ON THE DESIGN OF FIELD EXPERIMENTS UNDER A ONE-DIMENSIONAL NEIGHBOUR MODEL

This paper examines the effect of randomisation restrictions, either to satisfy conditions for a balanced incomplete block design or to attain a higher level of partial neighbour balance, on the average variance of pair-wise treatment contrasts under a neighbour model discussed by Gleeson & Cullis (1987). Results suggest that smaller average pairwise variances can be obtained by ignoring requirements for incomplete block designs and concentrating on achieving a higher level of partial neighbour balance. Field layout of the design, although often determined by practical constraints, e.g. size, shape of site, minimum plot size and experimental husbandry, may markedly affect average pairwise variance. For the one-dimensional (row-wise) neighbour model considered here, investigation of three different layouts suggests that for a rectangular array of plots, smaller average pairwise variances can generally be obtained from layouts with fewer rows and more plots per row.     

Bayesian methods for dealing with missing data problems

Missing data, a common but challenging issue in most studies, may lead to biased and inefficient inferences if handled inappropriately. As a natural and powerful way for dealing with missing data, Bayesian approach has received much attention in the literature. This paper reviews the recent developments and applications of Bayesian methods for dealing with ignorable and non-ignorable missing data. We firstly introduce missing data mechanisms and Bayesian framework for dealing with missing data, and then introduce missing data models under ignorable and non-ignorable missing data circumstances based on the literature. After that, important issues of Bayesian inference, including prior construction, posterior computation, model comparison and sensitivity analysis, are discussed. Finally, several future issues that deserve further research are summarized and concluded.     

Combining Inverse Probability Weighting and Multiple Imputation to Improve Robustness of Estimation

Inverse probability weighting (IPW) and multiple imputation are two widely adopted approaches dealing with missing data. The former models the selection probability, and the latter models data distribution. Consistent estimation requires correct specification of corresponding models. Although the augmented IPW method provides an extra layer of protection on consistency, it is usually not sufficient in practice as the true data‐generating process is unknown. This paper proposes a method combining the two approaches in the same spirit of calibration in sampling survey literature. Multiple models for both the selection probability and data distribution can be simultaneously accounted for, and the resulting estimator is consistent if any model is correctly specified. The proposed method is within the framework of estimating equations and is general enough to cover regression analysis with missing outcomes and/or missing covariates. Results on both theoretical and numerical investigation are provided.     

The performance of tests when observations have different variances

It is common to test if there is an effect due to a treatment. The commonly used tests have the assumption that the observations differ in location, and that their variances are the same over the groups. Different variances can arise if the observations being analyzed are means of different numbers of observations on individuals or slopes of growth curves with missing data. This study is concerned with cases in which the unequal variances are known, or known to a constant of proportionality. It examines the performance of the ttest, the Mann–Whitney–Wilcoxon Rank Sum test, the Median test, and the Van der Waerden test under these conditions. The t-test based on the weighted means is the likelihood ratio test under normality and has the usual optimality properties. The other tests are compared to it. One may align and scale the observations by subtracting the mean and dividing by the standard deviation of each point. This leads to other, analogous test statistics based on these adjusted observations. These statistics are also compared. Finally, the regression scores tests are compared to the other procedures.     

Missing covariates in generalized linear models when the missing data mechanism is non-ignorable

We propose a method for estimating parameters in generalized linear models with missing covariates and a non-ignorable missing data mechanism. We use a multinomial model for the missing data indicators and propose a joint distribution for them which can be written as a sequence of one-dimensional conditional distributions, with each one-dimensional conditional distribution consisting of a logistic regression. We allow the covariates to be either categorical or continuous. The joint covariate distribution is also modelled via a sequence of one-dimensional conditional distributions, and the response variable is assumed to be completely observed. We derive the E- and M-steps of the EM algorithm with non-ignorable missing covariate data. For categorical covariates, we derive a closed form expression for the E- and M-steps of the EM algorithm for obtaining the maximum likelihood estimates (MLEs). For continuous covariates, we use a Monte Carlo version of the EM algorithm to obtain the MLEs via the Gibbs sampler. Computational techniques for Gibbs sampling are proposed and implemented. The parametric form of the assumed missing data mechanism itself is not `testable' from the data, and thus the non-ignorable modelling considered here can be viewed as a sensitivity analysis concerning a more complicated model. Therefore, although a model may have `passed' the tests for a certain missing data mechanism, this does not mean that we have captured, even approximately, the correct missing data mechanism. Hence, model checking for the missing data mechanism and sensitivity analyses play an important role in this problem and are discussed in detail. Several simulations are given to demonstrate the methodology. In addition, a real data set from a melanoma cancer clinical trial is presented to illustrate the methods proposed.     

