An official website of the United States government
This paper studies inference in randomized controlled trials with covariate‐adaptive randomization when there are multiple treatments. More specifically, we study in this setting inference about the average effect of one or more treatments relative to other treatments or a control. As in Bugni, Canay, and Shaikh (2018), covariate‐adaptive randomization refers to randomization schemes that first stratify according to baseline covariates and then assign treatment status so as to achieve “balance” within each stratum. Importantly, in contrast to Bugni, Canay, and Shaikh (2018), we not only allow for multiple treatments, but further allow for the proportion of units being assigned to each of the treatments to vary across strata. We first study the properties of estimators derived from a “fully saturated” linear regression, that is, a linear regression of the outcome on all interactions between indicators for each of the treatments and indicators for each of the strata. We show that tests based on these estimators using the usual heteroskedasticity‐consistent estimator of the asymptotic variance are invalid in the sense that they may have limiting rejection probability under the null hypothesis strictly greater than the nominal level; on the other hand, tests based on these estimators and suitable estimators of the asymptotic variance that we provide are exact in the sense that they have limiting rejection probability under the null hypothesis equal to the nominal level. For the special case in which the target proportion of units being assigned to each of the treatments does not vary across strata, we additionally consider tests based on estimators derived from a linear regression with “strata fixed effects,” that is, a linear regression of the outcome on indicators for each of the treatments and indicators for each of the strata. We show that tests based on these estimators using the usual heteroskedasticity‐consistent estimator of the asymptotic variance are conservative in the sense that they have limiting rejection probability under the null hypothesis no greater than and typically strictly less than the nominal level, but tests based on these estimators and suitable estimators of the asymptotic variance that we provide are exact, thereby generalizing results in Bugni, Canay, and Shaikh (2018) for the case of a single treatment to multiple treatments. A simulation study and an empirical application illustrate the practical relevance of our theoretical results.
more »
« less
The role of randomization inference in unraveling individual treatment effects in early phase vaccine trials
Abstract Randomization inference is a powerful tool in early phase vaccine trials when estimating the causal effect of a regimen against a placebo or another regimen. Randomization-based inference often focuses on testing either Fisher’s sharp null hypothesis of no treatment effect for any participant or Neyman’s weak null hypothesis of no sample average treatment effect. Many recent efforts have explored conducting exact randomization-based inference for other summaries of the treatment effect profile, for instance, quantiles of the treatment effect distribution function. In this article, we systematically review methods that conduct exact, randomization-based inference for quantiles of individual treatment effects (ITEs) and extend some results to a special case where naïve participants are expected not to exhibit responses to highly specific endpoints. These methods are suitable for completely randomized trials, stratified completely randomized trials, and a matched study comparing two non-randomized arms from possibly different trials. We evaluate the usefulness of these methods using synthetic data in simulation studies. Finally, we apply these methods to HIV Vaccine Trials Network Study 086 (HVTN 086) and HVTN 205 and showcase a wide range of application scenarios of the methods.Rcode that replicates all analyses in this article can be found in first author’s GitHub page athttps://github.com/Zhe-Chen-1999/ITE-Inference.
