A class of treatment assignment rules for sequential experiments

In an experiment to compare K(<2) treatments, suppose that eligible subjects arrive at an experimental site sequentially and must be treated immediately. In this paper, we assume that the size of the experiment cannot be predetermined and propose and analyze a class of treatment assignment rules which offer compromises between the complete randomization and the perfect balance schemes, A special case of these assignment rules is thoroughly investigated and is featured in the numerical compu-tations. For practical use, a method of implementation of this special rule is provided.     

Rank regression in order restricted randomised designs

This paper uses order restricted randomised design (ORRD) to create a judgment ranked blocking factor based on available subjective information in a small set of experimental units (EUs). The design then performs a carefully designed randomisation scheme with certain restriction to assign the treatment levels to EUs across these subjective judgment blocks. Such an assignment induces positive dependence among within-set units, and the restrictions on the randomisation translate this positive dependence into a variance reduction technique. We provide a unified theory to analyse the data sets collected from an ORRD. The analysis uses the general framework of rank regression methodology in linear models, with some modification to our randomisation scheme, to estimate regression parameter and to test general linear hypotheses. It is shown that the estimators and test statistics have limiting normal and chi-square distributions regardless the quality of ranking information. A simulation study shows that the asymptotic results remain valid even for relatively small sample sizes. The proposed tests are applied to a clinical trial data set.     

Randomization of neighbour balanced generalized Youden designs

If a crossover design with more than two treatments is carryover balanced, then the usual randomization of experimental units and periods would destroy the neighbour structure of the design. As an alternative, Bailey [1985. Restricted randomization for neighbour-balanced designs. Statist. Decisions Suppl. 2, 237–248] considered randomization of experimental units and of treatment labels, which leaves the neighbour structure intact. She has shown that, if there are no carryover effects, this randomization validates the row–column model, provided the starting design is a generalized Latin square. We extend this result to generalized Youden designs where either the number of experimental units is a multiple of the number of treatments or the number of periods is equal to the number of treatments. For the situation when there are carryover effects we show for so-called totally balanced designs that the variance of the estimates of treatment differences does not change in the presence of carryover effects, while the estimated variance of this estimate becomes conservative.     

On the efficiency of some non-orthogonal split-plot×split-block designs with control treatments

Many split-plot×split-block (SPSB) type experiments used in agriculture, biochemistry or plant protection are designed to study new crop plant cultivars or chemical agents. In these experiments it is usually very important to compare test treatments with the so-called control treatments. It happens yet that experimental material is limited and it does not allow using a complete (orthogonal) SPSB design. In the paper we propose a non-orthogonal SPSB design for consideration. Two cases of the design are presented here, i.e. when its incompleteness is connected with a crossed treatment structure only or with a nested treatment structure only. It is assumed the factors' levels connected with the incompleteness of the design are split into two groups: a set of test treatments and a set of control treatments. The method of constructions involves applying augmented block designs for some factors' levels. In a modelling data obtained from such experiments the structure of experimental material and appropriate randomization scheme of the different kinds of units before they enter the experiment are taken into account. With respect to the analysis of the obtained randomization model the approach typical to the multistratum experiments with orthogonal block structure is adapted. The proposed statistical analysis of linear model obtained includes estimation of parameters, testing general and particular hypotheses defined by the (basic) treatment contrasts with special reference to the notion of general balance.     

Two-sample post-stratified or subgroup analysis with restricted randomization rules

In a clinical trial to compare two treatments, subjects may be allocated sequentially to treatment groups by a restricted randomization rule. Suppose that at the end of the trial, the investigator is interested in a post-stratified or subgroup analysis with respect to a particular demographic or clinical factor which was not selected prior to the trial for stratified randomization. Under a randomization model, large sample theory of two-sample post-stratified permutational tests is developed with a broad class of restricted randomization treatment allocation rules. The test procedures proposed here are illustrated with a real-life example. The results of this example indicate that it is not always possible to ignore the treatment rule used in the trial in the design-based analysis.     

