GENE-ENVIRONMENT INTERACTIONS IN AN AUTISM ......2010/07/08 · 2 Table of contents 1. Overview of the ABC study 1.a. Background 9 1.a.1. Autism spectrum disorders 9 1.a.2. Causes

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GENE-ENVIRONMENT INTERACTIONS IN AN AUTISM BIRTH COHORT - THE AUTISM BIRTH COHORT STUDY

STUDY PROTOCOL JULY, 2010

Principal Investigator (US) W. Ian Lipkin (Mailman School of Public Health, Columbia University) PI (Norway) Camilla Stoltenberg (Norwegian Institute of Public Health) Co-I (US) Ezra Susser (Mailman School of Public Health, Columbia University) Co-I (Norway) Per Magnus (Norwegian Institute of Public Health) PARTICIPATING INSTITUTIONS

Mailman School of Public Health Norwegian Institute of Public Health Columbia University Division of Epidemiology (Oslo) Biobank (Oslo) Medical Birth Registry of Norway (Bergen)

National Institutes of Health Nic Waals Institute National Institute of Neurological Disorders and Stroke Lovisenberg Hospital (Oslo) Scientific Program Officer: Deborah Hirtz Administrative Program Officer: Claudia Moy Grant number NIH/NINDS U01 NS47537

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Table of contents 1. Overview of the ABC study

1.a. Background 9

1.a.1. Autism spectrum disorders 9 1.a.2. Causes of ASD 9 1.a.3. Challenges of autism research 10

1.b. Study purpose and design 10

1.b.1. The Autism Birth Cohort (ABC) 10 1.b.2. The Norwegian Mother and Child Cohort (MoBa) 11 1.b.3. Case identification in the ABC study 12

1.c. Study institutions, staff and advisors 14

1.d. Organizational structure of the ABC study 17

1.d.1. The ABC Steering Committee 18 1.d.2. The ABC Scientific Advisory Board 18 1.d.3. The ABC administrative core 18 1.d.4. ABC project groups 18 1.d.5. Institutional Review Boards 19 1.d.6. The NIPH Board of Directors and the MoBa Scientific Management Group 19 2. ABC subject identification, selection and recruitment

2.a. Overview 20

2.b. Identification and invitation of potential (screen-positive) cases and controls 20

2.b.1. The ABC screening algorithm 20 2.b.2. Children born in transitional study start-up period 21 2.b.3. Case-base sampling of controls at three years of age 21 2.b.4. Subject selection process 22

2.c. Alternative procedures for identification of potential cases 23

2.c.1. Self-referrals 23 2.c.2. Professional referrals 23 2.c.3. The Autism Database 24 2.c.4. The MoBa 5/7/8-year questionnaires 24 2.c.5. Cross-referrals from the AD/HD study 24 2.c.6. Twins and triplets 25

2.d. Recruitment and scheduling of subjects for assessments 25

2.d.1. Invited potential participants with signed ABC consent forms 25 2.d.2. Invited potential participants without signed ABC consent forms 26 2.d.3 Potential participants identified through self-referrals 27 2.d.4. Potential participants identified through professional referrals 28 2.d.5 Potential participants identified through the Autism Database 29 2.d.6. Potential participants identified through the MoBa 5/7/8-year questionnaires 30 2.d.7. Potential participants identified through cross-referrals from the ADHD study 30

2.e. Telephone interviews 30

2.f. Travel arrangements 31

2.g. Withdrawal from the ABC study 31

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3. The ABC clinical assessment

3.a. Overview 32

3.b. Assessment schedule 32

3.c. Assessment staff 34

3.d. Description of standardized instruments 34

3.d.1. The Autism Diagnostic Interview – Revised (ADI-R) 35 3.d.2. The Autism Diagnostic Observation Schedule (ADOS) 36 3.d.3. The Stanford-Binet Intelligence Scales, 5th edition (SB5) 37 3.d.4. The Wechsler Abbreviated Scale of Intelligence (WASI) 37 3.d.5. The Mullen Scales of Early Learning 38 3.d.6. The Vineland Adaptive Behavior Scales 39 3.d.7. The Preschool Age Psychiatric Assessment (PAPA) 40 3.d.8. The NEPSY Language subtests 41 3.d.9. The Boston Naming Test (BNT) 41 3.d.10. The Bayley Pegboard Test (BPT) 41 3.d.11. The Grooved Pegboard Test (GPT) 41

3.e. Clinician history-taking 42

3.e.1. The ABC Child and Family Health History Form 42 3.e.2. The ABC Parent Report of Child Behavior Form 43 3.e.3. The ABC Teacher Report of Child Behavior Form 45

3.f. Diagnostic interview 46

3.g. Physician history-taking and physical examination 46

3.h. Anthropometric measures and photographic recordings 46

3.i. Blood sampling 47

3.j. Staff conference and diagnostic conclusion 48

3.k. Feedback to parents 49 4. The NIPH Biobank

4.a. MoBa biological materials 50

4.b. Sample processing and storage 51

4.b.1. Rationale for sample collection methods 51 4.b.2. Sample collection and transfer 51 4.b.3. Sample storage 52

4.c. ABC-specific biological materials 52

4.d. Biobank quality control 52

4.e. Sample retrieval 52

4.e.1. Administrative procedures 52 4.e.2. Practical procedures 53 5. ABC quality control

5.a. Translations of instruments 54

5.b. Qualifications of assessment staff 56

5.c. Training procedures 57

5.d. Monthly staff meeting and ongoing training 58

5.e. Inter-rater reliability 58

5.f. Quality control of diagnoses 59

5.g. Protocol review and revision 59

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6. ABC data collection and management

6.a. Bergen Data Group (BDG) 60

6.b. The MoBa Tracking Database 60

6.c. ABC-specific tracking files 61

6.d. Recording of data during clinical assessments 62

6.e. Data quality control 62

6.f. The ABC Data Summary Form 63

6.g. Release of data files 63

6.h. Data audit 63 7. ABC field reports

7.a MoBa – key numbers 64

7.b. ABC screening 65

7.c. ABC clinical assessments 66

7.d. ABC biological material transfers 67

7.e. ABC data transfers 68

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ABC STUDY PROTOCOL APPENDIX Table of contents All Appendix documents are in English except as noted PART A – MoBa procedures and key numbers

APPENDIX A1. MoBa study protocol

APPENDIX A2. MoBa 36-month questionnaire

APPENDIX A3. The Social Communication Questionnaire (SCQ)

APPENDIX A4 MoBa 5-year questionnaire

APPENDIX A5 MoBa 7-year questionnaire

APPENDIX A6. MoBa 8-year questionnaire PART B – ABC clinical assessments

PART B1. Standardized diagnostic instruments

APPENDIX B1-1. The Autism Diagnostic Interview – Revised (ADI-R)

APPENDIX B1-1a. Norwegian APPENDIX B1-1b. English APPENDIX B1-1c. ADI-R algorithms (Norwegian) APPENDIX B1-1d. ADI-R algorithms (English)

APPENDIX B1-2. The Autism Diagnostic Observation Schedule (ADOS)

APPENDIX B1-2a. Module 1 (Norwegian) APPENDIX B1-2b. Module 1 (English) APPENDIX B1-2c. Module 2 (Norwegian) APPENDIX B1-2d. Module 2 (English) APPENDIX B1-2e. Module 3 (Norwegian) APPENDIX B1-2f. Module 3 (English)

APPENDIX B1-3. The Stanford-Binet Intelligence Scales, Fifth Edition (SB5)

APPENDIX B1-4. The Wechsler Abbreviated Scale of Intelligence (WASI)

APPENDIX B1-4a. Norwegian APPENDIX B1-4b. English

APPENDIX B1-5. The Mullen Scales of Early Learning (Mullen)


APPENDIX B1-6. The Vineland Adaptive Behavior Scales (Vineland)


APPENDIX B1-7. The Preschool Age Psychiatric Assessment (PAPA)


APPENDIX B1-8. The NEPSY Language subtests


APPENDIX B1-9. The Boston Naming Test


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APPENDIX B1-10. The Bayley Pegboard Test (BPT)


APPENDIX B1-11. The Grooved Pegboard Test (GPT)


PART B2. ABC-specific assessment forms

APPENDIX B2-1. ABC Child and Family Health History Form, age 3-5


APPENDIX B2-2. ABC Child and Family Health History Form, age 6+


APPENDIX B2-3. ABC Parent Report of Child Behavior Form, age 3-5


APPENDIX B2-4. ABC Parent Report of Child Behavior Form, age 6+


APPENDIX B2-5. ABC Teacher Report of Child Behavior Form, age 3-5


APPENDIX B2-6. ABC Teacher Report of Child Behavior Form, age 6+


APPENDIX B2-7. ABC Physical Examination Review Form


APPENDIX B2-8. ABC Clinician DSM-IV Diagnostic Criteria Review Form


APPENDIX B2-9. ABC Clinician DSM-IV Diagnostic Summary Form


APPENDIX B2-10. ABC Staff Summaries for Reports to Families and Their Physicians


APPENDIX B2-11 ABC Telephone Interview Script


APPENDIX B2-13 ABC Data Summary Form (Norwegian only)

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PART C – ABC regulatory documents

APPENDIX C1. ABC Recruitment – Invitation Letter

APPENDIX C1a. Singleton, Twin, Triplet Letters (Norwegian) APPENDIX C1b. Singleton, Twin, Triplet Letters (English)

APPENDIX C2. ABC Recruitment – Invitation Brochure

APPENDIX C2a. Norwegian APPENDIX C2b. English

APPENDIX C3. ABC Recruitment – Consent Form


APPENDIX C4. ABC Recruitment – MoBa Newsletter


APPENDIX C5. ABC Recruitment – Information for Health Professionals


APPENDIX C6. ABC Recruitment – Information for Educational Services


APPENDIX C7. ABC Recruitment – Telephone Script for Reminder Call


APPENDIX C8. ABC Recruitment – Telephone Script for Scheduling Consenting Parents


APPENDIX C9. ABC Recruitment – Confirmation Letter for Clinical Assessment Visit


APPENDIX C10. ABC Recruitment – Brochure for Preparing Child for Clinical Assessments


APPENDIX C11. ABC Recruitment – 41-month Reminder Letter


APPENDIX C12. ABC Recruitment – Telephone Script for Initial Interview with Potential Self-Referrals


APPENDIX C13. ABC Recruitment – Consent Form for Obtaining Information from Daycare Staff


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PART D – ABC scientific collaboration policies

APPENDIX D1. Collaboration Agreement between the Norwegian Institute of Public Health and Columbia University, effective as of ___

APPENDIX D2. The Autism Birth Cohort: Procedures for Manuscript Preparation and Publication

APPENDIX D3. The Autism Birth Cohort: Agreement Terms for External Collaborations PART E – ABC Scientific Advisory Board (SAB) member biographies

APPENDIX E. ABC Scientific Advisory Board (SAB) member biographies

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1. OVERVIEW OF THE ABC STUDY 1.a. BACKGROUND 1.a.1. Autism spectrum disorders Autism is a heterogeneous neurodevelopmental disorder defined by the presence of three core symptoms: i) social skills deficit, ii) restricted, repetitive and stereotyped patterns of behavior, interests and activities and iii) significant language delay. Symptoms of autism may vary in their presence, intensity and time of onset, and present in a large variety of phenotypes. Many individuals exhibit autistic features without meeting the DSM-IV criteria for autistic disorder (classical autism). The concept of ‘autism spectrum disorders’ (ASD) was introduced to include a broader range of autistic phenotypes. Another term used interchangeably is ‘pervasive developmental disorders’. The diagnostic entities within the autistic spectrum are autistic disorder (childhood autism), Asperger syndrome and ‘pervasive developmental disorder not otherwise specified’ (usually called PDD NOS or atypical autism). Autistic disorder is rarely diagnosed before the age of three years. Other ASDs are typically diagnosed even later. There is no established ‘gold-standard’ population screen for ASD that has been validated for use in young children. Early diagnosis and intervention has been demonstrated to improve the prognosis of children with ASD – not in the sense that the disorder is ‘cured’, but by improving language and social skills and modifying troublesome behaviors. Children with ASD display wide variations in cognitive skills, ranging from high intelligence to profound mental retardation. Around 50% have IQ below normal levels, although the exact proportion is uncertain. Approximately 10% of children with ASD have comorbid associated medical conditions, usually genetic disease. Recent studies indicate that the prevalence of diagnosed cases of ASD in children is now approximately 6 per 1,000 in Europe and North America. The prevalence has increased rapidly in most developed countries over the past 20 years. It is unknown whether this reflects a true increase in the occurrence of ASDs, or whether it is merely a result of changing diagnostic practices. 1.a.2. Causes of ASD The knowledge about causes of ASD is still limited, but it is clear that genetic factors play a major role. The concordance rate in monozygotic twins is 70% for autistic disorder and 90% for ASD (i.e., all autism spectrum disorders, including autistic disorder). The recurrence rate of ASD in siblings is 5-6%. Twin studies have demonstrated that heritability may be linked to individual autistic traits, not necessarily the diagnosis in itself. The contributing genetic factors appear to be heterogeneous, and linkage analyses have found evidence for autism loci on 20 different chromosomes. It has been hypothesized that autism may be caused by de novo genetic and epigenetic events, i.e. mutations in the DNA of parents’ germline cells that are subsequently transmitted to their children. This may explain the findings from several epidemiological studies that advanced paternal age increases the risk of autism in the child. Older fathers have an increased risk of de novo point mutations in the germline, but it is still unknown whether there is also an increased risk of other types of mutations, such as DNA deletions, duplications and copy number mutations. Associations between ASDs and various prenatal and perinatal exposures have been found, but the results are somewhat conflicting, and further research is required. Studies have found that gestational age of less than 35 weeks and being small for gestational age are risk factors. Several indicators of obstetric complications, including low Apgar scores, also appear to be predictive of ASD risk. Epidemiological studies indicate that pre- or perinatal exposure to toxins or infections may be important co-factors, functioning as environmental triggers in genetically susceptible individuals. Studies have found increases in particular geographic regions, season-of-birth effects, and higher rates in some immigrant populations, possibly due to prenatal exposures to infectious agents to

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which the mother was not immune. However, the specific biological mechanisms leading to the development of ASD have yet to be elucidated. Over many years, there have been speculations that autism may be caused or triggered by vaccines, but no studies to date have found any evidence of such an association. 1.a.3. Challenges of autism research Several challenges must be addressed to advance the field of autism research:

• Large population samples are required to identify a sufficient number of ASD cases and achieve a high statistical power of scientific analyses.

• Genetic causes of ASD, and potential interactions between genes and environmental factors, should be further investigated. Such investigations require epidemiological data and DNA from complete family trios of mothers, fathers and children. Opportunities for gene expression studies would also be an advantage.

• Since epidemiological studies point towards pre- or perinatal exposures as important risk factors, collection of data and biological materials should start early, preferably in pregnancy.

• High-quality research requires a high validity of ASD diagnoses. Case ascertainment should correspond to the current research-standard methods for diagnosing ASD, which includes validated standardized assessment tools and psychometric testing.

• Different ASD phenotypes are still imprecisely delineated, and much is still unknown about developmental trajectories in children with ASD. This impedes research, because causal factors of ASD may be related to specific autistic traits or specific ASD phenotypes, and not to the broad diagnostic category of ASD. Therefore, studies should monitor child development at various points in time, and case ascertainment should include a detailed assessment of individual autistic traits and neuropsychiatric capacities, not just diagnostic conclusions.

1.b. STUDY PURPOSE AND DESIGN 1.b.1. The Autism Birth Cohort (ABC) The ABC study is a case-control study nested within the Norwegian Mother and Child Cohort (Den norske mor og barn-undersøkelsen, MoBa). It is designed and managed in collaboration between the Mailman School of Public Health of Columbia University (New York, NY, USA), the Norwegian Institute of Public Health (Norway) and the National Institutes of Health / National Institute of Neurological Disorders and Stroke (Bethesda, MD, USA). The data collection takes place in Norway. The present study (ABC-1) was funded by an NIH/NINDS grant of 12.9 million USD (grant no. NIH/NINDS U01 NS47537). The grant originally lasted from June 1, 2003 to May 31, 2008, but a no-cost extension was granted until May 31, 2010. Bridge funding is provided to run the study from June 1 to November 30, 2010, while awaiting the decision on a renewal grant from the NIH/NINDS. Funding is also provided by the Norwegian Institute of Public Health and the Research Council of Norway. Clinical assessments started in 2005. The study aims to identify cases of ASD in the MoBa cohort and utilize MoBa data and biological materials to study causes and trajectories of ASDs. The ABC-1 had the following scientific aims:

1. Establish the Autism Birth Cohort (ABC) through ascertainment of potential ASD cases and selection of controls from the MoBa cohort.

2. Identify environmental factors that may be directly or indirectly associated with ASD

including: prenatal or postnatal infection, mumps-measles-rubella vaccination, very low birth weight and prematurity, other obstetric risk factors in which infections are implicated, and dietary and/or environmental exposure to methylmercury during pregnancy and postnatal life.

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3. Describe the natural history of clinical, anthropometric, and neurobehavioral features of ASD.

1.b.2. The Norwegian Mother and Child Cohort (MoBa) MoBa is a pregnancy cohort study started by the Norwegian Institute of Public Health (NIPH) for studying causes of disease in mothers, fathers and children. Recruitment of mothers and children started in 1999, and fathers were included from 2000. The recruitment started in the county of Hordaland (in Western Norway), and was gradually stepped up to become nationwide from 2005. Since then, 50 out of 52 hospitals in Norway participated. Nationwide recruitment ended on May 31st, 2008, but recruitment continued at the eight largest hospitals in Norway until December 31st, 2008. By the end of recruitment, the cohort had enrolled 107,000 pregnancies, 90,700 mothers, and 71,500 fathers. The cohort includes approximately 108,000 live-born children. MoBa data are linked to the Medical Birth Registry of Norway (MBRN), which is also run by NIPH. MoBa is funded from a number of sources; the most important being the Norwegian Ministry of Health, the Research Council of Norway and contributions from various sub-studies. The MoBa study protocol is included as Appendix A1. MoBa participant mothers complete questionnaires during pregnancy (at 17, 22 and 30 weeks of gestation) and at intervals following birth (6, 18 and 36 months; 5, 7 and 8 years). Fathers have completed a questionnaire during pregnancy. These questionnaires query health, dietary intake, socio-economic factors, child development and behavior, and other factors relevant to child and parental health. Blood samples (plasma, full blood, DNA) were obtained from both parents during pregnancy and from mothers at birth. A urine sample was also taken from the mother during pregnancy. From the child, a blood sample (plasma, full blood, DNA, RNA) was taken from the umbilical cord right after birth. The blood samples are suitable for genetic analyses, transcript profiling, biomarker analyses and toxicology analyses. Amongst existing prospective child cohorts around the world, MoBa is unique in several respects:

• Collection of data and biological materials started during pregnancy - not after birth, as for most other child cohorts – providing excellent opportunities to study prenatal exposures.

