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BackgroundThis study measured serial plasma human immunodeficiency virus (HIV)-1-specific antibody (Ab) levels in children who initiated antiretroviral therapy (ART) prior to 2 years of age, and evaluated their relationship to peripheral blood HIV-1 RNA and DNA levels.MethodsWe studied 46 HIV-1-infected children, stratified by age at ART initiation (3 mo-2 years, late therapy [LT]) and by virologic response (R) or non-response (NR), before and up to 4 years following ART. We studied 20 HIV-1-uninfected children born to HIV-1-infected mothers (seroreverters [SR]) as controls. Plasma immunoglobulin G (IgG) Ab levels directed against HIV-1 envelope (gp160, gp41), gag (capsid, p24; matrix, p17), reverse transcriptase (p66/51), and integrase (p31) were serially measured using quantitative enzyme-linked immunosorbent assays. HIV-1 Ab rates of decline were estimated over the first 15 months of the study.ResultsThe HIV-1 Ab rates of decline in the ET-R group were similar to those in the SR group for all Ab specificities, except for p17 (P = .01). Ab decline rates in the LT-R group and the NR group were significantly slower than in the SR group for all tested Ab specificities. After 1 year of age, Ab levels to p31 and p17 were significantly associated with HIV-1 RNA levels (P < .001); Ab levels to gp160 (P < .001) and gp41 (P < .001) were significantly associated with cell-associated HIV-1 DNA levels.ConclusionsQuantitative HIV-1-specific Ab levels may be useful for screening children on ART for viral suppression or for residual, cell-associated HIV-1 DNA levels.Clinical trials registrationNCT00000872.

Individuals with psychiatric disorders have elevated rates of autoimmune comorbidity and altered immune signaling. It is unclear whether these altered immunological states have a shared genetic basis with those psychiatric disorders. The present study sought to use existing summary-level data from previous genome-wide association studies to determine if commonly varying single nucleotide polymorphisms are shared between psychiatric and immune-related phenotypes. We estimated heritability and examined pair-wise genetic correlations using the linkage disequilibrium score regression (LDSC) and heritability estimation from summary statistics methods. Using LDSC, we observed significant genetic correlations between immune-related disorders and several psychiatric disorders, including anorexia nervosa, attention deficit-hyperactivity disorder, bipolar disorder, major depression, obsessive compulsive disorder, schizophrenia, smoking behavior, and Tourette syndrome. Loci significantly mediating genetic correlations were identified for schizophrenia when analytically paired with Crohn's disease, primary biliary cirrhosis, systemic lupus erythematosus, and ulcerative colitis. We report significantly correlated loci and highlight those containing genome-wide associations and candidate genes for respective disorders. We also used the LDSC method to characterize genetic correlations among the immune-related phenotypes. We discuss our findings in the context of relevant genetic and epidemiological literature, as well as the limitations and caveats of the study.

ObjectiveAttention 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.MethodThe authors performed a genome-wide analysis of large, 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.ConclusionsThese 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=1.5–3.6), this locus could be an important contributor to ADHD etiology.

Abstract Background Bipolar disorder, particularly in children, is characterized by rapid cycling and switching, making circadian clock genes plausible molecular underpinnings for bipolar disorder. We previously reported work establishing mice lacking the clock gene D-box binding protein (DBP) as a stress-reactive genetic animal model of bipolar disorder. Microarray studies revealed that expression of two closely related clock genes, RAR-related orphan receptors alpha (RORA) and beta (RORB), was altered in these mice. These retinoid-related receptors are involved in a number of pathways including neurogenesis, stress response, and modulation of circadian rhythms. Here we report association studies between bipolar disorder and single-nucleotide polymorphisms (SNPs) in RORA and RORB. Methods We genotyped 355 RORA and RORB SNPs in a pediatric cohort consisting of a family-based sample of 153 trios and an independent, non-overlapping case-control sample of 152 cases and 140 controls. Bipolar disorder in children and adolescents is characterized by increased stress reactivity and frequent episodes of shorter duration; thus our cohort provides a potentially enriched sample for identifying genes involved in cycling and switching. Results We report that four intronic RORB SNPs showed positive associations with the pediatric bipolar phenotype that survived Bonferroni correction for multiple comparisons in the case-control sample. Three RORB haplotype blocks implicating an additional 11 SNPs were also associated with the disease in the case-control sample. However, these significant associations were not replicated in the sample of trios. There was no evidence for association between pediatric bipolar disorder and any RORA SNPs or haplotype blocks after multiple-test correction. In addition, we found no strong evidence for association between the age-at-onset of bipolar disorder with any RORA or RORB SNPs. Conclusion Our findings suggest that clock genes in general and RORB in particular may be important candidates for further investigation in the search for the molecular basis of bipolar disorder.

