Faculty Bibliography

IMPORTANCE/UNASSIGNED:Stimulants (methylphenidate and amphetamines) are often prescribed at unlicensed doses for adults with attention-deficit/hyperactivity disorder (ADHD). Whether dose escalation beyond US Food and Drug Administration recommendations is associated with positive risk benefits is unclear. OBJECTIVE/UNASSIGNED:To investigate the impact, based on averages, of stimulant doses on treatment outcomes in adults with ADHD and to determine, based on averages, whether unlicensed doses are associated with positive risk benefits compared with licensed doses. DATA SOURCES/UNASSIGNED:Twelve databases, including published (PubMed, Cochrane Library, Embase, Web of Sciences) and unpublished (ClinicalTrials.gov) literature, up to February 22, 2023, without language restrictions. STUDY SELECTION/UNASSIGNED:Two researchers independently screened records to identify double-blinded randomized clinical trials of stimulants against placebo in adults (18 years and older) with ADHD. DATA EXTRACTION AND SYNTHESIS/UNASSIGNED:Aggregate data were extracted and synthesized in random-effects dose-response meta-analyses and network meta-analyses. MAIN OUTCOME MEASURES/UNASSIGNED:Change in ADHD symptoms and discontinuations due to adverse events. RESULTS/UNASSIGNED:A total of 47 randomized clinical trials (7714 participants; mean age, 35 (SD, 11) years; 4204 male [56%]) were included. For methylphenidate, dose-response curves indicated additional reductions of symptoms with increments in doses, but the gains were progressively smaller and accompanied by continued additional risk of adverse events dropouts. Network meta-analyses showed that unlicensed doses were associated with greater reductions of symptoms compared with licensed doses (standardized mean difference [SMD], -0.23; 95% CI, -0.44 to -0.02; very low certainty of evidence), but the additional gain was small and accompanied by increased risk of adverse event dropouts (odds ratio, 2.02; 95% CI, 1.19-3.43; moderate certainty of evidence). For amphetamines, the dose-response curve approached a plateau and increments in doses did not indicate additional reductions of symptoms, but there were continued increments in the risk of adverse event dropouts. Network meta-analysis did not identify differences between unlicensed and licensed doses for reductions of symptoms (SMD, -0.08; 95% CI, -0.24 to 0.08; very low certainty of evidence). CONCLUSIONS AND RELEVANCE/UNASSIGNED:Based on group averages, unlicensed doses of stimulants may not have positive risk benefits compared with licensed doses for adults with ADHD. In general, practitioners should consider unlicensed doses cautiously. Practitioners may trial unlicensed doses if needed and tolerated but should be aware that there may not be large gains in the response to the medication with those further increments in dose. However, the findings are averages and will not generalize to every patient.

OBJECTIVE:To evaluate the reporting of race/ethnicity data in randomized controlled trials (RCTs) of attention-deficit/hyperactivity disorder (ADHD) medications. Secondary objectives were to estimate temporal trends in the reporting, and to compare the pooled prevalence of racial/ethnic groups in RCTs conducted in the US to national estimates. METHOD/METHODS:We drew on, adapted, and updated the search of a network meta-analysis by Cortese et al. (2018) up to March 2022. We calculated the percentage of RCTs reporting data on race/ethnicity of participants in the published article or in related unpublished material. Temporal trends were estimated with logistic regression. The pooled prevalence of each racial/ethnic group across US RCTs was calculated using random-effects model meta-analyses. RESULTS:We retained 310 RCTs (including 44,447 participants), of which 231 were conducted in children/adolescents, 78 in adults, and 1 in both. Data on race/ethnicity were reported in 59.3% of the RCTs (75% of which were conducted in children/adolescents and 25% in adults) in the published article, and in unpublished material in an additional 8.7% of the RCTs. Reporting improved over time. In the US RCTs, Asian and White individuals were under- and overrepresented, respectively, compared to national estimates in the most recent time period considered. CONCLUSION/CONCLUSIONS:More than 30% of the RCTs of ADHD medications retained in this review did not include data on race/ethnicity in their published or unpublished reports, and more than 40% in their published articles, even though reporting improved over time. Results should inform investigators, authors, editors, regulators, and study participants in relation to efforts to tackle inequalities in ADHD research. DIVERSITY & INCLUSION STATEMENT/UNASSIGNED:One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. We actively worked to promote sex and gender balance in our author group. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. While citing references scientifically relevant for this work, we also actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our reference list. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

