On evaluating how well a biomarker can predict treatment response with survival data

One of the objectives of personalized medicine is to take treatment decisions based on a biomarker measurement. Therefore, it is often interesting to evaluate how well a biomarker can predict the response to a treatment. To do so, a popular methodology consists of using a regression model and testing for an interaction between treatment assignment and biomarker. However, the existence of an interaction is not sufficient for a biomarker to be predictive. It is only necessary. Hence, the use of the marker‐by‐treatment predictiveness curve has been recommended. In addition to evaluate how well a single continuous biomarker predicts treatment response, it can further help to define an optimal threshold. This curve displays the risk of a binary outcome as a function of the quantiles of the biomarker, for each treatment group. Methods that assume a binary outcome or rely on a proportional hazard model for a time‐to‐event outcome have been proposed to estimate this curve. In this work, we propose some extensions for censored data. They rely on a time‐dependent logistic model, and we propose to estimate this model via inverse probability of censoring weighting. We present simulations results and three applications to prostate cancer, liver cirrhosis, and lung cancer data. They suggest that a large number of events need to be observed to define a threshold with sufficient accuracy for clinical usefulness. They also illustrate that when the treatment effect varies with the time horizon which defines the outcome, then the optimal threshold also depends on this time horizon.     

Selecting the regularization parameters in high-dimensional panel data models: Consistency and efficiency

This article considers panel data models in the presence of a large number of potential predictors and unobservable common factors. The model is estimated by the regularization method together with the principal components procedure. We propose a panel information criterion for selecting the regularization parameter and the number of common factors under a diverging number of predictors. Under the correct model specification, we show that the proposed criterion consistently identifies the true model. If the model is instead misspecified, the proposed criterion achieves asymptotically efficient model selection. Simulation results confirm these theoretical arguments.     

Oracle GMM estimation for misspecified models via thresholding

We propose a thresholding generalized method of moments (GMM) estimator for misspecified time series moment condition models. This estimator has the following oracle property: its asymptotic behavior is the same as of any efficient GMM estimator obtained under the a priori information that the true model were known. We propose data adaptive selection methods for thresholding parameter using multiple testing procedures. We determine the limiting null distributions of classical parameter tests and show the consistency of the corresponding block-bootstrap tests used in conjunction with thresholding GMM inference. We present the results of a simulation study for a misspecified instrumental variable regression model and for a vector autoregressive model with measurement error. We illustrate an application of the proposed methodology to data analysis of a real-world dataset.     

Effect of the sample on the posterior probability in bayesian analysis

This paper examines Bayesian posterior probabilities as a function of selected elements within the set of data, x, when the prior distribution is assumed fixed. The posterior probabilities considered here are those of the parameter vector lying in a subset of the total parameter space. The theorems of this paper provide insight into the effect of elements within x on this posterior probability. These results have applications, for example, in the study of the impact of outliers within the data and in the isolation of misspecified parameters in a model.     

On double hysteretic heteroskedastic model

ABSTRACT

This paper proposes a hysteretic autoregressive model with GARCH specification and a skew Student's t-error distribution for financial time series. With an integrated hysteresis zone, this model allows both the conditional mean and conditional volatility switching in a regime to be delayed when the hysteresis variable lies in a hysteresis zone. We perform Bayesian estimation via an adaptive Markov Chain Monte Carlo sampling scheme. The proposed Bayesian method allows simultaneous inferences for all unknown parameters, including threshold values and a delay parameter. To implement model selection, we propose a numerical approximation of the marginal likelihoods to posterior odds. The proposed methodology is illustrated using simulation studies and two major Asia stock basis series. We conduct a model comparison for variant hysteresis and threshold GARCH models based on the posterior odds ratios, finding strong evidence of the hysteretic effect and some asymmetric heavy-tailness. Versus multi-regime threshold GARCH models, this new collection of models is more suitable to describe real data sets. Finally, we employ Bayesian forecasting methods in a Value-at-Risk study of the return series.     

