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1.  Sieve Maximum Likelihood Estimation for Doubly Semiparametric Zero-Inflated Poisson Models 
Journal of multivariate analysis  2010;101(9):2026-2038.
For nonnegative measurements such as income or sick days, zero counts often have special status. Furthermore, the incidence of zero counts is often greater than expected for the Poisson model. This article considers a doubly semiparametric zero-inflated Poisson model to fit data of this type, which assumes two partially linear link functions in both the mean of the Poisson component and the probability of zero. We study a sieve maximum likelihood estimator for both the regression parameters and the nonparametric functions. We show, under routine conditions, that the estimators are strongly consistent. Moreover, the parameter estimators are asymptotically normal and first-order efficient, while the nonparametric components achieve the optimal convergence rates. Simulation studies suggest that the extra flexibility inherent from the doubly semiparametric model is gained with little loss in statistical efficiency. We also illustrate our approach with a dataset from a public health study.
doi:10.1016/j.jmva.2010.05.003
PMCID: PMC2909790  PMID: 20671990
Asymptotic efficiency; Partly linear model; Sieve maximum likelihood estimator; Zero-inflated Poisson model
2.  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
3.  Semiparametric Maximum Likelihood Estimation in Normal Transformation Models for Bivariate Survival Data 
Biometrika  2008;95(4):947-960.
SUMMARY
We consider a class of semiparametric normal transformation models for right censored bivariate failure times. Nonparametric hazard rate models are transformed to a standard normal model and a joint normal distribution is assumed for the bivariate vector of transformed variates. A semiparametric maximum likelihood estimation procedure is developed for estimating the marginal survival distribution and the pairwise correlation parameters. This produces an efficient estimator of the correlation parameter of the semiparametric normal transformation model, which characterizes the bivariate dependence of bivariate survival outcomes. In addition, a simple positive-mass-redistribution algorithm can be used to implement the estimation procedures. Since the likelihood function involves infinite-dimensional parameters, the empirical process theory is utilized to study the asymptotic properties of the proposed estimators, which are shown to be consistent, asymptotically normal and semiparametric efficient. A simple estimator for the variance of the estimates is also derived. The finite sample performance is evaluated via extensive simulations.
doi:10.1093/biomet/asn049
PMCID: PMC2600666  PMID: 19079778
Asymptotic normality; Bivariate failure time; Consistency; Semiparametric efficiency; Semiparametric maximum likelihood estimate; Semiparametric normal transformation
4.  On L∞ convergence of Neumann series approximation in missing data problems 
Statistics & probability letters  2010;80(9-10):864-873.
The inverse of the nonparametric information operator is key to finding doubly robust estimators and the semiparametric efficient estimator in missing data problems. It is known that no closed-form expression for the inverse of the nonparametric information operator exists when missing data form nonmonotone patterns. Neumann series is usually applied to approximate the inverse. However, Neumann series approximation is only known to converge in L2 norm, which is not sufficient for establishing statistical properties of the estimators yielded from the approximation. In this article, we show that L∞ convergence of the Neumann series approximations to the inverse of the non-parametric information operator and to the efficient scores in missing data problems can be obtained under very simple conditions. This paves the way to the study of the asymptotic properties of the doubly robust estimators and the locally semiparametric efficient estimator in those difficult situations.
doi:10.1016/j.spl.2010.01.021
PMCID: PMC2850222  PMID: 20383317
Auxiliary information; Induction; Rate of convergence; Weighted estimating equation
5.  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
6.  On cross-odds ratio for multivariate competing risks data 
Biostatistics (Oxford, England)  2012;13(4):680-694.
The cross-odds ratio is defined as the ratio of the conditional odds of the occurrence of one cause-specific event for one subject given the occurrence of the same or a different cause-specific event for another subject in the same cluster over the unconditional odds of occurrence of the cause-specific event. It is a measure of the association between the correlated cause-specific failure times within a cluster. The joint cumulative incidence function can be expressed as a function of the marginal cumulative incidence functions and the cross-odds ratio. Assuming that the marginal cumulative incidence functions follow a generalized semiparametric model, this paper studies the parametric regression modeling of the cross-odds ratio. A set of estimating equations are proposed for the unknown parameters and the asymptotic properties of the estimators are explored. Non-parametric estimation of the cross-odds ratio is also discussed. The proposed procedures are applied to the Danish twin data to model the associations between twins in their times to natural menopause and to investigate whether the association differs among monozygotic and dizygotic twins and how these associations have changed over time.
