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BIOBANK NORWAY February 12, 2013/sieh/cast

Work Package 2

Leaders: Camilla Stoltenberg, NIPH and Kristian Hveem, NTNU

Coordinator at NIPH: Siri Håberg, MD, PhD

Deliverable 1) High quality phenotype information from disease registries and other sources on the

CONOR and MoBa cohorts (2011-2013)

Contents

Plan for updating and publishing phenotype information from MoBa

1 Collecting phenotype information in the MoBa cohort 1.1 The Norwegian Mother and Child Cohort

Table 1: Participants in MoBa 1.2 The MoBa biobank Table2: MoBa Biological samples 2 Phenotypes 2.1 Phenotype definitions Table 3: Overview of phenotype information in MoBa

Table 4: Phenotype information in MoBa Questionnaires

2.2 Phenotypes obtainable through registry linkages Table 5: Phenotype information in National Health Registries Table 6: Phenotype information in National Clinical Registries Table 7: Phenotype information from other sources 2.3 Phenotype information from clinical assessments in MoBa MoBa Substudies with clinical assessments: The ABC study (autism spectrum disorders)

The ADHD study The BraMat study

The EPYC study (childhood epilepsy) The Childhood Cancer study

Planned: Clinical assessment (celiac disease and asthma) Other sub-studies 2.4 Reliability and validity studies 2.5 Current studies using biological samples in MoBa

Table 8: Phenotypes in current studies using biological samples in MoBa

3 Ethics and approvals 3.1 Approvals for linkages 3.2 Access to data and/or biological specimens 3.3 Access to results from biological analyses 3.4 Approvals for Sub-cohorts 3.5 Ethics and regulations

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1 Collecting phenotype information in the MoBa cohort

The CONOR and MoBa cohorts participate in Biobank Norway. These cohorts now have nearly 500 000 participants who have donated biological samples and health information. There is an acute need for identification of phenotypes in the cohorts in order to be ready for rapid participation in international research consortia. Without a streamlined system for additional phenotyping, information about phenotypes, and rapid access to available phenotypes, the biobanks cannot be used efficiently and their value cannot be maximized. Phenotyping and systems for access to available phenotypes are necessary components in a biobank infrastructure. We need to identify more phenotypes to make use of these systems, and we need to develop systems for making the phenotypes rapidly available for research in international consortia and other kinds of research projects.

1.1 The Norwegian Mother and Child Cohort

Between 1999 and 2008 pregnant women and their partners were invited to take part in the

MoBa study (Magnus P et al. Cohort profile, Int J Epidemiol 2006). Biological material has

been collected from mothers, fathers and children and has been stored in a biobank. Regular

questionnaires covers general health, diet and environmental exposures, and additional data

are obtained through analyses of biological material and linkages to health registries. The

cohort includes approximately 108,000 children, 90,700 women and 71,500 men.

Table 1: Participants in MoBa

(October 2010) Number

Pregnancies 107 008

Pregnancies with information from fathers 82 471

Children 108 639

Mothers participating 90 725

Fathers participating 71 574

Twin pairs 1 871

Triplet trios 21

Mothers participating with more than one child 15 256

1.2 The MoBa biobank

The purpose of MoBa is to investigate the causes of disease. Use of biological material and

laboratory research can reveal mechanisms that underlie disease processes, and lead to new

treatment forms. It is also important to disprove false theories regarding the cause of

disease and investigate which factors promote good health and absence of disease. MoBa

has the advantage of an extensive data collection including information on health, lifestyle

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and outcomes relevant in analyses of biological material. MoBa has one of the most

extensive biobanks in Norway with more than 4.8 million aliquots from biological samples

from mothers, fathers and children participating in the study.

Biological material EDTA whole blood from both parents and urine samples from mother were collected during

pregnancy, from the child’s umbilical cord right after birth, and from the mother post-

partum. RNA collection was initiated in 2005, and is available for approximately 52 500

children included in the cohort. In addition, collection of milk teeth from all children at 7

years of age is performed. For details of handling and available specimens see appendix 2

Biobank description.

