Biomedical subjects

George Casella

Publications and source records attributed to George Casella.

At least 19 recordsLinked to original sources

PubMed2005

Intrinsic meta-analysis of contingency tables.

Meta-analysis has a natural formulation as a Bayesian hierarchical model. The main theoretical difficulty is the construction of a sensible relationship between the parameters of the individual statistical experiments and the meta-parameter. Since that prior information on such a relationship is typically not available, we argue that this relationship should be dictated by the structure of the model at hand. We then propose a novel procedure based on intrinsic priors which we fully develop for the case of meta-analysis of 2 x 2 contingency tables. Illustrations on real and artificial tables are given.

Adrenergic beta-Antagonists↗

PubMed2004

FunMap: functional mapping of complex traits.

SUMMARY: FunMap is a Web-based user interface designed to map quantitative trait loci (QTL) affecting function-valued traits or infinite-dimensional traits in well-structured pedigrees or natural populations. User input includes three files: longitudinal trait data, marker genotypes and/or a linkage map. This software allows for a systematic genome-wide scan and significance test of QTL throughout the map. The dynamic change of QTL effects during the time course of growth is automatically drawn, from which specific biological hypotheses regarding the genetic control mechanisms of growth and development can be tested. AVAILABILITY: http://web.biostat.ufl.edu/~cma/genetics/software.html

Chromosome Mapping↗

PubMed2004

A mixed polyploid model for linkage analysis in outcrossing tetraploids using a pseudo-test backcross design.

Based on how chromosomes pair at meiosis, the nature of polyploids can be described by bivalent polyploids, multivalent polyploids, and mixed polyploids. In bivalent polyploids, only two chromosomes pair, during which two more similar chromosomes have a higher pairing probability (preferential pairing) than two less similar chromosomes, whereas in multivalent polyploids more than two chromosomes pair at a time, which results in double reduction. Preferential chromosome pairings and double reduction affect the frequencies of gamete formation and, therefore, linkage analysis of polymorphic markers in bivalent and multivalent polyploids, respectively. For mixed polyploids, in which both bivalent and multivalent formations occur simultaneously, linkage analysis is affected by both preferential pairings and double reduction. In this study, we develop a hierarchical maximum likelihood model for discerning gamete genotypes derived from different pairing mechanisms and different formation modes. The first-stage model in the hierarchy is formulated to characterize the relative frequencies of bivalent and multivalent pairing configurations in terms of the preferential pairing factor. The second-stage model is derived to rule out identical gamete genotypes into their different formation modes with relative probabilities determined by the recombination fraction. The first-stage pairing mechanism and second-stage formation mode are integrated to provide the simultaneous maximum likelihood estimates of the preferential pairing factor, the frequency of double reduction, and the recombination fraction, by implementing the EM algorithm. We performed extensive simulation studies to demonstrate the statistical properties of our hierarchical model for linkage analysis in tetraploids. The implications of our model for polyploid linkage mapping are discussed.

Algorithms↗

PubMed2004

Functional mapping of quantitative trait loci underlying growth trajectories using a transform-both-sides logistic model.

The incorporation of developmental control mechanisms of growth has proven to be a powerful tool in mapping quantitative trait loci (QTL) underlying growth trajectories. A theoretical framework for implementing a QTL mapping strategy with growth laws has been established. This framework can be generalized to an arbitrary number of time points, where growth is measured, and becomes computationally more tractable, when the assumption of variance stationarity is made. In practice, however, this assumption is likely to be violated for age-specific growth traits due to a scale effect. In this article, we present a new statistical model for mapping growth QTL, which also addresses the problem of variance stationarity, by using a transform-both-sides (TBS) model advocated by Carroll and Ruppert (1984, Journal of the American Statistical Association 79, 321-328). The TBS-based model for mapping growth QTL cannot only maintain the original biological properties of a growth model, but also can increase the accuracy and precision of parameter estimation and the power to detect a QTL responsible for growth differentiation. Using the TBS-based model, we successfully map a QTL governing growth trajectories to a linkage group in an example of forest trees. The statistical and biological properties of the estimates of this growth QTL position and effect are investigated using Monte Carlo simulation studies. The implications of our model for understanding the genetic architecture of growth are discussed.

