Randomized block factorial experiments are widely used in industrial engineering, clinical trials, and social science. Researchers often use a linear model and analysis of covariance to analyze experimental results; however, limited studies have addressed the validity and robustness of the resulting inferences because assumptions for a linear model might not be justified by randomization in randomized block factorial experiments. In this paper, we establish a new finite population joint central limit theorem for usual (unadjusted) factorial effect estimators in randomized block $2^K$ factorial experiments. Our theorem is obtained under a randomization-based inference framework, making use of an extension of the vector form of the Wald--Wolfowitz--Hoeffding theorem for a linear rank statistic. It is robust to model misspecification, numbers of blocks, block sizes, and propensity scores across blocks. To improve the estimation and inference efficiency, we propose four covariate adjustment methods. We show that under mild conditions, the resulting covariate-adjusted factorial effect estimators are consistent, jointly asymptotically normal, and generally more efficient than the unadjusted estimator. In addition, we propose Neyman-type conservative estimators for the asymptotic covariances to facilitate valid inferences. Simulation studies and a clinical trial data analysis demonstrate the benefits of the covariate adjustment methods.
We extend the randomization-based causal inference framework in Dasgupta et al. (2015) for general 2^K factorial designs, and demonstrate the equivalence between regression-based and randomization-based inferences. Consequently, we justify the use of regression-based methods in 2^K factorial designs from a finite-population perspective.
Under the potential outcomes framework, we introduce matched-pair factorial designs, and propose the matched-pair estimator of the factorial effects. We also calculate the randomization-based covariance matrix of the matched-pair estimator, and provide the "Neymanian" estimator of the covariance matrix.
We develop finite-population asymptotic theory for covariate adjustment in randomization-based causal inference for 2K factorial designs. In particular, we confirm that both the unadjusted and covariate-adjusted estimators of the factorial effects are asymptotically normal, and the latter is more precise than the former.
In medical research, a scenario often entertained is randomized controlled $2^2$ factorial design with a binary outcome. By utilizing the concept of potential outcomes, Dasgupta et al. (2015) proposed a randomization-based causal inference framework, allowing flexible and simultaneous estimations and inferences of the factorial effects. However, a fundamental challenge that Dasgupta et al. (2015)'s proposed methodology faces is that the sampling variance of the randomization-based factorial effect estimator is unidentifiable, rendering the corresponding classic "Neymanian" variance estimator s…
Latin hypercube designs (LHDs) with space-filling properties are widely used for emulating computer simulators. Over the last three decades, a wide spectrum of LHDs have been proposed with space-filling criteria like minimum correlation among factors, maximin interpoint distance, and orthogonality among the factors via orthogonal arrays (OAs). Projective geometric structures like spreads, covers and stars of PG(p-1,q) can be used to characterize the randomization restriction of multistage factorial experiments. These geometric structures can also be used for constructing OAs and nearly OAs (NO…
Factorial designs with randomization restrictions are often used in industrial experiments when a complete randomization of trials is impractical. In the statistics literature, the analysis, construction and isomorphism of factorial designs has been extensively investigated. Much of the work has been on a case-by-case basis -- addressing completely randomized designs, randomized block designs, split-plot designs, etc. separately. In this paper we take a more unified approach, developing theoretical results and an efficient relabeling strategy to both construct and check the isomorphism of mult…
Two commonly used methods for improving precision and power in clinical trials are stratified randomization and covariate adjustment. However, many trials do not fully capitalize on the combined precision gains from these two methods, which can lead to wasted resources in terms of sample size and trial duration. We derive consistency and asymptotic normality of model-robust estimators that combine these two methods, and show that these estimators can lead to substantial gains in precision and power. Our theorems cover a class of estimators that handle continuous, binary, and time-to-event outc…
Factorial designs are often used in various industrial and sociological experiments to identify significant factors and factor combinations that may affect the process response. In the statistics literature, several studies have investigated the analysis, construction, and isomorphism of factorial and fractional factorial designs. When there are multiple choices for a design, it is helpful to have an easy-to-use tool for identifying which are distinct, and which of those can be efficiently analyzed/has good theoretical properties. For this task, we present an R library called IsoCheck that che…
