arXiv subjects

Mark J. van der Laan

Publications and source records attributed to Mark J. van der Laan.

At least 73 records · Page 4Linked to original sources

arXiv2019

One-step Targeted Maximum Likelihood for Time-to-event Outcomes

Current Targeted Maximum Likelihood Estimation (TMLE) methods used to analyze time-to-event data estimate the survival probability for each time point separately, which result in estimates that are not necessarily monotone. In this paper, we present an extension of TMLE for observational time-to-event data, the one-step Targeted Maximum Likelihood Estimator for the treatment-rule specific survival curve. We construct a one-dimensional universal least favorable submodel that targets the entire survival curve, and thereby requires minimal extra fitting with data to achieve its goal of solving the efficient influence curve equation. Through the use of a simulation study, we will show that this method improves on previously proposed methods in both robustness and efficiency, and at the same time respects the monotone decreasing nature of the survival curve.

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arXiv2019

Targeted Estimation of L2 Distance Between Densities and its Application to Geo-spatial Data

We examine the integrated squared difference, also known as the L2 distance (L2D), between two probability densities. Such a distance metric allows for comparison of differences between pairs of distributions or changes in a distribution over time. We propose a targeted maximum likelihood estimator for this parameter based on samples of independent and identically distributed observations from both underlying distributions. We compare our method to kernel density estimation and demonstrate superior performance for our method with regards to confidence interval coverage rate and mean squared error.

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arXiv2019

Robust inference on the average treatment effect using the outcome highly adaptive lasso

Many estimators of the average effect of a treatment on an outcome require estimation of the propensity score, the outcome regression, or both. It is often beneficial to utilize flexible techniques such as semiparametric regression or machine learning to estimate these quantities. However, optimal estimation of these regressions does not necessarily lead to optimal estimation of the average treatment effect, particularly in settings with strong instrumental variables. A recent proposal addressed these issues via the outcome-adaptive lasso, a penalized regression technique for estimating the propensity score that seeks to minimize the impact of instrumental variables on treatment effect estimators. However, a notable limitation of this approach is that its application is restricted to parametric models. We propose a more flexible alternative that we call the outcome highly adaptive lasso. We discuss large sample theory for this estimator and propose closed form confidence intervals based on the proposed estimator. We show via simulation that our method offers benefits over several popular approaches.

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arXiv2018

Targeted Learning with Daily EHR Data

Electronic health records (EHR) data provide a cost and time-effective opportunity to conduct cohort studies of the effects of multiple time-point interventions in the diverse patient population found in real-world clinical settings. Because the computational cost of analyzing EHR data at daily (or more granular) scale can be quite high, a pragmatic approach has been to partition the follow-up into coarser intervals of pre-specified length. Current guidelines suggest employing a 'small' interval, but the feasibility and practical impact of this recommendation has not been evaluated and no formal methodology to inform this choice has been developed. We start filling these gaps by leveraging large-scale EHR data from a diabetes study to develop and illustrate a fast and scalable targeted learning approach that allows to follow the current recommendation and study its practical impact on inference. More specifically, we map daily EHR data into four analytic datasets using 90, 30, 15 and 5-day intervals. We apply a semi-parametric and doubly robust estimation approach, the longitudinal TMLE, to estimate the causal effects of four dynamic treatment rules with each dataset, and compare the resulting inferences. To overcome the computational challenges presented by the size of these data, we propose a novel TMLE implementation, the 'long-format TMLE', and rely on the latest advances in scalable data-adaptive machine-learning software, xgboost and h2o, for estimation of the TMLE nuisance parameters.

