Causal survival analysis under competing risks using longitudinal modified treatment policies

Longitudinal modified treatment policies (LMTP) have been recently developed as a novel method to define and estimate causal parameters that depend on the natural value of treatment. LMTPs represent an important advancement in causal inference for longitudinal studies as they allow the non-parametric definition and estimation of the joint effect of multiple categorical, numerical, or continuous exposures measured at several time points. We extend the LMTP methodology to problems in which the outcome is a time-to-event variable subject to right-censoring and competing risks. We present identification results and non-parametric locally efficient estimators that use flexible data-adaptive regression techniques to alleviate model misspecification bias, while retaining important asymptotic properties such as $\sqrt{n}$-consistency. We present an application to the estimation of the effect of the time-to-intubation on acute kidney injury amongst COVID-19 hospitalized patients, where death by other causes is taken to be the competing event

A generalization of moderated statistics to data adaptive semiparametric estimation in high-dimensional biology

The widespread availability of high-dimensional biological data has made the simultaneous screening of numerous biological characteristics a central statistical problem in computational biology. While the dimensionality of such datasets continues to increase, the problem of teasing out the effects of biomarkers in studies measuring baseline confounders while avoiding model misspecification remains only partially addressed. Efficient estimators constructed from data adaptive estimates of the data-generating distribution provide an avenue for avoiding model misspecification; however, in the context of high-dimensional problems requiring simultaneous estimation of numerous parameters, standard variance estimators have proven unstable, resulting in unreliable Type-I error control under standard multiple testing corrections. We present the formulation of a general approach for applying empirical Bayes shrinkage approaches to asymptotically linear estimators of parameters defined in the nonparametric model. The proposal applies existing shrinkage estimators to the estimated variance of the influence function, allowing for increased inferential stability in high-dimensional settings. A methodology for nonparametric variable importance analysis for use with high-dimensional biological datasets with modest sample sizes is introduced and the proposed technique is demonstrated to be robust in small samples even when relying on data adaptive estimators that eschew parametric forms. Use of the proposed variance moderation strategy in constructing stabilized variable importance measures of biomarkers is demonstrated by application to an observational study of occupational exposure. The result is a data adaptive approach for robustly uncovering stable associations in high-dimensional data with limited sample sizes

Revisiting the propensity score's central role: Towards bridging balance and efficiency in the era of causal machine learning

About forty years ago, in a now--seminal contribution, Rosenbaum & Rubin (1983) introduced a critical characterization of the propensity score as a central quantity for drawing causal inferences in observational study settings. In the decades since, much progress has been made across several research fronts in causal inference, notably including the re-weighting and matching paradigms. Focusing on the former and specifically on its intersection with machine learning and semiparametric efficiency theory, we re-examine the role of the propensity score in modern methodological developments. As Rosenbaum & Rubin (1983)'s contribution spurred a focus on the balancing property of the propensity score, we re-examine the degree to which and how this property plays a role in the development of asymptotically efficient estimators of causal effects; moreover, we discuss a connection between the balancing property and efficient estimation in the form of score equations and propose a score test for evaluating whether an estimator achieves balance.Comment: Accepted for publication in a forthcoming special issue of Observational Studie

A nonparametric framework for treatment effect modifier discovery in high dimensions

Heterogeneous treatment effects are driven by treatment effect modifiers, pre-treatment covariates that modify the effect of a treatment on an outcome. Current approaches for uncovering these variables are limited to low-dimensional data, data with weakly correlated covariates, or data generated according to parametric processes. We resolve these issues by developing a framework for defining model-agnostic treatment effect modifier variable importance parameters applicable to high-dimensional data with arbitrary correlation structure, deriving one-step, estimating equation and targeted maximum likelihood estimators of these parameters, and establishing these estimators' asymptotic properties. This framework is showcased by defining variable importance parameters for data-generating processes with continuous, binary, and time-to-event outcomes with binary treatments, and deriving accompanying multiply-robust and asymptotically linear estimators. Simulation experiments demonstrate that these estimators' asymptotic guarantees are approximately achieved in realistic sample sizes for observational and randomized studies alike. This framework is applied to gene expression data collected for a clinical trial assessing the effect of a monoclonal antibody therapy on disease-free survival in breast cancer patients. Genes predicted to have the greatest potential for treatment effect modification have previously been linked to breast cancer. An open-source R package implementing this methodology, unihtee, is made available on GitHub at https://github.com/insightsengineering/unihtee