Randomization tests for small samples: an application for genetic expression data

Summary. An advantage of randomization tests for small samples is that an exact P -value can be computed under an additive model. A disadvantage with very small sample sizes is that the resulting discrete distribution for P -values can make it mathematically impossible for a P -value to attain a particular degree of significance. We investigate a distribution of P -values that arises when several thousand randomization tests are conducted simultaneously using small samples, a situation that arises with microarray gene expression data. We show that the distribution yields valuable information regarding groups of genes that are differentially expressed between two groups: a treatment group and a control group. This distribution helps to categorize genes with varying degrees of overlap of genetic expression values between the two groups, and it helps to quantify the degree of overlap by using the P -value from a randomization test. Moreover, a statistical test is available that compares the actual distribution of P -values with an expected distribution if there are no genes that are differentially expressed. We demonstrate the method and illustrate the results by using a microarray data set involving a cell line for rheumatoid arthritis. A small simulation study evaluates the effect that correlated gene expression levels could have on results from the analysis.     

Minimum Size Survival Analysis Sampling Plans for Comparing Multiple Treatment Groups to a Single Control Group

We develop a sample size methodology that achieves specified Type-1 and Type-2 error rates when comparing the survivor functions of multiple treatment groups versus a control group. The designs will control family-wise Type-1 error rate. We assume the family of Weibull distributions adequately describes the underlying survivor functions, and we separately consider three of the most common study scenarios: (a) complete samples; (b) Type-1 censoring with a common censoring time; and (c) Type-1 censoring with an accrual period. A mice longevity study comparing the effect on survival of multiple low-calorie diets is used to motivate our work on this problem.     

Subject‐level matching for imbalance in cluster randomized trials with a small number of clusters

In a cluster randomized controlled trial (RCT), the number of randomized units is typically considerably smaller than in trials where the unit of randomization is the patient. If the number of randomized clusters is small, there is a reasonable chance of baseline imbalance between the experimental and control groups. This imbalance threatens the validity of inferences regarding post‐treatment intervention effects unless an appropriate statistical adjustment is used. Here, we consider application of the propensity score adjustment for cluster RCTs. For the purpose of illustration, we apply the propensity adjustment to a cluster RCT that evaluated an intervention to reduce suicidal ideation and depression. This approach to adjusting imbalance had considerable bearing on the interpretation of results. A simulation study demonstrates that the propensity adjustment reduced well over 90% of the bias seen in unadjusted models for the specifications examined. Copyright © 2013 John Wiley & Sons, Ltd.     

Learning causal structure from mixed data with missing values using Gaussian copula models

We consider the problem of causal structure learning from data with missing values, assumed to be drawn from a Gaussian copula model. First, we extend the ‘Rank PC’ algorithm, designed for Gaussian copula models with purely continuous data (so-called nonparanormal models), to incomplete data by applying rank correlation to pairwise complete observations and replacing the sample size with an effective sample size in the conditional independence tests to account for the information loss from missing values. When the data are missing completely at random (MCAR), we provide an error bound on the accuracy of ‘Rank PC’ and show its high-dimensional consistency. However, when the data are missing at random (MAR), ‘Rank PC’ fails dramatically. Therefore, we propose a Gibbs sampling procedure to draw correlation matrix samples from mixed data that still works correctly under MAR. These samples are translated into an average correlation matrix and an effective sample size, resulting in the ‘Copula PC’ algorithm for incomplete data. Simulation study shows that: (1) ‘Copula PC’ estimates a more accurate correlation matrix and causal structure than ‘Rank PC’ under MCAR and, even more so, under MAR and (2) the usage of the effective sample size significantly improves the performance of ‘Rank PC’ and ‘Copula PC.’ We illustrate our methods on two real-world datasets: riboflavin production data and chronic fatigue syndrome data.

     

An extreme null distribution approach to the problem of paired comparisons

David (1963) and Davidson & Farquhar(1976) contain extensive bibliographies of proposed approaches to problems involving paired comparisons. However, each of the discussed methods that is based on a hypothesis test, relies heavily on the assumption that all paired comparisons are made independently. In this paper we eliminate this assumption and develop a new procedure based on an adaptation of a statistic considered by Kendall & Babington Smith (1940). We show that their original test procedure substantially underestimates the true significance level if the comparisons are not made independently. Our modification utilizes the approach developed in Costello & Wolfe (1985) for the problem of agreement between two groups of judges and relies heavily on computer-generated tables.     

