A powerful association test of multiple genetic variants using a random-effects model
There is an emerging interest in sequencing‐based association studies of multiple rare variants. Most association tests suggested in the literature involve collapsing rare variants with or without weighting. Recently, a variance‐component score test [sequence kernel association test (SKAT)] was prop...
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Published in | Statistics in medicine Vol. 33; no. 11; pp. 1816 - 1827 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
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Blackwell Publishing Ltd
20.05.2014
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Abstract | There is an emerging interest in sequencing‐based association studies of multiple rare variants. Most association tests suggested in the literature involve collapsing rare variants with or without weighting. Recently, a variance‐component score test [sequence kernel association test (SKAT)] was proposed to address the limitations of collapsing method. Although SKAT was shown to outperform most of the alternative tests, its applications and power might be restricted and influenced by missing genotypes. In this paper, we suggest a new method based on testing whether the fraction of causal variants in a region is zero. The new association test, T REM, is derived from a random‐effects model and allows for missing genotypes, and the choice of weighting function is not required when common and rare variants are analyzed simultaneously. We performed simulations to study the type I error rates and power of four competing tests under various conditions on the sample size, genotype missing rate, variant frequency, effect directionality, and the number of non‐causal rare variant and/or causal common variant. The simulation results showed that T REM was a valid test and less sensitive to the inclusion of non‐causal rare variants and/or low effect common variants or to the presence of missing genotypes. When the effects were more consistent in the same direction, T REM also had better power performance. Finally, an application to the Shanghai Breast Cancer Study showed that rare causal variants at the FGFR2 gene were detected by T REM and SKAT, but T REM produced more consistent results for different sets of rare and common variants. Copyright © 2013 John Wiley & Sons, Ltd. |
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AbstractList | There is an emerging interest in sequencing‐based association studies of multiple rare variants. Most association tests suggested in the literature involve collapsing rare variants with or without weighting. Recently, a variance‐component score test [sequence kernel association test (SKAT)] was proposed to address the limitations of collapsing method. Although SKAT was shown to outperform most of the alternative tests, its applications and power might be restricted and influenced by missing genotypes. In this paper, we suggest a new method based on testing whether the fraction of causal variants in a region is zero. The new association test, T REM, is derived from a random‐effects model and allows for missing genotypes, and the choice of weighting function is not required when common and rare variants are analyzed simultaneously. We performed simulations to study the type I error rates and power of four competing tests under various conditions on the sample size, genotype missing rate, variant frequency, effect directionality, and the number of non‐causal rare variant and/or causal common variant. The simulation results showed that T REM was a valid test and less sensitive to the inclusion of non‐causal rare variants and/or low effect common variants or to the presence of missing genotypes. When the effects were more consistent in the same direction, T REM also had better power performance. Finally, an application to the Shanghai Breast Cancer Study showed that rare causal variants at the FGFR2 gene were detected by T REM and SKAT, but T REM produced more consistent results for different sets of rare and common variants. Copyright © 2013 John Wiley & Sons, Ltd. There is an emerging interest in sequencing-based association studies of multiple rare variants. Most association tests suggested in the literature involve collapsing rare variants with or without weighting. Recently, a variance-component score test [sequence kernel association test (SKAT)] was proposed to address the limitations of collapsing method. Although SKAT was shown to outperform most of the alternative tests, its applications and power might be restricted and influenced by missing genotypes. In this paper, we suggest a new method based on testing whether the fraction of causal variants in a region is zero. The new association test, T ..., is derived from a random-effects model and allows for missing genotypes, and the choice of weighting function is not required when common and rare variants are analyzed simultaneously. We performed simulations to study the type I error rates and power of four competing tests under various conditions on the sample size, genotype missing rate, variant frequency, effect directionality, and the number of non-causal rare variant and/or causal common variant. The simulation results showed that T ... was a valid test and less sensitive to the inclusion of non-causal rare variants and/or low effect common variants or to the presence of missing genotypes. When the effects were more consistent in the same direction, T ... also had better power performance. Finally, an application to the Shanghai Breast Cancer Study showed that rare causal variants at the FGFR2 gene were detected by T ... and SKAT, but T ... produced more