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1.  Collaborative Double Robust Targeted Maximum Likelihood Estimation* 
Collaborative double robust targeted maximum likelihood estimators represent a fundamental further advance over standard targeted maximum likelihood estimators of a pathwise differentiable parameter of a data generating distribution in a semiparametric model, introduced in van der Laan, Rubin (2006). The targeted maximum likelihood approach involves fluctuating an initial estimate of a relevant factor (Q) of the density of the observed data, in order to make a bias/variance tradeoff targeted towards the parameter of interest. The fluctuation involves estimation of a nuisance parameter portion of the likelihood, g. TMLE has been shown to be consistent and asymptotically normally distributed (CAN) under regularity conditions, when either one of these two factors of the likelihood of the data is correctly specified, and it is semiparametric efficient if both are correctly specified.
In this article we provide a template for applying collaborative targeted maximum likelihood estimation (C-TMLE) to the estimation of pathwise differentiable parameters in semi-parametric models. The procedure creates a sequence of candidate targeted maximum likelihood estimators based on an initial estimate for Q coupled with a succession of increasingly non-parametric estimates for g. In a departure from current state of the art nuisance parameter estimation, C-TMLE estimates of g are constructed based on a loss function for the targeted maximum likelihood estimator of the relevant factor Q that uses the nuisance parameter to carry out the fluctuation, instead of a loss function for the nuisance parameter itself. Likelihood-based cross-validation is used to select the best estimator among all candidate TMLE estimators of Q0 in this sequence. A penalized-likelihood loss function for Q is suggested when the parameter of interest is borderline-identifiable.
We present theoretical results for “collaborative double robustness,” demonstrating that the collaborative targeted maximum likelihood estimator is CAN even when Q and g are both mis-specified, providing that g solves a specified score equation implied by the difference between the Q and the true Q0. This marks an improvement over the current definition of double robustness in the estimating equation literature.
We also establish an asymptotic linearity theorem for the C-DR-TMLE of the target parameter, showing that the C-DR-TMLE is more adaptive to the truth, and, as a consequence, can even be super efficient if the first stage density estimator does an excellent job itself with respect to the target parameter.
This research provides a template for targeted efficient and robust loss-based learning of a particular target feature of the probability distribution of the data within large (infinite dimensional) semi-parametric models, while still providing statistical inference in terms of confidence intervals and p-values. This research also breaks with a taboo (e.g., in the propensity score literature in the field of causal inference) on using the relevant part of likelihood to fine-tune the fitting of the nuisance parameter/censoring mechanism/treatment mechanism.
doi:10.2202/1557-4679.1181
PMCID: PMC2898626  PMID: 20628637
asymptotic linearity; coarsening at random; causal effect; censored data; crossvalidation; collaborative double robust; double robust; efficient influence curve; estimating function; estimator selection; influence curve; G-computation; locally efficient; loss-function; marginal structural model; maximum likelihood estimation; model selection; pathwise derivative; semiparametric model; sieve; super efficiency; super-learning; targeted maximum likelihood estimation; targeted nuisance parameter estimator selection; variable importance
2.  Semiparametric estimation of covariance matrices for longitudinal data 
Estimation of longitudinal data covariance structure poses significant challenges because the data are usually collected at irregular time points. A viable semiparametric model for covariance matrices was proposed in Fan, Huang and Li (2007) that allows one to estimate the variance function nonparametrically and to estimate the correlation function parametrically via aggregating information from irregular and sparse data points within each subject. However, the asymptotic properties of their quasi-maximum likelihood estimator (QMLE) of parameters in the covariance model are largely unknown. In the current work, we address this problem in the context of more general models for the conditional mean function including parametric, nonparametric, or semi-parametric. We also consider the possibility of rough mean regression function and introduce the difference-based method to reduce biases in the context of varying-coefficient partially linear mean regression models. This provides a more robust estimator of the covariance function under a wider range of situations. Under some technical conditions, consistency and asymptotic normality are obtained for the QMLE of the parameters in the correlation function. Simulation studies and a real data example are used to illustrate the proposed approach.