Table 2: MoBa biological samples October 2010

Sample Time of collection Sample type Number of

participants

% received from

total

participants

Maternal pregnancy

sample Week 17-20 EDTA blood,

urine* 93 500 87,4%

Paternal sample Week 17-20 EDTA blood 67 800 81,5%

Maternal birth

sample

0-3 days after

birth

EDTA blood 83 500 78.0%

Child umbilical cord

sample Day of birth

EDTA blood,

**RNA Tempus

whole blood

89 600 82,5%

Child milk teeth

sample 6-7 years Milk teeth 5 788 24,2%

*Urine taken from a sub-group of 66.830 mothers

**RNA taken from 45.538 children

2 Phenotypes

2.1 Phenotype definitions A phenotype is defined as a health condition, obtained either from the questionnaire,

registries, clinical assessments, or markers in urine- or blood samples. The phenotype

variables usually become dependent variables in a analytical model, but they can also be

exposure variables associated with other health outcomes, for example at later ages.

Specific blood- and urine factors could similarly be either exposure variables or health

outcomes.

The following tables give examples on phenotypes that could be used in studies where

biobank samples can be used in exposure assessments. MoBa participants receive

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questionnaires at different time points, and include phenotype information from pregnancy

and after birth as the child grows older.

Table 3: Overview of phenotype information in MoBa

Exposures/biomarkers Phenotypes in children Phenotypes in parents

Nutrients

Environmental toxins

Smoking/alcohol/drugs

Genetics

Epigenetics

Gene activity (RNA)

Inflammatory markers

Occupational hazards

Medication

Other biomarkers

(enzymes, urine

markers etc)

Perinatal outcomes

Preterm birth

Birth weight

Asthma/allergy/atopy

Infections

Childhood cancer

Congenital malformations

Mental development

Autism spectrum disorders

ADHD

Cerebral palsy (2012)

Epilepsy

Childhood cancer

Diabetes

Autoimmune disorders

Chronic diseases

Height/weight/BMI

Time to pregnancy

Pregnancy complications/outcomes

Asthma/allergy/atopy

Infections

Cancer (breast, other types)

Depression

Diabetes

Pelvic pain

Rheumatism

Chronic diseases

Height/weight/BMI

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Table 4: Phenotype information in MoBa Questionnaires

Source Time Phenotype information Number

returned Response rate

Ultra-

sound

form

Pregnancy

week 17-20

Growth of fetus (estimate of gestation

age) malformations, numbers of fetus

and placenta position

87 600 81,9 %

Mother Pregnancy

Q1 Pregnancy

week 13-20

Previous pregnancy outcomes, medical

history, complications, medications,

occupation, exposures at work and at

home, lifestyle, mental health

101 828 95.2%

Q2 Week 22 Diet 97 275 92.3%

Q3 Week 30 Antenatal care, health changes, work

situation, lifestyle 94 362 91,0%

Mother Age of child

Q4 6 months Birth, development, early diseases and

nutrition, maternal health, lifestyle and

well-being

89 821 84.8%

Q5 18 months Child health, development, behaviour,

nutrition and daily life, maternal health,

lifestyle and well-being

74 976 72,4%

Q6 36 months Child health, development, behaviour,

nutrition and daily life, maternal health,

lifestyle and well-being

47 083 59,3%

Q7 5 y Neurodevelopmental disorders,

language delay

Q8 7 y Child health, lifestyle and nutrition

Q 9 8 y Psychological behavioural and language

skills

Q10 Children Influenza and vaccines June 2010 14 382 13,8%

Q10 Mothers Influenza and vaccines June 2010 11 766 13,5%

Father Pregnancy

QF Pregnancy

week 13-17

Medical history, health, occupation,

exposures, lifestyles, nutrition 77867 94.4%

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2.2 Phenotypes information obtainable through registry linkages

In MoBa , there are samples and data from fathers, mothers and children. Therefore

phenotypes in both adults and children are of interest. Data from the standard notification

form of the child’s birth from the Medical Birth Registry of Norway (MBRN) is already

included in the MoBa database. Several phenotypes can be collected through linkages to

other health registries. In 2012 there are 13 central health registries in Norway, and 19

medical quality registries, with the number growing and maybe reaching 60 - 70 national

medical quality registries in a few years. The national medical quality registries are not

mandatory and not all are national. However, they include detailed information on

phenotypes, test results and procedures. In addition to these 19 quality registers there are a

large number of local and regional registries. Most registries are linkable by using the

personal identification number held by all citizens in Norway. These registries can be linked

with MoBa and provide phenotypes in mothers and fathers, as well as in the children.

