Genes, environments, and developmental research: methods for a multi-site study of early substance abuse.

The importance of including developmental and environmental measures in genetic studies of human pathology is widely acknowledged, but few empirical studies have been published. Barriers include the need for longitudinal studies that cover relevant developmental stages and for samples large enough to deal with the challenge of testing gene-environment-development interaction. A solution to some of these problems is to bring together existing data sets that have the necessary characteristics. As part of the National Institute on Drug Abuse-funded Gene-Environment-Development Initiative, our goal is to identify exactly which genes, which environments, and which developmental transitions together predict the development of drug use and misuse. Four data sets were used of which common characteristics include (1) general population samples, including males and females; (2) repeated measures across adolescence and young adulthood; (3) assessment of nicotine, alcohol, and cannabis use and addiction; (4) measures of family and environmental risk; and (5) consent for genotyping DNA from blood or saliva. After quality controls, 2,962 individuals provided over 15,000 total observations. In the first gene-environment analyses, of alcohol misuse and stressful life events, some significant gene-environment and gene-development effects were identified. We conclude that in some circumstances, already collected data sets can be combined for gene-environment and gene-development analyses. This greatly reduces the cost and time needed for this type of research. However, care must be taken to ensure careful matching across studies and variables.

Generalized anxiety and C-reactive protein levels: a prospective, longitudinal analysis.

BACKGROUND: Generalized anxiety disorder (GAD) is highly co-morbid with depression. Depression is associated with elevated levels of the inflammation marker C-reactive protein (CRP), cross-sectionally and over time. To date, no studies have looked at the association between CRP and GAD. METHOD: A total of nine waves of data from the prospective population-based Great Smoky Mountains Study (n=1420) were used, covering children in the community aged 9-16, 19 and 21 years old. Structured interviews were used at each assessment to assess GAD symptoms, diagnosis and cumulative episodes. Blood spots were collected and assayed for high-sensitivity CRP levels. RESULTS: GAD was associated with increased levels of CRP in bivariate cross-sectional analyses. These bivariate associations, however, were attenuated after accounting for demographic, substance-use and health-related covariates. In longitudinal models, there was little evidence that CRP predicted later GAD. Associations from GAD to later CRP were attenuated in models adjusted for health-related coavariates and there was evidence that the GAD-CRP association was mediated by body mass index (BMI) and medication use. CONCLUSIONS: Similar to depression, GAD was associated with elevated levels of CRP, but the effect of GAD on CRP levels was explained by the effect of GAD on health-related behaviors such as BMI and medication use. This study suggests differences in the association between inflammation and depression and GAD.

Predicting persistent alcohol problems: a prospective analysis from the Great Smoky Mountain Study.

BACKGROUND: Rates of alcohol disorders peak in late adolescence and decrease substantially into the mid-20s. Our aim was to identify risk factors that predict alcohol problems that persist into the mid-20s. METHOD: Data are from the prospective, population-based Great Smoky Mountains Study (GSMS; n=1420), which followed children through late adolescence and into young adulthood. Alcohol persisters were defined as subjects with an alcohol disorder (abuse or dependence) in late adolescence (ages 19 and 21 years) that continued to meet criteria for an alcohol disorder at the mid-20s assessment. RESULTS: The 3-month prevalence of having an alcohol disorder (abuse or dependence) decreased markedly from late adolescence into the mid-20s. A third of late adolescents with an alcohol disorder continued to meet criteria for an alcohol disorder in young adulthood (37 of 144 who met criteria in late adolescence). Risk factors for persister status included multiple alcohol abuse criteria during late adolescence but no alcohol dependence criteria. Risk factors for persister status also included associated features of alcohol dependence such as craving alcohol and drinking to unconsciousness. Persister status was also associated with depression, cannabis dependence and illicit substance use, but not with other psychiatric disorders. More than 90% of late adolescents with three or more of the risk factors identified met criteria for a young adult alcohol disorder. CONCLUSIONS: Symptoms of alcohol abuse, not dependence, best predict long-term persistence of alcohol problems. The set of risk factors identified may be a useful screen for selective and indicated prevention efforts.

Child-, adolescent- and young adult-onset depressions: differential risk factors in development?

