# Journal of the Royal Statistical Society Series B (Statistical Methodology)

Published by Wiley

Online ISSN: 1467-9868

Print ISSN: 1369-7412

Published by Wiley

Online ISSN: 1467-9868

Print ISSN: 1369-7412

Publications

We consider the problem of estimating multiple related Gaussian graphical models from a high-dimensional data set with observations belonging to distinct classes. We propose the joint graphical lasso, which borrows strength across the classes in order to estimate multiple graphical models that share certain characteristics, such as the locations or weights of nonzero edges. Our approach is based upon maximizing a penalized log likelihood. We employ generalized fused lasso or group lasso penalties, and implement a fast ADMM algorithm to solve the corresponding convex optimization problems. The performance of the proposed method is illustrated through simulated and real data examples.

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- 788 Reads
- 730 Citations

Neuroimaging studies aim to analyze imaging data with complex spatial patterns in a large number of locations (called voxels) on a two-dimensional (2D) surface or in a 3D volume. Conventional analyses of imaging data include two sequential steps: spatially smoothing imaging data and then independently fitting a statistical model at each voxel. However, conventional analyses suffer from the same amount of smoothing throughout the whole image, the arbitrary choice of smoothing extent, and low statistical power in detecting spatial patterns. We propose a multiscale adaptive regression model (MARM) to integrate the propagation-separation (PS) approach (Polzehl and Spokoiny, 2000, 2006) with statistical modeling at each voxel for spatial and adaptive analysis of neuroimaging data from multiple subjects. MARM has three features: being spatial, being hierarchical, and being adaptive. We use a multiscale adaptive estimation and testing procedure (MAET) to utilize imaging observations from the neighboring voxels of the current voxel to adaptively calculate parameter estimates and test statistics. Theoretically, we establish consistency and asymptotic normality of the adaptive parameter estimates and the asymptotic distribution of the adaptive test statistics. Our simulation studies and real data analysis confirm that MARM significantly outperforms conventional analyses of imaging data.

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- 78 Reads
- 67 Citations

We study the heteroscedastic partially linear single-index model with an unspecified error variance function, which allows for high dimensional covariates in both the linear and the single-index components of the mean function. We propose a class of consistent estimators of the parameters by using a proper weighting strategy. An interesting finding is that the linearity condition which is widely assumed in the dimension reduction literature is not necessary for methodological or theoretical development: it contributes only to the simplification of non-optimal consistent estimation. We also find that the performance of the usual weighted least square type of estimators deteriorates when the non-parametric component is badly estimated. However, estimators in our family automatically provide protection against such deterioration, in that the consistency can be achieved even if the baseline non-parametric function is completely misspecified. We further show that the most efficient estimator is a member of this family and can be easily obtained by using non-parametric estimation. Properties of the estimators proposed are presented through theoretical illustration and numerical simulations. An example on gender discrimination is used to demonstrate and to compare the practical performance of the estimators.

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- 41 Reads
- 46 Citations

Local polynomial regression is a useful nonparametric regression tool to explore fine data structures and has been widely used in practice. In this paper, we propose a new nonparametric regression technique called local composite-quantile-regression (CQR) smoothing in order to further improve local polynomial regression. Sampling properties of the proposed estimation procedure are studied. We derive the asymptotic bias, variance and normality of the proposed estimate. Asymptotic relative efficiency of the proposed estimate with respect to the local polynomial regression is investigated. It is shown that the proposed estimate can be much more efficient than the local polynomial regression estimate for various non-normal errors, while being almost as efficient as the local polynomial regression estimate for normal errors. Simulation is conducted to examine the performance of the proposed estimates. The simulation results are consistent with our theoretical findings. A real data example is used to illustrate the proposed method.

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- 183 Reads
- 145 Citations

With the ready availability of spatial databases and geographical information system software, statisticians are increasingly encountering multivariate modelling settings featuring associations of more than one type: spatial associations between data locations and associations between the variables within the locations. Although flexible modelling of multivariate point-referenced data has recently been addressed by using a linear model of co-regionalization, existing methods for multivariate areal data typically suffer from unnecessary restrictions on the covariance structure or undesirable dependence on the conditioning order of the variables. We propose a class of Bayesian hierarchical models for multivariate areal data that avoids these restrictions, permitting flexible and order-free modelling of correlations both between variables and across areal units. Our framework encompasses a rich class of multivariate conditionally autoregressive models that are computationally feasible via modern Markov chain Monte Carlo methods. We illustrate the strengths of our approach over existing models by using simulation studies and also offer a real data application involving annual lung, larynx and oesophageal cancer death-rates in Minnesota counties between 1990 and 2000.

