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

14,541

105,422

96,840

10,627

245,000Jerusalem Perinatal Study-Israel

92,408

Collaborative Perinatal Project – USA

58,000

3rd 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 Tikellis1, Martha Linet2, Jean Golding3, Camilla Stoltenberg4, Mads Melbye5, China6, Anne-Louise Ponsonby1, Terence Dwyer1

Prepared for submission to Environmental Health Perspectives

Waiting for feedback from some co-authors

TIHS

ALSPAC BDSS-China

MoBaDNBC

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20 30 40 50 60 70Folic acid supplementation use (%)

CL incidence per millionFitted values

Risk Factor Mean increase in CL incidence (per million) -coefficient (95%CI)

Maternal prenatal folic acid supplementation 0.11 (-0.15 to 0.36) Maternal age (years) 1.24 (0.42 to 2.05)* Mother completed university degree (Yes, No) 0.23 (-0.43 to 0.89) Mother currently married (Yes, No) 0.11 (-0.13 to 0.35) Maternal smoking during pregnancy (Yes, No) 0.24 (0.09 to 0.39)* ‡

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

https://communities.nci.nih.gov/i4c

• 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 EnvironmentalWorking 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

1) Intake of folic acid supplementation during pregnancy by trimester(or weeks gestation when used)

2) Supplementation source: Folic acid on its own, with iron Or in a multi-vitamin

3) Other vitamins include: Calcium, Iron, Zinc, Multivitamins

CORE FROM FOUNDATION COHORTS

Obtain information from packaging/bottle brought into interview (OR collect information from manufacturers, supermarkets and pharmacies)1) Include 3 months prior to finding out about pregnancy (ALSPAC, NCS)2) Frequency of intake during each trimester- need to establish definition of 'regular' use ??3) Total micrograms of folic acid taken during pregnancy4) FFQ that calculates amount of folate obtained from diet (currently computed for ALSPAC, MoBa, DNBC)5) Other vitamins : Vits B1,2, 6,12; Vits A,C, D, E etc (collected in ALSPAC ,MoBa, DNBC and NCS )

ADDITIONAL COMPLEMENTARY DATA (includes source/cohort)

Excel workbook

Excel workbook cont.

VALIDATION

1) Milne E et al Maternal folate and other vit suppl during preg and risk of ALL. Int J Cancer 2010; 126 (11): 2690http://www3.interscience.wiley.com/cgi-bin/fulltext/122653296/PDFSTARTWeak protective effect of maternal folic acid supplmentation and ALL if taken before pregnancyExamined quantity, frequency and duration2) Dockerty et al Vitamin and mineral supplements in pregnancy and risk of ALL. BMC 2007; 7:136http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1925082/pdf/1471-2458-7-136.pdfExamined intake 3 months prepregnancy, during pregnancy and whilst breastfeeding; frequency and dosage. Looked at folate on i ts own, with i ron or as part of multivi tamin

QUESTION LABEL IN WORD DOCUMENT

FA

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 useFA_1 Have you taken any vitamin supplements in the 3 months prior to finding out you were pregnant or during your pregnancy? 1=Yes, 0=No, 999=Don’t know

Supplement Trimester 1 (0-13 weeks)

Trimester 2 (14-27 weeks)

Trimester 3 (>27 weeks)

Folic Acid Iron Calcium Zinc Multivitamins Other, please specify

ADDITIONAL COMPLIMENTARY DATA RECOMMENDED TO OBTAIN INFORMATION ON SUPPLEMENTS FROM

BOTTLE/PACKAGE OR FROM MANUFACTURER/PHARMACY OR SUPERMARKET WHERE SUPPLEMENTS PURCHASED.

FA_3 Complete table for all supplements (including folic acid) reported taking during each time period

3 months before finding out you were pregnant Supplement Brand Name Unit

type Amount per unit (ug or mg)

Start date

Stop date

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

1964-1976

~92,000 live births

166 cases childhood cancer

26 cases of ALL

Collaborative Perinatal Project

1959-1966

~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, 2011

361 048 - mothers and babies

* Includes subsample from DNBC (n=8803 live births)

24, 690 live birthsNovember, 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, HadassahMedical 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 steps1. 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