Patients often discontinue treatment in a clinical trial because their health condition is not improving. Consequently, the patients still in the study at the end of the trial have better health outcomes on average than the initial patient population would have had if every patient had completed the trial. If we only analyze the patients who complete the trial, then this missing data problem biases the estimator of a medication's efficacy because study outcomes are missing not at random (MNAR). One way to overcome this problem - the trimmed means approach for missing data - sets missing values as slightly worse than the worst observed outcome and then trims away a fraction of the distribution from each treatment arm before calculating differences in treatment efficacy (Permutt 2017, Pharmaceutical statistics 16.1:20-28). In this paper we derive sufficient and necessary conditions for when this approach can identify the average population treatment effect in the presence of MNAR data. Numerical studies show the trimmed means approach's ability to effectively estimate treatment efficacy when data are MNAR and missingness is strongly associated with an unfavorable outcome, but trimmed means fail when data are missing at random (MAR) when the better approach would be to multiply impute the missing values. If the reasons for discontinuation in a clinical trial are known analysts can improve estimates with a combination of multiple imputation (MI) and the trimmed means approach when the assumptions of each missing data mechanism hold. When the assumptions are justifiable, using trimmed means can help identify treatment effects notwithstanding MNAR data.
Missing exposure information is a very common feature of many observational studies. Here we study identifiability and efficient estimation of causal effects on vector outcomes, in such cases where treatment is unconfounded but partially missing. We consider a missing at random setting where missingness in treatment can depend not only on complex covariates, but also on post-treatment outcomes. We give a new identifying expression for average treatment effects in this setting, along with the efficient influence function for this parameter in a nonparametric model, which yields a nonparametric …
We focus on the problem of generalizing a causal effect estimated on a randomized controlled trial (RCT) to a target population described by a set of covariates from observational data. Available methods such as inverse propensity sampling weighting are not designed to handle missing values, which are however common in both data sources. In addition to coupling the assumptions for causal effect identifiability and for the missing values mechanism and to defining appropriate estimation strategies, one difficulty is to consider the specific structure of the data with two sources and treatment an…
Efficient Nonparametric Inference for Mediation Analysis with Nonignorable Missing Confounders
Institute of Statistics and Big Data, Renmin University of China（中国人民大学统计与大数据研究院）；Center for Applied Statistics and School of Statistics, Renmin University of China（中国人民大学应用统计中心及统计学院）；School of Management and Economics, The Chinese University of Hong Kong, Shenzhen（香港中文大学（深圳）经管学院）
Randomized Controlled Trials (RCTs) are often considered the gold standard for estimating causal effect, but they may lack external validity when the population eligible to the RCT is substantially different from the target population. Having at hand a sample of the target population of interest allows us to generalize the causal effect. Identifying the treatment effect in the target population requires covariates to capture all treatment effect modifiers that are shifted between the two sets. Standard estimators then use either weighting (IPSW), outcome modeling (G-formula), or combine the tw…
In the fight against hard-to-treat diseases such as cancer, it is often difficult to discover new treatments that benefit all subjects. For regulatory agency approval, it is more practical to identify subgroups of subjects for whom the treatment has an enhanced effect. Regression trees are natural for this task because they partition the data space. We briefly review existing regression tree algorithms. Then we introduce three new ones that are practically free of selection bias and are applicable to two or more treatments, censored response variables, and missing values in the predictor varia…
Identification of complier and noncomplier average causal effects in the presence of latent missing-at-random (LMAR) outcomes: a unifying view and choices of assumptions
Johns Hopkins Bloomberg School of Public Health（约翰斯·霍普金斯大学布隆伯格公共卫生学院）
The problem of estimating the size of a population based on a subset of individuals observed across multiple data sources is often referred to as capture-recapture or multiple-systems estimation. This is fundamentally a missing data problem, where the number of unobserved individuals represents the missing data. As with any missing data problem, multiple-systems estimation requires users to make an untestable identifying assumption in order to estimate the population size from the observed data. If an appropriate identifying assumption cannot be found for a data set, no estimate of the populat…
Pattern-mixture models provide a transparent approach for handling missing data, where the full-data distribution is factorized in a way that explicitly shows the parts that can be estimated from observed data alone, and the parts that require identifying restrictions. We introduce a nonparametric estimator of the full-data distribution based on the pattern-mixture model factorization. Our approach uses the empirical observed-data distribution and augments it with a nonparametric estimator of the missing-data distributions under a given identifying restriction. Our results apply to a large cla…
Trial-based economic evaluations are typically performed on cross-sectional variables, derived from the responses for only the completers in the study, using methods that ignore the complexities of utility and cost data (e.g. skewness and spikes). We present an alternative and more efficient Bayesian parametric approach to handle missing longitudinal outcomes in economic evaluations, while accounting for the complexities of the data. We specify a flexible parametric model for the observed data and partially identify the distribution of the missing data with partial identifying restrictions and…