The objective of this study was to determine the prevalence and predictors of testing for sexually transmitted infections (STIs) under an accountable care model of health care delivery. Data sources were claims and encounter records from the Massachusetts Medicaid and Children's Health Insurance Program (MassHealth) for enrollees aged 13 to 64 years in 2019. This cross-sectional study examines the one-year prevalence of STI testing and evaluates social determinants of health and other patient characteristics as predictors of such testing in both primary care and other settings. We identified visits with STI testing using procedure codes and primary care settings from provider code types. Among 740,417 members, 55% were female, 11% were homeless or unstably housed, and 15% had some level of disability. While the prevalence of testing in any setting was 20% (N = 151,428), only 57,215 members had testing performed in a primary care setting, resulting in an 8% prevalence of testing by primary care clinicians (PCCs). Members enrolled in a managed care organization (MCO) were significantly less likely to be tested by a primary care provider than those enrolled in accountable care organization (ACO) plans that have specific incentives for primary care practices to coordinate care. Enrollees in a Primary Care ACO had the highest rates of STI testing, both overall and by primary care providers. Massachusetts' ACO delivery systems may be able to help practices increase STI screening with explicit incentives for STI testing in primary care settings. [ABSTRACT FROM AUTHOR]

Objective: A potentially useful tool for understanding the distribution and determinants of emotional dysregulation in children is a Child Behavior Checklist profile, comprising the Attention Problems, Anxious/Depressed, and Aggressive Behavior clinical subscales (CBCL-DP). The CBCL-DP indexes a heritable trait that increases susceptibility for later psychopathology, including severe mood problems and aggressive behavior. We have conducted a genome-wide association study of the CBCL-DP in children with attention-deficit/hyperactivity disorder (ADHD). Method: Families were ascertained at Massachusetts General Hospital and University of California, Los Angeles. Genotyping was conducted with the Illumina Human1M or Human1M-Duo BeadChip platforms. Genome-wide association analyses were conducted with the MQFAM multivariate extension of PLINK. Results: CBCL data were available for 341 ADHD offspring from 339 ADHD affected trio families from the UCLA (N = 128) and the MGH (N = 213) sites. We found no genome-wide statistically significant associations but identified several plausible candidate genes among findings at p less than 5E-05: "TMEM132D," "LRRC7," "SEMA3A," "ALK," and "STIP1" Conclusions: We found suggestive evidence for developmentally expressed genes operant in hippocampal dependent memory and learning with the CBCL-DP. (Contains 2 figures and 3 tables.)

Objective: The main aim of this study was to examine the efficacy, tolerability, and compliance of an extended-release formulation of methylphenidate (OROS-MPH) in adults with ADHD receiving immediate-release methylphenidate (IR-MPH). Method: Participants were outpatient adults with ADHD who were stable on IR-MPH-administered TID. Participants were randomized (4:1) to equipotent doses of OROS-MPH or to continue IR-MPH and were assessed weekly for 6 weeks with the Adult ADHD Investigator System Symptom Report Scale (AISRS). Results: Randomization of 53 IR-MPH responders to IR- or OROS-MPH had no effect on AISRS score at endpoint (11.2 plus or minus 6.9 vs. 10.7 plus or minus 5.1, p = 0.8). Participants stabilized on IR-MPH and switched to OROS-MPH remained satisfied over 71% of the time. However, the IR-MPH group missed more doses (7.3 plus or minus 6.8 vs. 3.3 plus or minus 4.2, p = 0.02) than the OROS-MPH group. Conclusion: Findings showed that adults with ADHD can be successfully switched from an effective regimen of IR-MPH TID to once-daily OROS-MPH. Results also demonstrated better compliance with OROS-MPH than with IR-MPH treatment. (Contains 3 tables and 2 figures.)

Objective: The main aim of this study was to examine the age-dependent remission from ADHD in girls transitioning through childhood into adolescence and early adulthood. Method: We conducted a 5-year prospective follow-up study of 123 girls with ADHD and 106 non-ADHD control girls aged between 6 and 17 years at ascertainment. ADHD was considered persistent at follow-up if participants met full diagnostic criteria for "DSM-IV" ADHD or met residual criteria for "DSM-IV" ADHD with associated impairment (Global Age Forum [GAF] score less than 60). Results: By age 16 years, ADHD was persistent in 71% (95% CI = 61-79%) of girls with ADHD. Participants with persistent ADHD at follow-up had more psychiatric comorbidity, behavior problems, and functional impairment than girls with ADHD in remission. Remitted ADHD, however, continued to be associated with functional impairment relative to non-ADHD controls. Persistence at 5 years was predicted by increased behavioral impairment at baseline. Conclusion: This 5-year follow-up suggests that many girls with ADHD experience persistent symptoms and/or functional impairment through late adolescence and into early adulthood. (Contains 1 figure and 3 tables.)