Biometry↗

PubMed2004

Mapping quantitative trait Loci interactions from the maternal and offspring genomes.

The expression of most developmental or behavioral traits involves complex interactions between quantitative trait loci (QTL) from the maternal and offspring genomes. The maternal-offspring interactions play a pivotal role in shaping the direction and rate of evolution in terms of their substantial contribution to quantitative genetic (co)variation. To study the genetics and evolution of maternal-offspring interactions, a unifying statistical framework that embraces both the direct and indirect genetic effects of maternal and offspring QTL on any complex trait is developed. This model is derived for a simple backcross design within the maximum-likelihood context, implemented with the EM algorithm. Results from extensive simulations suggest that this model can provide reasonable estimation of additive and dominant effects of the QTL at different generations and their interaction effects derived from the maternal and offspring genomes. Although our model is framed to characterize the actions and interactions of maternal and offspring QTL affecting offspring traits, the idea can be readily extended to decipher the genetic machinery of maternal traits, such as maternal care. Our model provides a powerful means for studying the evolutionary significance of indirect genetic effects in any sexually reproductive organisms.

Animals↗

PubMed2004

A fast algorithm for functional mapping of complex traits.

By integrating the underlying developmental mechanisms for the phenotypic formation of traits into a mapping framework, functional mapping has emerged as an important statistical approach for mapping complex traits. In this note, we explore the feasibility of using the simplex algorithm as an alternative to solve the mixture-based likelihood for functional mapping of complex traits. The results from the simplex algorithm are consistent with those from the traditional EM algorithm, but the simplex algorithm has considerably reduced computational times. Moreover, because of its nonderivative nature and easy implementation with current software, the simplex algorithm enjoys an advantage over the EM algorithm in the dynamic modeling and analysis of complex traits.

Algorithms↗

PubMed2004

Sequencing complex diseases With HapMap.

Determining the patterns of DNA sequence variation in the human genome is a useful first step toward identifying the genetic basis of a common disease. A haplotype map (HapMap), aimed at describing these variation patterns across the entire genome, has been recently developed by the International HapMap Consortium. In this article, we present a novel statistical model for directly characterizing specific sequence variants that are responsible for disease risk based on the haplotype structure provided by HapMap. Our model is developed in the maximum-likelihood context, implemented with the EM algorithm. We perform simulation studies to investigate the statistical properties of this disease-sequencing model. A worked example from a human obesity study with 155 patients was used to validate this model. In this example, we found that patients carrying a haplotype constituted by allele Gly16 at codon 16 and allele Gln27 at codon 27 genotyped within the beta2AR candidate gene display significantly lower body mass index than patients carrying the other haplotypes. The implications and extensions of our model are discussed.

Body Mass Index↗

PubMed2004

A bivalent polyploid model for mapping quantitative trait loci in outcrossing tetraploids.

Two major aspects have made the genetic and genomic study of polyploids extremely difficult. First, increased allelic or nonallelic combinations due to multiple alleles result in complex gene actions and interactions for quantitative trait loci (QTL) in polyploids. Second, meiotic configurations in polyploids undergo a complex biological process including either bivalent or multivalent formation, or both. For bivalent polyploids, different degrees of preferential chromosome pairings may occur during meiosis. In this article, we develop a maximum-likelihood-based model for mapping QTL in tetraploids by considering the quantitative inheritance and meiotic mechanism of bivalent polyploids. This bivalent polyploid model is implemented with the EM algorithm to simultaneously estimate QTL position, QTL effects, and QTL-marker linkage phases by incorporating the impact of a cytological parameter determining bivalent chromosome pairings (the preferential pairing factor). Simulation studies are performed to investigate the performance and robustness of our statistical method for parameter estimation. The implication and extension of the bivalent polyploid model are discussed.

