Electronic health records identify timely trends in childhood mental health conditions.

BACKGROUND: Electronic health records (EHRs) data provide an opportunity to collect patient information rapidly, efficiently and at scale. National collaborative research networks, such as PEDSnet, aggregate EHRs data across institutions, enabling rapid identification of pediatric disease cohorts and generating new knowledge for medical conditions. To date, aggregation of EHR data has had limited applications in advancing our understanding of mental health (MH) conditions, in part due to the limited research in clinical informatics, necessary for the translation of EHR data to child mental health research. METHODS: In this cohort study, a comprehensive EHR-based typology was developed by an interdisciplinary team, with expertise in informatics and child and adolescent psychiatry, to query aggregated, standardized EHR data for the full spectrum of MH conditions (disorders/symptoms and exposure to adverse childhood experiences (ACEs), across 13 years (2010-2023), from 9 PEDSnet centers. Patients with and without MH disorders/symptoms (without ACEs), were compared by age, gender, race/ethnicity, insurance, and chronic physical conditions. Patients with ACEs alone were compared with those that also had MH disorders/symptoms. Prevalence estimates for patients with 1+ disorder/symptoms and for specific disorders/symptoms and exposure to ACEs were calculated, as well as risk for developing MH disorder/symptoms. RESULTS: The EHR study data set included 7,852,081 patients < 21 years of age, of which 52.1% were male. Of this group, 1,552,726 (19.8%), without exposure to ACEs, had a lifetime MH disorders/symptoms, 56.5% being male. Annual prevalence estimates of MH disorders/symptoms (without exposure to ACEs) rose from 10.6% to 2010 to 15.1% in 2023, a 44% relative increase, peaking to 15.4% in 2019, prior to the Covid-19 pandemic. MH categories with the largest increases between 2010 and 2023 were exposure to ACEs (1.7, 95% CI 1.6-1.8), anxiety disorders (2.8, 95% CI 2.8-2.9), eating/feeding disorders (2.1, 95% CI 2.1-2.2), gender dysphoria/sexual dysfunction (43.6, 95% CI 35.8-53.0), and intentional self-harm/suicidality (3.3, 95% CI 3.2-3.5). White youths had the highest rates in most categories, except for disruptive behavior disorders, elimination disorders, psychotic disorders, and standalone symptoms which Black youths had higher rates. Median age of detection was 8.1 years (IQR 3.5-13.5) with all standalone symptoms recorded earlier than the corresponding MH disorder categories. CONCLUSIONS: These results support EHRs' capability in capturing the full spectrum of MH disorders/symptoms and exposure to ACEs, identifying the proportion of patients and groups at risk, and detecting trends throughout a 13-year period that included the Covid-19 pandemic. Standardized EHR data, which capture MH conditions is critical for health systems to examine past and current trends for future surveillance. Our publicly available EHR-mental health typology codes can be used in other studies to further advance research in this area.

Rare copy number variants in over 100,000 European ancestry subjects reveal multiple disease associations.

Copy number variants (CNVs) are suggested to have a widespread impact on the human genome and phenotypes. To understand the role of CNVs across human diseases, we examine the CNV genomic landscape of 100,028 unrelated individuals of European ancestry, using SNP and CGH array datasets. We observe an average CNV burden of ~650 kb, identifying a total of 11,314 deletion, 5625 duplication, and 2746 homozygous deletion CNV regions (CNVRs). In all, 13.7% are unreported, 58.6% overlap with at least one gene, and 32.8% interrupt coding exons. These CNVRs are significantly more likely to overlap OMIM genes (2.94-fold), GWAS loci (1.52-fold), and non-coding RNAs (1.44-fold), compared with random distribution (P < 1 × 10-3). We uncover CNV associations with four major disease categories, including autoimmune, cardio-metabolic, oncologic, and neurological/psychiatric diseases, and identify several drug-repurposing opportunities. Our results demonstrate robust frequency definition for large-scale rare variant association studies, identify CNVs associated with major disease categories, and illustrate the pleiotropic impact of CNVs in human disease.

Application of Telemedicine Technology to Facilitate Diagnosis of Pediatric Postintensive Care Syndrome.

