# Related Articles

Targeted maximum likelihood estimation of a parameter of a data generating distribution, known to be an element of a semi-parametric model, involves constructing a parametric model through an initial density estimator with parameter ɛ representing an amount of fluctuation of the initial density estimator, where the score of this fluctuation model at ɛ = 0 equals the efficient influence curve/canonical gradient. The latter constraint can be satisfied by many parametric fluctuation models since it represents only a local constraint of its behavior at zero fluctuation. However, it is very important that the fluctuations stay within the semi-parametric model for the observed data distribution, even if the parameter can be defined on fluctuations that fall outside the assumed observed data model. In particular, in the context of sparse data, by which we mean situations where the Fisher information is low, a violation of this property can heavily affect the performance of the estimator. This paper presents a fluctuation approach that guarantees the fluctuated density estimator remains inside the bounds of the data model. We demonstrate this in the context of estimation of a causal effect of a binary treatment on a continuous outcome that is bounded. It results in a targeted maximum likelihood estimator that inherently respects known bounds, and consequently is more robust in sparse data situations than the targeted MLE using a naive fluctuation model.

When an estimation procedure incorporates weights, observations having large weights relative to the rest heavily influence the point estimate and inflate the variance. Truncating these weights is a common approach to reducing the variance, but it can also introduce bias into the estimate. We present an alternative targeted maximum likelihood estimation (TMLE) approach that dampens the effect of these heavily weighted observations. As a substitution estimator, TMLE respects the global constraints of the observed data model. For example, when outcomes are binary, a fluctuation of an initial density estimate on the logit scale constrains predicted probabilities to be between 0 and 1. This inherent enforcement of bounds has been extended to continuous outcomes. Simulation study results indicate that this approach is on a par with, and many times superior to, fluctuating on the linear scale, and in particular is more robust when there is sparsity in the data.

doi:10.2202/1557-4679.1260

PMCID: PMC3126669
PMID: 21731529

targeted maximum likelihood estimation; TMLE; causal effect

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

A concrete example of the collaborative double-robust targeted likelihood estimator (C-TMLE) introduced in a companion article in this issue is presented, and applied to the estimation of causal effects and variable importance parameters in genomic data. The focus is on non-parametric estimation in a point treatment data structure. Simulations illustrate the performance of C-TMLE relative to current competitors such as the augmented inverse probability of treatment weighted estimator that relies on an external non-collaborative estimator of the treatment mechanism, and inefficient estimation procedures including propensity score matching and standard inverse probability of treatment weighting. C-TMLE is also applied to the estimation of the covariate-adjusted marginal effect of individual HIV mutations on resistance to the anti-retroviral drug lopinavir. The influence curve of the C-TMLE is used to establish asymptotically valid statistical inference. The list of mutations found to have a statistically significant association with resistance is in excellent agreement with mutation scores provided by the Stanford HIVdb mutation scores database.

doi:10.2202/1557-4679.1182

PMCID: PMC3126668
PMID: 21731530

causal effect; cross-validation; collaborative double robust; double robust; efficient influence curve; penalized likelihood; penalization; estimator selection; locally efficient; maximum likelihood estimation; model selection; super efficiency; super learning; targeted maximum likelihood estimation; targeted nuisance parameter estimator selection; variable importance

Given causal graph assumptions, intervention-specific counterfactual distributions of the data can be defined by the so called G-computation formula, which is obtained by carrying out these interventions on the likelihood of the data factorized according to the causal graph. The obtained G-computation formula represents the counterfactual distribution the data would have had if this intervention would have been enforced on the system generating the data. A causal effect of interest can now be defined as some difference between these counterfactual distributions indexed by different interventions. For example, the interventions can represent static treatment regimens or individualized treatment rules that assign treatment in response to time-dependent covariates, and the causal effects could be defined in terms of features of the mean of the treatment-regimen specific counterfactual outcome of interest as a function of the corresponding treatment regimens. Such features could be defined nonparametrically in terms of so called (nonparametric) marginal structural models for static or individualized treatment rules, whose parameters can be thought of as (smooth) summary measures of differences between the treatment regimen specific counterfactual distributions.