BACKGROUND: Previous research reported that childhood adversity predicts juvenile- onset but not adult-onset depression, but studies confounded potentially genuine differences in adversity with differences in the recency with which adversity was experienced. The current study paper took into account the recency of risk when testing for differences among child-, adolescent- and young adult-onset depressions. METHOD: Up to nine waves of data were used per subject from two cohorts of the Great Smoky Mountains Study (GSMS; n=1004), covering children in the community aged 9-16, 19 and 21 years. Youth and one of their parents were interviewed using the Child and Adolescent Psychiatric Assessment (CAPA) between ages 9 and 16; these same youth were interviewed using the Young Adult Psychiatric Assessment (YAPA) at ages 19 and 21. The most common psychosocial risk factors for depression were assessed: poverty, life events, parental psychopathology, maltreatment, and family dysfunction. RESULTS: Consistent with previous research, most childhood psychosocial risk factors were more strongly associated with child-onset than with adolescent-/adult-onset depression. When potentially genuine risk differences among the depression-onset groups were disentangled from differences due to the recency of risk, child- and young adult-onset depression were no longer different from one another. Adolescent-onset depression was associated with few psychosocial risk factors. CONCLUSIONS: There were no differences in putative risk factors between child- and young adult-onset depression when the recency of risk was taken into account. Adolescent-onset depression was associated with few psychosocial risk factors. It is possible that some adolescent-onset depression cases differ in terms of risk from child- and young adult-onset depression.

Making sense of informant disagreement for overanxious disorder.

A community sample of 2798 8-17-year-old twins and their parents completed a personal interview about the child's current psychiatric history on two occasions separated by an average of 18 months. Parents also completed a personal interview about their own lifetime psychiatric history at entry to the study. Results indicate that informant agreement for overanxious disorder (OAD) was no better than chance, and most cases of OAD were based on only one informant's ratings. Disagreement about level of OAD symptoms or presence of another disorder (mostly phobias or depression) accounted for most cases of informant disagreement: 60% of cases based only on child interview, 67% of cases based only on maternal interview, and 100% of cases based only on paternal interview. OAD diagnosed only by maternal interview was also distinguished by an association with maternal alcoholism and increasingly discrepant parental reports of marital difficulties. Given the substantial overlap in case assignments for DSM-III-R OAD and DSM-IV GAD, these findings may identify sources of informant disagreement that generalize to juvenile GAD.

Epidemiology of psychiatric disability in childhood and adolescence.

The goal of the study was to ascertain the factor structure and prevalence of psychiatric disability in children and adolescents in relation to demographic variables and diagnosis. A representative sample of 1,420 children (9-13 years) from 11 countries in North Carolina was followed for up to 6 years. Children and caretakers were interviewed with the Child and Adolescent Psychiatric Assessment, which generates DSM-IV diagnoses and includes a measure of disability secondary to psychological symptoms. Three broad areas of disability were identified (relating to family, school, and peers). School disabilities were more common in boys than girls. while the reverse was true of family disability. Effects of age were complex, and partially gender-differentiated. Children from minority ethnic groups had a higher overall prevalence of school disabilities, and were more prone than Whites to the disabling effects of disruptive behavior disorders. Anxiety disorders were as likely to result in disability as depressive disorders, and oppositional defiant disorders were more strongly associated with disability in some areas than was conduct disorder. The areas where disability is manifested are different depending on race, gender, age, and the type of disorder suffered. The implications of these findings for nosology and prevention are discussed.

The prospective relation between dimensions of anxiety and the initiation of adolescent alcohol use.

Examined the relation between early anxiety symptomatology (generalized and separation) and initiation of alcohol use 4 years later in an epidemiological sample of 936 children (45% girls), assessed at ages 9, 11, and 13, while controlling for the effects of depression. Although earlier overall anxiety symptomatology was unrelated to later onset of drinking, children with early symptoms of generalized anxiety were found to be at increased risk for initiation of alcohol use, whereas children with early symptoms of separation anxiety were at decreased risk. The magnitude of these relations was equally strong for boys and girls. In addition, early depressive symptomatology was associated with increased risk for initiation of alcohol use in adolescence. Results indicate that it is important to consider specific dimensions of anxiety symptomatology when attempting to identify those individuals at risk for early initiation of alcohol use.

Poverty, race/ethnicity, and psychiatric disorder: a study of rural children.