Algorithms↗

PubMed2004

A general framework for analyzing the genetic architecture of developmental characteristics.

The genetic architecture of growth traits plays a central role in shaping the growth, development, and evolution of organisms. While a limited number of models have been devised to estimate genetic effects on complex phenotypes, no model has been available to examine how gene actions and interactions alter the ontogenetic development of an organism and transform the altered ontogeny into descendants. In this article, we present a novel statistical model for mapping quantitative trait loci (QTL) determining the developmental process of complex traits. Our model is constructed within the traditional maximum-likelihood framework implemented with the EM algorithm. We employ biologically meaningful growth curve equations to model time-specific expected genetic values and the AR(1) model to structure the residual variance-covariance matrix among different time points. Because of a reduced number of parameters being estimated and the incorporation of biological principles, the new model displays increased statistical power to detect QTL exerting an effect on the shape of ontogenetic growth and development. The model allows for the tests of a number of biological hypotheses regarding the role of epistasis in determining biological growth, form, and shape and for the resolution of developmental problems at the interface with evolution. Using our newly developed model, we have successfully detected significant additive x additive epistatic effects on stem height growth trajectories in a forest tree.

Algorithms↗

PubMed2003

Functional mapping for quantitative trait loci governing growth rates: a parametric model.

Are there-specific quantitative trait loci (QTL) governing growth rates in biology? This is emerging as an exciting but challenging question for contemporary developmental biology, evolutionary biology, and plant and animal breeding. In this article, we present a new statistical model for mapping QTL underlying age-specific growth rates. This model is based on the mechanistic relationship between growth rates and ages established by a variety of mathematical functions. A maximum likelihood approach, implemented with the EM algorithm, is developed to provide the estimates of QTL position, growth parameters characterized by QTL effects, and residual variances and covariances. Based on our model, a number of biologically important hypotheses can be formulated concerning the genetic basis of growth. We use forest trees as an example to demonstrate the power of our model, in which a QTL for stem growth diameter growth rates is successfully mapped to a linkage group constructed from polymorphic markers. The implications of the new model are discussed.

Age Factors↗

PubMed2003

Exponential mapping of quantitative trait loci governing allometric relationships in organisms.

Allometric scaling relationships or quarter-power rules, as a universal biological law, can be viewed as having some genetic component, and the particular genes (or quantitative trait loci, QTL) underlying these allometric relationships can be mapped using molecular markers. We develop a mathematical and statistical model for mapping allometric QTL on the basis of nonlinear power functions using Taylor's approximation theory. Simulation studies indicate that the QTL position and effect can be estimated using our model, but the estimation precision can be improved from the higher- over lower-order approximation when the sample size used and gene effects are small. The application of our approach in a real example from forest trees leads to successful detection of a QTL governing the allometric relationship between 3rd-year stem height and 3rd-year stem biomass. It is expected that our model will have broad implications for genetic, evolutionary, biomedical and breeding research.

Algorithms↗

PubMed2003

The extent and distribution of linkage disequilibrium in a multi-hierarchic outbred canine pedigree.

A canine integrated linkage-radiation map has been recently constructed by using microsatellite markers. This map, with a good coverage of the canine genome, allows for a genome-wide search for the extent and distribution of linkage disequilibrium derived from linkage and evolutionary forces. In this study, we genotyped an outbred pedigree between Labrador retriever and Greyhound breeds with a set of microsatellite markers (240) from the canine linkage map. Linkage disequilibrium was measured between all syntenic and nonsyntenic marker pairs. Analysis of syntenic pairs revealed a significant correlation (-0.229, P < 0.001) between linkage disequilibrium and genetic distance (log transformed). Significant linkage disequilibria were observed more frequently between syntenic pairs spaced <40 cM than those paced >40 cM. There is a clear trend for linkage disequilibrium to decline with marker distance. From our results, a genome-wide screen with markers at low to moderate density (1-2 per 10 cM) should take full advantage of linkage disequilibrium for quantitative trait locus mapping in dogs. This study supports the appropriateness of linkage disequilibrium analysis to detect and map quantitative trait loci underlying complex traits in dogs.