With many pretreatment covariates and treatment factors, the classical factorial experiment often fails to balance covariates across multiple factorial effects simultaneously. Therefore, it is intuitive to restrict the randomization of the treatment factors to satisfy certain covariate balance criteria, possibly conforming to the tiers of factorial effects and covariates based on their relative importances. This is rerandomization in factorial experiments. We study the asymptotic properties of this experimental design under the randomization inference framework without imposing any distributio…
Linear regression is arguably the most fundamental statistical model; however, the validity of its use in randomized clinical trials, despite being common practice, has never been crystal clear, particularly when stratified or covariate-adaptive randomization is used. In this paper, we investigate several of the most intuitive and commonly used regression models for estimating and inferring the treatment effect in randomized clinical trials. By allowing the regression model to be arbitrarily misspecified, we demonstrate that all these regression-based estimators robustly estimate the treatment…
Covariate-adaptive randomization schemes such as the minimization and stratified permuted blocks are often applied in clinical trials to balance treatment assignments across prognostic factors. The existing theoretical developments on inference after covariate-adaptive randomization are mostly limited to situations where a correct model between the response and covariates can be specified or the randomization method has well-understood properties. Based on stratification with covariate levels utilized in randomization and a further adjusting for covariates not used in randomization, in this ar…
In the presence of prognostic covariates, inference about the treatment effect with time-to-event endpoints is mostly conducted via the stratified log-rank test or the score test based on the Cox proportional hazards model. In their ground-breaking work Ye and Shao (2020) have demonstrated theoretically that when the model is misspecified, the robust score test (Wei and Lin, 1989) as well as the unstratified log-rank test are conservative in trials with stratified randomization. This fact, however, was not established for the Pocock and Simon covariate-adaptive allocation other than through si…
Accurate estimates of malaria vaccine efficacy require a reliable definition of a malaria case. However, the symptoms of clinical malaria are unspecific, overlapping with other childhood illnesses. Additionally, children in endemic areas tolerate varying levels of parasitemia without symptoms. Together, this makes finding a gold-standard case definition challenging. We present a method to identify and estimate malaria vaccine efficacy that does not require an observable gold-standard case definition. Instead, we leverage genetic traits that are protective against malaria but not against other …
Given two 2-level factors of interest, a 2^2 split-plot design} (a) takes each of the $2^2=4$ possible factorial combinations as a treatment, (b) identifies one factor as `whole-plot,' (c) divides the experimental units into blocks, and (d) assigns the treatments in such a way that all units within the same block receive the same level of the whole-plot factor. Assuming the potential outcomes framework, we propose in this paper a randomization-based estimation procedure for causal inference from 2^2 designs that are not necessarily balanced. Sampling variances of the point estimates are derive…
This paper proposes an adaptive randomization procedure for two-stage randomized controlled trials. The method uses data from a first-wave experiment in order to determine how to stratify in a second wave of the experiment, where the objective is to minimize the variance of an estimator for the average treatment effect (ATE). We consider selection from a class of stratified randomization procedures which we call stratification trees: these are procedures whose strata can be represented as decision trees, with differing treatment assignment probabilities across strata. By using the first wave t…
A framework for causal inference from two-level factorial designs is proposed. The framework utilizes the concept of potential outcomes that lies at the center stage of causal inference and extends Neyman's repeated sampling approach for estimation of causal effects and randomization tests based on Fisher's sharp null hypothesis to the case of 2-level factorial experiments. The framework allows for statistical inference from a finite population, permits definition and estimation of estimands other than "average factorial effects" and leads to more flexible inference procedures than those based…
Stratification and rerandomization are two well-known methods used in randomized experiments for balancing the baseline covariates. Renowned scholars in experimental design have recommended combining these two methods; however, limited studies have addressed the statistical properties of this combination. This paper proposes two rerandomization methods to be used in stratified randomized experiments, based on the overall and stratum-specific Mahalanobis distances. The first method is applicable for nearly arbitrary numbers of strata, strata sizes, and stratum-specific proportions of the treate…