doi:10.1198/016214508000000742
PMCID: PMC2631936  PMID: 19180247
Correlation structure; difference-based estimation; quasi-maximum likelihood; varying-coefficient partially linear model
3.  Repeated Measures Semiparametric Regression Using Targeted Maximum Likelihood Methodology with Application to Transcription Factor Activity Discovery 
In longitudinal and repeated measures data analysis, often the goal is to determine the effect of a treatment or aspect on a particular outcome (e.g., disease progression). We consider a semiparametric repeated measures regression model, where the parametric component models effect of the variable of interest and any modification by other covariates. The expectation of this parametric component over the other covariates is a measure of variable importance. Here, we present a targeted maximum likelihood estimator of the finite dimensional regression parameter, which is easily estimated using standard software for generalized estimating equations.
The targeted maximum likelihood method provides double robust and locally efficient estimates of the variable importance parameters and inference based on the influence curve. We demonstrate these properties through simulation under correct and incorrect model specification, and apply our method in practice to estimating the activity of transcription factor (TF) over cell cycle in yeast. We specifically target the importance of SWI4, SWI6, MBP1, MCM1, ACE2, FKH2, NDD1, and SWI5.
The semiparametric model allows us to determine the importance of a TF at specific time points by specifying time indicators as potential effect modifiers of the TF. Our results are promising, showing significant importance trends during the expected time periods. This methodology can also be used as a variable importance analysis tool to assess the effect of a large number of variables such as gene expressions or single nucleotide polymorphisms.
doi:10.2202/1544-6115.1553
PMCID: PMC3122882  PMID: 21291412
targeted maximum likelihood; semiparametric; repeated measures; longitudinal; transcription factors
4.  Nonparametric estimation for censored mixture data with application to the Cooperative Huntington’s Observational Research Trial 
This work presents methods for estimating genotype-specific distributions from genetic epidemiology studies where the event times are subject to right censoring, the genotypes are not directly observed, and the data arise from a mixture of scientifically meaningful subpopulations. Examples of such studies include kin-cohort studies and quantitative trait locus (QTL) studies. Current methods for analyzing censored mixture data include two types of nonparametric maximum likelihood estimators (NPMLEs) which do not make parametric assumptions on the genotype-specific density functions. Although both NPMLEs are commonly used, we show that one is inefficient and the other inconsistent. To overcome these deficiencies, we propose three classes of consistent nonparametric estimators which do not assume parametric density models and are easy to implement. They are based on the inverse probability weighting (IPW), augmented IPW (AIPW), and nonparametric imputation (IMP). The AIPW achieves the efficiency bound without additional modeling assumptions. Extensive simulation experiments demonstrate satisfactory performance of these estimators even when the data are heavily censored. We apply these estimators to the Cooperative Huntington’s Observational Research Trial (COHORT), and provide age-specific estimates of the effect of mutation in the Huntington gene on mortality using a sample of family members. The close approximation of the estimated non-carrier survival rates to that of the U.S. population indicates small ascertainment bias in the COHORT family sample. Our analyses underscore an elevated risk of death in Huntington gene mutation carriers compared to non-carriers for a wide age range, and suggest that the mutation equally affects survival rates in both genders. The estimated survival rates are useful in genetic counseling for providing guidelines on interpreting the risk of death associated with a positive genetic testing, and in facilitating future subjects at risk to make informed decisions on whether to undergo genetic mutation testings.
doi:10.1080/01621459.2012.699353
PMCID: PMC3905630  PMID: 24489419
Censored data; Finite mixture model; Huntington’s disease; Kin-cohort design; Quantitative trait locus
5.  SEMIPARAMETRIC ZERO-INFLATED MODELING IN MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA) 
The annals of applied statistics  2012;6(3):1236-1255.
We analyze the Agatston score of coronary artery calcium (CAC) from the Multi-Ethnic Study of Atherosclerosis (MESA) using semi-parametric zero-inflated modeling approach, where the observed CAC scores from this cohort consist of high frequency of zeroes and continuously distributed positive values. Both partially constrained and unconstrained models are considered to investigate the underlying biological processes of CAC development from zero to positive, and from small amount to large amount. Different from existing studies, a model selection procedure based on likelihood cross-validation is adopted to identify the optimal model, which is justified by comparative Monte Carlo studies. A shrinkaged version of cubic regression spline is used for model estimation and variable selection simultaneously. When applying the proposed methods to the MESA data analysis, we show that the two biological mechanisms influencing the initiation of CAC and the magnitude of CAC when it is positive are better characterized by an unconstrained zero-inflated normal model. Our results are significantly different from those in published studies, and may provide further insights into the biological mechanisms underlying CAC development in human. This highly flexible statistical framework can be applied to zero-inflated data analyses in other areas.