Animals↗

PubMed2003

Quantitative trait loci for growth trajectories in Populus.

Growth trajectories are a biological process important to plant and animal breeding, and to evolutionary genetic studies. In this article, we report the detection of quantitative trait loci (QTLs) responsible for growth trajectories in poplars that are used as a model system for the study of forest biology. These QTLs were localized on a genetic linkage map of polymorphic markers using a statistical mapping method incorporating growth-curve models. The effects of the QTLs on growth are described as a function of age, so that age-specific changes in QTL effects can be readily projected throughout the entire growth process. The QTLs identified display increased effects on growth when trees age, yet the timing of QTL activation is earlier for stem height than diameter, which is consistent with the ecological viewpoint of canopy competition. The implications of the results for breeding and silviculture are discussed.

Genetic Linkage↗

PubMed2003

A haplotype-based algorithm for multilocus linkage disequilibrium mapping of quantitative trait loci with epistasis.

For tightly linked loci, cosegregation may lead to nonrandom associations between alleles in a population. Because of its evolutionary relationship with linkage, this phenomenon is called linkage disequilibrium. Today, linkage disequilibrium-based mapping has become a major focus of recent genome research into mapping complex traits. In this article, we present a new statistical method for mapping quantitative trait loci (QTL) of additive, dominant, and epistatic effects in equilibrium natural populations. Our method is based on haplotype analysis of multilocus linkage disequilibrium and exhibits two significant advantages over current disequilibrium mapping methods. First, we have derived closed-form solutions for estimating the marker-QTL haplotype frequencies within the maximum-likelihood framework implemented by the EM algorithm. The allele frequencies of putative QTL and their linkage disequilibria with the markers are estimated by solving a system of regular equations. This procedure has significantly improved the computational efficiency and the precision of parameter estimation. Second, our method can detect marker-QTL disequilibria of different orders and QTL epistatic interactions of various kinds on the basis of a multilocus analysis. This can not only enhance the precision of parameter estimation, but also make it possible to perform whole-genome association studies. We carried out extensive simulation studies to examine the robustness and statistical performance of our method. The application of the new method was validated using a case study from humans, in which we successfully detected significant QTL affecting human body heights. Finally, we discuss the implications of our method for genome projects and its extension to a broader circumstance. The computer program for the method proposed in this article is available at the webpage http://www.ifasstat.ufl.edu/genome/~LD.

Algorithms↗

PubMed2003

Evaluation of multiple radiographic predictors of cartilage lesions in the hip joints of eight-month-old dogs.

OBJECTIVE: To determine the radiographic methods that best predict the development of osteoarthritis in the hip joints of a cohort of dogs with hip dysplasia and unaffected dogs. ANIMALS: 205 Labrador Retrievers, Greyhounds, and Labrador Retriever-Greyhound crossbred dogs. PROCEDURE: Pelvic radiography was performed when the dogs were 8 months old. Ventrodorsal extended-hip, distraction, and dorsolateral subluxation (DLS) radiographs were obtained. An Orthopedic Foundation for Animals-like hip score, distraction index, dorsolateral subluxation score, and Norberg angle were derived from examination of radiographs. Osteoarthritis was diagnosed at the time of necropsy in dogs > or = 8 months of age on the basis of detection of articular cartilage lesions. Multiple logistic regression was used to determine the radiographic technique or techniques that best predicted development of osteoarthritis. RESULTS: A combination of 2 radiographic methods was better than any single method in predicting a cartilage lesion or a normal joint, but adding a third radiographic method did not improve that prediction. A combination of the DLS score and Norberg angle best predicted osteoarthritis of the hip joint or an unaffected hip joint. All models that excluded the DLS score were inferior to those that included it. CONCLUSIONS AND CLINICAL RELEVANCE: A combination of the DLS score and Norberg angle was the best predictor of radiographic measures in 8-month-old dogs to determine whether a dog would have normal or osteoarthritic hip joints.

