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

Patterns of concurrent substance use among adolescent nonmedical ADHD stimulant users

Objectives: There are growing concerns about nonmedical use of ADHD stimulants among adolescents; yet, little is known whether there exist heterogeneous subgroups among adolescents with nonmedical ADHD stimulant use according to their concurrent substance use. Methods: We used latent class analysis (LCA) to examine patterns of past-year problematic substance use (meeting any criteria for abuse or dependence) in a sample of 2203 adolescent participants from the National Surveys on Drug Use and Health 2006–2011 who reported past-year nonmedical use of ADHD stimulants. Multivariable latent regression was used to assess the association of socio-demographic characteristics, mental health and behavioral problems with the latent classes. Results: The model fit indices favored a four-class model, including a large class with frequent concurrent use of alcohol and marijuana (Alcohol/marijuana class; 41.2%), a second large class with infrequent use of other substances (Low substance class, 36.3%), a third class characterized by more frequent misuse of prescription drugs as well as other substances (Prescription drug + class; 14.8%), and finally a class characterized by problematic use of multiple substances (Multiple substance class; 7.7%). Compared with individuals in Low substance class, those in the other three classes were all more likely to report mental health problems, deviant behaviors and substance abuse service use. Conclusions: Adolescent nonmedical ADHD stimulants users are a heterogeneous group with distinct classes with regard to concurrent substance use, mental health and behavioral problems. The findings have implications for planning of tailored prevention and treatment programs to curb stimulant use for this age group

Patterns of concurrent substance use among nonmedical ADHD stimulant users: Results from the National Survey on Drug Use and Health

Aims: To examine patterns of concurrent substance use among adults with nonmedical ADHD stimulant use. Methods: We used latent class analysis (LCA) to examine patterns of past-year problematic substance use (meeting any criteria for abuse or dependence) in a sample of 6103 adult participants from the National Surveys on Drug Use and Health 2006–2011 who reported past-year nonmedical use of ADHD stimulants. Multivariable latent regression was used to assess the association of socio-demographic characteristics, mental health and behavioral problems with the latent classes. Results: A four-class model had the best model fit, including (1) participants with low probabilities for any problematic substance use (Low substance class, 53.3%); (2) problematic users of all types of prescription drugs (Prescription drug class, 13.3%); (3) participants with high probabilities of problematic alcohol and marijuana use (Alcohol–marijuana class, 28.8%); and (4) those with high probabilities of problematic use of multiple drugs and alcohol (Multiple substance class, 4.6%). Participants in the 4 classes had distinct socio-demographic, mental health and service use profiles with those in the Multiple substance class being more likely to report mental health and behavioral problems and service use. Conclusion: Nonmedical users of ADHD stimulants are a heterogeneous group with a large subgroup with low prevalence of problematic use of other substances. These subgroups have distinct patterns of mental health comorbidity, behavior problems and service use, with implications for prevention and treatment of nonmedical stimulant use

Correlates of nonmedical use of stimulants and methamphetamine use in a national sample

BACKGROUND: Despite chemical similarities, ADHD stimulants and methamphetamine have distinct use patterns in the community. This study compared the characteristics of nonmedical ADHD stimulants users and methamphetamine users in a household sample. METHODS: In data from the 2009-2011 National Survey on Drug Use and Health, adult and adolescent stimulant users were categorized into three mutually exclusive subgroups: nonmedical ADHD stimulant users only (STM users), methamphetamine users (METH users), and both nonmedical ADHD stimulant and methamphetamine users (STM/METH users). Multivariate logistic regression analyses identified the substance comorbidity, mental health, and deviant behavior characteristics associated with these three groups. RESULTS: Compared to adolescent STM users, STM/METH users were more likely to be female, younger and uninsured while METH users were more likely to be younger, in a minority group and from a higher-income family. Compared to adult STM users, METH and STM/METH users were more likely to be male, older, uninsured, no longer married, and to be from rural areas. Adolescent METH users were more likely than STM users to report illegal drug use while adult METH users were less likely to report prescription drug use than their STM user counterparts. Overall, adult and adolescent STM/METH users were more likely to report substance use, mental health problems and deviant behaviors compared to STM users. CONCLUSION: The characteristics of STM users differ from METH and STM/METH users, and their associations with substance use and psychiatric comorbidities differ by age. Findings have implications for understanding the risks for stimulant use in different age subgroups

