Introduction to Helping to End Addiction Long-Term Prevention Cooperative: Overview and Strategies.

This supplemental issue describes the individual studies and collaborative efforts of the Helping to End Addiction Long-term Prevention Cooperative's (HPC's) innovative approaches to rapidly develop evidence-based prevention programs for widespread dissemination. This introduction succinctly reviews (1) the context that demands the rapid development of efficacious prevention programs and their scale-ups, (2) the unique objectives of the individual HPC research projects, and (3) collective efforts to harmonize research across studies to advance the prevention of opioid misuse and gain insight into opioid misuse etiology to inform improvements in preventive interventions. At the conclusion of HPC studies, we anticipate the availability of multiple evidence-based programs to prevent opioid misuse and use disorder for persons who experience particular sources of risk and for delivery in settings where prevention has traditionally been lacking. By harmonizing and coordinating efforts across 10 distinct outcomes studies of prevention programs and making data available for analysis by non-HPC researchers, the HPC's efficacy and etiology evidence will far surpass the additive contributions of 10 individual research projects.

Multidisciplinary Strategies for Preventing Opioid Misuse and Escalation by Targeting Mental Health Symptoms and Conditions.

We aim to review the association between childhood-onset mental health conditions and increased risk for early substance use including opioid misuse and opioid use disorders (OUD). The association between mental health conditions and opioid misuse suggests youth with mental health conditions may benefit from opioid prevention efforts that concurrently address mental health. To aid in the identification of youth with mental health conditions who could benefit from interventions, we will review opportunities and challenges associated with screening for mental health symptoms or substance use in settings where youth at high risk for mental health conditions present. We will also review how research projects within the National Institutes of Health's Helping to End Addiction Long-term (HEAL) Prevention Cooperative are addressing mental health within opioid misuse and OUD prevention interventions for youth.

Methodological Strategies for Prospective Harmonization of Studies: Application to 10 Distinct Outcomes Studies of Preventive Interventions Targeting Opioid Misuse.

The Helping to End Addiction Long-Term (HEAL) Prevention Cooperative (HPC) is rapidly developing 10 distinct evidence-based interventions for implementation in a variety of settings to prevent opioid misuse and opioid use disorder. One HPC objective is to compare intervention impacts on opioid misuse initiation, escalation, severity, and disorder and identify whether any HPC interventions are more effective than others for types of individuals. It provides a rare opportunity to prospectively harmonize measures across distinct outcomes studies. This paper describes the needs, opportunities, strategies, and processes that were used to harmonize HPC data. They are illustrated with a strategy to measure opioid use that spans the spectrum of opioid use experiences (termed involvement) and is composed of common "anchor items" ranging from initiation to symptoms of opioid use disorder. The limitations and opportunities anticipated from this approach to data harmonization are reviewed. Lastly, implications for future research cooperatives and the broader HEAL data ecosystem are discussed.

Power analysis for idiographic (within-subject) clinical trials: Implications for treatments of rare conditions and precision medicine.

Power analysis informs a priori planning of behavioral and medical research, including for randomized clinical trials that are nomothetic (i.e., studies designed to infer results to the general population based on interindividual variabilities). Far fewer investigations and resources are available for power analysis of clinical trials that follow an idiographic approach, which emphasizes intraindividual variabilities between baseline (control) phase versus one or more treatment phases. We tested the impact on statistical power to detect treatment outcomes of four idiographic trial design factors that are under researchers' control, assuming a multiple baseline design: sample size, number of observations per participant, proportion of observations in the baseline phase, and competing statistical models (i.e., hierarchical modeling versus piecewise regression). We also tested the impact of four factors that are largely outside of researchers' control: population size, proportion of intraindividual variability due to residual error, treatment effect size, and form of outcomes during the treatment phase (phase jump versus gradual change). Monte Carlo simulations using all combinations of the factors were sampled with replacement from finite populations of 200, 1750, and 3500 participants. Analyses characterized the unique relative impact of each factor individually and all two-factor combinations, holding all others constant. Each factor impacted power, with the greatest impact being from larger treatment effect sizes, followed respectively by more observations per participant, larger samples, less residual variance, and the unexpected improvement in power associated with assigning closer to 50% of observations to the baseline phase. This study's techniques and R package better enable a priori rigorous design of idiographic clinical trials for rare diseases, precision medicine, and other small-sample studies.

