A Follow-up, Family Study on Attention-deficit Hyperactivity Disorder
Condition: Attention Deficit Hyperactivity Disorder
MeSH terms: Hyperkinesis; Attention Deficit Disorder with Hyperactivity
Study type: Observational

Summary: 
      Background: Attention deficit hyperactivity disorder (ADHD), characterized by inattention,
      hyperactivity and impulsivity, is an early onset, common (5-10% worldwide; 7.5% in Taiwan),
      clinically heterogeneous, impairing disorder. Despite the abundance of research on ADHD, the
      vast majority of samples have been limited to Caucasians; there is limited information about
      the expressions, patterns, correlates, and outcomes for ADHD in the Taiwanese population.

      Specific Aims:

        1. to investigate the neuropsychological functioning, and psychiatric, academic, and social
           outcomes of ADHD at adolescence;

        2. to examine the psychopathology and neuropsychological functioning among parents and
           siblings of ADHD probands;

        3. to determine the components of ADHD and neuropsychological functioning with the greatest
           familial recurrence risks; and

        4. to validate the classification of ADHD and comorbid subtypes of ADHD using psychosocial,
           familial, neuropsychological and longitudinal data.

      Subjects and Methods: This 5-year proposal consists of two parts: (1) a 3 year-retrospective
      cohort study and family study design; and (2) a 2 year-prospective cohort study design.
      Several Chinese version of rating scales will be prepared in the first 6 months. The sample
      will consist of probands with (n=180) and without (n=90) ADHD, ages 11-16, recruited from the
      Children's Mental Health Center, NTUH and an epidemiological study. The ADHD diagnosis has
      been made 3-6 years ago prior to recruitment. Probands and their parents will be assessed
      using the following measures (n=810) in the first 3 years. Only probands will be reassessed
      in the last 2 years. The measures will include a psychiatric interview using K-SADS-E and
      self-reports covering the individual and familial/environmental domains; and
      neuropsychological tests (WISC-III, CPT, WCST, CANTAB). The informants include probands and
      their parents and teachers.

      Long-term Objectives: The long-term objectives are to identify the endophenotypes that are
      close to the biological expression of genes underlying ADHD, to determine the familial
      aggregation and its specificity regarding the components of ADHD, and neuropsychological
      deficit, and to identify the impact of ADHD on academic, psychiatric, family, and social
      outcomes; and to identify a cohort of families with ADHD for future neuroimaging,
      neurophysiological, and molecular genetic studies.
    

Detailed description: 
      (A) Specific Aims

      The ultimate goals of this family study are to identify the endophenotypes that are closer to
      the biological expression of genes underlying ADHD, to identify patterns of familial
      aggregation with regards to ADHD and neuropsychological function, to examine the impact of
      ADHD on family functioning and parental psychosocial adjustment, and to characterize the
      long-term outcome of ADHD at adolescence in a Taiwanese sample. We propose to replicate
      previous studies on ADHD using a novel approach (an ambispective follow-up, bottom-up family
      study design using a mixed clinical and epidemiological sample) to validate the findings of
      previous studies in terms of the correlates, patterns, expression, outcome, and familial
      aggregation for ADHD and to attempt to determine whether neurological, and neuropsychological
      dysfunctioning also run in ADHD probands. With the accomplishment of these goals, this study
      will resolve controversies over inconsistent findings in previous studies and contribute to
      the literature on the validity of ADHD and ADHD comorbid subtypes using family data. The
      specific aims of this study are:

        1. Follow-up component:

             1. to explore the potential risk factors for the developing ADHD;

             2. to investigate the expression and patterns of ADHD at adolescence in terms of
                symptoms, neuropsychological, neurological, familial, school and social functions;

             3. to examine the symptoms continuity and the determinants of persistent ADHD
                symptoms;

             4. to identify the symptomatic, academic, and social outcomes of ADHD at early and
                late adolescence, including the use of tobacco, betel nut, alcohol and drug; and

             5. to validate the comorbid subtypes of ADHD using psychopathological,
                neuropsychological, behavioral, familial and social correlates.

        2. Family study component:

             1. to examine the psychopathology and neuropsychological functioning among parents and
                probably siblings of ADHD probands in comparison with those of control probands;
                and

             2. to identify the most familial correlated components of ADHD symptoms and
                neuropsychological measures.

