@article{zhang_martin_morris_li_2009, title={Association Test for X-Linked QTL in Family-Based Designs}, volume={84}, ISSN={["1537-6605"]}, DOI={10.1016/j.ajhg.2009.02.010}, abstractNote={Family-based association methods for detecting quantitative trait loci (QTL) have been developed primarily for autosomes, and comparable methods for X-linked QTL have received less attention. We have developed a family-based association test for quantitative traits, named XQTL, which uses X-linked markers in a nuclear family design. XQTL adopts the framework of the orthogonal model implemented in the QTDT program, modifying the sex-specific score for X-linked genotypes. XQTL also takes into account the dosage effect due to female X chromosome inactivation. Restricted maximum likelihood (REML) and Fisher's scoring method are used to estimate variance components of random effects. Fixed effects, derived from the phenotypic differences among and within families, are estimated by the least-squares method. Our proposed XQTL can perform allelic and two-locus haplotypic association tests and can provide estimates of additive genetic effects and variance components. Simulation studies show correct type I error rates under the null hypothesis and robust statistical power under alternative scenarios. The loss of power observed when parental genotypes are missing can be compensated by an increase of offspring number. By treating age at onset of Parkinson disease as a quantitative trait, we illustrate our method, using MAO polymorphisms in 780 families. Family-based association methods for detecting quantitative trait loci (QTL) have been developed primarily for autosomes, and comparable methods for X-linked QTL have received less attention. We have developed a family-based association test for quantitative traits, named XQTL, which uses X-linked markers in a nuclear family design. XQTL adopts the framework of the orthogonal model implemented in the QTDT program, modifying the sex-specific score for X-linked genotypes. XQTL also takes into account the dosage effect due to female X chromosome inactivation. Restricted maximum likelihood (REML) and Fisher's scoring method are used to estimate variance components of random effects. Fixed effects, derived from the phenotypic differences among and within families, are estimated by the least-squares method. Our proposed XQTL can perform allelic and two-locus haplotypic association tests and can provide estimates of additive genetic effects and variance components. Simulation studies show correct type I error rates under the null hypothesis and robust statistical power under alternative scenarios. The loss of power observed when parental genotypes are missing can be compensated by an increase of offspring number. By treating age at onset of Parkinson disease as a quantitative trait, we illustrate our method, using MAO polymorphisms in 780 families.}, number={4}, journal={AMERICAN JOURNAL OF HUMAN GENETICS}, author={Zhang, Li and Martin, Eden R. and Morris, Richard W. and Li, Yi-Ju}, year={2009}, month={Apr}, pages={431–444} }
 @article{leehey_berry-kravis_goetz_zhang_hall_li_rice_lara_cogswell_reynolds_et al._2008, title={FMR1 CGG repeat length predicts motor dysfunction in premutation carriers}, volume={70}, number={16}, journal={Neurology (Minneapolis, Minn.)}, author={Leehey, M. A. and Berry-Kravis, E. and Goetz, C. G. and Zhang, L. and Hall, D. A. and Li, L. and Rice, C. D. and Lara, R. and Cogswell, J. and Reynolds, A. and et al.}, year={2008}, pages={1397–1402} }
 @article{zhang_martin_chung_li_morris_2008, title={X-LRT: A likelihood approach to estimate genetic risks and test association with X-linked markers using a case-parents design}, volume={32}, ISSN={["0741-0395"]}, DOI={10.1002/gepi.20311}, abstractNote={Abstract}, number={4}, journal={GENETIC EPIDEMIOLOGY}, author={Zhang, Li and Martin, Eden R. and Chung, Ren-Hua and Li, Yi-Ju and Morris, Richard W.}, year={2008}, month={May}, pages={370–380} }
 @article{chung_morris_zhang_li_martin_2007, title={X-APL: An improved family-based test of association in the presence of linkage for the X chromosome}, volume={80}, ISSN={["0002-9297"]}, DOI={10.1086/510630}, abstractNote={Family-based association methods have been developed primarily for autosomal markers. The X-linked sibling transmission/disequilibrium test (XS-TDT) and the reconstruction-combined TDT for X-chromosome markers (XRC-TDT) are the first association-based methods for testing markers on the X chromosome in family data sets. These are valid tests of association in family triads or discordant sib pairs but are not theoretically valid in multiplex families when linkage is present. Recently, XPDT and XMCPDT, modified versions of the pedigree disequilibrium test (PDT), were proposed. Like the PDT, XPDT compares genotype transmissions from parents to affected offspring or genotypes of discordant siblings; however, the XPDT can have low power if there are many missing parental genotypes. XMCPDT uses a Monte Carlo sampling approach to infer missing parental genotypes on the basis of true or estimated population allele frequencies. Although the XMCPDT was shown to be more powerful than the XPDT, variability in the statistic due to the use of an estimate of allele frequency is not properly accounted for. Here, we present a novel family-based test of association, X-APL, a modification of the test for association in the presence of linkage (APL) test. Like the APL, X-APL can use singleton or multiplex families and properly infers missing parental genotypes in linkage regions by considering identity-by-descent parameters for affected siblings. Sampling variability of parameter estimates is accounted for through a bootstrap procedure. X-APL can test individual marker loci or X-chromosome haplotypes. To allow for different penetrances in males and females, separate sex-specific tests are provided. Using simulated data, we demonstrated validity and showed that the X-APL is more powerful than alternative tests. To show its utility and to discuss interpretation in real-data analysis, we also applied the X-APL to candidate-gene data in a sample of families with Parkinson disease.}, number={1}, journal={AMERICAN JOURNAL OF HUMAN GENETICS}, author={Chung, Ren-Hua and Morris, Richard W. and Zhang, Li and Li, Yi-Ju and Martin, Eden R.}, year={2007}, month={Jan}, pages={59–68} }