In this paper new families of test statistics are introduced and studied for the problem of comparing two treatments in terms of the likelihood ratio order. The considered families are based on phi-divergence measures and arise as natural extensions of the classical likelihood ratio test and Pearson test statistics. It is proven that their asymptotic distribution is a common chi-bar random variable. An illustrative example is presented and the performance of these statistics is analysed through a simulation study. Through a simulation study it is shown that, for most of the proposed scenarios adjusted to be small or moderate, some members of this new family of test-statistic display clearly better performance with respect to the power in comparison to the classical likelihood ratio and the Pearson's chi-square test while the exact size remains closed to the nominal size. In view of the exact powers and significance levels, the study also shows that the Wilcoxon test-statistic is not as good as the two classical test-statistics.
In health-related experiments, treatment effects can be identified using paired data that consist of pre- and post-treatment measurements. In this framework, sequential testing strategies are widely accepted statistical tools in practice. Since performances of parametric sequential testing procedures vitally depend on the validity of the parametric assumptions regarding underlying data distributions, we focus on distribution-free mechanisms for sequentially evaluating treatment effects. In fixed sample size designs, the density-based empirical likelihood (DBEL) methods provide powerful nonpara…
Inference procedures in sequential trial emulation with survival outcomes: comparing confidence intervals based on the sandwich variance estimator, bootstrap and jackknife
Longitudinal targeted maximum likelihood estimation (LTMLE) has very rarely been used to estimate dynamic treatment effects in the context of time-dependent confounding affected by prior treatment when faced with long follow-up times, multiple time-varying confounders, and complex associational relationships simultaneously. Reasons for this include the potential computational burden, technical challenges, restricted modeling options for long follow-up times, and limited practical guidance in the literature. However, LTMLE has desirable asymptotic properties, i.e. it is doubly robust, and can y…
Targeted maximum likelihood estimation is a general methodology combining flexible ensemble learning and semiparametric efficiency theory in a two-step procedure for estimation of causal parameters. Proposed targeted maximum likelihood procedures for survival and competing risks analysis have so far focused on events taken values in discrete time. We here present a targeted maximum likelihood estimation procedure for event times that take values in R+. We focuson the estimation of intervention-specific mean outcomes with stochastic interventions on a time-fixed treatment. For data-adaptive est…
We propose an empirical likelihood ratio test for nonparametric model selection, where the competing models may be nested, nonnested, overlapping, misspecified, or correctly specified. It compares the squared prediction errors of models based on the cross-validation and allows for heteroscedasticity of the errors of models. We develop its asymptotic distributions for comparing additive models and varying-coefficient models and extend it to test significance of variables in additive models with massive data. The method is applicable to model selection among supervised learning models. To facili…
Response-adaptive allocation designs refer to a class of designs where the probability an observation is assigned to a treatment is changed throughout an experiment based on the accrued responses. Such procedures result in random treatment sample sizes. Most of the current literature considers unconditional inference procedures in the analysis of response-adaptive allocation designs. The focus of this work is inference conditional on the observed treatment sample sizes. The inverse of information is a description of the large sample variance of the parameter estimates. A simple form for the co…
Several recently developed methods have the potential to harness machine learning in the pursuit of target quantities inspired by causal inference, including inverse weighting, doubly robust estimating equations and substitution estimators like targeted maximum likelihood estimation. There are even more recent augmentations of these procedures that can increase robustness, by adding a layer of cross-validation (cross-validated targeted maximum likelihood estimation and double machine learning, as applied to substitution and estimating equation approaches, respectively). While these methods hav…
The primary analysis of clinical trials in diabetes therapeutic area often involves a mixed-model repeated measure (MMRM) approach to estimate the average treatment effect for longitudinal continuous outcome, and a generalized linear mixed model (GLMM) approach for longitudinal binary outcome. In this paper, we considered another estimator of the average treatment effect, called targeted maximum likelihood estimator (TMLE). This estimator can be a one-step alternative to model either continuous or binary outcome. We compared those estimators by simulation studies and by analyzing real data fro…
There is a long-standing debate in the statistical, epidemiological and econometric fields as to whether nonparametric estimation that uses data-adaptive methods, like machine learning algorithms in model fitting, confer any meaningful advantage over simpler, parametric approaches in real-world, finite sample estimation of causal effects. We address the question: when trying to estimate the effect of a treatment on an outcome, across a universe of reasonable data distributions, how much does the choice of nonparametric vs.~parametric estimation matter? Instead of answering this question with s…
