Designing field experiments which are subject to representation bias

The term 'representation bias' is used to describe the disparities that exist between treatment effects estimated from field experiments, and those effects that would be seen if treatments were used in the field. In this paper we are specifically concerned with representation bias caused by disease inoculum travelling between plots, or out of the experimental area altogether. The scope for such bias is maximized in the case of airborne spread diseases. This paper extends the work of Deardon et al. (2004), using simulation methods to explore the relationship between design and representation bias. In doing so, we illustrate the importance of plot size and spacing, as well as treatment-to-plot allocation. We examine a novel class of designs, incomplete column designs, to develop an understanding of the mechanisms behind representation bias. We also introduce general methods of designing field trials, which can be used to limit representation bias by carefully controlling treatment to block allocation in both incomplete column and incomplete randomized block designs. Finally, we show how the commonly used practice of sampling from the centres of plots, rather than entire plots, can also help to control representation bias.     

NEIGHBOUR ANALYSIS WITH ADJUSTMENT FOR INTERPLOT COMPETITION

In field experiments involving a large number of experimental plots, a neighbour analysis can be used to control environmental variation by estimating the trend within blocks. The effect of interplot competition is another important source of variation which has an influence on the estimation of treatment contrasts. To reduce the effect of the variation from these sources and to improve the precision of comparison between treatments, a spatial model is proposed for incorporating both trend effect and interplot competition. It is a modification to the residual maximum likelihood neighbour analysis of Gleeson & Cullis (1987) using the two neighbouring treatment effects to estimate interplot competition. A real example is used to illustrate this methodology. The results indicate that the extended model gives no appreciable difference in standard error of mean differences compared with the model taking into account the trend effect only. However, the rankings of estimated treatment means do differ. More research using both real and simulated data is required before such models that incorporate trend and competition effects can be confidently recommended.     

Sample-based Maximum Likelihood Estimation of the Autologistic Model

New recursive algorithms for fast computation of the normalizing constant for the autologistic model on the lattice make feasible a sample-based maximum likelihood estimation (MLE) of the autologistic parameters. We demonstrate by sampling from 12 simulated 420×420 binary lattices with square lattice plots of size 4×4, …, 7×7 and sample sizes between 20 and 600. Sample-based results are compared with ‘benchmark’ MCMC estimates derived from all binary observations on a lattice. Sample-based estimates are, on average, biased systematically by 3%–7%, a bias that can be reduced by more than half by a set of calibrating equations. MLE estimates of sampling variances are large and usually conservative. The variance of the parameter of spatial association is about 2–10 times higher than the variance of the parameter of abundance. Sample distributions of estimates were mostly non-normal. We conclude that sample-based MLE estimation of the autologistic parameters with an appropriate sample size and post-estimation calibration will furnish fully acceptable estimates. Equations for predicting the expected sampling variance are given.     

Estimation of land equivalent ratios

The estimation of the land equivalent ratios is proposed to be done by the (sum of) ratios of means of intercrop yield to sole crop yield. The bias and standard error of the estimates are obtained for large samples. Comparisons of the cropping systems have been made on the basis of these estimates and illustrated with field data.     

A Method for Ascertaining and Controlling Representation Bias in Field Trials for Airborne Plant Pathogens

The basic premise of running a field trial is that the estimates of treatment effects obtained are representative of how the different treatments will perform in the field. The disparities between the treatment effects observed experimentally, and those that would be observed were the treatments applied to the field, we term 'representation bias.' When looking at field trials testing the efficacies of treatment sprays on plant pathogens, representation bias can be caused by positive and negative inter-plot interference. The potential for such effects will be greatest when looking at pathogens that are dispersed by wind. In this paper, a computer simulation that simulates plant disease dispersal under such conditions is described. This program is used to quantify the amount of representation bias occurring in various experimental situations. Through this, the relationships between field design parameters and representation bias are explored, and the importance of plot dimension and spacing, as well as treatment to plot allocation, emphasized.     

Estimating crop yield via Gaussian quadrature

The present study proposes a method to estimate the yield of a crop. The proposed Gaussian quadrature (GQ) method makes it possible to estimate the crop yield from a smaller subsample. Identification of plots and corresponding weights to be assigned to the yield of plots comprising a subsample is done with the help of information about the full sample on certain auxiliary variables relating to biometrical characteristics of the plant. Computational experience reveals that the proposed method leads to about 78% reduction in sample size with absolute percentage error of 2.7%. Performance of the proposed method has been compared with that of random sampling on the basis of the values of average absolute percentage error and standard deviation of yield estimates obtained from 40 samples of comparable size. Interestingly, average absolute percentage error as well as standard deviation is considerably smaller for the GQ estimates than for the random sample estimates. The proposed method is quite general and can be applied for other crops as well-provided information on auxiliary variables relating to yield contributing biometrical characteristics is available.     

