日本における精神保健と援助要請行動の研究

政策研究大学院大学 / National Graduate Institute for Policy Studies博士 (公共経済学) / Ph.D. in Public Economics論文審査委員: 園部 哲史（主査）, 池田 真介, Robert Leon-Gonzalez, Alistair Munro, 澤田 康幸（東京大学）政策分析プログラム / Policy Analysis Programdoctoral thesi

Generalizability of randomized controlled trials of substance use disorder treatments

Randomized controlled trials (RCTs) are widely considered the gold standard to assess the effectiveness of new treatments. Decisions for clinical guidelines and health policies are often made based on findings of RCTs. While study designs of RCTs can mitigate threats to internal validity of the estimated treatment effectiveness, they do not assure external validity, which is how well findings from one particular sample can be applied to the target population of individuals for whom a treatment is intended. There is growing concern in the recent literature that the findings from RCTs may not be directly applicable to real world settings. Particularly in the context of RCTs of treatments for substance use disorders (SUD), there is a growing body of literature showing that strict eligibility criteria commonly used in RCTs of SUD treatment would exclude substantial proportions of individuals from the target population, which may adversely impact generalizability of the findings from SUD RCTs. However, very few past studies have assessed generalizability of findings of actual SUD RCTs to the intended target populations. The purpose of this dissertation was to assess generalizability of findings of SUD RCTs that were implemented in various settings, as compared with differently defined target populations. In Chapter 1, we provided an overview of the existing literature and described the data source and methodology used in this dissertation. In Chapter 2, we assessed generalizability of the findings from ten multi-site SUD RCTs to each target population of patients seeking SUD treatment in usual treatment settings in the United States. We weighted the RCT sample treatment effects on three outcomes, on retention, urine toxicology, and abstinence to make the RCT samples resemble the target populations, by using propensity scores representing the conditional probability of participating in RCTs. We found that weighting the samples changed the significance of estimated sample treatment effects. Most commonly, positive treatment effects of RCTs became statistically insignificant after weighting. In Chapter 3, we assessed generalizability of the treatment effects on retention and abstinence from a multi-site web-based SUD intervention to two types of target populations: SUD treatment-seeking individuals and community-dwelling individuals with recent substance use, whether or not they sought treatment. The population effect on abstinence became insignificant after weighting the data by the generalizability weights of both target populations. In Chapter 4, we conducted a meta-analysis of generalized treatment effects on retention and abstinence from four RCTs of cocaine dependence treatments to the same two types of target population used in the previous chapter. We also conducted a network meta-analysis to examine comparative treatment efficacies across these four treatments while taking into account the generalizability of the findings. We found that the overall generalized treatment effect on retention was significantly larger than the unweighted effect. We also found that weighting changed the ranking of the effectiveness across treatments. Lastly, in Chapter 5, we provided a summary of the findings and discussed public health implications in light of strengths and limitations of this dissertation

Model-Robust Inference for Clinical Trials that Improve Precision by Stratified Randomization and Adjustment for Additional Baseline Variables

We focus on estimating the average treatment effect in clinical trials that involve stratified randomization, which is commonly used. It is important to understand the large sample properties of estimators that adjust for stratum variables (those used in the randomization procedure) and additional baseline variables, since this can lead to substantial gains in precision and power. Surprisingly, to the best of our knowledge, this is an open problem. It was only recently that a simpler problem was solved by Bugni et al. (2018) for the case with no additional baseline variables, continuous outcomes, the analysis of covariance (ANCOVA) estimator, and no missing data. We generalize their results in three directions. First, in addition to continuous outcomes, we handle binary and time-to-event outcomes; this broadens the applicability of the results. Second, we allow adjustment for an additional, preplanned set of baseline variables, which can improve precision. Third, we handle missing outcomes under the missing at random assumption. We prove that a wide class of estimators is asymptotically normally distributed under stratified randomization and has equal or smaller asymptotic variance than under simple randomization. For each estimator in this class, we give a consistent variance estimator. This is important in order to fully capitalize on the combined precision gains from stratified randomization and adjustment for additional baseline variables. The above results also hold for the biased-coin covariate-adaptive design. We demonstrate our results using completed trial data sets of treatments for substance use disorder, where adjustment for additional baseline variables brings substantial variance reduction