      A. Specific Hypotheses

      The major research questions for the current proposal generated from prior research by our
      group and others are listed below. Under each question, specific hypotheses are provided:

        1. What are the major adolescent and young adult outcomes for children with ADHD? (Outcome
           of ADHD)

             1. Children with ADHD will be more likely to have comorbid psychiatric disorders such
                as oppositional defiant disorder, conduct disorder, depression, and substance use
                such as initial use of nicotine, betel nut, and alcohol at adolescence and
                depression, substance abuse, and antisocial personality disorder at young
                adulthood.

             2. Academic underachievement, impaired functioning in several social domains,
                interpersonal difficulties, and low self-esteem will be apparent at adolescence and
                young adulthood.

        2. What are the correlates and endophenotype of ADHD? (Validity of ADHD)

           a. Adolescents with ADHD will have more prenatal exposure to alcohol and nicotine,
           family dysfunction, parent-child conflict, sleep-related problems, somatic complaints,
           and neurological and neuropsychological dysfunctioning than those without ADHD.

        3. What are the specific components of ADHD that are familial?

             1. We hypothesize that parents of children with ADHD are at higher risks for ADHD and
                inattention will demonstrate more apparent family aggregation than hyperactivity.

             2. We also anticipate that deficit in executive function such as impaired working
                memory, impulsivity, and problem-solving difficulties will be familial among
                individuals with ADHD.

             3. In addition, associations between risk factors, and correlates that have not been
                addressed previously are also investigated post hoc. These analyses will be
                corrected for multiple comparisons.

      Significance and Background (deleted here) (E) Research Design and Methods This is a 5-year
      project with the first three years of a retrospective cohort study and family study designs
      and the last two years of a prospective follow-up cohort study design.

      A.1: The First Three-Year Study (2005.1~2007.12):

      The major tasks of the first 3-year of this study consisted of three parts: (1) 6
      months-development of several rating scales for adolescent and adult subjects, K-SADS-E
      interview training, pilot study of the Cambridge Neuropsychological Test Automated Batteries,
      and recruitment of subjects; (2) 2 years and 3 months-completion of recruitment and
      assessments of 180 ADHD families and 90 control families (n=810); and (3) 3 months-data
      management and analyses for the adolescent outcome and family aggregation of these 270
      families and preparation for the follow-up study in the young adulthood.

      A.1.1: Preparation phase-the first 6 months (2005.1~2005.6)

        1. Reliability and validity of instruments The Chinese version of the Conners Parent Rating
           Scale-Revised Short Form (CPRS-R: S), Conners Teacher Rating Scale-Revised Short Form
           (CTRS-R: S), Adult ADHD rating scale (ASRS), and Adult Self-Report Inventory (ASRI) will
           be prepared with culture-relevant colloquial expressions by the experienced child
           psychiatrists and professional translators.

        2. K-SADS-E and SAICA semi-structural interview training The interviewers will be trained
           to conduct the K-SADS-E interviews for parent report on themselves and probands, and
           proband report on themselves by the PI and staff child psychiatrists. (The details of
           training courses will be provided upon request).

        3. Training for administration and pilot study of neuropsychological tests including the
           Cambridge Neuropsychological Test Automated Batteries (CANTAB), CPT, and WSCT.

      A.1.2: Follow-up Studies for Children with ADHD-2 years and 3 months (2005.7~2007.9)

      a. Description of Subjects

        1. 1: Selection of Subjects The sample will consist of two groups: one exposed group
           including aged 12 to 15 adolescents with ADHD and one unexposed group including
           adolescents without ADHD. Their parents will be recruited in the family study. Their
           psychiatric diagnoses were made 3-6 years ago either at a clinical setting or in an
           epidemiological study. Recruitment will stop when we will have approximately 180
           probands with ADHD and 90 control probands.

             1. Inclusion Criteria The inclusion criteria for the exposed group are (1) that
                subjects either had the clinical diagnosis of DSM-IV ADHD, which was made by a
                full-time child psychiatrist at the first visit and following visits or by a child
                psychiatrist using the K-SADS-E as the second-stage case ascertainment at an
                epidemiological study; (2) the diagnoses of ADHD were made 3-6 years ago; (3) their
                ages range from 12 to 15 when we conduct study; (4) subjects have at least one
                sibling aged 6-18 and live with at least one biological parent; and (5) subjects
                and their family consent to participate in this study.