In this article, we develop a particular targeted maximum likelihood estimator of causal effects of multiple time point interventions. This involves the use of loss-based super-learning to obtain an initial estimate of the unknown factors of the G-computation formula, and subsequently, applying a target-parameter specific optimal fluctuation function (least favorable parametric submodel) to each estimated factor, estimating the fluctuation parameter(s) with maximum likelihood estimation, and iterating this updating step of the initial factor till convergence. This iterative targeted maximum likelihood updating step makes the resulting estimator of the causal effect double robust in the sense that it is consistent if either the initial estimator is consistent, or the estimator of the optimal fluctuation function is consistent. The optimal fluctuation function is correctly specified if the conditional distributions of the nodes in the causal graph one intervenes upon are correctly specified. The latter conditional distributions often comprise the so called treatment and censoring mechanism. Selection among different targeted maximum likelihood estimators (e.g., indexed by different initial estimators) can be based on loss-based cross-validation such as likelihood based cross-validation or cross-validation based on another appropriate loss function for the distribution of the data. Some specific loss functions are mentioned in this article.

Subsequently, a variety of interesting observations about this targeted maximum likelihood estimation procedure are made. This article provides the basis for the subsequent companion Part II-article in which concrete demonstrations for the implementation of the targeted MLE in complex causal effect estimation problems are provided.

doi:10.2202/1557-4679.1211

PMCID: PMC3126670
PMID: 20737021

causal effect; causal graph; censored data; cross-validation; collaborative double robust; double robust; dynamic treatment regimens; efficient influence curve; estimating function; estimator selection; locally efficient; loss function; marginal structural models for dynamic treatments; maximum likelihood estimation; model selection; pathwise derivative; randomized controlled trials; sieve; super-learning; targeted maximum likelihood estimation

Summary

Despite modern effective HIV treatment, hepatitis C virus (HCV) co-infection is associated with a high risk of progression to end-stage liver disease (ESLD) which has emerged as the primary cause of death in this population. Clinical interest lies in determining the impact of clearance of HCV on risk for ESLD. In this case study, we examine whether HCV clearance affects risk of ESLD using data from the multicenter Canadian Co-infection Cohort Study. Complications in this survival analysis arise from the time-dependent nature of the data, the presence of baseline confounders, loss to follow-up, and confounders that change over time, all of which can obscure the causal effect of interest. Additional challenges included non-censoring variable missingness and event sparsity.

In order to efficiently estimate the ESLD-free survival probabilities under a specific history of HCV clearance, we demonstrate the doubly-robust and semiparametric efficient method of Targeted Maximum Likelihood Estimation (TMLE). Marginal structural models (MSM) can be used to model the effect of viral clearance (expressed as a hazard ratio) on ESLD-free survival and we demonstrate a way to estimate the parameters of a logistic model for the hazard function with TMLE. We show the theoretical derivation of the efficient influence curves for the parameters of two different MSMs and how they can be used to produce variance approximations for parameter estimates. Finally, the data analysis evaluating the impact of HCV on ESLD was undertaken using multiple imputations to account for the non-monotone missing data.

doi:10.1111/biom.12105

PMCID: PMC3954273
PMID: 24571372

Double-robust; Inverse probability of treatment weighting; Kaplan-Meier; Longitudinal data; Marginal structural model; Survival analysis; Targeted maximum likelihood estimation

SUMMARY

Covariate adjustment using linear models for continuous outcomes in randomized trials has been shown to increase efficiency and power over the unadjusted method in estimating the marginal effect of treatment. However, for binary outcomes, investigators generally rely on the unadjusted estimate as the literature indicates that covariate-adjusted estimates based on the logistic regression models are less efficient. The crucial step that has been missing when adjusting for covariates is that one must integrate/average the adjusted estimate over those covariates in order to obtain the marginal effect. We apply the method of targeted maximum likelihood estimation (tMLE) to obtain estimators for the marginal effect using covariate adjustment for binary outcomes. We show that the covariate adjustment in randomized trials using the logistic regression models can be mapped, by averaging over the covariate(s), to obtain a fully robust and efficient estimator of the marginal effect, which equals a targeted maximum likelihood estimator. This tMLE is obtained by simply adding a clever covariate to a fixed initial regression. We present simulation studies that demonstrate that this tMLE increases efficiency and power over the unadjusted method, particularly for smaller sample sizes, even when the regression model is mis-specified.

doi:10.1002/sim.3445

PMCID: PMC2857590
PMID: 18985634

clinical trails; efficiency; covariate adjustment; variable selection

Background

When a large number of candidate variables are present, a dimension reduction procedure is usually conducted to reduce the variable space before the subsequent analysis is carried out. The goal of dimension reduction is to find a list of candidate genes with a more operable length ideally including all the relevant genes. Leaving many uninformative genes in the analysis can lead to biased estimates and reduced power. Therefore, dimension reduction is often considered a necessary predecessor of the analysis because it can not only reduce the cost of handling numerous variables, but also has the potential to improve the performance of the downstream analysis algorithms.