Generalizability of randomized controlled trials of substance use disorder treatments

Randomized controlled trials (RCTs) are widely considered the gold standard to assess the effectiveness of new treatments. Decisions for clinical guidelines and health policies are often made based on findings of RCTs. While study designs of RCTs can mitigate threats to internal validity of the estimated treatment effectiveness, they do not assure external validity, which is how well findings from one particular sample can be applied to the target population of individuals for whom a treatment is intended. There is growing concern in the recent literature that the findings from RCTs may not be directly applicable to real world settings. Particularly in the context of RCTs of treatments for substance use disorders (SUD), there is a growing body of literature showing that strict eligibility criteria commonly used in RCTs of SUD treatment would exclude substantial proportions of individuals from the target population, which may adversely impact generalizability of the findings from SUD RCTs. However, very few past studies have assessed generalizability of findings of actual SUD RCTs to the intended target populations. The purpose of this dissertation was to assess generalizability of findings of SUD RCTs that were implemented in various settings, as compared with differently defined target populations. In Chapter 1, we provided an overview of the existing literature and described the data source and methodology used in this dissertation. In Chapter 2, we assessed generalizability of the findings from ten multi-site SUD RCTs to each target population of patients seeking SUD treatment in usual treatment settings in the United States. We weighted the RCT sample treatment effects on three outcomes, on retention, urine toxicology, and abstinence to make the RCT samples resemble the target populations, by using propensity scores representing the conditional probability of participating in RCTs. We found that weighting the samples changed the significance of estimated sample treatment effects. Most commonly, positive treatment effects of RCTs became statistically insignificant after weighting. In Chapter 3, we assessed generalizability of the treatment effects on retention and abstinence from a multi-site web-based SUD intervention to two types of target populations: SUD treatment-seeking individuals and community-dwelling individuals with recent substance use, whether or not they sought treatment. The population effect on abstinence became insignificant after weighting the data by the generalizability weights of both target populations. In Chapter 4, we conducted a meta-analysis of generalized treatment effects on retention and abstinence from four RCTs of cocaine dependence treatments to the same two types of target population used in the previous chapter. We also conducted a network meta-analysis to examine comparative treatment efficacies across these four treatments while taking into account the generalizability of the findings. We found that the overall generalized treatment effect on retention was significantly larger than the unweighted effect. We also found that weighting changed the ranking of the effectiveness across treatments. Lastly, in Chapter 5, we provided a summary of the findings and discussed public health implications in light of strengths and limitations of this dissertation

Adverse childhood experiences (ACEs) and transitions in stages of alcohol involvement among US adults: Progression and regression.

BACKGROUND: Adverse childhood experiences (ACEs) are associated with a number of medical comorbidities. However, there is a paucity of data on the role ACEs play in transitions in stages of alcohol involvement. OBJECTIVE: To examine the association between ACEs and transitions in alcohol problems progression and regression between No Problems, Moderate Problems and Severe Problems stages. PARTICIPANTS AND SETTING: Data from 14,363 male and 19,774 female participants in Waves 1 and 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). METHODS: We used latent transition analysis (LTA) with propensity score adjustment to estimate the odds of transitioning across stages of alcohol involvement, between waves, based on the number of types of ACEs experienced. We hypothesized that ACEs would be associated with increased risk of progression and decreased risk of regression. RESULTS: ACEs were associated with progression to higher alcohol involvement stages, with greatest likelihood of progression from No Problems to Severe Problems for those reporting ≥3 ACEs (males: aOR = 4.78 [CI (1.84-12.44)]; females: aOR = 3.81 [CI (1.69-8.57)]). ACEs were also associated with decreased odds of regression to less problematic alcohol involvement stages, with some distinctive patterns of associations in males and in females. CONCLUSIONS: This study suggests that ACEs impact transitions in alcohol involvement in both males and females, affecting both progression and regression. The association is magnified for those with multiple types of ACE exposures. These results highlight the need for prevention, early identification and intervention to mitigate the risks associated with childhood maltreatment

