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.

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.

Pain management treatments and opioid use disorder risk in Medicaid patients.

INTRODUCTION: People with chronic pain are at increased risk of opioid-misuse. Less is known about the unique risk conferred by each pain management treatment, as treatments are typically implemented together, confounding their independent effects. This study estimated the extent to which pain management treatments were associated with risk of opioid use disorder (OUD) for those with chronic pain, controlling for baseline demographic and clinical confounding variables and holding other pain management treatments at their observed levels. METHODS: Data were analyzed in 2024 from two chronic pain subgroups within a cohort of non-pregnant Medicaid patients aged 35-64 years, 2016-2019, from 25 states: those with 1) chronic pain and physical disability (CPPD) (N=6,133) or 2) chronic pain without disability (CP) (N=67,438). Nine pain management treatments were considered: prescription opioid i) dose and ii) duration; iii) number of opioid prescribers; opioid co-prescription with iv) benzo- diazepines, v) muscle relaxants, and vi) gabapentinoids; vii) non-opioid pain prescription, viii) physical therapy, and ix) other pain treatment modality. The outcome was OUD risk. RESULTS: Having opioids co-prescribed with gabapentin or benzodiazepine was statistically significantly associated with a 37-45% increased OUD risk for the CP subgroup. Opioid dose and duration also were significantly associated with increased OUD risk in this subgroup. Physical therapy was significantly associated with an 18% decreased risk of OUD in the CP subgroup. CONCLUSIONS: Co-prescription of opioids with either gabapentin or benzodiazepines may substantially increase OUD risk. More positively, physical therapy may be a relatively accessible and safe pain management strategy.

The role of prescription opioid and cannabis supply policies on opioid overdose deaths.

Mandatory prescription drug monitoring programs and cannabis legalization have been hypothesized to reduce overdose deaths. We examined associations between prescription monitoring programs with access mandates ("must-query PDMPs"), legalization of medical and recreational cannabis supply, and opioid overdose deaths in United States counties in 2013-2020. Using data on overdose deaths from the National Vital Statistics System, we fit Bayesian spatiotemporal models to estimate risk differences and 95% credible intervals (CrI) in county-level opioid overdose deaths associated with enactment of these state policies. Must-query PDMPs were independently associated with on average 0.8 (95% CrI: 0.5, 1.0) additional opioid-involved overdose deaths per 100,000 person-years. Legal cannabis supply was not independently associated with opioid overdose deaths in this time period. Must-query PDMPs enacted in the presence of legal (medical or recreational) cannabis supply were associated with 0.7 (95% CrI: 0.4, 0.9) more opioid-involved deaths, relative to must-query PDMPs without any legal cannabis supply. In a time when overdoses are driven mostly by non-prescribed opioids, stricter opioid prescribing policies and more expansive cannabis legalization were not associated with reduced overdose death rates.

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.

Longitudinal patterns of natural hazard exposures and anxiety and depression symptoms among young adults in four low- and middle-income countries.

We estimated the effect of community-level natural hazard exposure during prior developmental stages on later anxiety and depression symptoms among young adults and potential differences stratified by gender. We analyzed longitudinal data (2002-2020) on 5585 young adults between 19 and 26 years in Ethiopia, India, Peru, and Vietnam. A binary question identified community-level exposure, and psychometrically validated scales measured recent anxiety and depression symptoms. Young adults with three exposure histories ("time point 1," "time point 2," and "both time points") were contrasted with their unexposed peers. We applied a longitudinal targeted minimum loss-based estimator with an ensemble of machine learning algorithms for estimation. Young adults living in exposed communities did not exhibit substantially different anxiety or depression symptoms from their unexposed peers, except for young women in Ethiopia who exhibited less anxiety symptoms (average causal effect [ACE] estimate = - 8.86 [95% CI: - 17.04, - 0.68] anxiety score). In this study, singular and repeated natural hazard exposures generally were not associated with later anxiety and depression symptoms. Further examination is needed to understand how distal natural hazard exposures affect lifelong mental health, which aspects of natural hazards are most salient, how disaster relief may modify symptoms, and gendered, age-specific, and contextual differences.

The COVID-19 Pandemic Period, SARS-CoV-2 Infection, and Perinatal Health.

This cohort study assesses population-level associations of COVID-19 with birth parent and infant health, distinguishing the COVID-19 pandemic period from individual SARS-CoV-2 infection.

Protocol for a nationwide case-control study of firearm violence prevention tactics and policies in K-12 schools.

BACKGROUND: Most U.S. K-12 schools have adopted safety tactics and policies like arming teachers and installing metal detectors, to address intentional school gun violence. However, there is minimal research on their effectiveness. Furthermore, sociodemographic factors may influence their implementation. Controlled studies are necessary to investigate their impact on gun violence and related disciplinary outcomes. OBJECTIVE: The paper outlines the protocol for a case-control study examining gun violence prevention policies in U.S. K-12 schools. The study aims to investigate if there is an association between the total number and type of specific safety tactics and policies and the occurrence of intentional shootings in K-12 public schools, student disciplinary outcomes, and if urbanicity, economic, and racial factors modify these associations. METHODS: We will create a nationally representative dataset for this study and ascertain a full census of case schools (schools that experienced intentional gunfire on the campus during school hours since 2015) through national school shooting databases. Matched control schools will be randomly selected from U.S. Department of Education's national database of all public schools. We will analyze 27 school safety strategies organized into seven key exposure groupings. RESULTS: Supported by the National Institutes for Child Health and Development (R01HD108027-01) and having received Institutional Review Board approval, our study is currently in the data collection phase. Our analytical plan will determine the association between the number and type of school safety tactics and policies with the occurrence of intentional shootings and suspensions and expulsions in a national sample of approximately 650 K-12 public schools. Additional analyses will investigate the effect modification of specific covariates. CONCLUSION: As the first national, controlled study, its results will provide novel and needed data on the effectiveness of school safety tactics and policies in preventing intentional shootings at K-12 public schools.