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arXiv2018

Causal Inference When Counterfactuals Depend on the Proportion of All Subjects Exposed

The assumption that no subject's exposure affects another subject's outcome, known as the no-interference assumption, has long held a foundational position in the study of causal inference. However, this assumption may be violated in many settings, and in recent years has been relaxed considerably. Often this has been achieved with either the aid of a known underlying network, or the assumption that the population can be partitioned into separate groups, between which there is no interference, and within which each subject's outcome may be affected by all the other subjects in the group via the proportion exposed (the stratified interference assumption). In this paper, we instead consider a complete interference setting, in which each subject affects every other subject's outcome. In particular, we make the stratified interference assumption for a single group consisting of the entire sample. This can occur when the exposure is a shared resource whose efficacy is modified by the number of subjects among whom it is shared. We show that a targeted maximum likelihood estimator for the i.i.d.~setting can be used to estimate a class of causal parameters that includes direct effects and overall effects under certain interventions. This estimator remains doubly-robust, semiparametric efficient, and continues to allow for incorporation of machine learning under our model. We conduct a simulation study, and present results from a data application where we study the effect of a nurse-based triage system on the outcomes of patients receiving HIV care in Kenyan health clinics.

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arXiv2018

Robust and Flexible Estimation of Stochastic Mediation Effects: A Proposed Method and Example in a Randomized Trial Setting

Causal mediation analysis can improve understanding of the mechanisms underlying epidemiologic associations. However, the utility of natural direct and indirect effect estimation has been limited by the assumption of no confounder of the mediator-outcome relationship that is affected by prior exposure---an assumption frequently violated in practice. We build on recent work that identified alternative estimands that do not require this assumption and propose a flexible and double robust semiparametric targeted minimum loss-based estimator for data-dependent stochastic direct and indirect effects. The proposed method treats the intermediate confounder affected by prior exposure as a time-varying confounder and intervenes stochastically on the mediator using a distribution which conditions on baseline covariates and marginalizes over the intermediate confounder. In addition, we assume the stochastic intervention is given, conditional on observed data, which results in a simpler estimator and weaker identification assumptions. We demonstrate the estimator's finite sample and robustness properties in a simple simulation study. We apply the method to an example from the Moving to Opportunity experiment. In this application, randomization to receive a housing voucher is the treatment/instrument that influenced moving to a low-poverty neighborhood, which is the intermediate confounder. We estimate the data-dependent stochastic direct effect of randomization to the voucher group on adolescent marijuana use not mediated by change in school district and the stochastic indirect effect mediated by change in school district. We find no evidence of mediation. Our estimator is easy to implement in standard statistical software, and we provide annotated R code to further lower implementation barriers.

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arXiv2018

Robust Estimation of Data-Dependent Causal Effects based on Observing a Single Time-Series

Consider the case that one observes a single time-series, where at each time t one observes a data record O(t) involving treatment nodes A(t), possible covariates L(t) and an outcome node Y(t). The data record at time t carries information for an (potentially causal) effect of the treatment A(t) on the outcome Y(t), in the context defined by a fixed dimensional summary measure Co(t). We are concerned with defining causal effects that can be consistently estimated, with valid inference, for sequentially randomized experiments without further assumptions. More generally, we consider the case when the (possibly causal) effects can be estimated in a double robust manner, analogue to double robust estimation of effects in the i.i.d. causal inference literature. We propose a general class of averages of conditional (context-specific) causal parameters that can be estimated in a double robust manner, therefore fully utilizing the sequential randomization. We propose a targeted maximum likelihood estimator (TMLE) of these causal parameters, and present a general theorem establishing the asymptotic consistency and normality of the TMLE. We extend our general framework to a number of typically studied causal target parameters, including a sequentially adaptive design within a single unit that learns the optimal treatment rule for the unit over time. Our work opens up robust statistical inference for causal questions based on observing a single time-series on a particular unit.