OBJECTIVE:Physical activity (PA) interventions are part of many interdisciplinary programs for the management of children and adolescents with or without physical or psychological conditions or disabilities. Aiming to summarize the available evidence, we conducted an umbrella review of meta-analyses of PA interventions that included psychosocial outcomes in populations of children and adolescents. METHOD/METHODS:Literature searches were conducted in PubMed, Cochrane Central, Web of Science, Medline, SPORTDiscus, and PsychInfo from January 1, 2010, to May 6, 2022. Meta-analyses of randomized and quasi-randomized studies investigating the efficacy of PA interventions for psychosocial outcomes in children and adolescents were included. Summary effects were recalculated using common metric and random-effects models. We assessed between-study heterogeneity, predictive intervals, publication bias, small study effects, and whether the results of the observed positive studies were greater than expected due to chance. On the basis of these calculations, strength of associations was assessed using quantitative umbrella review criteria, and credibility of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Quality was assessed using the AMSTAR 2 tool. This study is registered with the Open Science Framework, https://osf.io/ap8qu. RESULTS:A total of 112 studies from 18 meta-analyses generating 12 new meta-analyses comprising 21,232 children and adolescents in population groups including attention-deficit/hyperactivity disorder, cancer, cerebral palsy, chronic respiratory diseases, depression, neuromotor impairment, and obesity and in general populations were included. PA interventions were efficacious in reducing psychological symptoms in all meta-analyses across the different population groups using random-effects models. However, umbrella review criteria suggested a weak strength of association for this outcome, and GRADE credibility of evidence ranged from moderate to very low. For psychological well-being, 3 out of 5 meta-analyses identified significant effects, but the strength of these associations was weak, and GRADE credibility of evidence ranged from moderate to very low. Similarly, for social outcomes, meta-analyses reported a significant summary effect, but the strength of association was weak, and GRADE credibility of evidence ranged from moderate to very low. For self-esteem, one meta-analysis in children with obesity failed to show any effect. CONCLUSION/CONCLUSIONS:Even though existing meta-analyses suggested a beneficial effect of PA interventions on psychosocial outcomes across different population groups, the strength of associations was weak, and the credibility of evidence was variable depending on the target population, outcome, and condition or disability. Randomized studies of PA interventions in children and adolescents with and without different physical and psychological conditions or disabilities should always include psychosocial outcomes as an important dimension of social and mental health. STUDY PREREGISTRATION INFORMATION/UNASSIGNED:Prenatal Maternal Infection and Adverse Neurodevelopment: A Structural Equation Modelling Approach to Downstream Environmental Hits; https://osf.io/; cp85a.

OBJECTIVE:It is unclear how the functional brain hierarchy is organized in preschool-aged children, and whether alterations in the brain organization are linked to mental health in this age group. Here, we assessed whether preschool-aged children exhibit a brain organizational structure similar to that of older children, how this structure might change over time, and whether it might reflect mental health. METHOD/METHODS:This study derived functional gradients using diffusion embedding from resting state functional magnetic resonance imaging data of 4.5-year-old children (N = 100, 42 male participants) and 6.0-year-old children (N = 133, 62 male participants) from the longitudinal Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort. We then conducted partial least-squares correlation analyses to identify the association between the impairment ratings of different mental disorders and network gradient values. RESULTS:The main organizing axis of functional connectivity (ie, principal gradient) separated the visual and somatomotor regions (ie, unimodal) in preschool-aged children, whereas the second axis delineated the unimodal-transmodal gradient. This pattern of organization was stable from 4.5 to 6 years of age. The second gradient separating the high- and low-order networks exhibited a diverging pattern across mental health severity, differentiating dimensions related to attention-deficit/hyperactivity disorder and phobic disorders. CONCLUSION/CONCLUSIONS:This study characterized, for the first time, the functional brain hierarchy in preschool-aged children. A divergence in functional gradient pattern across different disease dimensions was found, highlighting how perturbations in functional brain organization can relate to the severity of different mental health disorders.

Children and adolescents with autism spectrum disorder (ASD) experience various sleep problems. Sleep problems co-occur in a bidirectional relationship with ASD core symptoms and behavioral problems. However, studies on how these three factors are intricately linked to each other are limited. This meta-analysis examined the differential relationship between specific sleep problems, core symptoms, and behavioral problems in this population. This study was registered in PROSPERO (CRD42022339695). We systematically searched the PubMed/MEDLINE, Web of Science, and Scopus databases from inception to April 27, 2022. Observational studies that reported correlations between measures of sleep problems, ASD core symptoms, or ASD behavioral problems were included, and participants aged 18 years or below were enrolled. The correlation coefficient (r) was assessed as the primary effect metric. Total 22 cross-sectional studies were included, which comprised 2655 participants (mean age = 6.60 years old; mean percentage of boys = 80.64%). We found correlations between total sleep problems and total core symptoms (r 0.293 [95% confidence interval - 0.095 to 0.604]), total sleep problems and total behavioral problems (r 0.429 [0.299-0.544]), and total core symptoms and total behavioral problems (r - 0.050 [- 0.177 to 0.079]) and identified statistically significant correlations between specific components of sleep problems, ASD core symptoms, and ASD behavioral problems. Each specific sleep problem showed a unique association with core symptoms and behavioral problems. Sleep problems in ASD should be explored in detail, and the closely linked core symptoms and behavioral problems should be common therapeutic targets.