more »
« less
- Award ID(s):
- 2400961
- PAR ID:
- 10628562
- Publisher / Repository:
- De Gruyter
- Date Published:
- Journal Name:
- Statistical Communications in Infectious Diseases
- Volume:
- 16
- Issue:
- 1
- ISSN:
- 2194-6310
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Abstract Randomisation inference (RI) is typically interpreted as testing Fisher’s ‘sharp’ null hypothesis that all unit-level effects are exactly zero. This hypothesis is often criticised as restrictive and implausible, making its rejection scientifically uninteresting. We show, however, that many randomisation tests are also valid for a ‘bounded’ null hypothesis under which the unit-level effects are all non-positive (or all non-negative) but are otherwise heterogeneous. In addition to being more plausible a priori, bounded nulls are closely related to substantively important concepts such as monotonicity and Pareto efficiency. Reinterpreting RI in this way expands the range of inferences possible in this framework. We show that exact confidence intervals for the maximum (or minimum) unit-level effect can be obtained by inverting tests for a sequence of bounded nulls. We also generalise RI to cover inference for quantiles of the individual effect distribution as well as for the proportion of individual effects larger (or smaller) than a given threshold. The proposed confidence intervals for all effect quantiles are simultaneously valid, in the sense that no correction for multiple analyses is required. In sum, our reinterpretation and generalisation provide a broader justification for randomisation tests and a basis for exact non-parametric inference for effect quantiles.more » « less
-
Summary Randomized experiments have been the gold standard for drawing causal inference. The conventional model-based approach has been one of the most popular methods of analysing treatment effects from randomized experiments, which is often carried out through inference for certain model parameters. In this paper, we provide a systematic investigation of model-based analyses for treatment effects under the randomization-based inference framework. This framework does not impose any distributional assumptions on the outcomes, covariates and their dependence, and utilizes only randomization as the reasoned basis. We first derive the asymptotic theory for $ Z $-estimation in completely randomized experiments, and propose sandwich-type conservative covariance estimation. We then apply the developed theory to analyse both average and individual treatment effects in randomized experiments. For the average treatment effect, we consider model-based, model-imputed and model-assisted estimation strategies, where the first two strategies can be sensitive to model misspecification or require specific methods for parameter estimation. The model-assisted approach is robust to arbitrary model misspecification and always provides consistent average treatment effect estimation. We propose optimal ways to conduct model-assisted estimation using generally nonlinear least squares for parameter estimation. For the individual treatment effects, we propose directly modelling the relationship between individual effects and covariates, and discuss the model’s identifiability, inference and interpretation allowing for model misspecification.more » « less
-
Infectious diseases, like COVID-19, pose serious challenges to university campuses, which typically adopt closure as a non-pharmaceutical intervention to control spread and ensure a gradual return to normalcy. Intervention policies, such as remote instruction (RI) where large classes are offered online, reduce potential contact but also have broad side-effects on campus by hampering the local economy, students’ learning outcomes, and community wellbeing. In this paper, we demonstrate that university policymakers can mitigate these tradeoffs by leveraging anonymized data from their WiFi infrastructure to learn community mobility—a methodology we refer to asWiFi mobility models(WiMob). This approach enables policymakers to explore more granular policies like localized closures (LC).WiMobcan construct contact networks that capture behavior in various spaces, highlighting new potential transmission pathways and temporal variation in contact behavior. Additionally,WiMobenables us to designLCpolicies that close super-spreader locations on campus. By simulating disease spread with contact networks fromWiMob, we find thatLCmaintains the same reduction in cumulative infections asRIwhile showing greater reduction in peak infections and internal transmission. Moreover,LCreduces campus burden by closing fewer locations, forcing fewer students into completely online schedules, and requiring no additional isolation.WiMobcan empower universities to conceive and assess a variety of closure policies to prevent future outbreaks.more » « less
-
Abstract Copy number aberrations (CNAs) are ubiquitous in many types of cancer. Inferring CNAs from cancer genomic data could help shed light on the initiation, progression, and potential treatment of cancer. While such data have traditionally been available via “bulk sequencing,” the more recently introduced techniques for single-cell DNA sequencing (scDNAseq) provide the type of data that makes CNA inference possible at the single-cell resolution. We introduce a new birth-death evolutionary model of CNAs and a Bayesian method, NestedBD, for the inference of evolutionary trees (topologies and branch lengths with relative mutation rates) from single-cell data. We evaluated NestedBD’s performance using simulated data sets, benchmarking its accuracy against traditional phylogenetic tools as well as state-of-the-art methods. The results show that NestedBD infers more accurate topologies and branch lengths, and that the birth-death model can improve the accuracy of copy number estimation. And when applied to biological data sets, NestedBD infers plausible evolutionary histories of two colorectal cancer samples. NestedBD is available athttps://github.com/Androstane/NestedBD.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1515/scid-2024-0001