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arXiv2018

Sequential Double Robustness in Right-Censored Longitudinal Models

Consider estimating the G-formula for the counterfactual mean outcome under a given treatment regime in a longitudinal study. Bang and Robins provided an estimator for this quantity that relies on a sequential regression formulation of this parameter. This approach is doubly robust in that it is consistent if either the outcome regressions or the treatment mechanisms are consistently estimated. We define a stronger notion of double robustness, termed sequential double robustness, for estimators of the longitudinal G-formula. The definition emerges naturally from a more general definition of sequential double robustness for the outcome regression estimators. An outcome regression estimator is sequentially doubly robust (SDR) if, at each subsequent time point, either the outcome regression or the treatment mechanism is consistently estimated. This form of robustness is exactly what one would anticipate is attainable by studying the remainder term of a first-order expansion of the G-formula parameter. We show that a particular implementation of an existing procedure is SDR. We also introduce a novel SDR estimator, whose development involves a novel translation of ideas used in targeted minimum loss-based estimation to the infinite-dimensional setting.

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arXiv2018

Collaborative targeted inference from continuously indexed nuisance parameter estimators

We wish to infer the value of a parameter at a law from which we sample independent observations. The parameter is smooth and we can define two variation-independent features of the law, its $Q$- and $G$-components, such that estimating them consistently at a fast enough product of rates allows to build a confidence interval (CI) with a given asymptotic level from a plain targeted minimum loss estimator (TMLE). Say that the above product is not fast enough and the algorithm for the $G$-component is fine-tuned by a real-valued $h$. A plain TMLE with an $h$ chosen by cross-validation would typically not yield a CI. We construct a collaborative TMLE (C-TMLE) and show under mild conditions that, if there exists an oracle $h$ that makes a bulky remainder term asymptotically Gaussian, then the C-TMLE yields a CI. We illustrate our findings with the inference of the average treatment effect. We conduct a simulation study where the $G$-component is estimated by the LASSO and $h$ is the bound on the coefficients' norms. It sheds light on small sample properties, in the face of low- to high-dimensional baseline covariates, and possibly positivity violation.

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arXiv2018

A new approach to hierarchical data analysis: Targeted maximum likelihood estimation for the causal effect of a cluster-level exposure

We often seek to estimate the impact of an exposure naturally occurring or randomly assigned at the cluster-level. For example, the literature on neighborhood determinants of health continues to grow. Likewise, community randomized trials are applied to learn about real-world implementation, sustainability, and population effects of interventions with proven individual-level efficacy. In these settings, individual-level outcomes are correlated due to shared cluster-level factors, including the exposure, as well as social or biological interactions between individuals. To flexibly and efficiently estimate the effect of a cluster-level exposure, we present two targeted maximum likelihood estimators (TMLEs). The first TMLE is developed under a non-parametric causal model, which allows for arbitrary interactions between individuals within a cluster. These interactions include direct transmission of the outcome (i.e. contagion) and influence of one individual's covariates on another's outcome (i.e. covariate interference). The second TMLE is developed under a causal sub-model assuming the cluster-level and individual-specific covariates are sufficient to control for confounding. Simulations compare the alternative estimators and illustrate the potential gains from pairing individual-level risk factors and outcomes during estimation, while avoiding unwarranted assumptions. Our results suggest that estimation under the sub-model can result in bias and misleading inference in an observational setting. Incorporating working assumptions during estimation is more robust than assuming they hold in the underlying causal model. We illustrate our approach with an application to HIV prevention and treatment.

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arXiv2018

Selecting optimal subgroups for treatment using many covariates

We consider the problem of selecting the optimal subgroup to treat when data on covariates is available from a randomized trial or observational study. We distinguish between four different settings including (i) treatment selection when resources are constrained, (ii) treatment selection when resources are not constrained, (iii) treatment selection in the presence of side effects and costs, and (iv) treatment selection to maximize effect heterogeneity. We show that, in each of these cases, the optimal treatment selection rule involves treating those for whom the predicted mean difference in outcomes comparing those with versus without treatment, conditional on covariates, exceeds a certain threshold. The threshold varies across these four scenarios but the form of the optimal treatment selection rule does not. The results suggest a move away from traditional subgroup analysis for personalized medicine. New randomized trial designs are proposed so as to implement and make use of optimal treatment selection rules in health care practice.

