Revisiting the effects of maternal education on adolescents' academic performance: Doubly robust estimation in a network-based observational study.

In many contexts, particularly when study subjects are adolescents, peer effects can invalidate typical statistical requirements in the data. For instance, it is plausible that a student's academic performance is influenced both by their own mother's educational level as well as that of their peers. Since the underlying social network is measured, the Add Health study provides a unique opportunity to examine the impact of maternal college education on adolescent school performance, both direct and indirect. However, causal inference on populations embedded in social networks poses technical challenges, since the typical no interference assumption no longer holds. While inverse probability-of-treatment weighted (IPW) estimators have been developed for this setting, they are often highly unstable. Motivated by the question of maternal education, we propose doubly robust (DR) estimators combining models for treatment and outcome that are consistent and asymptotically normal if either model is correctly specified. We present empirical results that illustrate the DR property and the efficiency gain of DR over IPW estimators even when the treatment model is misspecified. Contrary to previous studies, our robust analysis does not provide evidence of an indirect effect of maternal education on academic performance within adolescents' social circles in Add Health.

A retrospective and prospective study of biostatistics in Canada.

Biostatistics is foundational to public health research and Canada has a history of high impact contributions both in seminal methodological advances and in the rigorous application of methods for the design or analysis of public health studies. In this article, we provide a brief and personal review of selected contributions from Canadian biostatisticians to fields such as survival and life history analysis, sampling, clinical trial methodology, environmental risk assessment, infectious disease epidemiology, and early work on prediction. We also provide a brief look forward at the upcoming needs and future directions of biostatistical research.

RéSUMé: La biostatistique est fondamentale pour la recherche en santé publique et le Canada a un historique de contributions à fort impact, tant dans les avancées méthodologiques majeures que dans l'application rigoureuse de méthodes pour la conception ou l'analyse d'études de santé publique. Dans cet article, nous présentons un examen bref et personnel des contributions des biostatisticiens canadiens dans des domaines tels que l'analyse de la survie et de l'histoire de vie, l'échantillonnage, la méthodologie des essais cliniques, le risque environnemental, l'épidémiologie des maladies infectieuses et les premiers travaux sur la prédiction et la classification. Nous fournissons également un bref aperçu des besoins à venir et des orientations futures de la recherche biostatistique.

Variable selection for individualised treatment rules with discrete outcomes.

An individualised treatment rule (ITR) is a decision rule that aims to improve individuals' health outcomes by recommending treatments according to subject-specific information. In observational studies, collected data may contain many variables that are irrelevant to treatment decisions. Including all variables in an ITR could yield low efficiency and a complicated treatment rule that is difficult to implement. Thus, selecting variables to improve the treatment rule is crucial. We propose a doubly robust variable selection method for ITRs, and show that it compares favourably with competing approaches. We illustrate the proposed method on data from an adaptive, web-based stress management tool.

Using an intersectionality-based approach to evaluate mental health services use among gay, bisexual and other men who have sex with men in Montreal, Toronto and Vancouver.

AIMS: To cope with homonegativity-generated stress, gay, bisexual and other men who have sex with men (GBM) use more mental health services (MHS) compared with heterosexual men. Most previous research on MHS among GBM uses data from largely white HIV-negative samples. Using an intersectionality-based approach, we evaluated the concomitant impact of racialization and HIV stigma on MHS use among GBM, through the mediating role of perceived discrimination (PD). METHODS: We used baseline data from 2371 GBM enrolled in the Engage cohort study, collected between 2017 and 2019, in Montreal, Toronto and Vancouver, using respondent-driven sampling. The exposure was GBM groups: Group 1 (n = 1376): white HIV-negative; Group 2 (n = 327): white living with HIV; Group 3 (n = 577): racialized as non-white HIV-negative; Group 4 (n = 91): racialized as non-white living with HIV. The mediator was interpersonal PD scores measured using the Everyday Discrimination Scale (5-item version). The outcome was MHS use (yes/no) in the prior 6 months. We fit a three-way decomposition of causal mediation effects utilizing the imputation method for natural effect models. We obtained odds ratios (ORs) for pure direct effect (PDE, unmediated effect), pure indirect effect (PIE, mediated effect), mediated interaction effect (MIE, effect due to interaction between the exposure and mediator) and total effect (TE, overall effect). Analyses controlled for age, chronic mental health condition, Canadian citizenship, being cisgender and city of enrolment. RESULTS: Mean PD scores were highest for racialized HIV-negative GBM (10.3, SD: 5.0) and lowest for white HIV-negative GBM (8.4, SD: 3.9). MHS use was highest in white GBM living with HIV (GBMHIV) (40.4%) and lowest in racialized HIV-negative GBM (26.9%). Compared with white HIV-negative GBM, white GBMHIV had higher TE (OR: 1.71; 95% CI: 1.27, 2.29) and PDE (OR: 1.68; 95% CI: 1.27, 2.24), and racialized HIV-negative GBM had higher PIE (OR: 1.09; 95% CI: 1.02, 1.17). Effects for racialized GBMHIV did not significantly differ from those of white HIV-negative GBM. MIEs across all groups were comparable. CONCLUSIONS: Higher MHS use was observed among white GBMHIV compared with white HIV-negative GBM. PD positively mediated MHS use only among racialized HIV-negative GBM. MHS may need to take into account the intersecting impact of homonegativity, racism and HIV stigma on the mental health of GBM.