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- 47 Reads
- 88 Citations

Association models, like frailty and copula models, are frequently used to analyze clustered survival data and evaluate within-cluster associations. The assumption of noninformative censoring is commonly applied to these models, though it may not be true in many situations. In this paper, we consider bivariate competing risk data and focus on association models specified for the bivariate cumulative incidence function (CIF), a nonparametrically identifiable quantity. Copula models are proposed which relate the bivariate CIF to its corresponding univariate CIFs, similarly to independently right censored data, and accommodate frailty models for the bivariate CIF. Two estimating equations are developed to estimate the association parameter, permitting the univariate CIFs to be estimated either parametrically or nonparametrically. Goodness-of-fit tests are presented for formally evaluating the parametric models. Both estimators perform well with moderate sample sizes in simulation studies. The practical use of the methodology is illustrated in an analysis of dementia associations.

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- 93 Reads
- 14 Citations

We consider the development of Bayesian Nonparametric methods for product partition models such as Hidden Markov Models and change point models. Our approach uses a Mixture of Dirichlet Process (MDP) model for the unknown sampling distribution (likelihood) for the observations arising in each state and a computationally efficient data augmentation scheme to aid inference. The method uses novel MCMC methodology which combines recent retrospective sampling methods with the use of slice sampler variables. The methodology is computationally efficient, both in terms of MCMC mixing properties, and robustness to the length of the time series being investigated. Moreover, the method is easy to implement requiring little or no user-interaction. We apply our methodology to the analysis of genomic copy number variation.

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- 74 Reads
- 59 Citations

Existing Bayesian model selection procedures require the specification of prior distributions on the parameters appearing in every model in the selection set. In practice, this requirement limits the application of Bayesian model selection methodology. To overcome this limitation, we propose a new approach towards Bayesian model selection that uses classical test statistics to compute Bayes factors between possible models. In several test cases, our approach produces results that are similar to previously proposed Bayesian model selection and model averaging techniques in which prior distributions were carefully chosen. In addition to eliminating the requirement to specify complicated prior distributions, this method offers important computational and algorithmic advantages over existing simulation-based methods. Because it is easy to evaluate the operating characteristics of this procedure for a given sample size and specified number of covariates, our method facilitates the selection of hyperparameter values through prior-predictive simulation.

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- 90 Reads
- 22 Citations

Estimation of a regression function is a well-known problem in the context of errors in variables, where the explanatory variable is observed with random noise. This noise can be of two types, which are known as classical or Berkson, and it is common to assume that the error is purely of one of these two types. In practice, however, there are many situations where the explanatory variable is contaminated by a mixture of the two errors. In such instances, the Berkson component typically arises because the variable of interest is not directly available and can only be assessed through a proxy, whereas the inaccuracy that is related to the observation of the latter causes an error of classical type. We propose a non-parametric estimator of a regression function from data that are contaminated by a mixture of the two errors. We prove consistency of our estimator, derive rates of convergence and suggest a data-driven implementation. Finite sample performance is illustrated via simulated and real data examples.

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- 46 Reads
- 44 Citations

Testing the equality of two survival distributions can be difficult in a prevalent cohort study when non random sampling of subjects is involved. Due to the biased sampling scheme, independent censoring assumption is often violated. Although the issues about biased inference caused by length-biased sampling have been widely recognized in statistical, epidemiological and economical literature, there is no satisfactory solution for efficient two-sample testing. We propose an asymptotic most efficient nonparametric test by properly adjusting for length-biased sampling. The test statistic is derived from a full likelihood function, and can be generalized from the two-sample test to a k-sample test. The asymptotic properties of the test statistic under the null hypothesis are derived using its asymptotic independent and identically distributed representation. We conduct extensive Monte Carlo simulations to evaluate the performance of the proposed test statistics and compare them with the conditional test and the standard logrank test for different biased sampling schemes and right-censoring mechanisms. For length-biased data, empirical studies demonstrated that the proposed test is substantially more powerful than the existing methods. For general left-truncated data, the proposed test is robust, still maintains accurate control of type I error rate, and is also more powerful than the existing methods, if the truncation patterns and right-censoring patterns are the same between the groups. We illustrate the methods using two real data examples.

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- 78 Reads
- 25 Citations

We consider the problem of optimal design of experiments for random effects models, especially population models, where a small number of correlated observations can be taken on each individual, while the observations corresponding to different individuals are assumed to be uncorrelated. We focus on c-optimal design problems and show that the classical equivalence theorem and the famous geometric characterization of Elfving (1952) from the case of uncorrelated data can be adapted to the problem of selecting optimal sets of observations for the n individual patients. The theory is demonstrated by finding optimal designs for a linear model with correlated observations and a nonlinear random effects population model, which is commonly used in pharmacokinetics.