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arXiv2017

Uniform Consistency of the Highly Adaptive Lasso Estimator of Infinite Dimensional Parameters

Consider the case that we observe $n$ independent and identically distributed copies of a random variable with a probability distribution known to be an element of a specified statistical model. We are interested in estimating an infinite dimensional target parameter that minimizes the expectation of a specified loss function. In \cite{generally_efficient_TMLE} we defined an estimator that minimizes the empirical risk over all multivariate real valued cadlag functions with variation norm bounded by some constant $M$ in the parameter space, and selects $M$ with cross-validation. We referred to this estimator as the Highly-Adaptive-Lasso estimator due to the fact that the constrained can be formulated as a bound $M$ on the sum of the coefficients a linear combination of a very large number of basis functions. Specifically, in the case that the target parameter is a conditional mean, then it can be implemented with the standard LASSO regression estimator. In \cite{generally_efficient_TMLE} we proved that the HAL-estimator is consistent w.r.t. the (quadratic) loss-based dissimilarity at a rate faster than $n^{-1/2}$ (i.e., faster than $n^{-1/4}$ w.r.t. a norm), even when the parameter space is completely nonparametric. The only assumption required for this rate is that the true parameter function has a finite variation norm. The loss-based dissimilarity is often equivalent with the square of an $L^2(P_0)$-type norm. In this article, we establish that under some weak continuity condition, the HAL-estimator is also uniformly consistent.

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arXiv2017

On Adaptive Propensity Score Truncation in Causal Inference

The positivity assumption, or the experimental treatment assignment (ETA) assumption, is important for identifiability in causal inference. Even if the positivity assumption holds, practical violations of this assumption may jeopardize the finite sample performance of the causal estimator. One of the consequences of practical violations of the positivity assumption is extreme values in the estimated propensity score (PS). A common practice to address this issue is truncating the PS estimate when constructing PS-based estimators. In this study, we propose a novel adaptive truncation method, Positivity-C-TMLE, based on the collaborative targeted maximum likelihood estimation (C-TMLE) methodology. We demonstrate the outstanding performance of our novel approach in a variety of simulations by comparing it with other commonly studied estimators. Results show that by adaptively truncating the estimated PS with a more targeted objective function, the Positivity-C-TMLE estimator achieves the best performance for both point estimation and confidence interval coverage among all estimators considered.

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arXiv2017

Data-adaptive smoothing for optimal-rate estimation of possibly non-regular parameters

We consider nonparametric inference of finite dimensional, potentially non-pathwise differentiable target parameters. In a nonparametric model, some examples of such parameters that are always non pathwise differentiable target parameters include probability density functions at a point, or regression functions at a point. In causal inference, under appropriate causal assumptions, mean counterfactual outcomes can be pathwise differentiable or not, depending on the degree at which the positivity assumption holds. In this paper, given a potentially non-pathwise differentiable target parameter, we introduce a family of approximating parameters, that are pathwise differentiable. This family is indexed by a scalar. In kernel regression or density estimation for instance, a natural choice for such a family is obtained by kernel smoothing and is indexed by the smoothing level. For the counterfactual mean outcome, a possible approximating family is obtained through truncation of the propensity score, and the truncation level then plays the role of the index. We propose a method to data-adaptively select the index in the family, so as to optimize mean squared error. We prove an asymptotic normality result, which allows us to derive confidence intervals. Under some conditions, our estimator achieves an optimal mean squared error convergence rate. Confidence intervals are data-adaptive and have almost optimal width. A simulation study demonstrates the practical performance of our estimators for the inference of a causal dose-response curve at a given treatment dose.

