Joint modeling tumor burden and time to event data in oncology trials

The tumor burden (TB) process is postulated to be the primary mechanism through which most anticancer treatments provide benefit. In phase II oncology trials, the biologic effects of a therapeutic agent are often analyzed using conventional endpoints for best response, such as objective response rate and progression‐free survival, both of which causes loss of information. On the other hand, graphical methods including spider plot and waterfall plot lack any statistical inference when there is more than one treatment arm. Therefore, longitudinal analysis of TB data is well recognized as a better approach for treatment evaluation. However, longitudinal TB process suffers from informative missingness because of progression or death. We propose to analyze the treatment effect on tumor growth kinetics using a joint modeling framework accounting for the informative missing mechanism. Our approach is illustrated by multisetting simulation studies and an application to a nonsmall‐cell lung cancer data set. The proposed analyses can be performed in early‐phase clinical trials to better characterize treatment effect and thereby inform decision‐making. Copyright © 2014 John Wiley & Sons, Ltd.     

Sensitivity to imputation models and assumptions in receiver operating characteristic analysis with incomplete data

Modern statistical methods using incomplete data have been increasingly applied in a wide variety of substantive problems. Similarly, receiver operating characteristic (ROC) analysis, a method used in evaluating diagnostic tests or biomarkers in medical research, has also been increasingly popular problem in both its development and application. While missing-data methods have been applied in ROC analysis, the impact of model mis-specification and/or assumptions (e.g. missing at random) underlying the missing data has not been thoroughly studied. In this work, we study the performance of multiple imputation (MI) inference in ROC analysis. Particularly, we investigate parametric and non-parametric techniques for MI inference under common missingness mechanisms. Depending on the coherency of the imputation model with the underlying data generation mechanism, our results show that MI generally leads to well-calibrated inferences under ignorable missingness mechanisms.     

Adjusting overall survival for treatment switches: commonly used methods and practical application

In parallel group trials, long‐term efficacy endpoints may be affected if some patients switch or cross over to the alternative treatment arm prior to the event. In oncology trials, switch to the experimental treatment can occur in the control arm following disease progression and potentially impact overall survival. It may be a clinically relevant question to estimate the efficacy that would have been observed if no patients had switched, for example, to estimate ‘real‐life’ clinical effectiveness for a health technology assessment. Several commonly used statistical methods are available that try to adjust time‐to‐event data to account for treatment switching, ranging from naive exclusion and censoring approaches to more complex inverse probability of censoring weighting and rank‐preserving structural failure time models. These are described, along with their key assumptions, strengths, and limitations. Best practice guidance is provided for both trial design and analysis when switching is anticipated. Available statistical software is summarized, and examples are provided of the application of these methods in health technology assessments of oncology trials. Key considerations include having a clearly articulated rationale and research question and a well‐designed trial with sufficient good quality data collection to enable robust statistical analysis. No analysis method is universally suitable in all situations, and each makes strong untestable assumptions. There is a need for further research into new or improved techniques. This information should aid statisticians and their colleagues to improve the design and analysis of clinical trials where treatment switch is anticipated. Copyright © 2013 John Wiley & Sons, Ltd.     

Analysis of Panel Count Data with Dependent Observation Times

In this article, a semiparametric approach is proposed for the regression analysis of panel count data. Panel count data commonly arise in clinical trials and demographical studies where the response variable is the number of multiple recurrences of the event of interest and observation times are not fixed, varying from subject to subject. It is assumed that two processes exist in this data: the first is for a recurrent event and the second is for observation time. Many studies have been done to estimate mean function and regression parameters under the independency between recurrent event process and observation time process. In this article, the same statistical inference is studied, but the situation where these two processes may be related is also considered. The mixed Poisson process is applied for the recurrent event processes, and a frailty intensity function for the observation time is also used, respectively. Simulation studies are conducted to study the performance of the suggested methods. The bladder tumor data are applied to compare previous studie' results.     

