Prediction meets causal inference: the role of treatment in clinical prediction models
Nan van Geloven, Sonja Swanson, Chava Ramspek, Kim Luijken, Merel van Diepen, Tim Morris, Rolf Groenwold, Hans van Houwelingen, Hein Putter, Saskia le Cessie
In this paper we study approaches for dealing with treatment when developing a clinical prediction model. Analogous to the estimand framework recently proposed by the European Medicines Agency for clinical trials, we propose a `predictimand' framework of different questions that may be of interest when predicting risk in relation to treatment started after baseline. We provide a formal definition of the estimands matching these questions, give examples of settings in which each is useful and discuss appropriate estimators including their assumptions. We illustrate the impact of the predictimand choice in a dataset of patients with end-stage kidney disease. We argue that clearly defining the estimand is equally important in prediction research as in causal inference.
Background: In epidemiology, causal inference and prediction modeling methodologies have been historically distinct. Directed Acyclic Graphs (DAGs) are used to model a priori causal assumptions and inform variable selection strategies for causal questions. Although tools originally designed for prediction are finding applications in causal inference, the counterpart has remained largely unexplored. The aim of this theoretical and simulation-based study is to assess the potential benefit of using DAGs in clinical risk prediction modeling. Methods and Findings: We explore how incorporating knowl…
We consider the problem of predicting a response variable from a set of covariates on a data set that differs in distribution from the training data. Causal parameters are optimal in terms of predictive accuracy if in the new distribution either many variables are affected by interventions or only some variables are affected, but the perturbations are strong. If the training and test distributions differ by a shift, causal parameters might be too conservative to perform well on the above task. This motivates anchor regression, a method that makes use of exogeneous variables to solve a relaxati…
The Impact of Missing Data on Causal Discovery: A Multicentric Clinical Study
University of Milano - Bicocca（米兰比可卡大学）；F. Hoffmann - La Roche Ltd（罗氏公司）；Fondazione IRCCS Istituto Nazionale dei Tumori（意大利国家肿瘤研究所）；University of Twente（特文特大学）；RadboudUMC（拉德堡德大学医学中心）；Istituto Dalle Molle di Studi sull’Intelligenza Artificiale (IDSIA)（达勒莫莱人工智能研究所）
The ICH E9 addendum introduces the term intercurrent event to refer to events that happen after randomisation and that can either preclude observation of the outcome of interest or affect its interpretation. It proposes five strategies for handling intercurrent events to form an estimand but does not suggest statistical methods for estimation. In this paper we focus on the hypothetical strategy, where the treatment effect is defined under the hypothetical scenario in which the intercurrent event is prevented. For its estimation, we consider causal inference and missing data methods. We establi…
Mediation analysis allows one to use observational data to estimate the importance of each potential mediating pathway involved in the causal effect of an exposure on an outcome. However, current approaches to mediation analysis with multiple mediators either involve assumptions not verifiable by experiments, or estimate the effect when mediators are manipulated jointly which precludes the practical design of experiments due to curse of dimensionality, or are difficult to interpret when arbitrary causal dependencies are present. We propose a method for mediation analysis for multiple manipulab…
Estimating the causal effects of an intervention in the presence of confounding is a frequently occurring problem in applications such as medicine. The task is challenging since there may be multiple confounding factors, some of which may be missing, and inferences must be made from high-dimensional, noisy measurements. In this paper, we propose a decision-theoretic approach to estimate the causal effects of interventions where a subset of the covariates is unavailable for some patients during testing. Our approach uses the information bottleneck principle to perform a discrete, low-dimensiona…
Estimating Causal Treatment Effects in Placebo-Controlled Randomized Clinical Trials When High Placebo Response is Anticipated
Smith Center for Outcomes Research in Cardiology, Beth Israel Deaconess Medical Center（贝斯以色列女医生医疗中心心脏结局研究史密斯中心）；Department of Statistics, SungKyunKwan University（成均馆大学统计系）；Biostatistics Department, Boston University（波士顿大学生物统计学系）
Language Agents Meet Causality -- Bridging LLMs and Causal World Models
University of Amsterdam（阿姆斯特丹大学）；Institute for Logic, Language and Computation (ILLC)（逻辑、语言与计算研究所）；University of Edinburgh（爱丁堡大学）；Institute for Language, Cognition and Computation (ILCC)（语言、认知与计算研究所）
Pragmatic randomized trials are designed to provide evidence for clinical decision-making rather than regulatory approval. Common features of these trials include the inclusion of heterogeneous or diverse patient populations in a wide range of care settings, the use of active treatment strategies as comparators, unblinded treatment assignment, and the study of long-term, clinically relevant outcomes. These features can greatly increase the usefulness of the trial results for patients, clinicians, and other stakeholders. However, these features also introduce an increased risk of non-adherence,…