In many psychometric applications, the relationship between the mean of an outcome and a quantitative covariate is too complex to be described by simple parametric functions; instead, flexible nonlinear relationships can be incorporated using penalized splines. Penalized splines can be conveniently represented as a linear mixed effects model (LMM), where the coefficients of the spline basis functions are random effects. The LMM representation of penalized splines makes the extension to multivariate outcomes relatively straightforward. In the LMM, no effect of the quantitative covariate on the …
This study presents a family of stochastic models for the dynamics of influenza in a closed human population. We consider treatment for the disease in the form of vaccination, and incorporate the periods of effectiveness of the vaccine and infectiousness for the individuals in the population. Our model is a SVIR model, with trinomial transition probabilities, where all individuals who recover from the disease acquire permanent natural immunity against the strain of the disease. Special SVIR models in the family are presented, based on the structure of the probability of getting infection and v…
Over the past years, many applications aim to assess the causal effect of treatments assigned at the community level, while data are still collected at the individual level among individuals of the community. In many cases, one wants to evaluate the effect of a stochastic intervention on the community, where all communities in the target population receive probabilistically assigned treatments based on a known specified mechanism (e.g., implementing a community-level intervention policy that target stochastic changes in the behavior of a target population of communities). The tmleCommunity pac…
We identify the average dose-response function (ADRF) for a continuously valued error-contaminated treatment by a weighted conditional expectation. We then estimate the weights nonparametrically by maximising a local generalised empirical likelihood subject to an expanding set of conditional moment equations incorporated into the deconvolution kernels. Thereafter, we construct a deconvolution kernel estimator of ADRF. We derive the asymptotic bias and variance of our ADRF estimator and provide its asymptotic linear expansion, which helps conduct statistical inference. To select our smoothing p…
As the COVID-19 pandemic progresses, researchers are reporting findings of randomized trials comparing standard care with care augmented by experimental drugs. The trials have small sample sizes, so estimates of treatment effects are imprecise. Seeing imprecision, clinicians reading research articles may find it difficult to decide when to treat patients with experimental drugs. Whatever decision criterion one uses, there is always some probability that random variation in trial outcomes will lead to prescribing sub-optimal treatments. A conventional practice when comparing standard care and a…
Treatment effect estimation by comparing observed and predicted outcomes: conditions for valid inference and practical illustration
University Medical Center Utrecht, Utrecht University（乌得勒支大学医学中心，乌得勒支大学）；University Medical Center Groningen（格罗宁根大学医学中心）；MAASTRO Clinic（MAASTRO诊所）；Erasmus MC Cancer Institute（伊拉斯姆斯癌症研究所）
A simple and common type of medical research involves the comparison of one treatment against another. The logical aim should be both to establish which treatment is superior and the strength of evidence supporting this conclusion, a task for which null hypothesis significance testing is particularly ill-suited. This paper describes and evaluates a novel sequential inferential procedure based on the likelihood evidential paradigm with the likelihood ratio as its salient statistic. The real-world performance of the procedure as applied to the distribution of treatment effects seen in the Cochra…
There has been growing attention on how to effectively and objectively use covariate information when the primary goal is to estimate the average treatment effect (ATE) in randomized clinical trials (RCTs). In this paper, we propose an effective weighting approach to extract covariate information based on the empirical likelihood (EL) method. The resulting two-sample empirical likelihood weighted (ELW) estimator includes two classes of weights, which are obtained from a constrained empirical likelihood estimation procedure, where the covariate information is effectively incorporated into the f…
A dynamic treatment regimen (DTR) is a pre-specified sequence of decision rules which maps baseline or time-varying measurements on an individual to a recommended intervention or set of interventions. Sequential multiple assignment randomized trials (SMARTs) represent an important data collection tool for informing the construction of effective DTRs. A common primary aim in a SMART is the marginal mean comparison between two or more of the DTRs embedded in the trial. This manuscript develops a mixed effects modeling and estimation approach for these primary aim comparisons based on a continuou…
We study optimal block designs for comparing a set of test treatments with a control treatment. We provide the class of all E-optimal approximate block designs characterized by simple linear constraints. Employing this characterization, we obtain a class of E-optimal exact designs for treatment-control comparisons for unequal block sizes. In the studied model, we justify the use of E-optimality by providing a statistical interpretation for all E-optimal approximate designs and for the known classes of E-optimal exact designs. Moreover, we consider the R-optimality criterion, which minimizes th…
Basic propensity score methodology is designed to balance multivariate pre-treatment covariates when comparing one active treatment with one control treatment. Practical settings often involve comparing more than two treatments, where more complicated contrasts than the basic treatment-control one,(1,-1), are relevant. Here, we propose the use of contrast-specific propensity scores (CSPS). CSPS allow the creation of treatment groups of units that are balanced with respect to bifurcations of the specified contrasts and the multivariate space spanned by them.