Table 5: Phenotypes in National Health Registries

Central Health Registries Phenotype information

1. The Norwegian Cause of Death Register (DÅR) Causes of death

2. The Medical Birth Registry of Norway (MFR)* Maternal health, perinatal and child outcomes/birth outcomes

3. The Norwegian Surveillance System for Communicable Diseases (MSIS)

Selected Infectious diseases

4. The Norwegian Immunisation Registry (SYSVAK)* Vaccination records

5. The Norwegian Surveillance System for Resistence against Antibiotics in Microbes (NORM)

Antibiotic Resistence

6. The Norwegian Surveillance System for Infections in hospitals (NOIS)

Hospital infections

7. The Norwegian Prescription Database (NorPD)* Released medications

8.- The Norwegian Cardiovascular Disease Registry

(HKR)(HKR)

9. The Cancer Registry of Norway (KRG)* Cancer

10. The Norwegian Patient Registry (NPR)* Hospital inpatient/outpatient

11. The Norwegian Information System for The

Nursing and Care Sector (IPLOS)

12. The Registry of the Norwegian Armed Forces

Medical Services

Military Enrollment data

(BMI/health, IQ tests etc)

* Already linked to MoBa

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Table 6: Phenotypes in National Clinical Registries

National Medical Quality registries

1. Diabetes in childhood and

adolescence

11. Arthroplasties

2. Neonatal medicine 12. Hip fractures

3. Diabetes in adults

13. Cruciate ligaments

4. Cerebral palsy 14. Multiple sclerosis biobank)

5. Trauma 15. Acute myocardial infarction

6. Colorectal cancer 16. Stroke

7. Prostate cancer 17. Vascular diseases

8. Intensive care 18. Back surgery

9. Cleft lip and palate

19. Hereditary and congenital neuromuscular diseases

10. COPD (KOLS)

Table 7: Phenotype information from other sources (the list is not complete)

Other sources Phenotype information Number of subjects in study

The Norwegian Twin Registry Several health outcomes 35 000

Helsestasjonsdata* Growth, development,

diseases

National

Congenital heart defect

registry*

BERTHE

Congenital heart defects National

Hospital records*

Details from hospital stays National

KUHR-HELFO data

Primary care National

National Insurance Scheme

(Forløpsdatabasen trygd)

Welfare/benefit data National

CONOR (Cohort of Norway)

Several health outcomes 200 000

MIDIA* Health outcomes, diabetes 50 000

NORFLU*

Pandemic influenza in pregnancy and follow up similar to MoBa

3400

* Already linked to MoBa

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2.3 Phenotype information from clinical assessments in MoBa

Several substudies in MoBa have done or plan to do clinical assessments. The autism study – Autism Birth Cohort (ABC) The ABC Study is a substudy in MoBa done in collaboration with Columbia University in New York, USA. The goal is to investigate causes of autism and to study how autism spectrum disorders (ASD) develop in children. The recruitment of children into the ABC Study started in autumn 2005. About 800 children have been assessed at the ABC-clinic thus far. Children with symptoms and signs indicating ASD are invited to take part in a comprehensive one-day clinical assessment in Oslo. The clinical assessments are conducted by child psychologists and child psychiatrists from Nic Waals Institute, a child psychiatry clinic in Oslo, and take place at Lovisenberg Diakonale Hospital. A wide selection of standardized tests of development and psychiatric symptoms is used, and a medical examination is also included. A random sample of children is also selected as controls and invited to take part in the clinical assessments. The purpose of the control group is to serve as a comparison group to the children with ASD. The ADHD Study The study is a substudy within MoBa in collaboration with Oslo University Hospital, Ullevål, and began in January 2008. The ADHD study intends to identify early signs among pre-school children and to find the causes of ADHD. The ADHD study recruits children for clinical assessment of social development. Assessment of three-year-olds has been ongoing since the fall of 2007, and over 1200 children will be included by 2012. Assessment of eight-year-olds will begin in the fall of 2011. All who participated in the study at age three will receive a new invitation. Additionally, children who have not previously participated in the ADHD study will be recruited from MoBa. The BraMat study Bramat is a substudy including 200 of the MoBa women. This project is part of the international collaboration NewGeneris; Newborns and Genotoxic Exposure Risks, with 25 institutions from 15 European countries. The aim is to study toxic compounds in food and food safety. This study will collect blood samples from the children at age 3. The Epilepsy in Childhood Study (EPYC) The EPYC study is funded by RCN 2012-2014 and will collect detailed data on childhood epilepsy from medical records in child neurology departments across the country. Linkage with the NPR has already been performed and about 700? children with epilepsy have been identified. Altogether, we expect to identify about 1400? children with epilepsy. The Childhood Cancer and Epigenetics study In collaboration with a large international collaboration of birth cohorts in cancer research

(I4C). The International Childhood Cancer Cohort Consortium (14C) is an alliance of several

large-scale prospective cohort studies of children to pool data and biospecimens from

individual cohorts to study various modifiable and genetic factors in relation to cancer risk.