The regression discontinuity (RD) design is a quasi-experimental design that estimates the causal effects of a treatment by exploiting naturally occurring treatment rules. It can be applied in any context where a particular treatment or intervention is administered according to a pre-specified rule linked to a continuous variable. Such thresholds are common in primary care drug prescription where the RD design can be used to estimate the causal effect of medication in the general population. Such results can then be contrasted to those obtained from randomised controlled trials (RCTs) and info…
Noncompliance and missing data often occur in randomized trials, which complicate the inference of causal effects. When both noncompliance and missing data are present, previous papers proposed moment and maximum likelihood estimators for binary and normally distributed continuous outcomes under the latent ignorable missing data mechanism. However, the latent ignorable missing data mechanism may be violated in practice, because the missing data mechanism may depend directly on the missing outcome itself. Under noncompliance and an outcome-dependent nonignorable missing data mechanism, previous…
In clinical trials, it is often of interest to understand the principal causal effect (PCE), the average treatment effect for a principal stratum (a subset of patients defined by the potential outcomes of one or more post-baseline variables). Commonly used assumptions include monotonicity, principal ignorability, and cross-world assumptions of principal ignorability and principal strata independence. In this article, we evaluate these assumptions through a 2$\times$2 cross-over study in which the potential outcomes under both treatments can be observed, provided there are no carry-over and stu…
Integrating data from multiple heterogeneous sources has become increasingly popular to achieve a large sample size and diverse study population. This paper reviews development in causal inference methods that combines multiple datasets collected by potentially different designs from potentially heterogeneous populations. We summarize recent advances on combining randomized clinical trial with external information from observational studies or historical controls, combining samples when no single sample has all relevant variables with application to two-sample Mendelian randomization, distribu…
The analysis of causal effects when the outcome of interest is possibly truncated by death has a long history in statistics and causal inference. The survivor average causal effect is commonly identified with more assumptions than those guaranteed by the design of a randomized clinical trial or using sensitivity analysis. This paper demonstrates that individual level causal effects in the `always survivor' principal stratum can be identified with no stronger identification assumptions than randomization. We illustrate the practical utility of our methods using data from a clinical trial on pat…
University of Melbourne（墨尔本大学）；University of Tartu（塔尔图大学）
This paper proposes an approach to analyze an event log of a business process in order to generate case-level recommendations of treatments that maximize the probability of a given outcome. Users classify the attributes in the event log into controllable and non-controllable, where the former correspond to attributes that can be altered during an execution of the process (the possible treatments). We use an action rule mining technique to identify treatments that co-occur with the outcome under some conditions. Since action rules are generated based on correlation rather than causation, we the…
Data sharing barriers are paramount challenges arising from multicenter clinical trials where multiple data sources are stored in a distributed fashion at different local study sites. Merging such data sources into a common data storage for a centralized statistical analysis requires a data use agreement, which is often time-consuming. Data merging may become more burdensome when causal inference is of primary interest because propensity score modeling involves combining many confounding variables, and systematic incorporation of this additional modeling in meta-analysis has not been thoroughl…
In neoadjuvant trials on early-stage breast cancer, patients are usually randomized into a control group and a treatment group with an additional target therapy. Early efficacy of the new regimen is assessed via the binary pathological complete response (pCR) and the eventual efficacy is assessed via long-term clinical outcomes such as survival. Although pCR is strongly associated with survival, it has not been confirmed as a surrogate endpoint. To fully understand its clinical implication, it is important to establish causal estimands such as the causal effect in survival for patients who wou…
Intercurrent events (ICEs) and missing values are inevitable in clinical trials of any size and duration, making it difficult to assess the treatment effect for all patients in randomized clinical trials. Defining the appropriate estimand that is relevant to the clinical research question is the first step in analyzing data. The tripartite estimands, which evaluate the treatment differences in the proportion of patients with ICEs due to adverse events, the proportion of patients with ICEs due to lack of efficacy, and the primary efficacy outcome for those who can adhere to study treatment unde…