Post-stratification based direct adjustment approach to a missing data problem in clinical trials

In clinical trials we always expect some missing data. If data are missing completely at random, then missing data can be ignored for the purpose of statistical inference. In most situation, however, ignoring missing data will introduce bias. Adjustment is possible for missing data if the missing mechanism is known, which is rare in real problems. Our approach is to estimate directly the mean outcome of each treatment group in the presence of missing data. To this end, we post-stratify all the subjects by the expected value of outcome (or by a variable predictive of the outcome) so that subjects within a stratum may be considered homogeneous with respect to the expected outcome, and assume that subjects within a stratum are missing at random. We apply this post-stratification approach to a recently concluded clinical trial where a high proportion of data are missing and the missingness depends on the same factors affecting the outcome variable. A simulation study shows that the post-stratification approach reduces the bias substantially compared to the naive approach where only non-missing subjects are analyzed.     

Permuting incomplete paired data: a novel exact and asymptotic correct randomization test

Various statistical tests have been developed for testing the equality of means in matched pairs with missing values. However, most existing methods are commonly based on certain distributional assumptions such as normality, 0-symmetry or homoscedasticity of the data. The aim of this paper is to develop a statistical test that is robust against deviations from such assumptions and also leads to valid inference in case of heteroscedasticity or skewed distributions. This is achieved by applying a clever randomization approach to handle missing data. The resulting test procedure is not only shown to be asymptotically correct but is also finitely exact if the distribution of the data is invariant with respect to the considered randomization group. Its small sample performance is further studied in an extensive simulation study and compared to existing methods. Finally, an illustrative data example is analysed.     

Missing data in clinical trials: control‐based mean imputation and sensitivity analysis

In some randomized (drug versus placebo) clinical trials, the estimand of interest is the between‐treatment difference in population means of a clinical endpoint that is free from the confounding effects of “rescue” medication (e.g., HbA1c change from baseline at 24 weeks that would be observed without rescue medication regardless of whether or when the assigned treatment was discontinued). In such settings, a missing data problem arises if some patients prematurely discontinue from the trial or initiate rescue medication while in the trial, the latter necessitating the discarding of post‐rescue data. We caution that the commonly used mixed‐effects model repeated measures analysis with the embedded missing at random assumption can deliver an exaggerated estimate of the aforementioned estimand of interest. This happens, in part, due to implicit imputation of an overly optimistic mean for “dropouts” (i.e., patients with missing endpoint data of interest) in the drug arm. We propose an alternative approach in which the missing mean for the drug arm dropouts is explicitly replaced with either the estimated mean of the entire endpoint distribution under placebo (primary analysis) or a sequence of increasingly more conservative means within a tipping point framework (sensitivity analysis); patient‐level imputation is not required. A supplemental “dropout = failure” analysis is considered in which a common poor outcome is imputed for all dropouts followed by a between‐treatment comparison using quantile regression. All analyses address the same estimand and can adjust for baseline covariates. Three examples and simulation results are used to support our recommendations.     

Inverse Probability Weighting with Missing Predictors of Treatment Assignment or Missingness

Inverse probability weighting (IPW) can deal with confounding in non randomized studies. The inverse weights are probabilities of treatment assignment (propensity scores), estimated by regressing assignment on predictors. Problems arise if predictors can be missing. Solutions previously proposed include assuming assignment depends only on observed predictors and multiple imputation (MI) of missing predictors. For the MI approach, it was recommended that missingness indicators be used with the other predictors. We determine when the two MI approaches, (with/without missingness indicators) yield consistent estimators and compare their efficiencies.We find that, although including indicators can reduce bias when predictors are missing not at random, it can induce bias when they are missing at random. We propose a consistent variance estimator and investigate performance of the simpler Rubin’s Rules variance estimator. In simulations we find both estimators perform well. IPW is also used to correct bias when an analysis model is fitted to incomplete data by restricting to complete cases. Here, weights are inverse probabilities of being a complete case. We explain how the same MI methods can be used in this situation to deal with missing predictors in the weight model, and illustrate this approach using data from the National Child Development Survey.     