Objective: Genes likely play a substantial role in the etiology of attention-deficit/hyperactivity disorder (ADHD). However, the genetic architecture of the disorder is unknown, and prior genome-wide association studies (GWAS) have not identified a genome-wide significant association. We have conducted a third, independent, multisite GWAS of DSM-IV-TR ADHD. Method: Families were ascertained at Massachusetts General Hospital (MGH; N = 309 trios), Washington University at St. Louis (WASH-U; N = 272 trios), and University of California at Los Angeles (UCLA; N = 156 trios). Genotyping was conducted with the Illumina Human1M or Human1M-Duo BeadChip platforms. After applying quality control filters, association with ADHD was tested with 835,136 SNPs in 735 DSM-IV ADHD trios from 732 families. Results: Our smallest p value (6.7E-07) did not reach the threshold for genome-wide statistical significance (5.0E-08), but one of the 20 most significant associations was located in a candidate gene of interest for ADHD (SLC9A9, rs9810857, p = 6.4E-6). We also conducted gene-based tests of candidate genes identified in the literature and found additional evidence of association with SLC9A9. Conclusions: We and our colleagues in the Psychiatric GWAS Consortium are working to pool together GWAS samples to establish the large data sets needed to follow-up on these results and to identify genes for ADHD and other disorders. (Contains 3 figures and 5 tables.)

Objective: Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded significant results, we conducted a meta-analysis of existing studies to boost statistical power. Method: We used data from four projects: a) the Children's Hospital of Philadelphia (CHOP); b) phase I of the International Multicenter ADHD Genetics project (IMAGE); c) phase II of IMAGE (IMAGE II); and d) the Pfizer-funded study from the University of California, Los Angeles, Washington University, and Massachusetts General Hospital (PUWMa). The final sample size consisted of 2,064 trios, 896 cases, and 2,455 controls. For each study, we imputed HapMap single nucleotide polymorphisms, computed association test statistics and transformed them to z-scores, and then combined weighted z-scores in a meta-analysis. Results: No genome-wide significant associations were found, although an analysis of candidate genes suggests that they may be involved in the disorder. Conclusions: Given that ADHD is a highly heritable disorder, our negative results suggest that the effects of common ADHD risk variants must, individually, be very small or that other types of variants, e.g., rare ones, account for much of the disorder's heritability. (Contains 3 figures and 3 tables.)

Background: Little is known about the influence of sex on the course of attention-deficit/hyperactivity disorder (ADHD) and its comorbid psychiatric conditions. The purpose of this study was to examine the effect of sex on the course and psychiatric correlates of ADHD from childhood into adolescence. Methods: Two identically designed, longitudinal, case-control family studies of male and female probands with and without ADHD and their siblings were combined. All subjects were blindly assessed with structured diagnostic interviews. Among subjects with a lifetime history of ADHD (n = 471, mean age 11.5 [plus or minus] 4.3 years at baseline), we used linear growth curve models to estimate the effect of time on the change in ADHD symptoms, and whether this effect differed by sex. We also we examined the effect of sex on the association between ADHD and the longitudinal progression of comorbid psychopathology using structural equation models. Results: We found no evidence that sex moderated the effect of age on ADHD symptoms; in both genders, age exhibited a similar effect on the decline of ADHD symptoms. However, the female sample demonstrated greater stability in comorbid psychopathology from childhood into adolescence. Furthermore, we found that the stability of comorbid psychopathology in females remained significant after accounting for the correlation between adolescent psychopathology and adolescent ADHD. In males, childhood and adolescent comorbid psychopathology were no longer correlated when adolescent ADHD was taken into account. Conclusions: Our findings indicate that while the course of ADHD across childhood and adolescence did not differ between males and females, patterns of psychiatric comorbidity were conditional on sex. Future studies should explicitly test how sex modifies the associations between ADHD and risk factors and ADHD and associated functional outcomes.

