Evaluating linkage and linkage disequilibrium: use of excess sharing and transmission disequilibrium methods in affected sib pairs

Wicks, Jacqueline; Wilson, Susan R.

doi:10.1046/j.1469-1809.2000.6450419.x

Cited by 4 publications

(8 citation statements)

References 18 publications

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“…Incorporating this information, which FBATs fail to do, gives our LLD approach a higher power than that of FBATs. This type of phenomenon has also been widely observed with comparisons of the TDT, the conventional affected sib pairs, and combined methods (Huang and Jiang 1999;Wicks and Wilson 2000;Lazzeroni 2002). Both our simulation and real data studies support our theoretical expectation.…”

Section: Discussionmentioning

confidence: 96%

“…The LLD approach integrates populationbased association analysis and pedigree-based linkage analysis into a coherent framework so that it can handle diverse types of data, including full sibs, half sibs, cousins, nuclear families, extended nuclear families, complex pedigrees, and singletons, as well as their mixtures. Unlike those of Huang and Jiang (1999), Wicks and Wilson (2000), and Lazzeroni (2002), which require only affected pairs with at least one heterozygous parent, our approach allows for analyzing any type of data structure, including singletons and pedigrees without any informative meioses, which do not contribute information to linkage parameter(s) but do inform association parameter(s). Without dropping any type of mapping data, we make use of data to the maximum extent, leading to the possibility of improving mapping performance.…”

Section: Discussionmentioning

confidence: 99%

“…Li et al (2005) suggested an approach that identifies associated and potentially causal SNPs through joint modeling of linkage and association. Parallel to parametric ones, variance components (e.g., Allison et al 1999;Fulker et al 1999;Abecasis et al 2000) and nonparametric (Huang and Jiang 1999;Wicks 2000;Wicks and Wilson 2000;Lazzeroni 2002) methods have also been developed. However, those methods work mostly for specific data structures and types such as affected sib pairs, nuclear families, and categorical traits and/or can provide a solution only for specific problems such as single-point analysis.…”

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confidence: 99%

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Improvement of Mapping Accuracy by Unifying Linkage and Association Analysis

et al. 2006

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It is well known that pedigree/family data record information on the coexistence in founder haplotypes of alleles at nearby loci and the cotransmission from parent to offspring that reveal different, but complementary, profiles of the genetic architecture. Either conventional linkage analysis that assumes linkage equilibrium or family-based association tests (FBATs) capture only partial information, leading to inefficiency. For example, FBATs will fail to detect even very tight linkage in the case where no allelic association exists, while a violation of the assumption of linkage equilibrium will result in biased estimation and reduced efficiency in linkage mapping. In this article, by using a data augmentation technique and the EM algorithm, we propose a likelihood-based approach that embeds both linkage and association analyses into a unified framework for general pedigree data. Relative to either linkage or association analysis, the proposed approach is expected to have greater estimation accuracy and power. Monte Carlo simulations support our theoretical expectations and demonstrate that our new methodology: (1) is more powerful than either FBATs or classic linkage analysis; (2) can unbiasedly estimate genetic parameters regardless of whether association exists, thus remedying the bias and less precision of traditional linkage analysis in the presence of association; and (3) is capable of identifying tight linkage alone. The new approach also holds the theoretical advantage that it can extract statistical information to the maximum extent and thereby improve mapping accuracy and power because it integrates multilocus population-based association study and pedigree-based linkage analysis into a coherent framework. Furthermore, our method is numerically stable and computationally efficient, as compared to existing parametric methods that use the simplex algorithm or Newton-type methods to maximize high-order multidimensional likelihood functions, and also offers the computation of Fisher's information matrix. Finally, we apply our methodology to a genetic study on bone mineral density (BMD) for the vitamin D receptor (VDR) gene and find that VDR is significantly linked to BMD at the one-third region of the wrist. T WO approaches are commonly used in pedigreeor family-based gene mapping, i.e., linkage analysis (e.g., Elston and Stewart 1971;Haseman and Elston 1972;Ott 1974;Lander and Green 1987;Risch 1990;Ward 1993;Amos 1994;Kruglyak and Lander 1995;O'Connell and Weeks 1995;Kruglyak et al. 1996;Gudbjartsson et al. 2000;Abecasis et al. 2002) and family-based association tests (FBATs) (e.g., Falk and Rubinstein 1987;Spielman et al. 1993;Lazzeroni and Lange 1998;Laird et al. 2000;Rabinowitz and Laird 2000). Linkage analysis focuses on gene cosegregation that can be characterized by inheritance vectors or gene concordance between related individuals (identical-bydescent, IBD, or identical-in-state, IIS) at each locus, while association tests (which, when due to linkage, are tests of gametic association, als...

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Improvement of Mapping Accuracy by Unifying Linkage and Association Analysis

et al. 2006

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“…Each of these probabilities is a function of both the recombination parameter and the linkage disequilibrium parameter. These functions can be found in Sham and Curtis [8] and Wicks and Wilson [4], as well as the simplifications obtained by use of the BradleyTerry model, namely P A /(P A + P a ) = expa 1 /(expa 1 + expa 2 ) and P AA /(P AA + P aa ) = expb 1 / (expb 1 + expb 2 ) wherein, to prevent aliasing, one can arbitrarily set a 2 = b 2 = 0; in general a 1 0 b 1 .…”

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confidence: 99%

“…Various possible test statistics extending T S have been proposed for multi-allelic loci, but for simplicity of presentation, only the bi-allelic case is considered here. For data consisting of just ASPs and their parents, different tests of association between a complex disease and a multi-allelic genetic marker have been developed [3,4], which coincide for the bi-allelic case to be the (score) statistic…”

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confidence: 99%

Hypothesis Testing for Data from Different Family Study Designs

Wilson

2002

Hum Hered

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A test statistic that is valid for data collected according to a particular type of family study design is not necessarily valid when applied to data obtained from a different type of family study design. When this can occur, a different test that usually is valid is developed for each type of family study design. However, investigators might find that their data come from two (or more) different family study designs, each requiring a different test, yet they want an overall conclusion, essentially a valid hypothesis test that is as powerful as possible. When the underlying genetic model is unknown, it is not clear how to proceed, as several alternative approaches might appear feasible. By using as an example the development of a test of association for data concerning affected singletons and their parents and affected sib pairs and their parents, it is shown that it may not be possible to develop a universally optimal approach without knowledge of the underlying genetic model.

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Allele sharing and allelic association I: Sib pair tests with increased power

Lazzeroni

2002

Genetic Epidemiology

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Affected sib pair data contain information about allele sharing and allelic association. Either of these features can point to the presence of a risk-related gene. This study introduces the elliptical sib pair test, a generalization of traditional sib pair tests. The proposed test can be implemented using any of three strategies, the choice of which depends on the anticipated combination of sharing and association. The elliptical sib pair test can achieve substantial gains in power relative to traditional tests for likely alternative hypotheses at little or no cost for other alternatives. The proposed test is valid under most models of genetic risk, disease etiology, and genotype-haplotype distributions. This study also provides new insight into the trade-off between tests of allelic association and tests of allele sharing.

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Evaluating linkage and linkage disequilibrium: use of excess sharing and transmission disequilibrium methods in affected sib pairs

Cited by 4 publications

References 18 publications

Improvement of Mapping Accuracy by Unifying Linkage and Association Analysis

Improvement of Mapping Accuracy by Unifying Linkage and Association Analysis

Hypothesis Testing for Data from Different Family Study Designs

Allele sharing and allelic association I: Sib pair tests with increased power

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