Faculty Bibliography

BACKGROUND:Optimising the dosage of pharmacological treatments for ADHD is key to maximising their benefits, yet most clinical guidelines provide only limited information on this issue. Dose-effect relationships have not been comprehensively assessed across all ADHD medications and age groups, despite growing concerns about subtherapeutic prescribing. We aimed to estimate dose-effect curves for efficacy and tolerability of ADHD medications (stimulants and non-stimulants) across age groups. METHODS:We conducted a systematic review and dose-effect network meta-analysis of double-blind randomised controlled trials (RCTs) evaluating oral monotherapy (stimulants and non-stimulants) in individuals aged 5 years and older meeting standardised ADHD criteria. Studies involving genetic syndromes, treatment-resistant populations, or withdrawal-phase designs were excluded. We retrieved eligible studies from the MED-ADHD database, updated on Feb 17, 2025, without language restrictions. We included published and unpublished aggregated-level data. The primary outcome was efficacy (measured using validated clinical scales) and the secondary outcome was tolerability (discontinuation due to adverse events). Within-study bias was assessed with the Cochrane Risk of Bias Tool (version 2). We summarised dose-effect associations using a hierarchical Bayesian model with restricted cubic splines. Separate analyses were conducted for children or adolescents (aged <18 years) and adults (aged ≥18 years). The distribution of key effect modifiers was used to examine transitivity of the network. People with lived experience were involved in the conceptualisation and design of the study, and in the interpretation of the findings. The protocol was pre-registered on OSF. FINDINGS/RESULTS:Our 2017 search identified 9948 potential references for inclusion and our Feb 17, 2025 search identified 5148 references. Of these 15 096 references, 8467 were excluded after title and abstract screening, and a further 5862 references were excluded after a full-text read. Of the 767 remaining reports, 164 were included in the systematic review and 113 RCTs (45 in adults and 68 in children and adolescents) were included in the dose-effect network meta-analysis. The 68 RCTs on children and adolescents included 14 138 participants (9981 [70·6%] males and 4157 [29·4%] females) and the 45 RCTs on adults included 11 016 participants (5958 [54·0%] males and 5056 [46·0%] females). Data on ethnicity or race were inconsistently reported across RCTs. We found distinct dose-effect patterns by medication class and age group. In children and adolescents, methylphenidate, amphetamines, and guanfacine showed increasing median efficacy up to 45 mg/day, 25 mg/day and 4 mg/day, respectively, with no evidence of additional benefit at higher doses, although estimates at higher doses were characterised by wide credible intervals. In adults, amphetamines showed a plateau above approximatively 50 mg/day, whereas methylphenidate efficacy increased without evidence of a plateau, possibly due to sparse data. Dose-dependent increases in discontinuation probability due to adverse events were observed for amphetamines (above 25 mg/day for children and 50 mg/day for adults) and methylphenidate (above 50 mg/day for adults, with no clear dose-dependent risk for children). We found no evidence of dose-effect patterns for atomoxetine (in fixed-doses studies) and modafinil. Multiple sensitivity analyses confirmed the robustness of these findings. We found no evidence of intransitivity. INTERPRETATION/CONCLUSIONS:Our findings challenge both therapeutic inertia-accepting suboptimal response without further dose titration-and uncritical dose escalation beyond licensed limits, when potential harms outweigh expected benefits. Our findings can inform clinical guidelines and should support shared decision making regarding ADHD medication dosage. FUNDING/BACKGROUND:National Institute for Health and Care Research (NIHR303122).

Autistic youth visit the emergency department (ED) for psychiatric concerns, including suicidal ideation and behavior, at elevated rates. However, clinicians often report low levels of training and confidence in addressing suicide risk in autistic youth. In this pilot study, clinicians in a pediatric psychiatric emergency service were trained on community- and evidence-informed recommendations to improve suicide-related care for autistic youth and provided with resources to use with autistic youth for a 3-month period. Ratings on attitudes and confidence were obtained from ten providers before and after the training/implementation period and compared. Ratings of feasibility and utility of strategies and resources were obtained from 15 providers after training/implementation and analyzed. While no changes were found across attitudes items, confidence scores were significantly higher after the training/implementation period than before, particularly in the area of suicide risk assessment. Feasibility and utility ratings were generally high, with endorsement patterns aligning with common organizational and systems-level barriers. This pilot study demonstrated that targeted training and evidence-informed recommendations to improve suicide-related care for autistic youth were associated with increased clinician confidence. As research continues in the development of adapted suicide risk assessment tools and management strategies for autistic youth, it is important that both clinical guidance on best practices is provided and that systems-level barriers are addressed.