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- 49 Reads
- 6 Citations

We consider functional measurement error models, i.e. models where covariates are measured with error and yet no distributional assumptions are made about the mismeasured variable. We propose and study a score-type local test and an orthogonal series-based, omnibus goodness-of-fit test in this context, where no likelihood function is available or calculated-i.e. all the tests are proposed in the semiparametric model framework. We demonstrate that our tests have optimality properties and computational advantages that are similar to those of the classical score tests in the parametric model framework. The test procedures are applicable to several semiparametric extensions of measurement error models, including when the measurement error distribution is estimated non-parametrically as well as for generalized partially linear models. The performance of the local score-type and omnibus goodness-of-fit tests is demonstrated through simulation studies and analysis of a nutrition data set.

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- 50 Reads
- 17 Citations

In recent years, many methods have been developed for regression in high-dimensional settings. We propose covariance-regularized regression, a family of methods that use a shrunken estimate of the inverse covariance matrix of the features in order to achieve superior prediction. An estimate of the inverse covariance matrix is obtained by maximizing its log likelihood, under a multivariate normal model, subject to a constraint on its elements; this estimate is then used to estimate coefficients for the regression of the response onto the features. We show that ridge regression, the lasso, and the elastic net are special cases of covariance-regularized regression, and we demonstrate that certain previously unexplored forms of covariance-regularized regression can outperform existing methods in a range of situations. The covariance-regularized regression framework is extended to generalized linear models and linear discriminant analysis, and is used to analyze gene expression data sets with multiple class and survival outcomes.

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- 114 Reads
- 215 Citations

We consider the supervised classification setting, in which the data consist of p features measured on n observations, each of which belongs to one of K classes. Linear discriminant analysis (LDA) is a classical method for this problem. However, in the high-dimensional setting where p ≫ n, LDA is not appropriate for two reasons. First, the standard estimate for the within-class covariance matrix is singular, and so the usual discriminant rule cannot be applied. Second, when p is large, it is difficult to interpret the classification rule obtained from LDA, since it involves all p features. We propose penalized LDA, a general approach for penalizing the discriminant vectors in Fisher's discriminant problem in a way that leads to greater interpretability. The discriminant problem is not convex, so we use a minorization-maximization approach in order to efficiently optimize it when convex penalties are applied to the discriminant vectors. In particular, we consider the use of L(1) and fused lasso penalties. Our proposal is equivalent to recasting Fisher's discriminant problem as a biconvex problem. We evaluate the performances of the resulting methods on a simulation study, and on three gene expression data sets. We also survey past methods for extending LDA to the high-dimensional setting, and explore their relationships with our proposal.

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- 215 Reads
- 378 Citations

For high-dimensional classification, it is well known that naively performing the Fisher discriminant rule leads to poor results due to diverging spectra and noise accumulation. Therefore, researchers proposed independence rules to circumvent the diverging spectra, and sparse independence rules to mitigate the issue of noise accumulation. However, in biological applications, there are often a group of correlated genes responsible for clinical outcomes, and the use of the covariance information can significantly reduce misclassification rates. In theory the extent of such error rate reductions is unveiled by comparing the misclassification rates of the Fisher discriminant rule and the independence rule. To materialize the gain based on finite samples, a Regularized Optimal Affine Discriminant (ROAD) is proposed. ROAD selects an increasing number of features as the regularization relaxes. Further benefits can be achieved when a screening method is employed to narrow the feature pool before hitting the ROAD. An efficient Constrained Coordinate Descent algorithm (CCD) is also developed to solve the associated optimization problems. Sampling properties of oracle type are established. Simulation studies and real data analysis support our theoretical results and demonstrate the advantages of the new classification procedure under a variety of correlation structures. A delicate result on continuous piecewise linear solution path for the ROAD optimization problem at the population level justifies the linear interpolation of the CCD algorithm.

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- 87 Reads
- 105 Citations

Ecological studies, in which data are available at the level of the group, rather than at the level of the individual, are susceptible to a range of biases due to their inability to characterize within-group variability in exposures and confounders. In order to overcome these biases, we propose a hybrid design in which ecological data are supplemented with a sample of individual-level case-control data. We develop the likelihood for this design and illustrate its benefits via simulation, both in bias reduction when compared to an ecological study, and in efficiency gains relative to a conventional case-control study. An interesting special case of the proposed design is the situation where ecological data are supplemented with case-only data. The design is illustrated using a dataset of county-specific lung cancer mortality rates in the state of Ohio from 1988.

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- 55 Reads
- 30 Citations

This paper deals with the estimation of a high-dimensional covariance with a conditional sparsity structure and fast-diverging eigenvalues. By assuming sparse error covariance matrix in an approximate factor model, we allow for the presence of some cross-sectional correlation even after taking out common but unobservable factors. We introduce the Principal Orthogonal complEment Thresholding (POET) method to explore such an approximate factor structure with sparsity. The POET estimator includes the sample covariance matrix, the factor-based covariance matrix (Fan, Fan, and Lv, 2008), the thresholding estimator (Bickel and Levina, 2008) and the adaptive thresholding estimator (Cai and Liu, 2011) as specific examples. We provide mathematical insights when the factor analysis is approximately the same as the principal component analysis for high-dimensional data. The rates of convergence of the sparse residual covariance matrix and the conditional sparse covariance matrix are studied under various norms. It is shown that the impact of estimating the unknown factors vanishes as the dimensionality increases. The uniform rates of convergence for the unobserved factors and their factor loadings are derived. The asymptotic results are also verified by extensive simulation studies. Finally, a real data application on portfolio allocation is presented.

