Estimating standard error of intra-class correlation coefficients up to three level unbalanced nested clinical trials

ABSTRACT

Very often researchers plan a balanced design for cluster randomization clinical trials in conducting medical research, but unavoidable circumstances lead to unbalanced data. By adopting three or more levels of nested designs, they usually ignore the higher level of nesting and consider only two levels, this situation leads to underestimation of variance at higher levels. While calculating the sample size for three-level nested designs, in order to achieve desired power, intra-class correlation coefficients (ICCs) at individual level as well as higher levels need to be considered and must be provided along with respective standard errors. In the present paper, the standard errors of analysis of variance (ANOVA) estimates of ICCs for three-level unbalanced nested design are derived. To conquer the strong appeal of distributional assumptions, balanced design, equality of variances between clusters and large sample, general expressions for standard errors of ICCs which can be deployed in unbalanced cluster randomization trials are postulated. The expressions are evaluated on real data as well as highly unbalanced simulated data.     

Generalized staggered nested designs for variance components estimation

Staggered nested experimental designs are the most popular class of unbalanced nested designs in practical fields. The most important features of the staggered nested design are that it has a very simple open-ended structure and each sum of squares in the analysis of variance has almost the same degrees of freedom. Based on the features, a class of unbalanced nested designs that is a generalization of the staggered nested design is proposed in this paper. Formulae for the estimation of variance components and their sums are provided. Comparing the variances of the estimators to the staggered nested designs, it is found that some of the generalized staggered nested designs are more efficient than the traditional staggered nested design in estimating some of the variance components and their sums. An example is provided for illustration.     

General formulae for expectations, variances and covariances of the mean squares for staggered nested designs

Staggered nested experimental designs are the most popular class of unbalanced nested designs. Using a special notation which covers the particular structure of the staggered nested design, this paper systematically derives the canonical form for the arbitrary m-factors. Under the normality assumption for every random variable, a vector comprising m canonical variables from each experimental unit is normally independently and identically distributed. Every sum of squares used in the analysis of variance (ANOVA) can be expressed as the sum of squares of the corresponding canonical variables. Hence, general formulae for the expectations, variances and covariances of the mean squares are directly obtained from the canonical form. Applying the formulae, the explicit forms of the ANOVA estimators of the variance components and unbiased estimators of the ratios of the variance components are introduced in this paper. The formulae are easily applied to obtain the variances and covariances of any linear combinations of the mean squares, especially the ANOVA estimators of the variance components. These results are eff ectively applied for the standardization of measurement methods.     

Search for optimal designs in a three stagenested random model

In this paper we define a class of unbalanced designs, denoted by C_k,s,t, for estimating the components of variance in a k-stage nested random effects linear model. This class contains many of the designs proposed in the literature for nested components of variance models. We focus on the three-state model and discuss the determination of locally optimal designs within this class using a systematic computer search. For large sample sizes we show that approximate optimal designs may be obtained using a limit argument combined with numerical optimization. A comparison of our designs with previously published designs suggests that, in many cases, our designs result in substantial gains in efficiency.     

Estimation of variance components in staggered nested designs

SUMMARY Variance components are estimated by two different methods for a general p stage random-effects staggered nested design. In addition to estimation from an analysis of variance, a new approach is introduced. The main features of this new technique are its simplicity and its ability to yield non-negative estimates of the variance components. The performances of the two procedures are compared using simulation and the meansquared-error criterion.     

The mad estimator: when is it non-linear? applications to two-way design models

The mean absolute deviation (MAD) estimator has recently received a great deal of attention as applied to full-rank linear regression models. This paper provides a necessary and sufficient condition for the MAD estimator to be a non-linear estimator, in which case conditions for the variance of the MAD estimator to be larger or smaller than those for OLS are, in general, unknown. The non-linearity of the MAD estimator is examined for several two-way designs; in particular (1) randomized block design (2) two-way nested design (3) two-way classification with interaction and (4) partially balanced incomplete block design     

The three-fold nested random effects model

Estimation of the variance components and the mean of the balanced and unbalanced threefold nested design is considered. The relative merits of the following procedures are evaluated: Analysis of variance (ANOVA), maximum likelihood (ML), restricted maximum likelihood (REML), and minimum variance quadratic unbiased estimator (MIVQUE). A new procedure called the weighted analysis of means (WAM) estimator which utilizes prior information on the variance components is proposed. It is found to have optimum properties similar to the REML and MIVQUE, and it is also computationally simpler. For the mean, the overall sample average, grand mean, unweighted mean, and generalized least-squares (GLS) estimator with its weights obtained from the above estimators for the variance components are considered. Comparisons of the above procedures for the variance components and the mean are made from exact expressions for the biases and mean square errors (MSEs) of the estimators and from empirical investigations.     

