A multivariate family-based association test using generalized estimating equations: FBAT-GEE.

In this paper we propose a multivariate extension of family-based association tests based on generalized estimating equations. The test can be applied to multiple phenotypes and to phenotypic data obtained in longitudinal studies without making any distributional assumptions for the phenotypic observations. Methods for handling missing phenotypic information are discussed. Further, we compare the power of the multivariate test with permutation tests and with using separate tests for each outcome which are adjusted for multiple testing. Application of the proposed test to an asthma study illustrates the power of the approach.

[1]  S. Zeger,et al.  Longitudinal data analysis using generalized linear models , 1986 .

[2]  Daniel Rabinowitz,et al.  A Unified Approach to Adjusting Association Tests for Population Admixture with Arbitrary Pedigree Structure and Arbitrary Missing Marker Information , 2000, Human Heredity.

[3]  G. Abecasis,et al.  A general test of association for quantitative traits in nuclear families. , 2000, American journal of human genetics.

[4]  Heather Eliassen,et al.  The Childhood Asthma Management Program (CAMP): design, rationale, and methods. Childhood Asthma Management Program Research Group. , 1999, Controlled clinical trials.

[5]  Christoph Lange,et al.  On a general class of conditional tests for family‐based association studies in genetics: the asymptotic distribution, the conditional power, and optimality considerations , 2002, Genetic epidemiology.

[6]  Generalized estimating equations: A hybrid approach for mean parameters in multivariate regression models , 2002 .

[7]  G. Thomson Analysis of complex human genetic traits: an ordered-notation method and new tests for mode of inheritance. , 1995, American journal of human genetics.

[8]  D. Schaid General score tests for associations of genetic markers with disease using cases and their parents , 1996, Genetic epidemiology.

[9]  N M Laird,et al.  Family-based tests of association in the presence of linkage. , 2000, American journal of human genetics.

[10]  D Rabinowitz,et al.  A transmission disequilibrium test for quantitative trait loci. , 1997, Human heredity.

[11]  C. Lewis,et al.  Power comparisons of the transmission/disequilibrium test and sib-transmission/disequilibrium-test statistics. , 1999, American journal of human genetics.

[12]  E. Martin,et al.  A test for linkage and association in general pedigrees: the pedigree disequilibrium test. , 2000, American journal of human genetics.

[13]  N M Laird,et al.  Family-based tests of association and linkage that use unaffected sibs, covariates, and interactions. , 2000, American journal of human genetics.

[14]  N M Laird,et al.  A discordant-sibship test for disequilibrium and linkage: no need for parental data. , 1998, American journal of human genetics.

[15]  D. Allison,et al.  Transmission-disequilibrium tests for quantitative traits. , 1997, American journal of human genetics.

[16]  K. Lange,et al.  A Conditional Inference Framework for Extending the Transmission/Disequilibrium Test , 1998, Human Heredity.

[17]  S. Green,et al.  Genetic polymorphisms of the beta 2-adrenergic receptor in nocturnal and nonnocturnal asthma. Evidence that Gly16 correlates with the nocturnal phenotype. , 1995, The Journal of clinical investigation.

[18]  D. Rubin,et al.  Maximum likelihood from incomplete data via the EM - algorithm plus discussions on the paper , 1977 .

[19]  N. Laird,et al.  The family based association test method: strategies for studying general genotype–phenotype associations , 2001, European Journal of Human Genetics.

[20]  M. Kendall Theoretical Statistics , 1956, Nature.

[21]  E. Martin,et al.  Sibling-based tests of linkage and association for quantitative traits. , 1999, American journal of human genetics.

[22]  R. Erickson,et al.  Association between genetic polymorphisms of the beta2-adrenoceptor and response to albuterol in children with and without a history of wheezing. , 1997, The Journal of clinical investigation.

[23]  Xin Xu,et al.  Implementing a unified approach to family‐based tests of association , 2000, Genetic epidemiology.

[24]  W. Ewens,et al.  Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). , 1993, American journal of human genetics.

[25]  Y. Hochberg A sharper Bonferroni procedure for multiple tests of significance , 1988 .

[26]  D J Schaid,et al.  Comparison of statistics for candidate-gene association studies using cases and parents. , 1994, American journal of human genetics.

[27]  C. Heyde,et al.  Quasi-likelihood and its application , 1997 .

[28]  C. Ober,et al.  beta(2)-adrenergic receptor Arg16/Arg16 genotype is associated with reduced lung function, but not with asthma, in the Hutterites. , 2000, American journal of respiratory and critical care medicine.