Results

We propose a TMLE-VIM dimension reduction procedure based on the variable importance measurement (VIM) in the frame work of targeted maximum likelihood estimation (TMLE). TMLE is an extension of maximum likelihood estimation targeting the parameter of interest. TMLE-VIM is a two-stage procedure. The first stage resorts to a machine learning algorithm, and the second step improves the first stage estimation with respect to the parameter of interest.

Conclusions

We demonstrate with simulations and data analyses that our approach not only enjoys the prediction power of machine learning algorithms, but also accounts for the correlation structures among variables and therefore produces better variable rankings. When utilized in dimension reduction, TMLE-VIM can help to obtain the shortest possible list with the most truly associated variables.

doi:10.1186/1471-2105-12-312

PMCID: PMC3166941
PMID: 21849016

Summary

The natural direct effect (NDE), or the effect of an exposure on an outcome if an
intermediate variable was set to the level it would have been in the absence of the exposure, is
often of interest to investigators. In general, the statistical parameter associated with the NDE is
difficult to estimate in the non-parametric model, particularly when the intermediate variable is
continuous or high dimensional. In this paper we introduce a new causal parameter called the natural
direct effect among the untreated, discus identifiability assumptions, propose a sensitivity
analysis for some of the assumptions, and show that this new parameter is equivalent to the NDE in a
randomized controlled trial. We also present a targeted minimum loss estimator (TMLE), a locally
efficient, double robust substitution estimator for the statistical parameter associated with this
causal parameter. The TMLE can be applied to problems with continuous and high dimensional
intermediate variables, and can be used to estimate the NDE in a randomized controlled trial with
such data. Additionally, we define and discuss the estimation of three related causal parameters:
the natural direct effect among the treated, the indirect effect among the untreated and the
indirect effect among the treated.

doi:10.1111/biom.12022

PMCID: PMC3692606
PMID: 23607645

Causal inference; direct effect; indirect effect; mediation analysis; semiparametric models; targeted minimum loss estimation

The Cox proportional hazards model or its discrete time analogue, the logistic failure time model, posit highly restrictive parametric models and attempt to estimate parameters which are specific to the model proposed. These methods are typically implemented when assessing effect modification in survival analyses despite their flaws. The targeted maximum likelihood estimation (TMLE) methodology is more robust than the methods typically implemented and allows practitioners to estimate parameters that directly answer the question of interest. TMLE will be used in this paper to estimate two newly proposed parameters of interest that quantify effect modification in the time to event setting. These methods are then applied to the Tshepo study to assess if either gender or baseline CD4 level modify the effect of two cART therapies of interest, efavirenz (EFV) and nevirapine (NVP), on the progression of HIV. The results show that women tend to have more favorable outcomes using EFV while males tend to have more favorable outcomes with NVP. Furthermore, EFV tends to be favorable compared to NVP for individuals at high CD4 levels.

doi:10.2202/1557-4679.1307

PMCID: PMC3083138
PMID: 21556287

causal effect; semi-parametric; censored longitudinal data; double robust; efficient influence curve; influence curve; G-computation; Targeted Maximum Likelihood Estimation; Cox-proportional hazards; survival analysis

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

SUMMARY

Length-biased sampling has been well recognized in economics, industrial reliability, etiology applications, epidemiological, genetic and cancer screening studies. Length-biased right-censored data have a unique data structure different from traditional survival data. The nonparametric and semiparametric estimations and inference methods for traditional survival data are not directly applicable for length-biased right-censored data. We propose new expectation-maximization algorithms for estimations based on full likelihoods involving infinite dimensional parameters under three settings for length-biased data: estimating nonparametric distribution function, estimating nonparametric hazard function under an increasing failure rate constraint, and jointly estimating baseline hazards function and the covariate coefficients under the Cox proportional hazards model. Extensive empirical simulation studies show that the maximum likelihood estimators perform well with moderate sample sizes and lead to more efficient estimators compared to the estimating equation approaches. The proposed estimates are also more robust to various right-censoring mechanisms. We prove the strong consistency properties of the estimators, and establish the asymptotic normality of the semi-parametric maximum likelihood estimators under the Cox model using modern empirical processes theory. We apply the proposed methods to a prevalent cohort medical study. Supplemental materials are available online.