• MoBa is the only cohort study that has collected blood samples for RNA extraction and gene expression studies.

• MoBa includes fathers. The only other pregnancy cohort of comparable size, in Denmark (the Danish National Birth Cohort), does not include fathers.

• MoBa benefits from the well-established epidemiologic surveillance and database management of the Medical Birth Registry of Norway, which was established in 1967. Linkage can also be established to other national health registries.

Table 1.b.2.a. MoBa RECRUITMENT – KEY NUMBERS

Number % of invited Birth year # live-born children Pregnancies 107,000 38.5 % 1999 50 Live-born children 108,000 2000 2,200 Unique mothers 90,700 2001 4,300

2002 8,800 Pregnancies w/ father participating 82,400 77.0 % 2003 12,700 Unique fathers 71,500 2004 13,700 Twin pairs 1,865 2005 15,700 Triplet trios 21 2006 17,500 Total # of sibships 16,700 2007 16,200 2008 13,400

2009 3,400 Children alive and participating at 3 years

104,500 (est.)

Numbers updated per February 15, 2010

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Table 1.b.2.b. MoBa QUESTIONNAIRES

Time of receipt

Main focus

# sent out

# returned

Response rate

Midwife *

wks 13-20 of pregnancy

Prenatal U/S data: Growth parameters, pathological findings, placental characteristics

107,000 *

88,400

82.6 %

Mother In

pregnancy

Q1


Previous pregnancies and outcomes, medical history before and during pregnancy, medications, occupation, exposures in the workplace and at home, lifestyle, mental health

107,000

101,800

95.1 %

Q2

wk 22

Food frequency

105,300

97,300

92.4 %

Q3

wk 30

Antenatal care, health changes, work situation, lifestyle

103,800

94,300

90.8 %

Age of child Q4

6 mos

About the birth, child health, development and nutrition, maternal health, lifestyle and well-being

106,000

89,800

84.7 %

Q5

18 mos

Child health, development, behaviour, nutrition and daily life, maternal health, lifestyle and well-being

86,800

70,300

72.6 %

Q6

36 mos

Child health, development, behaviour, nutrition and daily life, maternal health, lifestyle and well-being

68,350

40,800

59.7 %

Q7

5 y

Neurodevelopmental disorders, language delay

Started Jan 2010

Q8

7 y

Child health, lifestyle and nutrition

11,600

6,700

57.7 %

Q9

8 y

Child development and behavior

Started April 2010

Father QF


Medical history, health, occupation, exposures, lifestyle and nutrition

82,400

77,800

94.4 %

* MoBa collected copy of U/S examination form Table 1.b.2.c MoBa BIOLOGICAL SAMPLE COLLECTIONS

Sample Time of collection Sample type # collected

Response rate

Maternal pregnancy sample Week 17-20 EDTA blood, urine 92,600 87.5 % Paternal sample Week 17-20 EDTA blood 67,700 82.2 %

Maternal birth sample 0-3 days after birth EDTA blood 83,200 77.8 %

Child umbilical cord sample Day of birth

EDTA blood, RNA Tempus whole blood * 88,800 81.9 %

Child milk teeth sample 6-7 years Milk teeth 3,400 24.4 %

* RNA samples were taken from children born in or after September 2005 (approx. 46,000 children). 1.b.3. Case identification in the ABC study Potential cases of ASD (autistic disorder, Asperger syndrome, PDD NOS) and a random sample of controls are invited to participate in the study. MoBa participants are screened for autistic traits at 36 months of age (MoBa 36-month questionnaire, Appendix A2). The screening algorithm is based on the Social Communication Questionnaire (SCQ) (Appendix A3), in addition to other selected questions. The SCQ is a selection of items from the original Autism Diagnostic Interview (ADI). It covers all three core symptom areas of ASD, and has been validated for autism screening in clinical samples. MoBa is the first study to use the SCQ for screening in a large unselected population, and at such an early age. The ASD screening procedures and the selection of controls have been carried out for MoBa participants born on or after July 1st, 2002.

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Following the screening, ASD caseness is confirmed through an extensive in-person clinical evaluation at Nic Waals Institute in Oslo. The assessment includes validated diagnostic tools (Autism Diagnostic Interview – Revised, Autism Diagnostic Observation Schedule), psychometric testing (Stanford-Binet Intelligence Scales 5th edition, Mullen Scales of Early Learning, Wechsler Abbreviated Scale of Intelligence), a standardized parent interview for developmental assessment (Vineland Adaptive Behavior Scales), a physical examination and a final diagnostic interview. Blood samples are collected from all children (plasma, full blood, DNA, RNA), and from parents, if they have not previously provided blood samples to MoBa. The clinical assessments have been substantially shortened from January 2009 onwards, as explained in Section 3. The ABC study has implemented several other mechanisms to enhance the identification of potential ASD cases within the MoBa cohort. Self-referrals (by parents) and professional referrals are accepted, if there is reason to suspect ASD in the children. Potential ASD cases are also identified through the Norwegian Patient Registry and hospital registries, and through the MoBa 5/7/8-year questionnaires. The alternative case-identification procedures are described in detail in Section 2. Children identified through the alternative procedures are invited at any age, as long as they are enrolled in MoBa. Under the current NIH/NINDS funding, clinical assessments are covered until November 30, 2010. The goal of the collaborating institutions is to continue the case identification procedures until all MoBa participants have turned seven years old, in 2016. The MoBa 5/7/8-year questionnaires (Appendix A5) contains specific questions about autism, autistic traits and Asperger syndrome, and this will contribute to the case identification. The 8-year questionnaire also repeats the SCQ. Figure 1.b.3. OVERVIEW OF CASE IDENTIFICATION IN THE ABC STUDY

Blue = ABC-specific procedure implemented 2005; yellow = ABC-specific procedure implemented 2010

MoBa participants

Parent and professional

referrals

Screen-positive, MoBa 36 mo

questionnaire

ADI-R phone interview

The Autism Database: Norwegian Patient Registry,

Hospital registries

MoBa 5/7/8 y

questionnaires

Selected controls

Invitation to participate

ASD DIAGNOSIS

Clinical assessment

Medical Birth Registry of Norway

Lost to follow-up

Participation declined

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1.c. STUDY INSTITUTIONS, STAFF AND ADVISORS Principal investigator (US) W. Ian Lipkin, MD Center for Infection and Immunity (CII) Mailman School of Public Health Columbia University 722 W. 168th St., Room 1801, New York, NY 10032, USA Telephone: +1 212 342 9031 E-mail: [email protected] Principal investigator (Norway) Camilla Stoltenberg, MD, PhD Division of Epidemiology Norwegian Institute of Public Health P.O. Box 4404 Nydalen, N-0403 Oslo, Norway Telephone: +47 23 40 82 38 E-mail: [email protected] Co-I for the ABC study (US) Ezra Susser, MD, DrPH

1. Department of Epidemiology Mailman School of Public Health Columbia University

2. New York State Psychiatric Institute MoBa director and Co-I for the ABC study (Norway) Per Magnus, MD, PhD Division of Epidemiology Norwegian Institute of Public Health NIH/NINDS representatives Deborah Hirtz, MD, Scientific Program Officer Claudia Moy, PhD, MPH, Administrative Program Officer Steering Committee W. Ian Lipkin Camilla Stoltenberg Ezra Susser Per Magnus Deborah Hirtz Consultants Catherine Lord, PhD; University of Michigan Autism and Communication Disorders Centre (US) Margaret Pericak-Vance, PhD; Miami Institute of Human Genomics, University of Miami Miller School of Medicine (US) Scientific Advisory Board Michael Rutter, CBE, MD, FRCP, FRCPsych, FMedSci, FRS; Institute of Psychiatry, University of London (UK) Alan Leviton, MD; Harvard Medical School (US) Tony Charman, PhD; Institute of Education, University of London (UK) Daniel Geschwind, MD, PhD; UCLA School of Medicine (US)

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Institutional participants 1. Mailman School of Public Health, Columbia University (New York, NY, USA) 2. Norwegian Institute of Public Health (Norway) Division of Epidemiology, Oslo MoBa Biobank, Oslo Medical Birth Registry of Norway (MBRN), Bergen 3. National Institutes of Health / National Institute of Neurological Disorders and Stroke

(Bethesda, MD, USA) 4. Nic Waals Institute, Lovisenberg Hospital (clinical site - Oslo, Norway)

Collaborators MAILMAN SCHOOL OF PUBLIC HEALTH Center for Infection and Immunity Thomas Briese, PhD; associate professor David Hirschberg, PhD; assistant professor Mady Hornig, MD, MA; associate professor, director of translational research Allison Kanas, BA; project coordinator Vishal Kapoor, MS; senior research worker Robert Serge, MS; data manager Department of Epidemiology/New York State Psychiatric Institute Michaeline Bresnahan, PhD; assistant professor Department of Biostatistics Myunghee Cho Paik, PhD; professor, senior biostatistician Bruce Levin, PhD; professor, senior biostatistician NORWEGIAN INSTITUTE OF PUBLIC HEALTH Oslo Gunnar Brunborg, PhD; MoBa Biobank Cathrine Dahl, MD; project coordinator for the Autism Database Ingvild Fjeldheim, MD; project coordinator Nina Gunnes, PhD; biostatistician Kari Harbak, MSc; director of MoBa Biobank Kari Kveim Lie, MD; MoBa liaison for the ABC study Ted Reichborn-Kjennerud, MD; Division of Mental Health Anders Skrondal, PhD; senior biostatistician Synnve Schjølberg, MA; clinical advisor Eili Sponheim, MD, PhD; child psychiatrist, clinical consultant for second opinions Nina Stenberg, MA; senior clinical psychologist / PhD candidate Pål Surén, MD, MPH; PhD candidate Britt Kveim Svendsen, MD; child psychiatrist / senior clinician Anne-Siri Øyen, PhD; director of ABC clinical assessments Bergen Elin Alsaker, MSc; data management Ole-Martin Kvinge, MSc; data management Patricia Schreuder; BA; data management Arild Sunde, MSc; data management Stein Emil Vollset, PhD; Director of MBRN UNIVERSITY OF MICHIGAN AUTISM AND COMMUNICATION DISORDERS CENTER Shanping Qui, MS; data analyst

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Clinical site staff (Nic Waals Institute) Full-time employees: Monica Grenaa Andersen; secretary Kristin Offer-Ohlsen; family coordinator Part-time employees: Psychologist Lise Skau Andersen Marte Ramstad Nina Stenberg Svetlana Tsarkova Child psychiatrists Britt Kveim Svendsen Nicolai Wergeland Research assistants Mads Friberg Alexandra Havdahl Anna Sara H. Romøren Kathrine Schjølberg Elin Tandberg Magnus Tøndevold Stian Barbo Valand (senior research assistant)

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1.d. ORGANIZATIONAL STRUCTURE OF THE ABC STUDY Figure 1.d. ABC STUDY ORGANIZATION

Columbia University IRB

Norwegian Data Inspectorate • Regional Committee of Medical

Research Ethics

ABC Steering

Committee IL, CS, ES, PM, DH

Project Groups

Administrative core IL, CS, ES, PM

Scientific Advisory Board

AL, DG, MR, TC

Aim 1

Aim 3

Bergen Data Group AS, EA, OMK, PS

MoBa Biobank GB, KH

CII laboratory IL, TB, VK, RS, DHI

Epidemiology CS, ES, MB, MH, PM, PSU cs,

Biostatistics ASK, NG, BL, MP

Quality assurance ASØ, BKS, MB, MH, NS

Aim 2

Archives/ web pages IF, KO, AK

Clinical assessments ASØ, BKS, KO, MH, MB, NS, SS

Financial management ALU, VV

KEY AL: Alan Leviton ALU: Ane Lunde AK: Allison Kanas AS: Arild Sunde ASK: Anders Skrondal ASØ: Anne-Siri Øyen BL: Bruce Levin BKS: Britt Kveim Svendsen CS: Camilla Stoltenberg DG: Daniel Geschwind DH: Deborah Hirtz DHI: David Hirschberg EA: Elin Alsaker ES: Ezra Susser GB: Gunnar Brunborg IF: Ingvild Fjeldheim IL: Ian Lipkin KH: Kari Harbak KO: Kristin Offer-Ohlsen MB: Micki Bresnahan MH: Mady Hornig MP: Myunghee Cho Paik MR: Michael Rutter NG: Nina Gunnes NS: Nina Stenberg OMK: Ole-Martin Kvinge PM: Per Magnus PS: Pat Schreuder PSU: Pål Surén RS: Robert Serge SS: Synnve Schjølberg TB: Thomas Briese TC: Tony Charman VK: Vishal Kapoor VV: Vera Vangler

Norway coordinator IF

US coordinator AK

Other projects / sub- studies

NIPH Board of Directors

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1.d.1. The ABC Steering Committee The ABC Steering Committee (SC) is the administrative organ of the study. The ABC SC follows the progress of the study at all levels through regular reports from the administrative core and the project groups. The functions of the ABC SC include: 1) monitoring and evaluating the progress of core functions to ensure timely completion of study goals; 2) facilitation of scientific activities; 3) implementation of scientific policies; 4) oversight of project groups to ensure integration of scientific activities. It also approves and oversees collaborations with investigators outside of the ABC study. The ABC SC is co-chaired by Ian Lipkin and Camilla Stoltenberg. 1.d.2. The ABC Scientific Advisory Board The ABC Scientific Advisory Board (SAB) advises the ABC SC in the design and implementation of the study and the review and prioritization of scientific analyses and projects. SAB members also complete site visits to Norway, to consult with ABC staff and provide advice regarding clinical assessment procedures. 1.d.3. The ABC administrative core The administrative core consists of staff at both Columbia University (CU) and the Norwegian Institute of Public Health (NIPH). The primary responsibilities and functions of each group are as follows: Coordinators: coordinate services between working groups; schedule conference calls and meetings; write meeting minutes; ensure regulatory oversight; facilitate distribution of reports; contribute to archives of documents, letters of agreement and other correspondence. Archives/web pages: maintain archives of ABC documents and publications; maintain the ABC-specific web pages at CU, NIPH, and Nic Waals Institute. Financial management: implement and track financial budget. The Bergen Data Group: implement screening procedures, potential control selection, participant enrollment and status tracking; manage ABC clinical data; provide MBRN, MoBa and ABC clinical data for ABC study collaborators; provide data documentation and programmer-constructed variables. The NIPH Biobank: store biological specimens collected in the MoBa and ABC studies; retrieve biological materials; facilitate transport of specimens to the Center for Infection and Immunity (CII) or other laboratories for analyses. CII laboratory: utilize biological specimens for DNA, RNA, and biomarker analyses. Clinical assessments: recruit and schedule families for clinical assessments; train staff for clinical assessments; conduct clinical assessments; input data from clinical assessments. The NIPH staff responsible for organizing the assessments and the clinical site staff at Nic Waals Institute are collectively referred to as the Oslo Assessment Group (OAG) further on in this protocol. Biostatistics: manage and integrate exposure and outcome data; develop and implement data analysis strategies. Epidemiology: implement research design; monitor recruitment, performance of screening algorithm and results of case-finding; oversee research analyses. Quality assurance: implement and assess information from quality assurance procedures employed for clinical assessments, laboratory, data management, and biological specimen management. 1.d.4. ABC project groups The ABC SC will establish project groups for specific research tasks. ABC SC members may also be members of such groups.

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1.d.5. Institutional Review Boards In the United States, the ABC Study is overseen by the Institutional Review Board of Columbia University. In Norway, the overseers are the Regional Committee of Medical Research Ethics and the Norwegian Data Inspectorate. This includes, but is not limited to, human subjects research, data access and management, privacy, and confidentiality. 1.d.6. The NIPH Board of Directors and the MoBa Scientific Management Group MoBa is administered by the NIPH Board of Directors. Scientific decisions are delegated to the MoBa Scientific Management Group, which has members from all divisions of NIPH.

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SECTION 2. ABC SUBJECT IDENTIFICATION, SELECTION AND RECRUITMENT 2.a. OVERVIEW This section describes the process for identifying and recruiting subjects for the ABC study. As explained in Section 1, the procedures for screening and control selection were implemented for MoBa participants born on or after July 1st, 2002. However, potential cases identified through alternative mechanisms are invited regardless of birth date, as long as the subjects are MoBa participants. MoBa subjects are excluded in instances where the mother or child has died, or the mother has been lost to follow-up (i.e. residence unknown). If the mother has withdrawn from MoBa, the child is no longer considered a MoBa participant, and hence, not eligible for the ABC study. Two ABC research sites are central in these procedures: the Bergen Data Group (BDG), which is primary in the selection and initial mailing to potential subjects, and later in tracking of ABC subjects; and the Oslo Assessment Group (OAG), which is primary in the recruitment, scheduling, and assessment of potential subjects. All printed materials and scripts associated with these procedures appear in the Appendix (Part C – ABC Regulatory documents). The overarching objective of the selection process is to identify all cases of autism spectrum disorders (ASD) in the MoBa cohort and to establish a representative and unbiased sample of MoBa controls for the ABC study. MoBa participants are screened on the basis of the 36-month questionnaire (Appendix A2) to identify children at high risk of a diagnosis of ASD. Controls are selected randomly from the MoBa cohort (regardless of screening results or whether the 36-month questionnaire has been returned). In addition, potential ASD cases among the MoBa participants are identified through self-referrals, professional referrals, the Norwegian Patient Registry, hospital registries, and the MoBa 5/7/8-year questionnaires (Appendices A4-A6). 2.b. IDENTIFICATION AND INVITATION OF POTENTIAL (SCREEN-POSITIVE) CASES AND CONTROLS 2.b.1. The ABC screening algorithm The 36-month questionnaire includes the Social Communication Questionnaire (SCQ, Appendix A3), which consists of 40 items from the original Autism Diagnostic Interview (ADI) and has been validated for autism screening in clinical samples. Seven of the items require that the child is able to combine words or use sentences. These items have been excluded from the screening algorithm, because the absence of such language skills is not necessarily abnormal in three-year-olds. The remaining 33 items are scored. Responses indicative of ASD are scored by one point each, whereas responses indicative of normal development are given a zero score. Original screening algorithm At the start of the study, children screened positive if meeting one or more of the following five criteria:

1. Total SCQ-33 score >= 12 2. Full score, i.e. 9 out of 9 points in the repetitive behavior sub-domain of the SCQ 3. Parent reports language delay AND the child has been referred to a specialist for it 4. Parent reports autism/autistic traits OR the child has been referred to a specialist for it 5. Parent reports that the child shows very little interest in playing with other children

Revision of screening algorithm The screening algorithm is reviewed by the ABC SC at six-month intervals, and adjustments are made if needed. In February 2007, the ABC SC decided to modify the screening algorithm, because the specificity for ASD was too low, and the number of normally developed children screening positive was too high. An additional item – criterion 6 – was added: Parent reports that others (family, daycare staff, well-baby nurse) have expressed worry for the child’s development.