Neuropsychiatric features of Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a genetic disorder characterized by hypotonia and poor feeding in infancy which progresses to hyperphagia in early-mid childhood, as well as developmental delays, a spectrum of behavioral and psychiatric concerns, endocrinopathies, orthopedic issues, and less commonly, seizures, sleep apnea, and narcolepsy with or without cataplexy. This study used data in the Global PWS Registry (N = 893) to explore the onset and severity over time of the neuropsychiatric features reported in individuals with PWS and explored its associations with sleep disorders, seizures, and psychiatric symptoms. Results demonstrate that seizures are more common in the deletion subtype and that narcolepsy and cataplexy are more common in individuals who have sleep-related seizures. Finally, this work shows that anxiety and compulsive behaviors are persistent features of PWS that may arise early in childhood, and that anxiety is associated with higher frequency of other comorbid psychiatric diagnoses. In conclusion, this study is one of the largest to date characterizing sleep disorders and neuropsychiatric characteristics of individuals with PWS and reports on the novel association between sleep disorders and seizures. This study is also one of the first to offer details on the nature of the progression of these features in individuals with PWS.

Addressing Barriers to Primary Care Screening and Referral to Prevention for Youth Risky Health Behaviors: Evidence Regarding Potential Cost-Savings and Provider Concerns.

Despite growing evidence and support for co-locating behavioral services in primary care to prevent risky health behaviors, implementation of these services has been limited due to a lack of reimbursement for services and negative perceptions among providers. We investigated potential to overcome these barriers based on new developments in healthcare funding and screening and referral to prevention (SRP) in primary care based on the Consolidated Framework for Implementation Research (CFIR), which could guide future SRP implementation strategies. To investigate the economic need for healthcare-based SRP, we quantified hospital charges to healthcare payors for services arising from adolescent risky behaviors (e.g., substance use, risky sex). Annual North Carolina (NC) hospital charges for these services exceeded $327 M (2019 dollars), suggesting high potential for cost savings if SRP can curb hospital services associated with risky behaviors. To investigate provider barriers and facilitators, we surveyed 151 NC pediatricians and 230 NC family therapists about their attitudes regarding a recently developed well-child visit SRP with family-based prevention. Both sets of professionals reported widespread need for and interest in the SRP but cited barriers of lack of reimbursement, training, and referrals to/from each other. Physicians, but not family therapists, reported concerns with poor patient or parent compliance. Many barriers could be resolved by co-locating family therapists in pediatric clinics to conduct well-child SRP. Our results support further research to develop business models for payor-funded SRP and CFIR-guided research to develop implementation strategies for primary care SRP to prevent adolescent risky health behaviors.

State of the Art in Substance Use Prevention and Early Intervention: Applications to Pediatric Primary Care Settings.

With changes to drug-related policies and increased availability of many drugs, we currently face a public health crisis related to substance use and associated health consequences. Substance use and substance use disorders (SU/SUDs) are complex developmental disorders with etiologies that emerge through the intergenerational transmission of biological, familial, and environmental factors. The family ecosystem both influences and is influenced by SU/SUDs, particularly in children and adolescents. Family dynamics and parent functioning and behaviors can represent either risk or protective factors for the development of SU/SUDs in children. Primary care providers who provide care for children, adolescents, and families are in an ideal position to deliver prevention messages and to intervene early in the development of substance misuse and SUD among their patients. Despite recommendations from the American Academy of Pediatrics, few pediatric primary care providers provide anticipatory guidance to prevent or screen for substance misuse. Many barriers to those practices can be overcome through the integration and application of findings from the field of prevention science and the many lessons learned from the implementation of evidence-based interventions. Consideration of the implications of prevention science findings would help clarify the relevant roles and responsibilities of the primary care clinician, and the benefit of referral to and consultation from addiction specialists. Additionally, the past decade has seen the development and validation of a continuum of evidence-based prevention and early SU/SUD intervention activities that can be adapted for use in primary care settings making wide-spread implementation of prevention feasible. We propose a paradigm shift away from a model based on diagnosis and pathology to one upstream, that of family-focused prevention and early intervention. Adapting and scaling out empirically based prevention and early SU/SUD interventions to primary care settings and removing barriers to collaborative care across primary care, addiction medicine, and mental health providers offer the potential to meaningfully impact intergenerational transmission of SU/SUD - addressing a leading health problem facing our nation.