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- 338 Reads
- 538 Citations

In high-dimensional model selection problems, penalized least-square approaches have been extensively used. This paper addresses the question of both robustness and efficiency of penalized model selection methods, and proposes a data-driven weighted linear combination of convex loss functions, together with weighted L(1)-penalty. It is completely data-adaptive and does not require prior knowledge of the error distribution. The weighted L(1)-penalty is used both to ensure the convexity of the penalty term and to ameliorate the bias caused by the L(1)-penalty. In the setting with dimensionality much larger than the sample size, we establish a strong oracle property of the proposed method that possesses both the model selection consistency and estimation efficiency for the true non-zero coefficients. As specific examples, we introduce a robust method of composite L1-L2, and optimal composite quantile method and evaluate their performance in both simulated and real data examples.

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- 290 Reads
- 155 Citations

Estimation of high-dimensional covariance matrices is known to be a difficult problem, has many applications, and is of current interest to the larger statistics community. In many applications including so-called the "large p small n" setting, the estimate of the covariance matrix is required to be not only invertible, but also well-conditioned. Although many regularization schemes attempt to do this, none of them address the ill-conditioning problem directly. In this paper, we propose a maximum likelihood approach, with the direct goal of obtaining a well-conditioned estimator. No sparsity assumption on either the covariance matrix or its inverse are are imposed, thus making our procedure more widely applicable. We demonstrate that the proposed regularization scheme is computationally efficient, yields a type of Steinian shrinkage estimator, and has a natural Bayesian interpretation. We investigate the theoretical properties of the regularized covariance estimator comprehensively, including its regularization path, and proceed to develop an approach that adaptively determines the level of regularization that is required. Finally, we demonstrate the performance of the regularized estimator in decision-theoretic comparisons and in the financial portfolio optimization setting. The proposed approach has desirable properties, and can serve as a competitive procedure, especially when the sample size is small and when a well-conditioned estimator is required.

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- 114 Reads
- 123 Citations

In semiparametric models, the dimension d of the maximum likelihood problem is potentially unlimited. Conventional estimation methods generally behave like O(d(3)). A new O(d) estimation procedure is proposed for a large class of semiparametric models. Potentially unlimited dimension is handled in a numerically efficient way through a Nelson-Aalen-like estimator. Discussion of the new method is put in the context of recently developed minorization-maximization algorithms based on surrogate objective functions. The procedure for semiparametric models is used to demonstrate three methods to construct a surrogate objective function: using the difference of two concave functions, the EM way and the new quasi-EM (QEM) approach. The QEM approach is based on a generalization of the EM-like construction of the surrogate objective function so it does not depend on the missing data representation of the model. Like the EM algorithm, the QEM method has a dual interpretation, a result of merging the idea of surrogate maximization with the idea of imputation and self-consistency. The new approach is compared with other possible approaches by using simulations and analysis of real data. The proportional odds model is used as an example throughout the paper.

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- 43 Reads
- 65 Citations

Multi-phased designs and biased sampling designs are two of the well recognized approaches to enhance study efficiency. In this paper, we propose a new and cost-effective sampling design, the two-phase probability dependent sampling design (PDS), for studies with a continuous outcome. This design will enable investigators to make efficient use of resources by targeting more informative subjects for sampling. We develop a new semiparametric empirical likelihood inference method to take advantage of data obtained through a PDS design. Simulation study results indicate that the proposed sampling scheme, coupled with the proposed estimator, is more efficient and more powerful than the existing outcome dependent sampling design and the simple random sampling design with the same sample size. We illustrate the proposed method with a real data set from an environmental epidemiologic study.

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- 46 Reads
- 9 Citations

Local polynomial regression has received extensive attention for the nonparametric estimation of regression functions when both the response and the covariate are in Euclidean space. However, little has been done when the response is in a Riemannian manifold. We develop an intrinsic local polynomial regression estimate for the analysis of symmetric positive definite (SPD) matrices as responses that lie in a Riemannian manifold with covariate in Euclidean space. The primary motivation and application of the proposed methodology is in computer vision and medical imaging. We examine two commonly used metrics, including the trace metric and the Log-Euclidean metric on the space of SPD matrices. For each metric, we develop a cross-validation bandwidth selection method, derive the asymptotic bias, variance, and normality of the intrinsic local constant and local linear estimators, and compare their asymptotic mean square errors. Simulation studies are further used to compare the estimators under the two metrics and to examine their finite sample performance. We use our method to detect diagnostic differences between diffusion tensors along fiber tracts in a study of human immunodeficiency virus.