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.

Direct potable reuse and birth defects prevalence in Texas: An augmented synthetic control method analysis of data from a population-based birth defects registry.

Background: Direct potable reuse (DPR) involves adding purified wastewater that has not passed through an environmental buffer into a water distribution system. DPR may help address water shortages and is approved or is under consideration as a source of drinking water for several water-stressed population centers in the United States, however, there are no studies of health outcomes in populations who receive DPR drinking water. Our objective was to determine whether the introduction of DPR for certain public water systems in Texas was associated with changes in birth defect prevalence. Methods: We obtained data on maternal characteristics for all live births and birth defects cases regardless of pregnancy outcome in Texas from 2003 to 2017 from the Texas Birth Defects Registry and birth and fetal death records. The ridge augmented synthetic control method was used to model changes in birth defect prevalence (per 10,000 live births) following the adoption of DPR by four Texas counties in mid-2013, with county-level data on maternal age, percent women without a high school diploma, percent who identified as Hispanic/Latina or non-Hispanic/Latina Black, and rural-urban continuum code as covariates. Results: There were nonstatistically significant increases in prevalence of all birth defects collectively (average treatment effect in the treated = 53.6) and congenital heart disease (average treatment effect in the treated = 287.3) since June 2013. The estimated prevalence of neural tube defects was unchanged. Conclusions: We estimated nonstatistically significant increases in birth defect prevalence following the implementation of DPR in four West Texas counties. Further research is warranted to inform water policy decisions.

Population Neuroscience: Understanding Concepts of Generalizability and Transportability and Their Application to Improving the Public's Health.

In population neuroscience, samples are not often selected with equal or known probability from an underlying population of interest; in other words, samples are not often formally representative of a specified underlying population. This chapter provides an overview of an epidemiological approach to considering the implications of selective participation on the value of our results for population health. We discuss definitions of generalizability and transportability, given the growing recognition that generalizability and transportability are central for interpreting data that are aiming to be population-based. We provide evidence that differences in the prevalence of effect measure modifiers between a study sample and a target population will lead to a lack of generalizability and transportability. We provide an example of an association between a poly-genetic risk score and depression, showing how an internally valid association can differ based on the prevalence of effect measure modifiers. We show that when estimating associations, inferences from a study sample to a population can depend on clearly defining a target population. Given that representative sampling from explicitly defined target populations may not be feasible or realistic in many situations, especially given the sample sizes needed for statistical power for many exposures of interest (and especially when interactions are being tested), researchers should be well versed in tools available to enhance the interpretability of samples regarding target populations.

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.

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.

Comparative effectiveness of extended release naltrexone and sublingual buprenorphine for treatment of opioid use disorder among Medicaid patients.

Aims: To compare the real-world effectiveness of extended release naltrexone (XR-NTX) and sublingual buprenorphine (SL-BUP) for the treatment of opioid use disorder (OUD). Design: An observational active comparator, new user cohort study. Setting: Medicaid claims records for patients in New Jersey and California, 2016-2019. Participants/Cases: Adult Medicaid patients aged 18-64 years who initiated XR-NTX or SL-BUP for maintenance treatment of OUD and did not use medications for OUD in the 90-days before initiation. Comparators: New initiation with XR-NTX versus SL-BUP for the treatment of OUD. Measurements: We examined two outcomes up to 180 days after medication initiation, 1) composite of medication discontinuation and death, and 2) composite of overdose and death. Findings: Our cohort included 1,755 XR-NTX and 9,886 SL-BUP patients. In adjusted analyses, treatment with XR-NTX was more likely to result in discontinuation or death by the end of follow-up than treatment with SL-BUP: cumulative risk 76% (95% confidence interval [CI] 75%, 78%) versus 62% (95% CI 61%, 63%), respectively (risk difference 14 percentage points, 95% CI 13, 16). There was minimal difference in the cumulative risk of overdose or death by the end of follow-up: XR-NTX 3.8% (95% CI 2.9%, 4.7%) versus SL-BUP 3.3% (95% 2.9%, 3.7%); risk difference 0.5 percentage points, 95%CI -0.5, 1.5. Results were consistent across sensitivity analyses. Conclusions: Longer medication retention is important because risks of negative outcomes are elevated after discontinuation. Our results support selection of SL-BUP over XR-NTX. However, most patients discontinued medication by 6 months indicating that more effective tools are needed to improve medication retention, particularly after initiation with XR-NTX, and to identify which patients do best on which medication.

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.

Has the opening of Amazon fulfillment centers affected demand for disability insurance?

An estimated 17.6% of blue-collar, manufacturing jobs were lost in the United States between 1970 and 2016. These jobs, often union-represented, provided relatively generous pay and benefits, creating a path to the middle class for individuals without a four-year college degree. Evidence suggests the closure of manufacturing facilities and resulting decline in economic opportunity increased demand for disability insurance (SSDI) among blue-collar workers. In recent years, the opening of Amazon Fulfillment Centers (FCs) has accelerated around the country, driving a wave of blue-collar job creation. We estimated the extent to which the opening of FCs affected SSDI application rates, including rates of approvals and denials, using a synthetic control group approach. We found that FC openings were associated with a 1.4% reduction in the SSDI application rate over the subsequent three years, translating to 5,528 fewer applications per year across commuting zones with an FC opening. Our findings are consistent with FC openings improving economic opportunities in local labor markets, though our confidence intervals were wide and included the null.

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.

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.

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.