Harmonization of risk factors for childhood cancer from I4C Cohorts Gabriella Tikellis (PhD) I4C International Data Coordinating Centre Murdoch Childrens Research Institute

Brief overview of progress presented at the third I4C workshop in Lyon in November, 2009 Update on progress from November 2009 to September 2011  Identifying common variables  Transfer of cohort data to I4C IDCC  Database management  Pooled data analysis

National Children’s Study – USA ALSPAC – UK Danish National Birth Cohort – Denmark Norwegian Mother & Child Cohort Study - Norway Sino-US CPBDDP – China Tasmanian Infant Health Survey – Australia 100,000 14, ,422 96,840 10, ,000 Jerusalem Perinatal Study-Israel 92,408 Collaborative Perinatal Project – USA 58,000

3 rd I4C International Workshop: Lyon, 2009 Work initiated as part of the folate hypothesis Prevalence of key exposure variables across five cohorts (TIHS, ALSPAC, DNBC, MoBa, BDSS- China) with folic acid data Preliminary pooled analysis based on data from TIHS and ALSPAC to show ‘proof of principle’

Ecological analysis using prevalence data reported by cohorts The Prevalence of Postulated Risk Factors for Childhood Cancer among Cohorts from the International Childhood Cancer Cohort Consortium (I4C) Gabriella Tikellis 1, Martha Linet 2, Jean Golding 3, Camilla Stoltenberg 4, Mads Melbye 5, China 6, Anne-Louise Ponsonby 1, Terence Dwyer 1  Prepared for submission to Environmental Health Perspectives  Waiting for feedback from some co-authors

Harmonization of variables at the I4C International Data Coordinating Centre (IDCC) Detailed examination of questionnaires from cohorts Document details on the type data available for factors associated with childhood cancer Aim is to create a pooled dataset for each hypothesis or research question being examined within the I4C

Outcome of the harmonization work... I4C New Cohort Protocol Support Package (NCPS) released July 2010

I4C New Cohort Protocol Support Package (NCPS) Provides a support guide for the collection of key environmental exposures associated with childhood cancer Accessed from the NIH I4C Portal at

The NCPS package comprises 2 main parts: 1)An Excel Workbook 2)A Word document

NCPS: Excel Workbook Consists of 5 spreadsheets  Prenatal  Birth  Postnatal  ‘Extra domains’ (areas not examined extensively in the cohorts; e.g. physical activity during pregnancy)  Biospecimens Each sheet contains information on the following:  Common aspects of each core variable  Additional complementary data  Question label in Word document  Validation documentation

Core data: represent aspects of each specific variable that are common to at least five of the six cohorts involved in the folate work. This constitutes the minimum information that any new cohort would be required to collect to be able to pool data with the current established cohorts. Additional complementary data: describes additional information that would complement the ‘core’ data collected. Question label: each variable in the Excel spreadsheet is linked to the Word document through the Question Label code. Validation documentation: provides references for the validation or use of the content included in each question.

Core items: Prenatal Maternal vitamin supplement intake (with a focus on FA) Maternal alcohol intake Maternal smoking/passive smoking Parental SES (education level, employment status, job classification/title*, marital status) Maternal BMI at beginning of pregnancy Previous pregnancies Maternal exposures (cleaning products, chemicals, radiation and animals/pets) Maternal infections during pregnancy- most heterogeneous *Standardization of job classifications currently being undertaken by I4C Environmental Working Group

Core items: At birth Child’s date of birth Gestation age Gender Plurality (twins, triplets etc) Birth outcome (live born, stillborn prior to labor, stillborn during labor, neonatal death) Congenital abnormalities Birth anthropometrics (birth weight, length and head circumference)

Core items: Post natal Maternal alcohol intake Maternal smoking Passive smoking (for child) Breastfeeding Early childhood exposures (infections, medications, childcare, products used in home)

Example of how to use the NCPS : Maternal prenatal maternal folic acid supplementation Excel workbook

Excel workbook cont.

NCPS: Word Document Outlines the wording of questions pertaining to each of the items relating to childhood cancers so that they can be utilized in a study setting Provides format for the responses based on categories generated from the pooling of data from the I4C cohorts.

