Browsing by Author "Guan, Yongtao"

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    Detecting local haplotype sharing and haplotype association.
    (Genetics, 2014-07) Xu, Hanli; Guan, Yongtao
    A novel haplotype association method is presented, and its power is demonstrated. Relying on a statistical model for linkage disequilibrium (LD), the method first infers ancestral haplotypes and their loadings at each marker for each individual. The loadings are then used to quantify local haplotype sharing between individuals at each marker. A statistical model was developed to link the local haplotype sharing and phenotypes to test for association. We devised a novel method to fit the LD model, reducing the complexity from putatively quadratic to linear (in the number of ancestral haplotypes). Therefore, the LD model can be fitted to all study samples simultaneously, and, consequently, our method is applicable to big data sets. Compared to existing haplotype association methods, our method integrated out phase uncertainty, avoided arbitrariness in specifying haplotypes, and had the same number of tests as the single-SNP analysis. We applied our method to data from the Wellcome Trust Case Control Consortium and discovered eight novel associations between seven gene regions and five disease phenotypes. Among these, GRIK4, which encodes a protein that belongs to the glutamate-gated ionic channel family, is strongly associated with both coronary artery disease and rheumatoid arthritis. A software package implementing methods described in this article is freely available at http://www.haplotype.org.
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    Detecting structure of haplotypes and local ancestry.
    (Genetics, 2014-03) Guan, Yongtao
    We present a two-layer hidden Markov model to detect the structure of haplotypes for unrelated individuals. This allows us to model two scales of linkage disequilibrium (one within a group of haplotypes and one between groups), thereby taking advantage of rich haplotype information to infer local ancestry of admixed individuals. Our method outperforms competing state-of-the-art methods, particularly for regions of small ancestral track lengths. Applying our method to Mexican samples in HapMap3, we found two regions on chromosomes 6 and 8 that show significant departure of local ancestry from the genome-wide average. A software package implementing the methods described in this article is freely available at http://bcm.edu/cnrc/mcmcmc.
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    Graphical Principal Component Analysis of Multivariate Functional Time Series
    (Journal of the American Statistical Association) Tan, Jianbin; Liang, Decai; Guan, Yongtao; Huang, Hui
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    Informative priors on fetal fraction increase power of the noninvasive prenatal screen.
    (Genetics in medicine : official journal of the American College of Medical Genetics, 2017-11-09) Xu, Hanli; Wang, Shaowei; Ma, Lin-Lin; Huang, Shuai; Liang, Lin; Liu, Qian; Liu, Yang-Yang; Liu, Ke-Di; Tan, Ze-Min; Ban, Hao; Guan, Yongtao; Lu, Zuhong
    PurposeNoninvasive prenatal screening (NIPS) sequences a mixture of the maternal and fetal cell-free DNA. Fetal trisomy can be detected by examining chromosomal dosages estimated from sequencing reads. The traditional method uses the Z-test, which compares a subject against a set of euploid controls, where the information of fetal fraction is not fully utilized. Here we present a Bayesian method that leverages informative priors on the fetal fraction.MethodOur Bayesian method combines the Z-test likelihood and informative priors of the fetal fraction, which are learned from the sex chromosomes, to compute Bayes factors. Bayesian framework can account for nongenetic risk factors through the prior odds, and our method can report individual positive/negative predictive values.ResultsOur Bayesian method has more power than the Z-test method. We analyzed 3,405 NIPS samples and spotted at least 9 (of 51) possible Z-test false positives.ConclusionBayesian NIPS is more powerful than the Z-test method, is able to account for nongenetic risk factors through prior odds, and can report individual positive/negative predictive values.Genetics in Medicine advance online publication, 9 November 2017; doi:10.1038/gim.2017.186.
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    On the Null Distribution of Bayes Factors in Linear Regression
    (Journal of the American Statistical Association, 2017-07-27) Zhou, Quan; Guan, Yongtao
    © 2018 The Author(s). Published with license by Taylor & Francis We show that under the null, the (Formula presented.) is asymptotically distributed as a weighted sum of chi-squared random variables with a shifted mean. This claim holds for Bayesian multi-linear regression with a family of conjugate priors, namely, the normal-inverse-gamma prior, the g-prior, and the normal prior. Our results have three immediate impacts. First, we can compute analytically a p-value associated with a Bayes factor without the need of permutation. We provide a software package that can evaluate the p-value associated with Bayes factor efficiently and accurately. Second, the null distribution is illuminating to some intrinsic properties of Bayes factor, namely, how Bayes factor quantitatively depends on prior and the genesis of Bartlett’s paradox. Third, enlightened by the null distribution of Bayes factor, we formulate a novel scaled Bayes factor that depends less on the prior and is immune to Bartlett’s paradox. When two tests have an identical p-value, the test with a larger power tends to have a larger scaled Bayes factor, a desirable property that is missing for the (unscaled) Bayes factor. Supplementary materials for this article are available online.
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    Strong Selection at MHC in Mexicans since Admixture.
    (PLoS genetics, 2016-02-10) Zhou, Quan; Zhao, Liang; Guan, Yongtao
    Mexicans are a recent admixture of Amerindians, Europeans, and Africans. We performed local ancestry analysis of Mexican samples from two genome-wide association studies obtained from dbGaP, and discovered that at the MHC region Mexicans have excessive African ancestral alleles compared to the rest of the genome, which is the hallmark of recent selection for admixed samples. The estimated selection coefficients are 0.05 and 0.07 for two datasets, which put our finding among the strongest known selections observed in humans, namely, lactase selection in northern Europeans and sickle-cell trait in Africans. Using inaccurate Amerindian training samples was a major concern for the credibility of previously reported selection signals in Latinos. Taking advantage of the flexibility of our statistical model, we devised a model fitting technique that can learn Amerindian ancestral haplotype from the admixed samples, which allows us to infer local ancestries for Mexicans using only European and African training samples. The strong selection signal at the MHC remains without Amerindian training samples. Finally, we note that medical history studies suggest such a strong selection at MHC is plausible in Mexicans.