CAUSAL GRAPHICAL MODELS IN SYSTEMS GENETICS: A UNIFIED FRAMEWORK FOR JOINT INFERENCE OF CAUSAL NETWORK AND GENETIC ARCHITECTURE FOR CORRELATED PHENOTYPES

Causal inference approaches in systems genetics exploit quantitative trait loci (QTL) genotypes to infer causal relationships among phenotypes. The genetic architecture of each phenotype may be complex, and poorly estimated genetic architectures may compromise the inference of causal relationships among phenotypes. Existing methods assume QTLs are known or inferred without regard to the phenotype network structure. In this paper we develop a QTL-driven phenotype network method (QTLnet) to jointly infer a causal phenotype network and associated genetic architecture for sets of correlated phenotypes. Randomization of alleles during meiosis and the unidirectional influence of genotype on phenotype allow the inference of QTLs causal to phenotypes. Causal relationships among phenotypes can be inferred using these QTL nodes, enabling us to distinguish among phenotype networks that would otherwise be distribution equivalent. We jointly model phenotypes and QTLs using homogeneous conditional Gaussian regression models, and we derive a graphical criterion for distribution equivalence. We validate the QTLnet approach in a simulation study. Finally, we illustrate with simulated data and a real example how QTLnet can be used to infer both direct and indirect effects of QTLs and phenotypes that co-map to a genomic region.     

Fence methods for backcross experiments

Model search strategies play an important role in finding simultaneous susceptibility genes that are associated with a trait. More particularly, model selection via the information criteria, such as the BIC with modifications, have received considerable attention in quantitative trait loci mapping. However, such modifications often depend upon several factors, such as sample size, prior distribution, and the type of experiment, for example, backcross, intercross. These changes make it difficult to generalize the methods to all cases. The fence method avoids such limitations with a unified approach, and hence can be used more broadly. In this article, this method is studied in the case of backcross experiments throughout a series of simulation studies. The results are compared with those of the modified BIC method as well as some of the most popular shrinkage methods for model selection.     

A new interval mapping approach based on a general sib-pair regression model with a modified Wald test

Various regression models based on sib-pair data have been developed for mapping quantitative trait loci (QTL) in humans since the seminal paper published in 1972 by Haseman and Elston. Fulker and Cardon [D.W. Fulker, L.R. Cardon, A sib-pair approach to interval mapping of quantitative trait loci, Am. J. Hum. Genet. 54 (1994) 1092–1103] adapted the idea of interval mapping [E.S. Lander, D. Botstein, Mapping Mendelian factors underlying quantitative traits using RFLP linkage maps, Genetics 121 (1989) 185–199] to the Haseman–Elston regression model in order to increase the power of QTL mapping. However, in the interval mapping approach of Fulker and Cardon, the statistic for testing QTL effects does not obey the classical statistical theory and hence critical values of the test can not be appropriately determined. In this article, we consider a new interval mapping approach based on a general sib-pair regression model. A modified Wald test is proposed for the testing of QTL effects. The asymptotic distribution of the modified Wald test statistic is provided and hence the critical values or the $p$-values of the test can be well determined. Simulation studies are carried out to verify the validity of the modified Wald test and to demonstrate its desirable power.     

SNP selection for predicting a quantitative trait

Molecular markers combined with powerful statistical tools have made it possible to detect and analyze multiple loci on the genome that are responsible for the phenotypic variation in quantitative traits. The objectives of the study presented in this paper are to identify a subset of single nucleotide polymorphism (SNP) markers that are associated with a particular trait and to construct a model that can best predict the value of the trait given the genotypic information of the SNPs using a three-step strategy. In the first step, a genome-wide association test is performed to screen SNPs that are associated with the quantitative trait of interest. SNPs with p-values of less than 5% are then analyzed in the second step. In the second step, a large number of randomly selected models, each consisting of a fixed number of randomly selected SNPs, are analyzed using the least angle regression method. This step will further remove redundant SNPs due to the complicated association among SNPs. A subset of SNPs that are shown to have a significant effect on the response trait more often than by chance are considered for the third step. In the third step, two alternative methods are considered: the least angle shrinkage and selection operation and sparse partial least squares regression. For both methods, the predictive ability of the fitted model is evaluated by an independent test set. The performance of the proposed method is illustrated by the analysis of a real data set on Canadian Holstein cattle.     

Bayesian parsimonious covariance estimation for hierarchical linear mixed models

We consider a non-centered parameterization of the standard random-effects model, which is based on the Cholesky decomposition of the variance-covariance matrix. The regression type structure of the non-centered parameterization allows us to use Bayesian variable selection methods for covariance selection. We search for a parsimonious variance-covariance matrix by identifying the non-zero elements of the Cholesky factors. With this method we are able to learn from the data for each effect whether it is random or not, and whether covariances among random effects are zero. An application in marketing shows a substantial reduction of the number of free elements in the variance-covariance matrix.     