Background: Postintensive care syndrome (PICS) is well-defined in the adult literature but has not received much attention in pediatrics. Introduction: We sought to use a telemedicine platform for the characterization of PICS by creating a convenient and effective virtual follow-up clinic. Materials and Methods: Prospective single-center study in a pediatric intensive care unit (ICU) of patients aged 4-17 years who underwent any invasive procedures while admitted to the ICU. Parents completed the Weiss Functional Impairment Rating Scale (WFIRS) based on baseline behaviors before ICU admission, with the scale readministered at 1 week, 1 month, and 3 months postdischarge via secure telehealth platform. Patients with a WFIRS baseline raw score of 10 or an interval increase of 2 were referred to psychiatry for evaluation and treatment. Results: Fifty patients were enrolled. Risk factors for PICS included number of procedural interventions, length of pediatric ICU stay, number of specialty consults, sex, race, and duration of sedation/airway instrumentation. In univariate analysis, age appeared to be the only statistically significant factor associated with the development of PICS. Variables associated with a higher change in WFIRS score showed a statistically significant correlation with the number of procedures completed, the number of specialists involved, and the need for a psychiatric referral. Only 34% of total telemedicine follow-ups were completed. Discussion: There is an association between age and the development of PICS and between change in WFIRS score and number of procedures, specialist involved, and psychiatric referral. Conclusions: The use of telemedicine did not result in an improved follow-up rate when compared to outpatient clinic studies.

Fasoracetam in adolescents with ADHD and glutamatergic gene network variants disrupting mGluR neurotransmitter signaling.

The glutamatergic neurotransmitter system may play an important role in attention-deficit hyperactivity disorder (ADHD). This 5-week, open-label, single-blind, placebo-controlled study reports the safety, pharmacokinetics and responsiveness of the metabotropic glutamate receptor (mGluR) activator fasoracetam (NFC-1), in 30 adolescents, age 12-17 years with ADHD, harboring mutations in mGluR network genes. Mutation status was double-blinded. A single-dose pharmacokinetic profiling from 50-800 mg was followed by a single-blind placebo at week 1 and subsequent symptom-driven dose advancement up to 400 mg BID for 4 weeks. NFC-1 treatment resulted in significant improvement. Mean Clinical Global Impressions-Improvement (CGI-I) and Severity (CGI-S) scores were, respectively, 3.79 at baseline vs. 2.33 at week 5 (P < 0.001) and 4.83 at baseline vs. 3.86 at week 5 (P < 0.001). Parental Vanderbilt scores showed significant improvement for subjects with mGluR Tier 1 variants (P < 0.035). There were no differences in the incidence of adverse events between placebo week and weeks on active drug. The trial is registered at https://clinicaltrials.gov/ct2/show/study/NCT02286817 .

Clinical Management of Pediatric Acute-Onset Neuropsychiatric Syndrome: Part I-Psychiatric and Behavioral Interventions.

OBJECTIVE: This article outlines the consensus guidelines for symptomatic treatment for children with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Syndrome Associated with Streptococcal Infection (PANDAS). METHODS: Extant literature on behavioral, psychotherapeutic, and psychopharmacologic treatments for PANS and PANDAS was reviewed. Members of the PANS Research Consortium pooled their clinical experiences to find agreement on treatment of PANS and PANDAS symptoms. RESULTS: Current guidelines result from consensus among the Consortium members. CONCLUSION: While underlying infectious and inflammatory processes in PANS and PANDAS patients are treated, psychiatric and behavioral symptoms need simultaneous treatment to decrease suffering and improve adherence to therapeutic intervention. Psychological, behavioral, and psychopharmacologic interventions tailored to each child's presentation can provide symptom improvement and improve functioning during both the acute and chronic stages of illness. In general, typical evidence-based interventions are appropriate for the varied symptoms of PANS and PANDAS. Individual differences in expected response to psychotropic medication may require marked reduction of initial treatment dose. Antimicrobials and immunomodulatory therapies may be indicated, as discussed in Parts 2 and 3 of this guideline series.

A link between perianal strep and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS).

Perianal streptococcal dermatitis is an infection caused by group A streptococcus (GAS). Children with a pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) phenotype may have tics or obsessive compulsive symptoms secondary to a systemic immune activation by GAS infecting perianal areas. In this retrospective case series, the authors describe three children with symptoms consistent with PANDAS and a confirmed perianal streptococcal dermatitis as the likely infectious trigger. Concomitant perianal dermatitis and new-onset obsessive-compulsive symptoms and/or tics are strong indications for perianal culture and rapid antigen detection test in young children.

Energy supply chain optimization of hybrid feedstock processes: a review.

The economic, environmental, and social performances of energy systems depend on their geographical locations and the surrounding market infrastructure for feedstocks and energy products. Strategic decisions to locate energy conversion facilities must take all upstream and downstream operations into account, prompting the development of supply chain modeling and optimization methods. This article reviews the contributions of energy supply chain studies that include heat, power, and liquid fuels production. Studies are categorized based on specific features of the mathematical model, highlighting those that address energy supply chain models with and without considerations of multiperiod decisions. Studies that incorporate uncertainties are discussed, and opportunities for future research developments are outlined.

