation. In our simulation studies, the maximum absolute difference between statistical power computed by simulation and analytic methods is 0.018. In an example sample size calculation, we observe that to maintain equivalent power, the required sample size increases when the disease prevalence decreases or when the misclassification rate increases. A 39-fold sample size increase is required when the misclassification rate is 5% and the disease prevalence is 1%. Given the potentially substantial power loss for the TDT in the presence of misclassification, we recommend that researchers incorporate phenotype misclassification into their study design for genetic association using trio data. We have developed freely available software that computes power loss for a fixed sample size or sample size for a fixed power in the presence of phenotype misclassification.
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Precision and type I error rate in the presence of genotype errors and missing parental data: a comparison between the original Transmission Disequilibrium Test (TDT) and TDTae statistics.
BMC genetics, 2005Co-Authors: Sandra Barral, Chad Haynes, Mark A Levenstien, Derek GordonAbstract:Two factors impacting robustness of the original Transmission Disequilibrium Test (TDT) are: i) missing parental genotypes and ii) undetected genotype errors. While it is known that independently these factors can inflate false-positive rates for the original TDT, no study has considered either the joint impact of these factors on false-positive rates or the precision score of TDT statistics regarding these factors. By precision score, we mean the absolute difference between disease gene position and the position of markers whose TDT statistic exceeds some threshold. We apply our Transmission Disequilibrium Test allowing for errors (TDTae) and the original TDT to phenotype and modified single-nucleotide polymorphism genotype simulation data from Genetic Analysis Workshop. We modify genotype data by randomly introducing genotype errors and removing a percentage of parental genotype data. We compute empirical distributions of each statistic's precision score for a chromosome harboring a simulated disease locus. We also consider inflation in type I error by studying markers on a chromosome harboring no disease locus. The TDTae shows median precision scores of approximately 13 cM, 2 cM, 0 cM, and 0 cM at the 5%, 1%, 0.1%, and 0.01% significance levels, respectively. By contrast, the original TDT shows median precision scores of approximately 23 cM, 21 cM, 15 cM, and 7 cM at the corresponding significance levels, respectively. For null chromosomes, the original TDT falsely rejects the null hypothesis for 28.8%, 14.8%, 5.4%, and 1.7% at the 5%, 1%, 0.1% and 0.01%, significance levels, respectively, while TDTae maintains the correct false-positive rate. Because missing parental genotypes and undetected genotype errors are unknown to the investigator, but are expected to be increasingly prevalent in multilocus datasets, we strongly recommend TDTae methods as a standard procedure, particularly where stricter significance levels are required.
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A Transmission Disequilibrium Test for general pedigrees that is robust to the presence of random genotyping errors and any number of untyped parents
European Journal of Human Genetics, 2004Co-Authors: Derek Gordon, Chad Haynes, Christopher Johnnidis, Shailendra B Patel, Anne M Bowcock, Jurg OttAbstract:Two issues regarding the robustness of the original Transmission Disequilibrium Test (TDT) developed by Spielman et al are: (i) missing parental genotype data and (ii) the presence of undetected genotype errors. While extensions of the TDT that are robust to items (i) and (ii) have been developed, there is to date no single TDT statistic that is robust to both for general pedigrees. We present here a likelihood method, the TDT_ae, which is robust to these issues in general pedigrees. The TDT_ae assumes a more general disease model than the traditional TDT, which assumes a multiplicative inheritance model for genotypic relative risk. Our model is based on Weinberg's work. To assess robustness, we perform simulations. Also, we apply our method to two data sets from actual diseases: psoriasis and sitosterolemia. Maximization under alternative and null hypotheses is performed using Powell's method. Results of our simulations indicate that our method maintains correct type I error rates at the 1, 5, and 10% levels of significance. Furthermore, a Kolmorogov–Smirnoff Goodness of Fit Test suggests that the data are drawn from a central χ ^2 with 2 df, the correct asymptotic null distribution. The psoriasis results suggest two loci as being significantly linked to the disease, even in the presence of genotyping errors and missing data, and the sitosterolemia results show a P -value of 1.5 × 10^−9 for the marker locus nearest to the sitosterolemia disease genes. We have developed software to perform TDT_ae calculations, which may be accessed from our ftp site.