PMCID: PMC3690929  PMID: 23805172
cardiovascular disease; coronary artery calcium; likelihood cross-validation; model selection; penalized spline; proportional constraint; shrinkage
6.  Modeling gene expression measurement error: a quasi-likelihood approach 
BMC Bioinformatics  2003;4:10.
Background
Using suitable error models for gene expression measurements is essential in the statistical analysis of microarray data. However, the true probabilistic model underlying gene expression intensity readings is generally not known. Instead, in currently used approaches some simple parametric model is assumed (usually a transformed normal distribution) or the empirical distribution is estimated. However, both these strategies may not be optimal for gene expression data, as the non-parametric approach ignores known structural information whereas the fully parametric models run the risk of misspecification. A further related problem is the choice of a suitable scale for the model (e.g. observed vs. log-scale).
Results
Here a simple semi-parametric model for gene expression measurement error is presented. In this approach inference is based an approximate likelihood function (the extended quasi-likelihood). Only partial knowledge about the unknown true distribution is required to construct this function. In case of gene expression this information is available in the form of the postulated (e.g. quadratic) variance structure of the data.
As the quasi-likelihood behaves (almost) like a proper likelihood, it allows for the estimation of calibration and variance parameters, and it is also straightforward to obtain corresponding approximate confidence intervals. Unlike most other frameworks, it also allows analysis on any preferred scale, i.e. both on the original linear scale as well as on a transformed scale. It can also be employed in regression approaches to model systematic (e.g. array or dye) effects.
Conclusions
The quasi-likelihood framework provides a simple and versatile approach to analyze gene expression data that does not make any strong distributional assumptions about the underlying error model. For several simulated as well as real data sets it provides a better fit to the data than competing models. In an example it also improved the power of tests to identify differential expression.
doi:10.1186/1471-2105-4-10
PMCID: PMC153502  PMID: 12659637
7.  The Relative Performance of Targeted Maximum Likelihood Estimators 
There is an active debate in the literature on censored data about the relative performance of model based maximum likelihood estimators, IPCW-estimators, and a variety of double robust semiparametric efficient estimators. Kang and Schafer (2007) demonstrate the fragility of double robust and IPCW-estimators in a simulation study with positivity violations. They focus on a simple missing data problem with covariates where one desires to estimate the mean of an outcome that is subject to missingness. Responses by Robins, et al. (2007), Tsiatis and Davidian (2007), Tan (2007) and Ridgeway and McCaffrey (2007) further explore the challenges faced by double robust estimators and offer suggestions for improving their stability. In this article, we join the debate by presenting targeted maximum likelihood estimators (TMLEs). We demonstrate that TMLEs that guarantee that the parametric submodel employed by the TMLE procedure respects the global bounds on the continuous outcomes, are especially suitable for dealing with positivity violations because in addition to being double robust and semiparametric efficient, they are substitution estimators. We demonstrate the practical performance of TMLEs relative to other estimators in the simulations designed by Kang and Schafer (2007) and in modified simulations with even greater estimation challenges.