doi:10.1093/biostatistics/kxs017
PMCID: PMC3440240  PMID: 22696688
Binomial modeling; Correlated cause-specific failure times; Danish twin data; Estimating equation; Generalized semiparametric additive model; Inverse censoring probability weighting; Joint cumulative incidence function; Large sample properties; Marginal cumulative incidence function; Parametric regression model
7.  Semiparametric location estimation under non-random sampling† 
Stat  2012;1(1):1-11.
We study a class of semiparametric skewed distributions arising when the sample selection process produces non-randomly sampled observations. Based on semiparametric theory and taking into account the symmetric nature of the population distribution, we propose both consistent estimators, i.e. robust to model mis-specification, and efficient estimators, i.e. reaching the minimum possible estimation variance, of the location of the symmetric population. We demonstrate the theoretical properties of our estimators through asymptotic analysis and assess their finite sample performance through simulations. We also implement our methodology on a real data example of ambulatory expenditures to illustrate the applicability of the estimators in practice.
doi:10.1002/sta4.2
PMCID: PMC3922234  PMID: 24532858
robustness; selection bias; semiparametric model; skewness; skew-symmetric distribution
8.  Semiparametric dimension reduction estimation for mean response with missing data 
Biometrika  2010;97(2):305-319.
Summary
Model misspecification can be a concern for high-dimensional data. Nonparametric regression obviates model specification but is impeded by the curse of dimensionality. This paper focuses on the estimation of the marginal mean response when there is missingness in the response and multiple covariates are available. We propose estimating the mean response through nonparametric functional estimation, where the dimension is reduced by a parametric working index. The proposed semiparametric estimator is robust to model misspecification: it is consistent for any working index if the missing mechanism of the response is known or correctly specified up to unknown parameters; even with misspecification in the missing mechanism, it is consistent so long as the working index can recover E(Y  |   X), the conditional mean response given the covariates. In addition, when the missing mechanism is correctly specified, the semiparametric estimator attains the optimal efficiency if E(Y  |   X) is recoverable through the working index. Robustness and efficiency of the proposed estimator is further investigated by simulations. We apply the proposed method to a clinical trial for HIV.
doi:10.1093/biomet/asq005
PMCID: PMC3412576  PMID: 23049121
Dimension reduction; Inverse probability weighting; Kernel regression; Missing at random; Robustness to model misspecification
9.  On Asymptotically Optimal Tests Under Loss of Identifiability in Semiparametric Models 
Annals of statistics  2009;37(5A):2409-2444.
We consider tests of hypotheses when the parameters are not identifiable under the null in semiparametric models, where regularity conditions for profile likelihood theory fail. Exponential average tests based on integrated profile likelihood are constructed and shown to be asymptotically optimal under a weighted average power criterion with respect to a prior on the nonidentifiable aspect of the model. These results extend existing results for parametric models, which involve more restrictive assumptions on the form of the alternative than do our results. Moreover, the proposed tests accommodate models with infinite dimensional nuisance parameters which either may not be identifiable or may not be estimable at the usual parametric rate. Examples include tests of the presence of a change-point in the Cox model with current status data and tests of regression parameters in odds-rate models with right censored data. Optimal tests have not previously been studied for these scenarios. We study the asymptotic distribution of the proposed tests under the null, fixed contiguous alternatives and random contiguous alternatives. We also propose a weighted bootstrap procedure for computing the critical values of the test statistics. The optimal tests perform well in simulation studies, where they may exhibit improved power over alternative tests.
PMCID: PMC2864541  PMID: 20454527
Change-point models; contiguous alternative; empirical processes; exponential average test; nonstandard testing problem; odds-rate models; optimal test; power; profile likelihood
10.  A SIEVE M-THEOREM FOR BUNDLED PARAMETERS IN SEMIPARAMETRIC MODELS, WITH APPLICATION TO THE EFFICIENT ESTIMATION IN A LINEAR MODEL FOR CENSORED DATA* 
Annals of statistics  2011;39(6):2795-3443.