Disruptions to naloxone training among lay and occupational responders in Maryland during the emergence of COVID-19: Early impacts, recovery, and lessons learned

Background: Opioid overdose death rates increased during the COVID-19 pandemic. Disruptions in community-based naloxone trainings could have reduced the likelihood of overdose reversal and increased the chances of a fatal overdose. We investigated changes in the number of people trained in naloxone administration and distribution in Maryland before, during, and after COVID-related stay-at-home orders. Methods: Data on naloxone training are from the Maryland Department of Health. We used interrupted time series models to estimate changes in average monthly number of people trained: [1] pre-interruption (4/2019–3/2020), [2] 1-month post-interruption (4/2020–5/2020), and [3] 12-month post-interruption (4/2020–3/2021). Trainees were classified as lay (e.g., people who use drugs) or occupational (e.g., law enforcement officers and harm reduction workers) responders. Results: There were 101,332 trainees; 54.1% lay, 21.5% occupational, and 23.4% unknown responder status. We observed a decrease in the average monthly number of trainees in the pre-interruption period (-235, p<0.001), a larger decrease of 93.2% during the 1-month post-interruption (-846, p = 0.013), and an increase during the 12-month post-interruption (+217, p<0.001). There was a significant decrease among occupational responders 1-month post-interruption, and a significant increase among lay responders in the 12-month post-interruption period. Conclusions: Findings suggest a marked decrease in naloxone trainees immediately after stay-at-home order, followed by a moderate rebound in the 12-months after stay-at-home order. The decrease in occupational responders trained may have limited access to naloxone, but would likely have been offset by increases in number of lay responders trained. Strengthening lay and occupational responder connections could maintain naloxone distribution during public health crises

Impact of early, weekly drinking on latent classes of alcohol involvement progression and recovery: Evidence from the NESARC Waves 1 and 2.

Partial funding for Open Access provided by the UMD Libraries' Open Access Publishing Fund.Introduction: Early drinkers have been found to have higher risk of developing alcohol use disorder; however, the association of early drinking with progression to problematic alcohol involvement that does not meet disorder criteria (i.e., subclinical problems) or to severe stages of alcohol involvement, sex-specific associations, and relationship of early drinking with alcohol recovery have rarely been investigated. Methods: Using data from Waves 1 and 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), we applied latent transition analyses to investigate the impact of weekly drinking before age 18 on alcohol progression and recovery operationalized as three classes of alcohol involvement using abuse and dependence indicators. We analyzed data separately for male (n = 12,276) and female (n = 14,750) drinkers and applied propensity score methods to address confounding. Results: We observed significant associations between early, weekly drinking and alcohol involvement class membership at Wave 1 for both males and females. For males, early, weekly drinking was also associated with greater odds of transitioning from moderate to severe alcohol problems (aOR = 3.19, 95% CI = 1.72, 5.35). For females, early, weekly drinking predicted the transition from no to severe problems (aOR = 2.98, 95% CI = 1.11–8.00). Contrary to our hypothesis, early, weekly drinking was associated with greater likelihood of transition from severe to no problems for males (aOR = 3.23, 95% CI = 1.26, 8.26). Discussion: Frequent, early drinking seems to be an important indicator of drinking progression with differential associations by sex. This information is useful to identify those at greater risk of progressing to severe drinking problems to intervene appropriately.https://doi.org/10.1016/j.abrep.2022.10041