Background: It has long been advised to account for baseline covariates in the analysis of confirmatory randomised trials, with the main statistical justifications being that this increases power and, when a randomisation scheme balanced covariates, permits a valid estimate of experimental error. There are various methods available to account for covariates but it is not clear how to choose among them. Methods: Taking the perspective of writing a statistical analysis plan, we consider how to choose between the three most promising broad approaches: direct adjustment, standardisation and inverse-probability-of-treatment weighting. Results: The three approaches are similar in being asymptotically efficient, in losing efficiency with mis-specified covariate functions, and in handling designed balance. If a marginal estimand is targeted (for example, a risk difference or survival difference), then direct adjustment should be avoided because it involves fitting non-standard models that are subject to convergence issues. Convergence is most likely with IPTW. Robust standard errors used by IPTW are anti-conservative at small sample sizes. All approaches can use similar methods to handle missing covariate data. With missing outcome data, each method has its own way to estimate a treatment effect in the all-randomised population. We illustrate some issues in a reanalysis of GetTested, a randomised trial designed to assess the effectiveness of an electonic sexually-transmitted-infection testing and results service. Conclusions: No single approach is always best: the choice will depend on the trial context. We encourage trialists to consider all three methods more routinely.
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The generalized g-formula can be used to estimate the probability of survival under a sustained treatment strategy. When treatment strategies are deterministic, estimators derived from the so-called efficient influence function (EIF) for the g-formula will be doubly robust to model misspecification. In recent years, several practical applications have motivated estimation of the g-formula under non-deterministic treatment strategies where treatment assignment at each time point depends on the observed treatment process. In this case, EIF-based estimators may or may not be doubly robust. In this paper, we provide sufficient conditions to ensure existence of doubly robust estimators for intervention treatment distributions that depend on the observed treatment process for point treatment interventions, and give a class of intervention treatment distributions dependent on the observed treatment process that guarantee model doubly and multiply robust estimators in longitudinal settings. Motivated by an application to pre-exposure prophylaxis (PrEP) initiation studies, we propose a new treatment intervention dependent on the observed treatment process. We show there exist 1) estimators that are doubly and multiply robust to model misspecification, and 2) estimators that when used with machine learning algorithms can attain fast convergence rates for our proposed intervention. Theoretical results are confirmed via simulation studies.
Most governments employ a set of quasi-standard measures to fight COVID-19 including wearing masks, social distancing, virus testing, contact tracing, and vaccination. However, combining these measures into an efficient holistic pandemic response instrument is even more involved than anticipated. We argue that some non-trivial factors behind the varying effectiveness of these measures are selfish decision making and the differing national implementations of the response mechanism. In this paper, through simple games, we show the effect of individual incentives on the decisions made with respect to mask wearing, social distancing and vaccination, and how these may result in sub-optimal outcomes. We also demonstrate the responsibility of national authorities in designing these games properly regarding data transparency, the chosen policies and their influence on the preferred outcome. We promote a mechanism design approach: it is in the best interest of every government to carefully balance social good and response costs when implementing their respective pandemic response mechanism; moreover, there is no one-size-fits-all solution when designing an effective solution.
We study regression adjustments with additional covariates in randomized experiments under covariate-adaptive randomizations (CARs) when subject compliance is imperfect. We develop a regression-adjusted local average treatment effect (LATE) estimator that is proven to improve efficiency in the estimation of LATEs under CARs. Our adjustments can be parametric in linear and nonlinear forms, nonparametric, and high-dimensional. Even when the adjustments are misspecified, our proposed estimator is still consistent and asymptotically normal, and their inference method still achieves the exact asymptotic size under the null. When the adjustments are correctly specified, our estimator achieves the minimum asymptotic variance. When the adjustments are parametrically misspecified, we construct a new estimator which is weakly more efficient than linearly and nonlinearly adjusted estimators, as well as the one without any adjustments. Simulation evidence and empirical application confirm efficiency gains achieved by regression adjustments relative to both the estimator without adjustment and the standard two-stage least squares estimator.
Platform trials evaluate multiple experimental treatments under a single master protocol, where new treatment arms are added to the trial over time. Given the multiple treatment comparisons, there is the potential for inflation of the overall type I error rate, which is complicated by the fact that the hypotheses are tested at different times and are not all necessarily pre-specified. Online error control methodology provides a possible solution to the problem of multiplicity for platform trials where a relatively large number of hypotheses are expected to be tested over time. In the online testing framework, hypotheses are tested in a sequential manner, where at each time-step an analyst decides whether to reject the current null hypothesis without knowledge of future tests but based solely on past decisions. Methodology has recently been developed for online control of the false discovery rate as well as the familywise error rate (FWER). In this paper, we describe how to apply online error control to the platform trial setting, present extensive simulation results, and give some recommendations for the use of this new methodology in practice. We show that the algorithms for online error rate control can have a substantially lower FWER than uncorrected testing, while still achieving noticeable gains in power when compared with the use of a Bonferroni procedure. We also illustrate how online error control would have impacted a currently ongoing platform trial.