Gabapentinoids and Risk for Severe Exacerbation in Chronic Obstructive Pulmonary Disease : A Population-Based Cohort Study.

BACKGROUND: North American and European health agencies recently warned of severe breathing problems associated with gabapentinoids, including in patients with chronic obstructive pulmonary disease (COPD), although supporting evidence is limited. OBJECTIVE: To assess whether gabapentinoid use is associated with severe exacerbation in patients with COPD. DESIGN: Time-conditional propensity score-matched, new-user cohort study. SETTING: Health insurance databases from the Régie de l'assurance maladie du Québec in Canada. PATIENTS: Within a base cohort of patients with COPD between 1994 and 2015, patients initiating gabapentinoid therapy with an indication (epilepsy, neuropathic pain, or other chronic pain) were matched 1:1 with nonusers on COPD duration, indication for gabapentinoids, age, sex, calendar year, and time-conditional propensity score. MEASUREMENTS: The primary outcome was severe COPD exacerbation requiring hospitalization. Hazard ratios (HRs) associated with gabapentinoid use were estimated in subcohorts according to gabapentinoid indication and in the overall cohort. RESULTS: The cohort included 356 gabapentinoid users with epilepsy, 9411 with neuropathic pain, and 3737 with other chronic pain, matched 1:1 to nonusers. Compared with nonuse, gabapentinoid use was associated with increased risk for severe COPD exacerbation across the indications of epilepsy (HR, 1.58 [95% CI, 1.08 to 2.30]), neuropathic pain (HR, 1.35 [CI, 1.24 to 1.48]), and other chronic pain (HR, 1.49 [CI, 1.27 to 1.73]) and overall (HR, 1.39 [CI, 1.29 to 1.50]). LIMITATION: Residual confounding, including from lack of smoking information. CONCLUSION: In patients with COPD, gabapentinoid use was associated with increased risk for severe exacerbation. This study supports the warnings from regulatory agencies and highlights the importance of considering this potential risk when prescribing gabapentin and pregabalin to patients with COPD. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research and Canadian Lung Association.

Dynamic Treatment Regimes Using Bayesian Additive Regression Trees for Censored Outcomes.

To achieve the goal of providing the best possible care to each individual under their care, physicians need to customize treatments for individuals with the same health state, especially when treating diseases that can progress further and require additional treatments, such as cancer. Making decisions at multiple stages as a disease progresses can be formalized as a dynamic treatment regime (DTR). Most of the existing optimization approaches for estimating dynamic treatment regimes including the popular method of Q-learning were developed in a frequentist context. Recently, a general Bayesian machine learning framework that facilitates using Bayesian regression modeling to optimize DTRs has been proposed. In this article, we adapt this approach to censored outcomes using Bayesian additive regression trees (BART) for each stage under the accelerated failure time modeling framework, along with simulation studies and a real data example that compare the proposed approach with Q-learning. We also develop an R wrapper function that utilizes a standard BART survival model to optimize DTRs for censored outcomes. The wrapper function can easily be extended to accommodate any type of Bayesian machine learning model.

Principal stratification for quantile causal effects under partial compliance.

