A Familial Risk Analysis of Emotional Dysregulation: A Controlled Study

Participants

Detailed study methods have been previously described (Wozniak, Faraone, Martelon, McKillop, & Biederman, 2012). Briefly, children with BP-I disorder 6 to 17 years of age of both sexes were recruited and assessed at the Clinical and Research Program in Pediatric Psychopharmacology at the Massachusetts General Hospital based on the presence of a diagnosis of BP-I disorder in the proband youth by structured diagnostic interview and clinical assessment (Wozniak et al., 2005; Wozniak et al., 2010). Comparators were youth with and without ADHD without BP-I disorder of similar age and sex (Biederman et al., 1992; Biederman et al., 1999; Biederman, Monuteaux, Mick, Spencer, Wilens, Klein, et al., 2006; Biederman, Monuteaux, Mick, Spencer, Wilens, Silva, et al., 2006). We recruited 239 BP-I probands. From families participating in our case-control ADHD studies, we randomly selected 136 non-ADHD control probands without mood disorders (BP-I or major depressive disorder [MDD] full or subthreshold) so that the age and gender distribution was similar to that of the BP-I probands. All studies used the same assessment methodology regardless of the disorder used to classify probands as cases with the exception that children with structured interview diagnosis of BP-I disorder were also assessed buy an expert clinician to confirm the diagnosis (Wozniak et al., 2003). All study procedures were reviewed and approved by the subcommittee for human participants of our institution. All participants’ parents or guardians signed written informed consent forms and children older than 7 years of age signed age-appropriate written assent forms.

Ascertainment Method

Potential BP-I probands were ascertained from our clinical service, referrals from local clinicians, or self-referral in response to advertisements. Participants were administered a phone screen reviewing symptoms of Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994) BP-I disorder and, if criteria were met, were scheduled for a face-to-face structured diagnostic interview. In addition to the structured diagnostic interview, an expert clinician (J.W.) met with each BP-I proband and his or her parents for a clinical interview to confirm the diagnosis of BP-I disorder using the Schedule for Affective Disorders and Schizophrenia for School-Age Children–Epidemiological version (KSADS-E) mania module. We have published data on the convergence of these clinical interviews with our structured interview diagnosis on the first 69 cases. We reported 97% agreement between the structured interview and clinical diagnosis in this analysis of 69 children (Wozniak et al., 2003). As previously reported (Biederman et al., 1992; Biederman et al., 1999; Wozniak et al., 2010), controls were ascertained from out-patients referred for routine physical examinations to pediatric medical clinics and from computerized records as not having ADHD and screening for not having ADHD.

Diagnostic Procedures

Psychiatric assessments of participants <18 years of age relied on the KSADS-E (Orvaschel, 1994) and for participants ≥18 years on the Structured Clinical Interview for the DSM (SCID) supplemented with modules from the KSADS-E to capture childhood disorders. Diagnoses of youth were based on independent interviews with mothers and direct interviews with children older than 12 years of age. Data were combined such that endorsement of a diagnosis by either report resulted in a positive diagnosis.

All interviews were conducted by extensively trained and supervised psychometricians with undergraduate degrees in psychology. This training involved several weeks of classroom instruction of interview mechanics, diagnostic criteria, and coding algorithms. They also observed interviews by experienced raters and clinicians and were observed while conducting interviews during the final training period. In addition, all diagnoses were reviewed by a sign-off committee of experienced board-certified child and adolescent psychiatrists or clinical psychologists. The committee members were blind to the participants’ ascertainment status, ascertainment site, and data collected from other family members. We computed kappa coefficients of agreement by having experienced clinicians diagnose participants from audio-taped interviews made by the assessment staff. Based on 500 interviews, the median kappa coefficient between raters and clinicians was 0.99. For individual diagnoses, the kappas were as follows: ADHD (0.88), conduct disorder (1.0), major depression (1.0), mania (0.95), separation anxiety (1.0), agoraphobia (1.0), panic (0.95), substance use disorder (1.0), and tics/Tourette’s (0.89). The median agreement between individual clinicians and the clinical review committee was 0.87 and for individual diagnoses was as follows: ADHD (1.0), CD (1.0), major depression (1.0), bipolar (0.78), separation anxiety (0.89), agoraphobia (0.80), panic (0.77), substance use disorder (1.0), and tics/Tourette’s (0.68).

Children and adolescents were diagnosed with BP-I disorder according to DSM-IV criteria. The DSM-IV requires participants to meet Criterion A for a distinct period of extreme and persistently elevated, expansive or irritable mood lasting at least 1 week, plus Criterion B, manifested by three (four if the mood is irritable only) of seven symptoms during the period of mood disturbance. To ensure that the Criterion B symptoms were concurrent with Criterion A mood disturbance, participants were directed to focus on the worst or most impairing episode of mood disturbance while being assessed for the presence of the confirmatory Criterion B symptoms, that is, the participant was asked to consider the time during which the screen was at its worst for the purpose of determining whether the remaining symptoms were also evident at the same time as the screening item. Also recorded was the onset of first episode, the number of episodes, offset of last episode, and total duration of illness. Any participant meeting criteria for bipolar II (BP-II) or bipolar disorder not otherwise specified (BP-NOS) was not included in this study. To gauge a distinct episode, our interviewers asked for “a distinct period (of at least 1 week) of extreme and persistently elevated, expansive or irritable mood” and further required that the irritability endorsed in this module is “super” and “extreme.”

Child Behavior Checklist

The parent (usually the mother) of each participant completed the 1991 version of the Child Behavior Checklist for ages 4 to 18 years (CBCL/4-18). The CBCL is an affordable pencil and paper test completed by the child’s caregiver, requiring no administration by a physician or rater. The CBCL queries the parent about the child’s behavior in the past 6 months and aggregates these data into behavioral problem T scores (Achenbach, 1991). A computer program calculates the T scores for each scale. Raw scores are converted to gender- and age-standardized scores (T scores having M = 50 and SD = 10). A minimum T score of 50 is assigned to scores that fall at midpoint percentiles of ≤50 on the syndrome scales to permit comparison of standardized scores across scales. As described previously, the CBCL–Severe Dysregulation profile (Biederman et al., 2009) was defined as positive by a score of ≥210 (2 SDs) on the sum of the Attention, Aggression, and Anxious/Depressed CBCL scales. An intermediate or subsyndromal emotional dysregulation profile was defined as positive by a score of ≥180 (≥ 60 on average on each scale) but <210 (average T score of ≥60 and <70; Spencer et al., 2011).

Statistical Analysis

Differences in demographics and clinical characteristics were assessed using an analysis of variance (ANOVA) for continuous outcomes, Pearson’s chi-square for binary outcomes, and the Poisson regression likelihood ratio test for socioeconomic status (SES). A Pearson correlation coefficient tested the association between proband and sibling CBCL-ED scores. Pairwise comparisons of emotional dysregulation scores were made between the five proband groups defined above using linear regression and Tukey’s correction for multiple comparisons; estimates and 95% confidence intervals (CIs) were reported. All tests were two-tailed, and our alpha level was 0.05 for all analyses.