Weighted log‐rank test for time‐to‐event data in immunotherapy trials with random delayed treatment effect and cure rate

A cancer clinical trial with an immunotherapy often has 2 special features, which are patients being potentially cured from the cancer and the immunotherapy starting to take clinical effect after a certain delay time. Existing testing methods may be inadequate for immunotherapy clinical trials, because they do not appropriately take the 2 features into consideration at the same time, hence have low power to detect the true treatment effect. In this paper, we proposed a piece‐wise proportional hazards cure rate model with a random delay time to fit data, and a new weighted log‐rank test to detect the treatment effect of an immunotherapy over a chemotherapy control. We showed that the proposed weight was nearly optimal under mild conditions. Our simulation study showed a substantial gain of power in the proposed test over the existing tests and robustness of the test with misspecified weight. We also introduced a sample size calculation formula to design the immunotherapy clinical trials using the proposed weighted log‐rank test.     

The analysis of multivariate recurrent events with partially missing event types

In many clinical studies, subjects are at risk of experiencing more than one type of potentially recurrent event. In some situations, however, the occurrence of an event is observed, but the specific type is not determined. We consider the analysis of this type of incomplete data when the objectives are to summarize features of conditional intensity functions and associated treatment effects, and to study the association between different types of event. Here we describe a likelihood approach based on joint models for the multi-type recurrent events where parameter estimation is obtained from a Monte-Carlo EM algorithm. Simulation studies show that the proposed method gives unbiased estimators for regression coefficients and variance–covariance parameters, and the coverage probabilities of confidence intervals for regression coefficients are close to the nominal level. When the distribution of the frailty variable is misspecified, the method still provides estimators of the regression coefficients with good properties. The proposed method is applied to a motivating data set from an asthma study in which exacerbations were to be sub-typed by cellular analysis of sputum samples as eosinophilic or non-eosinophilic.     

Identifiable finite mixtures of location models for clustering mixed-mode data

For clustering mixed categorical and continuous data, Lawrence and Krzanowski (1996) proposed a finite mixture model in which component densities conform to the location model. In the graphical models literature the location model is known as the homogeneous Conditional Gaussian model. In this paper it is shown that their model is not identifiable without imposing additional restrictions. Specifically, for g groups and m locations, (g!)m–1 distinct sets of parameter values (not including permutations of the group mixing parameters) produce the same likelihood function. Excessive shrinkage of parameter estimates in a simulation experiment reported by Lawrence and Krzanowski (1996) is shown to be an artifact of the model's non-identifiability. Identifiable finite mixture models can be obtained by imposing restrictions on the conditional means of the continuous variables. These new identified models are assessed in simulation experiments. The conditional mean structure of the continuous variables in the restricted location mixture models is similar to that in the underlying variable mixture models proposed by Everitt (1988), but the restricted location mixture models are more computationally tractable.     

Asymptotic properties of maximum quasi-likelihood estimator in quasi-likelihood nonlinear models with misspecified variance function

The quasi-likelihood function proposed by Wedderburn [Quasi-likelihood functions, generalized linear models, and the Gauss–Newton method. Biometrika. 1974;61:439–447] broadened the application scope of generalized linear models (GLM) by specifying the mean and variance function instead of the entire distribution. However, in many situations, complete specification of variance function in the quasi-likelihood approach may not be realistic. Following Fahrmeir's [Maximum likelihood estimation in misspecified generalized linear models. Statistics. 1990;21:487–502] treating with misspecified GLM, we define a quasi-likelihood nonlinear models (QLNM) with misspecified variance function by replacing the unknown variance function with a known function. In this paper, we propose some mild regularity conditions, under which the existence and the asymptotic normality of the maximum quasi-likelihood estimator (MQLE) are obtained in QLNM with misspecified variance function. We suggest computing MQLE of unknown parameter in QLNM with misspecified variance function by the Gauss–Newton iteration procedure and show it to work well in a simulation study.     

Stratified Gaussian graphical models

Gaussian graphical models represent the backbone of the statistical toolbox for analyzing continuous multivariate systems. However, due to the intrinsic properties of the multivariate normal distribution, use of this model family may hide certain forms of context-specific independence that are natural to consider from an applied perspective. Such independencies have been earlier introduced to generalize discrete graphical models and Bayesian networks into more flexible model families. Here, we adapt the idea of context-specific independence to Gaussian graphical models by introducing a stratification of the Euclidean space such that a conditional independence may hold in certain segments but be absent elsewhere. It is shown that the stratified models define a curved exponential family, which retains considerable tractability for parameter estimation and model selection.     