OBJECTIVES: This study examined the effect of poverty on the prevalence of psychiatric disorder in rural Black and White children. METHODS: A representative sample of 541 Black children and 379 White children aged 9 to 17 was drawn from 4 predominantly rural counties. Structured interviews with parents and children collected information on psychiatric disorders, absolute and relative poverty, and risk factors for psychiatric disorder. RESULTS: Three-month prevalence of psychiatric disorder was similar to that found in other community samples (20%). Federal criteria for poverty were met by 18% of the White and 52% of the Black families. Black and White children were exposed to equal numbers of risk factors overall, but the association between poverty and psychopathology was stronger for White children (odds ratio [OR] = 2.1; 95% confidence interval [CI] = 1.1, 4.2) than for Black children (OR = 1.5; 95% CI = 0.9, 2.6). Family history of mental illness, poor parenting, and residential instability mediated this association in both groups. CONCLUSIONS: In this rural sample, poverty was only weakly associated with child psychiatric disorders. Risk factors for both racial/ethnic groups were family mental illness, multiple moves, lack of parental warmth, lax supervision, and harsh punishment.

Do high-threat life events really provoke the onset of psychiatric disorder in children?

Studies on adults have suggested important effects of stressful life events in provoking onset of psychiatric disorder. Only a few comparable studies on children exist, and their results are inconsistent in relation to definite timing effects. Meeting some important methodological challenges overlooked in the past research, this study set out to examine whether the onset of psychiatric disorder in children was more likely to occur shortly after a severe event, as compared with other times. The sample consisted of 99 consecutive, newly referred patients, aged 8-16 years, from a child psychiatry service in London. PACE (Psychosocial Assessment of Childhood Experiences), an investigator-based, standardized interview was used to assess the timing and impact of life events over the preceding 18 months. CAPA (Child and Adolescent Psychiatric Assessment), a standardized diagnostic assessment, was used to establish the presence, timing, and consequential impairment of child and adolescent psychiatric symptoms. In a within-subject, over-time design, conditional logistic regression techniques were employed to examine whether risk of onset was greater in the 9 weeks following a high-threat life event than at other times. There was a small but statistically significant association between child-reported events and child-reported onset; the associations with parent-reported onset were inconsistent. Parent-reported events failed to relate to onset by either source. The study offers only quite limited support to the notion of negative life events provoking onset of psychiatric disorder in children and young people. The possible reasons for this are discussed, together with important conceptual and methodological issues to problems of defining onset, and the choice of appropriate designs for data analysis.

Bayesian analyses of longitudinal binary data using Markov regression models of unknown order.

We present non-homogeneous Markov regression models of unknown order as a means to assess the duration of autoregressive dependence in longitudinal binary data. We describe a subject's transition probability evolving over time using logistic regression models for his or her past outcomes and covariates. When the initial values of the binary process are unknown, they are treated as latent variables. The unknown initial values, model parameters, and the order of transitions are then estimated using a Bayesian variable selection approach, via Gibbs sampling. As a comparison with our approach, we also implement the deviance information criterion (DIC) for the determination of the order of transitions. An example addresses the progression of substance use in a community sample of n = 242 American Indian children who were interviewed annually four times. An extension of the Markov model to account for subject-to-subject heterogeneity is also discussed.

Multimodal treatment of ADHD in the MTA: an alternative outcome analysis.

OBJECTIVE: To conduct a post hoc investigation of the utility of a single composite measure of treatment outcome for the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA) at 14 months postbaseline. BACKGROUND: Examination of multiple measures one at a time in the main MTA intent-to-treat outcome analyses failed to detect a statistically significant advantage of combined treatment (Comb) over medication management (MedMgt). A measure that increases power and precision using a single outcome score may be a useful alternative to multiple outcome measures. METHOD: Factor analysis of baseline scores yielded two "source factors" (parent and teacher) and one "instrument factor" (parent-child interactions). A composite score was created from the average of standardized parent and teacher measures. RESULTS: The composite was internally consistent (alpha = .83), reliable (test-retest over 3 months = 0.86), and correlated 0.61 with clinician global judgments. In an intent-to-treat analysis, Comb was statistically significantly better than all other treatments, with effect sizes ranging from small (0.28) versus MedMgt, to moderately large (0.70) versus a community comparison group. CONCLUSIONS: A composite of ADHD variables may be an important tool in future treatment trials with ADHD and may avoid some of the statistical limitations of multiple measures.

Implications of early versus late onset of attention-deficit/hyperactivity disorder symptoms.