doi:10.1198/jasa.2011.tm10156

PMCID: PMC3273908
PMID: 22323840

Cox regression model; EM algorithm; Increasing failure rate; Non-parametric likelihood; Profile likelihood; Right-censored data

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

We propose a semiparametric approach for the analysis of case-control genome-wide association study. Parametric components are used to model both the conditional distribution of the case status given the covariates and the distribution of genotype counts, whereas the distribution of the covariates are modeled nonparametrically. This yields a direct and joint modeling of the case status, covariates and genotype counts, and gives better understanding of the disease mechanism and results in more reliable conclusions. Side information, such as the disease prevalence, can be conveniently incorporated into the model by empirical likelihood approach and leads to more efficient estimates and powerful test in the detection of disease-associated SNPs. Profiling is used to eliminate a nuisance nonparametric component, and the resulting profile empirical likelihood estimates are shown to be consistent and asymptotically normal. For the hypothesis test on disease association, we apply the approximate Bayes factor (ABF) which is computationally simple and most desirable in genome-wide association studies where hundreds of thousands to a million genetic markers are tested. We treat the approximate Bayes factor as a hybrid Bayes factor which replaces the full data by the maximum likelihood estimates of the parameters of interest in the full model and derive it under a general setting. The deviation from Hardy-Weinberg Equilibrium (HWE) is also taken into account and the ABF for HWE using cases is shown to provide evidence of association between a disease and a genetic marker. Simulation studies and an application are further provided to illustrate the utility of the proposed methodology.

doi:10.1080/00949655.2011.654119

PMCID: PMC3921884
PMID: 24532860

Approximate Bayes factor; association study; empirical likelihood; genetic model; Hardy-Weinberg Equilibrium; profile likelihood; robustness; side information

We consider a random effects quantile regression analysis of clustered data and propose a semiparametric approach using empirical likelihood. The random regression coefficients are assumed independent with a common mean, following parametrically specified distributions. The common mean corresponds to the population-average effects of explanatory variables on the conditional quantile of interest, while the random coefficients represent cluster specific deviations in the covariate effects. We formulate the estimation of the random coefficients as an estimating equations problem and use empirical likelihood to incorporate the parametric likelihood of the random coefficients. A likelihood-like statistical criterion function is yield, which we show is asymptotically concave in a neighborhood of the true parameter value and motivates its maximizer as a natural estimator. We use Markov Chain Monte Carlo (MCMC) samplers in the Bayesian framework, and propose the resulting quasi-posterior mean as an estimator. We show that the proposed estimator of the population-level parameter is asymptotically normal and the estimators of the random coefficients are shrunk toward the population-level parameter in the first order asymptotic sense. These asymptotic results do not require Gaussian random effects, and the empirical likelihood based likelihood-like criterion function is free of parameters related to the error densities. This makes the proposed approach both flexible and computationally simple. We illustrate the methodology with two real data examples.

doi:10.1198/jasa.2011.tm10470.

PMCID: PMC3280824
PMID: 22347760

Empirical likelihood; Markov Chain Monte Carlo; Quasi-posterior distribution

Abstract

The Tshepo study was the first clinical trial to evaluate outcomes of adults receiving nevirapine (NVP)-based versus efavirenz (EFV)-based combination antiretroviral therapy (cART) in Botswana. This was a 3 year study (n=650) comparing the efficacy and tolerability of various first-line cART regimens, stratified by baseline CD4+: <200 (low) vs. 201-350 (high). Using targeted maximum likelihood estimation (TMLE), we retrospectively evaluated the causal effect of assigned NNRTI on time to virologic failure or death [intent-to-treat (ITT)] and time to minimum of virologic failure, death, or treatment modifying toxicity [time to loss of virological response (TLOVR)] by sex and baseline CD4+. Sex did significantly modify the effect of EFV versus NVP for both the ITT and TLOVR outcomes with risk differences in the probability of survival of males versus the females of approximately 6% (p=0.015) and 12% (p=0.001), respectively. Baseline CD4+ also modified the effect of EFV versus NVP for the TLOVR outcome, with a mean difference in survival probability of approximately 12% (p=0.023) in the high versus low CD4+ cell count group. TMLE appears to be an efficient technique that allows for the clinically meaningful delineation and interpretation of the causal effect of NNRTI treatment and effect modification by sex and baseline CD4+ cell count strata in this study. EFV-treated women and NVP-treated men had more favorable cART outcomes. In addition, adults initiating EFV-based cART at higher baseline CD4+ cell count values had more favorable outcomes compared to those initiating NVP-based cART.