INTRODUCTION/UNASSIGNED:This article features the application of Causal Data Science (CDS) methods to determine the mechanism for Posttraumatic Stress (PTS) in young, maltreated children, in order to advance knowledge for prevention. Advances in prevention require research that identifies causal factors, but the scientific literature that would inform the identification of causes are almost exclusively based on the application of correlational methods to observational data. Causal inferences from such research will frequently be in error. We conducted the present study to explore the application of CDS methods as an alternative-or a supplement-to experimental methods, which can rarely be applied in human research on causal factors for PTS. METHODS/UNASSIGNED:A data processing pipeline that integrates state-of-the-art CDS algorithms was applied to an existing observational, longitudinal data set collected by the Consortium for Longitudinal Studies in Child Abuse and Neglect (LONGSCAN). This data set contains a sample of 1,354 children who were identified in infancy to early childhood as being maltreated or at risk. RESULTS/UNASSIGNED:A causal network model of 251 variables (nodes) and 818 bivariate relations (edges) was discovered, revealing four direct causes (Emotional Maltreatment at age 0-4, Physical Assault at age 8, Feeling of Safety at age 8, and Witnessing Violence at age 8) and two direct effects (Negative Self-Image and Severe Assault from a Non-Caregiver at age 8) of PTS at age 8, within a network containing a broad diversity of causal pathways. DISCUSSION/UNASSIGNED:These results indicate that CDS methods show promise for research on the complex etiology of PTS in young, maltreated children.

INTRODUCTION/UNASSIGNED:Autism spectrum disorder (ASD) is characterized in part by differences in pragmatic (i.e., social) language use. However, few studies on pragmatic language have included a meaningful number of autistic females, and even fewer have evaluated pragmatic language profiles for sex-specific differences. The existing literature on pragmatic language in autistic individuals without intellectual disability suggests that females may have stronger social communication skills compared to males, but findings are mixed, and there is not a clear profile of specific pragmatic skills that are liable to sex differences. It is also important to develop novel methodologies, such as computational methods, to characterize pragmatic language in ways less labor-intensive than gold-standard hand-coding methods, which are extremely time consuming and typically not feasible in clinical settings. METHODS/UNASSIGNED:The present study examined hand coding of pragmatic language data samples alongside multiple computational linguistic methodological approaches to characterize sex differences in pragmatic language in autistic males and females across narrative and semi-structured conversational tasks that might reveal context-specific patterns across sex and diagnostic groups. RESULTS/UNASSIGNED:Results indicated that most pragmatic domains differed between autistic and non-autistic groups, with autistic males showing the most obvious pragmatic differences, and that differences between diagnostic groups were more pronounced in the semi-structured conversational context. The alignment between computational and hand-coded findings was strongest in domains with clear theoretical overlap (e.g., frequency of emotional words) but was less consistent in areas that were less theoretically aligned (e.g., conversational dynamics and single word function). DISCUSSION/UNASSIGNED:These findings support the promise of computational methods for characterizing narrative abilities, though further study including validation against hand-coded approaches is warranted.

BACKGROUND:Autism spectrum disorder (ASD) has a complex inheritance pattern and is more common in males. Etiological models suggest that majority of ASD risk is transmitted through common and rare de-novo genetic variation. It has been hypothesized that rare variation could be inherited and therefore contribute to the overall risk-burden in subsequent generations, especially through female lineage in disorders with male-skewed sex-ratios. Here we test this hypothesis using multigeneration information on paternal age, because burden of de-novo mutations has been linked to paternal age, and there is a well-established association between older age of fathers and ASD. METHODS:We analyzed combined data from Sweden's, Denmark's and Finland's national registers totaling 12.6 million family-members, including information about parental ages at the time of birth of offspring in two generations, and ASD diagnosis in the third generation. RESULTS:Among the 1,808,892 children in the third generation, 23,397 (1.29%) were diagnosed with ASD. Increased paternal age at the time of birth of a daughter was associated with increased risk of ASD in the daughter's own offspring. Increased paternal age at the time of birth of a son was not associated with increased ASD risk in the son's offspring, nor was older maternal age in the first or second generations. We observed that young maternal age at birth of a son or a daughter was associated with ASD risk in their offspring. CONCLUSIONS:Collectively, our results suggest that etiologic risk-factors for ASD could extend over multiple generations through different underlying mechanisms, suggesting new directions for research on genetic and non-genetic risk-factors.

