Marginal modeling of cluster-period means and intraclass correlations in stepped wedge designs with binary outcomes.

Stepped wedge cluster randomized trials (SW-CRTs) with binary outcomes are increasingly used in prevention and implementation studies. Marginal models represent a flexible tool for analyzing SW-CRTs with population-averaged interpretations, but the joint estimation of the mean and intraclass correlation coefficients (ICCs) can be computationally intensive due to large cluster-period sizes. Motivated by the need for marginal inference in SW-CRTs, we propose a simple and efficient estimating equations approach to analyze cluster-period means. We show that the quasi-score for the marginal mean defined from individual-level observations can be reformulated as the quasi-score for the same marginal mean defined from the cluster-period means. An additional mapping of the individual-level ICCs into correlations for the cluster-period means further provides a rigorous justification for the cluster-period approach. The proposed approach addresses a long-recognized computational burden associated with estimating equations defined based on individual-level observations, and enables fast point and interval estimation of the intervention effect and correlations. We further propose matrix-adjusted estimating equations to improve the finite-sample inference for ICCs. By providing a valid approach to estimate ICCs within the class of generalized linear models for correlated binary outcomes, this article operationalizes key recommendations from the CONSORT extension to SW-CRTs, including the reporting of ICCs.

cvcrand and cptest: Commands for efficient design and analysis of cluster randomized trials using constrained randomization and permutation tests.

Cluster randomized trials (CRTs), where clusters (for example, schools or clinics) are randomized to comparison arms but measurements are taken on individuals, are commonly used to evaluate interventions in public health, education, and the social sciences. Because CRTs typically involve a small number of clusters (for example, fewer than 20), simple randomization frequently leads to baseline imbalance of cluster characteristics across study arms, threatening the internal validity of the trial. In CRTs with a small number of clusters, classic approaches to balancing baseline characteristics-such as matching and stratification-have several drawbacks, especially when the number of baseline characteristics the researcher desires to balance is large (Ivers et al., 2012, Trials 13: 120). An alternative design approach is covariate-constrained randomization, whereby a randomization scheme is randomly selected from a subset of all possible randomization schemes based on the value of a balancing criterion (Raab and Butcher, 2001, Statistics in Medicine 20: 351-365). Subsequently, a clustered permutation test can be used in the analysis, which provides increased power under constrained randomization compared with simple randomization (Li et al., 2016, Statistics in Medicine 35: 1565-1579). In this article, we describe covariate-constrained randomization and the permutation test for the design and analysis of CRTs and provide an example to demonstrate the use of our new commands cvcrand and cptest to implement constrained randomization and the permutation test.

A note on the estimation and inference with quadratic inference functions for correlated outcomes.

The quadratic inference function approach is a popular method in the analysis of correlated data. The quadratic inference function is formulated based on multiple sets of score equations (or extended score equations) that over-identify the regression parameters of interest, and improves efficiency over the generalized estimating equations under correlation misspecification. In this note, we provide an alternative solution to the quadratic inference function by separately solving each set of score equations and combining the solutions. We provide an insight that an optimally weighted combination of estimators obtained separately from the distinct sets of score equations is asymptotically equivalent to the estimator obtained via the quadratic inference function. We further establish results on inference for the optimally weighted estimator and extend these insights to the general setting with over-identified estimating equations. A simulation study is carried out to confirm the analytical insights and connections in finite samples.

MichiGAN: sampling from disentangled representations of single-cell data using generative adversarial networks.

Deep generative models such as variational autoencoders (VAEs) and generative adversarial networks (GANs) generate and manipulate high-dimensional images. We systematically assess the complementary strengths and weaknesses of these models on single-cell gene expression data. We also develop MichiGAN, a novel neural network that combines the strengths of VAEs and GANs to sample from disentangled representations without sacrificing data generation quality. We learn disentangled representations of three large single-cell RNA-seq datasets and use MichiGAN to sample from these representations. MichiGAN allows us to manipulate semantically distinct aspects of cellular identity and predict single-cell gene expression response to drug treatment.

An evaluation of quadratic inference functions for estimating intervention effects in cluster randomized trials.

Cluster randomized trials (CRTs) usually randomize groups of individuals to interventions, and outcomes are typically measured at the individual level. Marginal intervention effects are frequently of interest in CRTs due to their population-averaged interpretations. Such effects are estimated using generalized estimating equations (GEE), or a recent alternative called the quadratic inference function (QIF). However, the performance of QIF relative to GEE have not been extensively evaluated in the CRT context, especially when the marginal mean model includes additional covariates. Motivated by the HALI trial, we conduct simulation studies to compare the finite-sample operating characteristics of QIF and GEE. We demonstrate that QIF and GEE are equivalent under some conditions. When the marginal mean model includes individual-level covariates, QIF shows an efficiency improvement over GEE with overall larger power, but its test size may be more liberal than GEE and GEE achieves better coverage than QIF. The test size inflation may not by fully addressed from using finite-sample bias corrections. The estimates of QIF tend to be closer to GEE in the HALI data, although the former presents a small standard error. Overall, we confirm that the QIF approach generally has potentially better efficiency than GEE in our simulation studies but might be more cautiously used as a viable approach for the analysis of CRTs. More research is needed, however, to address the finite-sample bias in the variance estimation of the QIF to better control its test size.