In many semiparametric models that are parameterized by two types of parameters – a Euclidean parameter of interest and an infinite-dimensional nuisance parameter, the two parameters are bundled together, i.e., the nuisance parameter is an unknown function that contains the parameter of interest as part of its argument. For example, in a linear regression model for censored survival data, the unspecified error distribution function involves the regression coefficients. Motivated by developing an efficient estimating method for the regression parameters, we propose a general sieve M-theorem for bundled parameters and apply the theorem to deriving the asymptotic theory for the sieve maximum likelihood estimation in the linear regression model for censored survival data. The numerical implementation of the proposed estimating method can be achieved through the conventional gradient-based search algorithms such as the Newton-Raphson algorithm. We show that the proposed estimator is consistent and asymptotically normal and achieves the semiparametric efficiency bound. Simulation studies demonstrate that the proposed method performs well in practical settings and yields more efficient estimates than existing estimating equation based methods. Illustration with a real data example is also provided.
PMCID: PMC3890689  PMID: 24436500
Accelerated failure time model; B-spline; bundled parameters; efficient score function; semiparametric efficiency; sieve maximum likelihood estimation
11.  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
12.  Doubly Robust Estimation of Causal Effects 
American Journal of Epidemiology  2011;173(7):761-767.
Doubly robust estimation combines a form of outcome regression with a model for the exposure (i.e., the propensity score) to estimate the causal effect of an exposure on an outcome. When used individually to estimate a causal effect, both outcome regression and propensity score methods are unbiased only if the statistical model is correctly specified. The doubly robust estimator combines these 2 approaches such that only 1 of the 2 models need be correctly specified to obtain an unbiased effect estimator. In this introduction to doubly robust estimators, the authors present a conceptual overview of doubly robust estimation, a simple worked example, results from a simulation study examining performance of estimated and bootstrapped standard errors, and a discussion of the potential advantages and limitations of this method. The supplementary material for this paper, which is posted on the Journal's Web site (http://aje.oupjournals.org/), includes a demonstration of the doubly robust property (Web Appendix 1) and a description of a SAS macro (SAS Institute, Inc., Cary, North Carolina) for doubly robust estimation, available for download at http://www.unc.edu/∼mfunk/dr/.
doi:10.1093/aje/kwq439
PMCID: PMC3070495  PMID: 21385832
causal inference; epidemiologic methods; propensity score
13.  Test the reliability of doubly robust estimation with missing response data 
Biometrics  2014;70(2):289-298.
Summary
In statistical inference one has to make sure that the underlying regression model is correctly specified otherwise the resulting estimation may be biased. Model checking is an important method to detect any departure of the regression model from the true one. Missing data is a ubiquitous problem in social and medical studies. If the underlying regression model is correctly specified, recent researches show great popularity of the doubly robust estimates method for handling missing data because of its robustness to the misspecification of either the missing data model or the conditional mean model, i.e. the model for the conditional expectation of true regression model conditioning on the observed quantities. However, little work has been devoted to the goodness of fit test for doubly robust estimates method. In this paper, we propose a testing method to assess the reliability of the estimator derived from the doubly robust estimating equation with possibly missing response and always observed auxiliary variables. Numerical studies demonstrate that the proposed test can control type I errors well. Furthermore the proposed method can detect departures from model assumptions in the marginal mean model of interest powerfully. A real dementia data set is used to illustrate the method for the diagnosis of model misspecification in the problem of missing response with an always observed auxiliary variable for cross-sectional data.
doi:10.1111/biom.12150
PMCID: PMC4061274  PMID: 24571677
Auxiliary; doubly robust; estimating equation; goodness of fit; missing data
14.  Polynomial Spline Estimation for A Generalized Additive Coefficient Model 
We study a semiparametric generalized additive coefficient model, in which linear predictors in the conventional generalized linear models is generalized to unknown functions depending on certain covariates, and approximate the nonparametric functions by using polynomial spline. The asymptotic expansion with optimal rates of convergence for the estimators of the nonparametric part is established. Semiparametric generalized likelihood ratio test is also proposed to check if a nonparametric coefficient can be simplified as a parametric one. A conditional bootstrap version is suggested to approximate the distribution of the test under the null hypothesis. Extensive Monte Carlo simulation studies are conducted to examine the finite sample performance of the proposed methods. We further apply the proposed model and methods to a data set from a human visceral Leishmaniasis (HVL) study conduced in Brazil from 1994 to 1997. Numerical results outperform the traditional generalized linear model and the proposed generalized additive coefficient model is preferable.