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arXiv2017

Collaborative-controlled LASSO for Constructing Propensity Score-based Estimators in High-Dimensional Data

Propensity score (PS) based estimators are increasingly used for causal inference in observational studies. However, model selection for PS estimation in high-dimensional data has received little attention. In these settings, PS models have traditionally been selected based on the goodness-of-fit for the treatment mechanism itself, without consideration of the causal parameter of interest. Collaborative minimum loss-based estimation (C-TMLE) is a novel methodology for causal inference that takes into account information on the causal parameter of interest when selecting a PS model. This "collaborative learning" considers variable associations with both treatment and outcome when selecting a PS model in order to minimize a bias-variance trade off in the estimated treatment effect. In this study, we introduce a novel approach for collaborative model selection when using the LASSO estimator for PS estimation in high-dimensional covariate settings. To demonstrate the importance of selecting the PS model collaboratively, we designed quasi-experiments based on a real electronic healthcare database, where only the potential outcomes were manually generated, and the treatment and baseline covariates remained unchanged. Results showed that the C-TMLE algorithm outperformed other competing estimators for both point estimation and confidence interval coverage. In addition, the PS model selected by C-TMLE could be applied to other PS-based estimators, which also resulted in substantive improvement for both point estimation and confidence interval coverage. We illustrate the discussed concepts through an empirical example comparing the effects of non-selective nonsteroidal anti-inflammatory drugs with selective COX-2 inhibitors on gastrointestinal complications in a population of Medicare beneficiaries.

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arXiv2017

An Omnibus Nonparametric Test of Equality in Distribution for Unknown Functions

We present a novel family of nonparametric omnibus tests of the hypothesis that two unknown but estimable functions are equal in distribution when applied to the observed data structure. We developed these tests, which represent a generalization of the maximum mean discrepancy tests described in Gretton et al. [2006], using recent developments from the higher-order pathwise differentiability literature. Despite their complex derivation, the associated test statistics can be expressed rather simply as U-statistics. We study the asymptotic behavior of the proposed tests under the null hypothesis and under both fixed and local alternatives. We provide examples to which our tests can be applied and show that they perform well in a simulation study. As an important special case, our proposed tests can be used to determine whether an unknown function, such as the conditional average treatment effect, is equal to zero almost surely.

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arXiv2017

Conducting Simulations in Causal Inference with Networks-Based Structural Equation Models

The past decade has seen an increasing body of literature devoted to the estimation of causal effects in network-dependent data. However, the validity of many classical statistical methods in such data is often questioned. There is an emerging need for objective and practical ways to assess which causal methodologies might be applicable and valid in network-dependent data. This paper describes a set of tools implemented in the simcausal R package that allow simulating data based on user-specified structural equation model for connected units. Specification and simulation of counterfactual data is implemented for static, dynamic and stochastic interventions. A new interface aims to simplify the specification of network-based functional relationships between connected units. A set of examples illustrates how these simulations may be applied to evaluation of different statistical methods for estimation of causal effects in network-dependent data.

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arXiv2017

Doubly Robust Inference for Targeted Minimum Loss Based Estimation in Randomized Trials with Missing Outcome Data

Missing outcome data is one of the principal threats to the validity of treatment effect estimates from randomized trials. The outcome distributions of participants with missing and observed data are often different, which increases the risk of bias. Causal inference methods may aid in reducing the bias and improving efficiency by incorporating baseline variables into the analysis. In particular, doubly robust estimators incorporate estimates of two nuisance parameters: the outcome regression and the missingness mechanism, to adjust for differences in the observed and unobserved groups that can be explained by observed covariates. Such nuisance parameters are traditionally estimated using parametric models, which generally preclude consistent estimation, particularly in moderate to high dimensions. Recent research on missing data has focused on data-adaptive estimation of the nuisance parameters in order to achieve consistency, but the large sample properties of such estimators are poorly understood. In this article we discuss a doubly robust estimator that is consistent and asymptotically normal (CAN) under data-adaptive consistent estimation of the outcome regression or the missingness mechanism. We provide a formula for an asymptotically valid confidence interval under minimal assumptions. We show that our proposed estimator has smaller finite-sample bias compared to standard doubly robust estimators. We present a simulation study demonstrating the enhanced performance of our estimators in terms of bias, efficiency, and coverage of the confidence intervals. We present the results of an illustrative example: a randomized, double-blind phase II/III trial of antiretroviral therapy in HIV-infected persons, and provide R code implementing our proposed estimators.

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