Effects of Behavioral Treatment Modified to Fit Children with Conduct Problems and Callous-Unemotional (CU) Traits.

Research suggests that children with conduct problems (CP) and callous-unemotional (CU) traits show a diminished response to behavior therapy, perhaps due to a reward-oriented, punishment insensitive learning style. Children with CP and CU may benefit from personalizing behavioral treatment for them by emphasizing rewards and de-emphasizing punishments. This hypothesis was tested in a sample of 46 children (78.3% boys), ages 7.0 to 12.6 years (M = 9.3, SD = 1.4). All participants met criteria for ODD and ADHD and 63% also met criteria for CD. Participants were oversampled for high CU, but CU scores ranged from average to high. Children received four weeks of modified behavior therapy that emphasized rewards and de-emphasized punishments and four weeks of treatment as usual, which was standard behavior therapy that balanced rewards and punishments. Treatments were implemented in a summer treatment program and compared using a within-subjects design, with order of treatment counterbalanced. Disruptive behavior was equal or slightly higher in modified behavior therapy than in standard behavior therapy on point system measures, but lower on parent weekly ratings. End of treatment ratings showed both treatments produced significant improvements compared to pre-treatment ratings but did not differ from each other. Personalizing behavior therapy for children with CP and CU produced inconsistent findings relative to standard behavior therapy. Behavior therapy is likely to be a necessary part of treatment for children with CP and CU, but treatment personalization efforts may provide some benefit by addressing other deficits shown by these children.

Association With Deviant Peers Across Adolescence: Subtypes, Developmental Patterns, and Long-Term Outcomes.

Indices of deviant peer group involvement are inconsistent and confound type, frequency, and severity of deviant peer behaviors. These measurement approaches thus obfuscate potential meaningful differences in deviant peer involvement in terms of subtypes, developmental patterns, and long-term outcomes. The current study employed latent class analysis to derive subtypes of deviant peer involvement and examined relations to substance use disorder in adulthood, a common outcome of deviant peer involvement. Youth (76% Caucasian) completed assessments across four time points: ages 10-12 years (Time 1; N = 775, 71% male), 12-14 years (Time 2; n = 649, 72% male), 16 years (Time 3; n = 613, 73% male), and 22 years (Time 4; n = 425, 71% male). At Times 1 to 3, participants completed an interview assessing deviant peer involvement. At Time 4, participants completed a structured interview assessing substance use disorder. Classes of youth with different profiles of deviant peer associations were derived at Times 1, 2, and 3. Classes varied by type (conduct problems vs. substance use) and severity of deviant peer behavior. Youth reported higher levels of involvement with deviant peers across adolescence, suggesting that some of these deviant peer behaviors may be normative. Earlier involvement with deviant peers and involvement with groups defined by severe conduct problems and substance use were related to the greatest risk for substance use disorder at Time 4. Type and severity of peer deviant behavior differentially relate to long-term risk for substance use disorder and should be included in screening and assessment for risk across adolescence.

Profiles of individual assets and mental health symptoms in at-risk early adolescents.