Parametric simultaneous robust inferences for regression coefficient under generalized linear models

In this article, the parametric robust regression approaches are proposed for making inferences about regression parameters in the setting of generalized linear models (GLMs). The proposed methods are able to test hypotheses on the regression coefficients in the misspecified GLMs. More specifically, it is demonstrated that with large samples, the normal and gamma regression models can be properly adjusted to become asymptotically valid for inferences about regression parameters under model misspecification. These adjusted regression models can provide the correct type I and II error probabilities and the correct coverage probability for continuous data, as long as the true underlying distributions have finite second moments.     

Choice of Parametric Accelerated Life and Proportional Hazards Models for Survival Data: Asymptotic Results

We discuss the impact of misspecifying fully parametric proportional hazards and accelerated life models. For the uncensored case, misspecified accelerated life models give asymptotically unbiased estimates of covariate effect, but the shape and scale parameters depend on the misspecification. The covariate, shape and scale parameters differ in the censored case. Parametric proportional hazards models do not have a sound justification for general use: estimates from misspecified models can be very biased, and misleading results for the shape of the hazard function can arise. Misspecified survival functions are more biased at the extremes than the centre. Asymptotic and first order results are compared. If a model is misspecified, the size of Wald tests will be underestimated. Use of the sandwich estimator of standard error gives tests of the correct size, but misspecification leads to a loss of power. Accelerated life models are more robust to misspecification because of their log-linear form. In preliminary data analysis, practitioners should investigate proportional hazards and accelerated life models; software is readily available for several such models.     

Semiparametric estimation method for accelerated failure time model with dependent censoring

Independent censoring is commonly assumed in survival analysis. However, it may be questionable when censoring is related to event time. We model the event and censoring time marginally through accelerated failure time models, and model their association by a known copula. An iteration algorithm is proposed to estimate the regression parameters. Simulation results show the improvement of the proposed method compared to the naive method under independent censoring. Sensitivity analysis gives the evidences that the proposed method can obtain reasonable estimates even when the forms of copula are misspecified. We illustrate its application by analyzing prostate cancer data.     

A Bayesian shared parameter model for joint modeling of longitudinal continuous and binary outcomes

Joint modeling of associated mixed biomarkers in longitudinal studies leads to a better clinical decision by improving the efficiency of parameter estimates. In many clinical studies, the observed time for two biomarkers may not be equivalent and one of the longitudinal responses may have recorded in a longer time than the other one. In addition, the response variables may have different missing patterns. In this paper, we propose a new joint model of associated continuous and binary responses by accounting different missing patterns for two longitudinal outcomes. A conditional model for joint modeling of the two responses is used and two shared random effects models are considered for intermittent missingness of two responses. A Bayesian approach using Markov Chain Monte Carlo (MCMC) is adopted for parameter estimation and model implementation. The validation and performance of the proposed model are investigated using some simulation studies. The proposed model is also applied for analyzing a real data set of bariatric surgery.     

Closure of the class of binary generalized linear models in some non-standard settings

This paper considers fitting generalized linear models to binary data in nonstandard settings such as case–control samples, studies with misclassified responses and misspecified models. We develop simple methods for fitting models to case–control data and show that a closure property holds for generalized linear models in the nonstandard settings, i.e. if the responses follow a generalized linear model in the population of interest, then so will the observed response in the non-standard setting, but with a modified link function. These results imply that we can analyse data and study problems in the non-standard settings by using classical generalized linear model methods such as the iteratively reweighted least squares algorithm. Example data illustrate the results.     