doi:10.2202/1557-4679.1308
PMCID: PMC3173607  PMID: 21931570
censored data; collaborative double robustness; collaborative targeted maximum likelihood estimation; double robust; estimator selection; inverse probability of censoring weighting; locally efficient estimation; maximum likelihood estimation; semiparametric model; targeted maximum likelihood estimation; targeted minimum loss based estimation; targeted nuisance parameter estimator selection
8.  Lack of Fit in Self Modeling Regression: Application to Pulse Waveforms* 
Self modeling regression (SEMOR) is an approach for modeling sets of observed curves that have a common shape (or sequence of features) but have variability in the amplitude (y-axis) and/or timing (x-axis) of the features across curves. SEMOR assumes the x and y axes for each observed curve can be separately transformed in a parametric manner so that the features across curves are aligned with the common shape, usually represented by non-parametric function. We show that when the common shape is modeled with a regression spline and the transformational parameters are modeled as random with the traditional distribution (normal with mean zero), the SEMOR model may surprisingly suffer from lack of fit and the variance components may be over-estimated. A random effects distribution that restricts the predicted random transformational parameters to have mean zero or the inclusion of a fixed transformational parameter improves estimation. Our work is motivated by arterial pulse pressure waveform data where one of the variance components is a novel measure of short-term variability in blood pressure.
doi:10.2202/1557-4679.1190
PMCID: PMC2836211  PMID: 20305704
functional data; nonlinear mixed effects models; self-modeling
9.  A parametric method for cumulative incidence modeling with a new four-parameter log-logistic distribution 
Background
Competing risks, which are particularly encountered in medical studies, are an important topic of concern, and appropriate analyses must be used for these data. One feature of competing risks is the cumulative incidence function, which is modeled in most studies using non- or semi-parametric methods. However, parametric models are required in some cases to ensure maximum efficiency, and to fit various shapes of hazard function.
Methods
We have used the stable distributions family of Hougaard to propose a new four-parameter distribution by extending a two-parameter log-logistic distribution, and carried out a simulation study to compare the cumulative incidence estimated with this distribution with the estimates obtained using a non-parametric method. To test our approach in a practical application, the model was applied to a set of real data on fertility history.
Conclusions
The results of simulation studies showed that the estimated cumulative incidence function was more accurate than non-parametric estimates in some settings. Analyses of real data indicated that the proposed distribution showed a much better fit to the data than the other distributions tested. Therefore, the new distribution is recommended for practical applications to parameterize the cumulative incidence function in competing risk settings.
doi:10.1186/1742-4682-8-43
PMCID: PMC3713116  PMID: 22074546
10.  A Parametric k-Means Algorithm 
Computational statistics  2007;22(1):71-89.
Summary
The k points that optimally represent a distribution (usually in terms of a squared error loss) are called the k principal points. This paper presents a computationally intensive method that automatically determines the principal points of a parametric distribution. Cluster means from the k-means algorithm are nonparametric estimators of principal points. A parametric k-means approach is introduced for estimating principal points by running the k-means algorithm on a very large simulated data set from a distribution whose parameters are estimated using maximum likelihood. Theoretical and simulation results are presented comparing the parametric k-means algorithm to the usual k-means algorithm and an example on determining sizes of gas masks is used to illustrate the parametric k-means algorithm.
doi:10.1007/s00180-007-0022-7
PMCID: PMC2000854  PMID: 17917692
Cluster analysis; finite mixture models; principal component analysis; principal points
11.  A Partially Linear Regression Model for Data from an Outcome-Dependent Sampling Design 
Summary
The outcome dependent sampling scheme has been gaining attention in both the statistical literature and applied fields. Epidemiological and environmental researchers have been using it to select the observations for more powerful and cost-effective studies. Motivated by a study of the effect of in utero exposure to polychlorinated biphenyls on children’s IQ at age 7, in which the effect of an important confounding variable is nonlinear, we consider a semi-parametric regression model for data from an outcome-dependent sampling scheme where the relationship between the response and covariates is only partially parameterized. We propose a penalized spline maximum likelihood estimation (PSMLE) for inference on both the parametric and the nonparametric components and develop their asymptotic properties. Through simulation studies and an analysis of the IQ study, we compare the proposed estimator with several competing estimators. Practical considerations of implementing those estimators are discussed.
doi:10.1111/j.1467-9876.2010.00756.x
PMCID: PMC3181132  PMID: 21966030
Outcome dependent sampling; Estimated likelihood; Semiparametric method; Penalized spline
12.  Direct 4D List Mode Parametric Reconstruction for PET with a Novel EM Algorithm 
We present a direct method for producing images of kinetic parameters from list mode PET data. The time-activity curve for each voxel is described by a one-tissue compartment, 2-parameter model. Extending previous EM algorithms, a new spatiotemporal complete data space was introduced to optimize the maximum likelihood function. This leads to a straightforward parametric image update equation with moderate additional computation requirements compared to the conventional algorithm. Qualitative and quantitative evaluations were performed using 2D (x,t) and 4D (x,y,z,t) simulated list mode data for a brain receptor study. Comparisons with the two-step approach (frame-based reconstruction followed by voxel-by-voxel parameter estimation) show that the proposed method can lead to accurate estimation of the parametric image values with reduced variance, especially for the volume of distribution (VT).