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- 68 Reads
- 89 Citations

Partial least squares regression has been an alternative to ordinary least squares for handling multicollinearity in several areas of scientific research since the 1960s. It has recently gained much attention in the analysis of high dimensional genomic data. We show that known asymptotic consistency of the partial least squares estimator for a univariate response does not hold with the very large p and small n paradigm. We derive a similar result for a multivariate response regression with partial least squares. We then propose a sparse partial least squares formulation which aims simultaneously to achieve good predictive performance and variable selection by producing sparse linear combinations of the original predictors. We provide an efficient implementation of sparse partial least squares regression and compare it with well-known variable selection and dimension reduction approaches via simulation experiments. We illustrate the practical utility of sparse partial least squares regression in a joint analysis of gene expression and genomewide binding data.

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- 879 Reads
- 691 Citations

Variance estimation is a fundamental problem in statistical modelling. In ultrahigh dimensional linear regression where the dimensionality is much larger than the sample size, traditional variance estimation techniques are not applicable. Recent advances in variable selection in ultrahigh dimensional linear regression make this problem accessible. One of the major problems in ultrahigh dimensional regression is the high spurious correlation between the unobserved realized noise and some of the predictors. As a result, the realized noises are actually predicted when extra irrelevant variables are selected, leading to serious underestimate of the level of noise. We propose a two-stage refitted procedure via a data splitting technique, called refitted cross-validation, to attenuate the influence of irrelevant variables with high spurious correlations. Our asymptotic results show that the resulting procedure performs as well as the oracle estimator, which knows in advance the mean regression function. The simulation studies lend further support to our theoretical claims. The naive two-stage estimator and the plug-in one-stage estimators using the lasso and smoothly clipped absolute deviation are also studied and compared. Their performances can be improved by the reffitted cross-validation method proposed.

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- 191 Reads
- 236 Citations

Copy number variants (CNVs) are alternations of DNA of a genome that results in the cell having a less or more than two copies of segments of the DNA. CNVs correspond to relatively large regions of the genome, ranging from about one kilobase to several megabases, that are deleted or duplicated. Motivated by CNV analysis based on next generation sequencing data, we consider the problem of detecting and identifying sparse short segments hidden in a long linear sequence of data with an unspecified noise distribution. We propose a computationally efficient method that provides a robust and near-optimal solution for segment identification over a wide range of noise distributions. We theoretically quantify the conditions for detecting the segment signals and show that the method near-optimally estimates the signal segments whenever it is possible to detect their existence. Simulation studies are carried out to demonstrate the efficiency of the method under different noise distributions. We present results from a CNV analysis of a HapMap Yoruban sample to further illustrate the theory and the methods.

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- 23 Reads
- 28 Citations

Models of dynamic networks --- networks that evolve over time --- have
manifold applications. We develop a discrete-time generative model for social
network evolution that inherits the richness and flexibility of the class of
exponential-family random graph models. The model --- a Separable Temporal ERGM
(STERGM) --- facilitates separable modeling of the tie duration distributions
and the structural dynamics of tie formation. We develop likelihood-based
inference for the model, and provide computational algorithms for maximum
likelihood estimation. We illustrate the interpretability of the model in
analyzing a longitudinal network of friendship ties within a school.

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- 182 Reads
- 337 Citations

In many situations information from a sample of individuals can be supplemented by population level information on the relationship between a dependent variable and explanatory variables. Inclusion of the population level information can reduce bias and increase the efficiency of the parameter estimates.Population level information can be incorporated via constraints on functions of the model parameters. In general the constraints are nonlinear making the task of maximum likelihood estimation harder. In this paper we develop an alternative approach exploiting the notion of an empirical likelihood. It is shown that within the framework of generalised linear models, the population level information corresponds to linear constraints, which are comparatively easy to handle. We provide a two-step algorithm that produces parameter estimates using only unconstrained estimation. We also provide computable expressions for the standard errors. We give an application to demographic hazard modelling by combining panel survey data with birth registration data to estimate annual birth probabilities by parity.