Local model uncertainty and incomplete-data bias (with discussion)

Summary.  Problems of the analysis of data with incomplete observations are all too familiar in statistics. They are doubly difficult if we are also uncertain about the choice of model. We propose a general formulation for the discussion of such problems and develop approximations to the resulting bias of maximum likelihood estimates on the assumption that model departures are small. Loss of efficiency in parameter estimation due to incompleteness in the data has a dual interpretation: the increase in variance when an assumed model is correct; the bias in estimation when the model is incorrect. Examples include non-ignorable missing data, hidden confounders in observational studies and publication bias in meta-analysis. Doubling variances before calculating confidence intervals or test statistics is suggested as a crude way of addressing the possibility of undetectably small departures from the model. The problem of assessing the risk of lung cancer from passive smoking is used as a motivating example.     

Imputation of missing variance data using non-linear mixed effects modelling to enable an inverse variance weighted meta-analysis of summary-level longitudinal data: a case study

Missing variances, on the basis of the summary-level data, can be a problem when an inverse variance weighted meta-analysis is undertaken. A wide range of approaches in dealing with this issue exist, such as excluding data without a variance measure, using a function of sample size as a weight and imputing the missing standard errors/deviations. A non-linear mixed effects modelling approach was taken to describe the time-course of standard deviations across 14 studies. The model was then used to make predictions of the missing standard deviations, thus, enabling a precision weighted model-based meta-analysis of a mean pain endpoint over time. Maximum likelihood and Bayesian approaches were implemented with example code to illustrate how this imputation can be carried out and to compare the output from each method. The resultant imputations were nearly identical for the two approaches. This modelling approach acknowledges the fact that standard deviations are not necessarily constant over time and can differ between treatments and across studies in a predictable way.     

Simultaneous Confidence Intervals for Monotone Contrasts of Normal Means

The one-way ANOVA model is considered. The variances are assumed to be either equal but unknown or unequal and unknown. Two-stage procedures for generating simultaneous confidence intervals (SCI) for the class of monotone contrasts of the means are presented. The intervals are of fixed length and independent of the unknown variances.     

Missing data in clinical trials: from clinical assumptions to statistical analysis using pattern mixture models

The need to use rigorous, transparent, clearly interpretable, and scientifically justified methodology for preventing and dealing with missing data in clinical trials has been a focus of much attention from regulators, practitioners, and academicians over the past years. New guidelines and recommendations emphasize the importance of minimizing the amount of missing data and carefully selecting primary analysis methods on the basis of assumptions regarding the missingness mechanism suitable for the study at hand, as well as the need to stress‐test the results of the primary analysis under different sets of assumptions through a range of sensitivity analyses. Some methods that could be effectively used for dealing with missing data have not yet gained widespread usage, partly because of their underlying complexity and partly because of lack of relatively easy approaches to their implementation. In this paper, we explore several strategies for missing data on the basis of pattern mixture models that embody clear and realistic clinical assumptions. Pattern mixture models provide a statistically reasonable yet transparent framework for translating clinical assumptions into statistical analyses. Implementation details for some specific strategies are provided in an Appendix (available online as Supporting Information), whereas the general principles of the approach discussed in this paper can be used to implement various other analyses with different sets of assumptions regarding missing data. Copyright © 2013 John Wiley & Sons, Ltd.     

Identification of the variance components in the general two-variance linear model

Bayesian analyses frequently employ two-stage hierarchical models involving two-variance parameters: one controlling measurement error and the other controlling the degree of smoothing implied by the model's higher level. These analyses can be hampered by poorly identified variances which may lead to difficulty in computing and in choosing reference priors for these parameters. In this paper, we introduce the class of two-variance hierarchical linear models and characterize the aspects of these models that lead to well-identified or poorly identified variances. These ideas are illustrated with a spatial analysis of a periodontal data set and examined in some generality for specific two-variance models including the conditionally autoregressive (CAR) and one-way random effect models. We also connect this theory with other constrained regression methods and suggest a diagnostic that can be used to search for missing spatially varying fixed effects in the CAR model.     

