Systematically missing data in causally interpretable meta-analysis.

Causally interpretable meta-analysis combines information from a collection of randomized controlled trials to estimate treatment effects in a target population in which experimentation may not be possible but from which covariate information can be obtained. In such analyses, a key practical challenge is the presence of systematically missing data when some trials have collected data on one or more baseline covariates, but other trials have not, such that the covariate information is missing for all participants in the latter. In this article, we provide identification results for potential (counterfactual) outcome means and average treatment effects in the target population when covariate data are systematically missing from some of the trials in the meta-analysis. We propose three estimators for the average treatment effect in the target population, examine their asymptotic properties, and show that they have good finite-sample performance in simulation studies. We use the estimators to analyze data from two large lung cancer screening trials and target population data from the National Health and Nutrition Examination Survey (NHANES). To accommodate the complex survey design of the NHANES, we modify the methods to incorporate survey sampling weights and allow for clustering.

Safety and Durability of Accelerated Infliximab Dosing Strategies in Pediatric IBD: A Single Center, Retrospective Study.

OBJECTIVES: Infliximab (IFX) is commonly used to treat children with inflammatory bowel disease (IBD). We previously reported that patients with extensive disease started on IFX at a dose of 10 mg/kg had greater treatment durability at year one. The aim of this follow-up study is to assess the long-term safety and durability of this dosing strategy in pediatric IBD. METHODS: We performed a retrospective single-center study of pediatric IBD patients started on IFX over a 10-year period. RESULTS: Two hundred ninety-one patients were included (mean age = 12.61, 38% female) with a follow-up range of 0.1-9.7 years from IFX induction. One hundred fifty-five (53%) were started at a dose of 10 mg/kg. Only 35 patients (12%) discontinued IFX. The median duration of treatment was 2.9 years. Patients with ulcerative colitis ( P ≤ 0.01) and patients with extensive disease ( P = 0.01) had lower durability, despite a higher starting dose of IFX ( P = 0.03). Adverse events (AEs) were observed to occur at a rate of 234 per 1000 patient-years. Patients with a higher serum IFX trough level (≥20 µg/mL) had a higher rate of AEs ( P = 0.01). Use of combination therapy had no impact on risk of AEs ( P = 0.78). CONCLUSIONS: We observed an excellent IFX treatment durability, with only 12% of patients discontinuing therapy over the observed timeframe. The overall rate of AEs was low, the majority being infusion reactions and dermatologic conditions. Higher IFX dose and serum trough level> 20 µg/mL were associated with higher risk of AEs, the majority being mild and not resulting in cessation of therapy.

Addressing Systematic Missing Data in the Context of Causally Interpretable Meta-analysis.

Evidence synthesis involves drawing conclusions from trial samples that may differ from the target population of interest, and there is often heterogeneity among trials in sample characteristics, treatment implementation, study design, and assessment of covariates. Stitching together this patchwork of evidence requires subject-matter knowledge, a clearly defined target population, and guidance on how to weigh evidence from different trials. Transportability analysis has provided formal identifiability conditions required to make unbiased causal inference in the target population. In this manuscript, we review these conditions along with an additional assumption required to address systematic missing data. The identifiability conditions highlight the importance of accounting for differences in treatment effect modifiers between the populations underlying the trials and the target population. We perform simulations to evaluate the bias of conventional random effect models and multiply imputed estimates using the pooled trials sample and describe causal estimators that explicitly address trial-to-target differences in key covariates in the context of systematic missing data. Results indicate that the causal transportability estimators are unbiased when treatment effect modifiers are accounted for in the analyses. Results also highlight the importance of carefully evaluating identifiability conditions for each trial to reduce bias due to differences in participant characteristics between trials and the target population. Bias can be limited by adjusting for covariates that are strongly correlated with missing treatment effect modifiers, including data from trials that do not differ from the target on treatment modifiers, and removing trials that do differ from the target and did not assess a modifier.

Using Virtual Reality to Examine the Association Between Respiratory Sinus Arrhythmia and Adolescent Substance Use.

Early substance use is associated with long-term negative health outcomes. Emotion regulation (ER) plays an important role in reducing risk, but detecting those vulnerable because of ER deficits is challenging. Respiratory sinus arrhythmia (RSA), a biomarker of ER, may be useful for early identification of substance use risk. To examine this, we enrolled 23 adolescents (Mage = 14.0; 56% minority) with and without a history of substance use and collected RSA during a neutral baseline, virtual reality challenge scene, and neutral recovery. ANOVAs indicated that adolescents who reported having used a substance were not different from non-using peers on baseline or challenge RSA but demonstrated lower RSA during recovery. This suggests that adolescents with a history of substance use exhibit slower return to baseline RSA after experiencing a challenging situation compared to non-using peers. RSA, an index of ER, may be useful in identifying adolescents at risk for early substance use.