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- 27 Reads
- 55 Citations

It is now common to survey microbial communities by sequencing nucleic acid material extracted in bulk from a given environment. Comparative methods are needed that indicate the extent to which two communities differ given data sets of this type. UniFrac, which gives a somewhat ad hoc phylogenetics-based distance between two communities, is one of the most commonly used tools for these analyses. We provide a foundation for such methods by establishing that, if we equate a metagenomic sample with its empirical distribution on a reference phylogenetic tree, then the weighted UniFrac distance between two samples is just the classical Kantorovich-Rubinstein, or earth mover's, distance between the corresponding empirical distributions. We demonstrate that this Kantorovich-Rubinstein distance and extensions incorporating uncertainty in the sample locations can be written as a readily computable integral over the tree, we develop L(p) Zolotarev-type generalizations of the metric, and we show how the p-value of the resulting natural permutation test of the null hypothesis 'no difference between two communities' can be approximated by using a Gaussian process functional. We relate the L(2)-case to an analysis-of-variance type of decomposition, finding that the distribution of its associated Gaussian functional is that of a computable linear combination of independent [Formula: see text] random variables.

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- 188 Reads
- 124 Citations

This paper develops a new estimation of nonparametric regression functions for clustered or longitudinal data. We propose to use Cholesky decomposition and profile least squares techniques to estimate the correlation structure and regression function simultaneously. We further prove that the proposed estimator is as asymptotically efficient as if the covariance matrix were known. A Monte Carlo simulation study is conducted to examine the finite sample performance of the proposed procedure, and to compare the proposed procedure with the existing ones. Based on our empirical studies, the newly proposed procedure works better than the naive local linear regression with working independence error structure and the efficiency gain can be achieved in moderate-sized samples. Our numerical comparison also shows that the newly proposed procedure outperforms some existing ones. A real data set application is also provided to illustrate the proposed estimation procedure.

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- 118 Reads
- 55 Citations

We consider estimation, from a double-blind randomized trial, of treatment effect within levels of base-line covariates on an outcome that is measured after a post-treatment event E has occurred in the subpopulation 𝒫(E,E) that would experience event E regardless of treatment. Specifically, we consider estimation of the parameters γ indexing models for the outcome mean conditional on treatment and base-line covariates in the subpopulation 𝒫(E,E). Such parameters are not identified from randomized trial data but become identified if additionally it is assumed that the subpopulation 𝒫(Ē,E) of subjects that would experience event E under the second treatment but not under the first is empty and a parametric model for the conditional probability that a subject experiences event E if assigned to the first treatment given that the subject would experience the event if assigned to the second treatment, his or her outcome under the second treatment and his or her pretreatment covariates. We develop a class of estimating equations whose solutions comprise, up to asymptotic equivalence, all consistent and asymptotically normal estimators of γ under these two assumptions. In addition, we derive a locally semiparametric efficient estimator of γ. We apply our methods to estimate the effect on mean viral load of vaccine versus placebo after infection with human immunodeficiency virus (the event E) in a placebo-controlled randomized acquired immune deficiency syndrome vaccine tri.

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- 47 Reads
- 33 Citations

Primary analysis of case-control studies focuses on the relationship between disease D and a set of covariates of interest (Y, X). A secondary application of the case-control study, which is often invoked in modern genetic epidemiologic association studies, is to investigate the interrelationship between the covariates themselves. The task is complicated owing to the case-control sampling, where the regression of Y on X is different from what it is in the population. Previous work has assumed a parametric distribution for Y given X and derived semiparametric efficient estimation and inference without any distributional assumptions about X. We take up the issue of estimation of a regression function when Y given X follows a homoscedastic regression model, but otherwise the distribution of Y is unspecified. The semiparametric efficient approaches can be used to construct semiparametric efficient estimates, but they suffer from a lack of robustness to the assumed model for Y given X. We take an entirely different approach. We show how to estimate the regression parameters consistently even if the assumed model for Y given X is incorrect, and thus the estimates are model robust. For this we make the assumption that the disease rate is known or well estimated. The assumption can be dropped when the disease is rare, which is typically so for most case-control studies, and the estimation algorithm simplifies. Simulations and empirical examples are used to illustrate the approach.

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- 51 Reads
- 25 Citations

Microarrays are one of the most widely used high throughput technologies. One of the main problems in the area is that conventional estimates of the variances that are required in the t-statistic and other statistics are unreliable owing to the small number of replications. Various methods have been proposed in the literature to overcome this lack of degrees of freedom problem. In this context, it is commonly observed that the variance increases proportionally with the intensity level, which has led many researchers to assume that the variance is a function of the mean. Here we concentrate on estimation of the variance as a function of an unknown mean in two models: the constant coefficient of variation model and the quadratic variance-mean model. Because the means are unknown and estimated with few degrees of freedom, naive methods that use the sample mean in place of the true mean are generally biased because of the errors-in-variables phenomenon. We propose three methods for overcoming this bias. The first two are variations on the theme of the so-called heteroscedastic simulation-extrapolation estimator, modified to estimate the variance function consistently. The third class of estimators is entirely different, being based on semiparametric information calculations. Simulations show the power of our methods and their lack of bias compared with the naive method that ignores the measurement error. The methodology is illustrated by using microarray data from leukaemia patients.