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a Transmission Disequilibrium Test that allows for genotyping errors in the analysis of single nucleotide polymorphism data
American Journal of Human Genetics, 2001Co-Authors: Derek Gordon, Simon C Heath, Xin Liu, Jurg OttAbstract:The present study assesses the effects of genotyping errors on the type I error rate of a particular Transmission/Disequilibrium Test (TDT(std)), which assumes that data are errorless, and introduces a new Transmission/Disequilibrium Test (TDT(ae)) that allows for random genotyping errors. We evaluate the type I error rate and power of the TDT(ae) under a variety of simulations and perform a power comparison between the TDT(std) and the TDT(ae), for errorless data. Both the TDT(std) and the TDT(ae) statistics are computed as two times a log-likelihood difference, and both are asymptotically distributed as chi(2) with 1 df. Genotype data for trios are simulated under a null hypothesis and under an alternative (power) hypothesis. For each simulation, errors are introduced randomly via a computer algorithm with different probabilities (called "allelic error rates"). The TDT(std) statistic is computed on all trios that show Mendelian consistency, whereas the TDT(ae) statistic is computed on all trios. The results indicate that TDT(std) shows a significant increase in type I error when applied to data in which inconsistent trios are removed. This type I error increases both with an increase in sample size and with an increase in the allelic error rates. TDT(ae) always maintains correct type I error rates for the simulations considered. Factors affecting the power of the TDT(ae) are discussed. Finally, the power of TDT(std) is at least that of TDT(ae) for simulations with errorless data. Because data are rarely error free, we recommend that researchers use methods, such as the TDT(ae), that allow for errors in genotype data.
W J Ewens - One of the best experts on this subject based on the ideXlab platform.
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comments on the entropy based Transmission Disequilibrium Test
Human Genetics, 2008Co-Authors: W J EwensAbstract:It has recently been claimed in this journal (Zhao et al. in Hum Genet 121:357–367, 2007) that a so-called “entropy-based” TDT Test has improved power over the standard TDT Test of Spielman et al. (Am J Hum Genet 52:506–516, 1993). We show that this claim is contradicted by standard statistical theory as well as by our simulation results. We show that the incorrect claim arises because of inappropriate assumptions, and also show that the entropy-based statistic has various undesirable properties.
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relatives based Test for linkage Disequilibrium the Transmission Disequilibrium Test tdt
eLS, 2006Co-Authors: R S Spielman, W J EwensAbstract:Genes that contribute to complex genetic diseases can sometimes be identified by studies that show genetic linkage, or association, with marker genes. The Transmission/Disequilibrium Test is a procedure that Tests for the simultaneous presence of these two genetic phenomena. Keywords: linkage Disequilibrium; linkage; association; Transmission/ Disequilibrium Test; family-based Tests
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the Transmission Disequilibrium Test
Handbook of Statistical Genetics, 2004Co-Authors: W J Ewens, R S SpielmanAbstract:The Transmission-Disequilibrium Test (TDT) is an association-based Test for linkage. It is a family-based Test and thus avoids the problems potentially arising in case–control Tests from population stratification. However it does this at some loss of power. Various other positive and negative features of the Test are examined from a quantitative viewpoint. Keywords: Transmission-Disequilibrium Test; linkage; association; power; marker alleles; chi-square Tests
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a sibship Test for linkage in the presence of association the sib Transmission Disequilibrium Test
American Journal of Human Genetics, 1998Co-Authors: R S Spielman, W J EwensAbstract:Summary Linkage analysis with genetic markers has been successful in the localization of genes for many monogenic human diseases. In studies of complex diseases, however, Tests that rely on linkage Disequilibrium (the simultaneous presence of linkage and association) are often more powerful than those that rely on linkage alone. This advantage is illustrated by the Transmission/Disequilibrium Test (TDT). The TDT requires data (marker genotypes) for affected individuals and their parents; for some diseases, however, data from parents may be difficult or impossible to obtain. In this article, we describe a method, called the "sib TDT" (or "S-TDT"), that overcomes this problem by use of marker data from unaffected sibs instead of from parents, thus allowing application of the principle of the TDT to sibships without parental data. In a single collection of families, there might be some that can be analyzed only by the TDT and others that are suitable for analysis by the S-TDT. We show how all the data may be used jointly in one overall TDT - type procedure that Tests for linkage in the presence of association. These extensions of the TDT will be valuable for the study of diseases of late onset, such as non–insulin-dependent diabetes, cardiovascular diseases, and other diseases associated with aging.
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the Transmission Disequilibrium Test history subdivision and admixture
American Journal of Human Genetics, 1995Co-Authors: W J Ewens, R S SpielmanAbstract:Abstract Disease association with a genetic marker is often taken as a preliminary indication of linkage with disease susceptibility. However, population subdivision and admixture may lead to disease association even in the absence of linkage. In a previous paper, we described a Test for linkage (and linkage Disequilibrium) between a genetic marker and disease susceptibility; linkage is detected by this Test only if association is also present. This Transmission/Disequilibrium Test (TDT) is carried out with data on Transmission of marker alleles from parents heterozygous for the marker to affected offspring. The TDT is a valid Test for linkage and association, even when the association is caused by population subdivision and admixture. In the previous paper, we did not explicitly consider the effect of recent history on population structure. Here we extend the previous results by examining in detail the effects of subdivision and admixture, viewed as processes in population history. We describe two models for these processes. For both models, we analyze the properties of (a) the TDT as a Test for linkage (and association) between marker and disease and (b) the conventional contingency statistic used with family data to Test for population association. We show that the contingency Test statistic does not have a chi 2 distribution if subdivision or admixture is present. In contrast, the TDT remains a valid chi 2 statistic for the linkage hypothesis, regardless of population history.