doi:10.1111/j.1467-9469.2009.00655.x
PMCID: PMC2834255  PMID: 20216928
Conditional bootstrap; generalized additive models; knots; maximum likelihood estimation; optimal rate of convergence; spline approximation
15.  Robust estimation for homoscedastic regression in the secondary analysis of case–control data 
Summary
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.
doi:10.1111/j.1467-9868.2012.01052.x
PMCID: PMC3639015  PMID: 23637568
Biased samples; Homoscedastic regression; Secondary data; Secondary phenotypes; Semiparametric inference; Two-stage samples
16.  Mixtures of Varying Coefficient Models for Longitudinal Data with Discrete or Continuous Nonignorable Dropout 
Biometrics  2004;60(4):854-864.
SUMMARY
The analysis of longitudinal repeated measures data is frequently complicated by missing data due to informative dropout. We describe a mixture model for joint distribution for longitudinal repeated measures, where the dropout distribution may be continuous and the dependence between response and dropout is semiparametric. Specifically, we assume that responses follow a varying coefficient random effects model conditional on dropout time, where the regression coefficients depend on dropout time through unspecified nonparametric functions that are estimated using step functions when dropout time is discrete (e.g., for panel data) and using smoothing splines when dropout time is continuous. Inference under the proposed semiparametric model is hence more robust than the parametric conditional linear model. The unconditional distribution of the repeated measures is a mixture over the dropout distribution. We show that estimation in the semiparametric varying coefficient mixture model can proceed by fitting a parametric mixed effects model and can be carried out on standard software platforms such as SAS. The model is used to analyze data from a recent AIDS clinical trial and its performance is evaluated using simulations.
doi:10.1111/j.0006-341X.2004.00240.x
PMCID: PMC2677904  PMID: 15606405
Clinical trials; Equivalence trial; Linear mixed model; Missing data; Nonignorable dropout; Pattern-mixture model; Pediatric AIDS; Selection bias; Smoothing splines
17.  Analysis of Longitudinal Data with Semiparametric Estimation of Covariance Function 
Improving efficiency for regression coefficients and predicting trajectories of individuals are two important aspects in analysis of longitudinal data. Both involve estimation of the covariance function. Yet, challenges arise in estimating the covariance function of longitudinal data collected at irregular time points. A class of semiparametric models for the covariance function is proposed by imposing a parametric correlation structure while allowing a nonparametric variance function. A kernel estimator is developed for the estimation of the nonparametric variance function. Two methods, a quasi-likelihood approach and a minimum generalized variance method, are proposed for estimating parameters in the correlation structure. We introduce a semiparametric varying coefficient partially linear model for longitudinal data and propose an estimation procedure for model coefficients by using a profile weighted least squares approach. Sampling properties of the proposed estimation procedures are studied and asymptotic normality of the resulting estimators is established. Finite sample performance of the proposed procedures is assessed by Monte Carlo simulation studies. The proposed methodology is illustrated by an analysis of a real data example.
doi:10.1198/016214507000000095
PMCID: PMC2730591  PMID: 19707537
Kernel regression; local linear regression; profile weighted least squares; semiparametric varying coefficient model
18.  WEIGHTED LIKELIHOOD ESTIMATION UNDER TWO-PHASE SAMPLING 
Annals of statistics  2013;41(1):269-295.
We develop asymptotic theory for weighted likelihood estimators (WLE) under two-phase stratified sampling without replacement. We also consider several variants of WLEs involving estimated weights and calibration. A set of empirical process tools are developed including a Glivenko–Cantelli theorem, a theorem for rates of convergence of M-estimators, and a Donsker theorem for the inverse probability weighted empirical processes under two-phase sampling and sampling without replacement at the second phase. Using these general results, we derive asymptotic distributions of the WLE of a finite-dimensional parameter in a general semiparametric model where an estimator of a nuisance parameter is estimable either at regular or nonregular rates. We illustrate these results and methods in the Cox model with right censoring and interval censoring. We compare the methods via their asymptotic variances under both sampling without replacement and the more usual (and easier to analyze) assumption of Bernoulli sampling at the second phase.