                The inclusion criteria for the unexposed group are (1) that subjects were assessed
                either at a clinical setting or in an epidemiological study same as to those in the
                exposed group 6 years ago; (2) their ages range from 12 to 15 when we conduct
                study; (3) subjects have at least one sibling aged 6-18 and live with at least one
                biological parent; and (4) subjects and their family consent to participate in this
                study.

             2. Exclusion Criteria The subjects, including those who in the exposed and unexposed
                groups, will be excluded from the study if they currently meet criteria or have a
                history of the following condition as defined by DSM-IV: Schizophrenia,
                Schizoaffective Disorder, Organic Psychosis, Mental Retardation, or Pervasive
                Developmental Disorder. Moreover, the subjects will be excluded from the unexposed
                group if have a history of the following condition as defined by DSM-IV: ADHD, ODD,
                or CD in addition to the above exclusion criteria. a.2: Source of Subjects Half of
                the subjects will be recruited from the Department of Psychiatry, National Taiwan
                University Hospital and half from the community in Taipei city based on the
                diagnoses in a epidemiology survey for ADHD.

        2. Procedures A letter and telephone contact with explanation of the purpose and procedure
           of this study and reassurance of confidentiality will be done before the recruitment of
           subjects, followed by face-to-face explanation and written informed consent. The
           subjects and their parents will be interviewed separately to provide information about
           the subjects' family composition, prenatal, developmental, and medical history,
           psychiatric diagnoses, and social functioning. CANTAB and other neuropsychological tests
           will be administered to probands and their parents. We will implement a quality control
           procedure consisting of verification of the interviews of 20% of the sample. These
           subjects will have their interview verified with audiotape, which will be reviewed by a
           blinded rater. The child and parent self-reported questionnaires will be administered
           either before or after child and parent interviews. We will interview 270 families (# N
           of assessments = 810). For the second-part of follow-up study at late adolescence
           (2008.1~2009.9), we will try to obtain corresponding information such as the addresses,
           telephone numbers, and email addresses of their relatives or friends close to them in
           order to decrease the loss of follow-up rates.

      A.1.3: Data Analysis and Manuscript Preparation for the first part of study-Adolescent
      Outcome (2007.10~2007.12) The research team will concentrate on data management and analysis
      of the information gathered in the first three years to understand the adolescent outcome and
      endophenotype of ADHD. We will also try to prepare several manuscripts for publication.

      A.3: Interviews and Psychiatric Diagnosis: Interviewers will be supervised by staff child
      psychiatrists. We developed a formal training package including an overview of the study and
      its methods, the diagnostic instruments, and detailed descriptions of the instruments and
      interview procedures. DVD of psychiatric interviews with adolescents and adults with ADHD and
      other major diagnostic categories are available for training and developing inter-rater
      reliability. The quality control of interview will be carried out continuously.

      The PI got her training in best estimate for diagnoses in her doctoral study at Yale. The
      best estimate diagnosis, based upon all available information (interviews, questionnaires,
      family histories, and medical records), will be made by the PI who will be blind to the
      diagnostic status of the proband and who will not be involved in direct interviews of any of
      the probands or parents.

      B. Measures B.1: Interviews for Psychiatric Diagnostic Information and Social functioning
      using the Chinese K-SADS-E for making diagnosis of probands and their siblings and parents;
      and the Social Adjustment Inventory for Children and Adolescents B.1.2: Self-reported
      measures The assessments will cover individual and familial/environmental vulnerability
      factors. They include measures of symptomatology, temperament/personality, psychopathology,
      competence, pubertal status, sleep patterns as well as familial and school functioning (Table
      1). Chinese versions of these self-reported scales will be available including CBCL,
      CTRS-R:S, CPRS-R:S, EPQ-JR, PDS, MES, DOTS, SAICA-C, PBI-C, FACS-C, ASRI, and DAS.

      Long-term Objectives: The long-term objectives are to identify the endophenotypes that are
      close to the biological expression of genes underlying ADHD, to determine the familial
      aggregation and its specificity regarding the components of ADHD, and neuropsychological
      deficit, and to identify the impact of ADHD on academic, psychiatric, family, and social
      outcomes; and to identify a cohort of families with ADHD for future neuroimaging,
      neurophysiological, and molecular genetic studies.
    

Observational model: Case-Control
Sampling method: Non-Probability Sample
Study population: 
        Community-based sample & children with ADHD and their families
      
Keywords: ADHD, adolescence, family study, endophenotype, outcome