The effects of missing serial effects and/or heteroscedastic errors on mixed models using repeated growth data

When a two-level multilevel model (MLM) is used for repeated growth data, the individuals constitute level 2 and the successive measurements constitute level 1, which is nested within the individuals that make up level 2. The heterogeneity among individuals is represented by either the random-intercept or random-coefficient (slope) model. The variance components at level 1 involve serial effects and measurement errors under constant variance or heteroscedasticity. This study hypothesizes that missing serial effects or/and heteroscedasticity may bias the results obtained from two-level models. To illustrate this effect, we conducted two simulation studies, where the simulated data were based on the characteristics of an empirical mouse tumour data set. The results suggest that for repeated growth data with constant variance (measurement error) and misspecified serial effects (ρ > 0.3), the proportion of level-2 variation (intra-class correlation coefficient) increases with ρ and the two-level random-coefficient model is the minimum AIC (or AIC_c) model when compared with the fixed model, heteroscedasticity model, and random-intercept model. In addition, the serial effect (ρ > 0.1) and heteroscedasticity are both misspecified, implying that the two-level random-coefficient model is the minimum AIC (or AIC_c) model when compared with the fixed model and random-intercept model. This study demonstrates that missing serial effects and/or heteroscedasticity may indicate heterogeneity among individuals in repeated growth data (mixed or two-level MLM). This issue is critical in biomedical research.     

Frequentist model averaging for envelope models

The envelope method produces efficient estimation in multivariate linear regression, and is widely applied in biology, psychology, and economics. This paper estimates parameters through a model averaging methodology and promotes the predicting abilities of the envelope models. We propose a frequentist model averaging method by minimizing a cross-validation criterion. When all the candidate models are misspecified, the proposed model averaging estimator is proved to be asymptotically optimal. When correct candidate models exist, the coefficient estimator is proved to be consistent, and the sum of the weights assigned to the correct models, in probability, converges to one. Simulations and an empirical application demonstrate the effectiveness of the proposed method.     

Consistent GMM Residuals-Based Tests of Functional Form

This paper presents a consistent Generalized Method of Moments (GMM) residuals-based test of functional form for time series models. By relating two moments we deliver a vector moment condition in which at least one element must be nonzero if the model is misspecified. The test will never fail to detect misspecification of any form for large samples, and is asymptotically chi-squared under the null, allowing for fast and simple inference. A simulation study reveals randomly selecting the nuisance parameter leads to more power than supremum-tests, and can obtain empirical power nearly equivalent to the most powerful test for even relatively small n.     

Modeling the density of US yield curve using Bayesian semiparametric dynamic Nelson-Siegel model

Abstract

This paper proposes the Bayesian semiparametric dynamic Nelson-Siegel model for estimating the density of bond yields. Specifically, we model the distribution of the yield curve factors according to an infinite Markov mixture (iMM). The model allows for time variation in the mean and covariance matrix of factors in a discrete manner, as opposed to continuous changes in these parameters such as the Time Varying Parameter (TVP) models. Estimating the number of regimes using the iMM structure endogenously leads to an adaptive process that can generate newly emerging regimes over time in response to changing economic conditions in addition to existing regimes. The potential of the proposed framework is examined using US bond yields data. The semiparametric structure of the factors can handle various forms of non-normalities including fat tails and nonlinear dependence between factors using a unified approach by generating new clusters capturing these specific characteristics. We document that modeling parameter changes in a discrete manner increases the model fit as well as forecasting performance at both short and long horizons relative to models with fixed parameters as well as the TVP model with continuous parameter changes. This is mainly due to fact that the discrete changes in parameters suit the typical low frequency monthly bond yields data characteristics better.     

Penalized likelihood ratio test for a biomarker threshold effect in clinical trials based on generalized linear models

In a clinical trial, the responses to the new treatment may vary among patient subsets with different characteristics in a biomarker. It is often necessary to examine whether there is a cutpoint for the biomarker that divides the patients into two subsets of those with more favourable and less favourable responses. More generally, we approach this problem as a test of homogeneity in the effects of a set of covariates in generalized linear regression models. The unknown cutpoint results in a model with nonidentifiability and a nonsmooth likelihood function to which the ordinary likelihood methods do not apply. We first use a smooth continuous function to approximate the indicator function defining the patient subsets. We then propose a penalized likelihood ratio test to overcome the model irregularities. Under the null hypothesis, we prove that the asymptotic distribution of the proposed test statistic is a mixture of chi-squared distributions. Our method is based on established asymptotic theory, is simple to use, and works in a general framework that includes logistic, Poisson, and linear regression models. In extensive simulation studies, we find that the proposed test works well in terms of size and power. We further demonstrate the use of the proposed method by applying it to clinical trial data from the Digitalis Investigation Group (DIG) on heart failure.