Cross-cultural adaptation and validation of the self-reporting questionnaire among HIV+ individuals in a rural ART program in southern Uganda

Background: HIV treatment programs are in need of brief, valid instruments to identify common mental disorders such as depression. Aim: To translate and culturally adapt the Self-Reporting Questionnaire (SRQ-20) for use in Uganda and to investigate its psychometric properties in this setting. Methods: Following an initial translation of the SRQ-20 from English to Luganda, key informant interviews and focus-group discussions were used to produce a culturally adapted version of the instrument. The adapted SRQ-20 was administered to 200 HIV-positive individuals in a rural antiretroviral therapy program in southern Uganda. All study participants were also evaluated by a psychiatric clinical officer with the Mini International Neuropsychiatric Interview (MINI). Receiver-operating-characteristic analysis was used to examine the sensitivity and specificity of the SRQ-20 compared to the clinical diagnosis generated by the MINI. Results: The prevalence estimates of any depressive disorder and current depression were 24% (n = 48) and 12% (n = 24), respectively. The SRQ-20 scores discriminated well between subjects with and without current depression based on the MINI, with an area under the curve of 0.92, as well as between subjects with and without any current or past depressive disorder, with an area under the curve of 0.75. A score of 6 or more had 84% sensitivity and 93% specificity for current depression, and 75% sensitivity and 90% specificity for any depressive disorder. Conclusion: The SRQ-20 appears to be a reliable and valid screening measure for depression among rural HIV-positive individuals in southern Uganda. The use of this screening instrument can potentially improve detection and management of depression in this setting. © 2012 Nakimuli-Mpungu et al, publisher and licensee Dove Medical Press Ltd

Trends in sleep problems and patterns among Japanese adolescents: 2004 to 2017

Background Sleep problems in adolescence, such as insomnia and short sleep duration, are associated with physical and mental health problems. However, little is known about the recent trends in sleep problems among adolescents. Therefore, this study examined trends in sleep problems among Japanese adolescents. Methods Using data from the Lifestyle Survey of Adolescents collected in 2004 (n = 102,451), 2008 (n = 95,680), 2010 (n = 98,867), 2012 (n = 101,134), 2014 (n = 85,931), and 2017 (n = 64,417), we calculated the trends of insomnia, shorter sleep duration, late bedtimes, and poor sleep quality. Multivariable logistic regression analysis models were used to examine the association of each sleep problem and survey years. Findings We analyzed data from 545,285 Japanese adolescents. Results indicated that, since 2004, the odds ratio for insomnia have decreased (Adjusted odds ratio [AOR] 0•85, 95% CI 0•82–0•87), as have the odds ratio for poor sleep quality (AOR 0•92, 95% CI 0•88–0•95). However, the odds ratio for shorter sleep duration (AOR 1•13, 95% CI 1•10–1•17) and late bedtimes tended to increase (AOR 1•06, 95% CI 1•03–1•08) during this period. Interpretation The prevalence of insomnia symptoms and poor sleep quality among adolescents decreased from 2004 to 2017. However, there were increasing trends toward shorter sleep duration and late bedtimes. These changes are both relieving and concerning. Teachers, parents, and health professionals should consider educating adolescents regarding sleep hygiene, adjusting schedules of extracurricular activities, and enhancing time management to improve their sleep quantity

The impact of child psychiatric conditions on future educational outcomes among a community cohort in Brazil