The development of high-throughput sequencing and targeted therapies has led to the emergence of personalized medicine: a patient's molecular profile or the presence of a specific biomarker of drug response will correspond to a treatment recommendation made either by a physician or by a treatment assignment algorithm. The growing number of such algorithms raises the question of how to quantify their clinical impact knowing that a personalized medicine strategy will inherently include different versions of treatment. We thus specify an appropriate causal framework with multiple versions of trea…
Randomized clinical trials (RCTs) are ideal for estimating causal effects, because the distributions of background covariates are similar in expectation across treatment groups. When estimating causal effects using observational data, matching is a commonly used method to replicate the covariate balance achieved in a RCT. Matching algorithms have a rich history dating back to the mid-1900s, but have been used mostly to estimate causal effects between two treatment groups. When there are more than two treatments, estimating causal effects requires additional assumptions and techniques. We propo…
Background and Aims: The methods with which prediction models are usually developed mean that neither the parameters nor the predictions should be interpreted causally. However, when prediction models are used to support decision making, there is often a need for predicting outcomes under hypothetical interventions. We aimed to identify published methods for developing and validating prediction models that enable risk estimation of outcomes under hypothetical interventions, utilizing causal inference: their main methodological approaches, underlying assumptions, targeted estimands, and potenti…
Drug repurposing is an effective strategy to identify new uses for existing drugs, providing the quickest possible transition from bench to bedside. Existing methods for drug repurposing that mainly focus on pre-clinical information may exist translational issues when applied to human beings. Real world data (RWD), such as electronic health records and insurance claims, provide information on large cohorts of users for many drugs. Here we present an efficient and easily-customized framework for generating and testing multiple candidates for drug repurposing using a retrospective analysis of RW…
From Observational Data to Clinical Recommendations: A Causal Framework for Estimating Patient-level Treatment Effects and Learning Policies
Faculty of Data and Decision Sciences, Technion（数据与决策科学学院，技术ion）；Blavatnik School of Computer Science, Tel-Aviv University（Blavatnik计算机科学学院，特拉维夫大学）；Department of Cardiology, Rambam Health Care Campus（心内科部，拉马姆医疗中心）；The Bruce Rappaport Faculty of Medicine, Technion（布鲁斯·拉帕波特医学院，技术ion）；Department of Statistics and Operations Research, School of Mathematical Sciences, Tel Aviv University（统计与运筹学部，数学科学学院，特拉维夫大学）
Causal machine learning for predicting treatment outcomes
LMU Munich（慕尼黑大学）；Munich Center for Machine Learning（慕尼黑机器学习中心）；University of Cambridge（剑桥大学）；TU Munich（慕尼黑工业大学）；Helmholtz Munich（慕尼黑亥姆霍兹中心）；Harvard Medical School（哈佛医学院）；Cambridge Centre for AI in Medicine（剑桥人工智能医学中心）；The Alan Turing Institute（阿兰·图灵研究所）
Causal inference methods are gaining increasing prominence in pharmaceutical drug development in light of the recently published addendum on estimands and sensitivity analysis in clinical trials to the E9 guideline of the International Council for Harmonisation. The E9 addendum emphasises the need to account for post-randomization or `intercurrent' events that can potentially influence the interpretation of a treatment effect estimate at a trial's conclusion. Instrumental Variables (IV) methods have been used extensively in economics, epidemiology and academic clinical studies for `causal infe…
Causal Explainability of Machine Learning in Heart Failure Prediction from Electronic Health Records
Department of Computer Science（计算机科学系）；Tennessee State University（田纳西州立大学）；Department of Electrical and Computer Engineering（电气与计算机工程系）；Department of Mathematics and Statistics（数学与统计学系）；Old Dominion University（老奥尔巴尼大学）
Recent theoretical work in causal inference has explored an important class of variables which, when conditioned on, may further amplify existing unmeasured confounding bias (bias amplification). Despite this theoretical work, existing simulations of bias amplification in clinical settings have suggested bias amplification may not be as important in many practical cases as suggested in the theoretical literature.We resolve this tension by using tools from the semi-parametric regression literature leading to a general characterization in terms of the geometry of OLS estimators which allows us t…
Estimating treatment effects from observational data provides insights about causality guiding many real-world applications such as different clinical study designs, which are the formulations of trials, experiments, and observational studies in medical, clinical, and other types of research. In this paper, we describe causal inference for application in a novel clinical design called basket trial that tests how well a new drug works in patients who have different types of cancer that all have the same mutation. We propose a multi-task adversarial learning (MTAL) method, which incorporates fea…