Within the principal stratification framework in causal inference, the majority of the literature has focused on binary compliance with an intervention and modelling means. Yet in some research areas, compliance is partial, and research questions-and hence analyses-are concerned with causal effects on (possibly high) quantiles rather than on shifts in average outcomes. Modelling partial compliance is challenging because it can suffer from lack of identifiability. We develop an approach to estimate quantile causal effects within a principal stratification framework, where principal strata are defined by the bivariate vector of (partial) compliance to the two levels of a binary intervention. We propose a conditional copula approach to impute the missing potential compliance and estimate the principal quantile treatment effect surface at high quantiles, allowing the copula association parameter to vary with the covariates. A bootstrap procedure is used to estimate the parameter to account for inflation due to imputation of missing compliance. Moreover, we describe precise assumptions on which the proposed approach is based, and investigate the finite sample behavior of our method by a simulation study. The proposed approach is used to study the 90th principal quantile treatment effect of executive stay-at-home orders on mitigating the risk of COVID-19 transmission in the United States.

On "Reflections on the concept of optimality of single decision point treatment regimes".

This is a discussion of "Reflections on the concept of optimality of single decision point treatment regimes" by Trung Dung Tran, Ariel Alonso Abad, Geert Verbeke, Geert Molenberghs, and Iven Van Mechelen. The authors propose a thoughtful consideration of optimization targets and the implications of such targets for the resulting optimal treatment rule. However, we contest the assertation that targets of optimization have been overlooked and suggest additional considerations that researchers must contemplate as part of a complete framework for learning about optimal treatment regimes.

Variable selection in high dimensions for discrete-outcome individualized treatment rules: Reducing severity of depression symptoms.

Despite growing interest in estimating individualized treatment rules, little attention has been given the binary outcome setting. Estimation is challenging with nonlinear link functions, especially when variable selection is needed. We use a new computational approach to solve a recently proposed doubly robust regularized estimating equation to accomplish this difficult task in a case study of depression treatment. We demonstrate an application of this new approach in combination with a weighted and penalized estimating equation to this challenging binary outcome setting. We demonstrate the double robustness of the method and its effectiveness for variable selection. The work is motivated by and applied to an analysis of treatment for unipolar depression using a population of patients treated at Kaiser Permanente Washington.

Role of fatty liver in the epidemic of advanced chronic liver disease among people with HIV: protocol for the Canadian LIVEHIV multicentre prospective cohort.

INTRODUCTION: Advanced chronic liver disease (ACLD) is a major cause of death for people with HIV (PWH). While viral hepatitis coinfections are largely responsible for this trend, metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging concern for PWH. We aimed to assess the contribution of MASLD to incident ACLD in PWH. METHODS AND ANALYSIS: This multicentre prospective observational cohort study will enrol 968 consecutive HIV monoinfected patients from four Canadian sites, excluding subjects with alcohol abuse, liver disease other than MASLD, or ACLD at baseline. Participants will be followed annually for 4 years by clinical evaluation, questionnaires, laboratory testing and Fibroscan to measure liver stiffness measurement (LSM) and controlled attenuation parameter (CAP). The primary outcome will be incidence of ACLD, defined as LSM>10 kPa, by MASLD status, defined as CAP≥285 dB/m with at least one metabolic abnormality, and to develop a score to classify PWH according to their risk of ACLD. Secondary outcomes will include health-related quality of life (HRQoL) and healthcare resource usage. Kaplan-Meier survival method and Cox proportional hazards regression will calculate the incidence and predictors of ACLD, respectively. Propensity score methods and marginal structural models will account for time-varying exposures. We will split the cohort into a training set (to develop the risk score) and a validation set (for validation of the score). HRQoL scores and healthcare resource usage will be compared by MASLD status using generalised linear mixed effects model. ETHICS AND DISSEMINATION: This protocol has been approved by the ethics committees of all participating institutions. Written informed consent will be obtained from all study participants. The results of this study will be shared through scientific publications and public presentations to advocate for the inclusion of PWH in clinical trials of MASLD-targeted therapies and case-finding of ACLD in PWH.

A time-dependent Poisson-Gamma model for recruitment forecasting in multicenter studies.

Forecasting recruitments is a key component of the monitoring phase of multicenter studies. One of the most popular techniques in this field is the Poisson-Gamma recruitment model, a Bayesian technique built on a doubly stochastic Poisson process. This approach is based on the modeling of enrollments as a Poisson process where the recruitment rates are assumed to be constant over time and to follow a common Gamma prior distribution. However, the constant-rate assumption is a restrictive limitation that is rarely appropriate for applications in real studies. In this paper, we illustrate a flexible generalization of this methodology which allows the enrollment rates to vary over time by modeling them through B-splines. We show the suitability of this approach for a wide range of recruitment behaviors in a simulation study and by estimating the recruitment progression of the Canadian Co-infection Cohort.