Animals↗

PubMed2003

Power of a Labrador Retriever-Greyhound pedigree for linkage analysis of hip dysplasia and osteoarthritis.

OBJECTIVE: To estimate the number of dogs required to find linkage to heritable traits of hip dysplasia in dogs from an experimental pedigree. ANIMALS: 147 Labrador Retrievers, Greyhounds, and their crossbreed offspring. PROCEDURE: Labrador Retrievers with hip dysplasia were crossed with unaffected Greyhounds. Age at detection of femoral capital ossification, distraction index (DI), hip joint dorsolateral subluxation (DLS) score, and hip joint osteoarthritis (OA) were recorded. Power to find linkage of a single marker to a quantitative trait locus (QTL) controlling 100% of the variation in a dysplastic trait in the backcross dogs was determined. RESULTS: For the DI at the observed effect size, recombination fraction of 0.05, and heterozygosity of 0.75, 35 dogs in the backcross of the F1 to the Greyhound generation would yield linkage at a power of 0.8. For the DLS score, 35 dogs in the backcross to the Labrador Retriever generation would be required for linkage at the same power. For OSS, 45 dogs in the backcross to the founding Labrador Retrievers would yield linkage at the same power. Fewer dogs were projected to be necessary to find linkage to hip OA. Testing for linkage to the DLS at 4 loci simultaneously, each controlling 25% of the phenotypic variation, yielded an overall power of 0.7 CONCLUSIONS AND CLINICAL SIGNIFICANCE: Based on this conservative single-marker estimate, this pedigree has the requisite power to find microsatellites linked to susceptibility loci for hip dysplasia and hip OA by breeding a reasonable number of backcross dogs.

Aging↗

PubMed2002

A statistical model for the genetic origin of allometric scaling laws in biology.

Many biological processes, from cellular metabolism to population dynamics, are characterized by particular allometric scaling (power-law) relationships between size and rate. Although such allometric relationships may be under genetic determination, their precise genetic mechanisms have not been clearly understood due to a lack of a statistical analytical method. In this paper, we present a basic statistical framework for mapping quantitative genes (or quantitative trait loci, QTL) responsible for universal quarter-power scaling laws of organic structure and function with the entire body size. Our model framework allows the testing of whether a single QTL affects the allometric relationship of two traits or whether more than one linked QTL is segregating. Like traditional multi-trait mapping, this new model can increase the power to detect the underlying QTL and the precision of its localization on the genome. Beyond the traditional method, this model is integrated with pervasive scaling laws to take advantage of the mechanistic relationships of biological structures and processes. Simulation studies indicate that the estimation precision of the QTL position and effect can be improved when the scaling relationship of the two traits is considered. The application of our model in a real example from forest trees leads to successful detection of a QTL governing the allometric relationship of third-year stem height with third-year stem biomass. The model proposed here has implications for genetic, evolutionary, biomedicinal and breeding research.

Animals↗

PubMed2002

An improved genetic model generates high-resolution mapping of QTL for protein quality in maize endosperm.

The genetic mapping of polymorphic markers in a cross between two inbred plant lines has proven to be a powerful method for detecting quantitative trait loci (QTL) underlying complex traits. However, existing methods of QTL mapping were developed for disomic inheritance of both marker and QTL loci in a diploid population. To map QTL influencing traits expressed in the endosperm, a triploid embryo-nourishing tissue resulting from double fertilization, existing QTL mapping models require modification to consider the trisomic inheritance of the endosperm and the generation difference between the mapping population and the endosperm. Such a model requires simultaneous use of two successive generations, which theoretically can lead to an increase in resolution for QTL mapping compared with the use of a single backcross or F(2) generation. Using a newly developed model based on these considerations, we demonstrate the improved resolution of QTL, influencing protein quality traits in maize endosperm. The increased resolution made possible with this approach makes identified QTL accessible to positional cloning.

Chromosome Mapping↗