title: Mixed Model Association with Family-Biased Case-Control Ascertainment.
abstract: Mixed models have become the tool of choice for genetic association studies; however, standard mixed model methods may be poorly calibrated or underpowered under family sampling bias and/or case-control ascertainment. Previously, we introduced a liability threshold-based mixed model association statistic (LTMLM) to address case-control ascertainment in unrelated samples. Here, we consider family-biased case-control ascertainment, where case and control subjects are ascertained non-randomly with respect to family relatedness. Previous work has shown that this type of ascertainment can severely bias heritability estimates; we show here that it also impacts mixed model association statistics. We introduce a family-based association statistic (LT-Fam) that is robust to this problem. Similar to LTMLM, LT-Fam is computed from posterior mean liabilities (PML) under a liability threshold model; however, LT-Fam uses published narrow-sense heritability estimates to avoid the problem of biased heritability estimation, enabling correct calibration. In simulations with family-biased case-control ascertainment, LT-Fam was correctly calibrated (average χ2= 1.00-1.02 for null SNPs), whereas the Armitage trend test (ATT), standard mixed model association (MLM), and case-control retrospective association test (CARAT) were mis-calibrated (e.g., average χ2= 0.50-1.22 for MLM, 0.89-2.65 for CARAT). LT-Fam also attained higher power than other methods in some settings. In 1,259 type 2 diabetes-affected case subjects and 5,765 control subjects from the CARe cohort, downsampled to induce family-biased ascertainment, LT-Fam was correctly calibrated whereas ATT, MLM, and CARAT were again mis-calibrated. Our results highlight the importance of modeling family sampling bias in case-control datasets with related samples.
authors.affiliation: Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA; Department of Biostatistics, Columbia University, New York, NY 10032, USA. Electronic address: tjh488@mail.harvard.edu.
authors.forename: Tristan J
authors.initials: TJ
authors.lastname: Hayeck
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Po-Ru
authors.initials: PR
authors.lastname: Loh
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Samuela
authors.initials: S
authors.lastname: Pollack
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gusev
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Nick
authors.initials: N
authors.lastname: Patterson
authors.affiliation: Department of Medicine, Lung Biology Center, University of California, San Francisco, CA 94158, USA.
authors.forename: Noah A
authors.initials: NA
authors.lastname: Zaitlen
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. Electronic address: aprice@hsph.harvard.edu.
authors.forename: Alkes L
authors.initials: AL
authors.lastname: Price
mesh_terms: D015982:Bias; D002138:Calibration; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005190:Family; D056726:Genetic Association Studies / Q000379:methods*; D005838:Genotype; D006801:Humans; D008957:Models, Genetic; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012189:Retrospective Studies