This initiative brings together international multidisciplinary teams of epidemiologists, basic

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scientists, and clinicians, to collaborate on investigations into the role of early-life exposures

on cancer risk. This international alliance of longitudinal studies of children has the potential

to make major contributions in advancing understanding of the role of early-life exposures in

childhood cancers and other diseases. Most research to date has focused on cancer risk

factors in adulthood, but there is growing awareness that early-life exposures may be

important factors for cancer risk in both childhood and adulthood. The MoBa study and the

Danish birth cohort (DNBC) have initiated a project focusing on prenatal exposures,

epigenetics and leukemia in childhood, and there are several applications for funding

pending. The leukemia project will link cohort data to cancer registries, and use maternal

plasma analyses from pregnancy and cord blood DNA, in addition to look at DNA at later

ages in the child to investigate epigenetic markers related to cancer development.

Other planned substudies: Several other sub-studies with clinical examinations are being planned, for example a clinical

examination of children at around age 8, including respiratory outcomes and autoimmune

disorders.

2.4 Reliability and validity studies Biological markers in urine and blood may also be used to validate questionnaire information

in MoBa. This has been done for several nutrients, and for smoking.

2.5 Current studies using biological samples in MoBa

Several projects within MoBa have already used biological samples from the MoBa biobank.

The studies have used DNA from mothers and children, plasma and urine, and biological

markers have been studied both as exposures and outcomes. More projects are at different

stages of planning in using biobank material, some are close to retrieving samples, and some

are gathering approvals. In table 8 is a list of projects which have retrieved samples from the

biobank by 2012.

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Table 8: Phenotypes in current studies using biological samples in MoBa

Principal Investigator

Exposures Phenotype Year of Retrieval

Biological Material

Samples (n)

P Magnus NIPH

Folate and fatty acids

Neurodevelopmental disorders

2008 DNA Plasma

1440 539

W Nystad NIPH

Nutrients Smoking

Methylation of DNA Respiratory outcomes

2008 2010 2111

DNA Plasma DNA

436 436 1136 *2

SE Vollset, NIPH/MBRN

Nutrients one-carbon metabolism

2008 DNA Plasma

3000 3000

F Frøen, NIPH Genes Stillbirths 2009 DNA 165

G Brunborg, NIPH

Mutations DNA microsatelites in triads

2010 DNA 95

I Lipkin/ C Stoltenberg Un. Columbia/ NIPH

Prenatal biomarkers

Delayed language development and autism spectrum disorders (ABC)

2006 Plasma 133

B Jacobsson Sahlgrenska

Genetics and proteins

Spontaneous preterm birth:

2007 DNA Plasma

1076 29

B Jacobsson, Sahlgrenska

Systems biology

Spontaneous preterm birth

2009 DNA

2600 (3306)

R Austgulen, NTNU

CMV Preeclampsia 2008 Plasma 2500

AL Boyles, NIEHS, USA

Folate receptor auto-antibodies

Birth defects 2008 Plasma 334

MP Longnecker NIEHS, USA

Perfluorinated alkyl levels

Time-to-pregnancy 2009 Plasma PMI

1000

MP Longnecker NIEHS, USA

Temporal variability

organophosphate pesticides and BPA

2009 Urin 810

A Moffett Cambridge, UK

KIR and HLA-C-genes

Reproductive success

2009

DNA 600 1000

A Moffett University of Cambridge, UK

Genes, pre-eclampsia, IUGR

Reproductive success

2007 DNA 1181

C Bulic UNC USA

Genes Developmental factors

2008 DNA leftovers

2000

R Troisi NCI, USA

Pregnancy Breast Cancer 2011 Plasma 318

SM Engel, UNC, US

BPA Analyte measures 2011 Urine Urine

135 15

TW Skjerden, NIPH

Risk of sample exchange

2011 2012

DNA 384

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AK Daltveit NIPH/UiB

B vitamins Imprinted genes 2011 DNA 1136

RT Lie, UiB/NIPH

Environmental genetic

Orofacial clefts 2012 DNA 1569

3 Ethics and approvals

3.1 Approvals for linkages

Links to health registries, other than MBRN, must be approved by the MoBa SMG, the

Regional Ethical Committee (REK) and the owner of the register concerned. Also linking of

MoBa data and MBR from the mother’s own birth record requires approval from REK and

MoBa SMG. At present, MoBa data have been linked with several registries and several

studies using registry based phenotype information is in progress. Once a link is approved for

one study it may be referred to when applying for equivalent studies.

