Practical causal mediation analysis: extending nonparametric estimators to accommodate multiple mediators and multiple intermediate confounders.

Mediation analysis is appealing for its ability to improve understanding of the mechanistic drivers of causal effects, but real-world data complexities challenge its successful implementation, including (i) the existence of post-exposure variables that also affect mediators and outcomes (thus, confounding the mediator-outcome relationship), that may also be (ii) multivariate, and (iii) the existence of multivariate mediators. All three challenges are present in the mediation analysis we consider here, where our goal is to estimate the indirect effects of receiving a Section 8 housing voucher as a young child on the risk of developing a psychiatric mood disorder in adolescence that operate through mediators related to neighborhood poverty, the school environment, and instability of the neighborhood and school environments, considered together and separately. Interventional direct and indirect effects (IDE/IIE) accommodate post-exposure variables that confound the mediator-outcome relationship, but currently, no readily implementable nonparametric estimator for IDE/IIE exists that allows for both multivariate mediators and multivariate post-exposure intermediate confounders. The absence of such an IDE/IIE estimator that can easily accommodate both multivariate mediators and post-exposure confounders represents a significant limitation for real-world analyses, because when considering each mediator subgroup separately, the remaining mediator subgroups (or a subset of them) become post-exposure intermediate confounders. We address this gap by extending a recently developed nonparametric estimator for the IDE/IIE to allow for easy incorporation of multivariate mediators and multivariate post-exposure confounders simultaneously. We apply the proposed estimation approach to our analysis, including walking through a strategy to account for other, possibly co-occurring intermediate variables when considering each mediator subgroup separately.

Learning Optimal Dynamic Treatment Regimes from Longitudinal Data.

Studies often report estimates of the average treatment effect (ATE). While the ATE summarizes the effect of a treatment on average, it does not provide any information about the effect of treatment within any individual. A treatment strategy that uses an individual's information to tailor treatment to maximize benefit is known as an optimal dynamic treatment rule (ODTR). Treatment, however, is typically not limited to a single point in time; consequently, learning an optimal rule for a time-varying treatment may involve not just learning the extent to which the comparative treatments' benefits vary across the characteristics of individuals, but also learning the extent to which the comparative treatments' benefits vary as relevant circumstances evolve within an individual. The goal of this paper is to provide a tutorial for estimating ODTR from longitudinal observational and clinical trial data for applied researchers. We describe an approach that uses a doubly-robust unbiased transformation of the conditional average treatment effect. We then learn a time-varying ODTR for when to increase buprenorphine-naloxone (BUP-NX) dose to minimize return-to-regular-opioid-use among patients with opioid use disorder. Our analysis highlights the utility of ODTRs in the context of sequential decision making: the learned ODTR outperforms a clinically defined strategy.

Is nicotine vaping associated with subsequent initiation of cannabis or other substances from adolescence into young adulthood?

Prior studies estimating longitudinal associations between nicotine vaping and subsequent initiation of cannabis and other substances (e.g., cocaine, heroin) have been limited by short follow-up periods, convenience sampling, and possibly inadequate confounding control. We sought to address some of these gaps using the nationally representative Population Assessment of Tobacco and Health Study (PATH) to estimate longitudinal associations between nicotine vaping and the initiation of cannabis or other substances among adolescents transitioning to adulthood from2013 to 2019, adjusting for treatment-confounder feedback. Estimands like the longitudinal average treatment effect were not identified because of extensive practical positivity violations. Therefore, we estimated longitudinal incremental propensity score effects, which were identified. We found that reduced odds of nicotine vaping were associated with decreased risks of cannabis or other substance initiation; these associations strengthened over time. For example, by the final wave (2018-19), cannabis and other substance initiation risks were 6.2 (95%CI:4.6-7.7) and 1.8 (95%CI:0.4-3.2) percentage points lower when odds of nicotine vaping were reduced to be 90% lower in all preceding waves (2013-14 to 2016-18), as compared with observed risks. Strategies to lower nicotine vaping prevalence during this period may have resulted in fewer young people initiating cannabis and other substances.

Nonparametric causal mediation analysis for stochastic interventional (in)direct effects.

