Making Robust Use of Parental Genotype Data for Finding Effects of Variants on the X Chromosome

The X chromosome is generally understudied in association studies, in part because the analyst has limited methodological options. We are developing statistical methods for causal association for single nucleotide polymorphisms (SNP markers) on the X. The focus of our work is on case-parent triad association studies. Most current family-based methods extend the transmission disequilibrium test (TDT) to the X chromosome. We propose a new method to study association in case-parent triads: the parent-informed likelihood ratio test for the X chromosome (PIX-LRT). Our method provides estimation of relative risks and takes advantage of parental genotype information and the sex of the affected offspring. Under a parental allelic exchangeability assumption for the X, if for a given locus case-parent triads are complete, the parents of affected offspring provide an independent replication sample for the estimates based on transmission distortion to the affected offspring. For each offspring sex we can combine the parent-level and the offspring-level information to form a likelihood ratio test statistic; we then combine the two to form a single composite test statistic, which we show offers better power than existing methods. Maternal SNP effects can influence the development and later health of the offspring through prenatal effects, regardless of which alleles are transmitted by the mother to her offspring. Previously, using triads alone, no method had been developed without an assumption of Hardy-Weinberg Equilibrium (HWE) to test maternal effects on the X chromosome. For the second project we extended PIX-LRT to discover maternal X-chromosome SNP effects. Our third project concerns the identification and estimation of effects of X haplotypes. For case-parent triads, the X-chromosome haplotype phases can be inferred. With phase information, as is available when triad genotypes are nonmissing, the problem can be managed via an extension of the PIX-LRT from a two-allele problem to a k-allele problem, where the “alleles” are now the existing haplotypes at the locus under study. The extended approach relies on a permutation-based p-value based on the most significant individual haplotype effect. Our methods are applied to a dataset consisting of over 2000 triads in which the affected offspring have an oral cleft.Doctor of Public Healt

Yeast through the Ages: a Statistical Analysis of Genetic Changes in Aging Yeast

Microarray technology allows for the expression levels of thousands of genes in a cell to be measured simultaneously. The technology provides great potential in the fields of biology and medicine, as the analysis of data obtained from microarray experiments gives insight into the roles of specific genes and the associated changes across experimental conditions (e.g., aging, mutation, radiation therapy, drug dosage). The application of statistical tools to microarray data can help make sense of the experiment and thereby advance genetic, biological, and medical research. Likewise, microarrays provide an exciting means through which to explore statistical techniques

Expanding Our Classroom Walls: Enhancing Teaching and Learning Through Technology

The authors examine the reasons why law faculty should implement technology into the legal education experience, provide a brief overview of the learning theory supporting technology, discuss the thoughtful use of technology, and describe four specific projects they have used in their classrooms to aid in student learning

Expanding Our Classroom Walls: Enhancing Teaching and Learning Through Technology

The authors examine the reasons why law faculty should implement technology into the legal education experience, provide a brief overview of the learning theory supporting technology, discuss the thoughtful use of technology, and describe four specific projects they have used in their classrooms to aid in student learning

The role of inflammation in age-related disease.

The National Institutes of Health (NIH) Geroscience Interest Group (GSIG) sponsored workshop, The Role of Inflammation inAge-Related Disease, was held September 6th-7th, 2012 in Bethesda, MD. It is now recognized that a mild pro-inflammatory state is correlated with the major degenerative diseases of the elderly. The focus of the workshop was to better understand the origins and consequences of this low level chronic inflammation in order to design appropriate interventional studies aimed at improving healthspan. Four sessions explored the intrinsic, environmental exposures and immune pathways by which chronic inflammation are generated, sustained, and lead to age-associated diseases. At the conclusion of the workshop recommendations to accelerate progress toward understanding the mechanistic bases of chronic disease were identified