Sleep disturbance and suicidality in psychiatrically hospitalized adolescents: The role of specific emotion regulation domains.

BACKGROUND: Sleep disturbance is associated with broadband measurements of emotion regulation (ER). The linkage between ER, a multidimensional process, and suicidal ideation and suicide attempt is also documented in theoretical and empirical work. Recent research indicates that distinct profiles of ER are associated with psychiatric outcomes, including adolescent suicidal ideation and attempt. The present study examined whether specific domains of ER would explain the association between sleep disturbance, and ideation and attempt among psychiatrically hospitalized adolescents. METHOD: The sample included 284 adolescents who completed self-report measures on sleep disturbance, ER, suicidal ideation, suicide attempt, and psychiatric symptoms upon inpatient hospitalization. RESULTS: Findings indicated that sleep disturbance was associated with suicidal ideation. Further, a single ER domain (perceived limited access to ER strategies) fully accounted for the significant association between sleep disturbance and suicidal ideation. A reported suicide attempt in the past week was correlated with the nonacceptance of emotional responses, perceived limited access to ER strategies, and emotional clarity, but was not associated with sleep disturbance. DISCUSSION: The current findings highlight the importance of examining narrowband ER and indicate the presence of differential associations between sleep disturbance, ER, and suicide-related outcomes. Findings further elucidate the possible role of impaired cognitive responses to emotional experiences in the co-occurrence of sleep disturbance and youth psychiatric outcomes.

Causally Interpretable Meta-analysis: Application in Adolescent HIV Prevention.

Endowing meta-analytic results with a causal interpretation is challenging when there are differences in the distribution of effect modifiers among the populations underlying the included trials and the target population where the results of the meta-analysis will be applied. Recent work on transportability methods has described identifiability conditions under which the collection of randomized trials in a meta-analysis can be used to draw causal inferences about the target population. When the conditions hold, the methods enable estimation of causal quantities such as the average treatment effect and conditional average treatment effect in target populations that differ from the populations underlying the trial samples. The methods also facilitate comparison of treatments not directly compared in a head-to-head trial and assessment of comparative effectiveness within subgroups of the target population. We briefly describe these methods and present a worked example using individual participant data from three HIV prevention trials among adolescents in mental health care. We describe practical challenges in defining the target population, obtaining individual participant data from included trials and a sample of the target population, and addressing systematic missing data across datasets. When fully realized, methods for causally interpretable meta-analysis can provide decision-makers valid estimates of how treatments will work in target populations of substantive interest as well as in subgroups of these populations.

Sleep Problems and Autism Impairments in a Large Community Sample of Children and Adolescents.

Sleep problems are common in individuals with autism spectrum disorder (ASD). How sleep problems reflect specific ASD phenotypes is unclear. We studied whether sleep problems indexed functional impairment in a heterogeneous community sample of individuals with ASD. We analyzed 977 probands (233 females; age = 11.27 ± 4.13 years) from the Rhode Island Consortium for Autism Research and Treatment dataset, a unique public-private-academic collaboration involving all major points of service for families in Rhode Island. We found that individuals with a confirmed diagnosis of ASD were more likely to have sleep problems. However, across the whole sample and above and beyond a formal diagnosis, sleep problems were dimensionally associated with worse social impairment and poorer adaptive functioning. By using a large dataset reflective of the diversity of presentations in the community, this study underscores the importance of considering sleep problems in clinical practice to improve adaptive functioning in individuals with ASD.

Editorial Perspective: Adolescents' fragile sleep-shining light on a time of risk to mental health.

As many other facets of life-biological, behavioral, psychological, cognitive, and social-undergo change during adolescence, so too does sleep. The context of sleep behavior is modified by alterations to underlying bioregulatory processes that challenge sleep's timing, regularity, and quantity. The buildup of sleep pressure during the day gets slower, opening the door for youth to stay awake later; however, the amount of sleep required does not diminish. Further, the circadian timing system delays, again providing the biological impetus for later sleep. When these changes meet societal demands for early wake, most teens cannot find a way to get enough sleep at a consistent time from night to night. Insufficient and irregular sleep provides a fragile foundation to support mental health.

Evaluating the Role of Family Context Within a Randomized Adolescent HIV-Risk Prevention Trial.