Causal mediation analysis has historically been limited in two important ways: (i) a focus has traditionally been placed on binary exposures and static interventions and (ii) direct and indirect effect decompositions have been pursued that are only identifiable in the absence of intermediate confounders affected by exposure. We present a theoretical study of an (in)direct effect decomposition of the population intervention effect, defined by stochastic interventions jointly applied to the exposure and mediators. In contrast to existing proposals, our causal effects can be evaluated regardless of whether an exposure is categorical or continuous and remain well-defined even in the presence of intermediate confounders affected by exposure. Our (in)direct effects are identifiable without a restrictive assumption on cross-world counterfactual independencies, allowing for substantive conclusions drawn from them to be validated in randomized controlled trials. Beyond the novel effects introduced, we provide a careful study of nonparametric efficiency theory relevant for the construction of flexible, multiply robust estimators of our (in)direct effects, while avoiding undue restrictions induced by assuming parametric models of nuisance parameter functionals. To complement our nonparametric estimation strategy, we introduce inferential techniques for constructing confidence intervals and hypothesis tests, and discuss open-source software, the $\texttt{medshift}$$\texttt{R}$ package, implementing the proposed methodology. Application of our (in)direct effects and their nonparametric estimators is illustrated using data from a comparative effectiveness trial examining the direct and indirect effects of pharmacological therapeutics on relapse to opioid use disorder.

Overcoming data gaps in life course epidemiology by matching across cohorts.

Lifecourse epidemiology is hampered by the absence of large studies with exposures and outcomes measured at different life stages on the same individuals. We describe when the effect of an exposure (A) on an outcome (Y) in a target population is identifiable in a combined ("synthetic") cohort created by pooling an early-life cohort including measures of A with a late-life cohort including measures of Y. We enumerate causal assumptions needed for unbiased effect estimation in the synthetic cohort and illustrate by simulating target populations under four causal models. From each target population, we randomly sampled early- and late-life cohorts and created a synthetic cohort by matching individuals from the two cohorts based on mediators and confounders. We estimated the effect of A on Y in the synthetic cohort, varying matching variables, the match ratio, and the strength of association between matching variables and A. Finally, we compared bias in the synthetic cohort estimates when matching variables did not d-separate A and Y to the bias expected in the original cohort. When the set of matching variables includes all variables d-connecting exposure and outcome (i.e., variables blocking all back- and front-door pathways), the synthetic cohort yields unbiased effect estimates. Even when matching variables did not fully account for confounders, the synthetic cohort estimate was sometimes less biased than comparable estimates in the original cohort. Methods based on merging cohorts may hasten the evaluation of early- and mid-life determinants of late-life health but rely on available measures of both confounders and mediators.

Independent and joint contributions of physical disability and chronic pain to incident opioid use disorder and opioid overdose among Medicaid patients.

BACKGROUND: Chronic pain has been extensively explored as a risk factor for opioid misuse, resulting in increased focus on opioid prescribing practices for individuals with such conditions. Physical disability sometimes co-occurs with chronic pain but may also represent an independent risk factor for opioid misuse. However, previous research has not disentangled whether disability contributes to risk independent of chronic pain. METHODS: Here, we estimate the independent and joint adjusted associations between having a physical disability and co-occurring chronic pain condition at time of Medicaid enrollment on subsequent 18-month risk of incident opioid use disorder (OUD) and non-fatal, unintentional opioid overdose among non-elderly, adult Medicaid beneficiaries (2016-2019). RESULTS: We find robust evidence that having a physical disability approximately doubles the risk of incident OUD or opioid overdose, and physical disability co-occurring with chronic pain increases the risks approximately sixfold as compared to having neither chronic pain nor disability. In absolute numbers, those with neither a physical disability nor chronic pain condition have a 1.8% adjusted risk of incident OUD over 18 months of follow-up, those with physical disability alone have an 2.9% incident risk, those with chronic pain alone have a 3.6% incident risk, and those with co-occurring physical disability and chronic pain have a 11.1% incident risk. CONCLUSIONS: These findings suggest that those with a physical disability should receive increased attention from the medical and healthcare communities to reduce their risk of opioid misuse and attendant negative outcomes.

Using instrumental variables to address unmeasured confounding in causal mediation analysis.

