Summary: Results obtained in randomized trials may not easily generalize to target populations. Whereas in randomized trials the treatment assignment mechanism is known, the sampling mechanism by which individuals are selected to participate in the trial is typically not known and assuming random sampling from the target population is often dubious. We consider an inverse probability of sampling weighted (IPSW) estimator for generalizing trial results to a target population. The IPSW estimator is shown to be consistent and asymptotically normal. A consistent sandwich-type variance estimator is derived and simulation results are presented comparing the IPSW estimator with a previously proposed stratified estimator. The methods are then utilized to generalize results from two randomized trials of human immunodeficiency virus treatment to all people living with the disease in the USA.

In light of the accelerating and rapidly evolving overdose crisis in the United States (US), new strategies are needed to address the epidemic and to efficiently engage and retain individuals in care for opioid use disorder (OUD). Moreover, there is an increasing need for novel approaches to using health data to identify gaps in the cascade of care for persons with OUD. Between June 2018 and May 2019, we engaged a diverse stakeholder group (including directors of statewide health and social service agencies) to develop a statewide, patient-centered cascade of care for OUD for Rhode Island, a small state in New England, a region highly impacted by the opioid crisis. Through an iterative process, we modified the cascade of care defined by Williams et al. for use in Rhode Island using key national survey data and statewide health claims datasets to create a cross-sectional summary of 5 stages in the cascade. Approximately 47,000 Rhode Islanders (5.2%) were estimated to be at risk for OUD (stage 0) in 2016. At the same time, 26,000 Rhode Islanders had a medical claim related to an OUD diagnosis, accounting for 55% of the population at risk (stage 1); 27% of the stage 0 population, 12,700 people, showed evidence of initiation of medication for OUD (MOUD, stage 2), and 18%, or 8,300 people, had evidence of retention on MOUD (stage 3). Imputation from a national survey estimated that 4,200 Rhode Islanders were in recovery from OUD as of 2016, representing 9% of the total population at risk. Limitations included use of self-report data to arrive at estimates of the number of individuals at risk for OUD and using a national estimate to identify the number of individuals in recovery due to a lack of available state data sources. Our findings indicate that cross-sectional summaries of the cascade of care for OUD can be used as a health policy tool to identify gaps in care, inform data-driven policy decisions, set benchmarks for quality, and improve health outcomes for persons with OUD. There exists a significant opportunity to increase engagement prior to the initiation of OUD treatment (i.e., identification of OUD symptoms via routine screening or acute presentation) and improve retention and remission from OUD symptoms through improved community-supported processes of recovery. To do this more precisely, states should work to systematically collect data to populate their own cascade of care as a health policy tool to enhance system-level interventions and maximize engagement in care.

Comparative effectiveness evidence from randomized trials may not be directly generalizable to a target population of substantive interest when, as in most cases, trial participants are not randomly sampled from the target population. Motivated by the need to generalize evidence from two trials conducted in the AIDS Clinical Trials Group (ACTG), we consider weighting, regression and doubly robust estimators to estimate the causal effects of HIV interventions in a specified population of people living with HIV in the USA. We focus on a non-nested trial design and discuss strategies for both point and variance estimation of the target population average treatment effect. Specifically in the generalizability context, we demonstrate both analytically and empirically that estimating the known propensity score in trials does not increase the variance for each of the weighting, regression and doubly robust estimators. We apply these methods to generalize the average treatment effects from two ACTG trials to specified target populations and operationalize key practical considerations. Finally, we report on a simulation study that investigates the finite-sample operating characteristics of the generalizability estimators and their sandwich variance estimators.

Implementation trials often involve clustering via risk networks, where only some participants directly receive the intervention. The individual effect is that among directly treated persons beyond being in an intervention network; the disseminated effect is that among persons engaged with those directly treated. In this article, we employ a causal inference framework and discuss assumptions and estimators for individual and disseminated effects and apply them to the HIV Prevention Trials Network 037 Study. HIV Prevention Trials Network 037 was a phase III, network-level, randomized controlled human immunodeficiency virus (HIV) prevention trial conducted in the United States and Thailand from 2002 to 2006 that recruited injection drug users, who were assigned to either an intervention group or a control group, and their risk network members, who received no direct intervention. Combining individual and disseminated effects, we observed a 35% composite rate reduction in the adjusted model (risk ratio = 0.65, 95% confidence interval: 0.47, 0.90). Methodology is now available for estimating the full set of these effects, enhancing knowledge gained from network-randomized trials. Although the overall effect gains validity from network randomization, we show that it will generally be less than the composite effect. Additionally, if only index participants benefit from the intervention, as the network size increases, the overall effect tends toward the null-an unfortunate and misleading conclusion.

Preexposure prophylaxis (PrEP) for prevention of human immunodeficiency virus (HIV) infection may benefit not only the person who uses it but also their uninfected sexual risk contacts. We developed an agent-based model using a novel trial emulation approach to quantify disseminated effects of PrEP use among men who have sex with men in Atlanta, Georgia, from 2015 to 2017. Model components (subsets of agents connected through partnerships in a sexual network but not sharing partnerships with any other agents) were first randomized to an intervention coverage level or the control group; then, within intervention components, eligible agents were randomized to receive or not receive PrEP. We calculated direct and disseminated (indirect) effects using randomization-based estimators and report corresponding 95% simulation intervals across scenarios ranging from 10% coverage in the intervention components to 90% coverage. A population of 11,245 agents was simulated, with an average of 1,551 components identified. When comparing agents randomized to no PrEP in 70% coverage components with control agents, there was a 15% disseminated risk reduction in HIV incidence (risk ratio = 0.85, 95% simulation interval: 0.65, 1.05). Persons not on PrEP may receive a protective benefit by being in a sexual network with higher PrEP coverage. Agent-based models are useful for evaluating possible direct and disseminated effects of HIV prevention modalities in sexual networks.

Nonmedical use of prescription opioid medication (NMPO) in the United States is a public health crisis, resulting in high rates of emergency room visits, morbidity, and mortality. The purpose of this study was to explore prevalence estimates and correlates of NMPO among a convenience sample of college students in the northeast and southeast regions of the US to help generate directions for future research. Motivations for misuse, age of onset, access, concomitant substance use, and individual factors were investigated among a sample of undergraduate students from two universities. Participants (N = 847) completed a battery of various self-report measures. Findings revealed that 7.7% (Southeastern University) and 12.8% of students (Northeastern University) reported lifetime NMPO, whereas past-month NMPO was reported by 0.8% and 0.9% of participants, respectively. Lifetime history of regularly using alcohol, nonmedical use of benzodiazepine medication, nonmedical use of prescription stimulants, symptoms of depression and anxiety, and executive functioning (i.e., metacognition and behavioral regulation) were significantly related to lifetime history of NMPO in this college sample. These findings offer several potential subsequent lines of investigation regarding the associations between various demographic and psychological factors and NMPO. Future research is needed to help identify college students who are at risk of NMPO.