Improved estimation of variance components in mixed models

Taking Albert's (1976) formulation of a mixed model ANOVA, we consider improved estimation of the variance components for balanced designs under squared error loss. Two approaches are presented. One extends the ideas of Stein (1964), The other is developed from the fact that variance components can be expressed as linear combinations of chi-square scale parameters. Encouraging simulation results are presented.     

Random effects models for count data

Random effects models are considered for count data obtained in a cross or nested classification. The main feature of the proposed models is the use of the additive effects on the original scale in contrast to the commonly used log scale. The rationale behind this approach is given. The estimation of variance components is based on the usual mean square approach. Directly analogous results to those from the analysis of variance models for continuous data are obtained. The usual Poisson dispersion test procedure can be used not only to test for no overall random effects but also to assess the adequacy of the model. Individual variance component can be tested by using the usual F-test. To get a reliable estimate, a large number of factor levels seem to be required.     

Additional comparisons of designs to estimate variance components in a two-way classification model

In this paper, the research of Muse and Anderson is extended to include additional comparisons of designs, featuring planned unbalance, for the estimation of variance components in a two-way cross classification model. Their results are extended to Include the following: (i) a small sample study of the original off-diagonal (OD) design and (ii) an asymptotic maximum likelihood investigation of three modifica-tions of the balanced diagonal rectangles (BD) design and one modification of the 01) design to permit the estimation of row, column, interaction and error variance components. Also a general iterative least.     

Some Recent Developments in the Analysis and Design of Quantitative Genetic Experiments

The design and analysis of experiments to estimate heritability when data are available on both parents and progeny and the offspring have a hierarchical structure is considered. The method of analysis is related to a multivariate analysis of variance and to weighted least squares. It is shown that genetical theory gives a simple interpretation of both maximum likelihood (ML) and Rao's minimum norm quadratic unbiased (MINQUE) methods of estimation of variance components in unbalanced designs.     

On the recovery of intra- and interblock information in n-ary designs

This note presents an extension of Q-method of analysis for binary designs given by Rao (1956) to n-ary balanced and partially balanced block designs. Here a linked n-ary block (LNB) design is defined as the dual of balanced n-ary (BN) design. Having a note on Yates’ (1939, 1940) method of P-analysis, we further extend the expressions for binary linked block (LB) designs given by Rao (1956) to linked n-ary block (LNB) designs which admit easy estimation of parameters for these type of all n-ary designs.     

Graphical technique for comparing designs for random models

Methods for comparing designs for a random (or mixed) linear model have focused primarily on criteria based on single-valued functions. In general, these functions are difficult to use, because of their complex forms, in addition to their dependence on the model's unknown variance components. In this paper, a graphical approach is presented for comparing designs for random models. The one-way model is used for illustration. The proposed approach is based on using quantiles of an estimator of a function of the variance components. The dependence of these quantiles on the true values of the variance components is depicted by plotting the so-called quantile dispersion graphs (QDGs), which provide a comprehensive picture of the quality of estimation obtained with a given design. The QDGs can therefore be used to compare several candidate designs. Two methods of estimation of variance components are considered, namely analysis of variance and maximum-likelihood estimation.     

Robust estimation of variance components

New robust estimates for variance components are introduced. Two simple models are considered: the balanced one-way classification model with a random factor and the balanced mixed model with one random factor and one fixed factor. However, the method of estimation proposed can be extended to more complex models. The new method of estimation we propose is based on the relationship between the variance components and the coefficients of the least-mean-squared-error predictor between two observations of the same group. This relationship enables us to transform the problem of estimating the variance components into the problem of estimating the coefficients of a simple linear regression model. The variance-component estimators derived from the least-squares regression estimates are shown to coincide with the maximum-likelihood estimates. Robust estimates of the variance components can be obtained by replacing the least-squares estimates by robust regression estimates. In particular, a Monte Carlo study shows that for outlier-contaminated normal samples, the estimates of variance components derived from GM regression estimates and the derived test outperform other robust procedures.     

Interval estimation of the mean in a two-stage nested model

The problem of constructing confidence intervals to estimate the mean in a two-stage nested model is considered. Several approximate intervals, which are based on both linear and nonlinear estimators of the mean are investigated. In particular, the method of bootstrap is used to correct the bias in the ‘usual’ variance of the nonlinear estimators. It is found that the intervals based on the nonlinear estimators did not achieve the nominal confidence coefficient for designs involving a small number of groups. Further, it turns out that the intervals are generally conservative, especially at small values of the intraclass correlation coefficient, and that the intervals based on the nonlinear estimators are more conservative than those based on the linear estimators. Compared with the others, the intervals based on the unweighted mean of the group means performed well in terms of coverage and length. For small values of the intraclass correlation coefficient, the ANOVA estimators of the variance components are recommended, otherwise the unweighted means estimator of the between groups variance component should be used. If one is fortunate enough to have control over the design, he is advised to increase the number of groups, as opposed to increasing group sizes, while avoiding groups of size one or two.     