The collection of electroencephalography (EEG) data in neonates typically occurs during sleep. EEG activity is highly sleep-state dependent, therefore differentiating between states during data processing can provide important insights into neurodevelopment. Despite this, there have been a paucity of studies directly comparing how infant EEG data, especially event-related potentials, differ between these sleep states. Here, we adapted the Maryland Analysis of Developmental EEG pipeline (MADE) to integrate sleep-state coding into its automated preprocessing pipeline. We recorded EEG in 102 sleeping one month old infants and evaluated their responses during a resting state and during a three-stimuli auditory oddball paradigm. Examination of resting-state power revealed significant differences between two sleep states, namely active (AS) and quiet (QS) sleep across all frequency bands in both absolute and relative power. For the auditory oddball paradigm, we computed responses to both standard and deviant tones and then created a difference score reflecting the Mismatch Response (MMR). For the novel tones we examined the evoked response (P300). Results revealed for the MMR, a significant electrode cluster by sleep-state interaction (F = 5.36, p = .01), indicating that the MMR was present at all three electrode clusters during AS (p-values <.05), but only at the frontal cluster during QS (t = 2.05, p = .04). There were no differences in the amplitude of the P300 to the novel sound as a function of sleep state.

INTRODUCTION/UNASSIGNED:Poor dental health is linked to poor physical and mental health. This study was aimed to examine the characteristics of U.S. adults that are associated with having seen a dentist in the past year. METHODS/UNASSIGNED:A cross-section of adults aged 18-64 years (N=19,975) from the 2023 National Health Interview Survey was examined. Bivariate analyses examined the associations of sociodemographic and financial variables with recent dental visits in the last 12 months. Multinomial modeling was used to assess these variables to predict 3 outcomes of time since the last dental visit: in the last 12 months; over a year but <10 years; and over 10 years or never, which was the reference category. RESULTS/UNASSIGNED:In young and middle-aged adults, 4.8% of Americans, representing over 9 million people, had either never seen a dentist or not seen a dentist in 10 years or more. The likelihood of a dental visit in the last 12 months increased with education level (no high-school degree versus a graduate or professional degree [AOR=0.21, 95% CI=0.09, 0.50]) and income (income below the federal poverty line versus income in the highest quartile [AOR=0.20, 95% CI=0.11, 0.35]). Having dental coverage in a private plan or Medicaid, compared with having no coverage, predicted having a dental visit within the last 12 months in both multinomial and bivariate analyses. CONCLUSIONS/UNASSIGNED:Access to dental care in young and middle-aged adults is determined by financial ability. Increasing access to dental care could happen once the financial barriers to dental care are reduced, including increasing the age at which a young adult can be covered by a parent's plan and making dental coverage comparable with physical health coverage. Given the current data about the links between dental, mental, and physical health, parity for all care is warranted.

Youth are presenting to Emergency Departments (EDs) following a suicide-related crisis at higher rates and younger ages. Clinicians lack tools to effectively discern suicide risk in younger patients. The present investigation examines how ED-based, suicidal pre-adolescents and adolescents conceptualize death. One hundred and sixty-seven suicidal pre-adolescents and adolescents (10-17 years; M = 12, SD = 1.4) presenting to a psychiatric ED with a suicide-related chief complaint completed assessments of suicidal ideation (SI; passive and active thoughts), suicide attempt (SA), depressive symptoms, and death conceptualizations (Death Avoidance, Escape Acceptance, Neutral Acceptance). Post-discharge SI and SA were assessed via survey emailed to participants 6 months later and via electronic medical record. At baseline, lower levels of Death Avoidance and higher levels of Escape Acceptance were most robustly associated with active SI. Pre-adolescents reported higher levels of Death Avoidance and lower levels of Escape Acceptance than adolescents at baseline. Death conceptualizations did not predict follow-up SI and SA. Youth who have recently experienced a suicide-related crisis are more likely to accept death as an escape from painand spend less time avoiding thoughts about death. This profile appears to be more representative of adolescents, relativeto pre-adolescents who display the opposite pattern.