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Children now screen positive if: • Meeting criterion 4 (autism/autistic traits) • Meeting one or more of criteria 1/2/3/5 AND meeting criterion 6

The exact scoring of screening items – performed from February 7, 2007, and onwards - is summarized in Table 2.b.3.: Table 2.b.3. SCORING PROCEDURES FOR ABC SCREENING CRITERIA

Item #s on Q6

Scoring

Further criterion description

1

A. 24-9 and 25-19 to 25-40 B. 23-8 and 24-10 to 24-18

Count ‘1’ for each item in A where the answer associated with an ASD diagnosis is ‘no’ Count ‘1’ for each item in B where the answer associated with an ASD diagnosis is ‘yes‘ The score is the sum of scores for A and B. Criterion is met if score >= 12.

The score is the total SCQ-33 score. SCQ-33 is a version of the SCQ that excludes the language items.

2

23-8, 24-10 to 24-16, 24-18

Count 1 for each item with a response ‘yes’. Criterion is met if score >= 9.

The score is the sum of all items in the repetitive behavior domain of the SCQ

3

3-19-2, 3-19-4

Criterion is met if answer to 3-19-2 is ‘yes/now’ AND answer to 3-19-4 is ‘yes’

Identifies children whose parents report BOTH language delay AND referral to a specialist for it

4

3-23-2, 3-23-3, 3-23-4

Criterion is met if to answer to 3-23-2 is ‘yes/now’ OR answer to 3-23-3 is ‘yes’ OR answer to 3-23-4 is ‘yes’

Identifies children whose parents report autism/autistic trait OR referral to a specialist for it

5

31-4

Criterion is met if answer to 31-4 is ‘yes’

Identifies children whose parents report worry over child’s lack of interest in playing with other children

6

31-3

Criterion is met if answer to 31-3 is ‘yes’

Identifies children for whom others (family, daycare staff, well-baby nurse) have expressed concern

2.b.2. Children born in transitional study start-up period To ensure that children born in the period February 1, 2002 - June 30, 2002, with a high probability of an ASD diagnosis were not missed as the study initiated, MoBa participants born during that period were invited when scoring positive on criterion 4 or scoring positive on both criterion 3 and criterion 5. No controls were selected from this group of children. 2.b.3. Case-base sampling of controls at three years of age Potential controls are identified among MoBa-enrolled children reaching age 37 months and 2 weeks during the immediately preceding two weeks. On average, 1.63% of 37.5-month old subjects are randomly selected as potential controls in a given two-week period. From November, 2005, to February, 2007, all selected 37.5-month controls were invited to the clinical assessments. In conjunction with the modification of the screening algorithm in February, 2007, the ABC SC decided to reduce the number of 37.5-month old controls to be invited to the clinical assessments. There were two reasons: First, the assessments turned out to be more costly than expected at the start of the study. Second, the original plan (in 2003) was to establish a very large control group of about 1,000 clinically assessed children – however, the ABC SC decided that for most scientific

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purposes, a smaller control group would be sufficient, and the benefits of assessing all controls did not justify the large costs of doing so. From February 2007 to March 2010, three 37.5-month old controls per calendar week were invited to the clinical assessments. Since March 2010, the invitation of controls has been temporarily suspended in order to increase the pace of case-finding. The invitation of controls will be resumed when all potential cases from the Norwegian Patient registry and the 5/7/8-year questionnaires have been invited. From that time onwards, two 37.5-month old controls per calendar week will receive invitations. The non-invited 37.5-month controls are still considered members of the control group in the ABC sub-cohort, and their biological samples will be reserved for use by ABC study investigators. Potential controls are selected from all MoBa participants, regardless of whether Q6 has been completed or not. If a child is invited to the ABC study as a control and has not completed Q6, the parents are asked to do so prior to the clinical assessment. Consequently, there are instances in which controls screen positive after being selected and invited. 2.b.4. Subject selection process The practical procedures of subject selection and recruitment are described in Figure 2.b.5. and the corresponding steps 1-6 below: Figure 2.b.5. ABC SUBJECT SELECTION BY SCREENING AND RANDOM SAMPLING

1. On a weekly basis, the BDG mails the 36-month questionnaire (Q6) to enrolled MoBa parents

whose children reached 36 months of age in the previous week. If the Q6 is returned by the

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postal service because it is not deliverable at a given address, the BDG attempts to find the new address in the Norwegian Population Registry’s online service. The Norwegian Population Registry keeps continuously updated records of official residences for the whole Norwegian population. If a new address is found, the Q6 is re-sent to this address.

2. MoBa participants return Q6 to the BDG in a pre-addressed and pre-stamped envelope. 3. The BDG scans Q6 and enters responses into the MoBa database. Responses to the ASD

screening questions are scored according to the ABC screening algorithm. 4. Every second week, the BDG generates a list of children screening positive over the past two

weeks. Simultaneously, controls are selected as a random sample of all MoBa-enrolled children turning 37.5 months during the last two weeks. Three controls are selected to be invited to the ABC study, and these three controls are added to the list of screen-positive cases.

5. The BDG mails the ABC Invitation Letter (Appendix C1) and the ABC Invitation Brochure

(Appendix C2) to all children appearing on the bi-weekly lists. These documents explain the ABC study to parents and invite them to participate. The mailing also contains the ABC Consent Form (Appendix C3) to be signed and returned in an enclosed pre-addressed and pre-stamped envelope, if the parent chooses to participate. The invitation brochures and consent forms are identical for screen-positive children and controls. Mailings are conducted every second week following the generation of each new list of screen-positive and invited control children.

6. Every two weeks, the BDG sends the list of invited potential cases and controls to the OAG. For

each family on the list, the BDG provides the following information: mother’s name and address, mother’s national identity number, child’s ABC-specific study ID, date of invitation, whether or not a child is a screen-positive subject or a control subject, availability of MoBa blood samples (mother/father/child), and whether or not Q6 has been returned. Each list also contains updated information on subjects in previous lists sent to the OAG (e.g. subsequent receipt of Q6 and corresponding screening results, receipt of consent forms, changes in address or other contact information, mother or child death, withdrawal of mother from the MoBa cohort).

The names of potential ASD cases identified through alternative procedures (see Section 2.c.) are also added to the bi-weekly lists, including the same tracking information as for other invited participants. Lists are retired when all contacts have either been assessed or declined to participate, or children exceed 43 months of age.

2.c. ALTERNATIVE PROCEDURES FOR IDENTIFICATION OF POTENTIAL CASES 2.c.1. Self-referrals MoBa participants are informed about the ABC study (and other MoBa sub-studies) through the MoBa newsletter, which is sent to all participants once a year (Appendix C4). Information about the ABC study is also available on the NIPH website (www.fhi.no), in parallel Norwegian and English versions. The information includes an invitation for interested parents of children with suspected or diagnosed ASD to contact the ABC study for research purposes. Contact information includes the ABC-dedicated cell phone number and e-mail address. The main aim of these information efforts is to increase the identification of potential cases, but they may also promote participation of invited controls by giving all MoBa participants a deeper understanding of the purpose of the ABC study and the importance of autism research. 2.c.2. Professional referrals The Oslo Assessment Group (OAG) is working actively to obtain professional referrals to the ABC study. Newsletters are distributed to child psychiatry clinics and habilitation units (Appendix C5) and educational services (Appendix C6) at regular intervals. Information about professional referrals is also available at the NIPH website, www.fhi.no. Contact information is provided for OAG study offices, along with the ABC-dedicated cell phone number and e-mail address.

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Three seminars about autism and the ABC study have been held in Oslo, at which health professionals from across the country have taken part – one in 2006 and two in 2007. The ABC study covered travel expenses for the participants. 2.c.3. The Autism Database The Autism Database has been established by NIPH to collect data on all children diagnosed with autism spectrum disorders in the Norwegian healthcare system. The main source of data will be the Norwegian Patient Registry (NPR), which is nationwide and has collected national ID numbers and diagnoses from all parts of the Norwegian healthcare system from 2008 onwards. Data from the NPR will be linked to the MoBa cohort on a yearly basis, in order to identify potential ASD cases not identified through the regular screening procedures:

• Potential ASD cases among MoBa participants who do not return Q6 (and hence, are not screened)

• Potential ASD cases among those who never responded to the invitation to the ABC study. • Potential ASD cases among those who did not screen positive on the Q6 screening

(potential ‘false negatives’). All MoBa participants recorded with an ASD diagnosis in the NPR will be invited to the ABC clinical assessments. Participants will not be re-invited if they have previously been assessed, or previously declined to participate in the study. NIPH has also obtained the necessary legal permits to collect similar data directly from healthcare institutions, in case NPR data are delayed. 2.c.4. The MoBa 5/7/8-year questionnaires The MoBa 5-year questionnaire (Appendix A4) went into the field in January 2010, and has been sent out to all participants born in or after January 2004 (i.e. one year retroactively for the oldest recipients). The questionnaire is funded through a grant from the Norwegian Ministry of Education. The MoBa 7-year questionnaire (Appendix A5) went into the field in the winter of 2009, and the pilot went to MoBa participants born in or before June 2001. The participants born in the second half of 2001 never received any. The revised version was implemented for participants born in or after January 2002. The questionnaire is funded by the U.S. National Institute of Environmental Health Sciences (NIEHS). The MoBa 8-year questionnaire (Appendix A6) will go into the field in the summer of 2010, and will be sent out to all participants born in or after April 2001 (i.e. one year retroactively for the oldest recipients). The questionnaire is not fully funded. All three questionnaires contain two specific ASD-related questions: one asking whether the child has autistic features or autism and one asking whether the child has Asperger syndrome. Participants responding “yes” to any of these will be invited to participate in the ABC study. Participants will not be re-invited if they have previously been assessed, or have previously declined to participate in the study. The 8-year questionnaire also repeats the Social Communication Questionnaire (SCQ). The primary intention of including this is to study trajectories of ASD symptoms. Screening and invitations based upon the 8-year SCQ responses will be used as a back-up strategy in case other methods of case-finding does not bring in a sufficient number of ASD cases. 2.c.5. Cross-referrals from the ADHD study The AD/HD study is another ongoing MoBa sub-study, which is run in collaboration between NIPH and the Oslo University Hospital, Ullevål. The design is analogous to the design of the ABC study, and potential AD/HD cases are recruited based on screening for AD/HD symptoms in the 36-month questionnaire. In the event that a child is screen-positive in both studies, the child is invited to the ABC study, since the prevalence of ASD is much lower than the prevalence of AD/HD. However, if a child participates in the clinical assessment in the AD/HD study, and the assessment reveals that the

25

child has autistic traits, the family is informed about the ABC study and given the ABC invitation materials. A similar system for cross-referrals the other way, from the ABC study to the AD/HD study, has also been established. 2.c.6. Twins and triplets If an invited child is a twin or a triplet, the twins/triplets are also invited to participate in the ABC study. Twin and triplets undergo the same clinical assessment as the index participant. 2.d. RECRUITMENT AND SCHEDULING OF SUBJECTS FOR ASSESSMENTS The recruitment and scheduling procedures are coordinated by the clinical assessments coordinator. The family coordinator contacts the families and makes the practical arrangements for travel and accommodation. Recruiting and scheduling procedures differ based on the status of informed consent and the channel of recruitment. At any point in these processes, a parent has the right to refuse all participation in the ABC study. To complete the clinical assessment, a child has to be able to walk, hear and see. If that is not the case, the family is offered to participate in the telephone interview instead (Section 2.e.) 2.d.1. Invited potential participants with signed ABC consent forms Procedures for scheduling potential participants who have returned consent forms are described below in Figure 2.d.1 and the corresponding steps 1-10. Figure 2.d.1. INVITED POTENTIAL PARTICIPANTS WITH SIGNED ABC CONSENT FORMS

1. The list of potential cases and controls is sent by the BDG to the OAG, including the subset with

signed ABC consent forms; the family coordinator (FC) telephones this subset of parents to schedule the clinical assessment.

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2. The parent is contacted and an appointment for the clinical assessment is made. Information necessary for making travel arrangements is obtained from the parent. If the parent can not commit to a specific appointment time during the call, a date/time is scheduled when the parent will be available to complete this step.

3. The FC makes travel and lodging arrangements in consultation with the family. Two weeks prior

to the scheduled assessment, the FC sends the parents an appointment confirmation letter (Appendix C9), a brochure for preparing the child for the clinical assessment (Appendix C10) and three questionnaires to be completed prior to the clinical assessment: The ABC Child and Family Health History Form (Appendix B2-1/B2-2), the ABC Parent Report of Child Behavior Form (Appendix B2-3/B2-4), and the ABC Teacher Report of Child Behavior Form (Appendix B2-5/B2-6). The latter is to be completed by the child’s teacher. Enclosed is a separate consent form on which the parents consent to letting the daycare teacher provide information about the child (Appendix C13).

4. In the consent letter, parents provide contact details. If the FC can not reach the parents by

phone, repeated attempts are made to reach them by e-mail and SMS. If they are still unreachable, a reminder letter is sent to the parent (Appendix C11). If this approach also fails, the next contact must be initiated by the parent.

5. The parent reinitiates contact with the ABC study. 6. The FC schedules an assessment as per steps 2-3 above. 7. A parent is unresponsive to the contact efforts. The subject is classified as “inactive.” If

unresponsive at 43 months, the subject is classified as “non-responding”, and no further effort is made to contact the parents.

8. A parent declines participation in the ABC clinical assessment. 9. A parent declines the clinical assessment but consents to participate in the ABC telephone

interview. 10. A parent declines the clinical assessment and declines the ABC telephone interview; the subject

is classified as ‘declining’. 2.d.2. Invited potential participants without returned signed ABC consent forms Procedures for scheduling potential participants who have not yet returned ABC consent forms are described below in Figure 2.d.2. and the corresponding steps 1-8. 1. The list of BDG-invited potential cases and controls is sent to the OAG, including those who

have not yet returned consent forms. The FC telephones the parent of each child on the list, reminds the parent of the invitation and inquires as to willingness to participate in the study.

2. The parent agrees to participate in the study. The invitation letter, invitation brochure and

consent form are re-sent, and an assessment is scheduled as per Figure 2.d.1 steps 2-3. 3. A parent does not respond to the phone calls. A reminder letter is sent out when the child is 41

months of age (Appendix C11). 4. The parent responds to the reminder letter by contacting the ABC study. The invitation letter,

invitation brochure and consent form are re-sent, and an assessment is scheduled as per Figure 2.d.1 steps 2-3.

5. A parent is unresponsive to the reminder letter. The subject is classified as “inactive.” If

unresponsive at 43 months, the subject is classified as “non-responding”, and no further effort is made to contact the parents.

6. A parent declines participation in the ABC clinical assessment.

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7. A parent declines the clinical assessment but consents to participate in the ABC telephone interview.

8. A parent declines the clinical assessment and declines the ABC telephone interview; the subject

is classified as ‘declining’. Figure 2.d.2. INVITED POTENTIAL PARTICIPANTS WITHOUT RETURNED, SIGNED ABC CONSENT FORMS

2.d.3. Potential participants identified through self-referrals Procedures for scheduling self-referrals are described below in Figure 2.d.3. and the corresponding steps 1-3. 1. A parent contacts the family coordinator by phone or e-mail, using the contact details given in

MoBa newsletters or other ABC recruitment materials. The FC records the name and national ID number of the child and the child’s mother, and conducts a short interview to determine whether there is substantial reason to suspect the child of having ASD (Appendix C12).

2. The FC consults with the BDG to determine whether the child is a MoBa participant and eligible

for the ABC study. If eligibility is confirmed, and there is substantial reason to suspect the child of having ASD, the BDG enrolls the family as a potential case in the ABC tracking database, and the clinical assessment is scheduled as per Figure 2.d.1 steps 2-3.

1. If the child is ineligible, the parent is informed and contact is terminated.

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Figure 2.d.3. ABC SELF-REFERRALS

2.d.4. Potential participants identified through professional referrals Procedures for scheduling professional referrals are described below in Figure 2.d.4. and the corresponding steps 1-5. 1. A health or educational professional identifies a child diagnosed with ASD or suspected to have

ASD, and discusses the ABC study with the parent. If the parent expresses interest and the child is a MoBa participant, the professional contacts the OAG about the child on a “no names” basis. The professional obtains parental permission for study representatives to establish direct contact with the family.

2. The FC contacts parents to discuss participation. If the parent declines to participate in the ABC

study, contact is terminated. 3. If the parent is interested in participating, the FC determines whether the child is a MoBa

participant with the BDG. 4. If the child is not a MoBa participant, the parent is informed and contact is terminated. 5. If the child is a MoBa participant, the family is enrolled in the ABC tracking database, and the

clinical assessment is scheduled as per Figure 2.d.1 steps 2-3.

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Figure 2.d.4. PROFESSIONAL REFERRALS

2.d.5. Potential participants identified through the Autism Database Procedures for scheduling potential ASD cases identified through the Autism Database are described below in Figure 2.d.5. and the corresponding steps 1-8. 1. A MoBa participant with a diagnosis of ASD is identified through the Autism Database. 2. Former invitation status is checked with the BDG. If the participant has previously been

assessed, or has previously declined to participate in the ABC study, the participant is not re-invited.

3. If the participant has not previously been assessed, or not previously declined to participate in

the ABC study, the ABC Invitation Letter (Appendix C1), the ABC Invitation Brochure (Appendix C2) and the ABC Consent Form (Appendix C3) is mailed to the parents by the BDG.

4. The parent agrees to participate, and returns the consent form to the BDG. The child is enrolled

in the ABC tracking database, and the clinical assessment is scheduled as per Figure 2.d.1 steps 2-3.

5. A parent is unresponsive. The FC makes a reminder call to the family. 6. If the parent agrees to participation and returns the signed consent form, the clinical

assessment is scheduled as per Figure 2.d.1 steps 2-3. 7. If the parent is still unresponsive, the subject is classified as ‘non-responding’, and followed up

with a reminder letter that is similar to the ABC 41-Month Reminder Letter (Appendix C11), except that the age reference is removed. See Figure 2.d.2 steps 3-5.

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8. The contacted parent declines to participate in the clinical assessment. An offer is made to participate in the ABC telephone interview, as per Figure 2.d.1 steps 9-10.