INTRODUCTION: Few studies investigated the combined patterns of individual assets (e.g., social competence, positive identity) and mental health symptoms (MHS) in adolescents. This study examined the patterns of early adolescents' individual assets and MHS and whether identified patterns were associated with later adolescents' outcomes. METHODS: Participants were 352 (164 boys, 188 girls) adolescents who were primarily African-American and from low socioeconomic status families, participating in a prospective study of the effects of prenatal cocaine exposure from birth in the Midwest United States. Individual assets, using the Developmental Assets Profile, and MHS, using the Youth Self-Report, were assessed at age 12. Substance use, via self-report and biologic assays, early (before age 15) sexual behaviors, and behavioral adjustment were assessed at age 15. RESULTS: Latent profile analysis indicated four distinctive profiles: low assets with elevated MHS (P1, n = 54, 15.3%); adequate assets with thought and social problems (P2, n = 84, 23.9%); low assets without MHS (P3, n = 101, 28.7%); and high assets without MHS (P4, n = 113, 32.1%). Children in the profile with high assets without MHS (P4) were more likely to have a higher IQ and to be in a more optimal environment (higher parental monitoring and less family conflict) than those in other profiles. Although profiles with MHS were associated with adolescent risk behaviors, this relationship was more pronounced for girls than for boys. CONCLUSIONS: Girls in the low assets with elevated MHS (P1) should be a primary concern for preventive intervention. Our study demonstrates the heterogeneity of individual patterns of adaptation and maladaptation.

Residential Transience Among Adults: Prevalence, Characteristics, and Association with Mental Illness and Mental Health Service Use.

This study examined the association between frequent residential mobility (i.e., residential transience) and mental illness, mental health service use, and unmet need for services. Data are from the 2010 to 2014 National Surveys on Drug Use and Health (n = ~ 229,600). Logistic regression models examined the relationship between proximal (past year) and distal (past 2-5 years) residential transience and past year any mental illness (AMI), serious mental illness (SMI), mental health service use among adults with mental illness, and unmet need for services. Adults with transience had greater odds of AMI and SMI than those without transience. Proximal and distal transience were unrelated to past year mental health service use among adults with mental illness, but the odds of unmet need for services were greater among adults with transience compared with those without, suggesting a level of unmet service need among those with transience.

Clinically differentiating life-course-persistent and adolescence-limited conduct problems: Is age-of-onset really enough?

One important subtyping of behavior problems is Moffitt's (1993) "life-course-persistent" (LCP) and "adolescent limited" (AL) categories of antisocial behavior, which she differentiated in terms of high impulsivity, poor academic performance, and aggression. These problems may be exacerbated by the cumulative effects of chronic stress. Copious evidence has documented validity and developmental differences between these subtypes, whereas far fewer data exist regarding their clinical utility, in spite of the Diagnostic and Statistical Manual's nomenclature including corresponding subtypes based on age-of-onset of behavioral symptoms. The present study evaluated how well age-of-onset based subtyping identifies distinct developmental patterns of antisocial behavior corresponding to Moffitt's subtypes in terms of risk factors and gender between LCP and AL in a prospective sample of chronically stressed youth. A computerized assessment tool (ALEXSA©) was used to obtain data from 1,147 youth aged 8-16. Implications for clinical assessment and intervention strategy, particularly with stressed youth, are discussed.

Genetic relationship between the addiction diagnosis in adults and their childhood measure of addiction liability.

Transmissible liability index (TLI), developed employing a high-risk design and item response theory, enables quantification of the latent trait of liability to drug use disorders (DUD) in children. TLI has been shown to have high heritability and predict DUD in young adulthood. This study extends prior research and determines the genetic contribution of DUD liability measured by TLI to adult liability as indexed by DUD diagnosis. The study utilizes data from a twin sample tracked from age 11 to age 25. In addition to confirming TLI's high heritability and predictive validity, it shows that the genetic component of variance in TLI assessed in childhood accounts for over half of the genetic variance in DUD diagnosis and the entire phenotypic relationship between the two liability measures. This validates TLI as an early measure of DUD liability and supports its utility in early-age genetic and other mechanistic studies of DUD.