doi:10.1109/NSSMIC.2008.4774103
PMCID: PMC2901873  PMID: 20628540
13.  SPLINDID: a semi-parametric, model-based method for obtaining transcription rates and gene regulation parameters from genomic and proteomic expression profiles 
Bioinformatics (Oxford, England)  2005;21(20):3873-3879.
Purpose
To evaluate a semi-parametric, model-based approach for obtaining transcription rates from mRNA and protein expression.
Methods
The transcription profile input was modeled using an exponential function of a cubic spline and the dynamics of translation; mRNA and protein degradation were modeled using the Hargrove–Schmidt model. The transcription rate profile and the translation, and mRNA and protein degradation rate constants were estimated by the maximum likelihood method.
Results
Simulated datasets generated from the stochastic, transit compartment and dispersion signaling models were used to test the approach. The approach satisfactorily fit the mRNA and protein data, and accurately recapitulated the parameter and the normalized transcription rate profile values. The approach was successfully used to model published data on tyrosine aminotransferase pharmacodynamics.
Conclusions
The semi-parametric approach is effective and could be useful for delineating the genomic effects of drugs.
Availability
Code suitable for use with the ADAPT software program is available from the corresponding author.
doi:10.1093/bioinformatics/bti624
PMCID: PMC2607482  PMID: 16096347
14.  Finding Quantitative Trait Loci Genes with Collaborative Targeted Maximum Likelihood Learning 
Statistics & probability letters  2011;81(7):792-796.
Quantitative trait loci mapping is focused on identifying the positions and effect of genes underlying an an observed trait. We present a collaborative targeted maximum likelihood estimator in a semi-parametric model using a newly proposed 2-part super learning algorithm to find quantitative trait loci genes in listeria data. Results are compared to the parametric composite interval mapping approach.
doi:10.1016/j.spl.2010.11.001
PMCID: PMC3090625  PMID: 21572586
collaborative targeted maximum likelihood estimation; quantitative trait loci; super learner; machine learning
15.  A mixed-effects model approach for estimating the distribution of usual intake of nutrients: The NCI method 
Statistics in medicine  2010;29(27):10.1002/sim.4063.
It is of interest to estimate the distribution of usual nutrient intake for a population from repeat 24-h dietary recall assessments. A mixed effects model and quantile estimation procedure, developed at the National Cancer Institute (NCI), may be used for this purpose. The model incorporates a Box–Cox parameter and covariates to estimate usual daily intake of nutrients; model parameters are estimated via quasi-Newton optimization of a likelihood approximated by the adaptive Gaussian quadrature. The parameter estimates are used in a Monte Carlo approach to generate empirical quantiles; standard errors are estimated by bootstrap. The NCI method is illustrated and compared with current estimation methods, including the individual mean and the semi-parametric method developed at the Iowa State University (ISU), using data from a random sample and computer simulations. Both the NCI and ISU methods for nutrients are superior to the distribution of individual means. For simple (no covariate) models, quantile estimates are similar between the NCI and ISU methods. The bootstrap approach used by the NCI method to estimate standard errors of quantiles appears preferable to Taylor linearization. One major advantage of the NCI method is its ability to provide estimates for subpopulations through the incorporation of covariates into the model. The NCI method may be used for estimating the distribution of usual nutrient intake for populations and subpopulations as part of a unified framework of estimation of usual intake of dietary constituents.
doi:10.1002/sim.4063
PMCID: PMC3865776  PMID: 20862656
statistical distributions; diet surveys; nutrition assessment; mixed-effects model; nutrients; percentiles
16.  Regression-assisted deconvolution 
Statistics in Medicine  2011;30(14):1722-1734.