Mediation analysis is a strategy for understanding the mechanisms by which interventions affect later outcomes. However, unobserved confounding concerns may be compounded in mediation analyses, as there may be unobserved exposure-outcome, exposure-mediator, and mediator-outcome confounders. Instrumental variables (IVs) are a popular identification strategy in the presence of unobserved confounding. However, in contrast to the rich literature on the use of IV methods to identify and estimate a total effect of a non-randomized exposure, there has been almost no research into using IV as an identification strategy to identify mediational indirect effects. In response, we define and nonparametrically identify novel estimands-double complier interventional direct and indirect effects-when 2, possibly related, IVs are available, one for the exposure and another for the mediator. We propose nonparametric, robust, efficient estimators for these effects and apply them to a housing voucher experiment.

Adverse childhood experiences among black sexually minoritized men and Black transgender women in Chicago.

BACKGROUND: Adverse childhood experiences (ACE) are important predictors of mental health outcomes in adulthood. However, commonly used ACE measures such as the Behavioural Risk Factor Surveillance System (BRFSS) have not been validated among Black sexually minoritized men (SMM) nor transgender women (TW), whom are known to have higher rates of ACE and poorer mental health outcomes. Assessing the psychometric properties of the measure is important for health equity research, as measurements that are not valid for some populations will render uninterpretable results. METHODS: Data are drawn from the Neighborhoods and Networks (N2) study, a longitudinal cohort of Black SMM and TW living in Southern Chicago. We conducted confirmatory factor analysis, correlation analysis and a two-parameter Item Response Theory (IRT) on the BRFSS ACE measure, an 11-item measure with 8 domains of ACE. RESULTS: One hundred forty seven participants (85% cisgender male) completed the BRFSS ACE measurement in the N2 study with age ranges from 16-34. The cohort were from a low socioeconomic background: about 40% of the cohort were housing insecure and made than $10,000 or less annually. They also have a high number of ACEs; 34% had endorsed 4 or more ACE domains. The three-factor structure fit the BRFSS ACE measure best; the measurement consisted of three subscales: of "Household Dysfunction", "Emotional / Physical", and "Sexual Abuse" (CFI = 0.975, TLI = 0.967, and RMSEA = 0.051). When the 8 domains of ACE were summed to one score, the total score was is correlated with depressive symptoms and anxiety scores, establishing concurrent validity. Item Response Theory model indicated that the "parental separation" domain had a low discrimination (slope) parameter, suggesting that this domain does not distinguish well between those with and without high ACE. CONCLUSIONS: The BRFFS ACE measure had adequate reliability, a well-replicated structure and some moderate evidence of concurrent validity among Black SMM and TW. The parental separation domain does not discriminate between those with high and low ACE experiences in this population. With changing population demographics and trends in marriage, further examination of this item beyond the current study is warranted to improve health equity research for all.

Optimally Choosing Medication Type for Patients With Opioid Use Disorder.

Patients with opioid use disorder (OUD) tend to get assigned to one of 3 medications based on the treatment program to which the patient presents (e.g., opioid treatment programs tend to treat patients with methadone, while office-based practices tend to prescribe buprenorphine). It is possible that optimally matching patients with treatment type would reduce the risk of return to regular opioid use (RROU). We analyzed data from 3 comparative effectiveness trials from the US National Institute on Drug Abuse Clinical Trials Network (CTN0027, 2006-2010; CTN0030, 2006-2009; and CTN0051 2014-2017), in which patients with OUD (n = 1,459) were assigned to treatment with either injection extended-release naltrexone (XR-NTX), sublingual buprenorphine-naloxone (BUP-NX), or oral methadone. We learned an individualized rule by which to assign medication type such that risk of RROU during 12 weeks of treatment would be minimized, and then estimated the amount by which RROU risk could be reduced if the rule were applied. Applying our estimated treatment rule would reduce risk of RROU compared with treating everyone with methadone (relative risk (RR) = 0.79, 95% confidence interval (CI): 0.60, 0.97) or treating everyone with XR-NTX (RR = 0.71, 95% CI: 0.47, 0.96). Applying the estimated treatment rule would have resulted in a similar risk of RROU to that of with treating everyone with BUP-NX (RR = 0.92, 95% CI: 0.73, 1.11).