OBJECTIVE:Although evidence suggests significant cross-sectional relationships between attention-deficit/hyperactivity disorder (ADHD) and several physical health conditions, less is known about their longitudinal associations. We investigated the cumulative effect of childhood physical health conditions on ADHD symptoms at age 17 years, controlling for environmental factors, ADHD medication status, and ADHD symptoms at age 3 years. METHOD/METHODS:Using Millennium Cohort Study data (weighted n = 8,059), we assessed whether 4 physical health clusters (sensory, neurological, atopic, and cardio-metabolic) were associated with scores on the ADHD subscale from the Strengths and Difficulties Questionnaire at age 17 years. Environmental factors were grouped into 5 cumulative risk indices: prenatal, perinatal, postnatal environment, postnatal maternal well-being, and sociodemographic factors. Regression analyses determined whether each physical health cluster was associated with ADHD score while controlling for environmental factors, ADHD medication, and earlier symptoms. RESULTS: = 0.06), but the cardio-metabolic cluster was no longer a significant predictor. CONCLUSION/CONCLUSIONS:Sensory or neurological conditions in childhood were associated with higher ADHD symptoms aged 17 after adjustment of confounders. This was not the case for atopic or cardio-metabolic conditions. These findings have implications for the care of children with sensory/neurological conditions and future research examining ADHD etiopathophysiology.

OBJECTIVE:We aimed to quantify the clinical utility of continuous performance tests (CPTs) for the diagnosis of attention-deficit/hyperactivity disorder (ADHD) compared to a clinical diagnosis in children and adolescents. METHOD/METHODS:Four databases (MEDLINE, PsycINFO, EMBASE, and PubMed) were screened until January 2023. Risk of bias of included results was judged with the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). We statistically pooled the area under the curve, the sensitivity, and the specificity of 3 commonly used CPTs subscales: omission/inattention, commission/impulsivity, and total number of errors/ADHD subscales (PROSPERO registration: CRD42020168091). RESULTS:A total of 19 studies using commercially available CPTs were identified. Results from up to 835 control individuals and 819 cases were combined in the summary receiver operating characteristic (ROC) curve analyses (sensitivity and specificity pooling), and up to 996 cases and 1,083 control individuals in the area under the curve (AUC) analyses. Clinical utility as measured by AUCs could be considered as barely acceptable (between 0.7 and 0.8) for the most part, with the best results for the total/ADHD score, followed by omissions/inattention, and poorest for commission/impulsivity scores. A similar pattern was found when pooling sensitivity and specificity: 0.75 (95% CI = 0.66-0.82) and 0.71 (0.62-0.78) for the total/ADHD score; 0.63 (0.49-0.75) and 0.74 (0.65-0.81) for omissions; and 0.59 (0.38-0.77) and 0.66 (CI = 0.50-0.78) for commissions. CONCLUSION/CONCLUSIONS:At the clinical level, CPTs as a stand-alone tool have only a modest to moderate ability to differentiate ADHD from non-ADHD samples. Hence, they should be used only within a more comprehensive diagnostic process.

OBJECTIVE:To systematically investigate if there is a significant association between markers of autonomic functioning and emotional dysregulation (ED) in children and adolescents. METHOD/METHODS:April 2021) and included empirical studies reporting indices of autonomic nervous system (ANS) functioning in youths meeting DSM/ICD criteria for any psychopathological/neurodevelopmental condition and assessed for ED with a validated scale. Eligible outcomes included correlation coefficients between ED and ANS measures or differences in ANS measures between youths with and without ED. Study quality was assessed with the Appraisal tool for Cross-Sectional Studies (AXIS) and the Newcastle-Ottawa Scale (NOS) for cohort studies. Random-effects meta-analyses were used for data synthesis. RESULTS:Twelve studies (1016 participants) were included in the descriptive review and nine (567 participants) in the meta-analyses. We did not find evidence of a significant association between ED and altered cardiac or electrodermal functioning. However, exploratory meta-regressions suggested a possible association between reduced resting-state cardiac vagal control and increased ED. CONCLUSION/CONCLUSIONS:Our study did not find evidence of an association between ED and autonomic dysfunction. However, we found preliminary evidence that reduced vagal control at rest might be a transdiagnostic marker of ED in young people. Additional future studies comparing autonomic measures in youths with and without ED are needed, and should also assess the effects of interventions for ED on ANS functioning.