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When analyzing a selected sample from a general population, selection bias can arise relative to the causal average treatment effect (ATE) for the general population, and also relative to the ATE for the selected sample itself. We provide simple graphical rules that indicate: (1) if a selected-sample analysis will be unbiased for each ATE; (2) whether adjusting for certain covariates could eliminate selection bias. The rules can easily be checked in a standard single-world intervention graph. When the treatment could affect selection, a third estimand of potential scientific interest is the "net treatment difference", namely the net change in outcomes that would occur for the selected sample if all members of the general population were treated versus not treated, including any effects of the treatment on which individuals are in the selected sample . We provide graphical rules for this estimand as well. We decompose bias in a selected-sample analysis relative to the general-population ATE into: (1) "internal bias" relative to the net treatment difference; (2) "net-external bias", a discrepancy between the net treatment difference and the general-population ATE. Each bias can be assessed unambiguously via a distinct graphical rule, providing new conceptual insight into the mechanisms by which certain causal structures produce selection bias.
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We introduce an itemwise modeling approach called "self-censoring" for multivariate nonignorable nonmonotone missing data, where the missingness process of each outcome can be affected by its own value and associated with missingness indicators of other outcomes, while conditionally independent of the other outcomes. The self-censoring model complements previous graphical approaches for the analysis of multivariate nonignorable missing data. It is identified under a completeness condition stating that any variability in one outcome can be captured by variability in the other outcomes among complete cases. For estimation, we propose a suite of semiparametric estimators including doubly robust estimators that deliver valid inferences under partial misspecification of the full-data distribution. We also provide a novel and flexible global sensitivity analysis procedure anchored at the self-censoring. We evaluate the performance of the proposed methods with simulations and apply them to analyze a study about the effect of highly active antiretroviral therapy on preterm delivery of HIV-positive mothers.
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Modelos Estadísticos , Madres , Recién Nacido , Femenino , HumanosRESUMEN
In sequential experiments, subjects become available for the study over a period of time, and covariates are often measured at the time of arrival. We consider the setting where the sample size is fixed but covariate values are unknown until subjects enrol. Given a model for the outcome, a sequential optimal design approach can be used to allocate treatments to minimize the variance of the estimator of the treatment effect. We extend existing optimal design methodology so it can be used within a nonmyopic framework, where treatment allocation for the current subject depends not only on the treatments and covariates of the subjects already enrolled in the study, but also the impact of possible future treatment assignments within a specified horizon. The nonmyopic approach requires recursive formulae and suffers from the curse of dimensionality. We propose a pseudo-nonmyopic approach which has a similar aim to the nonmyopic approach, but does not involve recursion and instead relies on simulating trajectories of future possible decisions. Our simulation studies show that, for the simple case of a logistic regression with a single binary covariate and a binary treatment, and a more realistic case with four binary covariates, binary treatment and treatment-covariate interactions, the nonmyopic and pseudo-nonmyopic approaches provide no competitive advantage over the myopic approach, both in terms of the size of the estimated treatment effect and also the efficiency of the designs. Results are robust to the size of the horizon used in the nonmyopic approach, and the number of simulated trajectories used in the pseudo-nonmyopic approach.
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Huang proposes a method for assessing the impact of a point treatment on mortality either directly or mediated by occurrence of a nonterminal health event, based on data from a prospective cohort study in which the occurrence of the nonterminal health event may be preemptied by death but not vice versa. The author uses a causal mediation framework to formally define causal quantities known as natural (in)direct effects. The novelty consists of adapting these concepts to a continuous-time modeling framework based on counting processes. In an effort to posit "scientifically interpretable estimands," statistical and causal assumptions are introduced for identification. In this commentary, we argue that these assumptions are not only difficult to interpret and justify, but are also likely violated in the hepatitis B motivating example and other survival/time to event settings as well.