A local projection model is defined by a set of linear regressions that account for the associations between exogenous variables and an endogenous variable observed at different time points. While it is standard practice to separately estimate individual regressions using the ordinary least squares estimator, some recent studies treat a local projection model as a multivariate regression with correlated errors, i.e., seemingly unrelated regressions, and propose Bayesian and non-Bayesian methods to improve the estimation accuracy. However, it is not clear how and when this way of treatment of l…
In this paper, we propose a data-adaptive empirical likelihood-based approach for treatment effect estimation and inference, which overcomes the obstacle of the traditional empirical likelihood-based approaches in the high-dimensional setting by adopting penalized regression and machine learning methods to model the covariate-outcome relationship. In particular, we show that our procedure successfully recovers the true variance of Zhang's treatment effect estimator (Zhang, 2018) by utilizing a data-splitting technique. Our proposed estimator is proved to be asymptotically normal and semiparame…
Brown University School of Public Health（布朗大学公共卫生学院）；Center for Gerontology and Health Care Research, Brown University School of Public Health（布朗大学公共卫生学院老年学与医疗保健研究中心）；Harvard T.H. Chan School of Public Health（哈佛陈曾熙公共卫生学院）；Richard A. and Susan F. Smith Center for Outcomes Research, Beth Israel Deaconess Medical Center, Harvard Medical School（理查德·A和苏珊·F·史密斯结果研究中心，贝斯以色列女执事医疗中心，哈佛医学院）
Otto-von-Guericke University Magdeburg（奥托·冯·古尔克马格德堡大学）；RWTH Aachen University（亚琛工业大学）；National Center for Tumor Diseases (NCT) Heidelberg（海德堡国家肿瘤疾病中心）；German Cancer Research Center (DKFZ)（德国癌症研究中心）；German Cancer Consortium (DKTK)（德国癌症联盟）；Heidelberg University（海德堡大学）
Clinicians and researchers alike are increasingly interested in how best to personalize interventions. A dynamic treatment regimen (DTR) is a sequence of pre-specified decision rules which can be used to guide the delivery of a sequence of treatments or interventions that are tailored to the changing needs of the individual. The sequential multiple-assignment randomized trial (SMART) is a research tool which allows for the construction of effective DTRs. We derive easy-to-use formulae for computing the total sample size for three common two-stage SMART designs in which the primary aim is to co…
We propose a general approach to construct weighted likelihood estimating equations with the aim of obtain robust estimates. The weight, attached to each score contribution, is evaluated by comparing the statistical data depth at the model with that of the sample in a given point. Observations are considered regular when the ratio of these two depths is close to one, whereas, when the ratio is large the corresponding score contribution may be downweigthed. Details and examples are provided for the robust estimation of the parameters in the multivariate normal model. Because of the form of the …
Considering parallel tempering and comparing post-treatment procedures in Bayesian Profile Regression Models for a survival outcome and correlated exposures
Autorité de Sûreté Nucléaire et de Radioprotection (ASNR)（核安全与辐射防护局）；PSE-SANTE/SESANE/LEPID；Université Paris Cité（巴黎西岱大学）；CNRS, Inserm, P-MIM, BioSTM（法国国家科学研究中心、INSERM、P-MIM、BioSTM）