Psychological dysregulation during adolescence mediates the association of parent-child attachment in childhood and substance use disorder in adulthood.

OBJECTIVE: This prospective study tested the hypothesis that psychological dysregulation in mid-adolescence (age 16) mediates the association between parent-child attachment in late childhood (age 10-12) and development of substance use disorder (SUD) in adulthood (age 22). METHOD: The Youth Attachment to Parents Scale (YAPS) was developed in 10-12-year-old boys and girls (N = 694) at baseline residing in western Pennsylvania. Psychological dysregulation was measured by the neurobehavior disinhibition trait. Substance use was assessed at ages 10-12, 12-14, 16 and 19. SUD was diagnosed at age 22 using the Structured Clinical Interview for DSM Disorders. The mediation of parent-child attachment and SUD by neurobehavior disinhibition was tested separately for mothers and fathers while controlling for baseline substance use. RESULTS: Psychological dysregulation mediates the association between attachment to mothers and SUD, and partially mediates the association between attachment to fathers and SUD. Significant mediation effects remains after controlling for baseline substance use. CONCLUSION: Optimal prevention of SUD should include ameliorating both psychological dysregulation predisposing to SUD and quality of the parent-child relationship.

Interplay Among Self-Regulation Processes Over Time for Adolescents in the Context of Chronic Stress.

Developmental changes in self-regulation are theorized to underlie adolescents' engagement in risky behaviors, physical health, mental health, and transition to adulthood. Two central processes involved in self-regulation, self-management (i.e., planning, concentration, and problem-solving) and disinhibition (e.g., distractibility and impulsivity) appear to develop asynchronously and may be differentially activated based on contextual factors. Using a sample identified based on exposure to chronic stressors, we investigated how changes in self-management and disinhibition affect each other over time and whether these changes occur differently for boys and girls. Youth aged 8-16 (N = 708) who attended a U.S. summer camp self-reported on components of disinhibition and self-management. Cross-lagged structural equation modeling revealed a reciprocal relationship between self-management and disinhibition, with anger coping and distractibility emerging as critical factors in shaping this relationship. Changes in concentration, planning, and problem-solving were components of self-management that drove subsequent changes in boys' disinhibition (for girls, however, planning did not). Autocorrelations for both broad processes remained strong from year to year, indicating a high degree of stability in rank order despite the myriad of physical, cognitive and socioemotional changes that occur during adolescence. We discuss implications of the reciprocal model with a focus on the relative pliability of components from each process and strategies for shaping them. Planning, concentration and distractibility are highlighted as potential targets for intervention.

Toward rigorous idiographic research in prevention science: comparison between three analytic strategies for testing preventive intervention in very small samples.

Psychosocial prevention research lacks evidence from intensive within-person lines of research to understand idiographic processes related to development and response to intervention. Such data could be used to fill gaps in the literature and expand the study design options for prevention researchers, including lower-cost yet rigorous studies (e.g., for program evaluations), pilot studies, designs to test programs for low prevalence outcomes, selective/indicated/adaptive intervention research, and understanding of differential response to programs. This study compared three competing analytic strategies designed for this type of research: autoregressive moving average, mixed model trajectory analysis, and P-technique. Illustrative time series data were from a pilot study of an intervention for nursing home residents with diabetes (N = 4) designed to improve control of blood glucose. A within-person, intermittent baseline design was used. Intervention effects were detected using each strategy for the aggregated sample and for individual patients. The P-technique model most closely replicated observed glucose levels. ARIMA and P-technique models were most similar in terms of estimated intervention effects and modeled glucose levels. However, ARIMA and P-technique also were more sensitive to missing data, outliers and number of observations. Statistical testing suggested that results generalize both to other persons as well as to idiographic, longitudinal processes. This study demonstrated the potential contributions of idiographic research in prevention science as well as the need for simulation studies to delineate the research circumstances when each analytic approach is optimal for deriving the correct parameter estimates.