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Modelos Estadísticos , Causalidad , Humanos , Estudios ProspectivosRESUMEN
Identifying causal parameters from observational data is fraught with subtleties due to the issues of selection bias and confounding. In addition, more complex questions of interest, such as effects of treatment on the treated and mediated effects may not always be identified even in data where treatment assignment is known and under investigator control, or may be identified under one causal model but not another. Increasingly complex effects of interest, coupled with a diversity of causal models in use resulted in a fragmented view of identification. This fragmentation makes it unnecessarily difficult to determine if a given parameter is identified (and in what model), and what assumptions must hold for this to be the case. This, in turn, complicates the development of estimation theory and sensitivity analysis procedures. In this paper, we give a unifying view of a large class of causal effects of interest, including novel effects not previously considered, in terms of a hierarchy of interventions, and show that identification theory for this large class reduces to an identification theory of random variables under interventions from this hierarchy. Moreover, we show that one type of intervention in the hierarchy is naturally associated with queries identified under the Finest Fully Randomized Causally Interpretable Structure Tree Graph (FFRCISTG) model of Robins (via the extended g-formula), and another is naturally associated with queries identified under the Non-Parametric Structural Equation Model with Independent Errors (NPSEM-IE) of Pearl, via a more general functional we call the edge g-formula. Our results motivate the study of estimation theory for the edge g-formula, since we show it arises both in mediation analysis, and in settings where treatment assignment has unobserved causes, such as models associated with Pearl's front-door criterion.
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The causal inference literature has provided a clear formal definition of confounding expressed in terms of counterfactual independence. The causal inference literature has not, however, produced a clear formal definition of a confounder, as it has given priority to the concept of confounding over that of a confounder. We consider a number of candidate definitions arising from various more informal statements made in the literature. We consider the properties satisfied by each candidate definition, principally focusing on (i) whether under the candidate definition control for all "confounders" suffices to control for "confounding" and (ii) whether each confounder in some context helps eliminate or reduce confounding bias. Several of the candidate definitions do not have these two properties. Only one candidate definition of those considered satisfies both properties. We propose that a "confounder" be defined as a pre-exposure covariate C for which there exists a set of other covariates X such that effect of the exposure on the outcome is unconfounded conditional on (X, C) but such that for no proper subset of (X, C) is the effect of the exposure on the outcome unconfounded given the subset. A variable that helps reduce bias but not eliminate bias we propose referring to as a "surrogate confounder."
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OBJECTIVE: We aimed to learn the causal determinants of postoperative length of stay in cardiac surgery patients undergoing isolated coronary artery bypass grafting or aortic valve replacement surgery. METHODS: For patients undergoing isolated coronary artery bypass grafting or isolated aortic valve replacement surgeries between 2011 and 2016, we used causal graphical modeling on electronic health record data. The Fast Causal Inference (FCI) algorithm from the Tetrad software was used on data to estimate a Partial Ancestral Graph (PAG) depicting direct and indirect causes of postoperative length of stay, given background clinical knowledge. Then, we used the latent variable intervention-calculus when the directed acyclic graph is absent (LV-IDA) algorithm to estimate strengths of causal effects of interest. Finally, we ran a linear regression for postoperative length of stay to contrast statistical associations with what was learned by our causal analysis. RESULTS: In our cohort of 2610 patients, the mean postoperative length of stay was 219 hours compared with the Society of Thoracic Surgeons 2016 national mean postoperative length of stay of approximately 168 hours. Most variables that clinicians believe to be predictors of postoperative length of stay were found to be causes, but some were direct (eg, age, diabetes, hematocrit, total operating time, and postoperative complications), and others were indirect (including gender, race, and operating surgeon). The strongest average causal effects on postoperative length of stay were exhibited by preoperative dialysis (209 hours); neuro-, pulmonary-, and infection-related postoperative complications (315 hours, 89 hours, and 131 hours, respectively); reintubation (61 hours); extubation in operating room (-47 hours); and total operating room duration (48 hours). Linear regression coefficients diverged from causal effects in magnitude (eg, dialysis) and direction (eg, crossclamp time). CONCLUSIONS: By using retrospective electronic health record data and background clinical knowledge, causal graphical modeling retrieved direct and indirect causes of postoperative length of stay and their relative strengths. These insights will be useful in designing clinical protocols and targeting improvements in patient management.