Project STYLE is a multi-site 3-arm RCT comparing family-based, adolescent-only, and general health promotion interventions with 721 adolescents in mental health treatment. This study reports 12-month outcomes for family context and sexual risk behaviors, and explores the role of baseline family context in modifying treatment response. Using the full sample, there were sustained benefits for parent-reported sexual communication (d = 0.28), and adolescent-reported parental monitoring (d = 0.24), with minimal differences in risk behaviors. Latent profile analysis identified four family context classes: struggling (n = 177), authoritative (n = 183), authoritarian (n = 175), and permissive (n = 181). The authoritarian and permissive classes were also distinguished by disagreement between parent and adolescent report of family context. Classes differed in terms of baseline mental health burden and baseline sexual risk behavior. Classes showed different patterns of treatment effects, with the struggling class showing consistent benefit for both family context and sexual risk. In contrast, the authoritarian class showed a mixed response for family context and increased sexual risk.

Using Composite Scores to Summarize Adolescent Sexual Risk Behavior: Current State of the Science and Recommendations.

Composite scores offer the advantage of summarizing across multiple sexual risk behaviors to both simplify results and better capture the influence of core contextual, interpersonal, and intrapersonal dynamics that affect multiple sexual risk behaviors. There is inconsistency in how researchers utilize composite scores with minimal guidance on the advantages and disadvantages of frequently used approaches. Strengths and weaknesses of each approach are discussed in the context of assessing adolescent sexual risk behavior. A latent variable model and three commonly used composites were applied to data combined across four clinical trials (n = 1322; 50% female). Findings suggested that the latent variable approach was limited due to minimal correlations among sexual risk behaviors, that choice of composite had minimal impact on cross-sectional results so long as there is sufficient variability in risk behavior in the sample, but composite choice could impact results from clinical trials particularly for subgroup analyses. There are unique challenges to creating composites of adolescent risk behavior, including the fluidity and infrequency of adolescent sexual relationships that result in many participants reporting no sexual behavior at any given assessment and a low correlation between the number of partners and condomless sex acts. These challenges impede application of data-driven approaches to defining sexual risk composites. Recommendations to improve consistency in reporting include: (1) reporting each type of risk behavior separately prior to forming a composite, (2) aggregating across assessments to increase the chance of observing sexual risk behaviors, and (3) continued work toward a unified definition of adolescent sexual risk behavior that can guide the development of appropriate measurement models.

Examining the Stability of the Hospital Anxiety and Depression Scale Factor Structure in Adolescents and Young Adults With Cystic Fibrosis: A Confirmatory Factor Analysis.

Objective: The Hospital Anxiety and Depression Scale (HADS) is a widely used screening measure of anxiety and depression symptoms. However, prior analyses of the measure have found heterogeneous factor structures and called into question its ability to differentiate between symptoms of anxiety and depression. As part of efforts to implement mental health screening in cystic fibrosis (CF) care, the European Cystic Fibrosis Society (ECFS) and Cystic Fibrosis Foundation (CFF) conducted an international survey of 1,454 CF professionals. The HADS was the most commonly used measure in Europe and third most across all 48 countries surveyed. However, the HADS has not been validated for CF. Thus, the objective of this study was to examine its factor structure in a sample of adolescents and young adults with CF. Methods: Three theory-based models were tested in 727 individuals with CF (ages 12-25 years, 54% female) using confirmatory factor analyses, with an additional two models tested to improve model fit. Results: Chi-square difference tests and majority of fit indices indicated a three-factor structure based on Clark and Watson's tripartite model best fit the data. Conclusions: The original HADS two-factor structure demonstrated problematic fit in this sample, indicating poor discrimination between symptoms of anxiety and depression. A three-factor structure demonstrated best fit, indicating existing scoring guidelines and cutoffs would be inappropriate for use with this patient population. Use of the HADS to screen for anxiety and depression in CF could lead to an underestimation of clinically relevant symptomatology for depression and potential overestimation of anxiety symptoms.

The Influence of Circadian Timing on Olfactory Sensitivity.

