Power calculations for a general class of family-based association tests: dichotomous traits.
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ABSTRACT:
SUBMITTER: Lange C
PROVIDER: S-EPMC379194 | biostudies-other | 2002 Sep
REPOSITORIES: biostudies-other
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Project description:In the present article, we address family-based association tests (FBATs) for quantitative traits. We propose an approach to analytical power and sample-size calculations for general FBATs; this approach can be applied to virtually any scenario (missing parental information, multiple offspring per family, etc.). The power calculations are used to discuss optimal choices of the phenotypes for the FBAT statistic and its power's dependence on ascertainment conditions, on study design, and on the correct specification of the distributional assumptions for the phenotypes. We also compare the general FBAT approach with PDT and QTDT. The practical relevance of our theoretical considerations is illustrated by their application to an asthma study.
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Project description:The availability of a large number of dense SNPs, high-throughput genotyping and computation methods promotes the application of family-based association tests. While most of the current family-based analyses focus only on individual traits, joint analyses of correlated traits can extract more information and potentially improve the statistical power. However, current TDT-based methods are low-powered. Here, we develop a method for tests of association for bivariate quantitative traits in families. In particular, we correct for population stratification by the use of an integration of principal component analysis and TDT. A score test statistic in the variance-components model is proposed. Extensive simulation studies indicate that the proposed method not only outperforms approaches limited to individual traits when pleiotropic effect is present, but also surpasses the power of two popular bivariate association tests termed FBAT-GEE and FBAT-PC, respectively, while correcting for population stratification. When applied to the GAW16 datasets, the proposed method successfully identifies at the genome-wide level the two SNPs that present pleiotropic effects to HDL and TG traits.
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Project description:We propose a set of family-based burden and kernel tests for censored traits (FamBAC and FamKAC). Here, censored traits refer to time-to-event outcomes, for instance, age-at-onset of a disease. To model censored traits in family-based designs, we used the frailty model, which incorporated not only fixed genetic effects of rare variants in a region of interest but also random polygenic effects shared within families. We first partitioned genotype scores of rare variants into orthogonal between- and within-family components, and then derived their corresponding efficient score statistics from the frailty model. Finally, FamBAC and FamKAC were constructed by aggregating the weighted efficient scores of the within-family components across rare variants and subjects. FamBAC collapsed rare variants within subject first to form a burden test that followed a chi-squared distribution; whereas FamKAC was a variant component test following a mixture of chi-squared distributions. For FamKAC, p-values can be computed by permutation tests or for computational efficiency by approximation methods. Through simulation studies, we showed that type I error was correctly controlled by FamBAC for various variant weighting schemes (0.0371 to 0.0527). However, FamKAC type I error rates based on approximation methods were deflated (max 0.0376) but improved by permutation tests. Our simulations also demonstrated that burden test FamBAC had higher power than kernel test FamKAC when high proportion (e.g. ≥ 80%) of causal variants had effects in the same direction. In contrast, when the effects of causal variants on the censored trait were in mixed directions, FamKAC outperformed FamBAC and had comparable or higher power than an existing method, RVFam. Our proposed framework has the flexibility to accommodate general nuclear families, and can be used to analyze sequence data for censored traits such as age-at-onset of a complex disease of interest.
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Project description:Next generation sequencing technology has propelled the development of statistical methods to identify rare polygenetic variation associated with complex traits. The majority of these statistical methods are designed for case-control or population-based studies, with few methods that are applicable to family-based studies. Moreover, existing methods for family-based studies mainly focus on trios or nuclear families; there are far fewer existing methods available for analyzing larger pedigrees of arbitrary size and structure. To fill this gap, we propose a method for rare-variant analysis in large pedigree studies that can utilize information from all available relatives. Our approach is based on a kernel-machine regression (KMR) framework, which has the advantages of high power, as well as fast and easy calculation of p-values using the asymptotic distribution. Our method is also robust to population stratification due to integration of a QTDT framework (Abecasis, et al. 2000b) with the KMR framework. In our method, we first calculate the expected genotype (between-family component) of a non-founder using all founders' information and then calculate the deviates (within-family component) of observed genotype from the expectation, where the deviates are robust to population stratification by design. The test statistic, which is constructed using within-family component, is thus robust to population stratification. We illustrate and evaluate our method using simulated data and sequence data from Genetic Analysis Workshop 18 (GAW18).
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Project description:BackgroundFamily-based association tests are important tools for investigating genetic risk factors of complex diseases. These tests are especially valuable for being robust to population structure. We introduce a tool, EFBAT, which performs exact family-based tests of association for X-chromosome and autosomal biallelic markers.ResultsThe program EFBAT extends a network algorithm previously applied to autosomal markers to include the X-chromosome and to perform tests of association under the null hypotheses "no association, no linkage" and "no association in the presence of linkage" under additive, dominant and recessive genetic models. These tests are valid regardless of patterns of missing familial data.ConclusionThe general framework for performing exact family-based association tests has been usefully extended to the X-chromosome, particularly for the hypothesis of "no association in the presence of linkage" and for different genetic models.
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Project description:With millions of single-nucleotide polymorphisms (SNPs) identified and characterized, genomewide association studies have begun to identify susceptibility genes for complex traits and diseases. These studies involve the characterization and analysis of very-high-resolution SNP genotype data for hundreds or thousands of individuals. We describe a computationally efficient approach to testing association between SNPs and quantitative phenotypes, which can be applied to whole-genome association scans. In addition to observed genotypes, our approach allows estimation of missing genotypes, resulting in substantial increases in power when genotyping resources are limited. We estimate missing genotypes probabilistically using the Lander-Green or Elston-Stewart algorithms and combine high-resolution SNP genotypes for a subset of individuals in each pedigree with sparser marker data for the remaining individuals. We show that power is increased whenever phenotype information for ungenotyped individuals is included in analyses and that high-density genotyping of just three carefully selected individuals in a nuclear family can recover >90% of the information available if every individual were genotyped, for a fraction of the cost and experimental effort. To aid in study design, we evaluate the power of strategies that genotype different subsets of individuals in each pedigree and make recommendations about which individuals should be genotyped at a high density. To illustrate our method, we performed genomewide association analysis for 27 gene-expression phenotypes in 3-generation families (Centre d'Etude du Polymorphisme Humain pedigrees), in which genotypes for ~860,000 SNPs in 90 grandparents and parents are complemented by genotypes for ~6,700 SNPs in a total of 168 individuals. In addition to increasing the evidence of association at 15 previously identified cis-acting associated alleles, our genotype-inference algorithm allowed us to identify associated alleles at 4 cis-acting loci that were missed when analysis was restricted to individuals with the high-density SNP data. Our genotype-inference algorithm and the proposed association tests are implemented in software that is available for free.
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