Asymptotic posterior distributions for balanced nested multi-way models with a large number of main effect levels

We derive the explicit form for the asymptotic posterior distribution of the balanced nested multi-way variance components model with the assumption that the number of the main factor levels tends to infinity while the number of any specific effect factor levels remains fixed. Under the multi-way model, we also study two different parameterizations, called the standard and the centering, and the relationship between certain quadratic forms of random effects and the variance component parameters. The asymptotic results are illustrated by a three-way model and by a simulation study under a two-way case.     

Optimal partially balanced nested row-column designs

A partially balanced nested row-column design, referred to as PBNRC, is defined as an arrangement of v treatments in b p × q blocks for which, with the convention that p q, the information matrix for the estimation of treatment parameters is equal to that of the column component design which is itself a partially balanced incomplete block design. In this paper, previously known optimal incomplete block designs, and row-column and nested row-column designs are utilized to develop some methods of constructing optimal PBNRC designs. In particular, it is shown that an optimal group divisible PBNRC design for v = mn kn treatments in p × q blocks can be constructed whenever a balanced incomplete block design for m treatments in blocks of size k each and a group divisible PBNRC design for kn treatments in p × q blocks exist. A simple sufficient condition is given under which a group divisible PBNRC is Ψ_f-better for all f> 0 than the corresponding balanced nested row-column designs having binary blocks. It is also shown that the construction techniques developed particularly for group divisible designs can be generalized to obtain PBNRC designs based on rectangular association schemes.     

Food shelf life: estimation and optimal design

Shelf life is a specified percentile of the time-until-spoilage distribution of a food product. This paper investigates statistical properties of various estimators of shelf life and develops a genetic algorithm for finding near-optimal staggered designs for estimation of shelf life. MLEs and their associated confidence intervals for shelf life have smaller bias, better performance, and better coverage than the corresponding ad hoc regression-based estimates. However, performance of MLEs for common sample sizes must be evaluated by simulation. The genetic algorithm, coded as an SAS macro, searched the design space well and generated near-optimal designs as measured by improvement to a simulation-based performance measure.     

Simulation-based model comparison methodology with application to road accident models

This article assumes the goal of proposing a simulation-based theoretical model comparison methodology with application to two time series road accident models. The model comparison exercise helps to quantify the main differences and similarities between the two models and comprises of three main stages: (1) simulation of time series through a true model with predefined properties; (2) estimation of the alternative model using the simulated data; (3) sensitivity analysis to quantify the effect of changes in the true model parameters on alternative model parameter estimates through analysis of variance, ANOVA. The proposed methodology is applied to two time series road accident models: UCM (unobserved components model) and DRAG (Demand for Road Use, Accidents and their Severity). Assuming that the real data-generating process is the UCM, new datasets approximating the road accident data are generated, and DRAG models are estimated using the simulated data. Since these two methodologies are usually assumed to be equivalent, in a sense that both models accurately capture the true effects of the regressors, we are specifically addressing the modeling of the stochastic trend, through the alternative model. Stochastic trend is the time-varying component and is one of the crucial factors in time series road accident data. Theoretically, it can be easily modeled through UCM, given its modeling properties. However, properly capturing the effect of a non-stationary component such as stochastic trend in a stationary explanatory model such as DRAG is challenging. After obtaining the parameter estimates of the alternative model (DRAG), the estimates of both true and alternative models are compared and the differences are quantified through experimental design and ANOVA techniques. It is observed that the effects of the explanatory variables used in the UCM simulation are only partially captured by the respective DRAG coefficients. This a priori, could be due to multicollinearity but the results of both simulation of UCM data and estimating of DRAG models reveal that there is no significant static correlation among regressors. Moreover, in fact, using ANOVA, it is determined that this regression coefficient estimation bias is caused by the presence of the stochastic trend present in the simulated data. Thus, the results of the methodological development suggest that the stochastic component present in the data should be treated accordingly through a preliminary, exploratory data analysis.     

On the difference between ML and REML estimators in the modelling of multivariate longitudinal data

A random effects model is examined in the multivariate setting where more than one characteristics are measured at each time point. ML and REML estimators are obtained under the restriction that estimates of variance matrices being at least p.s.d. It is shown that REML has greater probability of giving full rank estimates of variance components matrices but as regards the efficiency in the estimation of the location parameter, correct specification of the number of random effects is needed. In general, REML provides larger estimates of variance of model parameters than ML.