Adjusted estimates for time-to-event endpoints

In the analysis of retrospective data or when interpreting results from a single-arm phase II clinical trial relative to historical data, it is often of interest to show plots summarizing time-to-event outcomes comparing treatment groups. If the groups being compared are imbalanced with respect to factors known to influence outcome, these plots can be misleading and seemingly incompatible with results obtained from a regression model that accounts for these imbalances. We consider ways in which covariate information can be used to obtain adjusted curves for time-to-event outcomes. We first review a common model-based method and then suggest another model-based approach that is not as reliant on model assumptions. Finally, an approach that is partially model free is suggested. Each method is applied to an example from hematopoietic cell transplantation.     

Robustness of a Class of Partial Diallel Cross Designs to the Unavailability of a Complete Block of Observations

Complete and partial diallel cross designs are examined as to their construction and robustness against the loss of a block of observations. A simple generalized inverse is found for the information matrix of the line effects, which allows evaluation of expressions for the variances of the line-effect differences with and without the missing block. A-efficiencies, based on average variances of the elementary contrasts of the line-effects, suggest that these designs are fairly robust. The loss of efficiency is generally less than 10%, but it is shown that specific comparisons might suffer a loss of efficiency of as much as 40%.     

测量误差模型稳健方法及应用研究

回归模型在经济学、生物医学、流行病学、工农业生产等众多领域有着广泛的应用,而在实际数据收集时常常出现无法获得变量的精确数据或全部数据的情况,即常碰到测量误差数据、缺失数据等复杂数据情形。对于回归模型中存在测量误差的情况,如在参数估计时不加以修正,则易产生估计偏差,使得估计精度下降。对于数据缺失情形,如不采取合理的处理方法也会导致模型分析结果不佳。故此,本文研究含有测量误差数据时,解释变量具有随机缺失时的线性测量误差模型和部分线性测量误差模型的稳健参数估计问题。本文提出了一种在测量误差服从拉普拉斯分布时参数的损失修正估计,通过蒙特卡洛模拟和医学研究中的实证分析,显示本文所提的估计方法具有偏差小、精度高、稳健性强的优势。     

Minimum breakdown designs in blocks of size two

In scientific investigations, there are many situations where each two experimental units have to be grouped into a block of size two. For planning such experiments, the variance-based optimality criteria like A-, D- and E-criterion are typically employed to choose efficient designs, if the estimation efficiency of treatment contrasts is primarily concerned. Alternatively, if there are observations which tend to become lost during the experimental period, the robustness criteria against the unavailability of data should be strongly recommended for selecting the planning scheme. In this study, a new criterion, called minimum breakdown criterion, is proposed to quantify the robustness of designs in blocks of size two. Based on the proposed criterion, a new class of robust designs, called minimum breakdown designs, is defined. When various numbers of blocks are missing, the minimum breakdown designs provide the highest probabilities that all the treatment contrasts are estimable. An exhaustive search procedure is proposed to generate such designs. In addition, two classes of uniformly minimum breakdown designs are theoretically verified.     

Missing values in replicated Latin squares

Designs based on any number of replicated Latin squares are examined for their robustness against the loss of up to three observations randomly scattered throughout the design. The information matrix for the treatment effects is used to evaluate the average variances of the treatment differences for each design in terms of the number of missing values and the size of the design. The resulting average variances are used to assess the overall robustness of the designs. In general, there are 16 different situations for the case of three missing values when there are at least three Latin square replicates in the design. Algebraic expressions may be determined for all possible configurations, but here the best and worst cases are given in detail. Numerical illustrations are provided for the average variances, relative efficiencies, minimum and maximum variances and the frequency counts, showing the effects of the missing values for a range of design sizes and levels of replication.     

Evaluation of multiple-imputation procedures for three-mode component models

Three-mode analysis is a generalization of principal component analysis to three-mode data. While two-mode data consist of cases that are measured on several variables, three-mode data consist of cases that are measured on several variables at several occasions. As any other statistical technique, the results of three-mode analysis may be influenced by missing data. Three-mode software packages generally use the expectation–maximization (EM) algorithm for dealing with missing data. However, there are situations in which the EM algorithm is expected to break down. Alternatively, multiple imputation may be used for dealing with missing data. In this study we investigated the influence of eight different multiple-imputation methods on the results of three-mode analysis, more specifically, a Tucker2 analysis, and compared the results with those of the EM algorithm. Results of the simulations show that multilevel imputation with the mode with the most levels nested within cases and the mode with the least levels represented as variables gives the best results for a Tucker2 analysis. Thus, this may be a good alternative for the EM algorithm in handling missing data in a Tucker2 analysis.