We present a semi-parametric deconvolution estimator for the density function of a random variable X that is measured with error, a common challenge in many epidemiological studies. Traditional deconvolution estimators rely only on assumptions about the distribution of X and the error in its measurement, and ignore information available in auxiliary variables. Our method assumes the availability of a covariate vector statistically related to X by a mean–variance function regression model, where regression errors are normally distributed and independent of the measurement errors. Simulations suggest that the estimator achieves a much lower integrated squared error than the observed-data kernel density estimator when models are correctly specified and the assumption of normal regression errors is met. We illustrate the method using anthropometric measurements of newborns to estimate the density function of newborn length.
doi:10.1002/sim.4186
PMCID: PMC3307103  PMID: 21284016
density estimation; measurement error; mean–variance function model
17.  Bayesian non-parametrics and the probabilistic approach to modelling 
Modelling is fundamental to many fields of science and engineering. A model can be thought of as a representation of possible data one could predict from a system. The probabilistic approach to modelling uses probability theory to express all aspects of uncertainty in the model. The probabilistic approach is synonymous with Bayesian modelling, which simply uses the rules of probability theory in order to make predictions, compare alternative models, and learn model parameters and structure from data. This simple and elegant framework is most powerful when coupled with flexible probabilistic models. Flexibility is achieved through the use of Bayesian non-parametrics. This article provides an overview of probabilistic modelling and an accessible survey of some of the main tools in Bayesian non-parametrics. The survey covers the use of Bayesian non-parametrics for modelling unknown functions, density estimation, clustering, time-series modelling, and representing sparsity, hierarchies, and covariance structure. More specifically, it gives brief non-technical overviews of Gaussian processes, Dirichlet processes, infinite hidden Markov models, Indian buffet processes, Kingman’s coalescent, Dirichlet diffusion trees and Wishart processes.
doi:10.1098/rsta.2011.0553
PMCID: PMC3538441  PMID: 23277609
probabilistic modelling; Bayesian statistics; non-parametrics; machine learning
18.  Non-homogeneous models of sequence evolution in the Bio++ suite of libraries and programs 
Background
Accurately modeling the sequence substitution process is required for the correct estimation of evolutionary parameters, be they phylogenetic relationships, substitution rates or ancestral states; it is also crucial to simulate realistic data sets. Such simulation procedures are needed to estimate the null-distribution of complex statistics, an approach referred to as parametric bootstrapping, and are also used to test the quality of phylogenetic reconstruction programs. It has often been observed that homologous sequences can vary widely in their nucleotide or amino-acid compositions, revealing that sequence evolution has changed importantly among lineages, and may therefore be most appropriately approached through non-homogeneous models. Several programs implementing such models have been developed, but they are limited in their possibilities: only a few particular models are available for likelihood optimization, and data sets cannot be easily generated using the resulting estimated parameters.
Results
We hereby present a general implementation of non-homogeneous models of substitutions. It is available as dedicated classes in the Bio++ libraries and can hence be used in any C++ program. Two programs that use these classes are also presented. The first one, Bio++ Maximum Likelihood (BppML), estimates parameters of any non-homogeneous model and the second one, Bio++ Sequence Generator (BppSeqGen), simulates the evolution of sequences from these models. These programs allow the user to describe non-homogeneous models through a property file with a simple yet powerful syntax, without any programming required.
Conclusion
We show that the general implementation introduced here can accommodate virtually any type of non-homogeneous models of sequence evolution, including heterotachous ones, while being computer efficient. We furthermore illustrate the use of such general models for parametric bootstrapping, using tests of non-homogeneity applied to an already published ribosomal RNA data set.
doi:10.1186/1471-2148-8-255
PMCID: PMC2559849  PMID: 18808672
19.  A Hierarchical Bayesian Model for Calibrating Estimates of Species Divergence Times 
Systematic Biology  2012;61(5):793-809.