Figure 2.d.5. PARTICIPANTS IDENTIFIED THROUGH THE AUTISM DATABASE

2.d.6. Potential participants identified through the MoBa 5/7/8-year questionnaires Every other week, the BDG generates a list of MoBa participants responding “yes” to the questions about autistic features/autism or Asperger syndrome in the 5/7/8-year questionnaires over the past two weeks. These potential cases are invited to participate in the ABC study. The recruitment procedures are similar to the procedures for three-year-olds, as described in Section 2.b.4. The invitation materials are the same, except that the age references have been changed. 2.d.7. Potential participants identified through cross-referrals from the ADHD study When a participant in the AD/HD study has been invited to participate in the ABC study (as explained in Section 2.c.5.), the family has to make contact with the ABC family coordinator. If the family volunteers to participate, the scheduling of the clinical assessment proceeds as per Figure 2.d.1. If the family does not contact the ABC FC, no further follow-up is conducted. 2.e. TELEPHONE INTERVIEWS From 2005 to June 2010, parents who declined to participate in clinical assessments were asked to participate in a telephone interview instead (Appendix B2-11). The interview lasted for about 20 minutes, and contained a few selected questions about development, language and autism. The interview was not diagnostic; the purpose was only to determine whether the child had been diagnosed with ASD in the regular healthcare system. It is expected that an ADI-R adapted for phone interviews will be available in the fall of 2010. At that time, this will replace the current ABC phone interview. From June 2010 onwards, participants

31

consenting to phone interviews will be put on hold while awaiting the implementation of the phone ADI-R. 2.f. TRAVEL ARRANGEMENTS Travel and lodging are arranged by the ABC family coordinator and paid for directly with funds allocated to this purpose from the ABC study budget. Lodging: Families stay at lodging provided by the Lovisenberg Hospital or at hotels offering reduced rates to hospital patients. If the family wants to make other lodging arrangements, they can be reimbursed for their actual expenses up to the limit of lodging at ABC sites. Families are not reimbursed for ancillary items such as bar charges, babysitting in Oslo, spa services, or telephone calls (unless related to the ABC study). Food: Families are reimbursed for dinners during their stay in Oslo, within bounds established by NIPH. Breakfast is included in the stay at the lodging site, and lunch is provided at the clinical assessment site. Transportation: Travel by private car or public conveyance is supported by the ABC study within bounds established by NIPH. Plane tickets are booked and paid for by the ABC family coordinator directly. Childcare: If parents do not have childcare for siblings, and that is an obstacle to participation, the ABC study offers to pay for childcare for siblings staying at home, within bounds established by NIPH. Loss of salary: If parents lose salary due to participation, and that is an obstacle to participation, the ABC study offers to compensate for the loss of salary, within bounds established by NIPH. Reimbursement: At the end of the clinical assessment, parents are given a reimbursement form and a pre-stamped envelope addressed to the FC. The FC reviews receipts and makes a recommendation to the NIPH accountant. Reimbursements are given by wire transfer. 2.g. WITHDRAWAL FROM THE ABC STUDY ABC study participants may withdraw from the study at any time. If requested, data and blood specimens are destroyed. It is not necessary for a participant to state reasons for withdrawal.

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SECTION 3. THE ABC CLINICAL ASSESSMENT 3.a. OVERVIEW The goals of the clinical assessment are to:

1. Ascertain cases of ASD through research-standard autism-specific diagnostic instruments. 2. Describe specific clinical features of ASD and differentiate between clinical subtypes within

the autism spectrum. 3. Determine whether assessed children have psychiatric or neurodevelopmental disorders

other than, or in addition to, ASD. 4. Develop comprehensive neuropsychological profiles of assessed children by testing

cognitive function, verbal and non-verbal communication, and gross motor and fine motor skills.

5. Describe sub-diagnostic difficulties or abnormalities in assessed children. The following standardized instruments are included: Children age 3-5

1. Autism Diagnostic Interview, Revised (ADI-R) 2. Autism Diagnostic Observation Schedule (ADOS) 3. Stanford-Binet Intelligence Scales, 5th ed. (SB5) 4. Items from the Mullen Scales of Early Learning (Mullen) – gross and fine motor. Full Mullen

if child is too low-functioning for SB5. 5. Vineland Adaptive Behavior Scales (Vineland) – Communication Domain only

Children age 6 and older

1. Autism Diagnostic Interview, Revised (ADI-R) 2. Autism Diagnostic Observation Schedule (ADOS) 3. Wechsler Abbreviated Scale of Intelligence (WASI) 4. Stanford-Binet Intelligence Scales, 5th ed. (SB5) if child is too low-functioning for WASI. 5. Vineland Adaptive Behavior Scales (Vineland) – Communication Domain only

Over the course of the study, the following instruments have also been used.

1. Preschool Age Psychiatric Assessment (PAPA) (2005-08) 2. Items from the NEPSY Language subtests (2009-10) 3. The Boston Naming Test (BNT) (2009-10) 4. The Bailey Pegboard Test (BPT) (2005-08) 5. The Grooved Pegboard Test (GPT) (2009-10)

Throughout the study, the assessment has also included a physical examination, a blood draw and a parent interview reviewing the child’s medical and developmental history. The interview includes a parent-child interaction task based on the Emotional Availability Scales (EAS). All parts of the assessment are videotaped to permit later review for quality control ratings and second-opinion evaluations. Section 3.d. describes the purpose and content of each instrument. The details of training, translations and other quality control measures are provided in Section 5. 3.b. ASSESSMENT SCHEDULE The daily assessment schedule is outlined in Table 3.b. There is a capacity to assess six children per week. The schedule is identical for potential cases and controls. Families living more than one hour of travel distance away from Oslo usually arrive in the city the night before the assessment, whereas families living in Oslo, or close to Oslo, arrive in the morning. Upon arrival at the clinical assessment site in the morning, the families are greeted by the clinic secretary. From 8.30 – 9 am, the secretary has an introductory session with the parents in which the following is included:

1. Consent form review: If the ABC Consent Form (Appendix C3) has not been returned to the BDG, the form is completed and signed by the parents. The clinical assessment does not proceed until the informed consent process is complete.

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2. MoBa Q6 review: If the child is < 5 years old and the MoBa 36-month questionnaire (Appendix A2) has not been completed and returned to the BDG previously, it is collected and reviewed for completeness. If the child is >= 5 years and has no completed 36-month questionnaire, the SCQ is completed at the assessment, prior to the ADI-R interview.

3. Collection of the ABC Child and Family Health History Form (Appendix B2-1) and the ABC Parent Report of Child Behavior Form (Appendix B2-2); review for completeness.

4. Review of assessment schedule with parents. 5. Anthropometric measurements. 6. Photographic recordings.

For children age 3-5, a parent is always present during testing. For children age 6+, parent interviews are conducted in parallel with the testing if the child is comfortable being tested alone. Table 3.b. DAILY CLINICAL ASSESSMENT SCHEDULE

CHILDREN AGE 3-5 CHILDREN AGE 6+

Time Child 1 Child 2 Child 1 Child 2

08:30 Measures, photo, introduction

Measures, photo, introduction



09:00

09:30 SB5, Mullen SB5, Mullen WASI WASI

10:00

10:30 ADOS ADOS ADOS ADOS

11:00 Physical exam ADI-R Physical exam ADI-R

11:30 Lunch Lunch Lunch Lunch

Noon Blood draw Blood draw Blood draw Blood draw

12:30

13.00

ADI-R, cont. ADI-R, cont.

VABS-CD VABS-CD 13:30

ADI-R ADI-R

VABS-CD Physical exam

VABS-CD Physical exam

14:00

14:30

Diagnostic interview, EAS




15:00 Staff conference Staff conference Staff conference Staff conference

15:30 Feedback to parents Feedback to parents Feedback to parents Feedback to parents

Key: Measures, anthropometric measurements; Photo, photographic recordings; SB5, Stanford-Binet Intelligence Scales, 5th edition; Mullen, Mullen Scales of Early Learning; WASI, Wechsler Abbreviated Scale of Intelligence; ADOS, Autism Diagnostic Observation Schedule; ADI-R, Autism Diagnostic Interview, Revised; VABS CD, Vineland Adaptive Behavior Scales, Communication Domain; EAS, Emotional Availability Scale

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3.c. ASSESSMENT STAFF The assessment team is made up of one child psychiatrist, two psychologists (one for each child) and two research assistants (one for each child). An additional research assistant is present to administer the videotaping. The team members have the following responsibilities: Child psychiatrist:

• Review of the ABC Child and Family Health History Form (Appendix B2-1/B2-2) • Physical examination • Diagnostic interview and diagnostic conclusion (for child 1) • Leading staff conference and feedback to parents (for child 1)

Psychologist:

• Administration of psychometric instruments (ADOS, SB5, WASI, Mullen) • Review of the ABC Parent Report of Child Behavior Form (Appendix B2-3/B2-4) and the

ABC Teacher Report of Child Behavior Form (Appendix B2-5/B2-6) • Diagnostic interview and diagnostic conclusion (for child 2). Only specialists in clinical

psychology are allowed to have diagnostic responsibility. • Leading staff conference and feedback to parents (for child 2)

Research assistant:

• Administration of clinical interviews with parents (ADI-R, VABS CD) • Scoring of instruments included in the ABC Parent Report of Child Behavior Form (Appendix

B2-3/B2-4) and the ABC Teacher Report of Child Behavior Form (Appendix B2-5/B2-6) • Participation at staff conference • From 2005-2008, the research assistant was also responsible for conducting the PAPA

interview. 3.d. DESCRIPTION OF STANDARDIZED INSTRUMENTS Table 3.d. STANDARDIZED INSTRUMENTS IN THE ABC STUDY

INSTRUMENT

ADMINISTRATION TIME

SCORING PROCEDURE

LICENSE HOLDER

ADI-R

90 minutes

Manual scoring: ADI-R algorithm

International: Western Psychological Services Scandinavia: Dansk Psykologisk forlag

ADOS

40 minutes

Manual scoring: ADOS algorithm

International: Western Psychological Services Scandinavia: Dansk Psykologisk forlag

SB5

Full version: 120 minutes Short version: 40 minutes

Software scoring: Riverside Publishing test and scoring program, American norms

International, incl. Scandinavia: Riverside Publishing

WASI 45 minutes Manual scoring, Norwegian version, American norms

International, including Scandinavia: Pearson Assessment

Mullen

Full version: 60 minutes Short version: 20 minutes

Software scoring: American Guidance Services test and scoring program, American norms

International, incl. Scandinavia: American Guidance Services Inc.

Vineland

Full version: 40 minutes Communication Subdomain: 10 minutes

Software scoring: American Guidance Services test and scoring program, American norms

International, incl. Scandinavia: American Guidance Services Inc.

PAPA (version 3)

90 minutes

Manual scoring, algorithm derived from DSM-IV-TR criteria

International, incl. Scandinavia: Egger & Angold, Duke University, NC, USA

NEPSY Language 15 minutes, with BNT

Manual scoring, Swedish norms

International, incl. Scandinavia: Pearson Assessment

BNT 15 minutes, with NEPSY

Manual scoring, Swedish and study-specific norms

International, incl. Scandinavia: Hogräfe

GPT 10 minutes Manual scoring, Canadian and study-specific norms

International, incl. Scandinavia: Lafayette Instrument

BPT 10 minutes Manual scoring, American and study-specific norms

International, incl. Scandinavia: John Wiley

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3.d.1. The Autism Diagnostic Interview – Revised (ADI-R) (Appendix B1-1) The ADI-R (Lord et al. 1994) is a semi-structured, standardized diagnostic interview for the assessment of autism and autistic spectrum disorders in children and adults. The interview has been in use since the mid-1990s. It is administered to parents or caregivers, and can be used for subjects who are 18 months or older. The interview includes questions relevant to current functioning, and for older children, functioning when the child was 4-5 years old, and ascertains probable onset of abnormalities in development. Responses are scored by the interviewer on 93 items. Separate scores are generated in the domains of

• Reciprocal social interaction (e.g. emotional sharing, offering and seeking comfort, and responding to others)

• Communication (e.g. pronoun reversal and stereotyped sounds) • Restricted, repetitive and stereotyped behaviors (e.g. unusual preoccupations, hand and

finger movements, and unusual sensory movements) Elevated scores indicate problem areas. A diagnostic algorithm has been established that links subscale scores to ICD-10 and DSM-IV criteria for Autistic Disorder. The results of the assessment can also aid the clinician in differentiating Autistic Disorder from other autism spectrum disorders, but there is no established scoring algorithm for other diagnoses. The cut-off levels in each domain for a diagnosis of Autistic Disorder are:

• Reciprocal social interaction: 10 • Communication: 8 for verbal children and 7 for non-verbal children • Restricted, repetitive and stereotyped behaviors: 3

To achieve an overall conclusion of Autistic Disorder, the child must score above cut-off level in each of the three domains and exhibit some abnormality in at least one area by age 36 months. The original study validated the questionnaire in a sample of 200 individuals ranging from 4 years to 44 years, all with neurodevelopmental disorders. 148 had an ASD, and had already been diagnosed. It is not well known how the psychometric properties of the ADI will be influenced when used in a population of “naïve” parents who do not necessarily know about autism and do not expect such a diagnosis in their own child. One could expect under-reporting, both from the perspective of children being younger than in the validation sample, as well as parents’ lack of knowledge about key features of ASD and therefore not recognizing the particular behavioral features asked for in the interview. Lowering the cut-off for being screen-positive will counteract the effect of under-reporting, though it remains to be seen what the implications may be in terms of number of false positives. Several studies (Rutter et al 2003) have evaluated inter-rater reliability on domain scores, using children with clinician-diagnosed, documented autism and mentally handicapped age-matched controls. Weighted kappa’s for each item range from .70 to .95. Intra-class correlation coefficients for domain scores approximate .90. Internal consistency, estimated by coefficient alpha, is .70 for restricted and repetitive behaviors, .80 for communication and .95 for reciprocal social interaction. Validity of the ADI-R, as assessed by discrimination between known autistic children and children with other developmental delays, is excellent. From the start of the study in November 2005 until September 2008, the ADI-R was only administered to screen-positive and referred potential cases; not to controls. From September 2008 onwards, the ADI-R is administered to all participants, and the assessment staff is blind as to how the child was invited into the study. References:

• Lord C, Rutter M, Le Couteur A. Autism Diagnostic Interview – Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord 1994: 24(5); 659-85.

• Rutter M et al (2003) Autism Diagnostic Interview-Revised, Manual. Western Psychological Services Los Angeles CA

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3.d.2. The Autism Diagnostic Observation Schedule (ADOS) (Appendix B1-2) The ADOS (Lord et al. 2000) is a semi-structured assessment of communication, social interaction, and play or imaginative use of materials, designed for individuals suspected of having autism or other pervasive developmental disorders. The assessment has been in use since the mid-1990s, and is applicable for subjects from 18 months to adulthood. It requires an administrator that has completed graduate training and has experience in clinical infant assessment. The assessment has four modules, and each individual is tested using one module, depending on chronological age and expressive language level. Guidance provided in the manual informs the selection of the appropriate module for the subject. Module 1 is intended for individuals who do not consistently use phrase speech. Module 2 is intended for individuals who have some phrase speech but are not verbally fluent. Module 3 is used for children who are verbally fluent. Module 4 is used for verbally fluent adolescents and adults. The test consists of standardized, structured and unstructured activities that allow the examiner to observe the occurrence or non-occurrence of behaviors identified as important to the diagnosis of autism and other pervasive developmental disorders. These activities are designed to offer the child an opportunity to exhibit social, communicative, and other behaviors of interest. Behaviors are recorded, and an overall rating is made at the end of the module for diagnostic purposes. The initial validation sample for the ADOS consisted of 381 consecutive referrals to the Developmental Disorders Clinic at the University of Chicago in addition to referrals to other research centers. Inter-rater reliability was high for Module 1 items. Mean exact agreement for all items was 91.5% (all items had more than 80% exact agreement across raters). All Kappas exceeded .60 except for items describing repetitive behaviors. Inter-rater reliability for Modules 2 and 3 was similar, indicating that the scoring categories were adequately operationalized. Internal consistency was assessed using all three domains. Cronbach’s alpha was consistently highest for the social domain (.86-.91 for each module), slightly lower for Communication (.74- .84) and lowest for the Stereotyped Behavior and Restricted Interests (.63-.65 for Modules 1 and 2; .47-.56 for Module 3), although still indicating good agreement. Items in each domain seem to load on individual factors necessary for defining discriminative feature of ASD. The ADOS-G algorithm yielded the expected classification for individuals pooled across modules, for nearly 95% of those with autism and 92% of those outside the spectrum, but only categorized 33% of the PDD-nos as having non-autism PDD (53% of these falling in the range of autism). Separate scoring algorithms for the different ADOS modules have been generated. Generally, the criteria for Autistic Disorder require reaching cut-off on both the Social domain as well as the Communication domain; in addition, the sum of both Social and Communication has to reach a separate cut-off. Adequate inter-rater reliability for items has been established. However, only small samples have been examined; thus, replication will be important. A study based on psychometric data for a limited sample (n=223) of disabled children and adults with and without ASD reported substantial inter-rater and test-retest reliability for individual ADOS items, and excellent inter-rater reliability with regards to ADOS domains and internal consistency (Lord et al. 2000). Mean test scores were found to consistently differentiate between ASD and non-ASD subjects. The ADOS (in combination with the ADI-R) has been demonstrated to be useful in the differential diagnosis of children with high-functioning autism from those with a receptive language disorder (Noterdaeme et al. 2002). However, the ADOS was less consistently able to differentiate between the ASDs (Klinger & Renner 2000). References

• Lord C, Risi S, Lambrecht L et al. The Autism Diagnostic Observation Schedule–Generic: A Standard Measure of Social and Communication Deficits Associated with the Spectrum of Autism. J Autism Dev Disord 2000: 30; 205-23.

• Noterdaeme M, Mildenberger K, Sitter S, Amorosa H. Parent information and direct observation in the diagnosis of pervasive and specific developmental disorders. Autism 2002; 6(2):159-68.

• Klinger LG, Renner P. Performance-based measures in autism: implications for diagnosis, early detection, and identification of cognitive profiles. J Clin Child Psychol 2000; 29(4): 479-92.