doi:10.1214/12-AOS1073
PMCID: PMC3929280  PMID: 24563559
Calibration; estimated weights; weighted likelihood; semiparametric model; regular; nonregular
19.  Evaluating Statistical Hypotheses Using Weakly-Identifiable Estimating Functions 
Many statistical models arising in applications contain non- and weakly-identified parameters. Due to identifiability concerns, tests concerning the parameters of interest may not be able to use conventional theories and it may not be clear how to assess statistical significance. This paper extends the literature by developing a testing procedure that can be used to evaluate hypotheses under non- and weakly-identifiable semiparametric models. The test statistic is constructed from a general estimating function of a finite dimensional parameter model representing the population characteristics of interest, but other characteristics which may be described by infinite dimensional parameters, and viewed as nuisance, are left completely unspecified. We derive the limiting distribution of this statistic and propose theoretically justified resampling approaches to approximate its asymptotic distribution. The methodology’s practical utility is illustrated in simulations and an analysis of quality-of-life outcomes from a longitudinal study on breast cancer.
doi:10.1111/j.1467-9469.2012.00811.x
PMCID: PMC3685206  PMID: 23788826
estimating equations; global sensitivity analysis; infimum and supremum statistics; missing not at random; model misspecification; pseudolikelihood
20.  On a Closed-Form Doubly Robust Estimator of the Adjusted Odds Ratio for a Binary Exposure 
American Journal of Epidemiology  2013;177(11):1314-1316.
Epidemiologic studies often aim to estimate the odds ratio for the association between a binary exposure and a binary disease outcome. Because confounding bias is of serious concern in observational studies, investigators typically estimate the adjusted odds ratio in a multivariate logistic regression which conditions on a large number of potential confounders. It is well known that modeling error in specification of the confounders can lead to substantial bias in the adjusted odds ratio for exposure. As a remedy, Tchetgen Tchetgen et al. (Biometrika. 2010;97(1):171–180) recently developed so-called doubly robust estimators of an adjusted odds ratio by carefully combining standard logistic regression with reverse regression analysis, in which exposure is the dependent variable and both the outcome and the confounders are the independent variables. Double robustness implies that only one of the 2 modeling strategies needs to be correct in order to make valid inferences about the odds ratio parameter. In this paper, I aim to introduce this recent methodology into the epidemiologic literature by presenting a simple closed-form doubly robust estimator of the adjusted odds ratio for a binary exposure. A SAS macro (SAS Institute Inc., Cary, North Carolina) is given in an online appendix to facilitate use of the approach in routine epidemiologic practice, and a simulated data example is also provided for the purpose of illustration.
doi:10.1093/aje/kws377
PMCID: PMC3664333  PMID: 23558352
case-control sampling; doubly robust estimator; logistic regression; odds ratio; SAS macro
21.  SEMIPARAMETRIC QUANTILE REGRESSION WITH HIGH-DIMENSIONAL COVARIATES 
Statistica Sinica  2012;22(4):1379-1401.
This paper is concerned with quantile regression for a semiparametric regression model, in which both the conditional mean and conditional variance function of the response given the covariates admit a single-index structure. This semiparametric regression model enables us to reduce the dimension of the covariates and simultaneously retains the flexibility of nonparametric regression. Under mild conditions, we show that the simple linear quantile regression offers a consistent estimate of the index parameter vector. This is a surprising and interesting result because the single-index model is possibly misspecified under the linear quantile regression. With a root-n consistent estimate of the index vector, one may employ a local polynomial regression technique to estimate the conditional quantile function. This procedure is computationally efficient, which is very appealing in high-dimensional data analysis. We show that the resulting estimator of the quantile function performs asymptotically as efficiently as if the true value of the index vector were known. The methodologies are demonstrated through comprehensive simulation studies and an application to a real dataset.
doi:10.5705/ss.2010.199
PMCID: PMC3910001  PMID: 24501536
Dimension reduction; heteroscedasticity; linearity condition; local polynomial regression; quantile regression; single-index model
22.  A new estimation with minimum trace of asymptotic covariance matrix for incomplete longitudinal data with a surrogate process 
Statistics in medicine  2013;32(27):10.1002/sim.5875.