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Procedimientos Quirúrgicos Cardíacos , Diálisis Renal , Humanos , Estudios Retrospectivos , Tiempo de Internación , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/terapiaRESUMEN
BACKGROUND: An important epidemiological question is understanding how vascular risk factors contribute to cognitive impairment. Using data from the Cardiovascular Health Cognition Study, we investigated how subclinical cardiovascular disease (sCVD) relates to cognitive impairment risk and the extent to which the hypothesized risk is mediated by the incidence of clinically manifested cardiovascular disease (CVD), both overall and within apolipoprotein E-4 (APOE-4) subgroups. METHODS: We adopted a novel "separable effects" causal mediation framework that assumes that sCVD has separably intervenable atherosclerosis-related components. We then ran several mediation models, adjusting for key covariates. RESULTS: We found that sCVD increased overall risk of cognitive impairment (risk ratio [RR] = 1.21, 95% confidence interval [CI]: 1.03, 1.44); however, there was little or no mediation by incident clinically manifested CVD (indirect effect RR = 1.02, 95% CI: 1.00, 1.03). We also found attenuated effects among APOE-4 carriers (total effect RR = 1.09, 95% CI: 0.81, 1.47; indirect effect RR = 0.99, 95% CI: 0.96, 1.01) and stronger findings among noncarriers (total effect RR = 1.29, 95% CI: 1.05, 1.60; indirect effect RR = 1.02, 95% CI: 1.00, 1.05). In secondary analyses restricting cognitive impairment to only incident dementia cases, we found similar effect patterns. CONCLUSIONS: We found that the effect of sCVD on cognitive impairment does not seem to be mediated by CVD, both overall and within APOE-4 subgroups. Our results were critically assessed via sensitivity analyses, and they were found to be robust. Future work is needed to fully understand the relationship between sCVD, CVD, and cognitive impairment.
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Enfermedades Cardiovasculares , Disfunción Cognitiva , Humanos , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Disfunción Cognitiva/epidemiología , Factores de Riesgo , Cognición , Apolipoproteína E4/genéticaRESUMEN
Objectives: Access to patient information may affect how home-infusion surveillance staff identify central-line-associated bloodstream infections (CLABSIs). We characterized information hazards in home-infusion CLABSI surveillance and identified possible strategies to mitigate information hazards. Design: Qualitative study using semistructured interviews. Setting and participants: The study included 21 clinical staff members involved in CLABSI surveillance at 5 large home-infusion agencies covering 13 states and the District of Columbia. Methods: Interviews were conducted by 1 researcher. Transcripts were coded by 2 researchers; consensus was reached by discussion. Results: Data revealed the following barriers: information overload, information underload, information scatter, information conflict, and erroneous information. Respondents identified 5 strategies to mitigate information chaos: (1) engage information technology in developing reports; (2) develop streamlined processes for acquiring and sharing data among staff; (3) enable staff access to hospital electronic health records; (4) use a single, validated, home-infusion CLABSI surveillance definition; and (5) develop relationships between home-infusion surveillance staff and inpatient healthcare workers. Conclusions: Information chaos occurs in home-infusion CLABSI surveillance and may affect the development of accurate CLABSI rates in home-infusion therapy. Implementing strategies to minimize information chaos will enhance intra- and interteam collaborations in addition to improving patient-related outcomes.
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OBJECTIVE: Central-line-associated bloodstream infection (CLABSI) surveillance in home infusion therapy is necessary to track efforts to reduce infections, but a standardized, validated, and feasible definition is lacking. We tested the validity of a home-infusion CLABSI surveillance definition and the feasibility and acceptability of its implementation. DESIGN: Mixed-methods study including validation of CLABSI cases and semistructured interviews with staff applying these approaches. SETTING: This study was conducted in 5 large home-infusion agencies in a CLABSI prevention collaborative across 14 states and the District of Columbia. PARTICIPANTS: Staff performing home-infusion CLABSI surveillance. METHODS: From May 2021 to May 2022, agencies implemented a home-infusion CLABSI surveillance definition, using 3 approaches to secondary bloodstream infections (BSIs): National Healthcare Safety Program (NHSN) criteria, modified NHSN criteria (only applying the 4 most common NHSN-defined secondary BSIs), and all home-infusion-onset bacteremia (HiOB). Data on all positive blood cultures were sent to an infection preventionist for validation. Surveillance staff underwent semistructured interviews focused on their perceptions of the definition 1 and 3-4 months after implementation. RESULTS: Interrater reliability scores overall ranged from κ = 0.65 for the modified NHSN criteria to κ = 0.68 for the NHSN criteria to κ = 0.72 for the HiOB criteria. For the NHSN criteria, the agency-determined rate was 0.21 per 1,000 central-line (CL) days, and the validator-determined rate was 0.20 per 1,000 CL days. Overall, implementing a standardized definition was thought to be a positive change that would be generalizable and feasible though time-consuming and labor intensive. CONCLUSIONS: The home-infusion CLABSI surveillance definition was valid and feasible to implement.