Propensity score matched augmented controls in randomized clinical trials: A case study

Existing statutes in the United States and Europe require manufacturers to demonstrate evidence of effectiveness through the conduct of adequate and well‐controlled studies to obtain marketing approval of a therapeutic product. What constitutes adequate and well‐controlled studies is usually interpreted as randomized controlled trials (RCTs). However, these trials are sometimes unfeasible because of their size, duration, cost, patient preference, or in some cases, ethical concerns. For example, RCTs may not be fully powered in rare diseases or in infections caused by multidrug resistant pathogens because of the low number of enrollable patients. In this case, data available from external controls (including historical controls and observational studies or data registries) can complement information provided by RCT. Propensity score matching methods can be used to select or “borrow” additional patients from the external controls, for maintaining a one‐to‐one randomization between the treatment arm and active control, by matching the new treatment and control units based on a set of measured covariates, ie, model‐based pairing of treatment and control units that are similar in terms of their observable pretreatment characteristics. To this end, 2 matching schemes based on propensity scores are explored and applied to a real clinical data example with the objective of using historical or external observations to augment data in a trial where the randomization is disproportionate or asymmetric.     

Randomization-Based Inference within Principal Strata

In randomized studies, treatment comparisons conditional on intermediate post-randomization outcomes using standard analytic methods do not have a causal interpretation. An alternate approach entails treatment comparisons within principal strata defined by the potential outcomes for the intermediate outcome that would be observed under each treatment assignment. In this paper, we develop methods for randomization-based inference within principal strata. The proposed methods are compared with existing large-sample methods as well as traditional intent-to-treat approaches. This research is motivated by HIV prevention studies where few infections are expected and inference is desired within the always-infected principal stratum, i.e., all individuals who would become infected regardless of randomization assignment.     

A method for obtaining randomized block designs in preclinical studies with multiple quantitative blocking variables

A method is proposed for block randomization of treatments to experimental units that can accommodate both multiple quantitative blocking variables and unbalanced designs. Hierarchical clustering in conjunction with leaf‐order optimization is used to block experimental units in multivariate space. The method is illustrated in the context of a diabetic mouse assay. A simulation study is presented to explore the utility of the proposed randomization method relative to that of a completely randomized approach, both in the presence and absence of covariate adjustment. An example R function is provided to illustrate the implementation of the method. Copyright © 2010 John Wiley & Sons, Ltd.     

START: single‐to‐double arm transition design for phase II clinical trials

Phase II clinical trials designed for evaluating a drug's treatment effect can be either single‐arm or double‐arm. A single‐arm design tests the null hypothesis that the response rate of a new drug is lower than a fixed threshold, whereas a double‐arm scheme takes a more objective comparison of the response rate between the new treatment and the standard of care through randomization. Although the randomized design is the gold standard for efficacy assessment, various situations may arise where a single‐arm pilot study prior to a randomized trial is necessary. To combine the single‐ and double‐arm phases and pool the information together for better decision making, we propose a Single‐To‐double ARm Transition design (START) with switching hypotheses tests, where the first stage compares the new drug's response rate with a minimum required level and imposes a continuation criterion, and the second stage utilizes randomization to determine the treatment's superiority. We develop a software package in R to calibrate the frequentist error rates and perform simulation studies to assess the trial characteristics. Finally, a metastatic pancreatic cancer trial is used for illustrating the decision rules under the proposed START design.     

Design and Evaluation of Prophylactic Interventions Using Infectious Disease Incidence Data from Close Contact Groups

Summary.  Prophylaxis of contacts of infectious cases such as household members and treatment of infectious cases are methods to prevent the spread of infectious diseases. We develop a method based on maximum likelihood to estimate the efficacy of such interventions and the transmission probabilities. We consider both the design with prospective follow-up of close contact groups and the design with ascertainment of close contact groups by an index case as well as randomization by groups and by individuals. We compare the designs by using simulations. We estimate the efficacy of the influenza antiviral agent oseltamivir in reducing susceptibility and infectiousness in two case-ascertained household trials.     