Longitudinal modeling of transmissible risk in boys who subsequently develop cannabis use disorder.

BACKGROUND: Risk for substance use disorder is frequently transmitted across generations due to significant heritability. OBJECTIVE: This longitudinal study tests the hypothesis that initial exposure to cannabis in youths having high transmissible risk is a signal event promoting development of cannabis use disorder (CUD). METHODS: At age 22, 412 men were classified into three groups: (1) lifetime CUD, (2) cannabis use without CUD, and (3) no lifetime cannabis use. Transmissible risk, quantified on a continuous scale using the previously validated transmissible liability index (TLI), along with cannabis use and CUD were documented at 10-12, 12-14, 16, 19, and 22 years of age. RESULTS: The CUD group scored higher on the TLI before they began cannabis use compared to the other two groups. In addition, a progressive increase in TLI severity was evinced by the CUD group beginning at the time of initiation of cannabis use whereas cannabis users who did not subsequently develop CUD exhibited a decline in transmissible risk following first exposure. CONCLUSION: Initial use of cannabis potentiates development of CUD in youths who are at high transmissible risk but is inconsequential in youths having low risk. The practical ramifications of these results for prevention are discussed.

High and low neurobehavior disinhibition clusters within locales: implications for community efforts to prevent substance use disorder.

BACKGROUND: Knowledge of where substance use and other such behavioral problems frequently occur has aided policing, public health, and urban planning strategies to reduce such behaviors. Identifying locales characterized by high childhood neurobehavioral disinhibition (ND), a strong predictor of substance use and consequent disorder (SUD), may likewise improve prevention efforts. OBJECTIVES: The distribution of ND in 10-12-year olds was mapped to metropolitan Pittsburgh, PA, and tested for clustering within locales. METHODS: The 738 participating families represented the population in terms of economic status, race, and population distribution. ND was measured using indicators of executive cognitive function, emotion regulation, and behavior control. Innovative geospatial analyzes statistically tested clustering of ND within locales while accounting for geographic barriers (large rivers, major highways), parental SUD severity, and neighborhood quality. RESULTS: Clustering of youth with high and low ND occurred in specific locales. Accounting for geographic barriers better delineated where high ND is concentrated, areas which also tended to be characterized by greater parental SUD severity and poorer neighborhood quality. CONCLUSIONS AND SIGNIFICANCE: Offering programs that have been demonstrated to improve inhibitory control in locales where youth have high ND on average may reduce youth risk for SUD and other problem behaviors. As demonstrated by the present results, geospatial analysis of youth risk factors, frequently used in community coalition strategies, may be improved with greater statistical and measurement rigor.

Feasibility of combining biosensor and ecological momentary assessment to measure stress experiences among economically disadvantaged adolescents.

Adolescent stress is complex and impairing. Novel measures are needed to understand stress variability within individuals over time from a physiological as well as a subjective perspective. To test the feasibility of combining ecological momentary assessment (EMA) and wearable biosensors to assess adolescent stress, using an idiographic approach with experience sampling methods. A small sample (n = 23) of predominantly African American, economically disadvantaged adolescents were asked to complete EMA surveys four times per day and wear an armband measuring Heart rate (HR) and skin response for a 2-week period. Descriptive analyses examined number of hours of armband wear, percentage of viable data, and percentage of surveys completed by gender and race. Associations between biosensor data and EMA reports within and across individuals were also examined using hierarchical linear regression. EMA survey completion was good (81%) as was adherence to biosensor protocols, although technological difficulties interfered with collection of HR variability for youth with darker skin tones. Youth reported stressful events in 12.79% of EMA surveys, although 43% reported no negative mood experiences. Convergent validity was supported for detecting between-person (EMA) and within-person (EMA and biosensors) variability in stress across time, although associations across youth were highly variable. Results suggest value for biobehavioral methods in understanding day-to-day stress in adolescents but highlight variability in stress experiences as well as technological limitations, especially for youth of colour.