Model selection for infinite variance time series

In this we consider the problem of model selection for infinite variance time series. We introduce a group of model selection critera based on a general loss function Ψ. This family includes various generalizations of predictive least square and AIC Parameter estimation is carried out using Ψ. We use two loss functions commonly used in robust estimation and show that certain criteria out perform the conventional approach based on least squares or Yule-Walker estima­tion for heavy tailed innovations. Our conclusions are based on a comprehensive study of the performance of competing criteria for a wide selection of AR(2) models. We also consider the performance of these techniques when the ‘true’ model is not contained in the family of candidate models.     

A robust QTL mapping procedure

In quantitative trait linkage studies using experimental crosses, the conventional normal location-shift model or other parameterizations may be unnecessarily restrictive. We generalize the mapping problem to a genuine nonparametric setup and provide a robust estimation procedure for the situation where the underlying phenotype distributions are completely unspecified. Classical Wilcoxon–Mann–Whitney statistics are employed for point and interval estimation of QTL positions and effects.     

Optimal consumption and portfolio selection with negative wealth constraints,subsistence consumption constraints,and CARA utility

We consider the optimal consumption and portfolio selection problem with constant absolute risk aversion (CARA) utility. The economic agent in this model receives constant labor income, and her economic behavior is restricted on consumption and wealth, which are called the subsistence consumption constraint and the negative wealth constraint. We use the convex duality method to derive the value function and the optimal policies in closed-form solutions. Also we illustrate some numerical examples.     

Non-nested model selection based on the quantiles and it’s application in time series

We consider the problem of model selection based on quantile analysis and with unknown parameters estimated using quantile leasts squares. We propose a model selection test for the null hypothesis that the competing models are equivalent against the alternative hypothesis that one model is closer to the true model. We follow with two applications of the proposed model selection test. The first application is in model selection for time series with non-normal innovations. The second application is in model selection in the NoVas method, short for normalizing and variance stabilizing transformation, forecast. A set of simulation results also lends strong support to the results presented in the paper.     

Bayesian model-averaged regularization for Gaussian graphical models

The graphical lasso has now become a useful tool to estimate high-dimensional Gaussian graphical models, but its practical applications suffer from the problem of choosing regularization parameters in a data-dependent way. In this article, we propose a model-averaged method for estimating sparse inverse covariance matrices for Gaussian graphical models. We consider the graphical lasso regularization path as the model space for Bayesian model averaging and use Markov chain Monte Carlo techniques for the regularization path point selection. Numerical performance of our method is investigated using both simulated and real datasets, in comparison with some state-of-art model selection procedures.     

Consistent fractional Bayes factor for nested normal linear models

In the Bayesian approach to parametric model comparison, the use of improper priors is problematic due to the indeterminacy of the resulting Bayes factor (BF). The need for developing automatic and robust methods for model comparison has led to the introduction of alternative BFs. Intrinsic Bayes factors (Berger and Pericchi, 1996a) and fractional Bayes factors (FBF) (O'Hagan, 1995) are two alternative strategies for default model selection. We show in this paper that the FBF can be inconsistent. To overcome this problem, we propose a generalization of the FBF approach that leads to the usual FBF or to some variants of it in some special cases. As an important problem, we consider and discuss this generalization for model selection in nested linear models.     

Asymptotic test of mixture model and its applications to QTL interval mapping

Quantitative trait loci (QTL) mapping has been a standard means in identifying genetic regions harboring potential genes underlying complex traits. Likelihood ratio test (LRT) has been commonly applied to assess the significance of a genetic locus in a mixture model content. Given the time constraint in commonly used permutation tests to assess the significance of LRT in QTL mapping, we study the behavior of the LRT statistic in mixture model when the proportions of the distributions are unknown. We found that the asymptotic null distribution is stationary Gaussian process after suitable transformation. The result can be applied to one-parameter exponential family mixture model. Under certain condition, such as in a backcross mapping model, the tail probability of the supremum of the process is calculated and the threshold values can be determined by solving the distribution function. Simulation studies were performed to evaluate the asymptotic results.     

Order-restricted hypothesis testing in a variation of the normal mixture model

This paper examines likelihood-ratio tests concerning the relationships among a fixed number of univariate normal means given a sample of normal observations whose population membership is uncertain. The asymptotic null distributions of likelihood-ratio test statistics are derived for a class of tests including hypotheses which place linear inequality constraints on the normal means. The use of such tests in the interval mapping of quantitative trait loci is addressed.     