Some statistical issues in weather experimentation

A number of topics of statistical methodology in weather modification are discussed. The time sequence of unit definition, classification and randomization is shown to affect the types of units that can be used validly, and this casts doubt on the value of blocking. Re-randomization (permutation) tests are recommended as the only reliable method of confirmatory inference for weather experiments. Some aspects of such tests are examined, including a procedure for multiple comparisons. The plague of multiplicity of tests is discussed and warned against. Doubts about cumulative evaluations of "all" experiment's are expressed. A case is argued for examination of some non-randomized seeding operations. Consid¬ering the dearth of randomized data, it is argued that careful evaluation of seeding operations should be undertaken.     

SAMPLE SURVEYS VERSUS EXPERIMENTS,CONTROLLED OBSERVATIONS,CENSUSES, REGISTERS,AND LOCAL STUDIES1 2

Can we find some common principle in the three comparisons? Lacking adequate time for a thorough exploration, let me suggest that representation is that common principle. I suggested (section 4) that judgment selection of spatial versus temporal extensions distinguish “longitudinal” local studies from “cross-section” population sampling. We had noted (section 3) that censuses are taken for detailed representation of the spatial dimension but they depend on judgmental selection of the temporal. Survey sampling lacks spatial detail but is spatially representative with randomization, and it can be made timely. Periodic samples can be designed that are representative of temporal extension. Furthermore, spatial and temporal detail can be obtained either through estimation or through cumulated samples [Purcell and Kish 1979, 1980; Kish 1979b, 1981, 1986 6.6]. Registers and administrative records can have good spatial and temporal representation, but representation may be lacking in population content, and surely in representation of variables. Representation of variables and of the relations between variables and over the population are the issues in conflict between surveys, experiments, and observations. This is a deep subject, and too deep to be explored again, as it was in section 2. A final point about limits for randomization to achieve representation through sampling: randomization for selecting samples of variables is beyond me generally, because I cannot conceive of frames for defined populations of variables. Yet we can find attempts at randomized selection of variables: in the selection of items for the consumer price index, also of items for tests of IQ or of achievements. Generally I believe that randomization is the way to achieve representation without complete coverage, and that it can be applied and practised in many dimensions.     

Designing fractional factorial split-plot experiments with few whole-plot factors

Summary.  When it is impractical to perform the experimental runs of a fractional factorial design in a completely random order, restrictions on the randomization can be imposed. The resulting design is said to have a split-plot, or nested, error structure. Similarly to fractional factorials, fractional factorial split-plot designs can be ranked by using the aberration criterion. Techniques that generate the required designs systematically presuppose unreplicated settings of the whole-plot factors. We use a cheese-making experiment to demonstrate the practical relevance of designs with replicated settings of these factors. We create such designs by splitting the whole plots according to one or more subplot effects. We develop a systematic method to generate the required designs and we use the method to create a table of designs that is likely to be useful in practice.     

Combining multi‐observer information in partially rank‐ordered judgment post‐stratified and ranked set samples

This paper develops two sampling designs to create artificially stratified samples. These designs use a small set of experimental units to determine their relative ranks without measurement. In each set, the units are ranked by all available observers (rankers), with ties whenever the units cannot be ranked with high confidence. The rankings from all the observers are then combined in a meaningful way to create a single weight measure. This weight measure is used to create judgment strata in both designs. The first design constructs the strata through judgment post‐stratification after the data has been collected. The second design creates the strata before any measurements are made on the experimental units. The paper constructs estimators and confidence intervals, and develops testing procedures for the mean and median of the underlying distribution based on these sampling designs. We show that the proposed sampling designs provide a substantial improvement over their competitor designs in the literature. The Canadian Journal of Statistics 41: 304–324; 2013 © 2013 Statistical Society of Canada     

Crossover designs for comparing test treatments to a control treatment when subject effects are random

We study crossover designs for the comparisons of several test treatments versus a control treatment and partially generalize the results of Hedayat and Yang (2005) to the situation in which subject effects are assumed to be random. More specifically, we establish lower bounds for the trace of the inverse of the information matrix for the test treatments versus control comparisons under a random subject effects model and show that most of the small size (3-, 4- and 5-period) designs introduced by Hedayat and Yang (2005) are highly efficient in the class of designs in which the control treatment appears equally often in all periods and no treatment is immediately preceded by itself.