arXiv subjects

Daniel O. Scharfstein

Publications and source records attributed to Daniel O. Scharfstein.

11 recordsLinked to original sources

arXiv2026

Inverse probability weighting for auxiliary variable dependent sampling in observational studies of Long COVID

Selective testing based on values of auxiliary variables is an increasingly popular design strategy in observational studies and is ubiquitous in electronic health record data. Ignoring this underlying sampling mechanism can lead to biased estimation and erroneous scientific conclusions. Yet, rigorous analytic methods for accounting for two-phase sampling designs in observational settings remain under-utilized. Motivated by the Researching COVID to Enhance Recovery (RECOVER) Adult and Pediatric observational cohort studies, we describe common pitfalls and an approach for analysis of data collected via auxiliary variable dependent sampling.

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arXiv2025

SensIAT: An R Package for Conducting Sensitivity Analysis of Randomized Trials with Irregular Assessment Times

This paper introduces an R package SensIAT that implements a sensitivity analysis methodology, based on augmented inverse intensity weighting, for randomized trials with irregular and potentially informative assessment times. Targets of inference involve the population mean outcome in each treatment arm as well as the difference in these means (i.e., treatment effect) at specified times after randomization. This methodology is useful in settings where there is concern that study participants are either more, or less, likely to have assessments at times when their outcomes are worse. In such settings, unadjusted estimates can be biased. The methodology allows researchers to see how inferences are impacted by a range of assumptions about the strength and direction of informative timing in each arm, while incorporating flexible semi-parametric modeling. We describe the functions implemented in SensIAT and illustrate them through an analysis of a synthetic dataset motivated by the HAP2 asthma randomized clinical trial.

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arXiv2025

Semiparametric sensitivity analysis: unmeasured confounding in observational studies

Establishing cause-effect relationships from observational data often relies on untestable assumptions. It is crucial to know whether, and to what extent, the conclusions drawn from non-experimental studies are robust to potential unmeasured confounding. In this paper, we focus on the average causal effect (ACE) as our target of inference. We generalize the sensitivity analysis approach developed by Robins et al. (2000), Franks et al. (2020), and Zhou and Yao (2023). We use semiparametric theory to derive the non-parametric efficient influence function of the ACE, for fixed sensitivity parameters. We use this influence function to construct a one-step, split sample, truncated estimator of the ACE. Our estimator depends on semiparametric models for the distribution of the observed data; importantly, these models do not impose any restrictions on the values of sensitivity analysis parameters. We establish sufficient conditions ensuring that our estimator has root-n asymptotics. We use our methodology to evaluate the causal effect of smoking during pregnancy on birth weight. We also evaluate the performance of estimation procedure in a simulation study.

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arXiv2024

Semi-Parametric Sensitivity Analysis for Trials with Irregular and Informative Assessment Times

Many trials are designed to collect outcomes at or around pre-specified times after randomization. If there is variability in the times when participants are actually assessed, this can pose a challenge to learning the effect of treatment, since not all participants have outcome assessments at the times of interest. Furthermore, observed outcome values may not be representative of all participants' outcomes at a given time. Methods have been developed that account for some types of such irregular and informative assessment times; however, since these methods rely on untestable assumptions, sensitivity analyses are needed. We develop a methodology that is benchmarked at the explainable assessmen (EA) assumption, under which assessment and outcomes at each time are related only through data collected prior to that time. Our method uses an exponential tilting assumption, governed by a sensitivity analysis parameter, that posits deviations from the EA assumption. Our inferential strategy is based on a new influence function-based, augmented inverse intensity-weighted estimator. Our approach allows for flexible semiparametric modeling of the observed data, which is separated from specification of the sensitivity parameter. We apply our method to a randomized trial of low-income individuals with uncontrolled asthma, and we illustrate implementation of our estimation procedure in detail.

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arXiv2024

Markov-Restricted Analysis of Randomized Trials with Non-Monotone Missing Binary Outcomes

Scharfstein et al. (2021) developed a sensitivity analysis model for analyzing randomized trials with repeatedly measured binary outcomes that are subject to nonmonotone missingness. Their approach becomes computationally intractable when the number of measurements is large (e.g., greater than 15). In this paper, we repair this problem by introducing mth-order Markovian restrictions. We establish identification results for the joint distribution of the binary outcomes by representing the model as a directed acyclic graph (DAG). We develop a novel estimation strategy for a smooth functional of the joint distribution. We illustrate our methodology in the context of a randomized trial designed to evaluate a web-delivered psychosocial intervention to reduce substance use, assessed by evaluating abstinence twice weekly for 12 weeks, among patients entering outpatient addiction treatment.

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arXiv2024

Sensitivity analysis for principal ignorability violation in estimating complier and noncomplier average causal effects

An important strategy for identifying principal causal effects, which are often used in settings with noncompliance, is to invoke the principal ignorability (PI) assumption. As PI is untestable, it is important to gauge how sensitive effect estimates are to its violation. We focus on this task for the common one-sided noncompliance setting where there are two principal strata, compliers and noncompliers. Under PI, compliers and noncompliers share the same outcome-mean-given-covariates function under the control condition. For sensitivity analysis, we allow this function to differ between compliers and noncompliers in several ways, indexed by an odds ratio, a generalized odds ratio, a mean ratio, or a standardized mean difference sensitivity parameter. We tailor sensitivity analysis techniques (with any sensitivity parameter choice) to several types of PI-based main analysis methods, including outcome regression, influence function (IF) based and weighting methods. We illustrate the proposed sensitivity analyses using several outcome types from the JOBS II study. This application estimates nuisance functions parametrically -- for simplicity and accessibility. In addition, we establish rate conditions on nonparametric nuisance estimation for IF-based estimators to be asymptotically normal -- with a view to inform nonparametric inference.