Objective: The authors assessed the psychometric properties of the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-QSF) in adults with ADHD. Method: One hundred fifty ADHD and 134 non-ADHD adults from a case-control study and 173 adults randomized to placebo or methylphenidate were assessed with the Q-LES-QSF and the Social Adjustment Scale (SAS). Response to change was estimated by comparing change in Q-LES-QSF scores in responders and nonresponders in our randomized clinical trial. Results: Internal consistency of the Q-LES-QSF items was 0.88, and the correlation between the Q-LES-QSF total score and the SAS total T score was 0.72 in adults with ADHD. ADHD cases had statistically significantly poorer scores on the Q-LES-QSF than controls (76.5 [plus or minus] 10.9 vs. 59.2 [plus or minus] 17.3, p greater than 0.001), whereas ADHD responders showed Q-LES-QSF improvement compared to nonresponders (76.1 [plus or minus] 12.0 versus 67.9 [plus or minus] 14.5, p greater than 0.001). Conclusion: These results support the validity of the Q-LES-QSF as a measure of quality of life in adults with ADHD. (Contains 1 table and 1 figure.)

This study examined neuropsychological deficits among children with bipolar disorder while attending to its comorbidity with attention-deficit/hyperactivity disorder (ADHD). Seventy-three unmedicated children (ages 6-17 years) with Diagnostic and Statistical Manual of Mental Disorders (4th ed.; American Psychiatric Association, 1994) bipolar disorder plus ADHD (BPD + ADHD) were compared with 102 unmedicated children with ADHD without bipolar disorder, and 120 children without bipolar disorder or ADHD. Ninety-four percent of participants were Caucasian, 58% were male, and 42% were female. On average participants were of middle to upper socioeconomic status. Participants were assessed with a comprehensive neuropsychological battery and measures of academic achievement, school failure, and special education placement. Participants with BPD + ADHD and with ADHD were impaired in interference control, verbal learning, and arithmetic achievement and had higher rates of special school services. Across all of the measures of neuropsychological functioning, the only difference observed between youths with BPD + ADHD and youths with ADHD was that youths with BPD + ADHD performed more poorly on one measure of processing speed. Thus, comorbidity with ADHD may account for many of the neuropsychological deficits observed in children with bipolar disorder.

Objective: Background: Children with velocardiofacial syndrome (VCFS), a contiguous deletion syndrome, have an increased prevalence of attention deficit/hyperactivity disorder (ADHD). Method: The authors compared youth with VCFS+ADHD (from the SUNY Upstate VCFS Research Program) to those with ADHD but not VCFS (from the Massachusetts General Hospital Longitudinal Family Studies of ADHD). Results: Children with VCFS+ADHD were more likely to be diagnosed with the inattentive subtype and differed from idiopathic ADHD in the frequency of several inattentive symptoms that appear linked to general cognitive functioning. After controlling for IQ differences, parents of children with VCFS+ADHD endorsed more thought and social problems on a rating checklist. Patterns of comorbidity also differed between the two groups of children with ADHD: Children with idiopathic ADHD had higher rates of comorbid major depression and disruptive behavior disorders. Conclusion: Children with VCFS+ADHD may have a different profile of ADHD symptoms and comorbidity when compared to children with idiopathic ADHD. (Contains 1 figure and 2 tables.)

Objective: We evaluated correlates of the diagnosis of ADHD in youth by informant source. Method: Ninety-four pairs of mother reports and youth self-reports on ADHD were independently assessed, using diagnostic interviews from a large study of youth of both genders with and without ADHD. Comparisons were made on measures of interpersonal, school, and family functioning; treatment history; and parental psychopathology by informant source. Results: With the exception of higher rates of ADHD-associated impairment and higher frequency of treatment for ADHD in the combined youth-mother group. There were no other differences in any other clinical or familial correlates by informant source; both informant groups had higher levels of impairment in multiple nonoverlapping measures of dysfunction than controls. Males were overrepresented among the mother-only group. Conclusion: Maternal reports of ADHD result in a meaningful diagnosis of ADHD with high levels of impairment, regardless of endorsement by the affected youth. (Contains 3 tables.)

A scan of family-based genome-wide associations in attention-deficit hyperactivity disorder is conducted using data from Washington University, Massachusetts General Hospital, and University of California. Findings show that the smallest p value, 6.7E-07, was not able to reach the threshold for significant genome-wide association.

A novel family-based association tests (FBATs) is developed for ascertained samples that integrates unselected, genotyped controls from a population-based study into an over-all statistical test. The performance of the approach is demonstrated by an application to a genome-wide association studies (GWAS) of attention deficit hyperactivity disorder parent-offspring trios and publicly available controls.