Investigating a Paradox: Toward a Better Understanding of the Relationships Between Racial Group Membership, Stress, and Major Depressive Disorder.

Epidemiologic studies in the United States routinely report a lower or equal prevalence of major depressive disorder (MDD) for Black people relative to White people. Within racial groups, individuals with greater life stressor exposure experience greater prevalence of MDD; however, between racial groups this pattern does not hold. Informed by theoretical and empirical literature seeking to explain this "Black-White depression paradox," we outline 2 proposed models for the relationships between racial group membership, life stressor exposure, and MDD: an effect modification model and an inconsistent mediator model. Either model could explain the paradoxical within- and between-racial group patterns of life stressor exposure and MDD. We empirically estimated associations under each of the proposed models using data from 26,960 self-identified Black and White participants in the National Epidemiologic Survey on Alcohol and Related Conditions III (United States, 2012-2013). Under the effect modification model, we estimated relative risk effect modification using parametric regression with a cross-product term, and under the inconsistent mediation model, we estimated interventional direct and indirect effects using targeted minimum loss-based estimation. We found evidence of inconsistent mediation (i.e., direct and indirect effects operating in opposite directions), suggesting a need for greater consideration of explanations for racial patterns in MDD that operate independent of life stressor exposure. This article is part of a Special Collection on Mental Health.

Neighborhood Built Environment and Sleep Health: A Longitudinal Study in Low-Income and Predominantly African-American Neighborhoods.

In the present study, we examined the associations between physical characteristics of neighborhoods and sleep health outcomes and assessed the mediating role of physical activity in these associations. A longitudinal study (the Pittsburgh Hill/Homewood Research on Eating, Shopping, and Health (PHRESH) Zzz Study; n = 1,051) was conducted in 2 low-income, predominately African-American neighborhoods in Pittsburgh, Pennsylvania, with repeated measures of neighborhood characteristics and sleep health outcomes from 2013 to 2018. Built environment measures of walkability, urban design, and neighborhood disorder were captured from systematic field observations. Sleep health outcomes included insufficient sleep, sleep duration, wakefulness after sleep onset, and sleep efficiency measured from 7-day actigraphy data. G-computations based on structural nested mean models were used to examine the total effects of each built environment feature, and causal mediation analyses were used to evaluate direct and indirect effects operating through physical activity. Urban design features were associated with decreased wakefulness after sleep onset (risk difference (RD) = -1.26, 95% confidence interval (CI): -4.31, -0.33). Neighborhood disorder (RD = -0.46, 95% CI: -0.86, -0.07) and crime rate (RD = -0.54, 95% CI: -0.93, -0.08) were negatively associated with sleep efficiency. Neighborhood walkability was not associated with sleep outcomes. We did not find a strong and consistent mediating role of physical activity. Interventions to improve sleep should target modifiable factors, including urban design and neighborhood disorder.

Efficiently transporting causal direct and indirect effects to new populations under intermediate confounding and with multiple mediators.

The same intervention can produce different effects in different sites. Existing transport mediation estimators can estimate the extent to which such differences can be explained by differences in compositional factors and the mechanisms by which mediating or intermediate variables are produced; however, they are limited to consider a single, binary mediator. We propose novel nonparametric estimators of transported interventional (in)direct effects that consider multiple, high-dimensional mediators and a single, binary intermediate variable. They are multiply robust, efficient, asymptotically normal, and can incorporate data-adaptive estimation of nuisance parameters. They can be applied to understand differences in treatment effects across sites and/or to predict treatment effects in a target site based on outcome data in source sites.

Depression networks: a systematic review of the network paradigm causal assumptions.