In Bayesian divergence time estimation methods, incorporating calibrating information from the fossil record is commonly done by assigning prior densities to ancestral nodes in the tree. Calibration prior densities are typically parametric distributions offset by minimum age estimates provided by the fossil record. Specification of the parameters of calibration densities requires the user to quantify his or her prior knowledge of the age of the ancestral node relative to the age of its calibrating fossil. The values of these parameters can, potentially, result in biased estimates of node ages if they lead to overly informative prior distributions. Accordingly, determining parameter values that lead to adequate prior densities is not straightforward. In this study, I present a hierarchical Bayesian model for calibrating divergence time analyses with multiple fossil age constraints. This approach applies a Dirichlet process prior as a hyperprior on the parameters of calibration prior densities. Specifically, this model assumes that the rate parameters of exponential prior distributions on calibrated nodes are distributed according to a Dirichlet process, whereby the rate parameters are clustered into distinct parameter categories. Both simulated and biological data are analyzed to evaluate the performance of the Dirichlet process hyperprior. Compared with fixed exponential prior densities, the hierarchical Bayesian approach results in more accurate and precise estimates of internal node ages. When this hyperprior is applied using Markov chain Monte Carlo methods, the ages of calibrated nodes are sampled from mixtures of exponential distributions and uncertainty in the values of calibration density parameters is taken into account.
doi:10.1093/sysbio/sys032
PMCID: PMC3417043  PMID: 22334343
Bayesian divergence time estimation; Dirichlet process prior; fossil calibration; hyperprior; MCMC; relaxed clock
20.  A Semiparametric Approach to Source Separation using Independent Component Analysis 
Data processing and source identification using lower dimensional hidden structure plays an essential role in many fields of applications, including image processing, neural networks, genome studies, signal processing and other areas where large datasets are often encountered. One of the common methods for source separation using lower dimensional structure involves the use of Independent Component Analysis, which is based on a linear representation of the observed data in terms of independent hidden sources. The problem thus involves the estimation of the linear mixing matrix and the densities of the independent hidden sources. However, the solution to the problem depends on the identifiability of the sources. This paper first presents a set of sufficient conditions to establish the identifiability of the sources and the mixing matrix using moment restrictions of the hidden source variables. Under such sufficient conditions a semi-parametric maximum likelihood estimate of the mixing matrix is obtained using a class of mixture distributions. The consistency of our proposed estimate is established under additional regularity conditions. The proposed method is illustrated and compared with existing methods using simulated and real data sets.
doi:10.1016/j.csda.2012.09.012
PMCID: PMC3921001  PMID: 24526802
Constrained EM-algorithm; Mixture Density Estimation; Source Identification
21.  Change point models for cognitive tests using semi-parametric maximum likelihood 
Random-effects change point models are formulated for longitudinal data obtained from cognitive tests. The conditional distribution of the response variable in a change point model is often assumed to be normal even if the response variable is discrete and shows ceiling effects. For the sum score of a cognitive test, the binomial and the beta-binomial distributions are presented as alternatives to the normal distribution. Smooth shapes for the change point models are imposed. Estimation is by marginal maximum likelihood where a parametric population distribution for the random change point is combined with a non-parametric mixing distribution for other random effects. An extension to latent class modelling is possible in case some individuals do not experience a change in cognitive ability. The approach is illustrated using data from a longitudinal study of Swedish octogenarians and nonagenarians that began in 1991. Change point models are applied to investigate cognitive change in the years before death.
doi:10.1016/j.csda.2012.07.024
PMCID: PMC3587404  PMID: 23471297
Beta-binomial distribution; Latent class model; Mini-mental state examination; Random-effects model
22.  Drawing Inferences about the Coancestry Coefficient 
Theoretical population biology  2009;75(4):312-319.
The coancestry coefficient, also known as the population structure parameter, is of great interest in population genetics. It can be thought of as the intraclass correlation of pairs of alleles within populations and it can serve as a measure of genetic distance between populations. For a general class of evolutionary models it determines the distribution of allele frequencies among populations. Under more restrictive models it can be regarded as the probability of identity by descent of any pair alleles at a locus within a random mating population. In this paper we review estimation procedures that use the method of moments or are maximum likelihood under the assumption of normally distributed allele frequencies. We then consider the problem of testing hypotheses about this parameter. In addition to parametric and non-parametric bootstrap tests we present an asymptotically-distributed chi-square test. This test reduces to the contingency-table test for equal sample sizes across populations. Our new test appears to be more powerful than previous tests, especially for loci with multiple alleles. We apply our methods to HapMap SNP data to confirm that the coancestry coefficient for humans is strictly positive.