doi:10.1089/aid.2011.0349

PMCID: PMC3423643
PMID: 22309114

We define a new measure of variable importance of an exposure on a continuous outcome, accounting for potential confounders. The exposure features a reference level x0 with positive mass and a continuum of other levels. For the purpose of estimating it, we fully develop the semi-parametric estimation methodology called targeted minimum loss estimation methodology (TMLE) [23, 22]. We cover the whole spectrum of its theoretical study (convergence of the iterative procedure which is at the core of the TMLE methodology; consistency and asymptotic normality of the estimator), practical implementation, simulation study and application to a genomic example that originally motivated this article. In the latter, the exposure X and response Y are, respectively, the DNA copy number and expression level of a given gene in a cancer cell. Here, the reference level is x0 = 2, that is the expected DNA copy number in a normal cell. The confounder is a measure of the methylation of the gene. The fact that there is no clear biological indication that X and Y can be interpreted as an exposure and a response, respectively, is not problematic.

doi:10.1214/12-EJS703

PMCID: PMC3546832
PMID: 23336014

Variable importance measure; non-parametric estimation; targeted minimum loss estimation; robustness; asymptotics

Rationale and Objectives

Semiparametric methods provide smooth and continuous receiver operating characteristic (ROC) curve fits to ordinal test results and require only that the data follow some unknown monotonic transformation of the model's assumed distributions. The quantitative relationship between cutoff settings or individual test-result values on the data scale and points on the estimated ROC curve is lost in this procedure, however. To recover that relationship in a principled way, we propose a new algorithm for “proper” ROC curves and illustrate it by use of the proper binormal model.

Materials and Methods

Several authors have proposed the use of multinomial distributions to fit semiparametric ROC curves by maximum-likelihood estimation. The resulting approach requires nuisance parameters that specify interval probabilities associated with the data, which are used subsequently as a basis for estimating values of the curve parameters of primary interest. In the method described here, we employ those “nuisance” parameters to recover the relationship between any ordinal test-result scale and true-positive fraction, false-positive fraction, and likelihood ratio. Computer simulations based on the proper binormal model were used to evaluate our approach in estimating those relationships and to assess the coverage of its confidence intervals for realistically sized datasets.

Results

In our simulations, the method reliably estimated simple relationships between test-result values and the several ROC quantities.

Conclusion

The proposed approach provides an effective and reliable semiparametric method with which to estimate the relationship between cutoff settings or individual test-result values and corresponding points on the ROC curve.

doi:10.1016/j.acra.2011.08.003

PMCID: PMC3368704
PMID: 22055797

Receiver operating characteristic (ROC) analysis; proper binormal model; likelihood ratio; test-result scale; maximum likelihood estimation (MLE)

We consider two-stage sampling designs, including so-called nested case control studies, where one takes a random sample from a target population and completes measurements on each subject in the first stage. The second stage involves drawing a subsample from the original sample, collecting additional data on the subsample. This data structure can be viewed as a missing data structure on the full-data structure collected in the second-stage of the study. Methods for analyzing two-stage designs include parametric maximum likelihood estimation and estimating equation methodology. We propose an inverse probability of censoring weighted targeted maximum likelihood estimator (IPCW-TMLE) in two-stage sampling designs and present simulation studies featuring this estimator.

doi:10.2202/1557-4679.1217

PMCID: PMC3083136
PMID: 21556285

two-stage designs; targeted maximum likelihood estimators; nested case control studies; double robust estimation