Models for potentially biased evidence in meta-analysis using empirically based priors

Summary.  We present models for the combined analysis of evidence from randomized controlled trials categorized as being at either low or high risk of bias due to a flaw in their conduct. We formulate a bias model that incorporates between-study and between-meta-analysis heterogeneity in bias, and uncertainty in overall mean bias. We obtain algebraic expressions for the posterior distribution of the bias-adjusted treatment effect, which provide limiting values for the information that can be obtained from studies at high risk of bias. The parameters of the bias model can be estimated from collections of previously published meta-analyses. We explore alternative models for such data, and alternative methods for introducing prior information on the bias parameters into a new meta-analysis. Results from an illustrative example show that the bias-adjusted treatment effect estimates are sensitive to the way in which the meta-epidemiological data are modelled, but that using point estimates for bias parameters provides an adequate approximation to using a full joint prior distribution. A sensitivity analysis shows that the gain in precision from including studies at high risk of bias is likely to be low, however numerous or large their size, and that little is gained by incorporating such studies, unless the information from studies at low risk of bias is limited. We discuss approaches that might increase the value of including studies at high risk of bias, and the acceptability of the methods in the evaluation of health care interventions.     

Efficient circular neighbour designs for spatial interference model

We consider circular block designs for field-trials when there are two-sided spatial interference between neighbouring plots of the same blocks. The parameter of interest is total effects that is the sum of direct effect of treatment and neighbour effects, which correspond to the use of a single treatment in the whole field. We determine universally optimal approximate designs. When the number of blocks may be large, we propose efficient exact designs generated by a single sequence of treatment. We also give efficiency factors of the usual binary block neighbour balanced designs which can be used when the number of blocks is small.     

Econometrics exams and round numbers: Use or misuse of indirect estimation methods?

The use of Monte Carlo methods to generate exam datasets is nowadays a well-established practice among econometrics and statistics examiners all over the world. Its advantages are well known: providing each student a different data set ensures that estimates are actually computed individually, rather than copied from someone sitting nearby. The method however has a major fault: initial “random errors,” such as mistakes in downloading the assigned dataset, might generate downward bias in student evaluation. We propose a set of calibration algorithms, typical of indirect estimation methods, that solve the issue of initial “random errors” and reduce evaluation bias. Ensuring round initial estimates of the parameters for each individual dataset, our calibration procedures allow the students to determine if they have started the exam correctly. When initial estimates are not round numbers, this random error in the initial stage of the exam can be corrected for immediately, thus reducing evaluation bias. The procedure offers the further advantage of rounding markers’ life by allowing them to check round numbers answers only, rather than lists of numbers with many decimal digits¹.     

Two-step jackknife bias reduction for logistic regression mles

Maximum likelihood estimates (MLEs) for logistic regression coefficients are known to be biased in finite samples and consequently may produce misleading inferences. Bias adjusted estimates can be calculated using the first-order asymptotic bias derived from a Taylor series expansion of the log likelihood. Jackknifing can also be used to obtain bias corrected estimates, but the approach is computationally intensive, requiring an additional series of iterations (steps) for each observation in the dataset.Although the one-step jackknife has been shown to be useful in logistic regression diagnostics and i the estimation of classification error rates, it does not effectively reduce bias. The two-step jackknife, however, can reduce computation in moderate-sized samples, provide estimates of dispersion and classification error, and appears to be effective in bias reduction. Another alternative, a two-step closed-form approximation, is found to be similar to the Taylo series method in certain circumstances. Monte Carlo simulations indicate that all the procedures, but particularly the multi-step jackknife, may tend to over-correct in very small samples. Comparison of the various bias correction proceduresin an example from the medical literature illustrates that bias correction can have a considerable impact on inference     

Detection of biomass change in a Norwegian mountain forest area using small footprint airborne laser scanner data

Different approaches for estimation of change in biomass between two points in time by means of airborne laser scanner data were tested. Both field and laser data were collected at two occasions on 52 sample plots in a mountain forest in southeastern Norway. In the first approach, biomass change was estimated as the difference between predicted biomass for the two measurement occasions. Joint models for the biomass at both occasions were fitted using different height and density variables from laser data as explanatory variables. The second approach modelled the observed change directly using the change in different variables extracted from the laser data as explanatory variables. In the third approach we modelled the relative change in biomass. The explanatory variables were also expressed as relative change between measurement occasions. In all approaches we allowed spline terms to be entered. We also investigated the aptness of models for which the residual variance was modeled by allowing it to be proportional to the area of the plot on which biomass was assessed. All alternative models were initially assessed by AIC. All models were also evaluated by estimating biomass change on the model development data. This evaluation indicated that the two direct approaches (approach 2 and 3) were better than relying on modeling biomass at both occasions and taking change as the difference between biomass estimates. Approach 2 seemed to be slightly better than approach 3 based on assessments of bias in the evaluation.     