In clinical trials, response-adaptive randomization (RAR) has the appealing ability to assign more subjects to better-performing treatments based on interim results. The traditional RAR strategy alters the randomization ratio on a patient-by-patient basis; this has been heavily criticized for bias due to time-trends. An alternate approach is blocked RAR, which groups patients together in blocks and recomputes the randomization ratio in a block-wise fashion; the final analysis is then stratified by block. However, the typical blocked RAR design divides patients into equal-sized blocks, which is…
In randomized experiments, treatment and control groups should be roughly the same--balanced--in their distributions of pretreatment variables. But how nearly so? Can descriptive comparisons meaningfully be paired with significance tests? If so, should there be several such tests, one for each pretreatment variable, or should there be a single, omnibus test? Could such a test be engineered to give easily computed $p$-values that are reliable in samples of moderate size, or would simulation be needed for reliable calibration? What new concerns are introduced by random assignment of clusters? Wh…
In randomized controlled trials (RCTs), treatment is often assigned by stratified randomization. I show that among all stratified randomization schemes which treat all units with probability one half, a certain matched-pair design achieves the maximum statistical precision for estimating the average treatment effect (ATE). In an important special case, the optimal design pairs units according to the baseline outcome. In a simulation study based on datasets from 10 RCTs, this design lowers the standard error for the estimator of the ATE by 10% on average, and by up to 34%, relative to the origi…
The Fisher randomization test (FRT) is appropriate for any test statistic, under a sharp null hypothesis that can recover all missing potential outcomes. However, it is often sought after to test a weak null hypothesis that the treatment does not affect the units on average. To use the FRT for a weak null hypothesis, we must address two issues. First, we need to impute the missing potential outcomes although the weak null hypothesis cannot determine all of them. Second, we need to choose a proper test statistic. For a general weak null hypothesis, we propose an approach to imputing missing pot…
The injunction to `analyze the way you randomize' is well-known to statisticians since Fisher advocated for randomization as the basis of inference. Yet even those convinced by the merits of randomization-based inference seldom follow this injunction to the letter. Bernoulli randomized experiments are often analyzed as completely randomized experiments, and completely randomized experiments are analyzed as if they had been stratified; more generally, it is not uncommon to analyze an experiment as if it had been randomized differently. This paper examines the theoretical foundation behind this …
We consider the problem of estimating and inferring treatment effects in randomized experiments. In practice, stratified randomization, or more generally, covariate-adaptive randomization, is routinely used in the design stage to balance the treatment allocations with respect to a few variables that are most relevant to the outcomes. Then, regression is performed in the analysis stage to adjust the remaining imbalances to yield more efficient treatment effect estimators. Building upon and unifying the recent results obtained for ordinary least squares adjusted estimators under covariate-adapti…
Suppose one wishes to estimate the effect of a binary treatment on a binary endpoint conditional on a post-randomization quantity in a counterfactual world in which all subjects received treatment. It is generally difficult to identify this parameter without strong, untestable assumptions. It has been shown that identifiability assumptions become much weaker under a crossover design in which subjects not receiving treatment are later given treatment. Under the assumption that the post-treatment biomarker observed in these crossover subjects is the same as would have been observed had they rece…
Nonparametric covariate adjustment is considered for log-rank type tests of treatment effect with right-censored time-to-event data from clinical trials applying covariate-adaptive randomization. Our proposed covariate-adjusted log-rank test has a simple explicit formula and a guaranteed efficiency gain over the unadjusted test. We also show that our proposed test achieves universal applicability in the sense that the same formula of test can be universally applied to simple randomization and all commonly used covariate-adaptive randomization schemes such as the stratified permuted block and P…
Fisher's randomization test (FRT) delivers exact $p$-values under the strong null hypothesis of no treatment effect on any units whatsoever and allows for flexible covariate adjustment to improve the power. Of interest is whether the procedure could also be valid for testing the weak null hypothesis of zero average treatment effect. Towards this end, we evaluate two general strategies for FRT with covariate-adjusted test statistics: that based on the residuals from an outcome model with only the covariates, and that based on the output from an outcome model with both the treatment and the cova…