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3.d.3. The Stanford Binet Intelligence Scale, 5th Edition (SB5) (Appendix B1-3) The Stanford-Binet Intelligence Scales 5th Edition (SB5) (Roid 2003) is a standardized, widely used test of intelligence and cognition for use in children and adults, originally developed in 1908. It covers five cognitive areas: knowledge, fluid reasoning, visual-spatial processing, quantitative reasoning, and working memory. The SB5 is used as a tool for school placement, for determining the presence of developmental delays, and for tracking development. It is standardized for use from ages 2 to 85 years. However, caution must be used when screening very young children for developmental delays. The test requires an administrator that has completed graduate training in psychology and has experience in clinical child assessment. According to the SB5 manual, the time required is 45-90 minutes, but the total testing time varies greatly, depending on the subject’s developmental level and ability to cooperate. In the ABC clinical assessment, where most participants are between 36.5 and 43 months old, the full test requires 120 minutes on average. Although measuring intelligence at young ages is problematic, valid estimates of intelligence can be made reliably at 30 months of age using the Stanford-Binet, 4th edition (SB4). Scores on the SB4 correlate with those of the Peabody Picture Vocabulary Test – Revised and the Wechsler Intelligence Scale for Children – Revised (WISC-R), and are sensitive to change over time. More recent data for SB5 indicate a similar pattern of results, though additional follow up studies will be required to address the challenges of assessing milder levels of cognitive difficulty in preschool age children. It is anticipated that less severe degrees of mental retardation are not likely to be detected at this early age with any existing instrument. Raw scores are based on the number of items answered, and are converted into a standardized score corresponding to age group. A composite (total) score is obtained, similar to the Full Scale IQ of the WISC, along with scores on specific subtests. The test has a mean of 100 and a standard deviation of 15; subtests have a mean of 10 and a standard deviation of 3. Reliability of administration (internal consistency) has been reported to range from .95 to .98 for the total, verbal, and nonverbal scores across all ages. Reliabilities for individual subtests range from .84 to .89. From 2005-2008, and from June 2010 onwards, the full version of the SB5 is administered. From January 2009 to July 2010, only the following subscales were included:

• Nonverbal Fluid Reasoning (nonverbal routing) • Verbal Knowledge (verbal routing) • Verbal Fluid Reasoning • Verbal Working Memory • Non-verbal Working Memory

With this shortened version, only verbal IQ can be calculated, whereas total IQ and nonverbal IQ can not be calculated. However, an estimate of total IQ (Abbreviated Battery IQ, ABIQ) can be derived from the nonverbal and verbal routing subscales. Reference

• Roid GH. Stanford-Binet Intelligence Scales (5th ed.). Itasca, IL: Riverside Publishing; 2003. 3.d.4. The Wechsler Abbreviated Scale of Intelligence (WASI) (Appendix B1-8) The WASI was designed to be a brief test of intelligence for both children and adults and was published in 1999. It is based on the widely used Wechsler tests of intelligence (WPPSI, WISC and WAIS). The WASI test is individually administered and designed for use with individuals from age 6 to age 89. The WASI is standardized in the United States, but was recently published in an official Norwegian version by Harcourt Assessment (now Pearson Assessment 2007). WASI consists of four subtests, two from the Verbal Domain (Vocabulary and Similarities) and two from the Performance Domain (Block Design and Matrix Reasoning). The test yields the three traditional Verbal, Perfomance and Full Scale IQ scores and can be viewed as parallel versions to the same subtests in the WAIS-III (for adults) and WISC-III (for children 6-16). The complete test can be administered in about 30 minutes.

38

The limitations of the WASI is that it sacrifices some degree of clinical accuracy for the conservation of time. It is however a standardized test that provides a quick estimate of cognitive functioning. International reported results indicates that it gives a reliable and valid estimate of IQ, but the Norwegian researchers who developed the Norwegian version cautions that the terms Verbal IQ and Performance IQ should be replaced by the index names Verbal Understanding and Perceptual Organization. References

• WASI – Wechsler Abbreviated Scale of Intelligence. Manual.Toronto, Canada: PsychCorp (Harcourt Assessment/Pearson Assessment); 1999.

• WASI – Norsk versjon. Manualsupplement. (Norwegian version. Manual supplement). Oslo, Norway: Harcourt Assessment/Pearson Assessment; 2007.

3.d.5. The Mullen Scales of Early Learning (Appendix B1-4) The Mullen Scales of Early Learning (Mullen 1995) provides a comprehensive measure of a child’s motor, perceptual and language abilities. It tests the domains of gross motor skills, receptive and expressive language skills, visual-perceptual skills, and visual-motor skills (including fine motor capacities). It is used to help determine the need for special services and to assess learning styles, strengths and weaknesses. The test requires an administrator that has completed graduate training in psychology and has experience in clinical infant assessment. The Mullen Scales were first developed as a measure of early development. The Preschool version was an upward extension of the Infant Mullen Scales. The AGS edition combines the two earlier versions into a single test with continuous norms for children from birth through 68 months. However, the gross motor domain is appropriate only for ages birth to 33 months. Gross motor skills tests include standing, walking and running. Fine motor skills tests include stacking blocks, drawing and stringing beads. For each scale, a percentile rank is available by age. The normative group is a census sample. The reported test-retest reliability of the Mullen ranges from .71-.79, and the inter-rater reliability ranges from .98-.99 across the Mullen subscales. Procedure for combining the SB5 and Mullen To assess the child with a minimum of overlap between the Mullen and the SB5, testing proceeds as follows: 1. First, the SB5 nonverbal routing task is administered. If the child receives a score of < 4- (i.e.

indicating a mental age < 2 years according to the SB5 manual), the remaining SB5 nonverbal domains are discontinued.

2. Second, the SB5 verbal routing task is administered. If the child receives a score of < 4 (i.e. indicating a mental age below < 2 years according to the SB5 manual), the SB5 verbal domains are discontinued.

3. For children discontinuing the SB5 due to scores below the SB5 nonverbal routing item cut-off, the nonverbal mental level is further evaluated with the Mullen Visual Receptive and Fine Motor subscales.

4. For children discontinuing the SB5 due to scores below the SB5 verbal routing item cutoff, the verbal mental level is further evaluated with the Mullen Expressive Language and Receptive Language subscales.

5. For children with scores above the cutoff on either the SB5 nonverbal or the SB5 verbal routing items, the mental level / IQ will be based solely on the scores on the SB5.

6. All children were until January 2009 administered both the Fine Motor and Gross Motor subscales of the Mullen.

From January 2009 onwards, the full Gross Motor subscale is replaced by a shortened gross motor assessment in which six gross motor tasks from the Mullen are administered as part of the physical examination. The scorings integrate 10 different items from the Mullen gross motor area representing different levels of competence. Abbreviated gross motor assessment

1. Walk up stairs – scoring covers Mullen items 20 and 25

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2. Walk down stairs – scoring covers Mullen item 30 3. Jump down from bench – scoring covers Mullen item 26 4. Get to stand/forward to sit – scoring covers Mullen items 18 and 31 5. Walk on line – scoring covers Mullen items 24, 29, and 35 6. Hop two times on one foot – scoring covers Mullen item 34

From August 2010 onwards, the full Fine Motor subscale is replaced by a shortened fine motor assessment in which five fine motor tasks from the Mullen are administered. The scorings integrate items from the Mullen fine motor area representing different levels of competence. Abbreviated fine motor assessment

1. Stack blocks vertically – scoring covers Mullen item FM17 2. String beads – scoring covers Mullen item FM20 3. Cut with scissors – scoring covers Mullen item FM24 4. Copy shapes and letters – scoring covers Mullen item FM26 5. Touch fingers – scoring covers Mullen item FM28

Reference

• Mullen EM. Mullen Scales of Early Learning AGS Edition. Circle Pines, MN: American Guidance Service; 1995.

3.d.6. The Vineland Adaptive Behavior Scales (Appendix B1-5) The Vineland Adaptive Behavior Scales provide assessment for a wide range of developmental disabilities, including mental retardation, developmental delays, functional skills impairment, and speech/language impairment. The assessment focuses on skills of daily living, as reported by the parent. The Vineland can be used throughout the life span. The assessment covers the following domains:

• Communication (receptive, expressive, written) • Daily living skills (personal, domestic, community) • Socialization (interpersonal relationships, play and leisure time, coping skills) • Motor skills (gross, fine)

The overall composite score (the adaptive behavior composite score) and the scores for each domain all have a mean of 100 and a standard deviation of 15. The scales have been normed primarily in populations of adults with various degrees of mental retardation, but it is used extensively in children as well. Internal consistency for the adaptive behavior composite score ranges from .94 to .98; for the domain scores it ranges from .80 to .95. Test-retest reliability for the adaptive behavior composite is .88 and for the domains ranges from .81 to .86. Finally, inter-rater reliability for the adaptive behavior composite is .74 and for the domains ranges from .62 to .78. To minimize repetition across interviews, the Vineland is scored, whenever possible, on the basis of information acquired through the ADI-R. Prior to 2009, it was also scored based on information from the PAPA. From 2005-2008, the full version of the Vineland was administered. From 2009 onwards, only the Communication Domain has been included. Reference

• Sparrow S, Balla D, Cicchetti D. Vineland Adaptive Behavior Scales. Circle Pines, MN: American Guidance Services; 1984.

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3.d.7. The Preschool Age Psychiatric Assessment (PAPA) (Appendix B1-7) The PAPA interview (Egger et al 2006) was part of the ABC clinical assessment from 2005-2008. It is a structured interview with the purpose of identifying problem areas or, where relevant, diagnosing psychiatric disorders in children aged 2 to 5 years. PAPA-derived diagnoses are consistent with diagnoses in the DSM-IV and Diagnostic Classification 0-3 diagnostic systems, as well as with other behaviors and symptoms that do not appear in these diagnostic classification schemes. However, the PAPA does not provide diagnostic classifications for specific autism spectrum disorders; rather, it informs the clinician whether more detailed testing is needed to establish these diagnoses (e.g., ADOS, ADI-R). When used in the ABC study, the interview was substantially shortened from its original form, to accommodate the diagnostic focus of the study and limit the duration of the interview to 90 minutes. The editing was conducted in close collaboration with Edward Potts at Duke University, the senior trainer working with the research group that developed PAPA (Egger, Ascher & Angold). The PAPA sections administered are noted in bold. Sections where only selected items were included are identified with an asterisk:

• Introduction • Brief developmental assessment • Family structure and function • Daycare/school experiences and behaviors • Play and peer relationships • Depression* (9 minor depression items only) • Hypomania and mania • Oppositional defiant disorder/conduct problems • Attention deficit hyperactivity disorder • Tics and trichotillomania • Stereotypies and unusual speech* (selected items only) • Regulation/habits • Eating and other food-related behaviors • Somatization • Elimination behaviors • Separation anxiety • Sleep behaviors • Anxious affect • Worries • Compulsions • Psychosis • Reactive Attachment Disorder • Life events* (presence/absence of specific events only) • Post-traumatic Stress Disorder: A events • Post-traumatic Stress Disorder: B events* (9 items if severe traumatic events of event

type B) • Incapacity • Child and Adolescent Impact Assessment (CAIA) • Socioeconomic factors • Thank you/ending the interview

Interviewers ask a series of mandatory probe questions for each section. The answers to these probe questions inform the interviewer as to whether to proceed with the section. These may be supplemented by discretionary probe questions when the information gathered through the initial probe questions is deemed by the interviewer to be inadequate to render a decision as to whether or not to proceed. Most data in the PAPA are obtained for the three-month period preceding the interview. However, as in the “Life Events” section, several queries are also made for lifetime symptoms. References

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• Egger HL, Erkanli A, Keeler G, Potts E, Walter BK, Angold A. Test-Retest Reliability of the Preschool Age Psychiatric Assessment (PAPA). J Am Acad Child Adolesc Psychiatry 2006; 45(5): 538-49.

3.d.8. The NEPSY Language subtests (Appendix B1-8) Items from the NEPSY Language subtests were part of the ABC clinical assessment from 2009-10. NEPSY, a Developmental Neuropsychological Assessment (Korkman 2000) is the Swedish version of the neuropsychological assessment instrument published by Korkman, Kirk, and Kemp in the United States (1998). It consists of five domains and 27 subtests designed specifically for children from 3 to 12 years of age. The five domains are Attention/Executive Functions, Language, Sensorimotor, Visuospatial, and Memory and Learning. NEPSY is built on the framework of Luria’s clinical methods as well as child neuropsychological traditions. The test has been standardized on 500 Swedish children and these norms are presently used throughout Scandinavia. The authorized translated version of the NEPSY in Norwegian is distributed by Pearson Assessment. The two NEPSY subtests used in the ABC-study were Phonological Processing and Comprehension of Instructions. Reliability testing employed a split-half method with age held constant in the form of a partial correlation coefficient. The reliability for the two NEPSY language tests for the age group 3:0-4:11 is .84 and .82 respectively. Reference

• Korkman M. NEPSY Handbok. Sweden: Psykologiförlaget AB; 2000. (Swedish standardization.) 3.d.9. The Boston Naming Test (BNT) (Appendix B1-9) The Boston Naming Test (Kaplan et al. 1983) was part of the ABC clinical assessment from 2009-10. The test is used worldwide for examination of word retrieval in children and adults from age 5-79 years. It consists of 60 black and white line drawings of objects presented in increasing order of difficulty. Brusewitz & Tallberg (2009) underline the importance of having specific norms for different languages and report norms for the first study to collect normative data for Swedish-speaking children from kindergarten age to grade 9. The results found mean scores to be somewhat lower than in North American studies. References

• Kaplan E, Goodglass H, Weintraub S. The Boston Naming Test (2nd ed). Philadelphia: Lea & Febiger; 1983.

• Brusewitz K, Tallberg IM. The Boston Naming Test and Swedish children: Normative data and response analysis. Eur J Dev Psychol 2009.

3.d.10. The Bayley Pegboard Test (BPT) (Appendix B1-10) The Bayley Pegboard test was part of the ABC clinical assessment from 2005-08. It is part of the motor development scale of the Bayley Scales of Infant Development II (BSID-II), and measures motor dexterity. The BSID-II is a more recent version of the Gesell scales, which were originally developed in 1933. Reference

• Black MM, Matula K. Essentials of Bayley Scales of Infant Development II Assessment. New York, NY: John Wiley; 1999.

3.d.11. The Grooved Pegboard Test (Appendix B1-11) The Grooved Pegboard is a manipulative dexterity test that was part of the ABC clinical assessment from 2009-10. The test unit consists of 25 holes with randomly positioned slots. Pegs, which have a key along one side, must be rotated to match the hole before the peg can be inserted in the hole. This test requires more complex visual-motor coordination than most pegboards. The “kiddie-version” for children aged 5 years 0 months to 8 years 12 months consists of only the two first rows of the Pegboard, totaling 10 pegs. For children under the age of 5, the ABC study used only one row of the Pegboard with a total of 5 pegs. Particular care was taken to point out the correct direction as well as the correct sequential order. Information was recorded for the length of time, in seconds, the child uses to place the pegs, the number of times the pegs are dropped, the number of pegs placed correctly, as well as the number of times the child uses two hands to manipulate the pegs. The task was performed first with the dominant hand, then by the non-dominant hand. The

42

User Manual contains age curve data for the Neuropsychological Test Manual developed by Dr. Ronald Trites, Royal Ottawa Hospital, Ottawa, Ontario, Canada. Study-specific norms for the ABC study will be created in collaboration with the ADHD study. Reference

• Grooved Pegboard Test User Instructions. Indiana, USA: Lafayette Instrument; 2002. 3.e. CLINICIAN HISTORY-TAKING The history-taking is based on three questionnaires completed prior to the assessment: the ABC Child and Family Health History Form (Appendix B2-1/B2-2), the ABC Parent Report of Child Behavior Form (Appendix B2-3/B2-4) and the ABC Teacher Report of Child Behavior Form (Appendix B2-5/B2-6). 3.e.1. The ABC Child and Family Health History Form (Appendix B2-1 for children age 3-5, Appendix B2-2 for children age 6 and older) On this form, parents provide detailed information about the child’s medical history and family medical history. Sections on the following topics are included:

• Medically relevant information about pregnancy, birth and neonatal care • Early child development • Medical examinations and hospital admissions • Medical diagnoses assigned to the child • Gastrointestinal disturbances • Autoimmune diseases in the child’s family • Psychiatric and neurodevelopmental disorders in the child’s family

The form includes the Gastrointestinal (GI) Problems Severity Rating Scale (GIPSI), which has been developed by the Center for Infection and Immunity (Mailman School of Public Health, Columbia University) in conjunction with the Collaborative Program of Excellence in Autism (CPEA). It has been validated in a study in the CPEA network, demonstrating increased gastrointestinal disturbances in ASD children with regression (Richler et al. 2006). On the other hand, another study by Lord and colleagues on early medical problems in ASD children, utilizing retrospective chart review, failed to replicate earlier findings and found only a non-significant trend toward increased total number of chronic GI problems in the total ASD population. However, for individual items, significant differences were found between ASD cases and controls and between ASD with regression as compared to ASD without regression (Niehus and Lord, 2006). These results suggest that the sensitivity of the scale to capture the course and type of GI symptoms observed in the ASD population, which may or may not be unique, makes it feasible to more definitively assess this area of potential abnormality in ASD. A family history of autoimmune disease in ASD is described in several reports based on retrospective chart review or questionnaires mailed or distributed to the families of referred populations of children. Maternal autoimmune thyroid disease is one of the most commonly reported immune-mediated disorders. The autoimmune disease questionnaire included in the form queries parents for the presence of several broad categories of autoimmune disorders in family members. Reference • Niehus R, Lord C. Early medical history of children with autism spectrum disorders. J Dev Behav Pediatr

2006; 27 (2 Suppl): S120-7. • Richler J, Luyster R, Risi S et al. Is there a 'regressive phenotype' of Autism Spectrum Disorder

associated with the measles-mumps-rubella vaccine? A CPEA Study. J Autism Dev Disord 2006; 36(3): 299-316.

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3.e.2. The ABC Parent Report of Child Behavior Form (Appendix B2-3 for children age 3-5, Appendix B2-4 for children age 6 and older) Children age 3-5

• Child Development Inventory (CDI) – expressive language subscale • Early Childhood Inventory – version 4 (ECI-4) • Behavior Rating Inventory of Executive Function – Preschool Version (BRIEF-P) • Child Behavior Questionnaire (CBQ)

Children age 6 and older

• Child Development Inventory (CDI) – expressive language subscale • Child Symptom Inventory – version 4 (CSI-4) • Behavior Rating Inventory of Executive Function (BRIEF)

Child Development Inventory (CDI) The CDI is designed to measure developmental progress in young children from infancy to school age. The ABC study uses only the Expressive Communication subscale. This subscale generates a measure of expressive language skills and language age level for children ranging from 1 to 6 years. Scores are compared to age norms, and language delay is defined by the number of standard deviations at which the child scores below same-age peers. For the Expressive Language subscale, the correlation between subscale score and age is 0.83. The internal consistency of each CDI subscale depends on the age of the child. Cronbach’s alphas range from .87 – .96 for children between 1 and 5 years, indicating excellent reliability at these ages. Reference

• Ireton H. Child Development Inventory. Minneapolis, MN: Behavior Science Systems Inc.; 1992. Early Childhood Inventory – version 4 (ECI-4) The Early Childhood Inventory is a checklist screening for behavioral, emotional and cognitive symptoms of childhood psychiatric disorders, adapted to match DSM-IV-TR criteria. Although individual items are based on DSM-IV-TR criteria, they are worded in such a manner as to be easily understood by parents and teachers. In addition to marking the presence of a symptom, respondents are required to indicate the frequency at which the child engages in the behaviors (never/sometimes/often/very often). A specific number of symptoms must be present to score above cut-off levels for each diagnosis, and only symptoms rated as clinically significant and occurring often or very often are counted. Individual items can be scored in two different ways: The Screening Criteria Cut-Off Score Method and the Symptom Severity Method. The DSM-IV-TR specifies the number of symptoms that must be present to warrant a diagnosis (Symptom Criteria Score), which is the basis for determining the Screening Cut-Off Score. The Symptom Severity Score is simply a sum of item scores, which ranges from 0 to 3, where high scores indicate problem behaviors. There are screening items for all the major child psychiatric diagnoses in the ECI-4; ADHD, Oppositional Defiant Disorder, Conduct Disorder, Generalized Anxiety Disorder, Social Phobia, Separation Anxiety Disorder, Obsessive Compulsive Disorder, Post-traumatic Stress Disorder, Specific Phobia, Panic Attack, Selective Mutism, Major Depressive Disorder, Dysthymic Disorder, Bipolar Disorder, Eating Disorder, Elimination Disorder, Pervasive Developmental Disorder, Reactive Attachment Disorder, Sleep Disturbances and Tic Disorder. Test-retest reliability of ECI-4 across a 3-month period varies across diagnoses, but most are in the range of .51 to .77. Analyses of sensitivity and specificity comparing clinical diagnoses in an outpatient clinic with ECI-4 scores showed very encouraging results (Gadow & Sprafkin 1997). For example, for AD/HD, specificity is 0.82 and sensitivity 0.74; for ODD, specificity is 0.77 and sensitivity 0.72.