This paper presents a hybrid numerical method for linear collisional kinetic equations with diffusive scaling. The aim of the method is to reduce the computational cost of kinetic equations by taking advantage of the lower dimensionality of the asymptotic fluid model while reducing the error induced by the latter approach. It relies on two criteria motivated by a pertubative approach to obtain a dynamic domain decomposition. The first criterion quantifies how far from a local equilibrium in velocity the distribution function of particles is. The second one depends only on the macroscopic quantities that are available on the whole computing domain. Interface conditions are dealt with using a micro-macro decomposition and the method is significantly more efficient than a standard full kinetic approach. Some properties of the hybrid method are also investigated, such as the conservation of mass.
In 2019, the World Health Organization identified dengue as one of the top ten global health threats. For the control of dengue, the Applying Wolbachia to Eliminate Dengue (AWED) study group conducted a cluster-randomized trial in Yogyakarta, Indonesia, and used a novel design, called the cluster-randomized test-negative design (CR-TND). This design can yield valid statistical inference with data collected by a passive surveillance system and thus has the advantage of cost-efficiency compared to traditional cluster-randomized trials. We investigate the statistical assumptions and properties of CR-TND under a randomization inference framework, which is known to be robust and efficient for small-sample problems. We find that, when the differential healthcare-seeking behavior comparing intervention and control varies across clusters (in contrast to the setting of Dufault and Jewell, 2020 where the differential healthcare-seeking behavior is constant across clusters), current analysis methods for CR-TND can be biased and have inflated type I error. We propose the log-contrast estimator that can eliminate such bias and improve precision by adjusting for covariates. Furthermore, we extend our methods to handle partial intervention compliance and a stepped-wedge design, both of which appear frequently in cluster-randomized trials. Finally, we demonstrate our results by simulation studies and re-analysis of the AWED study.
Missing data is frequently encountered in practice. Propensity score estimation is a popular tool for handling such missingness. The propensity score is often developed using a model for the response probability, which can be subject to model misspecification. In this paper, we consider an alternative approach of estimating the inverse of the propensity scores using the density ratio function. The smoothed density ratio function is obtained by the solution to the information projection onto the space satisfying the moment conditions on the balancing scores. By including the covariates for the outcome regression models only into the density ratio model, we can achieve efficient propensity score estimation. Penalized regression is used to identify important covariates. We further extend the proposed approach to the multivariate missing case. Some limited simulation studies are presented to compare with the existing methods.
We present methods for causally interpretable meta-analyses that combine information from multiple randomized trials to estimate potential (counterfactual) outcome means and average treatment effects in a target population. We consider identifiability conditions, derive implications of the conditions for the law of the observed data, and obtain identification results for transporting causal inferences from a collection of independent randomized trials to a new target population in which experimental data may not be available. We propose an estimator for the potential (counterfactual) outcome mean in the target population under each treatment studied in the trials. The estimator uses covariate, treatment, and outcome data from the collection of trials, but only covariate data from the target population sample. We show that it is doubly robust, in the sense that it is consistent and asymptotically normal when at least one of the models it relies on is correctly specified. We study the finite sample properties of the estimator in simulation studies and demonstrate its implementation using data from a multi-center randomized trial.
The design of experiments involves an inescapable compromise between covariate balance and robustness. This paper provides a formalization of this trade-off and introduces an experimental design that allows experimenters to navigate it. The design is specified by a robustness parameter that bounds the worst-case mean squared error of an estimator of the average treatment effect. Subject to the experimenter's desired level of robustness, the design aims to simultaneously balance all linear functions of potentially many covariates. The achieved level of balance is better than previously known possible and considerably better than what a fully random assignment would produce. We show that the mean squared error of the estimator is bounded by the minimum of the loss function of an implicit ridge regression of the potential outcomes on the covariates. The estimator does not itself conduct covariate adjustment, so one can interpret the approach as regression adjustment by design. Finally, we provide non-asymptotic tail bounds for the estimator, which facilitate the construction of conservative confidence intervals.
Missing data is a systemic problem in practical scenarios that causes noise and bias when estimating treatment effects. This makes treatment effect estimation from data with missingness a particularly tricky endeavour. A key reason for this is that standard assumptions on missingness are rendered insufficient due to the presence of an additional variable, treatment, besides the individual and the outcome. Having a treatment variable introduces additional complexity with respect to why some variables are missing that is not fully explored by previous work. In our work we identify a new missingness mechanism, which we term mixed confounded missingness (MCM), where some missingness determines treatment selection and other missingness is determined by treatment selection. Given MCM, we show that naively imputing all data leads to poor performing treatment effects models, as the act of imputation effectively removes information necessary to provide unbiased estimates. However, no imputation at all also leads to biased estimates, as missingness determined by treatment divides the population in distinct subpopulations, where estimates across these populations will be biased. Our solution is selective imputation, where we use insights from MCM to inform precisely which variables should be imputed and which should not. We empirically demonstrate how various learners benefit from selective imputation compared to other solutions for missing data.
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