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- 38 Reads
- 22 Citations

In this article, a stepwise procedure, correlation pursuit (COP), is developed for variable selection under the sufficient dimension reduction framework, in which the response variable Y is influenced by the predictors X(1), X(2), …, X(p) through an unknown function of a few linear combinations of them. Unlike linear stepwise regression, COP does not impose a special form of relationship (such as linear) between the response variable and the predictor variables. The COP procedure selects variables that attain the maximum correlation between the transformed response and the linear combination of the variables. Various asymptotic properties of the COP procedure are established, and in particular, its variable selection performance under diverging number of predictors and sample size has been investigated. The excellent empirical performance of the COP procedure in comparison with existing methods are demonstrated by both extensive simulation studies and a real example in functional genomics.

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- 231 Reads
- 32 Citations

With scientific data available at geocoded locations, investigators are increasingly turning to spatial process models for carrying out statistical inference. Over the last decade, hierarchical models implemented through Markov chain Monte Carlo methods have become especially popular for spatial modelling, given their flexibility and power to fit models that would be infeasible with classical methods as well as their avoidance of possibly inappropriate asymptotics. However, fitting hierarchical spatial models often involves expensive matrix decompositions whose computational complexity increases in cubic order with the number of spatial locations, rendering such models infeasible for large spatial data sets. This computational burden is exacerbated in multivariate settings with several spatially dependent response variables. It is also aggravated when data are collected at frequent time points and spatiotemporal process models are used. With regard to this challenge, our contribution is to work with what we call predictive process models for spatial and spatiotemporal data. Every spatial (or spatiotemporal) process induces a predictive process model (in fact, arbitrarily many of them). The latter models project process realizations of the former to a lower dimensional subspace, thereby reducing the computational burden. Hence, we achieve the flexibility to accommodate non-stationary, non-Gaussian, possibly multivariate, possibly spatiotemporal processes in the context of large data sets. We discuss attractive theoretical properties of these predictive processes. We also provide a computational template encompassing these diverse settings. Finally, we illustrate the approach with simulated and real data sets.

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- 405 Reads
- 889 Citations

Marginal log-linear (MLL) models provide a flexible approach to multivariate discrete data. MLL parametrizations under linear constraints induce a wide variety of models, including models defined by conditional independences. We introduce a subclass of MLL models which correspond to Acyclic Directed Mixed Graphs (ADMGs) under the usual global Markov property. We characterize for precisely which graphs the resulting parametrization is variation independent. The MLL approach provides the first description of ADMG models in terms of a minimal list of constraints. The parametrization is also easily adapted to sparse modelling techniques, which we illustrate using several examples of real data.

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- 39 Reads
- 29 Citations

This paper develops nonparametric methods based on contact intervals for the analysis of infectious disease data. The contact interval from person i to person j is the time between the onset of infectiousness in i and infectious contact from i to j, where we define infectious contact as a contact sufficient to infect a susceptible individual. The hazard function of the contact interval distribution equals the hazard of infectious contact from i to j, so it provides a summary of the evolution of infectiousness over time. When who-infects-whom is observed, the Nelson-Aalen estimator produces an unbiased estimate of the cumulative hazard function of the contact interval distribution. When who-infects-whom is not observed, we use an EM algorithm to average the Nelson-Aalen estimates from all possible combinations of who-infected-whom consistent with the observed data. This converges to a nonparametric maximum likelihood estimate of the cumulative hazard function that we call the marginal Nelson-Aalen estimate. We study the behavior of these methods in simulations and use them to analyze household surveillance data from the 2009 influenza A(H1N1) pandemic.

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- 73 Reads
- 15 Citations

Motivated from the problem of testing for genetic effects on complex traits in the presence of gene-environment interaction, we develop score tests in general semiparametric regression problems that involves Tukey style 1 degree-of-freedom form of interaction between parametrically and non-parametrically modelled covariates. We find that the score test in this type of model, as recently developed by Chatterjee and co-workers in the fully parametric setting, is biased and requires undersmoothing to be valid in the presence of non-parametric components. Moreover, in the presence of repeated outcomes, the asymptotic distribution of the score test depends on the estimation of functions which are defined as solutions of integral equations, making implementation difficult and computationally taxing. We develop profiled score statistics which are unbiased and asymptotically efficient and can be performed by using standard bandwidth selection methods. In addition, to overcome the difficulty of solving functional equations, we give easy interpretations of the target functions, which in turn allow us to develop estimation procedures that can be easily implemented by using standard computational methods. We present simulation studies to evaluate type I error and power of the method proposed compared with a naive test that does not consider interaction. Finally, we illustrate our methodology by analysing data from a case-control study of colorectal adenoma that was designed to investigate the association between colorectal adenoma and the candidate gene NAT2 in relation to smoking history.