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Reference • Gadow KD, Sprafkin J. Early Childhood Inventory 4. Screening manual. Stony Brook NY. Checkmate

Plus, Ltd.; 2000. • Gadow KD, Sprafkin J. Early Childhood Inventory 4. Norms manual. Stony Brook NY. Checkmate

Plus, Ltd.; 1997 Child Symptom Inventory – version 4 (CSI-4) The Child Symptom Inventory version 4 is a behavioral rating scale screening for DSM-IV behavioral and emotional symptoms for children 5 to 12 years of age. There is one checklist for parents and one for teachers. The items are worded in such a manner as to be easily understood by parents and teachers. In addition to marking the presence of a symptom, respondents are required to indicate the frequency at which the child engages in the behaviors (never/sometimes/often/very often). A specific number of symptoms must be present to score above cut-off levels for each diagnosis, and only symptoms rated as clinically significant and occurring often or very often are counted. The CSI-4 Parent Checklist contains 97 items that screen for 15 emotional and behavioral disorders. The CSI-4 Teacher Checklist contains 77 items that screen for 13 emotional and behavioral disorders. Administration time is approximately 10-15 minutes. The CSI-4 can be scored to derive Symptom Count scores (diagnostic model) or Symptom Severity scores (Normative data model. There are screening items for all the major child psychiatric diagnoses in the CSI-4; ADHD, Oppositional Defiant Disorder, Conduct Disorder, Generalized Anxiety Disorder, Specific Phobia, Obsessive Compulsive Disorder, Post-traumatic Stress Disorder, Tic Disorder, Schizophrenia, Depression (Major Depressive Disorder and Dysthymia), Pervasive Developmental Disorder (Autism and Asperger syndrome), Social Phobia, Separation Anxiety Disorder, Elimination Disorder. The CSI-4 is the latest version of this screening tool, developed over several years and tested on several samples of both clinic and normative samples. The findings from several studies indicate that the CSI-4 is a reliable and valid screening instrument for emotional and behavioral disorders in children. Reference

• Gadow KD, Sprafkin J. Child Symptom Inventory 4. Screening and norms manual. Stony Brook NY. Checkmate Plus, Ltd.; 2002.

Behavior Rating Inventory of Executive Function – Preschool Version (BRIEF-P) The Behavior Rating Inventory of Executive Function – Preschool Version is a questionnaire for parents and teachers of preschool children to assess executive function in the home and in the preschool environment. It is designed for children ages 2 – 5 years, including children with emerging learning disabilities and attention deficit disorders, language disorders, and other developmental disorders. It contains 63 items within five non-overlapping theoretically and empirically derived clinical scales measuring different aspects of executive functioning: Inhibit, Shift, Emotional control, Working memory and Plan/Organize. Completing the questionnaire takes approximately 10-15 minutes. Parent/teacher responses indicate whether a certain behavior/deficit has never, sometimes or often been a problem. The categories correspond to a score of 1, 2 or 3, respectively, and a high score on any scale indicates possible problems within that domain. The BRIEF-P is normed, and generates T-scores and percentile scores. Internal consistency, as measured by Cronbach’s alpha, of each of subscale ranges from .80 to .97. The test-retest stability for parents and teachers as measured 4.5 weeks apart ranged for .78 to .90 with a mean across subscales of .86. Reference

• Gioia GA, Espy KA Isquith PK. Behavior rating inventory of executive function – preschool version. Florida: Avn. Lutz Psychological Assessment Resources, Inc.; 2003

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Behavior Rating Inventory of Executive Function (BRIEF) The Behavior Rating Inventory of Executive Function consists of two rating forms, one for parents and one for teachers, designed to assess executive functioning in the home and school environment for children 5-18 years of age. The BRIEF is useful in evaluating children with a wide spectrum of developmental and aquired neurological conditions, including learning disabilities, low birth weight, ADHD, Tourette’s, traumatic brain injury and Pervasive developmental disorders/autism. It contains 86 items in eight non-overlapping theoretically and empirically derived clinical scales measuring different aspects of executive functioning: Inhibit, Shift, Emotional control, Initiate, Working memory, Plan/Organize, Organization of Materials and Monitor. There are two validity scales as well for Inconsistency and Negativity. Completing the questionnaire takes approximately 10-15 minutes. Parent/teacher responses indicate whether a certain behavior/deficit has never, sometimes or often been a problem. The categories correspond to a score of 1, 2 or 3, respectively, and a high score on any scale indicates possible problems within that domain. The BRIEF is normed in the US, and generates T-scores and percentile scores. There is high internal consistency (alphas = .80-.98); test-retest reliability (.82 for parents, .88 for teachers). Moderate correlation has been found between teacher and parent ratings (.32-.34). Reference

• Gioia GA, Isquith PK, Guy SC, Kenworthy L.Behavior rating inventory of executive function – Professional Manual. Lutz, FL: Psychological Assessment Resources, Inc.; 2000.

Child Behavior Questionnaire (CBQ) The Children’s Behavior Questionnaire assesses temperament in early to middle childhood (ages 3-7 years). Temperament dimensions for which CBQ scales have been developed have been adapted from dimensions studied in both infants and adults. The CBQ assesses 15 dimensions of temperament: Activity level, Anger/Frustration, Approach, Attentional Focusing, Discomfort, Falling Reactivity & Soothability, Fear, High Intensity Pleasure, Impulsivity, Inhibitory Control, Low Intensity Pleasure, Perceptual Sensitivity, Sadness, Shyness, Smiling & Laughter. Three factors have been reliably recovered from this instrument, including Negative Affectivity, Surgency Extraversion and Effortful Control. The CBQ is widely used in developmental research and is available on the web in several languages and lengths. The Norwegian versions are available in Standard Form, Short Form and Very Short Form. A Teacher-Report version of the CBQ short form has also been created. The CBQ is available at www.bowdoin.edu/~sputnam/rothbart-temperament.questionnaires. References

• Rothbart, MK, Ahadi, SA, Hershey, KL & Fisher, P. Investigations of temperament at 3-7 yeras: The Children’s Behavior Questionnaire. Child Development 2001; 72: 1394-408.

• Putnam SP, Rothbart MK. Development of Short and Very Short forms of the Children’s Behavior Questionnaire. Journal of Personality Assessment 2006; 87: 103-13.

3.e.3. The ABC Teacher Report of Child Behavior Form (Appendix B2-5 for children age 3-5, Appendix B2-6 for children age 6 and older) This form is completed by the child’s teacher. If a pre-school child does not attend daycare, the form is not completed. The form for children age 3-5 is equivalent to the parents’ form, with the addition of the Preschool Play Behavior Scale (see below). The form for children age 6 and older is equal to the parents’ form. Preschool Play Behavior Scale (PPBS) The PPBS is intended to measure children’s social and non-social play. It consists of 18 questions describing the child’s complexity of play as well as whether play is performed in solitary or social contexts. A factor analysis of the total scale resulted in a five factor solution. The factors are: 1) Social Play (6 items) referring to group and socio-dramatic play and peer conversation; 2) Solitary-Passive Behavior (4 items) referring to solitary constructive and exploratory behavior; 3) Reticent Behavior (4 items) referring to unoccupied and on-looking behaviors; 4) Rough Play (2 items) referring to rough and tumble play; and 5) Solitary-Active Play (6 items) referring to solitary active play.

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The subscales have demonstrated moderate to high inter-rater reliability coefficients despite small sample sizes. Rough Play and Reticent Play showed relatively high inter-rater reliability; .54 and .89. Cronbach’s alpha for the subscales varied from .76 to .96, indicating high internal consistency. The PPBS is administered to teachers only, Reference

• Coplan RJ, Rubin KH. Exploring and assessing nonsocial play in preschool: The development and validation of preschool play behavior. Social Development 1998; 7(1): 72 – 91.

3.f. DIAGNOSTIC INTERVIEW Prior to the diagnostic interview, the clinician reviews all available information. The forms completed by the parents are checked to ensure that all questions have been answered and that the instructions have been followed accurately. Additional questions are asked in more detail to understand the clinical significance of any reported problem. A semi-structured “dyadic” interaction task is included during the clinician interview session. It is videotaped for later scoring and is intended to develop a richer, contextual awareness of the child’s potential. Its theoretical basis is the Emotional Availability Scale. The task consists of two 5-minute parent-child interactions in which the parent is asked to engage their child in play with their choice of two toys from a standardized group of six toys. Parents are instructed to begin play with only one of the two toys and to wait until they are told to switch to the second toy. References

• Biringen Z, Robinson J, Emde R. Emotional Availability (EA) Scales, 3rd Edition. Unpublished Manual; 1998. (www.emotionalavailability.com)

• Biringen Z, Fidler DJ, Barrett KC, Kubicek L. Applying the Emotional Availability Scales to children with disabilites. Infant Mental Health Journal 2005; 26: 369-91.

3.g. PHYSICIAN HISTORY-TAKING AND PHYSICAL EXAMINATION. The physician history-taking is based on the ABC Child and Family Health History Form. Additional questions are asked in more detail to understand the clinical significance of any reported problem. The physical examination (Appendix B2-7) includes a basic assessment of neurological function (muscle tone, muscle strength, reflexes, coordination, gait, eye movements) and stigmata and malformations (head anomalies, asymmetries of head and face, traits of fetal alcohol syndrome, abnormalities of the eyes and ears, Simian creases, finger anomalies, and birthmarks and skin abnormalities). This examination is always performed by a physician. 3.h. ANTHROPOMETRIC MEASURES AND PHOTOGRAPHIC RECORDINGS Anthropometric measures and photographs are made and recorded by the clinic secretary. (Children in wheelchairs are not measured for height and weight.) Height Height is measured with a Seca 222 wall-mounted stadiometer. The measurement is made according to the following steps:

1. Children remove their shoes before height measurement, 2. The measuring slide is positioned horizontally above the height of the child and below 130.5

cm. 3. The child is instructed to stand still with his/her back to the measuring rod. The back and

head must be straight; arms are to be at the child’s sides and shoulder blades, buttocks and heels touch the measurement surface. The weight of the participant is to be evenly distributed on both feet, and the heels of the feet are placed together with feet pointed slightly outward at a 60 degree angle. The secretary assists children in acquiring and maintaining the appropriate position and stance when required.

4. When the child is in the proper position, he/she is asked to breathe in, and the measuring slide is pushed down gently onto the child’s head so that it abuts the head without bending. For children unable to comply with the request to hold position and breathe in at the time of measurement, staff members attempt to take the recording when the child’s position is optimal.

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5. The read-off mark is the height of the child that is recorded. The height is recorded to the nearest 0.5 cm.

Weight Each child’s weight is measured on a Soehnle model 7411.00.900 scale. The measurement is made with the following steps:

1. Children remove their shoes and wear only light clothing before stepping onto the scale. 2. Children stand in the center of the weight scale platform. 3. The read-off mark that is obtained when the child is standing still is the weight of the child

that is recorded. The measurement is recorded to the nearest 50 g, corresponding to the accuracy of the scale.

4. The scale is checked for accuracy one a year. Head circumference Head circumference is taken with a Seca insertion tape, model 212. The procedure is as follows:

1. The child sits on a chair for the measurement. 2. Hair ornaments or braids are removed. 3. The tape is placed across the frontal bones just above the eyebrows, around the head and

above the ears on each side, and over the occipital prominence at the back of the head. 4. The measurer holds the tape snugly around the head. 5. The tape is then moved up and down over the back of the head to locate the maximal

circumference of the head. The tape should be perpendicular to the long axis of the face. When the tape is positioned correctly, it is pulled firmly to compress hair and underlying soft tissues. The measurement is recorded to the nearest 0.1 cm.

6. Two independent measures are taken of each child to secure accuracy. If the two measurements are identical then this circumference measure is recorded; if the two measurements differ, a third measurement is used to determine head circumference. If discrepancy still exists a middle value is recorded.

Photographs Photographs are taken with a Nikon Digital D80 camera. The camera is installed on a tripod that is adjusted to the height needed to photograph the child’s head. The tripod is placed at a distance of 1 meter and 35 centimeters from a wall on which a black and white checkered grid, made up of one centimeter by one centimeter squares, has been placed. The distance between the wall and the tripod on which the camera sits is marked on the floor. The child is positioned on a chair placed as close to the wall as possible (touching the wall) which makes the child’s head approximately 15 cm from the wall both in sidewise and frontal position. The chair is turned for right and left profiles against the wall. Pictures are taken at the maximum zoom setting of the camera. Two photographs are taken of the child from the front, and two of each profile (left and right). 3.i. BLOOD SAMPLING Blood is drawn at approximately the same time of day (right after lunch) to standardize sample collections for peripheral blood analytes that might be subject to circadian variation, as well as to ensure that samples arrive rapidly to the MoBa Biobank. One 10 ml EDTA tube is drawn to derive a plasma sample and full blood suitable for DNA extraction. A 3 ml Tempus tube is drawn for later extraction of RNA. (See Section 4 for additional information.) To reduce the possibility of the blood draw having an effect on the child’s test performance, blood sampling procedures are always scheduled after lunch, after most direct testing of the child is complete. The use of EMLA band-aids, which contain a mild topical anesthetic, serves to minimize the child’s discomfort. If a parent does not have blood samples stored in the MoBa Biobank, two 7 ml EDTA tubes drawn; transported to and handled at the BioBank in the same manner as described for the children (Section 4). 3.j. STAFF CONFERENCE AND DIAGNOSTIC CONCLUSION The staff conference is held at the end of all assessments, in which all the information relevant to reach a diagnostic conclusion is reviewed. The clinician systematically reviews the DSM-IV-TR

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diagnostic criteria for any suspected diagnoses, and marks off a response to each of the criteria on the ABC Clinician DSM-IV Diagnostic Criteria Review Form (Appendix B2-8). The DSM-IV-TR criteria for Autistic Disorder are always checked off yes/no. The review is modeled after the format of the DSM-IV Autistic Disorder Field Trial. The diagnostic conclusion is reached through a stepwise procedure:

1. First, it is determined whether there is a diagnosis within the autism spectrum (e.g., any ASD).

2. If there is a diagnosis within the autism spectrum, it is determined whether or not it is 299.00 Autistic Disorder.

3. If it is not Autistic Disorder but within the autism spectrum, it is determined which one of the following disorders is present: 299.80 Pervasive Developmental Disorder Not Otherwise Specified (PDD NOS), 299.80 Asperger Syndrome, 299.80 Rett Syndrome, or 299.10 Childhood Disintegrative Disorder.

4. The degree of mental retardation (MR), if any, is determined, and it is determined if MR is present without Autistic Disorder/other ASD.

5. Lastly, it is determined whether there is another psychiatric disorder present outside the autism spectrum. This diagnosis may stand alone or in the presence of a diagnosis of ASD or MR. The ABC clinical assessment is designed to provide a basis for the following categories of psychiatric/neurodevelopmental disorders: • Communication disorder (Expressive, 315.31; Combined Impressive-Expressive, 315.32;

Phonological, 315.39; Stuttering, 307.00; Communication disorder NOS, 307.9) • Attention Deficit/Hyperactivity Disorder (AD/HD: Combined form, 314.01; Predominantly

Inattention, 314.00; Predominantly Hyperactivity-impulsivity, 314.01; AD/HD NOS, 314.9) • Behavior disorder (Conduct, 312.8; Oppositional-Defiant, 313.81; Disruptive behavior

disorder NOS, 312.9) • Motor disorder (Coordination, 315.4; Tourette, 307.23; Chronic vocal/motor tics, 307.22;

Transient tics, 307.21; Tics NOS 307.20; Stereotypic movement disorder, 307.3) • Anxiety disorder (Separation anxiety, 309.21; Selective mutism, 313.23; Reactive

attachment, 313.89; Disorder of infancy, childhood, adolescence NOS, 313.9; Social anxiety, 300.23; Specific phobia, 300.29; Generalized anxiety, 300.02)

• Eating disorder (Pica, 307.52; Rumination, 307.53; Eating disorder, 307.59) • Sleep disorder, or other (327.30, or other codes from DSM-IV-TR)

Rett’s Disorder is diagnosed/registered but is excluded from the case definition in all analyses and summaries, as these children likely diverge genetically from children with other ASD. Childhood Disintegrative Disorder is also excluded, as the average onset of symptoms in these children is after 36 months of age, precluding effective use of ABC screening procedures. The whole assessment team takes part in the discussion, but the lead clinician makes the final decision. In the end, the diagnostic conclusion is entered onto the ABC DSM-IV Diagnostic Summary Form (Appendix B2-9). Sub-threshold diagnoses In some cases, children may display clinically significant symptom patterns or severity of problems that together are not sufficient to render a diagnosis according to DSM-IV criteria. In such instances, the clinician assigns a so-called sub-threshold diagnosis, indicating that the child has clinically significant problems pointing towards a given diagnosis, but does not meet all the criteria set for that particular diagnosis. Criteria for caseness of Autistic Disorder and other ASD; analytical strategy For a diagnosis of Autistic Disorder, subjects must:

• meet ADI-R criteria for autism • meet ADOS criteria for autism • receive a diagnosis of Autistic Disorder from the clinician

For a diagnosis of other ASD (Asperger’s Disorder, PDD-NOS), subjects will:

• fail the above criteria for Autistic Disorder

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• come within one point of meeting criteria on the ADI-R social domain score • come within one point of meeting criteria on at least one other ADI-R domain score • meet ADOS criteria for Autistic Disorder or ASD • receive an overall clinical diagnosis of Autistic Disorder or one of the other ASD

3.k. FEEDBACK TO PARENTS Following the staff meeting, clinicians prepare a summary of diagnostic impressions on the ABC Staff Summary for Reports to Families and Their Physicians (Appendix B2-10). Clinicians meet with parents for about half an hour after the staff conference to convey information regarding the assessments. If the assessment leads to a conclusion of a diagnosis within the autism spectrum, this conclusion is conveyed to the families. If the assessment leads to a conclusion of a diagnosis other than ASD, the parents are provided with a summarized description of the symptoms and problems encountered through the assessment of the child. Recommendations are given with respect to further assessments or consultations by local mental health professionals, laboratory workups, and services for children. These recommendations are tailored to diagnosis. All parents are provided with a 1- 2 page report that summarizes results from the assessments, any diagnoses, as well as the information and recommendations provided to parents during the family feedback session regarding further assessments or follow-up. A copy of the report is sent to local healthcare services and/or educational services that parents have designated at the end of the ABC Child and Family Health History Form. In the event the child has been previously assessed elsewhere, the parents are asked for written consent to obtain copies of reports from such assessments.