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Bacteriemia , Infecciones Relacionadas con Catéteres , Cateterismo Venoso Central , Infección Hospitalaria , Sepsis , Humanos , Infección Hospitalaria/epidemiología , Infecciones Relacionadas con Catéteres/diagnóstico , Infecciones Relacionadas con Catéteres/epidemiología , Infecciones Relacionadas con Catéteres/prevención & control , Reproducibilidad de los Resultados , Sepsis/epidemiología , Bacteriemia/diagnóstico , Bacteriemia/epidemiología , Bacteriemia/prevención & control , Cateterismo Venoso Central/efectos adversosRESUMEN
Whilst estimation of the marginal (total) causal effect of a point exposure on an outcome is arguably the most common objective of experimental and observational studies in the health and social sciences, in recent years, investigators have also become increasingly interested in mediation analysis. Specifically, upon evaluating the total effect of the exposure, investigators routinely wish to make inferences about the direct or indirect pathways of the effect of the exposure not through or through a mediator variable that occurs subsequently to the exposure and prior to the outcome. Although powerful semiparametric methodologies have been developed to analyze observational studies, that produce double robust and highly efficient estimates of the marginal total causal effect, similar methods for mediation analysis are currently lacking. Thus, this paper develops a general semiparametric framework for obtaining inferences about so-called marginal natural direct and indirect causal effects, while appropriately accounting for a large number of pre-exposure confounding factors for the exposure and the mediator variables. Our analytic framework is particularly appealing, because it gives new insights on issues of efficiency and robustness in the context of mediation analysis. In particular, we propose new multiply robust locally efficient estimators of the marginal natural indirect and direct causal effects, and develop a novel double robust sensitivity analysis framework for the assumption of ignorability of the mediator variable.
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We study the identification and estimation of statistical functionals of multivariate data missing non-monotonically and not-at-random, taking a semiparametric approach. Specifically, we assume that the missingness mechanism satisfies what has been previously called "no self-censoring" or "itemwise conditionally independent nonresponse," which roughly corresponds to the assumption that no partially-observed variable directly determines its own missingness status. We show that this assumption, combined with an odds ratio parameterization of the joint density, enables identification of functionals of interest, and we establish the semiparametric efficiency bound for the nonparametric model satisfying this assumption. We propose a practical augmented inverse probability weighted estimator, and in the setting with a (possibly high-dimensional) always-observed subset of covariates, our proposed estimator enjoys a certain double-robustness property. We explore the performance of our estimator with simulation experiments and on a previously-studied data set of HIV-positive mothers in Botswana.
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BACKGROUND: Hospital readmission within 30 days of discharge is a well-studied outcome. Predicting readmission after cardiac surgery, however, is notoriously challenging; the best-performing models in the literature have areas under the curve around .65. A reliable predictive model would enable clinicians to identify patients at risk for readmission and to develop prevention strategies. METHODS: We analyzed The Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database at our institution, augmented with electronic medical record data. Predictors included demographics, preoperative comorbidities, proxies for intraoperative risk, indicators of postoperative complications, and time series-derived variables. We trained several machine learning models, evaluating each on a held-out test set. RESULTS: Our analysis cohort consisted of 4924 cases from 2011 to 2016. Of those, 723 (14.7%) were readmitted within 30 days of discharge. Our models included 141 STS-derived and 24 electronic medical records-derived variables. A random forest model performed best, with test area under the curve 0.76 (95% confidence interval, 0.73 to 0.79). Using exclusively preoperative variables, as in STS calculated risk scores, degraded the area under the curve, to 0.64 (95% confidence interval, 0.60 to 0.68). Key predictors included length of stay (12.5 times more important than the average variable) and whether the patient was discharged to a rehabilitation facility (11.2 times). CONCLUSIONS: Our approach, augmenting STS variables with electronic medical records data and using flexible machine learning modeling, yielded state-of-the-art performance for predicting 30-day readmission. Separately, the importance of variables not directly related to inpatient care, such as discharge location, amplifies questions about the efficacy of assessing care quality by readmissions.
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Procedimientos Quirúrgicos Cardíacos , Readmisión del Paciente , Adulto , Humanos , Alta del Paciente , Aprendizaje Automático , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Estudios de Cohortes , Factores de Riesgo , Estudios RetrospectivosRESUMEN
We propose a new criterion for confounder selection when the underlying causal structure is unknown and only limited knowledge is available. We assume all covariates being considered are pretreatment variables and that for each covariate it is known (i) whether the covariate is a cause of treatment, and (ii) whether the covariate is a cause of the outcome. The causal relationships the covariates have with one another is assumed unknown. We propose that control be made for any covariate that is either a cause of treatment or of the outcome or both. We show that irrespective of the actual underlying causal structure, if any subset of the observed covariates suffices to control for confounding then the set of covariates chosen by our criterion will also suffice. We show that other, commonly used, criteria for confounding control do not have this property. We use formal theory concerning causal diagrams to prove our result but the application of the result does not rely on familiarity with causal diagrams. An investigator simply need ask, "Is the covariate a cause of the treatment?" and "Is the covariate a cause of the outcome?" If the answer to either question is "yes" then the covariate is included for confounder control. We discuss some additional covariate selection results that preserve unconfoundedness and that may be of interest when used with our criterion.