Attention deficit hyperactivity disorder characteristics: II. Clinical correlates of irritable mood.

BACKGROUND: This study describes the relationship of irritable mood (IRR) with affective disorders in youths with attention deficit hyperactivity disorder (ADHD). METHODS: Five hundred ADHD subjects were assessed with the childhood version of the Schedule for Affective Disorder & Schizophrenia. Subjects were in a genetic ADHD protocol and limited to those of Caucasian/European descent. RESULTS: The most prevalent concurrent diagnoses were oppositional defiant disorder (ODD) (43.6%), minor depression/dysthymic disorder (MDDD) (18.8%), and generalized anxiety (13.2%)/overanxious disorder (12.4%). IRR subjects (21.0%) compared to the non-IRR (NIRR) group had higher rates of all affective disorders (76.2% vs. 9.6%) and ODD (83.8% vs. 32.9%) but lower rates of hyperactive ADHD (1.9% vs. 8.9%). Among those without comorbidities, 98.3% were NIRR. Logistic regression found IRR mood significantly associated with major depressive disorder (odds ratio [OR]: 33.4), MDDD (OR: 11.2), ODD (OR: 11.6), and combined ADHD (OR: 1.7) but not with anxiety disorders. Among symptoms, it associated IRR mood with a pattern of dysthymic and ODD symptoms but with fewer separation anxiety symptoms. Diagnostic and symptomatic parameters were unaffected by demographic variables. LIMITATIONS: Potential confounders influencing these results include patient recruitment from only one clinical service; a cohort specific sample effect because some presumed affective disorders and non-Caucasians were excluded; and the young mean age (10.2 years) limiting comorbid patterns. CONCLUSIONS: The prominence of an MDDD pattern suggests this IRR group is appropriate in the DSM V's proposed chronic depressive disorder, possibly with or without temper dysregulation. A new diagnosis of disruptive mood dysregulation disorder may be unwarranted.

Pediatric cardiovascular safety: challenges in drug and device development and clinical application.

Development of pediatric medications and devices is complicated by differences in pediatric physiology and pathophysiology (both compared with adults and within the pediatric age range), small patient populations, and practical and ethical challenges to designing clinical trials. This article summarizes the discussions that occurred at a Cardiac Safety Research Consortium-sponsored Think Tank convened on December 10, 2010, where members from academia, industry, and regulatory agencies discussed important issues regarding pediatric cardiovascular safety of medications and cardiovascular devices. Pediatric drug and device development may use adult data but often requires additional preclinical and clinical testing to characterize effects on cardiac function and development. Challenges in preclinical trials include identifying appropriate animal models, clinically relevant efficacy end points, and methods to monitor cardiovascular safety. Pediatric clinical trials have different ethical concerns from adult trials, including consideration of the subjects' families. Clinical trial design in pediatrics should assess risks and benefits as well as incorporate input from families. Postmarketing surveillance, mandated by federal law, plays an important role in both drug and device safety assessment and becomes crucial in the pediatric population because of the limitations of premarketing pediatric studies. Solutions for this wide array of issues will require collaboration between academia, industry, and government as well as creativity in pediatric study design. Formation of various epidemiologic tools including registries to describe outcomes of pediatric cardiac disease and its treatment as well as cardiac effects of noncardiovascular medications, should inform preclinical and clinical development and improve benefit-risk assessments for the patients. The discussions in this article summarize areas of emerging consensus and other areas in which consensus remains elusive and provide suggestions for additional research to further our knowledge and understanding of this topic.

Attention-deficit/hyperactivity disorder genomics: update for clinicians.

Attention deficit, hyperactivity disorder (ADHD) is familial and highly heritable. Several candidate genes involved in neurotransmission have been identified, however these confer minimal risk, suggesting that for the most part, ADHD is not caused by single common genetic variants. Advances in genotyping enabling investigation at the level of the genome have led to the discovery of rare structural variants suggesting that ADHD is a genomic disorder, with potentially thousands of variants, and common neuronal pathways disrupted by numerous rare variants resulting in similar ADHD phenotypes. Heritability studies in humans also indicate the importance of epigenetic factors, and animal studies are deciphering some of the processes that confer risk during gestation and throughout the post-natal period. These and future discoveries will lead to improved diagnosis, individualized treatment, cures, and prevention. These advances also highlight ethical and legal issues requiring management and interpretation of genetic data and ensuring privacy and protection from misuse.