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SECTION 4. THE NIPH BIOBANK 4.a. MoBa BIOLOGICAL MATERIALS MoBa biological materials are stored at the NIPH Biobank, which is responsible for the storage of biological samples collected through MoBa and the MoBa sub-studies, as well as several other large-scale population studies in Norway. Table 4.a.1. MoBa BIOLOGICAL MATERIALS Sample

Time of collection

Materials collected at hospitals

# collected

Response rate

K1 – mother

Week 17-20 of gestation

Tube 1: 7 ml EDTA blood spun down at hospital lab. 1.a. 5 ml concentrated whole blood 1.b. 2 ml plasma Tube 2: 7 ml EDTA blood Tube 3: 7 ml EDTA blood Tube 4: 3 ml EDTA blood (environmental sample) Urine (environmental sample): 8 ml urine in transport tube with chlorhexidine

92,600

87.5 %

F – father

Week 17-20 of gestation

Tube 1: 7 ml EDTA blood spun down at hospital lab. 1.a. 5 ml concentrated whole blood 1.b. 2 ml plasma Tube 2: 7 ml EDTA blood

67,700

82.2 %

N – child umbilical cord

Day of birth

Tube 1: Tempus RNA collection tube – 3 ml whole blood Tube 2: 10 ml EDTA blood

83,200

77.8 %

K2 – mother

0-3 days after birth

Tube 1: 7 ml EDTA blood spun down at hospital lab. 1.a. 5 ml concentrated whole blood 1.b. 2 ml plasma Tube 2: 7 ml EDTA blood

88,800

81.9 %

T – child

6-7 years

Milk teeth

3,400

24.4 %

Numbers updated per February 15, 2010 Methods for sample collections changed over the course of MoBa, due to expanding research interests and technologies:

• K1 – mother: Environmental samples of blood and urine were added in January 2002. From January 2002 to May 2003, the environmental samples comprised 7 ml heparin blood, 3 ml EDTA blood and 10 ml urine on a clean tube. From May 2003 onwards, this was changed to 3 ml EDTA blood and 8 ml urine on a transport tube with chlorhexidine.

• F – father: Sample collection started in the fall of 2000

• N – child umbilical cord: RNA samples were added in May 2005

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Table 4.a.2. BIOBANK ALIQUOTING / STORAGE Sample

Aliquoting

Storage

Whole blood (K1, K2, F, N)

2 x 930 µl

Plates with 96 wells, - 80 ˚C

Plasma (K1, K2, F, N)

1 - 6 x 300 µl

Plates with 96 wells/ single Matrix tubes, - 80 ˚C *

DNA (K1, K2, F, N)

1 – 5 x 930 µl, approximate concentration of 100 ng/µl


RNA Tempus whole blood (N)

1 x 3 ml

3 ml Tempus tubes, - 80 ˚C

Plasma (K1 environmental sample)

3 x 930 µl

Single Matrix tubes, - 80 ˚C

Whole blood (K1 environmental sample)

3 ml, no handling

3 ml EDTA tubes, - 20 ˚C

Urine (K1 environmental sample)

8 x 930 µl **

Single Matrix tubes, - 80 ˚C

Whole Blood (A)

1 – 5 x 930 µl


RNA Tempus whole blood (A)

1 x 3 ml

Tempus tubes, - 80 ˚C

* Single Matrix tubes for plasma samples were introduced in February 2008. When retrievals of plasma are made from plates with 96 wells, the remaining contents are transferred to single Matrix tubes.

** Before July 2008, the aliquoting was 6 x 930 µl. 4.b. SAMPLE PROCESSING AND STORAGE 4.b.1. Rationale for sample collection methods EDTA tubes are standard for DNA and plasma collections. Pilot studies of plasma (Luminex, proteomics) indicate that the sample quality is excellent. Tempus tubes were chosen for RNA collection based on pilot studies with 9 blood donors where Tempus and PAXGene systems were compared for RNA quantity and quality, and for cost. Performance was similar with the two systems. RNA integrity was comparable, as judged by 28S and 18S rRNA imaging and real-time PCR measurements of several housekeeping genes. Although RNA quantity was 20% higher with Tempus, the final decision was based on competitive bids, wherein PAXGene tubes were twice as expensive as Tempus tubes. 4.b.2. Sample collection and transfer MoBa samples were collected at hospitals where subjects were recruited, and shipped to the NIPH Biobank overnight in packing materials provided to the hospitals by NIPH. Most samples were received the day after collection. Samples were processed on the day of receipt at the NIPH Biobank, except for samples arriving on Saturdays or Sundays – these were stored at 4 degrees centigrade until the following Monday. The Biobank tracking database, which was developed specifically for this purpose, was used to track the identity and location of the samples as they were processed. The specimen tubes were registered upon receipt; specimen status was noted (complete vs. incomplete volume); a Biobank ID was assigned; bar codes with unique identifier were automatically printed for further sample processing. A sample code was assigned when samples were stored, and the personal national identity number was encrypted. Decryption files are strictly limited to authorized personnel. With the exception of whole blood for DNA extraction, all samples were aliquoted and placed in long-term storage on the day of registration. A robot-aided pipetting system was used to subdivide the full blood and plasma samples into plates. All plates were sealed before freezing. DNA was extracted within five days of arrival of the sample at the Biobank.

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4.b.3. Sample storage Aliquoted samples were assigned to freezers set to optimal storage temperature for sample type (Table 4.a.2.). RNA tubes were stored overnight at -20 degrees centigrade before moving to storage at -80 degrees centigrade. Aliquoted samples from the same individual are stored in at least two different freezers. Backup freezers are available in the event of freezer failure. Each freezer is fitted with an alarm system that is activated when freezer temperature reaches 10 degrees centigrade above the optimal temperature. The storage location for each sample is defined by location on plate, plate number, rack number, and freezer number. This information is saved in the Biobank’s tracking database. 4.c. ABC-SPECIFIC BIOLOGICAL MATERIALS Table 4.c. ABC-SPECIFIC BIOLOGICAL MATERIALS Sample

Time of collection

Materials collected

# collected

Response rate

A – Child (singletons) Twins: A1, A2

Clinical assessment

Tube 1: Tempus RNA collection tube – 3 ml whole blood Tube 2: 10 ml EDTA blood

To be

completed

To be

completed

Children’s blood tubes are labeled with the mother’s name, the mother’s personal identity number, the date of collection, and the child # (for singletons A, for multiple births A1 (firstborn), A2 (second born), and so on. Tubes are delivered to the NIPH Biobank by the clinic secretary immediately after the blood draw. The total travel time for samples from the ABC clinic to the NIPH Biobank is 10-15 minutes. Samples are processed and stored as the N (child umbilical cord) samples of the MoBa sample collection schedule (Table 4.a.1.). If any of the parents have not previously provided blood samples for MoBa, they are asked to do so on the day of assessment. Blood from parents is collected and processed as the K2/F samples of the MoBa sample collection schedule (Table 4.a.1.). 4.d. BIOBANK QUALITY CONTROL The following measures have been implemented to reduce the risk of damage to the stored materials: • Sample processing and handling is expedited by using computerized/robotic systems. • All procedures are printed. • Freezers have backup generators and alarm systems. • Samples are split and stored in at least two separate freezer units.

4.e. SAMPLE RETRIEVAL 4.e.1. Administrative procedures Prior to retrieval of biological materials, the subject selection criteria must be approved by the ABC Steering Committee. Once the criteria have been approved, the Bergen Data Group (BDG) will generate a list of study subjects containing the unique MoBa identifiers for each subject, i.e., STUD_ID (pregnancy ID) and BARN_NR (child’s number of total in birth). A similar list will be generated at the Center for Infection and Immunity (CII). The two lists will be compared to ensure correctness in programming. Retrievals of biological materials require separate approvals from the Regional Committee of Medical Research Ethics (REK). The following information must be submitted:

• Outline of the research questions and hypotheses. • Description of the laboratory methods. • Power calculations. • Description of laboratories in which analyses will be performed, including contact details for

principal investigators or other persons responsible for the analyses.

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• Sample specifications: Sample type, # samples, volume per sample. Once the REK approval is obtained, the retrieval request, including the list of study subjects, is submitted to the NIPH Biobank. The project coordinator at NIPH is responsible for coordinating communication between the BDG, the CII, and the Biobank, as well as obtaining the REK approval. 4.e.2. Practical procedures For samples stored in the 96-well format, retrieval is accomplished using a partially automated pipetting robot that retrieves and transfers samples to a delivery plate. Other retrievals are made manually. After the request is filled, remaining materials are returned to long-term storage. The process is tracked in the Biobank tracking database, which is linked to the MoBa tracking database (Section 6.b.).

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SECTION 5. ABC QUALITY CONTROL 5.a. TRANSLATIONS OF INSTRUMENTS Only a few of the standardized instruments used for screening and clinical assessments were available in Norwegian prior to inception of ABC study (WASI, NEPSY, BNT, BRIEF, BRIEF-P, CBQ). The remaining instruments have been translated from English into Norwegian. The Norwegian versions are in bokmål, the more common form of the language found in print. Translations have been performed by individuals with expertise in psychology or psychiatry, to ensure that the psychological constructs underlying the original English wording of items is preserved. Back-translations have been performed to ascertain any discrepancies between the translated version and the original. Table 5.a. TRANSLATION OF INSTRUMENTS Instrument

Translations

ADI-R Autism Diagnostic Interview – Revised

• Translated by professional translators specializing in psychology/psychiatry (BH, AS) • Translation controlled independently by two specialists in clinical psychology (SS, NPT); discrepancies

resolved in collaboration with author, professor Catherine Lord (University of Michigan) • Translation approved by Western Psychological Services (WPS), the publishing company holding the license

for ADI-R internationally • Back-translation provided by Dansk Psykologisk Forlag (DPS), the publishing company holding the ADI-R

license for Scandinavia ADOS Autism Diagnostic Observation Schedule

• Translated by professional translator specializing in psychology/psychiatry (BH) • Translation controlled independently by two specialists in clinical psychology (SS, NPT); discrepancies

resolved in collaboration with author, professor Catherine Lord (University of Michigan) • ADOS workshop conducted in Norwegian and English in 2005 to test control words for soliciting intended

semantics (SS, NPT, MFL) • Translation approved by Western Psychological Services (WPS), the publishing company holding the license

for ADOS internationally • Back-translation provided by Dansk Psykologisk Forlag (DPS), the publishing company holding the ADOS

license for Scandinavia Stanford-Binet Intelligence Scales, 5th edition

• Translated by two graduate students in psychology and a specialist in clinical psychology (MF, GM, JL) • Translation controlled by specialists in clinical psychology with test certification (SS, NS) • Translation controlled and revised independently by three specialists in clinical psychology experienced in

testing children (ASO, JS, IBN) Mullen Scales of Early Learning

• Translated by professional translator specializing in psychology/psychiatry (GA) and two graduate students in psychology (MF, GM)

• Translation controlled by specialist in clinical psychology with test certification (SS) • Translation controlled and revised independently by three specialists in clinical psychology with experience in

testing children (ASO, JS, IBN) Vineland Adaptive Behavior Scales

• Translated by professional translator specializing in psychology/psychiatry (BH) • Translation controlled and revised independently by two specialists in clinical psychology (NPT, SS);

discrepancies resolved by consensus • Back-translation by professional translator specializing in psychology/psychiatry (AS)

PAPA Preschool Age Psychiatric Assessment

• Translated by professional translator specializing in psychology/psychiatry (DB, BC) • Translation controlled and revised independently by three specialists in clinical psychology (SS, ASØ, NS);

discrepancies resolved in consultation with Edward Potts, senior PAPA trainer at Duke University • Back-translation by child psychiatrist (LW)

ABC Child and Family Health History Form

• All medical terms translated and controlled by two physicians (NW, KKL)

SCQ Social Communication Questionnaire

• Translated by professional translator specializing in psychology/psychiatry (BC) • Translation controlled by specialist in clinical psychology (SS) and by author, professor Catherine Lord

(University of Michigan) • Back-translation by professional translator with specializing in psychology/ psychiatry (GA) The SCQ version used in the MoBa 36-month questionnaire was intended to be the Current version (as opposed to the Lifetime version). However, during translation, 12 items ended up having the Lifetime wording in Norwegian (items 3, 4, 7, 8, 10-16, 18). The error was not discovered during quality control.

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CDI Child Development Inventory

• Translated by specialist in clinical psychology (SS) • Back-translation by professional translator specializing in psychology/psychiatry (TC)

ECI-4 Early Childhood Inventory – version 4

• Translated by specialist in clinical psychology (SS, HA) • Back-translation by professional translator specializing in psychology/psychiatry (TC)

CSI-4 Child Symptom Inventory – version 4

• Translated by specialist in clinical psychology (ASO) • Back-translation will be obtained 2010

PPBS Preschool Play Behavior Scale

• Translated by specialist in clinical psychology (SS) • Back-translation by professional translator specializing in psychology/psychiatry (TC)

Table 5.a. Name key ASO Anne-Siri Øyen, specialist in clinical psychology AS Anne Swick, professional translator with psychology/psychiatry specialty BC Bente Christensen, professional translator with psychology/psychiatry specialty BH Brit Henchen, professional translator with psychology/psychiatry specialty GA Gail Adams, professional translator with psychology/psychiatry specialty GM Gjertrud Myrhaug, graduate student in psychology HA Heidi Aase, specialist in clinical psychology IBN Ida Brandtzaeg Naess, specialist in clinical psychology JS Julie Stephenson, specialist in clinical psychology JL Joan Lesley, Specialist in clinical psychology KKL Kari Kveim Lie, pediatrician LW Lars Wichstrøm, child psychiatrist MFL Marianne Fjugstad, graduate student in psychology NPT Niels Petter Torkildsen, specialist in clinical psychology NS Nina Stenberg, Specialist in clinical psychology NW Nicolai Wergeland, child psychiatrist SS Synnve Schjølberg, specialist in clinical psychology TC Tim Challman, professional translator with psychology/psychiatry specialty

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5.b. QUALIFICATIONS OF ASSESSMENT STAFF Professional qualifications of the clinical assessment personnel and of those responsible for training them are indicated in Tables 5.b.1 and 5.b.2.

Table 5.b.1. TRAINING AND QUALIFICATIONS OF ASSESSMENT PERSONNEL

Test / measurement Higher education

Test-specific training

Test certification required

Ongoing training

Periodic training

Re-certification

ADI-R Minimum BA Yes Yes Yes Yes No ADOS Psychologist Yes Yes Yes Yes No SB5 Psychologist Yes No Yes Yes No Mullen Psychologist Yes No Yes Yes No Vineland Minimum BA Yes No Yes Yes No WASI Psychologist Yes No Yes Yes No PAPA Minimum BA Yes No Yes Yes No NEPSY Psychologist Yes No Yes Yes No BNT Psychologist Yes No Yes Yes No BPT Psychologist Yes No Yes Yes No GPT Psychologist Yes No Yes Yes No Physical examination MD Yes No Yes Yes No Anthropometric measurements None Yes No Yes Yes No Photography None Yes No Yes No No

Clinical diagnosis

Specialist in clinical psychology/ child psychiatrist Yes No Yes Yes No

57

Table 5.b.2. TRAINER QUALIFICATIONS

Test / measurement

Trainer(s)

Additional training tools

Trainer qualifications

ADI-R

Synnve Schjølberg

ADI-R training DVD tapes

Specialist in clinical psychology, certified ADI-R instructor

ADOS

Synnve Schjølberg

ADOS training DVD tapes

Specialist in clinical psychology, certified ADOS instructor

SB5

Synnve Schjølberg, Anne-Siri Øyen, Nina Stenberg

Training DVDs provided by WPS

Specialist in clinical psychology

WASI

Anne-Siri Øyen, Nina Stenberg

Instruction manuals


Mullen

Synnve Schjølberg, Anne-Siri Øyen, Nina Stenberg

Training DVDs provided by WPS


Vineland

Synnve Schjølberg

Audio training tapes provided by AGS


PAPA

Edward Potts

Audio tapes

PhD

NEPSY


Instruction manuals


BNT


Instruction manuals


BPT

Synnve Schjølberg

Instruction manuals


GPT


Instruction manuals


Physical examination

Kari Kveim Lie

None

MD

Anthropometric measurements

Kari Kveim Lie

Instruction manuals

MD

Photography

Kari Kveim Lie

None

MD

Clinical diagnosis

Jan Buitelaar, Sophie Willems-Swinkels, Michael Rutter, Catherine Lord

None

MD/PhD, experts in child psychiatry research

5.c. TRAINING PROCEDURES ADI-R Trainees complete the ADI-R video-training package distributed by Western Psychological Services (WPS) over a three-week period. Following completion of video-training, a formal, three-day ADI-R workshop is run in which up to four families interviewed are scored. ADI-R interviews are scored independently by all trainees. The criterion for acceptable performance is an agreement of 0.90 or more with a study trained and reliable interviewer. Agreement is calculated based in the scores 0, 1 or 2 (all 3’s are converted to 2’s). The trainee will have to demonstrate acceptable agreement (90% agreement) on three consecutively-scored live interviews, both on the total items scores as well as on algorithm scores.