Olfactory sensitivity has traditionally been viewed as a trait that varies according to individual differences but is not expected to change with one's momentary state. Recent research has begun to challenge this position and time of day has been shown to alter detection levels. Links between obesity and the timing of food intake further raise the issue of whether odor detection may vary as a function of circadian processes. To investigate this question, 37 (21 male) adolescents (M age = 13.7 years) took part in a 28-h forced desynchrony (FD) protocol with 17.5 h awake and 10.5 h of sleep, for 7 FD cycles. Odor threshold was measured using Sniffin' Sticks 6 times for each FD cycle (total threshold tests = 42). Circadian phase was determined by intrinsic period derived from dim light melatonin onsets. Odor threshold showed a significant effect of circadian phase, with lowest threshold occurring on average slightly after the onset of melatonin production, or about 1.5○ (approximately 21:08 h). Considerable individual variability was observed, however, peak olfactory acuity never occurred between 80.5○ and 197.5○ (~02:22-10:10 h). These data are the first to show that odor threshold is differentially and consistently influenced by circadian timing, and is not a stable trait. Potential biological relevance for connections between circadian phase and olfactory sensitivity are discussed.

An approach to understanding sleep and depressed mood in adolescents: person-centred sleep classification.

Depressive mood in youth has been associated with distinct sleep dimensions, such as timing, duration and quality. To identify discrete sleep phenotypes, we applied person-centred analysis (latent class mixture models) based on self-reported sleep patterns and quality, and examined associations between phenotypes and mood in high-school seniors. Students (n = 1451; mean age = 18.4 ± 0.3 years; 648 M) completed a survey near the end of high-school. Indicators used for classification included school night bed- and rise-times, differences between non-school night and school night bed- and rise-times, sleep-onset latency, number of awakenings, naps, and sleep quality and disturbance. Mood was measured using the total score on the Center for Epidemiologic Studies-Depression Scale. One-way anova tested differences between phenotype for mood. Fit indexes were split between 3-, 4- and 5-phenotype solutions. For all solutions, between phenotype differences were shown for all indicators: bedtime showed the largest difference; thus, classes were labelled from earliest to latest bedtime as 'A' (n = 751), 'B' (n = 428) and 'C' (n = 272) in the 3-class solution. Class B showed the lowest sleep disturbances and remained stable, whereas classes C and A each split in the 4- and 5-class solutions, respectively. Associations with mood were consistent, albeit small, with class B showing the lowest scores. Person-centred analysis identified sleep phenotypes that differed in mood, such that those with the fewest depressive symptoms had moderate sleep timing, shorter sleep-onset latencies and fewer arousals. Sleep characteristics in these groups may add to our understanding of how sleep and depressed mood associate in teens.

A genetic marker of risk in HIV-infected individuals with a history of hazardous drinking.

Impulsivity and sensation seeking have been linked to hazardous drinking, increased sexual risk behaviors, and lower treatment adherence among persons living with HIV (PLH). The dopamine active transporter1 (DAT1or SLC6A3) gene has been linked to impulsivity and sensation seeking in several populations but has not been investigated among populations of PLH. This study used data from 201 PLH who report a recent history of heavy episodic drinking. Results indicate that DAT1*10R vs DAT1*9R genotype was related to higher propensity for risk taking (standardized difference score (d) = 0.30 [95% CI: 0.02;0.59]), more hazardous drinking (d = 0.35 [0.05;0.64]), and more condomless sex (rate ratio (RR)= 2.35[1.94; 2.85]), but were counter-intuitively associated with fewer sexual partners (RR = 0.65[0.43;0.91]) and possibly better treatment adherence (d = 0.32 [-0.01;0.65]). Results are consistent with the suggested associations between DAT1 and risk-taking behavior. The counter-intuitive finding for partner selection and treatment adherence may be evidence of additional factors that place PLH at risk for engaging in hazardous drinking as well as relationship difficulties and problems with treatment adherence (e.g., depressive symptoms, avoidant coping, trauma history). Caution is required when using a single gene variant as a marker of complex behaviors and these findings need to be replicated using larger samples and additional variants.

Quality of life among Ghanaian adolescents living with perinatally acquired HIV: a mixed methods study.

In Sub-Saharan Africa, increasing numbers of children with perinatally acquired HIV (PAHIV) are living into adolescence. These adolescents face numerous unique challenges such as parent illness/death and years of medication use. Optimizing care for these youth requires an understanding of the factors that contribute to physical health, psychological well-being, social relationships, and quality of life (QOL). This mixed methods study collected quantitative questionnaire data from 40 Ghanaian adolescents with PAHIV (50% female, 12-19 years old) who received care through an adolescent HIV clinic in Kumasi, Ghana. The study also presents results from qualitative interviews conducted with 20 adolescents. Results from quantitative analyses suggested that a significant number of participants were not virally suppressed (67%) and participants reported barriers to treatment adherence, limited social support, concerns about disclosure and HIV-related stigma, limited resources, and lower than expected QOL. Salient themes from the qualitative analyses included limited understanding of how HIV is transmitted, the interplay between food insecurity and treatment adherence and the need for developing safe relationships through which adolescents can discuss their illness without fear of accidental disclosure of their HIV status.