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- 50 Reads
- 32 Citations

Modern technologies are producing a wealth of data with complex structures. For instance, in two-dimensional digital imaging, flow cytometry and electroencephalography, matrix-type covariates frequently arise when measurements are obtained for each combination of two underlying variables. To address scientific questions arising from those data, new regression methods that take matrices as covariates are needed, and sparsity or other forms of regularization are crucial owing to the ultrahigh dimensionality and complex structure of the matrix data. The popular lasso and related regularization methods hinge on the sparsity of the true signal in terms of the number of its non-zero coefficients. However, for the matrix data, the true signal is often of, or can be well approximated by, a low rank structure. As such, the sparsity is frequently in the form of low rank of the matrix parameters, which may seriously violate the assumption of the classical lasso. We propose a class of regularized matrix regression methods based on spectral regularization. A highly efficient and scalable estimation algorithm is developed, and a degrees-of-freedom formula is derived to facilitate model selection along the regularization path. Superior performance of the method proposed is demonstrated on both synthetic and real examples.

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- 258 Reads
- 149 Citations

Increasingly, scientific studies yield functional data, in which the ideal units of observation are curves and the observed data consist of sets of curves that are sampled on a fine grid. We present new methodology that generalizes the linear mixed model to the functional mixed model framework, with model fitting done by using a Bayesian wavelet-based approach. This method is flexible, allowing functions of arbitrary form and the full range of fixed effects structures and between-curve covariance structures that are available in the mixed model framework. It yields nonparametric estimates of the fixed and random-effects functions as well as the various between-curve and within-curve covariance matrices. The functional fixed effects are adaptively regularized as a result of the non-linear shrinkage prior that is imposed on the fixed effects' wavelet coefficients, and the random-effect functions experience a form of adaptive regularization because of the separately estimated variance components for each wavelet coefficient. Because we have posterior samples for all model quantities, we can perform pointwise or joint Bayesian inference or prediction on the quantities of the model. The adaptiveness of the method makes it especially appropriate for modelling irregular functional data that are characterized by numerous local features like peaks.

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- 104 Reads
- 328 Citations

We introduce a path following algorithm for "L"<sub>1</sub>-regularized generalized linear models. The "L"<sub>1</sub>-regularization procedure is useful especially because it, in effect, selects variables according to the amount of penalization on the "L"<sub>1</sub>-norm of the coefficients, in a manner that is less greedy than forward selection-backward deletion. The generalized linear model path algorithm efficiently computes solutions along the entire regularization path by using the predictor-corrector method of convex optimization. Selecting the step length of the regularization parameter is critical in controlling the overall accuracy of the paths; we suggest intuitive and flexible strategies for choosing appropriate values. We demonstrate the implementation with several simulated and real data sets. Copyright 2007 Royal Statistical Society.

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We propose goodness-of-fit tests for testing generalized linear models and semiparametric regression models against smooth alternatives. The focus is on models having both continuous and factorial covariates. As a smooth extension of a parametric or semiparametric model we use generalized varying-coefficient models as proposed by T. Hastie and R. Tibshirani [J. R. Stat. Soc., Ser. B 55, No. 4, 757-796 (1993; Zbl 0796.62060)]. A likelihood ratio statistic is used for testing. Asymptotic expansions allow us to write the estimates as linear smoothers which in turn guarantees simple and fast bootstrapping of the test statistic. The test is shown to have n-power, but in contrast with parametric tests it is powerful against smooth alternatives in general.

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- 43 Reads
- 28 Citations

We consider the problem of testing null hypotheses that include restrictions on the variance component in a linear mixed model with one variance component and we derive the finite sample and asymptotic distribution of the likelihood ratio test and the restricted likelihood ratio test. The spectral representations of the likelihood ratio test and the restricted likelihood ratio test statistics are used as the basis of efficient simulation algorithms of their null distributions. The large sample "χ"-super-2 mixture approximations using the usual asymptotic theory for a null hypothesis on the boundary of the parameter space have been shown to be poor in simulation studies. Our asymptotic calculations explain these empirical results. The theory of Self and Liang applies only to linear mixed models for which the data vector can be partitioned into a large number of independent and identically distributed subvectors. One-way analysis of variance and penalized splines models illustrate the results. Copyright 2004 Royal Statistical Society.

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- 526 Reads
- 377 Citations

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Integer-valued autoregressive (INAR) processes have been introduced to model nonnegative integer-valued phenomena that evolve over time. The distribution of an INAR(p) process is essentially described by two parameters: a vector of autoregression coefficients and a probability distribution on the nonnegative integers, called an immigration or innovation distribution. Traditionally, parametric models are considered where the innovation distribution is assumed to belong to a parametric family. This paper instead considers a more realistic semiparametric INAR(p) model where there are essentially no restrictions on the innovation distribution. We provide an (semiparametrically) efficient estimator of both the autoregression parameters and the innovation distribution.

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- 59 Citations

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