James J. Hudziak

Latent Class and Factor Analysis of DSM-IV ADHD: A Twin Study of Female Adolescents

OBJECTIVE In an attempt to validate the current DSM-IV criteria for attention-deficit/hyperactivity disorder (ADHD) in females and to determine whether symptoms are continuously distributed or categorically discrete, the authors performed factor and latent class analysis on ADHD symptom data from a large general population of adolescent female twins (1,629 pairs). METHOD A structured diagnostic assessment of DSM-IV ADHD was completed with at least one parent of 1,629 pairs by telephone. ADHD symptoms from 1,549 pairs were subjected to latent class and factor analysis. RESULTS Latent class and factor analyses were consistent with the presence of separate continuous domains of inattention (ATT), hyperactivity-impulsivity (H-I), and combined ATT with H-I problems. Severe latent classes corresponding to the predominantly inattentive, predominantly hyperactive-impulsive, and combined types were identified with lifetime prevalence estimates of 4.0%, 2.2%, and 3.7%, respectively. Membership in the severe ATT class predicted academic problems, family problems, and referral to health care providers. Membership in the H-I and combined classes also predicted impaired social relationships. CONCLUSIONS These results suggest that DSM-IV ADHD subtypes can be thought of as existing on separate continua of inattention, hyperactivity-impulsivity, and combined type problems. Membership in any of there severe ADHD latent classes did not preclude academic excellence, but it was associated with different types of impairment and health care-seeking behavior. These data have implications in the areas of diagnosis, classification, treatment, and research.

Symptoms versus Impairment: The Case for Respecting "DSM-IV"'s Criterion D.

Diagnosing ADHD based primarily on symptom reports assumes that the number/frequency of symptoms is tied closely to the impairment imposed on an individual’s functioning. That presumed linkage encourages diagnosis more by Diagnostic and Statistical Manual of Mental Disorders (4th ed.) style symptom lists than well-defined, psychometrically sound assessments of impairment. The current study correlated measures reflecting each construct in four separate, large-scale ADHD research samples. Average correlation between symptoms and impairment accounted for less than 10% of variance. Symptoms never predicted more than 25% of the variance in impairment. When an ADHD group was formed according to a measure of current symptoms, the sample size shrunk by 77% when a criterion-based measure of impairment was added. The partial unlinking of symptoms and impairment has implications for decisions about the diagnostic process, research criteria for participant inclusion, prevalence estimates, gender ratios, evaluation of treatment effects, service delivery, and many other issues.

Contributions of parental alcoholism, prenatal substance exposure, and genetic transmission to child ADHD risk: a female twin study

BACKGROUND Genetic influences have been shown to play a major role in determining the risk of attention-deficit hyperactivity disorder (ADHD). In addition, prenatal exposure to nicotine and/or alcohol has also been suggested to increase risk of the disorder. Little attention, however, has been directed to investigating the roles of genetic transmission and prenatal exposure simultaneously. METHOD Diagnostic telephone interview data from parents of Missouri adolescent female twin pairs born during 1975-1985 were analyzed. Logistic regression models were fitted to interview data from a total of 1936 twin pairs (1091 MZ and 845 DZ pairs) to determine the relative contributions of parental smoking and drinking behavior (both during and outside of pregnancy) as risk factors for DSM-IV ADHD. Structural equation models were fitted to determine the extent of residual genetic and environmental influences on ADHD risk while controlling for effects of prenatal and parental predictors on risk. RESULTS ADHD was more likely to be diagnosed in girls whose mothers or fathers were alcohol dependent, whose mothers reported heavy alcohol use during pregnancy, and in those with low birth weight. Controlling for other risk factors, risk was not significantly increased in those whose mothers smoked during pregnancy. After allowing for effects of prenatal and childhood predictors, 86% of the residual variance in ADHD risk was attributable to genetic effects and 14% to non-shared environmental influences. CONCLUSIONS Prenatal and parental risk factors may not be important mediators of influences on risk with much of the association between these variables and ADHD appearing to be indirect.

The use of the DSM-III-R Checklist for initial diagnostic assessments

The DSM-III-R Checklist is an efficient method for screening psychiatric patients for major psychiatric disorders while amassing a data base that can be used for later clinical and research activities. It yields valid diagnoses and key adjunctive symptoms. Patients enjoyed the interview, demonstrating an interest in the computer as well as a feeling of confidence in the complete review of symptoms. The psychiatry resident users in this project found the Checklist to be a valuable teaching instrument, a way to develop their thinking about symptoms and diagnostic rules, an efficient means of collecting an automated clinical data base, and a stimulus to pursue further research activities. Finally, the Checklist is an ideal diagnostic tool to amass a research data base and is currently being used in numerous studies by clinicians and nonclinicians.