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arXiv2020

Causal Effects in Twin Studies: the Role of Interference

The use of twins designs to address causal questions is becoming increasingly popular. A standard assumption is that there is no interference between twins---that is, no twin's exposure has a causal impact on their co-twin's outcome. However, there may be settings in which this assumption would not hold, and this would (1) impact the causal interpretation of parameters obtained by commonly used existing methods; (2) change which effects are of greatest interest; and (3) impact the conditions under which we may estimate these effects. We explore these issues, and we derive semi-parametric efficient estimators for causal effects in the presence of interference between twins. Using data from the Minnesota Twin Family Study, we apply our estimators to assess whether twins' consumption of alcohol in early adolescence may have a causal impact on their co-twins' substance use later in life.

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arXiv2019

Causal Inference for Comprehensive Cohort Studies

In a comprehensive cohort study of two competing treatments (say, A and B), clinically eligible individuals are first asked to enroll in a randomized trial and, if they refuse, are then asked to enroll in a parallel observational study in which they can choose treatment according to their own preference. We consider estimation of two estimands: (1) comprehensive cohort causal effect -- the difference in mean potential outcomes had all patients in the comprehensive cohort received treatment A vs. treatment B and (2) randomized trial causal effect -- the difference in mean potential outcomes had all patients enrolled in the randomized trial received treatment A vs. treatment B. For each estimand, we consider inference under various sets of unconfoundedness assumptions and construct semiparametric efficient and robust estimators. These estimators depend on nuisance functions, which we estimate, for illustrative purposes, using generalized additive models. Using the theory of sample splitting, we establish the asymptotic properties of our proposed estimators. We also illustrate our methodology using data from the Bypass Angioplasty Revascularization Investigation (BARI) randomized trial and observational registry to evaluate the effect of percutaneous transluminal coronary balloon angioplasty versus coronary artery bypass grafting on 5-year mortality. To evaluate the finite sample performance of our estimators, we use the BARI dataset as the basis of a realistic simulation study.

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arXiv2019

Brand vs. Generic: Addressing Non-Adherence, Secular Trends, and Non-Overlap

While generic drugs offer a cost-effective alternative to brand name drugs, regulators need a method to assess therapeutic equivalence in a post market setting. We develop such a method in the context of assessing the therapeutic equivalence of immediate release (IM) venlafaxine, based on a large insurance claims dataset provided by OptumLabs\textsuperscript{\textregistered}. To properly address this question, our methodology must deal with issues of non-adherence, secular trends in health outcomes, and lack of treatment overlap due to sharp uptake of the generic once it becomes available. We define, identify (under assumptions) and estimate (using G-computation) a causal effect for a time-to-event outcome by extending regression discontinuity to survival curves. We do not find evidence for a lack of therapeutic equivalence of brand and generic IM venlafaxine.

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arXiv2018

Bayesian inference for a principal stratum estimand to assess the treatment effect in a subgroup characterized by post-randomization events

The treatment effect in a specific subgroup is often of interest in randomized clinical trials. When the subgroup is characterized by the absence of certain post-randomization events, a naive analysis on the subset of patients without these events may be misleading. The principal stratification framework allows one to define an appropriate causal estimand in such settings. Statistical inference for the principal stratum estimand hinges on scientifically justified assumptions, which can be included with Bayesian methods through prior distributions. Our motivating example is a large randomized placebo-controlled trial of siponimod in patients with secondary progressive multiple sclerosis. The primary objective of this trial was to demonstrate the efficacy of siponimod relative to placebo in delaying disability progression for the whole study population. However, the treatment effect in the subgroup of patients who would not relapse during the trial is relevant from both a scientific and regulatory perspective. Assessing this subgroup treatment effect is challenging as there is strong evidence that siponimod reduces relapses. Aligned with the draft regulatory guidance ICH E9(R1), we describe in detail the scientific question of interest, the principal stratum estimand, the corresponding analysis method for binary endpoints and sensitivity analyses.

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arXiv2014

Estimation of Treatment Effects in Matched-Pair Cluster Randomized Trials by Calibrating Covariate Imbalance between Clusters

We address estimation of intervention effects in experimental designs in which (a) interventions are assigned at the cluster level; (b) clusters are selected to form pairs, matched on observed characteristics; and (c) intervention is assigned to one cluster at random within each pair. One goal of policy interest is to estimate the average outcome if all clusters in all pairs are assigned control versus if all clusters in all pairs are assigned to intervention. In such designs, inference that ignores individual level covariates can be imprecise because cluster-level assignment can leave substantial imbalance in the covariate distribution between experimental arms within each pair. However, most existing methods that adjust for covariates have estimands that are not of policy interest. We propose a methodology that explicitly balances the observed covariates among clusters in a pair, and retains the original estimand of interest. We demonstrate our approach through the evaluation of the Guided Care program.

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