Extending the Mann–Whitney–Wilcoxon rank sum test to longitudinal regression analysis

Outliers are commonly observed in psychosocial research, generally resulting in biased estimates when comparing group differences using popular mean-based models such as the analysis of variance model. Rank-based methods such as the popular Mann–Whitney–Wilcoxon (MWW) rank sum test are more effective to address such outliers. However, available methods for inference are limited to cross-sectional data and cannot be applied to longitudinal studies under missing data. In this paper, we propose a generalized MWW test for comparing multiple groups with covariates within a longitudinal data setting, by utilizing the functional response models. Inference is based on a class of U-statistics-based weighted generalized estimating equations, providing consistent and asymptotically normal estimates not only under complete but missing data as well. The proposed approach is illustrated with both real and simulated study data.     

On estimation of covariate-specific residual time quantiles under the proportional hazards model

Estimation and inference in time-to-event analysis typically focus on hazard functions and their ratios under the Cox proportional hazards model. These hazard functions, while popular in the statistical literature, are not always easily or intuitively communicated in clinical practice, such as in the settings of patient counseling or resource planning. Expressing and comparing quantiles of event times may allow for easier understanding. In this article we focus on residual time, i.e., the remaining time-to-event at an arbitrary time t given that the event has yet to occur by t. In particular, we develop estimation and inference procedures for covariate-specific quantiles of the residual time under the Cox model. Our methods and theory are assessed by simulations, and demonstrated in analysis of two real data sets.     

Statistical modelling of individual animal movement: an overview of key methods and a discussion of practical challenges

With the influx of complex and detailed tracking data gathered from electronic tracking devices, the analysis of animal movement data has recently emerged as a cottage industry among biostatisticians. New approaches of ever greater complexity are continue to be added to the literature. In this paper, we review what we believe to be some of the most popular and most useful classes of statistical models used to analyse individual animal movement data. Specifically, we consider discrete-time hidden Markov models, more general state-space models and diffusion processes. We argue that these models should be core components in the toolbox for quantitative researchers working on stochastic modelling of individual animal movement. The paper concludes by offering some general observations on the direction of statistical analysis of animal movement. There is a trend in movement ecology towards what are arguably overly complex modelling approaches which are inaccessible to ecologists, unwieldy with large data sets or not based on mainstream statistical practice. Additionally, some analysis methods developed within the ecological community ignore fundamental properties of movement data, potentially leading to misleading conclusions about animal movement. Corresponding approaches, e.g. based on Lévy walk-type models, continue to be popular despite having been largely discredited. We contend that there is a need for an appropriate balance between the extremes of either being overly complex or being overly simplistic, whereby the discipline relies on models of intermediate complexity that are usable by general ecologists, but grounded in well-developed statistical practice and efficient to fit to large data sets.     

Model diagnostics for the proportional hazards model with length-biased data

Length-biased data are frequently encountered in prevalent cohort studies. Many statistical methods have been developed to estimate the covariate effects on the survival outcomes arising from such data while properly adjusting for length-biased sampling. Among them, regression methods based on the proportional hazards model have been widely adopted. However, little work has focused on checking the proportional hazards model assumptions with length-biased data, which is essential to ensure the validity of inference. In this article, we propose a statistical tool for testing the assumed functional form of covariates and the proportional hazards assumption graphically and analytically under the setting of length-biased sampling, through a general class of multiparameter stochastic processes. The finite sample performance is examined through simulation studies, and the proposed methods are illustrated with the data from a cohort study of dementia in Canada.

     

Statistical Inference Enables Bad Science; Statistical Thinking Enables Good Science

ABSTRACT

Scientific research of all kinds should be guided by statistical thinking: in the design and conduct of the study, in the disciplined exploration and enlightened display of the data, and to avoid statistical pitfalls in the interpretation of the results. However, formal, probability-based statistical inference should play no role in most scientific research, which is inherently exploratory, requiring flexible methods of analysis that inherently risk overfitting. The nature of exploratory work is that data are used to help guide model choice, and under these circumstances, uncertainty cannot be precisely quantified, because of the inevitable model selection bias that results. To be valid, statistical inference should be restricted to situations where the study design and analysis plan are specified prior to data collection. Exploratory data analysis provides the flexibility needed for most other situations, including statistical methods that are regularized, robust, or nonparametric. Of course, no individual statistical analysis should be considered sufficient to establish scientific validity: research requires many sets of data along many lines of evidence, with a watchfulness for systematic error. Replicating and predicting findings in new data and new settings is a stronger way of validating claims than blessing results from an isolated study with statistical inferences.     