Bupropion XL in adults with attention-deficit/hyperactivity disorder : A randomized, placebo-controlled study

BACKGROUND Data remain limited on treatment strategies for adults with attention-deficit/hyperactivity disorder (ADHD). This study evaluated the efficacy and safety of an extended-release, once-daily formulation of bupropion (XL) in the treatment of adults with ADHD. METHODS This multisite, placebo-controlled, 8-week prospective trial evaluated 162 adult patients diagnosed with ADHD (combined and inattentive types). Subjects were treated with up to 450 mg/day of bupropion XL. The primary efficacy endpoint was the proportion of ADHD responders (defined as at least a 30% reduction in the investigator-rated ADHD Rating Scale score) at week 8 (last observation carried forward [LOCF]). RESULTS Bupropion XL responders (53%) exceeded placebo responders (31%) (p =.004 at week 8) with a significantly greater proportion of bupropion XL responders as early as week 2 (p = .01). Treatment effect size calculated for the ADHD Rating Scale total score was .6. Bupropion XL appeared to provide sustained benefit throughout the day compared with placebo (morning p =.033, afternoon p =.004, evening p = .024). Bupropion XL was safe and well tolerated, with no serious or unexpected adverse events and a low rate of drug-related study discontinuation (5%). CONCLUSIONS The results from this multisite study indicate that bupropion XL is an effective and well-tolerated nonstimulant treatment for adult ADHD.

Causes of Stability of Aggression from Early Childhood to Adolescence: A Longitudinal Genetic Analysis in Dutch Twins

This study investigated the contribution of genetic and environmental influences on the stability of aggressive behavior from early childhood to adolescence. Two developmental models, the simplex model and the common factor model, were tested to study the underlying processes of stability and change. Measures of aggressive behavior (AGG) were obtained from maternal CBCL data as part of a large ongoing longitudinal study of the Netherlands Twin Registers (NTR) and included data from 6488 three-year-old twin pairs, 5475 seven-year-old twin pairs, 2983 ten-year-old twin pairs, and 1509 twelve-year-old twin pairs. AGG showed moderate to high stability during childhood. The stability coefficients ranged from 0.41 to 0.77 across varying intervals. Averaged across boys and girls, genetic factors accounted for approximately 65% of the total stability. Longitudinal genetic analysis indicated a simplex model for genetic effects, which suggests a dynamic development process consisting of transmission of existing genetic effects interacting with new genetic influences. This is especially true at age 7, when the influence of new genetic factors was large. Shared environmental factors accounted for approximately 25% of phenotypic stability, and it seemed that a stable set of the same shared environmental factors underlay the development of AGG. Nonshared environmental factors, when important, are age specific. Sex-specific differences for stability were identified. For boys, genetic influences were greater, whereas for girls shared environmental factors were more important. These data support the idea that both genetic and environmental influences play a role in the stability of AGG from age 3 to 12.

Adult Outcomes of Childhood Dysregulation: A 14-Year Follow-up Study.

OBJECTIVE Using a general population sample, the adult outcomes of children who presented with severe problems with self-regulation defined as being concurrently rated highly on attention problems, aggressive behavior, and anxious-depression on the Child Behavior Checklist-Dysregulation Profile (CBCL-DP) were examined. METHOD Two thousand seventy-six children from 13 birth cohorts 4 to 16 years of age were drawn from Dutch birth registries in 1983. CBCLs were completed by parents at baseline when children from the different cohorts were 4 to 16 years of age and sampled every 2 years for the next 14 years. At year 14 the CBCL and DSM interview data were collected. Logistic regression was used to compare and contrast outcomes for children with and without dysregulation, as measured by the latent-class-defined CBCL-DP. Sex and age were covaried and concurrent DSM diagnoses were included in regression models. RESULTS Presence of childhood CBCL-DP at wave 1 was associated with increased rates of adult anxiety disorders, mood disorders, disruptive behavior disorders, and drug abuse 14 years later. After controlling for co-occurring disorders in adulthood, associations with anxiety and disruptive behavior disorders with the CBCL-DP remained, whereas the others were not significant. CONCLUSIONS A child reported to be in the CBCL-DP class is at increased risk for problems with regulating affect, behavior, and cognition in adulthood.