Missing data is a very common problem in medical and social studies, especially when data are collected longitudinally. It is a challenging problem to utilize observed data effectively. Many papers on missing data problems can be found in statistical literature. It is well known that the inverse weighted estimation is neither efficient nor robust. On the other hand, the doubly robust (DR) method can improve the efficiency and robustness. As is known, the DR estimation requires a missing data model (i.e., a model for the probability that data are observed) and a working regression model (i.e., a model for the outcome variable given covariates and surrogate variables). Because the DR estimating function has mean zero for any parameters in the working regression model when the missing data model is correctly specified, in this paper, we derive a formula for the estimator of the parameters of the working regression model that yields the optimally efficient estimator of the marginal mean model (the parameters of interest) when the missing data model is correctly specified. Furthermore, the proposed method also inherits the DR property. Simulation studies demonstrate the greater efficiency of the proposed method compared with the standard DR method. A longitudinal dementia data set is used for illustration.
doi:10.1002/sim.5875
PMCID: PMC3808493  PMID: 23744541
longitudinal data; missing data; optimal; surrogate outcome
23.  A SEMIPARAMETRIC MODEL FOR CLUSTER DATA 
Annals of statistics  2009;37(5A):2377-2408.
In the analysis of cluster data the regression coefficients are frequently assumed to be the same across all clusters. This hampers the ability to study the varying impacts of factors on each cluster. In this paper, a semiparametric model is introduced to account for varying impacts of factors over clusters by using cluster-level covariates. It achieves the parsimony of parametrization and allows the explorations of nonlinear interactions. The random effect in the semiparametric model accounts also for within cluster correlation. Local linear based estimation procedure is proposed for estimating functional coefficients, residual variance, and within cluster correlation matrix. The asymptotic properties of the proposed estimators are established and the method for constructing simultaneous confidence bands are proposed and studied. In addition, relevant hypothesis testing problems are addressed. Simulation studies are carried out to demonstrate the methodological power of the proposed methods in the finite sample. The proposed model and methods are used to analyse the second birth interval in Bangladesh, leading to some interesting findings.
doi:10.1214/08-AOS662
PMCID: PMC2987698  PMID: 21103023
Varying-coefficient models; local linear modelling; cluster level variable; cluster effect
24.  Penalized Estimating Functions and Variable Selection in Semiparametric Regression Models 
We propose a general strategy for variable selection in semiparametric regression models by penalizing appropriate estimating functions. Important applications include semiparametric linear regression with censored responses and semiparametric regression with missing predictors. Unlike the existing penalized maximum likelihood estimators, the proposed penalized estimating functions may not pertain to the derivatives of any objective functions and may be discrete in the regression coefficients. We establish a general asymptotic theory for penalized estimating functions and present suitable numerical algorithms to implement the proposed estimators. In addition, we develop a resampling technique to estimate the variances of the estimated regression coefficients when the asymptotic variances cannot be evaluated directly. Simulation studies demonstrate that the proposed methods perform well in variable selection and variance estimation. We illustrate our methods using data from the Paul Coverdell Stroke Registry.
doi:10.1198/016214508000000184
PMCID: PMC2850080  PMID: 20376193
Accelerated failure time model; Buckley-James estimator; Censoring; Least absolute shrinkage and selection operator; Least squares; Linear regression; Missing data; Smoothly clipped absolute deviation
25.  Semiparametric Analysis of Heterogeneous Data Using Varying-Scale Generalized Linear Models 
This article describes a class of heteroscedastic generalized linear regression models in which a subset of the regression parameters are rescaled nonparametrically, and develops efficient semiparametric inferences for the parametric components of the models. Such models provide a means to adapt for heterogeneity in the data due to varying exposures, varying levels of aggregation, and so on. The class of models considered includes generalized partially linear models and nonparametrically scaled link function models as special cases. We present an algorithm to estimate the scale function nonparametrically, and obtain asymptotic distribution theory for regression parameter estimates. In particular, we establish that the asymptotic covariance of the semiparametric estimator for the parametric part of the model achieves the semiparametric lower bound. We also describe bootstrap-based goodness-of-scale test. We illustrate the methodology with simulations, published data, and data from collaborative research on ultrasound safety.
doi:10.1198/016214508000000210
PMCID: PMC2681270  PMID: 19444331
Generalized linear regression; Heteroscedasticity; Nonparametric regression; Partially linear model; Semiparametric efficiency; Varying-coefficient model

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