Performance of the empirical Bayes estimator for fixed parameters

When the unbiased estimators of a set of parameters are independently and normally distributed, the Empirical Bayes Estimator (EB) for each of the parameters depends on all the parameters. When these parameters are considered to be fixed, Rao and Shinozaki (1978) [7] compared the mean square error (MSE) of this estimator for an individual parameter with the variance of its unbiased estimator, and cautioned that its bias may be large. In this article, the conditions required for (a) the MSE of the EB to be smaller than the variance of the unbiased estimator and (b) at the same time, for its bias to be smaller than a specified fraction of the square root of the MSE are evaluated. To satisfy these conditions, critical limits for the difference of the parameter from the average of all the parameters and the sum of such differences over all the parameters are determined. As an illustration, for the daily inpatient hospital expenses in the Metropolitan Statistical Areas (MSAs) of 15 states in the US, the sample means and EBs are compared through the estimates of these limits.     

A hierarchical modelling approach to combining environmental data at different scales

Summary. Long-transported air pollution in Europe is monitored by a combination of a highly complex mathematical model and a limited number of measurement stations. The model predicts deposition on a 150 km × 150 km square grid covering the whole of the continent. These predictions can be regarded as spatial averages, with some spatially correlated model error. The measurement stations give a limited number of point estimates, regarded as error free. We combine these two sources of data by assuming that both are observations of an underlying true process. This true deposition is made up of a smooth deterministic trend, due to gradual changes in emissions over space and time, and two stochastic components. One is non- stationary and correlated over long distances; the other describes variation within a grid square. Our approach is through hierarchical modelling with predictions and measurements being independent conditioned on the underlying non-stationary true deposition. We assume Gaussian processes and calculate maximum likelihood estimates through numerical optimization. We find that the variation within a grid square is by far the largest component of the variation in the true deposition. We assume that the mathematical model produces estimates of the mean over an area that is approximately equal to a grid square, and we find that it has an error that is similar to the long-range stochastic component of the true deposition, in addition to a large bias.     

Random regression models for human immunodeficiency virus ribonucleic acid data subject to left censoring and informative drop-outs

Objectives in many longitudinal studies of individuals infected with the human immunodeficiency virus (HIV) include the estimation of population average trajectories of HIV ribonucleic acid (RNA) over time and tests for differences in trajectory across subgroups. Special features that are often inherent in the underlying data include a tendency for some HIV RNA levels to be below an assay detection limit, and for individuals with high initial levels or high ranges of change to drop out of the study early because of illness or death. We develop a likelihood for the observed data that incorporates both of these features. Informative drop-outs are handled by means of an approach previously published by Schluchter. Using data from the HIV Epidemiology Research Study, we implement a maximum likelihood procedure to estimate initial HIV RNA levels and slopes within a population, compare these parameters across subgroups of HIV-infected women and illustrate the importance of appropriate treatment of left censoring and informative drop-outs. We also assess model assumptions and consider the prediction of random intercepts and slopes in this setting. The results suggest that marked bias in estimates of fixed effects, variance components and standard errors in the analysis of HIV RNA data might be avoided by the use of methods like those illustrated.     

On totally balanced block designs for competition effects

Competition between neighbouring units in field experiments is a serious source of bias. The study of a competing situation needs construction of an environment in which it can happen and the competing units have to appear in a predetermined pattern. This paper describes methods of constructing incomplete block designs balanced for neighbouring competition effects. The designs obtained are totally balanced in the sense that all the effects, direct and neighbours, are estimated with the same variance. The efficiency of these designs has been computed as compared to a complete block design balanced for neighbours and a catalogue has also been prepared.     