doi:10.1016/j.tpb.2009.03.005
PMCID: PMC2722911  PMID: 19345237
coancestry coefficient; F-statistics; parametric bootstrap; population structure; genetic drift; HapMap data
23.  Estimation of the disease-specific diagnostic marker distribution under verification bias 
We consider the estimation of the parameters indexing a parametric model for the conditional distribution of a diagnostic marker given covariates and disease status. Such models are useful for the evaluation of whether and to what extent a marker’s ability to accurately detect or discard disease depends on patient characteristics. A frequent problem that complicates the estimation of the model parameters is that estimation must be conducted from observational studies. Often, in such studies not all patients undergo the gold standard assessment of disease. Furthermore, the decision as to whether a patient undergoes verification is not controlled by study design. In such scenarios, maximum likelihood estimators based on subjects with observed disease status are generally biased. In this paper, we propose estimators for the model parameters that adjust for selection to verification that may depend on measured patient characteristics and additonally adjust for an assumed degree of residual association. Such estimators may be used as part of a sensitivity analysis for plausible degrees of residual association. We describe a doubly robust estimator that has the attractive feature of being consistent if either a model for the probability of selection to verification or a model for the probability of disease among the verified subjects (but not necessarily both) is correct.
doi:10.1016/j.csda.2008.06.021
PMCID: PMC3475507  PMID: 23087495
Missing at Random; Nonignorable; Missing Covariate; Sensitivity Analysis; Semiparametric; Diagnosis
24.  Likelihood-based analysis of longitudinal data from outcome-related sampling designs 
Biometrics  2013;70(1):44-52.
Summary
Investigators commonly gather longitudinal data to assess changes in responses over time and to relate these changes to within-subject changes in predictors. With rare or expensive outcomes such as uncommon diseases and costly radiologic measurements, outcome-dependent, and more generally outcome-related, sampling plans can improve estimation efficiency and reduce cost. Longitudinal follow up of subjects gathered in an initial outcome-related sample can then be used to study the trajectories of responses over time and to assess the association of changes in predictors within subjects with change in response. In this paper we develop two likelihood-based approaches for fitting generalized linear mixed models (GLMMs) to longitudinal data from a wide variety of outcome-related sampling designs. The first is an extension of the semi-parametric maximum likelihood approach developed in and applies quite generally. The second approach is an adaptation of standard conditional likelihood methods and is limited to random intercept models with a canonical link. Data from a study of Attention Deficit Hyperactivity Disorder in children motivates the work and illustrates the findings.
doi:10.1111/biom.12108
PMCID: PMC3954410  PMID: 24571396
Conditional likelihood; Retrospective sampling; Subject-specific models
25.  Semiparametric latent covariate mixed-effects models with application to a colon carcinogenesis study 
We study a mixed-effects model in which the response and the main covariate are linked by position. While the covariate corresponding to the observed response is not directly observable, there exists a latent covariate process that represents the underlying positional features of the covariate. When the positional features and the underlying distributions are parametric, the expectation-maximization (EM) is the most commonly used procedure. Though without the parametric assumptions, the practical feasibility of a semi-parametric EM algorithm and the corresponding inference procedures remain to be investigated. In this paper, we propose a semiparametric approach, and identify the conditions under which the semiparametric estimators share the same asymptotic properties as the unachievable estimators using the true values of the latent covariate; that is, the oracle property is achieved. We propose a Monte Carlo graphical evaluation tool to assess the adequacy of the sample size for achieving the oracle property. The semiparametric approach is later applied to data from a colon carcinogenesis study on the effects of cell DNA damage on the expression level of oncogene bcl-2. The graphical evaluation shows that, with moderate size of subunits, the numerical performance of the semiparametric estimator is very close to the asymptotic limit. It indicates that a complex EM-based implementation may at most achieve minimal improvement and is thus unnecessary.
PMCID: PMC2818699  PMID: 20148130
Carcinogenesis; Consistency; Generalized estimating equation; Local linear smoothing; Mixed-effects model

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