Bayesian inference for optimal dynamic treatment regimes in practice.

In this work, we examine recently developed methods for Bayesian inference of optimal dynamic treatment regimes (DTRs). DTRs are a set of treatment decision rules aimed at tailoring patient care to patient-specific characteristics, thereby falling within the realm of precision medicine. In this field, researchers seek to tailor therapy with the intention of improving health outcomes; therefore, they are most interested in identifying optimal DTRs. Recent work has developed Bayesian methods for identifying optimal DTRs in a family indexed by ψ via Bayesian dynamic marginal structural models (MSMs) (Rodriguez Duque D, Stephens DA, Moodie EEM, Klein MB. Semiparametric Bayesian inference for dynamic treatment regimes via dynamic regime marginal structural models. Biostatistics; 2022. (In Press)); we review the proposed estimation procedure and illustrate its use via the new BayesDTR R package. Although methods in Rodriguez Duque D, Stephens DA, Moodie EEM, Klein MB. (Semiparametric Bayesian inference for dynamic treatment regimes via dynamic regime marginal structural models. Biostatistics; 2022. (In Press)) can estimate optimal DTRs well, they may lead to biased estimators when the model for the expected outcome if everyone in a population were to follow a given treatment strategy, known as a value function, is misspecified or when a grid search for the optimum is employed. We describe recent work that uses a Gaussian process ( G P ) prior on the value function as a means to robustly identify optimal DTRs (Rodriguez Duque D, Stephens DA, Moodie EEM. Estimation of optimal dynamic treatment regimes using Gaussian processes; 2022. Available from: https://doi.org/10.48550/arXiv.2105.12259). We demonstrate how a G P approach may be implemented with the BayesDTR package and contrast it with other value-search approaches to identifying optimal DTRs. We use data from an HIV therapeutic trial in order to illustrate a standard analysis with these methods, using both the original observed trial data and an additional simulated component to showcase a longitudinal (two-stage DTR) analysis.

Monte Carlo sensitivity analysis for unmeasured confounding in dynamic treatment regimes.

Data-driven methods for personalizing treatment assignment have garnered much attention from clinicians and researchers. Dynamic treatment regimes formalize this through a sequence of decision rules that map individual patient characteristics to a recommended treatment. Observational studies are commonly used for estimating dynamic treatment regimes due to the potentially prohibitive costs of conducting sequential multiple assignment randomized trials. However, estimating a dynamic treatment regime from observational data can lead to bias in the estimated regime due to unmeasured confounding. Sensitivity analyses are useful for assessing how robust the conclusions of the study are to a potential unmeasured confounder. A Monte Carlo sensitivity analysis is a probabilistic approach that involves positing and sampling from distributions for the parameters governing the bias. We propose a method for performing a Monte Carlo sensitivity analysis of the bias due to unmeasured confounding in the estimation of dynamic treatment regimes. We demonstrate the performance of the proposed procedure with a simulation study and apply it to an observational study examining tailoring the use of antidepressant medication for reducing symptoms of depression using data from Kaiser Permanente Washington.

Benefits of the PRISM Shelter-Based Program for Attainment of Stable Housing and Functional Outcomes by People Experiencing Homelessness and Mental Illness: A Quantitative Analysis.

OBJECTIVE: To explore the housing trajectory, personal recovery, functional level, and quality of life of clients at discharge and 1 year after completing Projet Réaffiliation Itinérance Santé Mentale (PRISM), a shelter-based mental health and rehabilitation program intended to provide individuals experiencing homelessness and severe mental illness with transition housing and to reconnect them with mental health and social services. METHOD: Housing status, psychiatric follow-up trajectory, personal recovery (Canadian Personal Recovery Outcome Measure), functional level (Multnomah Community Ability Scale), and quality of life (Lehman Quality of Life Interview) were assessed at program entry, at program discharge and 1 year later. RESULTS: Of the 50 clients who participated in the study from May 31, 2018, to December 31, 2019, 43 completed the program. Of these, 76.7% were discharged to housing modalities and 78% were engaged with psychiatric follow-up at the program's end. Housing stability, defined as residing at the same permanent address since discharge, was achieved for 62.5% of participants at 1-year follow-up. Functional level and quality of life scores improved significantly both at discharge and at 1-year follow-up from baseline. CONCLUSIONS: Admission to PRISM helped clients secure long-term stable housing and appropriate psychiatric follow-up. Stable housing was maintained for most clients at 1-year follow-up, and they benefited from sustained functional and quality of life outcomes in long-term follow-up.