A family-school intervention for children with ADHD: results of a randomized clinical trial.

OBJECTIVE: Accumulating evidence highlights the importance of using psychosocial approaches to intervention for children with attention-deficit/hyperactivity disorder (ADHD) that target the family and school, as well as the intersection of family and school. This study evaluated the effectiveness of a family-school intervention, Family-School Success (FSS), designed to improve the family and educational functioning of students in Grades 2-6 who meet criteria for ADHD combined and inattentive types. Key components of FSS were conjoint behavioral consultation, daily report cards, and behavioral homework interventions. METHOD: FSS was provided over 12 weekly sessions, which included 6 group sessions, 4 individualized family sessions, and 2 school-based consultations. Participating families were given the choice of placing their children on medication; 43% of children were on medication at the time of random assignment. Children (n = 199) were randomly assigned to FSS or a comparison group controlling for non-specific treatment effects (Coping With ADHD Through Relationships and Education [CARE]). Outcomes were assessed at post-intervention and 3-month follow-up. The analyses controlled for child medication status. RESULTS: FSS had a significant effect on the quality of the family-school relationship, homework performance, and parenting behavior. CONCLUSIONS: The superiority of FSS was demonstrated even though about 40% of the participants in FSS and CARE were on an optimal dose of medication and there were significant time effects on each measure. This relatively brief intervention produced effect sizes comparable to those of the more intensive Multimodal Treatment Study of Children With ADHD (MTA) behavioral intervention.

Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3.

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Because of its multifactorial etiology, however, identifying the genes involved has been difficult. The authors followed up on recent findings suggesting that rare copy number variants (CNVs) may be important for ADHD etiology. METHOD: The authors performed a genome-wide analysis of large, rare CNVs (<1% population frequency) in children with ADHD (N=896) and comparison subjects (N=2,455) from the IMAGE II Consortium. RESULTS: The authors observed 1,562 individually rare CNVs >100 kb in size, which segregated into 912 independent loci. Overall, the rate of rare CNVs >100 kb was 1.15 times higher in ADHD case subjects relative to comparison subjects, with duplications spanning known genes showing a 1.2-fold enrichment. In accordance with a previous study, rare CNVs >500 kb showed the greatest enrichment (1.28-fold). CNVs identified in ADHD case subjects were significantly enriched for loci implicated in autism and in schizophrenia. Duplications spanning the CHRNA7 gene at chromosome 15q13.3 were associated with ADHD in single-locus analysis. This finding was consistently replicated in an additional 2,242 ADHD case subjects and 8,552 comparison subjects from four independent cohorts from the United Kingdom, the United States, and Canada. Presence of the duplication at 15q13.3 appeared to be associated with comorbid conduct disorder. CONCLUSIONS: These findings support the enrichment of large, rare CNVs in ADHD and implicate duplications at 15q13.3 as a novel risk factor for ADHD. With a frequency of 0.6% in the populations investigated and a relatively large effect size (odds ratio=2.22, 95% confidence interval=1.5­3.6), this locus could be an important contributor to ADHD etiology.

Associations between psychiatric comorbidities and sleep disturbances in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: Children with attention-deficit/hyperactivity disorder (ADHD) often have sleep complaints and also higher rates of psychiatric comorbidities such as mood and anxiety disorders that may affect sleep. The authors hypothesized that children with ADHD and psychiatric comorbidities would have higher overall sleep disturbance scores as measured by a sleep questionnaire than children with ADHD without comorbidities. METHODS: This cross-sectional analysis in an academic center studied 317 children with ADHD; 195 subjects had no comorbid conditions, 60 were anxious and 62 were depressed. Participants completed the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present State, 4th Revised Edition and the Children's Sleep Habits Questionnaire. RESULTS: Median age (range) was 8.9 (6-18.7) years; 78% were male. Median (interquartile range) Total Sleep Disturbance Score (TSDS) on Children's Sleep Habits Questionnaire for subjects with no comorbidities was 44 (40-49); anxiety, 48 (43-54); and depression, 46 (41-52). Compared with subjects without comorbidities, TSDS in anxious subjects was greater (p = .008). TSDS in depressed subjects was not significantly different. Compared with subjects without comorbidities, anxious subjects had higher Bedtime Resistance, Sleep Onset Delay, and Night Wakings subscales (p = .03, .007, and .007, respectively); depressed subjects had higher Sleep Onset Delay and Sleep Duration subscales (p = .003 and .01, respectively). CONCLUSIONS: Anxiety in children with ADHD contributed to higher overall sleep disturbance scores, compared with children with ADHD alone. Both comorbidities were associated with higher Sleep Onset Latency subscale scores. Further study of the impact of psychiatric comorbidities on sleep in children with ADHD is warranted.