With nonignorable missing data, likelihood-based inference should be based on the joint distribution of the study variables and their missingness indicators. These joint models cannot be estimated from the data alone, thus requiring the analyst to impose restrictions that make the models uniquely obtainable from the distribution of the observed data. We present an approach for constructing classes of identifiable nonignorable missing data models. The main idea is to use a sequence of carefully set up identifying assumptions, whereby we specify potentially different missingness mechanisms for d…
Longitudinal data are common in clinical trials and observational studies, where missing outcomes due to dropouts are always encountered. Under such context with the assumption of missing at random, the weighted generalized estimating equations (WGEE) approach is widely adopted for marginal analysis. Model selection on marginal mean regression is a crucial aspect of data analysis, and identifying an appropriate correlation structure for model fitting may also be of interest and importance. However, the existing information criteria for model selection in WGEE have limitations, such as separate…
Integrative analysis of datasets generated by multiple cohorts is a widely-used approach for increasing sample size, precision of population estimators, and generalizability of analysis results in epidemiological studies. However, often each individual cohort dataset does not have all variables of interest for an integrative analysis collected as a part of an original study. Such cohort-level missingness poses methodological challenges to the integrative analysis since missing variables have traditionally: (1) been removed from the data for complete case analysis; or (2) been completed by miss…
We introduce the concept of pattern graphs--directed acyclic graphs representing how response patterns are associated. A pattern graph represents an identifying restriction that is nonparametrically identified/saturated and is often a missing not at random restriction. We introduce a selection model and a pattern mixture model formulations using the pattern graphs and show that they are equivalent. A pattern graph leads to an inverse probability weighting estimator as well as an imputation-based estimator. We also study the semi-parametric efficiency theory and derive a multiply-robust estimat…
In some multivariate problems with missing data, pairs of variables exist that are never observed together. For example, some modern biological tools can produce data of this form. As a result of this structure, the covariance matrix is only partially identifiable, and point estimation requires that identifying assumptions be made. These assumptions can introduce an unknown and potentially large bias into the inference. This paper presents a method based on semidefinite programming for automatically quantifying this potential bias by computing the range of possible equal-likelihood inferred va…
Multiple imputation is a straightforward method for handling missing data in a principled fashion. This paper presents an overview of multiple imputation, including important theoretical results and their practical implications for generating and using multiple imputations. A review of strategies for generating imputations follows, including recent developments in flexible joint modeling and sequential regression/chained equations/fully conditional specification approaches. Finally, we compare and contrast different methods for generating imputations on a range of criteria before identifying p…
PURPOSE: Clinical examinations are performed on the basis of necessity. However, our decisions to investigate and document are influenced by various other factors, such as workload and preconceptions. Data missingness patterns may contain insights into conscious and unconscious norms of clinical practice. METHODS: We examine data from the SPOTLIGHT study, a multi-centre cohort study of the effect of prompt ICU admission on mortality. We identify missing values and generate an auxiliary dataset indicating the missing entries. We deploy sparse Gaussian Graphical modelling techniques to identify …
Clinical trials that investigate interventions on physical activity often use accelerometers to measure step count at a very granular level, often in 5-second epochs. Participants typically wear the accelerometer for a week-long period at baseline, and for one or more week-long follow-up periods after the intervention. The data is usually aggregated to provide daily or weekly step counts for the primary analysis. Missing data are common as participants may not wear the device as per protocol. Approaches to handling missing data in the literature have largely defined missingness on the day leve…
A Unified Framework for Variable Selection in Model-Based Clustering with Missing Not at Random
Faculty of Mathematics and Computer Science, University of Science, Ho Chi Minh City, Vietnam（越南科技大学数学与计算机科学学院）；Vietnam National University Ho Chi Minh City, Vietnam（越南胡志明市国家大学）；School of Information and Communications Technology, Hanoi University of Science and Technology, Ha Noi, Vietnam（河内科学技术大学信息与通信技术学院）；ARC Centre of Excellence for the Mathematical Analysis of Cellular Systems（细胞系统数学分析卓越中心）；School of Mathematical Sciences, Queensland University of Technology, Brisbane City, Australia（昆士兰科技大学数学科学学院）
We consider identification and inference about mean functionals of observed covariates and an outcome variable subject to nonignorable missingness. By leveraging a shadow variable, we establish a necessary and sufficient condition for identification of the mean functional even if the full data distribution is not identified. We further characterize a necessary condition for $\sqrt{n}$-estimability of the mean functional. This condition naturally strengthens the identifying condition, and it requires the existence of a function as a solution to a representer equation that connects the shadow va…
Doubly robust target inference for generalized linear regression with completely missing covariates
School of Mathematics and Statistics, Huazhong University of Science and Technology（华中科技大学数学与统计学院）；Department of Statistics and Data Science, Tsinghua University（清华大学统计与数据科学系）
Identifying expanding TCR clonotypes with a longitudinal Bayesian mixture model and their associations with cancer patient prognosis, metastasis-directed therapy, and VJ gene enrichment
Department of Biostatistics（生物统计系）；Department of Radiation Oncology, Mayo Clinic（梅奥诊所放射肿瘤科）；Department of Translational Molecular Pathology（转化分子病理学系）；Departments of Thoracic/Head and Neck Medical Oncology（胸部/头颈医学肿瘤科）；Department of Radiation Oncology, University of Texas MD Anderson Cancer Center（德克萨斯大学安德森癌症中心放射肿瘤科）