Learning about the X from our parents

The X chromosome is generally understudied in association studies, in part because the analyst has had limited methodological options. For nuclear-family-based association studies, most current methods extend the transmission disequilibrium test (TDT) to the X chromosome. We present a new method to study association in case-parent triads: the parent-informed likelihood ratio test for the X chromosome (PIX-LRT). Our method enables estimation of relative risks and takes advantage of parental genotype information and the sex of the affected offspring to increase statistical power to detect an effect. Under a parental exchangeability assumption for the X, if case-parent triads are complete, the parents of affected offspring provide an independent replication sample for estimates based on transmission distortion to their affected offspring. For each offspring sex we combine the parent-level and the offspring-level information to form a likelihood ratio test statistic; we then combine the two to form a combined test statistic. Our method can estimate relative risks under different modes of inheritance or a more general co-dominant model. In triads with missing parental genotypes, the method accounts for missingness with the Expectation-Maximization algorithm. We calculate non-centrality parameters to assess the power gain and robustness of our method compared to alternative methods. We apply PIX-LRT to publically available data from an international consortium of genotyped families affected by the birth defect oral cleft and find a strong, internally-replicated signal for a SNP marker related to cleft lip with or without cleft palate

Learning about the X from our parents

The X chromosome is generally understudied in association studies, in part because the analyst has had limited methodological options. For nuclear-family-based association studies, most current methods extend the transmission disequilibrium test (TDT) to the X chromosome. We present a new method to study association in case-parent triads: the parent-informed likelihood ratio test for the X chromosome (PIX-LRT). Our method enables estimation of relative risks and takes advantage of parental genotype information and the sex of the affected offspring to increase statistical power to detect an effect. Under a parental exchangeability assumption for the X, if case-parent triads are complete, the parents of affected offspring provide an independent replication sample for estimates based on transmission distortion to their affected offspring. For each offspring sex we combine the parent-level and the offspring-level information to form a likelihood ratio test statistic; we then combine the two to form a combined test statistic. Our method can estimate relative risks under different modes of inheritance or a more general co-dominant model. In triads with missing parental genotypes, the method accounts for missingness with the Expectation-Maximization algorithm. We calculate non-centrality parameters to assess the power gain and robustness of our method compared to alternative methods. We apply PIX-LRT to publically available data from an international consortium of genotyped families affected by the birth defect oral cleft and find a strong, internally-replicated signal for a SNP marker related to cleft lip with or without cleft palate

Strategic Activity and Financial Performance of U.S. Rural Hospitals: A National Study, 1983 to 1988

This study examines the effect of 13 strategic management activities on the financial performance of a national sample of 797 U.S. rural hospitals during the period of 1983-1988. Controlled for environment-market, geographic-region, and hospital-related variables, the results show almost no measurable effect of strategic adoption on rural hospital profitability and liquidity. Where statistically significant relationships existed, they were more often negative than positive. These findings were not expected; it was hypothesized that positive effects across a broad range of strategies would emerge, other things being equal. Discussed are possible explanations for these findings as well as their implication for a rural health policy relying on individual rural hospital strategic adaptation to environmental change.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72301/1/j.1748-0361.1994.tb00225.x.pd

Maternal Genotype and Gestational Diabetes

To determine whether genetic variants associated with glucose homeostasis are associated with gestational diabetes (GDM)

Pathotype Diversity of Phytophthora sojae in Eleven States in the United States

Pathotype diversity of Phytophthora sojae was assessed in 11 states in the United States during 2012 and 2013. Isolates of P. sojae were recovered from 202 fields, either from soil samples using a soybean seedling bioassay or by isolation from symptomatic plants. Each isolate was inoculated directly onto 12 soybean differentials; no Rps gene or Rps 1a, 1b, 1c, 1k, 3a, 3b, 3c, 4, 6, 7, or 8. There were 213 unique virulence pathotypes identified among the 873 isolates collected. None of the Rps genes were effective against all the isolates collected but Rps6 and Rps8 were effective against the majority of isolates collected in the northern regions of the sampled area. Virulence toward Rps1a, 1b, 1c, and 1k ranged from 36 to 100% of isolates collected in each state, while virulence to Rps6 and Rps8 was less than 36 and 10%, respectively. Depending on the state, the effectiveness of Rps3a ranged from totally effective to susceptible to more than 40% of the isolates. Pathotype complexity has increased in populations of P. sojae in the United States, emphasizing the increasing importance of stacked Rps genes in combination with high partial resistance as a means of limiting losses to P. sojae