Flexible models of change: using structural equations to match statistical and theoretical models of multiple change processes.

OBJECTIVE: To introduce and illustrate recent advances in statistical approaches to simultaneous modeling of multiple change processes. METHODS: Provide a general overview of how to use structural equations to simultaneously model multiple change processes and illustrate the use of a theoretical model of change to guide selection of an appropriate specification from competing alternatives. The selected latent change score model is then fit to data collected during an adolescent weight-control treatment trial. RESULTS: A latent change score model is built starting with the foundation of repeated-measures analysis of variance and illustrated using graphical notation. CONCLUSIONS: The assumptions behind using structural equations to model change are discussed as well as limitations of the approach. Practical guidance is provided on matching the statistical model to the theory underlying the observed change processes and the research question(s) being answered by the analyses.

Longitudinal associations among change in overweight status, fear of negative evaluation, and weight-related teasing among obese adolescents.

OBJECTIVE: To examine longitudinal bidirectional associations between changes in adolescents' weight status and psychosocial constructs. METHOD: 118 obese adolescents aged 13-16 years participated in a behavioral weight control intervention. Percent overweight (OW), fear of negative evaluation (FNE), and frequency of weight-related teasing (WRT) were collected at baseline, end of intervention, and 12 and 24 months post-randomization. 3 multivariate latent change score models were estimated to examine longitudinal cross-lagged associations between: (1) OW and FNE; (2) OW and WRT; and (3) FNE and WRT. RESULTS: Decreases in OW were prospectively associated with subsequent decreases in both FNE and WRT; however, changes in FNE and WRT were not prospectively associated with subsequent change in OW. Decreases in FNE were prospectively associated with subsequent decreases in WRT. CONCLUSION: Moderate weight loss in the context of a behavioral weight control intervention has positive long-term implications for obese adolescents' peer relations.

Eliciting affect via immersive virtual reality: a tool for adolescent risk reduction.

OBJECTIVE: A virtual reality environment (VRE) was designed to expose participants to substance use and sexual risk-taking cues to examine the utility of VR in eliciting adolescent physiological arousal. METHODS: 42 adolescents (55% male) with a mean age of 14.54 years (SD = 1.13) participated. Physiological arousal was examined through heart rate (HR), respiratory sinus arrhythmia (RSA), and self-reported somatic arousal. A within-subject design (neutral VRE, VR party, and neutral VRE) was utilized to examine changes in arousal. RESULTS: The VR party demonstrated an increase in physiological arousal relative to a neutral VRE. Examination of individual segments of the party (e.g., orientation, substance use, and sexual risk) demonstrated that HR was significantly elevated across all segments, whereas only the orientation and sexual risk segments demonstrated significant impact on RSA. CONCLUSIONS: This study provides preliminary evidence that VREs can be used to generate physiological arousal in response to substance use and sexual risk cues.

Costs of Severe to Profound Hearing Loss & Cost Savings of Cochlear Implants.

OBJECTIVE: To estimate costs of severe to profound hearing loss, including costs and cost-savings associated with cochlear implantation. METHODS: Data was obtained from the National Health Interview Survey, the National Health and Nutrition Examination Survey and national Medicare rates. We used continuous time state transition models with individual patient simulations to estimate the costs of severe to profound hearing loss (SPHL) across the lifespan. The model included four states, normal hearing, severe to profound hearing loss, cochlear implantation, and death. RESULTS: The estimated lifetime cost of an individual born with SPHL is $489,274 [377,518; 616,519]. Costs are lower for those who received a cochlear implant before 18 months of age $390,931 [311,976; 471,475], compared to those who are not implanted $608,167 [442,544; 791,719]. For individuals with a later onset of hearing loss (60 years old) lifetime costs were $154,536 [7,093; 302,936]. The annual societal costs for the US population were estimated to be $37 [8; 187] billion. CONCLUSIONS: SPHL is a costly condition, with the primary driver being lost productivity. Medical costs were higher for cochlear implantation, however, the higher income earnings offset the higher medical costs. Overall, early implantation substantially reduced lifetime costs. Access to hearing health care and technology is critical given the documented benefits for language, education, and quality of life. Government and insurance policies should be modified to allow for equal access and coverage for hearing technology, which will ultimately reduce lifetime and societal costs. LEVELS OF EVIDENCE: N/A The current study used existing nationally representative datasets. Thus, these levels of evidence do not apply. Laryngoscope, 2024.