Defining and identifying causal intervention effects for transmissible infectious disease outcomes is challenging because a treatment -- such as a vaccine -- given to one individual may affect the infection outcomes of others. Epidemiologists have proposed causal estimands to quantify effects of interventions under contagion using a two-person partnership model. These simple conceptual models have helped researchers develop causal estimands relevant to clinical evaluation of vaccine effects. However, many of these partnership models are formulated under structural assumptions that preclude rea…
A causal viewpoint on prediction model performance under changes in case-mix: discrimination and calibration respond differently for prognosis and diagnosis predictions
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, The Netherlands, Department of Data Science and Biostatistics（朱利叶斯健康科学与初级保健中心，乌得勒支大学医学中心，乌得勒支大学，荷兰，数据科学与生物统计学系）
Principal stratification is a causal framework to analyze randomized experiments with a post-treatment variable between the treatment and endpoint variables. Because the principal strata defined by the potential outcomes of the post-treatment variable are not observable, we generally cannot identify the causal effects within principal strata. Motivated by a real data set of phase III adjuvant colon clinical trials, we propose approaches to identifying and estimating the principal causal effects via multiple trials. For the identifiability, we remove the commonly-used exclusion restriction assu…
A tutorial on discovering and quantifying the effect of latent causal sources of multimodal EHR data
Department of Biomedical Informatics Vanderbilt University Medical Center（生物医学信息学系范德堡大学医学中心）；Department of Biomedical Informatics University of Pittsburgh（生物医学信息学系匹兹堡大学）；Departments of Medicine & Biomedical Informatics Vanderbilt University Medical Center（医学与生物医学信息学系范德堡大学医学中心）；Departments of Biomedical Informatics & Computer Science Vanderbilt University Medical Center & Vanderbilt University（生物医学信息学与计算机科学系范德堡大学医学中心及范德堡大学）
Motivated by a potential-outcomes perspective, the idea of principal stratification has been widely recognized for its relevance in settings susceptible to posttreatment selection bias such as randomized clinical trials where treatment received can differ from treatment assigned. In one such setting, we address subtleties involved in inference for causal effects when using a key covariate to predict membership in latent principal strata. We show that when treatment received can differ from treatment assigned in both study arms, incorporating a stratum-predictive covariate can make estimates of…
The usual development cycles are too slow for the development of vaccines, diagnostics and treatments in pandemics such as the ongoing SARS-CoV-2 pandemic. Given the pressure in such a situation, there is a risk that findings of early clinical trials are overinterpreted despite their limitations in terms of size and design. Motivated by a non-randomized open-label study investigating the efficacy of hydroxychloroquine in patients with COVID-19, we describe in a unified fashion various alternative approaches to the analysis of non-randomized studies. A widely used tool to reduce the impact of t…
University of Science and Technology of China（中国科学技术大学）；Southern University of Science and Technology（南方科技大学）
Type 2 diabetes (T2DM), one of the most prevalent chronic diseases, affects the glucose metabolism of the human body, which decreases the quantity of life and brings a heavy burden on social medical care. Patients with T2DM are more likely to suffer bone fragility fracture as diabetes affects bone mineral density (BMD). However, the discovery of the determinant factors of BMD in a medical way is expensive and time-consuming. In this paper, we propose a novel algorithm, Prior-Knowledge-driven local Causal structure Learning (PKCL), to discover the underlying causal mechanism between BMD and its…
Centre for Big Data Research in Health (CBDRH)（健康大数据研究中心）
Causal inference for observational longitudinal studies often requires the accurate estimation of treatment effects on time-to-event outcomes in the presence of time-dependent patient history and time-dependent covariates. To tackle this longitudinal treatment effect estimation problem, we have developed a time-variant causal survival (TCS) model that uses the potential outcomes framework with an ensemble of recurrent subnetworks to estimate the difference in survival probabilities and its confidence interval over time as a function of time-dependent covariates and treatments. Using simulated …
New York University（纽约大学）；Columbia University（哥伦比亚大学）
Causal inference from observational data requires assumptions. These assumptions range from measuring confounders to identifying instruments. Traditionally, causal inference assumptions have focused on estimation of effects for a single treatment. In this work, we construct techniques for estimation with multiple treatments in the presence of unobserved confounding. We develop two assumptions based on shared confounding between treatments and independence of treatments given the confounder. Together, these assumptions lead to a confounder estimator regularized by mutual information. For this e…