Epigenetics: genetics versus life experiences.

Epigenetics is the field of research that examines alterations in gene expression caused by mechanisms other than changes in DNA sequence. ADHD is highly heritable; however, epigenetics are considered relevant in potentially explaining the variance not accounted for by genetic influence. In this chapter, some of the well-known processes of epigenetics, such as chromosome organization, DNA methylation, and effects of transcriptional factors are reviewed along with studies examining the role of these processes in the pathophysiology of ADHD. Potential epigenetic factors conferring risk for ADHD at various developmental stages, such as alcohol, tobacco, toxins, medications, and psychosocial stressor are discussed. Animal studies investigating ADHD medications and changes in CNS Gene/Protein Expression are also explored since they provide insight into the neuronal pathways involved in ADHD pathophysiology. The current limited data suggest that identification of the epigenetic processes involved in ADHD is extremely important and may lead to potential interventions that may be applied to modify the expression of deleterious, as well as protective, genes.

What can ADHD without comorbidity teach us about comorbidity?

Neuropsychiatric comorbidity in ADHD is frequent, impairing and poorly understood. In this report, characteristics of comorbid and comorbid-free ADHD subjects are investigated in an attempt to identify differences that could potentially advance our understanding of risk factors. In a clinically-referred ADHD cohort of 449 youths (ages 6-18), age, gender, IQ, SES and ADHD symptoms were compared among ADHD comorbid free subjects and ADHD with internalizing and externalizing disorders. Logistic regression analyses were also carried out to investigate the relationship between comorbidity and parental psychiatric status. Age range was younger in the ADHD without comorbidity and older in ADHD+internalizing disorders. No significant difference in IQ or SES was found among ADHD comorbid and comorbid-free groups. ADHD with internalizing disorder has a significantly greater association with paternal psychiatric conditions. After matching by age, gender, IQ and SES, ADHD with externalizing disorders had significantly higher total ADHD, hyperactivity/impulsivity score and single item score of difficulty awaiting turn than ADHD without comorbidity and ADHD with internalizing disorders. Older age ranges, ADHD symptom severity and parental psychopathology may be risk factors for comorbidity.

Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10(-9)). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 × 10(-6)). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in ∼10% of the cases (P = 4.38 × 10(-10)) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts.

Methylphenidate transdermal system: clinical applications for attention-deficit/hyperactivity disorder.

The methylphenidate transdermal system (MTS) provides a novel method of delivery for methylphenidate, a well-studied and effective medication for attention-deficit/hyperactivity disorder. The MTS achieves two major goals. First, the delivery system allows for administration throughout the day with a single patch, thus improving adherence. Second, it is the first approved attention-deficit/hyperactivity disorder medication that is not administered orally, thus bypassing gastrointestinal absorption and first-pass metabolism through the enteric circulation. In this article, we review the current data on MTS, including preclinical, clinical and post-marketing studies, and compare efficacy and tolerability to currently available treatments.

Exome sequencing and unrelated findings in the context of complex disease research: ethical and clinical implications.

Exome sequencing has identified the causes of several Mendelian diseases, although it has rarely been used in a clinical setting to diagnose the genetic cause of an idiopathic disorder in a single patient. We performed exome sequencing on a pedigree with several members affected with attention deficit/hyperactivity disorder (ADHD), in an effort to identify candidate variants predisposing to this complex disease. While we did identify some rare variants that might predispose to ADHD, we have not yet proven the causality for any of them. However, over the course of the study, one subject was discovered to have idiopathic hemolytic anemia (IHA), which was suspected to be genetic in origin. Analysis of this subject's exome readily identified two rare non-synonymous mutations in PKLR gene as the most likely cause of the IHA, although these two mutations had not been documented before in a single individual. We further confirmed the deficiency by functional biochemical testing, consistent with a diagnosis of red blood cell pyruvate kinase deficiency. Our study implies that exome and genome sequencing will certainly reveal additional rare variation causative for even well-studied classical Mendelian diseases, while also revealing variants that might play a role in complex diseases. Furthermore, our study has clinical and ethical implications for exome and genome sequencing in a research setting; how to handle unrelated findings of clinical significance, in the context of originally planned complex disease research, remains a largely uncharted area for clinicians and researchers.