The network paradigm for psychiatric disorder nosology was proposed based on the hypothesis that mental disorders are caused by networks of symptoms that are themselves causally related. Researchers have widely applied and integrated this paradigm to examine a variety of mental disorders, particularly depression. Existing studies generally focus on the correlation structure of symptoms, inferring causal relationships. Thus, presumption of causality may not be justified. The goal of this review was to examine the assumptions necessary for causal inference in network studies of depression. Specifically, we examined whether and how network studies address common violations of causal assumptions (i.e. no measurement error, exchangeability, and positivity). Of the 41 studies reviewed, five (12%) studies discussed sources of confounding unrelated to measurement error; none discussed positivity; and five conducted post-hoc analysis for measurement error. Depression network studies, in principle, are conducted under the assumption that symptom relationships are causal. Yet, in practice, studies seldomly discussed or adequately tested assumptions required to infer causality. Researchers continue to design studies that are unable to support the credibility of the network paradigm for the study of depression. There is a critical need to ensure scientific efforts cease to perpetuate problematic designs and findings to a potentially unsubstantiated paradigm.

Efficient and flexible estimation of natural direct and indirect effects under intermediate confounding and monotonicity constraints.

Natural direct and indirect effects are mediational estimands that decompose the average treatment effect and describe how outcomes would be affected by contrasting levels of a treatment through changes induced in mediator values (in the case of the indirect effect) or not through induced changes in the mediator values (in the case of the direct effect). Natural direct and indirect effects are not generally point-identified in the presence of a treatment-induced confounder; however, they may be identified if one is willing to assume monotonicity between the treatment and the treatment-induced confounder. We argue that this assumption may be reasonable in the relatively common encouragement-design trial setting, where the intervention is randomized treatment assignment and the treatment-induced confounder is whether or not treatment was actually taken/adhered to. We develop efficiency theory for the natural direct and indirect effects under this monotonicity assumption, and use it to propose a nonparametric, multiply robust estimator. We demonstrate the finite sample properties of this estimator using a simulation study, and apply it to data from the Moving to Opportunity Study to estimate the natural direct and indirect effects of being randomly assigned to receive a Section 8 housing voucher-the most common form of federal housing assistance-on risk developing any mood or externalizing disorder among adolescent boys, possibly operating through various school and community characteristics.

Adult Child Schooling and Older Parents' Cognitive Outcomes in the Survey of Health, Aging and Retirement in Europe (SHARE): A Quasi-Experimental Study.

A growing body of research suggests that adult child educational attainment benefits older parents' cognitive outcomes via financial (e.g., direct monetary transfers) and nonfinancial (e.g., psychosocial) mechanisms. Quasi-experimental studies are needed to circumvent confounding bias. No such quasi-experimental studies have been completed in higher-income countries, where financial transfers from adult children to aging parents are rare. Using data on 8,159 adults aged ≥50 years in the Survey for Health, Aging and Retirement in Europe (2004/2005), we leveraged changes in compulsory schooling laws as quasi-experiments. Each year of increased schooling among respondents' oldest children was associated with better verbal fluency (ß = 0.07, 95% CI: 0.02, 0.12) scores; overall associations with verbal memory scores were null, with mixed and imprecise evidence of association in models stratified by parent gender. We also evaluated associations with psychosocial outcomes as potentially important mechanisms. Increased schooling among respondents' oldest children was associated with higher quality-of-life scores and fewer depressive symptoms. Our findings present modest albeit inconsistent evidence that increases in schooling may have an "upward" influence on older parents' cognitive performance even in settings where financial transfers from adult children to their parents are uncommon. Associations with parents' psychosocial outcomes were more robust.

Use of an Inverted Synthetic Control Method to Estimate Effects of Recent Drug Overdose Good Samaritan Laws, Overall and by Black/White Race/Ethnicity.

Overdose Good Samaritan laws (GSLs) aim to reduce mortality by providing limited legal protections when a bystander to a possible drug overdose summons help. Most research into the impact of these laws is dated or potentially confounded by coenacted naloxone access laws. Lack of awareness and trust in GSL protections, as well as fear of police involvement and legal repercussions, remain key deterrents to help-seeking. These barriers may be unequally distributed by race/ethnicity due to racist policing and drug policies, potentially producing racial/ethnic disparities in the effectiveness of GSLs for reducing overdose mortality. We used 2015-2019 vital statistics data to estimate the effect of recent GSLs on overdose mortality, overall (8 states) and by Black/White race/ethnicity (4 states). Given GSLs' near ubiquity, few unexposed states were available for comparison. Therefore, we generated an "inverted" synthetic control method (SCM) to compare overdose mortality in new-GSL states with that in states that had GSLs throughout the analytical period. The estimated relationships between GSLs and overdose mortality, both overall and stratified by Black/White race/ethnicity, were consistent with chance. An absence of effect could result from insufficient protection provided by the laws, insufficient awareness of them, and/or reticence to summon help not addressable by legal protections. The inverted SCM may be useful for evaluating other widespread policies.