Aims Mental health problems early in life can negatively impact educational attainment, which in turn have negative long-term effects on health, social and economic opportunities. Our aims were to: (i) estimate the impacts of different types of psychiatric conditions on educational outcomes and (ii) to estimate the proportion of adverse educational outcomes which can be attributed to psychiatric conditions. Methods Participants (N = 2511) were from a school-based community cohort of Brazilian children and adolescents aged 6-14 years enriched for high family risk of psychiatric conditions. We examined the impact of fear-(panic, separation and social anxiety disorder, specific phobia, agoraphobia and anxiety conditions not otherwise specified), distress-(generalised anxiety disorder, major depressive disorder and depressive disorder not otherwise specified, bipolar, obsessive-compulsive, tic, eating and post-traumatic stress disorder) and externalising-related conditions (attention deficit and hyperactivity disorder, conduct and oppositional-defiant conditions) on grade repetition, dropout, age-grade distortion, literacy performance and bullying perpetration, 3 years later. Psychiatric conditions were ascertained by psychiatrists, using the Development and Well-Being Behaviour Assessment. Propensity score and inverse probability weighting were used to adjust for potential confounders, including comorbidity, and sample attrition. We calculated the population attributable risk percentages to estimate the proportion of adverse educational outcomes in the population which could be attributed to psychiatric conditions. Analyses were conducted separately for males and females. Results Fear and distress conditions in males were associated with school dropout (odds ratio (OR) = 2.76; 95% confidence interval (CI) = 1.06, 7.22; p < 0.05) and grade repetition (OR = 2.76; 95% CI = 1.32, 5.78; p < 0.01), respectively. Externalising conditions were associated with grade repetition in males (OR = 1.66; 95% CI = 1.05, 2.64; p < 0.05) and females (OR = 2.03; 95% CI = 1.15, 3.58; p < 0.05), as well as age-grade distortion in males (OR = 1.66; 95% CI = 1.05, 2.62; p < 0.05) and females (OR = 2.88; 95% CI = 1.61, 5.14; p < 0.001). Externalising conditions were also associated with lower literacy levels (β =-0.23; 95% CI =-0.34,-0.12; p < 0.001) and bullying perpetration (OR = 3.12; 95% CI = 1.50, 6.51; p < 0.001) in females. If all externalising conditions were prevented or treated, we estimate that 5.0 and 4.8% of grade repetition would not have occurred in females and males, respectively, as well as 10.2 (females) and 5.3% (males) of age-grade distortion cases and 11.4% of female bullying perpetration. Conclusions The study provides evidence of the negative impact of psychiatric conditions on educational outcomes in a large Brazilian cohort. Externalising conditions had the broadest and most robust negative impacts on education and these were particularly harmful to females which are likely to limit future socio-economic opportunities

Long-Term Effect of Group Support Psychotherapy on Depression and HIV Treatment Outcomes: Secondary Analysis of a Cluster Randomized Trial in Uganda

OBJECTIVE: We aimed to determine the effect of group support psychotherapy (GSP) compared with group HIV education (GHE) on depression and HIV treatment outcomes 24 months after treatment. We further aimed to investigate the mediating role of depression and antiretroviral therapy (ART) adherence in the relationship between GSP and viral load suppression. METHODS: Thirty HIV clinics across three districts were randomly assigned to deliver either GSP or GHE for depression. Depression and optimal (≥95%) ART adherence was assessed at baseline and 6, 12, 18, and 24 months after treatment. Viral load was drawn from the medical charts at baseline and 12 and 24 months after treatment. Multilevel mixed-effects regression models and generalized structural equation modeling were used to estimate 24-month outcomes and mediation effects. RESULTS: Participants ( N = 1140) were enrolled from HIV clinics offering either GSP ( n = 578 [51%]) or GHE ( n = 562 [49%]). Fewer GSP than GHE participants met the criteria for depression at 24 months after treatment (1% versus 25%; adjusted odds ratio [aOR] = 0.002, 95% confidence interval [CI] = 0.0002-0.018). More GSP than GHE participants reported optimal (≥95%) ART adherence (96% versus 88%; aOR = 20.88, 95% CI = 5.78-75.33) and improved viral suppression (96% versus 88%; aOR = 3.38, 95% CI = 1.02-11.02). The indirect effects of GSP through sequential reduction in depression and improvement in ART adherence at 12 months may partially explain the higher viral suppression rates at 24 months in GSP than GHE groups. CONCLUSION: In settings where the HIV epidemic persists, depression treatment with GSP may be critical for optimal HIV treatment outcomes.Trial Registration: The Pan African Clinical Trials Registry, number PACTR201608001738234