Power analysis for cluster randomized trials with binary outcomes modeled by generalized linear mixed-effects models

Power analysis for cluster randomized control trials is difficult to perform when a binary response is modeled using the generalized linear mixed-effects model (GLMM). Although methods for clustered binary responses exist such as the generalized estimating equations, they do not apply to the context of GLMM. Also, because popular statistical packages such as R and SAS do not provide correct estimates of parameters for the GLMM for binary responses, Monte Carlo simulation, a popular ad-hoc method for estimating power when the power function is too complex to evaluate analytically or numerically, fails to provide correct power estimates within the current context as well. In this paper, a new approach is developed to estimate power for cluster randomized control trials when a binary response is modeled by the GLMM. The approach is easy to implement and seems to work quite well, as assessed by simulation studies. The approach is illustrated with a real intervention study to reduce suicide reattempt rates among US Veterans.     

Repeated Confidence Intervals Under Fractional Brownian Motion in Long-Term Clinical Trials

Repeated confidence interval (RCI) is an important tool for design and monitoring of group sequential trials according to which we do not need to stop the trial with planned statistical stopping rules. In this article, we derive RCIs when data from each stage of the trial are not independent thus it is no longer a Brownian motion (BM) process. Under this assumption, a larger class of stochastic processes fractional Brownian motion (FBM) is considered. Comparisons of RCI width and sample size requirement are made to those under Brownian motion for different analysis times, Type I error rates and number of interim analysis. Power family spending functions including Pocock, O'Brien-Fleming design types are considered for these simulations. Interim data from BHAT and oncology trials is used to illustrate how to derive RCIs under FBM for efficacy and futility monitoring.     

Partitioning large-scale artificial society on distributed cluster with statistical movement graph

Distributed agent-based simulation is a popular method to realize computational experiment on large-scale artificial society. Meanwhile, the partitioning strategy of the artificial society models among hosts is playing an essential role for simulation engine to offer high execution efficiency as it has great impact on the communication overheads and computational load-balancing during simulation. Aiming at the problem, we firstly analyze the execution and scheduling process of agents during simulation and model it as wide-sense cyclostationary random process. Then, a static statistical partitioning model is proposed to obtain the optimal partitioning strategy with minimum average communication cost and load imbalance factor. To solve the static statistical partitioning model, this paper turns it into a graph-partitioning problem. A statistical movement graph-based partitioning algorithm is then devised which generates task graph model by mining the statistical movement information from initialization data of simulation model. In the experiments, two other popular partitioning methods are used to evaluate the performance of proposed graph-partitioning algorithm. Furthermore, this paper compares the graph-partitioning performance under different task graph model. The results indicate that our proposed statistical movement graph-based static partitioning method outperforms all other methods in reducing the communication overhead while satisfying the load balance constraint.     

Features and performance of some outlier detection methods

A review of several statistical methods that are currently in use for outlier identification is presented, and their performances are compared theoretically for typical statistical distributions of experimental data, considering values derived from the distribution of extreme order statistics as reference terms. A simple modification of a popular, broadly used method based upon box-plot is introduced, in order to overcome a major limitation concerning sample size. Examples are presented concerning exploitation of methods considered on two data sets: a historical one concerning evaluation of an astronomical constant performed by a number of leading observatories and a substantial database pertaining to an ongoing investigation on absolute measurement of gravity acceleration, exhibiting peculiar aspects concerning outliers. Some problems related to outlier treatment are examined, and the requirement of both statistical analysis and expert opinion for proper outlier management is underlined.     

Stepwise local influence in generalized autoregressive conditional heteroskedasticity models

Detection of outliers or influential observations is an important work in statistical modeling, especially for the correlated time series data. In this paper we propose a new procedure to detect patch of influential observations in the generalized autoregressive conditional heteroskedasticity (GARCH) model. Firstly we compare the performance of innovative perturbation scheme, additive perturbation scheme and data perturbation scheme in local influence analysis. We find that the innovative perturbation scheme give better result than other two schemes although this perturbation scheme may suffer from masking effects. Then we use the stepwise local influence method under innovative perturbation scheme to detect patch of influential observations and uncover the masking effects. The simulated studies show that the new technique can successfully detect a patch of influential observations or outliers under innovative perturbation scheme. The analysis based on simulation studies and two real data sets show that the stepwise local influence method under innovative perturbation scheme is efficient for detecting multiple influential observations and dealing with masking effects in the GARCH model.     