Varghese George - One of the best experts on this subject based on the ideXlab platform.
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a bayesian approach to the Transmission Disequilibrium Test for binary traits
Genetic Epidemiology, 2002Co-Authors: Varghese George, Purushottam W LaudAbstract: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 (θ) and Disequilibrium coefficient (δ) 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.
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Transmission Disequilibrium Test analysis of total serum ige levels in the hutterite and collaborative study on the genetics of asthma data sets
Genetic Epidemiology, 2001Co-Authors: Catherine M Jedrey, Varghese George, Chienhsiun Chen, Kathy L Moser, Geoffrey C Wedig, Hemant K TiwariAbstract:The Hutterite and Collaborative Study on the Genetics of Asthma data sets provided by Genetic Analysis Workshop 12 were analyzed using a regression-based Transmission/Disequilibrium Test that assesses linkage between a marker locus and quantitative trait locus when allelic association is present, as proposed by George et al. [Am J Hum Genet 65:236-45, 1999]. Because the same marker set and analytical technique was used, the results from these data sets are amenable for comparison. Statistically significant results common to both data sets were found on chromosomes 1 and 3. A noteworthy result, significant at p < 10(-4), was detected on chromosome 18 in the Hutterites.
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linkage and association analyses of alcoholism using a regression based Transmission Disequilibrium Test
Genetic Epidemiology, 1999Co-Authors: Varghese George, Hemant K Tiwari, Youyi Shu, Xiaofeng Zhu, Robert C ElstonAbstract:Recently, George et al. proposed a regression-based Transmission/Disequilibrium Test for linkage using information on the parent-to-offspring Transmission status of an allele at a marker locus. We extended this Test by simultaneously Testing for any population association by incorporating the presence/absence status of the associated allele as a covariate in the model. We used this method to analyze markers on chromosomes 1 through 21 of the Collaborative Study on the Genetics of Alcoholism data on alcoholism for possible association and linkage. We found nominal significance (at the 0.02 level) at eight different regions for linkage, though statistical significance may not be concluded due to multiple Testing. The strongest evidence of linkage was observed for markers D4S2639 and D12S397 with p-values less than 0.005. We also found strong association between the trait and alleles 149 of D7S691 and 131 of D21S1437.
Robert C Elston - One of the best experts on this subject based on the ideXlab platform.
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comparison of a unified analysis approach for family and unrelated samples with the Transmission Disequilibrium Test to study associations of hypertension in the framingham heart study
BMC Proceedings, 2009Co-Authors: Xiangqing Sun, Robert C Elston, Tao Feng, Yeunjoo Song, Xiaofeng ZhuAbstract:Population stratification is one of the major causes of spurious associations in association studies. A unified association approach based on principal-component analysis can overcome the effect of population stratification, as well as make use of both family and unrelated samples combined to increase power (family-case-control, or FamCC). In this study, we compared FamCC and the Transmission-Disequilibrium Test (TDT) using data on hypertension, systolic blood pressure, and diastolic blood pressure in the Framingham Heart Study. Our study indicated FamCC has reasonable type I error for both the unrelated sample and the family sample for all three traits. For these three traits, we found results from FamCC were inconsistent with those from the TDT. We discuss the reasons for this inconsistency. After correcting for multiple Tests, we did not detect any significant single-nucleotide polymorphisms by either FamCC or the TDT.
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linkage and association analyses of alcoholism using a regression based Transmission Disequilibrium Test
Genetic Epidemiology, 1999Co-Authors: Varghese George, Hemant K Tiwari, Youyi Shu, Xiaofeng Zhu, Robert C ElstonAbstract:Recently, George et al. proposed a regression-based Transmission/Disequilibrium Test for linkage using information on the parent-to-offspring Transmission status of an allele at a marker locus. We extended this Test by simultaneously Testing for any population association by incorporating the presence/absence status of the associated allele as a covariate in the model. We used this method to analyze markers on chromosomes 1 through 21 of the Collaborative Study on the Genetics of Alcoholism data on alcoholism for possible association and linkage. We found nominal significance (at the 0.02 level) at eight different regions for linkage, though statistical significance may not be concluded due to multiple Testing. The strongest evidence of linkage was observed for markers D4S2639 and D12S397 with p-values less than 0.005. We also found strong association between the trait and alleles 149 of D7S691 and 131 of D21S1437.