Bias in the last observation carried forward method under informative dropout

Subject dropout is an inevitable problem in longitudinal studies. It makes the analysis challenging when the main interest is the change in outcome from baseline to endpoint of study. The last observation carried forward (LOCF) method is a very common approach for handling this problem. It assumes that the last measured outcome is frozen in time after the point of dropout, an unrealistic assumption given any time trends. Though existence and direction of the bias can sometimes be anticipated, the more important statistical question involves the actual magnitude of the bias and this requires computation. This paper provides explicit expressions for the exact bias in the LOCF estimates of mean change and its variance when the longitudinal data follow a linear mixed-effects model with linear time trajectories. General dropout patterns are considered that may depend on treatment group, subject-specific trajectories and follow different time to dropout distributions. In our case studies, the magnitude of bias for mean change estimators linearly increases as time to dropout decreases. The bias depends heavily on the dropout interval. The variance term is always underestimated.     

An application of the mixed-effects model and pattern mixture model to treatment groups with differential missingness suspected not-missing-at-random

Likelihood-based, mixed-effects models for repeated measures (MMRMs) are occasionally used in primary analyses for group comparisons of incomplete continuous longitudinal data. Although MMRM analysis is generally valid under missing-at-random assumptions, it is invalid under not-missing-at-random (NMAR) assumptions. We consider the possibility of bias of estimated treatment effect using standard MMRM analysis in a motivational case, and propose simple and easily implementable pattern mixture models within the framework of mixed-effects modeling, to handle the NMAR data with differential missingness between treatment groups. The proposed models are a new form of pattern mixture model that employ a categorical time variable when modeling the outcome and a continuous time variable when modeling the missingness-data patterns. The models can directly provide an overall estimate of the treatment effect of interest using the average of the distribution of the missingness indicator and a categorical time variable in the same manner as MMRM analysis. Our simulation results indicate that the bias of the treatment effect for MMRM analysis was considerably larger than that for the pattern mixture model analysis under NMAR assumptions. In the case study, it would be dangerous to interpret only the results of the MMRM analysis, and the proposed pattern mixture model would be useful as a sensitivity analysis for treatment effect evaluation.     

Selection bias for treatments with positive Phase 2 results

In drug development, treatments are most often selected at Phase 2 for further development when an initial trial of a new treatment produces a result that is considered positive. This selection due to a positive result means, however, that an estimator of the treatment effect, which does not take account of the selection is likely to over‐estimate the true treatment effect (ie, will be biased). This bias can be large and researchers may face a disappointingly lower estimated treatment effect in further trials. In this paper, we review a number of methods that have been proposed to correct for this bias and introduce three new methods. We present results from applying the various methods to two examples and consider extensions of the examples. We assess the methods with respect to bias of estimation of the treatment effect and compare the probabilities that a bias‐corrected treatment effect estimate will exceed a decision threshold. Following previous work, we also compare average power for the situation where a Phase 3 trial is launched given that the bias‐corrected observed Phase 2 treatment effect exceeds a launch threshold. Finally, we discuss our findings and potential application of the bias correction methods.     

New modified moment estimators for the two-parameter weighted Lindley distribution

We propose a modification of the moment estimators for the two-parameter weighted Lindley distribution. The modification replaces the second sample moment (or equivalently the sample variance) by a certain sample average which is bounded on the unit interval for all values in the sample space. In this method, the estimates always exist uniquely over the entire parameter space and have consistency and asymptotic normality over the entire parameter space. The bias and mean squared error of the estimators are also examined by means of a Monte Carlo simulation study, and the empirical results show the small-sample superiority in addition to the desirable large sample properties. Monte Carlo simulation study showed that the proposed modified moment estimators have smaller biases and smaller mean-square errors than the existing moment estimators and are compared favourably with the maximum likelihood estimators in terms of bias and mean-square error. Three illustrative examples are finally presented.     

An Approach for Estimating Causal Effects in Randomized Trials with Noncompliance

We developed methods for estimating the causal risk difference and causal risk ratio in randomized trials with noncompliance. The developed estimator is unbiased under the assumption that biases due to noncompliance are identical between both treatment arms. The biases are defined as the difference or ratio between the expectations of potential outcomes for a group that received the test treatment and that for the control group in each randomly assigned group. Although the instrumental variable estimator yields an unbiased estimate under a sharp null hypothesis but may yield a biased estimate under a non-null hypothesis, the bias of the developed estimator does not depend on whether this hypothesis holds. Then the estimate of the causal effect from the developed estimator may have a smaller bias than that from the instrumental variable estimator when the treatment effect exists. There is not yet a standard method for coping with noncompliance, and thus it is important to evaluate estimates under different assumptions. The developed estimator can serve this purpose. Its application to a field trial for coronary heart disease is provided.