consistent results for different sets of rare and common variants. (ProQuest: ... denotes formulae/symbols omitted.) There is an emerging interest in sequencing-based association studies of multiple rare variants. Most association tests suggested in the literature involve collapsing rare variants with or without weighting. Recently, a variance-component score test, SKAT, was proposed to address the limitations of collapsing method. Although SKAT was shown to outperform most of the alternative tests, its applications and power might be restricted and influenced by missing genotypes. In this paper, we suggest a new method based on testing whether the fraction of causal variants in a region is zero. The new association test, T REM , is derived from a random-effects model, allows for missing genotypes and the choice of weighting function is not required when common and rare variants are analyzed simultaneously. We performed simulations to study the type I error rates and power of four competing tests under various conditions on the sample size, genotype missing rate, variant frequency, effect directionality, and the number of non-causal rare variant and/or causal common variant. The simulation results showed that T REM was a valid test and less sensitive to the inclusion of non-causal rare variants and/or low effect common variants, or to the presence of missing genotypes. When the effects were more consistent in the same direction, T REM also had better power performance. Finally, an application to the Shanghai breast cancer study showed that rare causal variants at the FGFR2 gene were detected by T REM and SKAT, but T REM produced more consistent results for different sets of rare and common variants. There is an emerging interest in sequencing-based association studies of multiple rare variants. Most association tests suggested in the literature involve collapsing rare variants with or without weighting. Recently, a variance-component score test [sequence kernel association test (SKAT)] was proposed to address the limitations of collapsing method. Although SKAT was shown to outperform most of the alternative tests, its applications and power might be restricted and influenced by missing genotypes. In this paper, we suggest a new method based on testing whether the fraction of causal variants in a region is zero. The new association test, T REM , is derived from a random-effects model and allows for missing genotypes, and the choice of weighting function is not required when common and rare variants are analyzed simultaneously. We performed simulations to study the type I error rates and power of four competing tests under various conditions on the sample size, genotype missing rate, variant frequency, effect directionality, and the number of non-causal rare variant and/or causal common variant. The simulation results showed that T REM was a valid test and less sensitive to the inclusion of non-causal rare variants and/or low effect common variants or to the presence of missing genotypes. When the effects were more consistent in the same direction, T REM also had better power performance. Finally, an application to the Shanghai Breast Cancer Study showed that rare causal variants at the FGFR2 gene were detected by T REM and SKAT, but T REM produced more consistent results for different sets of rare and common variants. |
Author | Li, C. Zheng, W. Cheng, K.F. Lee, J.Y. |
AuthorAffiliation | 3 Vanderbilt Epidemiology Center, Department of Medicine, Vanderbilt University, Nashville, TN, USA 4 Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA 5 Department of Biostatistics, Vanderbilt University, Nashville, TN, USA 2 Graduate Institute of Statistics, National Central University, Chungli, Taiwan 1 Biostatistics Center and Department of Public Health, Taipei Medical University, Taiwan |
AuthorAffiliation_xml | – name: 4 Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA – name: 1 Biostatistics Center and Department of Public Health, Taipei Medical University, Taiwan – name: 3 Vanderbilt Epidemiology Center, Department of Medicine, Vanderbilt University, Nashville, TN, USA – name: 2 Graduate Institute of Statistics, National Central University, Chungli, Taiwan – name: 5 Department of Biostatistics, Vanderbilt University, Nashville, TN, USA |
Author_xml | – sequence: 1 givenname: K.F. surname: Cheng fullname: Cheng, K.F. email: Correspondence to: K. F. Cheng, Biostatistics Center, Taipei Medical University, Taipei, Taiwan., kfcheng@tmu.edu.tw organization: Biostatistics Center and Department of Public Health, Taipei Medical University, Taiwan – sequence: 2 givenname: J.Y. surname: Lee fullname: Lee, J.Y. organization: Graduate Institute of Statistics, National Central University, Chungli, Taiwan – sequence: 3 givenname: W. surname: Zheng fullname: Zheng, W. organization: Vanderbilt Epidemiology Center, Department of Medicine, Vanderbilt University, TN, Nashville, U.S.A – sequence: 4 givenname: C. surname: Li fullname: Li, C. organization: Center for Human Genetics Research, Vanderbilt University, Nashville, TN, U.S.A |
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SubjectTerms | association test Biological variation Breast cancer Breast Neoplasms - genetics China Computer Simulation Female Genetic Association Studies - methods Genetic Predisposition to Disease Genetic Variation - genetics Genotype Genotype & phenotype Humans Medical statistics Models, Genetic random-effects model rare variant Receptor, Fibroblast Growth Factor, Type 2 - genetics Sample Size sequencing-based study Simulation |
Title | A powerful association test of multiple genetic variants using a random-effects model |
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