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Algoritmos , Biometría/métodos , Factores de Confusión Epidemiológicos , Interpretación Estadística de Datos , Modelos Estadísticos , Evaluación de Resultado en la Atención de Salud/métodos , Modelos de Riesgos Proporcionales , Simulación por Computador , Intervalos de Confianza , Métodos Epidemiológicos , Humanos , Análisis Numérico Asistido por Computador , Medición de Riesgo/métodos , Factores de Riesgo , Distribuciones EstadísticasRESUMEN
Methods for inferring average causal effects have traditionally relied on two key assumptions: (i) the intervention received by one unit cannot causally influence the outcome of another; and (ii) units can be organized into nonoverlapping groups such that outcomes of units in separate groups are independent. In this article, we develop new statistical methods for causal inference based on a single realization of a network of connected units for which neither assumption (i) nor (ii) holds. The proposed approach allows both for arbitrary forms of interference, whereby the outcome of a unit may depend on interventions received by other units with whom a network path through connected units exists; and long range dependence, whereby outcomes for any two units likewise connected by a path in the network may be dependent. Under network versions of consistency and no unobserved confounding, inference is made tractable by an assumption that the networks outcome, treatment and covariate vectors are a single realization of a certain chain graph model. This assumption allows inferences about various network causal effects via the auto-g-computation algorithm, a network generalization of Robins' well-known g-computation algorithm previously described for causal inference under assumptions (i) and (ii). Supplementary materials for this article are available online.
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Targets of inference that establish causality are phrased in terms of counterfactual responses to interventions. These potential outcomes operationalize cause effect relationships by means of comparisons of cases and controls in hypothetical randomized controlled experiments. In many applied settings, data on such experiments is not directly available, necessitating assumptions linking the counterfactual target of inference with the factual observed data distribution. This link is provided by causal models. Originally defined on potential outcomes directly (Rubin, 1976), causal models have been extended to longitudinal settings (Robins, 1986), and reformulated as graphical models (Spirtes et al., 2001; Pearl, 2009). In settings where common causes of all observed variables are themselves observed, many causal inference targets are identified via variations of the expression referred to in the literature as the g-formula (Robins, 1986), the manipulated distribution (Spirtes et al., 2001), or the truncated factorization (Pearl, 2009). In settings where hidden variables are present, identification results become considerably more complicated. In this manuscript, we review identification theory in causal models with hidden variables for common targets that arise in causal inference applications, including causal effects, direct, indirect, and path-specific effects, and outcomes of dynamic treatment regimes. We will describe a simple formulation of this theory (Tian and Pearl, 2002; Shpitser and Pearl, 2006b,a; Tian, 2008; Shpitser, 2013) in terms of causal graphical models, and the fixing operator, a statistical analogue of the intervention operation (Richardson et al., 2017).
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Causal parameters may not be point identified in the presence of unobserved confounding. However, information about non-identified parameters, in the form of bounds, may still be recovered from the observed data in some cases. We develop a new general method for obtaining bounds on causal parameters using rules of probability and restrictions on counterfactuals implied by causal graphical models. We additionally provide inequality constraints on functionals of the observed data law implied by such causal models. Our approach is motivated by the observation that logical relations between identified and non-identified counterfactual events often yield information about non-identified events. We show that this approach is powerful enough to recover known sharp bounds and tight inequality constraints, and to derive novel bounds and constraints.
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Missing data has the potential to affect analyses conducted in all fields of scientific study including healthcare, economics, and the social sciences. Several approaches to unbiased inference in the presence of non-ignorable missingness rely on the specification of the target distribution and its missingness process as a probability distribution that factorizes with respect to a directed acyclic graph. In this paper, we address the longstanding question of the characterization of models that are identifiable within this class of missing data distributions. We provide the first completeness result in this field of study - necessary and sufficient graphical conditions under which, the full data distribution can be recovered from the observed data distribution. We then simultaneously address issues that may arise due to the presence of both missing data and unmeasured confounding, by extending these graphical conditions and proofs of completeness, to settings where some variables are not just missing, but completely unobserved.