OBJECTIVE: The current diagnostic criteria for attention-deficit/hyperactivity disorder (ADHD) require that symptoms emerge prior to age 7 in order for a formal diagnosis to be considered. However, this age-of-onset criterion (AOC) has recently been questioned on both theoretical and empirical grounds. METHOD: Data from 4 annual waves of interviews with 9- to 16-year-olds from the Great Smoky Mountains Study were analyzed. RESULTS: Confirming previous studies, a majority of youths who had enough symptoms to meet criteria for ADHD were reported to have first exhibited these symptoms prior to age 7. Early onset of ADHD symptoms was associated with worse clinical outcomes in youths with the combined subtype of ADHD but not youths with the inattentive subtype. CONCLUSIONS: Findings support the continued inclusion of the AOC for the assessment of the combined but not necessarily the inattentive subtype of ADHD. Too few youths had a late onset of solely hyperactive-impulsive symptoms to evaluate the AOC for that group. However, regardless of the age of onset, youths who had elevated levels of ADHD symptoms were at increased risk for negative outcomes that may necessitate intervention.

Epstein-Barr virus antibodies in whole blood spots: a minimally invasive method for assessing an aspect of cell-mediated immunity.

OBJECTIVE: Study 1: Introduce and validate a method for measuring EBV p18-VCA antibodies in whole blood spots to provide a minimally invasive marker of cell-mediated immune function. Study 2: Apply this method to a large community-based study of psychopathology in children and adolescents. METHODS: The EBV antibody method was evaluated through analysis of precision, reliability, stability, and comparisons with plasma and indirect immunofluorescence methods. The effects of life events on p18-VCA antibody level were considered in a subsample of 9, 11, and 13 year-old children participating in the Great Smoky Mountains Study in North Carolina. The subsample was stratified by age, sex, and degree of overall life strain. RESULTS: Dried blood spots provided a convenient, sensitive, precise, and reliable method for measuring EBV p18-VCA antibody titer. Life events were positively associated with p18-VCA antibodies in girls but not in boys. CONCLUSIONS: The validity of the blood spot EBV p18-VCA antibody assay, as well as the ease of sample collection, storage, and transportation, may provide an opportunity for psychoneuroimmunology to explore a wider range of stress models in larger, community-based studies.

Stimulant treatment for children: a community perspective.

OBJECTIVE: To examine the use of prescribed stimulants in relation to research diagnoses of attention-deficit hyperactivity disorder (ADHD) in a community sample of children. METHOD: Data from 4 annual waves of interviews with 9- to 16-year-olds from the Great Smoky Mountains Study were analyzed. RESULTS: Over a 4-year period, almost three quarters of children with an unequivocal diagnosis of ADHD received stimulant medications. However, girls and older children with ADHD were less likely to receive such treatment. Most children with impairing ADHD symptoms not meeting full criteria for DSM-III-R ADHD did not receive stimulant treatment. Stimulant treatment in this group was significantly related to the level of symptoms reported by parents and teachers and was much more common in individuals who met criteria for oppositional defiant disorder. The majority of individuals who received stimulants were never reported by their parents to have any impairing ADHD symptoms. They did have higher levels of nonimpairing parent-reported ADHD symptoms, higher levels of teacher-reported ADHD symptoms, and interviewer-observed ADHD behaviors, but these typically fell far below the threshold for a DSM-III-R diagnosis of ADHD. CONCLUSIONS: In this area of the Great Smoky Mountains, stimulant treatment was being used in ways substantially inconsistent with current diagnostic guidelines.

Effectiveness of nonresidential specialty mental health services for children and adolescents in the "real world".

OBJECTIVE: Although many studies demonstrate the efficacy of a variety of treatments for child and adolescent psychiatric disorders, studies showing the effectiveness of such treatments in ordinary clinical settings have not been forthcoming. This report presents a study of the effectiveness of outpatient treatment in a community sample of 9- to 16-year-olds. METHOD: Four annual waves of data were collected from a representative sample of 1,422 children and their parents in the southeastern United States. Interviews were conducted with the Child and Adolescent Psychiatric Assessment to determine clinical status and the Child and Adolescent impact Assessment to measure the impact of psychiatric disorder on the lives of the children's families. RESULTS: Treated individuals were more severely disturbed and showed deterioration in their clinical status, even before they received treatment, indicating that comparisons with untreated individuals required controls not only for pretreatment clinical status, but for pretreatment clinical trajectory. A significant dose-response relationship was found between the number of specialty mental health treatment sessions received and improvement in symptoms at follow-up. However, no effect of treatment on secondary psychosocial impairment or parental impact was identified. CONCLUSIONS: Child and adolescent outpatient psychiatric treatment has positive effects on psychiatric symptoms, even when conducted outside the academic units where efficacy research usually takes place. The dose of treatment required to produce such effects (more than 8 sessions) suggests that attempts to limit child psychiatric treatment to very short-term interventions may be counterproductive.

The Child and Adolescent Psychiatric Assessment (CAPA).