Childhood intelligence is heritable, highly polygenic and associated with FNBP1L.

Intelligence in childhood, as measured by psychometric cognitive tests, is a strong predictor of many important life outcomes, including educational attainment, income, health and lifespan. Results from twin, family and adoption studies are consistent with general intelligence being highly heritable and genetically stable throughout the life course. No robustly associated genetic loci or variants for childhood intelligence have been reported. Here, we report the first genome-wide association study (GWAS) on childhood intelligence (age range 6–18 years) from 17 989 individuals in six discovery and three replication samples. Although no individual single-nucleotide polymorphisms (SNPs) were detected with genome-wide significance, we show that the aggregate effects of common SNPs explain 22–46% of phenotypic variation in childhood intelligence in the three largest cohorts (P=3.9 × 10−15, 0.014 and 0.028). FNBP1L, previously reported to be the most significantly associated gene for adult intelligence, was also significantly associated with childhood intelligence (P=0.003). Polygenic prediction analyses resulted in a significant correlation between predictor and outcome in all replication cohorts. The proportion of childhood intelligence explained by the predictor reached 1.2% (P=6 × 10−5), 3.5% (P=10−3) and 0.5% (P=6 × 10−5) in three independent validation cohorts. Given the sample sizes, these genetic prediction results are consistent with expectations if the genetic architecture of childhood intelligence is like that of body mass index or height. Our study provides molecular support for the heritability and polygenic nature of childhood intelligence. Larger sample sizes will be required to detect individual variants with genome-wide significance.

Deficits in reciprocal Social Behavior in male twins: Evidence for a genetically independent domain of psychopathology

OBJECTIVE Previous studies have demonstrated substantial genetic influences on many child psychiatric disorders, including autism. In this study the authors attempted to quantify the degree to which genetic influences on deficits in reciprocal social behavior (a defining feature of pervasive developmental disorders) are shared with genetic influences on other domains of behavior in children. METHOD Child Behavior Checklists (CBCL) and Social Responsiveness Scales (SRS) were completed for an epidemiological sample of 219 pairs of male twins. The SRS (formerly known as the Social Reciprocity Scale) is a measure of social impairment that distinguishes children with autism spectrum disorders from those with other child psychiatric disorders. RESULTS Regression analysis indicated that CBCL syndromes account for 43% of the variance in SRS scores. Bivariate analyses revealed that SRS scores are affected, in part, by phenotypic influences from the CBCL Social Problem syndrome. Forty-four percent of the causal influences on SRS scores, however, are independent from those on CBCL syndromes and are genetic in nature (90% confidence interval: 0.38-0.49). CONCLUSION These results support the existence of a continuous distribution of deficits in reciprocal social behavior in the population, which are substantially genetically independent from other domains of child psychopathology.

Heritability of Attention Problems in Children: I. Cross-Sectional Results From a Study of Twins, Age 3-12 Years

Multiple twin studies of attention problems (AP) from the Child Behavior Checklist or ADHD from the DSM criteria have reported on the genetic and environmental influences on these behaviors. The majority of these have studied AP and ADHD symptoms in twin samples combined across wide age spans, combined rater information and both genders. Thus, it is possible that the results are complicated by developmental, informant, and gender differences. The purpose of this study was to assess for the genetic and environmental contributions to overactive behavior (a syndrome highly related to AP in 7‐, 10‐, and 12‐years olds) in 3‐years olds (3,671 twin pairs), and attention problems in 7‐ (3,373 twin pairs), 10‐ (2,485 twin pairs), and 12‐years olds (1,305 twin pairs) while controlling for developmental, gender and rater contrast contributions. Using a cross‐sectional twin design, contributions from genetic additive, genetic dominance, unique environmental and rater contrast effects were estimated for CBCL maternal reports. We found that genetic influences on overactive behavior and attention problems are high across an age span that covers pre‐school and elementary school age. Although girls display less problem behavior compared to boys, heritability estimates were found equal for both genders at each age. Environmental experiences that are unique to the individual accounted for the remaining influence. At the age of 3 years, a rater contrast effect was detected. We hypothesize that the contrast effect represents a maternal rater bias effect that is dependent on the age of the twins. The implications of these findings are discussed with reference to the clinical setting and in the context of future research.