When Effects Cannot be Estimated: Redefining Estimands to Understand the Effects of Naloxone Access Laws.

Violations of the positivity assumption (also called the common support condition) challenge health policy research and can result in significant bias, large variance, and invalid inference. We define positivity in the single- and multiple-timepoint (i.e., longitudinal) health policy evaluation setting, and discuss real-world threats to positivity. We show empirical evidence of the practical positivity violations that can result when attempting to estimate the effects of health policies (in this case, Naloxone Access Laws). In such scenarios, an alternative is to estimate the effect of a shift in law enactment (e.g., the effect if enactment had been delayed by some number of years). Such an effect corresponds to what is called a modified treatment policy, and dramatically weakens the required positivity assumption, thereby offering a means to estimate policy effects even in scenarios with serious positivity problems. We apply the approach to define and estimate the longitudinal effects of Naloxone Access Laws on opioid overdose rates.

Effects of building demolitions on firearm violence in Detroit, Michigan.

Former industrial cities facing economic challenges and depopulation often experience high levels of firearm and other forms of violence. Within these cities, violent crime often clusters in neighborhoods affected by high levels of vacant and abandoned housing. This study estimates the effects of building demolition in Detroit, Michigan on the subsequent risk of violent crime using property-level data and longitudinal targeted maximum likelihood estimation. The primary outcome is violent Crime Index crimes (homicide, rape, robbery and aggravated assault). We estimate effects for this category of crimes as a whole and for the subset involving firearms. Drug and other lower-level crimes are included as secondary outcomes. We compare the risk of experiencing each crime type following building demolition in Census blocks and block groups to an estimate of the risk had there been no demolition in the 1-3 quarters prior in 2017. There were >2600 total demolitions in about 1700 blocks in 2017 in Detroit. Nearly all demolished buildings were sourced from tax foreclosures. Estimates suggest the risk for all crime types tested would have been statistically indistinguishable from the observed crime risk had demolitions in the prior 1-3 quarters of 2017 not occurred. Our results run counter to most previous research on this topic, which tends to show a protective effect of demolition on violent crime. Understanding why our results differ may provide important insights into the types of demolition programs with the greatest potential to reduce violent crime.

A Warning About Using Predicted Values From Regression Models for Epidemiologic Inquiry.

In many settings, researchers may not have direct access to data on 1 or more variables needed for an analysis and instead may use regression-based estimates of those variables. Using such estimates in place of original data, however, introduces complications and can result in uninterpretable analyses. In simulations and observational data, we illustrate the issues that arise when an average treatment effect is estimated from data where the outcome of interest is predicted from an auxiliary model. We show that bias in any direction can result, under both the null and alternative hypotheses.

California's Mental Health Services Act and Mortality Due to Suicide, Homicide, and Acute Effects of Alcohol: A Synthetic Control Application.

California's Mental Health Services Act (MHSA) substantially expanded funding of county mental health services through a state tax, and led to broad prevention efforts and intensive services for individuals experiencing serious mental disorders. We estimated the associations between MHSA and mortality due to suicide, homicide, and acute effects of alcohol. Using annual cause-specific mortality data for each US state and the District of Columbia from 1976-2015, we used a generalization of the quasi-experimental synthetic control method to predict California's mortality rate for each outcome in the absence of MHSA using a weighted combination of comparison states. We calculated the association between MHSA and each outcome as the absolute difference and percentage difference between California's observed and predicted average annual rates over the postintervention years (2007-2015). MHSA was associated with modest decreases in average annual rates of homicide (-0.81/100,000 persons, corresponding to a 13% reduction) and mortality from acute alcohol effects (-0.35/100,000 persons, corresponding to a 12% reduction). Placebo test inference suggested that the associations were unlikely to be due to chance. MHSA was not associated with suicide. Protective associations with mortality due to homicide and acute alcohol effects provide evidence for modest health benefits of MHSA at the population level.