3.2 Access to data and/or biological specimens

Detailed information on access to MoBa data and how to apply for data are described in

MoBa conditions for access to data and biological materials (Appendix 3).

All use of data should be in accordance with Norwegian and international legislation and

guidelines for epidemiologic research. All research should be based on respect for the well-

being and integrity of the participants. The Director General at the NIPH is responsible for

the MoBa database. Researchers can apply for access to data. Any access to data will be

considered as a sub-study of MoBa. For each sub-study, a contract will be written between

the NIPH and the PI of the research project and his/her research institute. The agreement

regulates the right to study one or more specific research questions during a defined limited

period of time. All sub-studies that use MoBa data must have a defined scientific

administrator or institution responsible for the necessary legal and ethical approvals, and a

PI with scientific responsibility for the project.

3.3 Access to results from biological analyses

In addition to access to data, the researchers may apply for use of the collected biological

material. Projects that perform analyses on the biological material will have exclusive rights

to the obtained results for a limited time period as regulated in the collaboration contract

with NIPH. Results of the analyses, including the description of methods and its quality

parameters, will subsequently be made available for other studies. Results from analysis of

biological material will be stored in the MoBa database. Large amounts of results from

genome wide association (GWAs) studies and DNA sequencing will be stored in appropriate

facilities that provide secure storage and access to the data. All results will be harmonized so

they can be linked with health data from the questionnaire database. Merged data of

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questionnaire and analytic results can be applied for by researchers and will be available

according to contracts.

3.4 Approvals for Sub-cohorts

There are several sub-cohorts based on MoBa data. The sub-cohorts focus on particular

exposures and/or outcomes. Sub-cohorts are conducting separate data collections, covering

new data and biological samples, in addition to MoBa data. Such sub-cohorts use the MoBa

infrastructure, but are organised as a separate research project with a steering committee

and a research protocol, and they have their own regulatory approvals. Access to data from

the subcohorts is governed by the steering committee in each sub-cohort and the MoBa

SMG. All approved sub-studies in MoBa are registered in a project database at NIPH, and

given a unique reference number. An updated list of all sub-studies with the names of

principal investigators and titles of sub-studies will be posted on www.fhi.no/moba. A list of

publications based on MoBa data will also be found there.

3.5 Ethics and regulations

Participation in MoBa is voluntary and based on informed consent. The participants agree to

donate biological material and information about themselves. The participant may at any

time withdraw from the study. Data already included in data analyses will not automatically

be deleted, unless the withdrawal specifies this. Children are included after consent from the

mother. Children will be informed personally about the study when they are 15 years. Once

the child reaches18 years old, MoBa will need informed consent from the child for further

storage of the data.

New sub-studies, which require active participation (completion of new questionnaires,

clinical investigations, evaluation of exposure or new biological samples) beyond that

explicitly stated in the signed consent form, will require a new consent. The consent should

also include access to transfer new data into the main database. Sub-studies that require

collection of new data will need approval from REK. As a main guideline, invitations to

participate in sub-studies will be sent by post to avoid undue influence of the researcher on

the participant. Only the MoBa data management unit will be able to identify and contact

the participant.

Participants can be recruited to sub-studies on the basis of disease information (e.g. pelvic

pain or incontinence) or pregnancy outcomes about which they are already informed (e.g.

congenital abnormalities) or based on geographical location, child's date of birth etc. As a

guiding principle, recruitment cannot occur based on lifestyle habits; for example, smoking.

If participants are to be recruited on the basis of findings from blood- and urine analyses,

they must previously have given written consent stating that they are aware that they will be

informed of the results of the blood- and urine analyses.

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Data from the standard notification form of the child’s birth from the Medical Birth Registry

of Norway (MBRN) is included in the MoBa database. The Norwegian Data Inspectorate has

granted a concession for this.