ADOS Trainees complete the video-training packages distributed by WPS on two consecutive days. Following completion of video-training, a formal three-day ADOS workshop is run in which two children are assessed, usually one normally developed child and one child with an autism spectrum disorder. ADOS tests are scored independently by all staff on site. The criterion for acceptable performance is an agreement of 0.80 or more with a study trained and reliable tester on each individual item as well as on the algorithm items. Agreement is calculated based in the scores 0, 1 or 2 (all 3’s are converted to 2’s). Reliability for a certain research assistant is counted across Module 1 and 2 and on Module 3 separately. SB5, WASI, Mullen, NEPSY, BNT, BPT, GPT The training for all these instruments follow the same procedure: The trainees go through the tests and the administration and scoring for each test with a senior psychologist. The trainee then observes and scores the administration of three assessments with each test by the senior psychologist. This is followed by three administrations of each test by the trainee with the senior psychologist observing and scoring the tests in parallel inside the assessment room. The protocols and test administration is evaluated by the senior psychologist, who in particular pays attention to

58

the appropriate administration of each item. The criterion for acceptable performance is that each item is correctly administered and that the scoring rules of each item is understood. Vineland Trainees complete the training in administering the Vineland in the same time slot as the ADI-R training has been done. The reason for this is that the ADI-R comprises a series of questions concerning social and communication skills, two of the domains in Vineland. After finalizing the ADI-R a relatively limited set of extra questions are needed to complete these two domains in the Vineland. The initial training is completed over two days. The training consist of scoring three taped interviews and doing three live interviews under supervision of a reliable and study trained staff. One is considered reliable if the individual is not deviating more than 5 raw points per domain, which implicates no more than about 3 standard scores difference for each of the four sub-domains. Across all domains, the Composite Adaptive Behavior will show still show high reliability. PAPA Trainees complete a workshop lasting for 2 days. At first, trainees review two video-taped interviews, video-training package from Angold and Eggers group, provided by Ed Potts as well as video-taped assessments from the ABC clinical assessments). ‘Live’ parents are interviewed by the PAPA trainer, and trainees score the items independently. The trainees will have to do at least 3 interviews by themselves with a reliable and study trained staff achieving at least and agreement of 0.80 on all items that rate if a symptom is present or not. After each interview, the trainer and trainee discussed the individual scores throughout the interview and calculate the % items agreed upon. Clinical diagnosis Diagnosticians were at the start of the study trained through one-and-a-half-day workshops with consultants from the University Medical Center St.Radboud in Nijmegen, Netherlands (Sophie Willems-Swinkels and Jan Buitelaar). The first part of the workshop focuses on the procedures for reaching a diagnostic conclusion. The second part consists of reviews of video-recordings of difficult diagnostic cases. After completing the workshop, diagnosticians in training complete a series of diagnostic staff-meetings with a senior diagnostician in the study to complete the procedures in the study for concluding with a diagnosis. Each child is reviewed by the clinical director and senior clinician to ensure consistency in diagnostic conclusion and the clinician’s documentation of information used in the diagnostic process. If information is lacking, the clinician is asked to review the case again and complete all information (i.e. review rating of symptoms accounting for diagnostic conclusion etc). The diagnostician in each case has the final decision in diagnosis. Diagnostic procedures have also been evaluated during visits by professor Catherine Lord, who is a consultant on the study, and by professor Michael Rutter, who is serving on the ABC study’s Scientific Advisory Board. These visits have included reviews of video-recordings and test results from difficult diagnostic cases. 5.d. MONTHLY STAFF MEETING AND ONGOING TRAINING All ABC staff has monthly two-hour meetings to assure that the instruments are being properly and reliably administered and scored. There are separate meetings for clinicians and research assistants. All are supervised by the clinic director. At each meeting, clinical cases, diagnostic issues or instrument issues are discussed. At regular intervals a video-recording of the administration of a chosen instrument is re-scored by each staff member and discussed in the group. These meetings are supplemented with ongoing supervision of staff by the director of clinical assessments and the senior clinician. 5.e. INTER-RATER RELIABILITY Training phase: During the training phase, all testers/interviewers double-score three tests/interviews with a fully-trained staff member. Reliability is calculated, and discrepancies are resolved through discussions and reviews of test/interview manuals. Before conducting any test/interview independently, a trainee must complete another three live interviews / tests under close supervision of a senior study trained staff member and achieve instrument–specific reliability.

59

Routine monitoring: The scoring of ADI-R and ADOS is monitored on a regular basis by having all staff members re-score the instruments from a randomly selected sample of 5% of participants. The clinicians re-score the ADOS and the research assistants re-score the ADI-R. The re-scoring is done from video-recordings. The sample to be re-scored is selected by the Bergen Data Group (BDG). At the end of each quarter of the year, the BDG selects a random sample of 6% of the children who have undergone clinical assessments during the past three months. The reason for sampling 6% is to take into account that some children may not have completed both the ADI-R and the ADOS or the recording/DVD can be of low quality/not scorable – ensuring that the final sample to be re-scored constitutes at least 5% of the participants. 5.f. QUALITY CONTROL OF DIAGNOSES The diagnostician/clinician who is responsible for the diagnostic conclusion for a given child, has maximum two weeks to finalize the summary and report writing. Every week, the clinical director and the senior clinician are reviewing the workup of each child, looking in particular at the documentation in each case of how the clinician has arrived at a given conclusion. Inconsistencies are reported to the clinician and he/she might be requested to document the information/data used for a specific conclusion. The diagnostician has the final decision for the conclusion about the child. 5.g. PROTOCOL REVIEW AND REVISION The performance of screening criteria and the status of recruitment are reviewed every six months to assure that recruitment objectives are being achieved and to decide whether protocol changes or other efforts to increase recruitment are required. Components of the protocol routinely reviewed include: • recruitment procedures with the potential to cause sample bias • procedures affecting participation and case ascertainment • procedures affecting completion of clinical assessments or adversely affecting subject ‘comfort’

during the assessment Protocol revision is required for any changes that have scientific implications or affect the participants in the study. All protocol changes must be approved by the ABC Steering Committee. If changes affect MoBa, the MoBa Executive Committee must also approve. As a rule, the ABC Scientific Advisory Board is consulted before scientifically important revisions are made. A revised version of the protocol is submitted to the Columbia University IRB upon final approval.

60

SECTION 6. ABC DATA COLLECTION AND MANAGEMENT 6.a. THE BERGEN DATA GROUP (BDG) The BDG is responsible for the management of MoBa data, and for the technical aspects of ABC data management. The group is located at the Medical Birth Registry of Norway (MBRN) in Bergen; both are parts of the Norwegian Institute of Public Health. The ABC-specific responsibilities of the BDG include:

• Selection and invitation of potential ABC participants, as described in Section 2 • Administration of the ABC-specific tracking system, which enables the Oslo Assessment

Group (OAG) to follow up on invitations and schedule clinical assessments • Integration of data collected during ABC clinical assessments with MoBa data • Distribution of data files to investigators • Provision of MoBa and MBRN data documentation • Provision of programmer-constructed variables • Selection of random samples of ABC participants for reliability testing

6.b. THE MoBa TRACKING DATABASE The MoBa Tracking Database is used to register and follow the progress of MoBa participants through various phases of the study. The database is developed in house using MS SQL Server 2005 and MS Visual Studio 2005 C#. The database is installed at computers within the local secured network at MBRN. The MoBa Tracking Database generates a unique MoBa study ID number for each recruited pregnancy, which is linked to the national ID numbers of the mother, father, and subsequently the child (after birth). The database is updated quarterly with data from MBRN and information about changes of addresses and deaths of mothers or children from the Norwegian Population Registry. Table 6.b. VARIABLES IN THE MoBa TRACKING DATABASE

Mother

Pregnancy

Ultrasound

Child

MoBa status

Mother (pregnancy) study ID# Name Address National ID#

Mother (pregnancy) study ID# Child no. of total in birth Child blood (N) + date MBRN form Date of birth Date of death

Father

ABC

Father study ID# Name Address National ID#

Mother (pregnancy) study ID Mother national ID# Ultrasound due date No. of fetuses Mother consent + date Mother blood (K1, K2) + dates Father study ID# Father consent + date Father blood (F) + date

Mother (pregnancy) study ID# Ultrasound date Ultrasound institution

Mother (pregnancy) study ID# Child no. of total in birth Child ABC-specific ID# ABC consent date Child name ABC invitation source (screen-positive/ control/referral/NPR/5YQ/7YQ) Q6 returned yes/no Child blood (N) yes/no Contact information

Registered Invited Participant Abortion Stillbirth Withdrawn Deleted Moved Unknown address Mother died On hold

All questionnaires are sent from the BDG; questionnaire mailing and return dates are entered into the tracking system. Questionnaire response data are stored in a separate MoBa questionnaire database (Oracle 9.2) indexed on pregnancy study ID (not national ID). In practical terms, returned

61

questionnaires are scanned and stored as optical images and then read into the questionnaire database by Eyes and Hands in Windows NT. The MoBa tracking database is integrated with the Biobank tracking database, so that an updated inventory of biological materials is always available for each study subject. 6.c. ABC-SPECIFIC TRACKING FILES Every two weeks, updated lists of invited children are sent from the BDG to the OAG in a password-protected, encrypted file. The following variables are included in the file:

- ABC-specific ID (ABC_ID) - Invitation date - Consent date - Mothers national ID - Mother’s name, address and e-mail address - Child’s no. in sibship - Plurality (singleton, twin, triplet) - Source of invitation (screen-positive, control, referral, twin/triplet, Norwegian Patient

Registry, 7-year questionnaire) - Child’s name - Telephone number(s) - Suitable time for phone contact (as stated on ABC consent form) - Blood sample from mother in MoBa Biobank yes/no - Blood sample from father in MoBa Biobank yes/no - Q6 returned yes/no

The ABC-specific ID is a study ID generated specifically for participants in the ABC study. The MoBa study ID is not used for the ABC-specific tracking. In order to protect confidentiality, the BDG is not permitted to release MoBa study IDs together with any information revealing personal identity. The OAG uses only the ABC-specific study ID for scheduling and data entry. When research files are prepared by the BDG, the ABC-specific study ID is linked to the MoBa study ID, and only the MoBa study ID is included in the research files. If changes occur in any of the above-mentioned variables for subjects on previous lists, those changes are also included in the encrypted files. Invitation lists are classified as ‘active’ until the children reach 43 months of age (for 36-month screen-positives and controls) or until six months have passed since the invitation data (for older children). At that time, the classification is changed to ‘retired’, and data on the final results of ABC recruitment are returned from OAG to BDG. Upon ‘retirement’, the subjects are removed from the ABC-specific tracking files. Potential participants identified through alternative case identification procedures (as described in Section 2.c.) are kept on the lists until the clinical assessment is completed or the parents have declined to participate. If the family is not reached within six months after invitation, the subjects are removed from the ABC-specific tracking files. Figure 6.c.1. on the following page provides an overview of the ABC invitation and tracking algorithms administered by the BDG.

62

Figure 6.c.1. OVERVIEW OF ABC INVITATION AND TRACKING ALGORITHMS

6.d. RECORDING OF DATA DURING CLINICAL ASSESSMENTS The initial recording of data from the clinical assessments is done manually on paper forms, i.e., the testers/interviewers record results and responses on instrument-specific paper forms. Prior to each assessment, the clinical site secretary prepares a folder for each child, containing one form for each instrument labeled with the child’s ABC study ID, birth date and assessment date. The forms completed by parents and daycare teachers prior to assessments are also put in this folder, and the secretary controls that they are properly labeled. The SB5, Mullen and Vineland are scored by digital scoring software provided by the publishing companies holding the test licenses (see Section 3). Testers/interviewers calculate sub-domain scores manually and enter the sub-domain scores into the scoring program. The child’s birth date and assessment date are also entered. Based upon these raw data, standardized scores are generated and printed out as a score sheet. The score sheet is stapled onto the test form. Scoring of other test/interview results is done manually by testers/interviewers. 6.e. DATA QUALITY-CONTROL Prior to data entry, folders are controlled according to the following procedure:

1. All forms are re-checked to ensure correct labeling with ABC-specific study ID. Responsible: Clinic secretary. 2. All DVDs and MPEG2 video files are checked to ensure correct labeling with ABC-specific

study ID and assessment date. Responsible: Senior research assistant. 3. ADI-R and ADOS quality control: In these instruments, almost all items have response

options for every conceivable response, including ‘not applicable’, ‘do not know’ and ‘not

63

asked’. As long as the instruments have been administered correctly, the items will have valid responses, and there will not be missing data. The forms are reviewed to detect invalid or missing values. If any such values are found, the forms and/or the corresponding video-recordings are reviewed. If there is sufficient information available, the invalid/missing values are corrected. If there is not sufficient information, the response option ‘not asked’ is chosen. If ‘not asked’ is not a response option, the response is set to ‘missing’.

Responsible: Senior research assistant (ADI-R) and senior clinical psychologist (ADOS). 4. SB5, WASI, Mullen and Vineland quality control: All sub-domain scores are re-calculated

manually. The score sheets are controlled to ensure that sub-domain scores have been correctly entered into the scoring software. The child’s birth date and assessment date are also controlled for correctness. If errors are found, corrected score sheets are generated.

Responsible: Senior clinical psychologist (SB5, WASI, Mullen) and senior research assistant (Vineland).

6.f. THE ABC DATA SUMMARY FORM After the completion of diagnosis quality control (Section 5.f.) and data quality control (Section 6.e.), test and interview results are transferred manually onto the ABC Test and Interview Summary Form (Appendix B2-12). This form is printed in a format that allows direct scanning of data. Each formed is labeled with the ABC-specific study ID. Responsible for manual data transfer: The clinic director is responsible for DSM-IV diagnoses and diagnostic criteria, while the senior research assistant is responsible for the other data. Responsible for cross-checking accuracy of manual data transfer: Administrative coordinator. Completed forms are sent by registered mail to the BDG every two months. Upon receipt in Bergen, the forms are scanned in the same manner as regular MoBa questionnaires. The data extracted from the forms are converted to SPSS files. 6.g. RELEASE OF DATA FILES Updated ABC research files are transferred from the BDG to ABC study collaborators at CU and NIPH on March 31 and September 30 of each year. The data files are updated as of December 31 and June 30, respectively. Access to ABC clinical assessments data is regulated by the ABC Steering Committee. Data files are encrypted and password-protected. Clinical assessment data are released in conjunction with complete data from MoBa and MBRN, to include linked NPR data. For specific scientific purposes, analytical files will be made, in which selected ABC and MoBa variables are assembled into one SPSS file. The purpose of tailoring analytical files according to the scientific purpose is to limit the size of the files and avoid having to release complete sets of ABC, MoBa and MBRN data to all investigators. The analytical files will contain information about the biological materials available for every study subject. The data files are accompanied by the data documentation necessary to work with the files:

• Reverse data dictionaries: ABC instrument forms, MoBa questionnaires and MBRN forms with SPSS variable names included, to help researchers navigate between forms/questionnaires and SPSS files

• Syntax for the creation of programmer-constructed variables, for researchers to control that the variables are correctly generated

6.h. DATA AUDIT Following each half-yearly release of clinical assessments data, the BDG performs a data audit on a randomly selected sample of 5% children assessed during the previous six months. The purpose of the data audit is to control the accuracy of the entire data entry process. For the audit, the OAG scans all paper forms from the folders of selected children and sends pdf-copies of the forms in an encrypted, password-protected file to the BDG. The BDG compares the responses on the forms to the SPSS file data. A summary of findings from the data audit is sent to ABC study collaborators at CU and NIPH within two months after each half-yearly release of clinical assessments data (i.e., by May 31 and November 30).

64

7. ABC FIELD REPORTS Field reports are made by the BDG and the project coordinator at NIPH four times per year: April 30, July 31, September 30, and December 31. Completed field reports are then transferred to CU within one week of the aforementioned annual dates. 7.1. MoBa – KEY NUMBERS Table 7.1.a. and Figure 7.1.a. are only included once a year (December 31). Table 7.1.a. MoBa RECRUITMENT – KEY NUMBERS

Number % of invited Birth year # live-born children Pregnancies 107,000 38.5 % 1999 50 Live-born children 108,000 2000 2,200 Unique mothers 90,700 2001 4,300

2002 8,800 Pregnancies w/ father participating 82,400 77.0 % 2003 12,700 Unique fathers 71,500 2004 13,700 Twin pairs 1,865 2005 15,700 Triplet trios 21 2006 17,500 Total # of sibships 16,700 2007 16,200 2008 13,400

2009 3,400 Children alive and participating at 3 years

104,500 (est.)

Numbers updated per Dec 31, 2009 Figure 7.1.a. MoBa MILESTONES

65

Table 7.1.b. MoBa QUESTIONNAIRES

Questionnaire

Time of receipt

# sent out

# returned

Response rate

Q4 6 mos Q5 18 mos Q6 36 mos

Q7 5 y Q8 7 y Q9 8 y 7.2. ABC SCREENING Table 7.2.a. ABC SCREENING

SOURCE

OVERALL LAST QUARTER

# screen-positive (%)

# identified elsewhere

# invited

# screen-positive

# identified elsewhere

# invited

36M Q 5Y Q 7Y Q

8 YQ NPR Table 7.2.b. ABC SCREENING RESULTS

# sc

reen

ed

# sc

reen

+

% s

cree

n+

scre

en+

asse

ssed

% p

artic

ipat

ion

scre

en+

PPV

(ASD

)

PPV

(ASD

+

autis

tic tr

aits

)

PPV

(any

di

agno

sis)

*

PPV

(any

di

agno

sis

or

prob

lem

**)

36M revised algorithm 36M original algorithm

5Y Q 7Y Q 8Y Q NPR

* Any diagnosis = any psychiatric or neurodevelopmental disorder ** Problem = clinically significant developmental problem, but not sufficient to render a diagnosis

66

7.3. ABC CLINICAL ASSESSMENTS Table 7.3.a. ABC PARTICIPATION

Source # invited # clinic

# phone # not

reached # declined

% clinic % clinic +

phone Screen+, revised criteria

Screen+, original criteria only

Twins/triplets

Controls

5Y Q

7Y Q

8 YQ

NPR

Table 7.3.b. ABC CLINIC DIAGNOSES

DIAGNOSIS S+ REF NPR 5YQ 7YQ TWIN CON Total Autistic disorder Profound disability with autism PDD NOS Asperger syndrome Childhood disintegrative disorder Rett syndrome Total ASD Sub-threshold ASD Total ASD + sub-threshold ASD Other ND/psychiatric diagnosis Clinically significant ND/psychiatric problem No diagnosis and no psychiatric/ND problem Total Table 7.3.c. ASD DIAGNOSES – TOTAL

Birth year CLINIC

ASD 5Y Q ASD 7Y Q ASD 8Y Q ASD NPR ASD

Total ASD MoBa total

% ASD

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

Total

67

Table 7.3.d. ABC CLINIC CAPACITY (2010 used as example)

2010 Easter holiday: Week 13 Summer vacation: Weeks 26-30 Christmas holiday: Weeks 51-52 Public holidays: May 1, May 13, May 17, May 31 Month

Regular clinic capacity

Capacity/ month

# assessed

January 4 / week February 4 / week March 4 / week April 4 / week

May 6 / week June 6 / week July 6 / week August 6 / week

September 6 / week October 6 / week November 6 / week December 6 / week

Total 7.4. ABC BIOLOGICAL MATERIAL TRANSFERS Table 7.4.a. ABC BIOLOGICAL MATERIALS – PLANNED TRANSFERS

PI

Laboratory

Sample type

Sample volume

# samples

Due date

study ID list

Expected date of IRB

approval

Expected retrieval

date

Table 7.4.b ABC BIOLOGICAL MATERIALS – COMPLETED TRANSFERS

PI

Laboratory

Sample type

Sample volume

# samples

Retrieval date

Shipping date

Date of receipt

68

7.5. ABC DATA TRANSFERS Table 7.5.a. ABC RESEARCH FILES – PLANNED TRANSFERS

File

Recipient

Expected date of IRB approval

Expected transfer date

File cut-off date

Table 7.5.b. ABC RESEARCH FILES – COMPLETED TRANSFERS

File

Recipient

IRB approval date

Transfer date

File cut-off date

Confirmation of receipt

Table 7.5.c. ABC RESEARCH FILES – RETURN OF DATA TO THE MoBa DATABASE

File

Sender

Transfer date

Confirmation of receipt

Documents

GENE-ENVIRONMENT INTERACTIONS IN AN AUTISM ......2010/07/08 · 2 Table of contents 1. Overview of the ABC study 1.a. Background 9 1.a.1. Autism spectrum disorders 9 1.a.2. Causes