Variable Selection in Linear Mixed Models Using an Extended Class of Penalties

There is an emerging need to advance linear mixed model technology to include variable selection methods that can simultaneously choose and estimate important effects from a potentially large number of covariates. However, the complex nature of variable selection has made it difficult for it to be incorporated into mixed models. In this paper we extend the well known class of penalties and show that they can be integrated succinctly into a linear mixed model setting. Under mild conditions, the estimator obtained from this mixed model penalised likelihood is shown to be consistent and asymptotically normally distributed. A simulation study reveals that the extended family of penalties achieves varying degrees of estimator shrinkage depending on the value of one of its parameters. The simulation study also shows there is a link between the number of false positives detected and the number of true coefficients when using the same penalty. This new mixed model variable selection (MMVS) technology was applied to a complex wheat quality data set to determine significant quantitative trait loci (QTL).     

Joint Estimation of Intersecting Context Tree Models

We study a problem of model selection for data produced by two different context tree sources. Motivated by linguistic questions, we consider the case where the probabilistic context trees corresponding to the two sources are finite and share many of their contexts. In order to understand the differences between the two sources, it is important to identify which contexts and which transition probabilities are specific to each source. We consider a class of probabilistic context tree models with three types of contexts: those which appear in one, the other, or both sources. We use a BIC penalized maximum likelihood procedure that jointly estimates the two sources. We propose a new algorithm which efficiently computes the estimated context trees. We prove that the procedure is strongly consistent. We also present a simulation study showing the practical advantage of our procedure over a procedure that works separately on each data set.     

Model selection consistency of U-statistics with convex loss and weighted lasso penalty

In the paper we consider minimisation of U-statistics with the weighted Lasso penalty and investigate their asymptotic properties in model selection and estimation. We prove that the use of appropriate weights in the penalty leads to the procedure that behaves like the oracle that knows the true model in advance, i.e. it is model selection consistent and estimates nonzero parameters with the standard rate. For the unweighted Lasso penalty, we obtain sufficient and necessary conditions for model selection consistency of estimators. The obtained results strongly based on the convexity of the loss function that is the main assumption of the paper. Our theorems can be applied to the ranking problem as well as generalised regression models. Thus, using U-statistics we can study more complex models (better describing real problems) than usually investigated linear or generalised linear models.     

A sign based loss approach to model selection in nonparametric regression

In parametric regression models the sign of a coefficient often plays an important role in its interpretation. One possible approach to model selection in these situations is to consider a loss function that formulates prediction of the sign of a coefficient as a decision problem. Taking a Bayesian approach, we extend this idea of a sign based loss for selection to more complex situations. In generalized additive models we consider prediction of the sign of the derivative of an additive term at a set of predictors. Being able to predict the sign of the derivative at some point (that is, whether a term is increasing or decreasing) is one approach to selection of terms in additive modelling when interpretation is the main goal. For models with interactions, prediction of the sign of a higher order derivative can be used similarly. There are many advantages to our sign-based strategy for selection: one can work in a full or encompassing model without the need to specify priors on a model space and without needing to specify priors on parameters in submodels. Also, avoiding a search over a large model space can simplify computation. We consider shrinkage prior specifications on smoothing parameters that allow for good predictive performance in models with large numbers of terms without the need for selection, and a frequentist calibration of the parameter in our sign-based loss function when it is desired to control a false selection rate for interpretation.     

Summer temperature effects on deaths and hospital admissions among the elderly population in two Italian cities

In developed countries the effects of climate on health status are mainly due to temperature. Our analysis is aimed to deepen statistically the relationship between summer climate conditions and daily frequency of health episodes: deaths or hospital admissions. We expect to find a U-shaped relationship between temperature and frequencies of events occurring in summer regarding the elderly population resident in Milano and Brescia. We use as covariates hourly records of temperature recorded at observation sites located in Milano and Brescia. The analysis is performed using Generalized Additive Models (GAM), where the response variable is the daily number of events, which varies as a possibly non-linear function of meteorological variables measured on the same or previous day. We consider separate models for Milano and Brescia and then we compare temperature effects among the two towns and among different age classes. Moreover we consider separate models for all diagnosed events, for those due to respiratory disease and those due to circulatory pathologies. Model selection is a central problem, the basic methods used are the UBRE and GCV criteria but, instead of conditioning all final conclusions on the best model according to the chosen criterion, we investigated the effect of model selection by implementing a bootstrap procedure.     

Penalized regression models with autoregressive error terms

Penalized regression methods have recently gained enormous attention in statistics and the field of machine learning due to their ability of reducing the prediction error and identifying important variables at the same time. Numerous studies have been conducted for penalized regression, but most of them are limited to the case when the data are independently observed. In this paper, we study a variable selection problem in penalized regression models with autoregressive (AR) error terms. We consider three estimators, adaptive least absolute shrinkage and selection operator, bridge, and smoothly clipped absolute deviation, and propose a computational algorithm that enables us to select a relevant set of variables and also the order of AR error terms simultaneously. In addition, we provide their asymptotic properties such as consistency, selection consistency, and asymptotic normality. The performances of the three estimators are compared with one another using simulated and real examples.