Performance of information criteria for spatial models

Model choice is one of the most crucial aspect in any statistical data analysis. It is well known that most models are just an approximation to the true data-generating process but among such model approximations, it is our goal to select the ‘best’ one. Researchers typically consider a finite number of plausible models in statistical applications, and the related statistical inference depends on the chosen model. Hence, model comparison is required to identify the ‘best’ model among several such candidate models. This article considers the problem of model selection for spatial data. The issue of model selection for spatial models has been addressed in the literature by the use of traditional information criteria-based methods, even though such criteria have been developed based on the assumption of independent observations. We evaluate the performance of some of the popular model selection critera via Monte Carlo simulation experiments using small to moderate samples. In particular, we compare the performance of some of the most popular information criteria such as Akaike information criterion (AIC), Bayesian information criterion, and corrected AIC in selecting the true model. The ability of these criteria to select the correct model is evaluated under several scenarios. This comparison is made using various spatial covariance models ranging from stationary isotropic to nonstationary models.     

On a new family of shifted logarithmic transformations

Most parametric statistical methods are based on a set of assumptions: normality, linearity and homoscedasticity. Transformation of a metric response is a popular method to meet these assumptions. In particular, transformation of the response of a linear model is a popular method when attempting to satisfy the Gaussian assumptions on the error components in the model. A particular problem with common transformations such as the logarithm or the Box–Cox family is that negative and zero data values cannot be transformed. This paper proposes a new transformation which allows negative and zero data values. The method for estimating the transformation parameter consider an objective criteria based on kurtosis and skewness for achieving normality. Use of the new transformation and the method for estimating the transformation parameter are illustrated with three data sets.     

On the advantages of the non-concave penalized likelihood model selection method with minimum prediction errors in large-scale medical studies

Variable and model selection problems are fundamental to high-dimensional statistical modeling in diverse fields of sciences. Especially in health studies, many potential factors are usually introduced to determine an outcome variable. This paper deals with the problem of high-dimensional statistical modeling through the analysis of the trauma annual data in Greece for 2005. The data set is divided into the experiment and control sets and consists of 6334 observations and 112 factors that include demographic, transport and intrahospital data used to detect possible risk factors of death. In our study, different model selection techniques are applied to the experiment set and the notion of deviance is used on the control set to assess the fit of the overall selected model. The statistical methods employed in this work were the non-concave penalized likelihood methods, smoothly clipped absolute deviation, least absolute shrinkage and selection operator, and Hard, the generalized linear logistic regression, and the best subset variable selection.The way of identifying the significant variables in large medical data sets along with the performance and the pros and cons of the various statistical techniques used are discussed. The performed analysis reveals the distinct advantages of the non-concave penalized likelihood methods over the traditional model selection techniques.     

Analytic expressions for maximum likelihood estimators in a nonparametric model of tumor incidence and death

This research focuses on the estimation of tumor incidence rates from long-term animal studies which incorporate interim sacrifices. A nonparametric stochastic model is described with transition rates between states corresponding to the tumor incidence rate, the overall death rate, and the death rate for tumor-free animals. Exact analytic solutions for the maximum likelihood estimators of the hazard rates are presented, and their application to data from a long-term animal study is illustrated by an example. Unlike many common methods for estimation and comparison of tumor incidence rates among treatment groups, the estimators derived in this paper require no assumptions regarding tumor lethality or treatment lethality. The small sample operating characteristics of these estimators are evaluated using Monte Carlo simulation studies.     

A simple two-stage design for quantitative responses with application to a study in diabetic neuropathic pain

Two-stage designs offer substantial advantages for early phase II studies. The interim analysis following the first stage allows the study to be stopped for futility, or more positively, it might lead to early progression to the trials needed for late phase II and phase III. If the study is to continue to its second stage, then there is an opportunity for a revision of the total sample size. Two-stage designs have been implemented widely in oncology studies in which there is a single treatment arm and patient responses are binary. In this paper the case of two-arm comparative studies in which responses are quantitative is considered. This setting is common in therapeutic areas other than oncology. It will be assumed that observations are normally distributed, but that there is some doubt concerning their standard deviation, motivating the need for sample size review. The work reported has been motivated by a study in diabetic neuropathic pain, and the development of the design for that trial is described in detail.