Wording of question and response format Maternal folic acid and nutrient supplement use BLACK font indicates the ‘Core from Foundation cohorts’ questions. BLUE font indicates the ‘Additional complementary data’ Lengthier ‘Additional Complementary Data’ is contained in the blue shaded boxes. Question label

Initial Requests for NCPS Japan Environmental Child’s Study New UK Study New German Study Campinas Infant Health Survey- Brazil NINFEA-Italy

Progress in data transfer to IDCC

Additional cohort data transferred to I4C IDCC in 2011 Jerusalem Perinatal Study   ~92,000 live births  166 cases childhood cancer  26 cases of ALL Collaborative Perinatal Project   ~58,000 live births  50 cases childhood cancer  11 cases of ALL

September 2011 DNBC  Dataset consisting of cancer cases (n=151, ALL=58) and random selection of cohort (10%, n=8803) transferred to IDCC  Approval for data to be used for folate proposal –complete  Approval for data to be used for BW proposal – pending MoBa  MoBa linkage to cancer registry completed  Dataset consisting of cancer cases (n=106, ALL=33) and random selection of cohort (10%, ~10,000) - being compiled  Approval for use of data in folate and BW proposals- complete

Childhood cancer cases from I4C cohorts available at IDCC : Sept 2011

Total number of cancer cases at I4C IDCC: Sept 2011

Tally of available data at IDCC 183,880- live births * September, mothers and babies * Includes subsample from DNBC (n=8803 live births) 24, 690 live births November, 2009

Current hypotheses being examined within I4C (by order of commencement) 1.Maternal prenatal folic acid supplementation and the risk of childhood cancer (Led by Terry Dwyer, Murdoch Childrens Research Institute) 2.Paternal age and childhood cancer (Led by Jorn Olson, UCLA) 3.Birth weight and childhood cancer (Epigenetics Working Group led by Zdenko Herceg, IARC) (Environmental Birth weight Working Group led by Ora Paltiel, Hadassah Medical Organization, Israel) 4.Pesticide exposure and childhood cancer (Environmental Pesticide Working Groups led by (a)Joachim Schüz (IARC) and (b) Martha Linet, Mary Ward, NCI; Kurt Straif- IARC)

Establishment of I4C Working Groups  Expansion of harmonization and pooling efforts  Examine associations between 1) Birth weight and childhood cancer 2) Pesticide exposure

We have identified 22 variables that are common amongst the hypotheses

Parental age Parental education Marital status Parental occupation Parental/passive smoking Alcohol consumption Radiation exposure Maternal prepregnancy BMI Maternal pregnancy weight gain Parity Prior foetal loss Duration of stages of labour Delivery mode Placental weight Congenital abnormalities

Gestation age Birth weight Gender Birth length Birth order Childhood infections/ day care attendance Growth trajectories

Progress in data management

Web-based Data Pooling Application at IDCC (being developed by Luke Stevens)

Data Pooling Application Web-based MCRI’s secure e-Research portal Restricted access  I4C team only  Can restrict user access at dataset level Ongoing development

Data Pooling Application Dataset summary

Data Pooling Application Variable metadata  Variable name  Label  Type  Coding

Data Pooling Application Select from any dataset Select variables to download Database joins the datasets returning a combined data file

Data Pooling Application Select from any dataset combined data file Database joins the datasets returning a combined data file

Data Pooling Application Edit or Save your query

Data Pooling Application Download –Raw data file –Stats package syntax file

Progress in pooled data analysis

BW and childhood cancer: Sept 2011 Pooled data from 4 cohorts (TIHS, ALSPAC, CPP and JPS) Analysis based on case-cohort design Total number of cases:  130 Childhood cancers  33 Leukemia  25 ALL Models adjusted for gestation age, gender, maternal DM, parental education (>= 12 years)

Results from pooled analysis... To be presented by Ora Paltiel

Next steps: Birth weight Complete the transfer of additionally requested data from ALSPAC and JPS to add additional covariates /confounders (maternal prepregnancy BMI, breastfeeding, maternal prenatal smoking) Incorporate data from MoBa (dataset being compiled) and DNBC (waiting on approval) Complete the cleaning and harmonization of data Consolidate the pooled dataset with data dictionary Begin formal analysis of pooled data from 6 cohorts

Next steps 1.Maternal prenatal folic acid supplementation  Recently received data from DNBC and pending data from MoBa to be incorporated into pooled dataset 2.Birth weight and childhood cancer  Epigenetics WG: awaiting biospecimens  Environmental WG: currently preparing pooled dataset 3.Pesticide exposure  Occupational exposure: working on standardization of job matrix  Farming exposure to pesticides: identifying cohorts with relevant data

Thanks to... MCRI  Terry Dwyer  Anne-Louise Ponsonby  Luke Stevens  Elizabeth Williamson NIH/NCI  Martha Linet  Somdat Mahabir ALSPAC  Jean Golding  Kate Northstone JPS  Ora Paltiel MoBa  Camilla Stoltenberg  Therese Bakke DNBC  Sjurdur Olsen  Jorn Olsen  Marin Ström