OBJECTIVE: To describe the Child and Adolescent Psychiatric Assessment (CAPA). The base interview covers the age range from 9 to 17 years. METHOD: The interview glossary that provides detailed operational definitions of symptoms and severity ratings is described, and psychometric data and further developments of the interview are presented. RESULTS: Across 5,962 parent-child interviews, the core sections of the CAPA (psychiatric symptoms, functional impairment, demographics, family structure and functioning) took on average 59 minutes for children and 66 minutes for parents. Test-retest reliability for diagnoses ranged from kappa = 0.55 for conduct disorder (CD) to kappa = 1.0 for substance abuse/dependence. Validity as judged by 10 different criteria was good. Developments of the CAPA include a shorter "gateway" version using core symptoms as screen items, a Spanish version, and versions for twin studies, use with young adults (YAPA), and preschool-age children (PAPA). CONCLUSIONS: There is a place in both research and clinical settings for a rigorously operationalized interview (such as the CAPA) that focuses on ensuring that respondents understand what is being asked and on clearly defining levels of symptom severity and functional impairment.

Developmental psychopathology and public health: past, present, and future.

Children's healthy mental development has never been the focus of long-term, committed public health policy in the way that early physical health and development have been. We discuss four types of societal response to illness-cure, care, control, and prevention--and trace the history of public health in terms of its special responsibility to control and prevent disease. We identify four periods in the history of public health: the Sanitarian era (up to 1850), the Bacterial era (1850-1950), the Behavioral era (1950-present), and the Communitarian era (the next century). Looking at this history from the viewpoint of the developmental psychopathology of the first 2 decades of life, we trace progress in public health responses to children with mental illness, from a philosophy of control by isolation toward one of preventive intervention. We examine primary, or universal, prevention strategies that have been tried, and we suggest some that might be worth reconsidering.

Pubertal changes in hormone levels and depression in girls.

BACKGROUND: Throughout their reproductive years, women suffer from a higher prevalence of depression than men. Before puberty, however, this is not the case. In an earlier study, we found that reaching Tanner Stage III of puberty was associated with increased levels of depression in girls. This paper examines whether the morphological changes associated with puberty (as measured by Tanner stage) or the hormonal changes underlying them are more strongly associated with increased rates of depression in adolescent girls. METHODS: Data from three annual waves of interviews with 9 to 15-year-olds from the Great Smoky Mountains study were analysed. RESULTS: Models including the effects of testosterone and oestradiol eliminated the apparent effect of Tanner stage. The effect of testosterone was non-linear. FSH and LH had no effects on the probability of being depressed. CONCLUSIONS: These findings argue against theories that explain the emergence of the female excess of depression in adulthood in terms of changes in body morphology and their resultant psychosocial effects on social interactions and self-perception. They suggest that causal explanations of the increase in depression in females need to focus on factors associated with changes in androgen and oestrogen levels rather than the morphological changes of puberty.

Managed behavioral health care: a Medicaid carve-out for youth.

This DataWatch assesses the impact of a public sector-managed Medicaid mental health carve-out pilot for North Carolina youth. Access to, volume of, and costs of mental health/substance abuse services are reported. We compared a pilot managed care program, with an incentive to shift hospital use and costs to community-based services, with usual fee-for-service Medicaid. Aggregate data from Medicaid claims for youth (from birth to age seventeen) statewide are reported for five years. We found dramatic reductions in use of inpatient care, with a shift to intensive outpatient services, and less growth in mental health costs. These findings demonstrate that public sector-managed care can be viable and more efficient than a fee-for-service model.

Development of psychiatric comorbidity with substance abuse in adolescents: effects of timing and sex.

Examined the impact of childhood psychiatric disorders on the prevalence and timing of substance use and abuse and tested for sex differences. A representative population sample of 1,420 children, ages 9, 11, and 13 at intake, were interviewed annually. American Indians and youth with behavioral problems were oversampled; data were weighted back to population levels for analysis. By age 16, more than half the sample reported substance use, and 6% had abuse or dependence. Alcohol use began by age 9, and smoking in the 13th year. Mean onset of dependence was 14.8 years, and mean onset of abuse was 15.1 years. Substance use began earlier in boys, but not girls, who later developed abuse or dependence. Disruptive behavior disorders and depression were associated with a higher rate and earlier onset of substance use and abuse in both sexes, but anxiety predicted later onset of smoking. Family drug problems were the strongest correlate of early onset. Despite differences in prevalence of psychopathology, boys and girls showed more similarities than differences in the course of early substance use and abuse, and its associations with psychopathology.