Variable selection in regression-based estimation of dynamic treatment regimes.

Dynamic treatment regimes (DTRs) consist of a sequence of decision rules, one per stage of intervention, that aim to recommend effective treatments for individual patients according to patient information history. DTRs can be estimated from models which include interactions between treatment and a (typically small) number of covariates which are often chosen a priori. However, with increasingly large and complex data being collected, it can be difficult to know which prognostic factors might be relevant in the treatment rule. Therefore, a more data-driven approach to select these covariates might improve the estimated decision rules and simplify models to make them easier to interpret. We propose a variable selection method for DTR estimation using penalized dynamic weighted least squares. Our method has the strong heredity property, that is, an interaction term can be included in the model only if the corresponding main terms have also been selected. We show our method has both the double robustness property and the oracle property theoretically; and the newly proposed method compares favorably with other variable selection approaches in numerical studies. We further illustrate the proposed method on data from the Sequenced Treatment Alternatives to Relieve Depression study.

Semiparametric Bayesian inference for optimal dynamic treatment regimes via dynamic marginal structural models.

Considerable statistical work done on dynamic treatment regimes (DTRs) is in the frequentist paradigm, but Bayesian methods may have much to offer in this setting as they allow for the appropriate representation and propagation of uncertainty, including at the individual level. In this work, we extend the use of recently developed Bayesian methods for Marginal Structural Models to arrive at inference of DTRs. We do this (i) by linking the observational world with a world in which all patients are randomized to a DTR, thereby allowing for causal inference and then (ii) by maximizing a posterior predictive utility, where the posterior distribution has been obtained from nonparametric prior assumptions on the observational world data-generating process. Our approach relies on Bayesian semiparametric inference, where inference about a finite-dimensional parameter is made all while working within an infinite-dimensional space of distributions. We further study Bayesian inference of DTRs in the double robust setting by using posterior predictive inference and the nonparametric Bayesian bootstrap. The proposed methods allow for uncertainty quantification at the individual level, thereby enabling personalized decision-making. We examine the performance of these methods via simulation and demonstrate their utility by exploring whether to adapt HIV therapy to a measure of patients' liver health, in order to minimize liver scarring.

Impact of Hepatitis C Virus Cure on Depressive Symptoms in the Human Immunodeficiency Virus-Hepatitis C Virus Coinfected Population in Canada.

BACKGROUND: Depression is common in people with human immunodeficiency virus (HIV) and hepatitis C virus (HCV), with biological and psychosocial mechanisms at play. Direct acting antivirals (DAA) result in high rates of sustained virologic response (SVR), with minimal side-effects. We assessed the impact of SVR on presence of depressive symptoms in the HIV-HCV coinfected population in Canada during the second-generation DAA era (2013-2020). METHODS: We used data from the Canadian CoInfection Cohort (CCC), a multicenter prospective cohort of people with a HIV and HCV coinfection, and its associated sub-study on food security. Because depression screening was performed only in the sub-study, we predicted Center for Epidemiologic Studies Depression Scale-10 classes in the CCC using a random forest classifier and corrected for misclassification. We included participants who achieved SVR and fit a segmented modified Poisson model using an interrupted time series design, adjusting for time-varying confounders. RESULTS: We included 470 participants; 58% had predicted depressive symptoms at baseline. The median follow-up was 2.4 years (interquartile range [IQR]: 1.0-4.5.) pre-SVR and 1.4 years (IQR: 0.6-2.5) post-SVR. The pre-SVR trend suggested depressive symptoms changed little over time, with no immediate level change at SVR. However, post-SVR trends showed a reduction of 5% per year (risk ratio: 0.95 (95% confidence interval [CI]: .94-.96)) in the prevalence of depressive symptoms. CONCLUSIONS: In the DAA era, predicted depressive symptoms declined over time following SVR. These improvements reflect possible changes in biological pathways and/or better general health. If such improvements in depression symptoms are durable, this provides an additional reason for treatment and early cure of HCV.