skip to main content

Title: SMIM: A unified framework of survival sensitivity analysis using multiple imputation and martingale

Censored survival data are common in clinical trial studies. We propose a unified framework for sensitivity analysis to censoring at random in survival data using multiple imputation and martingale, called SMIM. The proposed framework adopts the δ‐adjusted and control‐based models, indexed by the sensitivity parameter, entailing censoring at random and a wide collection of censoring not at random assumptions. Also, it targets a broad class of treatment effect estimands defined as functionals of treatment‐specific survival functions, taking into account missing data due to censoring. Multiple imputation facilitates the use of simple full‐sample estimation; however, the standard Rubin's combining rule may overestimate the variance for inference in the sensitivity analysis framework. We decompose the multiple imputation estimator into a martingale series based on the sequential construction of the estimator and propose the wild bootstrap inference by resampling the martingale series. The new bootstrap inference has a theoretical guarantee for consistency and is computationally efficient compared to the nonparametric bootstrap counterpart. We evaluate the finite‐sample performance of the proposed SMIM through simulation and an application on an HIV clinical trial.

more » « less
Award ID(s):
Author(s) / Creator(s):
 ;  ;  ;  
Publisher / Repository:
Date Published:
Journal Name:
Page Range / eLocation ID:
p. 230-240
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. Missing data is inevitable in longitudinal clinical trials. Conventionally, the missing at random assumption is assumed to handle missingness, which however is unverifiable empirically. Thus, sensitivity analyses are critically important to assess the robustness of the study conclusions against untestable assumptions. Toward this end, regulatory agencies and the pharmaceutical industry use sensitivity models such as return-to-baseline, control-based, and washout imputation, following the ICH E9(R1) guidance. Multiple imputation is popular in sensitivity analyses; however, it may be inefficient and result in an unsatisfying interval estimation by Rubin’s combining rule. We propose distributional imputation in sensitivity analysis, which imputes each missing value by samples from its target imputation model given the observed data. Drawn on the idea of Monte Carlo integration, the distributional imputation estimator solves the mean estimating equations of the imputed dataset. It is fully efficient with theoretical guarantees. Moreover, we propose weighted bootstrap to obtain a consistent variance estimator, taking into account the variabilities due to model parameter estimation and target parameter estimation. The superiority of the distributional imputation framework is validated in the simulation study and an antidepressant longitudinal clinical trial.

    more » « less
  2. Summary

    Recently personalized medicine and dynamic treatment regimes have drawn considerable attention. Dynamic treatment regimes are rules that govern the treatment of subjects depending on their intermediate responses or covariates. Two-stage randomization is a useful set-up to gather data for making inference on such regimes. Meanwhile, the number of clinical trials involving competing risk censoring has risen, where subjects in a study are exposed to more than one possible failure and the specific event of interest may not be observed because of competing events. We aim to compare several treatment regimes from a two-stage randomized trial on survival outcomes that are subject to competing risk censoring. The cumulative incidence function (CIF) has been widely used to quantify the cumulative probability of occurrence of the target event over time. However, if we use only the data from those subjects who have followed a specific treatment regime to estimate the CIF, the resulting estimator may be biased. Hence, we propose alternative non-parametric estimators for the CIF by using inverse probability weighting, and we provide inference procedures including procedures to compare the CIFs from two treatment regimes. We show the practicality and advantages of the proposed estimators through numerical studies.

    more » « less
  3. Abstract

    With advances in biomedical research, biomarkers are becoming increasingly important prognostic factors for predicting overall survival, while the measurement of biomarkers is often censored due to instruments' lower limits of detection. This leads to two types of censoring: random censoring in overall survival outcomes and fixed censoring in biomarker covariates, posing new challenges in statistical modeling and inference. Existing methods for analyzing such data focus primarily on linear regression ignoring censored responses or semiparametric accelerated failure time models with covariates under detection limits (DL). In this paper, we propose a quantile regression for survival data with covariates subject to DL. Comparing to existing methods, the proposed approach provides a more versatile tool for modeling the distribution of survival outcomes by allowing covariate effects to vary across conditional quantiles of the survival time and requiring no parametric distribution assumptions for outcome data. To estimate the quantile process of regression coefficients, we develop a novel multiple imputation approach based on another quantile regression for covariates under DL, avoiding stringent parametric restrictions on censored covariates as often assumed in the literature. Under regularity conditions, we show that the estimation procedure yields uniformly consistent and asymptotically normal estimators. Simulation results demonstrate the satisfactory finite‐sample performance of the method. We also apply our method to the motivating data from a study of genetic and inflammatory markers of Sepsis.

    more » « less
  4. Abstract

    Structural nested mean models (SNMMs) are useful for causal inference of treatment effects in longitudinal observational studies. Most existing works assume that the data are collected at prefixed time points for all subjects, which, however, may be restrictive in practice. To deal with irregularly spaced observations, we assume a class of continuous‐time SNMMs and a martingale condition of no unmeasured confounding (NUC) to identify the causal parameters. We develop the semiparametric efficiency theory and locally efficient estimators for continuous‐time SNMMs. This task is nontrivial due to the restrictions from the NUC assumption imposed on the SNMM parameter. In the presence of ignorable censoring, we show that the complete‐case estimator is optimal among a class of weighting estimators including the inverse probability of censoring weighting estimator, and it achieves a double robustness feature in that it is consistent if at least one of the models for the potential outcome mean function and the treatment process is correctly specified. The new framework allows us to conduct causal analysis respecting the underlying continuous‐time nature of data processes. The simulation study shows that the proposed estimator outperforms existing approaches. We estimate the effect of time to initiate highly active antiretroviral therapy on the CD4 count at year 2 from the observational Acute Infection and Early Disease Research Program database.

    more » « less
  5. Abstract Many causal processes have spatial and temporal dimensions. Yet the classic causal inference framework is not directly applicable when the treatment and outcome variables are generated by spatio-temporal point processes. We extend the potential outcomes framework to these settings by formulating the treatment point process as a stochastic intervention. Our causal estimands include the expected number of outcome events in a specified area under a particular stochastic treatment assignment strategy. Our methodology allows for arbitrary patterns of spatial spillover and temporal carryover effects. Using martingale theory, we show that the proposed estimator is consistent and asymptotically normal as the number of time periods increases. We propose a sensitivity analysis for the possible existence of unmeasured confounders, and extend it to the Hájek estimator. Simulation studies are conducted to examine the estimators' finite sample performance. Finally, we illustrate the proposed methods by estimating the effects of American airstrikes on insurgent violence in Iraq from February 2007 to July 2008. Our analysis suggests that increasing the average number of daily airstrikes for up to 1 month may result in more insurgent attacks. We also find some evidence that airstrikes can displace attacks from Baghdad to new locations up to 400 km away. 
    more » « less