One of the paradoxes of modern genetics is the contrast between the tremendous technological advances in sequencing and genotyping during the past decade and the slow progress in identifying genes for complex diseases. These diseases involve subtle disruptions of biochemical and developmental pathways and display substantial genetic heterogeneity and gene-by-gene and gene-by-environment interactions. In response to these challenges, geneticists are collecting much larger samples and genotyping enormous numbers of SNPs (single nucleotide polymorphisms). To handle the massive increases in data flow and extract the maximum amount of information from available data, better statistical analysis tools must be made available to the human genetics community. The current grant supports construction of new statistical methods and their translation into user friendly software via the widely distributed program Mendel. Under the auspices of the grant, we will tackle a series of related projects on computational statistics, association mapping, estimation of DNA copy numbers, population genetics, and software for managing and displaying human pedigree data. Our research in computational statistics revolves around three classes of optimization algorithms - MM and EM algorithms, block relaxation methods, and lasso penalized estimation. We will apply these methods to estimation in random graphs, nonnegative matrix factorization, and multicategory discriminant analysis. These methods are also pertinent to fast logistic regression with case-control data and fast mapping of QTLs (quantitative trait loci). We further plan to develop fast tests of association based on contingency tables, robust testing procedures for multivariate traits, and algorithms for modeling gene-by-gene and gene-by-environment interactions. Our efforts on copy number variation will focus on penalized estimation of DNA copy number by signal intensity, and hidden Markov modeling of copy numbers from the Illumina genotyping platform. In population genetics we will develop methods and software for testing Hardy-Weinberg equilibrium in pedigree data, penalized estimation of haplotype frequencies, and estimation of ethnic admixture. Finally our software development efforts will concentrate on making Mendel more conducive to dense, genome-wide SNP data, including: parallelization of the existing Mendel code;restructuring of the data structures in Mendel;making it easier to run complete analysis routines within Mendel;and perfection of MendelPro, the graphical user interface to Mendel. This ambitious agenda is all part of our coherent effort to provide a single platform for managing, displaying, and analyzing genetic data. This kind of software infrastructure is necessary if genetic epidemiology is to move rapidly forward in the twenty-first century.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Genomics, Computational Biology and Technology Study Section (GCAT)
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Krasnewich, Donna M
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University of California Los Angeles
Biostatistics & Other Math Sci
Schools of Medicine
Los Angeles
United States
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Lake, James A; Larsen, Joseph; Tran, Dan Thy et al. (2018) Uncovering the Genomic Origins of Life. Genome Biol Evol 10:1705-1714
vonHoldt, Bridgett M; Ji, Sarah S; Aardema, Matthew L et al. (2018) Activity of Genes with Functions in Human Williams-Beuren Syndrome Is Impacted by Mobile Element Insertions in the Gray Wolf Genome. Genome Biol Evol 10:1546-1553
Paul, Kimberly C; Sinsheimer, Janet S; Cockburn, Myles et al. (2018) NFE2L2, PPARGC1?, and pesticides and Parkinson's disease risk and progression. Mech Ageing Dev 173:1-8
Lin, Liang-Yu; Chun Chang, Sunny; O'Hearn, Jim et al. (2018) Systems Genetics Approach to Biomarker Discovery: GPNMB and Heart Failure in Mice and Humans. G3 (Bethesda) 8:3499-3506
Gilbert, Princess S; Wu, Jing; Simon, Margaret W et al. (2018) Filtering nucleotide sites by phylogenetic signal to noise ratio increases confidence in the Neoaves phylogeny generated from ultraconserved elements. Mol Phylogenet Evol 126:116-128
Zhang, Yiwen; Zhou, Hua; Zhou, Jin et al. (2017) Regression Models For Multivariate Count Data. J Comput Graph Stat 26:1-13
Paul, Kimberly C; Sinsheimer, Janet S; Cockburn, Myles et al. (2017) Organophosphate pesticides and PON1 L55M in Parkinson's disease progression. Environ Int 107:75-81
Mancuso, Nicholas; Shi, Huwenbo; Goddard, Pagé et al. (2017) Integrating Gene Expression with Summary Association Statistics to Identify Genes Associated with 30 Complex Traits. Am J Hum Genet 100:473-487
Zhou, Hua; Blangero, John; Dyer, Thomas D et al. (2017) Fast Genome-Wide QTL Association Mapping on Pedigree and Population Data. Genet Epidemiol 41:174-186
Kichaev, Gleb; Roytman, Megan; Johnson, Ruth et al. (2017) Improved methods for multi-trait fine mapping of pleiotropic risk loci. Bioinformatics 33:248-255

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