In this paper, we are concerned with how to select significant variables in semiparametric modeling. Variable selection for semiparametric regression models consists of two components: model selection for nonparametric components and select significant variables for parametric portion. Thus, it is much more challenging than that for parametric models such as linear models and generalized linear models because traditional variable selection procedures including stepwise regression and the best subset selection require model selection to nonparametric components for each submodel. This leads to very heavy computational burden. In this paper, we propose a class of variable selection procedures for semiparametric regression models using nonconcave penalized likelihood. The newly proposed procedures are distinguished from the traditional ones in that they delete insignificant variables and estimate the coefficients of significant variables simultaneously. This allows us to establish the sampling properties of the resulting estimate. We first establish the rate of convergence of the resulting estimate. With proper choices of penalty functions and regularization parameters, we then establish the asymptotic normality of the resulting estimate, and further demonstrate that the proposed procedures perform as well as an oracle procedure. Semiparametric generalized likelihood ratio test is proposed to select significant variables in the nonparametric component. We investigate the asymptotic behavior of the proposed test and demonstrate its limiting null distribution follows a chi-squared distribution, which is independent of the nuisance parameters. Extensive Monte Carlo simulation studies are conducted to examine the finite sample performance of the proposed variable selection procedures.

doi:10.1214/009053607000000604

PMCID: PMC2605629
PMID: 19122808

Nonconcave penalized likelihood; SCAD; efficient score; local linear regression; partially linear model; varying coefficient models

Summary

Meta-analysis is widely used to synthesize the results of multiple studies. Although meta-analysis is traditionally carried out by combining the summary statistics of relevant studies, advances in technologies and communications have made it increasingly feasible to access the original data on individual participants. In the present paper, we investigate the relative efficiency of analyzing original data versus combining summary statistics. We show that, for all commonly used parametric and semiparametric models, there is no asymptotic efficiency gain by analyzing original data if the parameter of main interest has a common value across studies, the nuisance parameters have distinct values among studies, and the summary statistics are based on maximum likelihood. We also assess the relative efficiency of the two methods when the parameter of main interest has different values among studies or when there are common nuisance parameters across studies. We conduct simulation studies to confirm the theoretical results and provide empirical comparisons from a genetic association study.

doi:10.1093/biomet/asq006

PMCID: PMC3412575
PMID: 23049122

Cox regression; Evidence-based medicine; Genetic association; Individual patient data; Information matrix; Linear regression; Logistic regression; Maximum likelihood; Profile likelihood; Research synthesis

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

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

Background

When boosting algorithms are used for building survival models from high-dimensional data, it is common to fit a Cox proportional hazards model or to use least squares techniques for fitting semiparametric accelerated failure time models. There are cases, however, where fitting a fully parametric accelerated failure time model is a good alternative to these methods, especially when the proportional hazards assumption is not justified. Boosting algorithms for the estimation of parametric accelerated failure time models have not been developed so far, since these models require the estimation of a model-specific scale parameter which traditional boosting algorithms are not able to deal with.

Results

We introduce a new boosting algorithm for censored time-to-event data which is suitable for fitting parametric accelerated failure time models. Estimation of the predictor function is carried out simultaneously with the estimation of the scale parameter, so that the negative log likelihood of the survival distribution can be used as a loss function for the boosting algorithm. The estimation of the scale parameter does not affect the favorable properties of boosting with respect to variable selection.

Conclusion

The analysis of a high-dimensional set of microarray data demonstrates that the new algorithm is able to outperform boosting with the Cox partial likelihood when the proportional hazards assumption is questionable. In low-dimensional settings, i.e., when classical likelihood estimation of a parametric accelerated failure time model is possible, simulations show that the new boosting algorithm closely approximates the estimates obtained from the maximum likelihood method.

doi:10.1186/1471-2105-9-269

PMCID: PMC2453145
PMID: 18538026

Summary

We show that the proportional likelihood ratio model proposed recently by Luo & Tsai (2012) enjoys model-invariant properties under certain forms of nonignorable missing mechanisms and randomly double-truncated data, so that target parameters in the population can be estimated consistently from those biased samples. We also construct an alternative estimator for the target parameters by maximizing a pseudo-likelihood that eliminates a functional nuisance parameter in the model. The corresponding estimating equation has a U-statistic structure. As an added advantage of the proposed method, a simple score-type test is developed to test a null hypothesis on the regression coefficients. Simulations show that the proposed estimator has a small-sample efficiency similar to that of the nonparametric likelihood estimator and performs well for certain nonignorable missing data problems.

doi:10.1093/biomet/ass056

PMCID: PMC3809024
PMID: 24179236

Double truncation; Nonignorable missingness; Pairwise pseudolikelihood; U-statistic

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