The Childhood Leukemia International Consortium and I4C

1. The Childhood Leukemia International Consortium and I4C • CLIC is a global consortium of case-control studies of childhood leukema – the most common subtype of childhood cancer • CLIC and I4C are complementary to each other in helping solve puzzles of childhood leukemia

2. Case-control vs Prospective Cohort studies cases Healthy subjects some exposed some not Questionnaires Questionnaires

3. Childhood Leukemia International Consortium (CLIC) Patricia A. Buffler, PhD, MPH, CPH University of California, Berkeley School of Public Health Division of Epidemiology Children with Cancer Scientific Conference April 26, 2012 Website: https://Clic.berkeley.edu CLIC_Centraloffice@berkeley.edu

4. Map of Childhood Leukemia Studies participating in CLIC 9,10,11 13 6,7 12 1 14 4 15 2 3 16 5 8 17 18 Principal Investigators/designated co-investigators, study area (from left to right): 1) Beth Mueller, Parveen Bhatti, Washington State, USA; 2) Patricia Buffler, Catherine Metayer, California State, USA; 3) Michael Scheurer, Melissa Bondy, Texas State, USA; 4) Logan Spector, USA; 5) Patricia Monge, Costa Rica; 6) Claire Infante-Rivard, Quebec, Canada; 7) Daniel Sinnett, Quebec, Canada; 8) Maria Pombo-de-Oliveira, Sergio Koifman, Brazil; 9) Eve Roman, Jill Simpson, UK; 10) Jill Birch, Malcolm Taylor, Manchester, UK; 11) Michael Murphy, UK; 12) Jacqueline Clavel, France; 13) Joachim Schüz, Peter Kaatsch, Germany; 14) Corrado Magnani, Italy; 15) Eleni Petridou, Nick Dissypris, Greece; 16) Sameera Ezzat, Egypt; 17) Elizabeth Milne, Bruce Armstrong, Australia; 18) John Dockerty, New Zealand.

5. Summary of CLIC Member Studies • As of 2012, CLIC has 18 Principal Investigators (PIs) representing 22 childhood leukemia studies from mid 1970’s to present • ~50% of the studies have biospecimens

6. History of CLIC The Children with Cancer UK, the National Cancer Institute, the National Institutes of Environ-mental Health Sciences (NIEHS), and Environ-mental Protection Agency (EPA), US and the Cancer Council Western Australia have provided support for CLIC organization and/or pooled analyses.

7. Mission of CLIC • Develop and support collaborations between scientists involved in CL research to accelerate knowledge on factors that influence the risk of childhood leukemia through epidemiological studies and related research. • Encourage free exchange of results (published or unpublished) and ideas in a collegial environment without fear of competition.

8. CLIC Management Group A Management Group (Executive Committee) is elected by the Coordination Group every two years.

9. “Lessons Learned” • FUNDING is imperative to support a consortium. • Regular communication and timely feedback between steering committee members and PIs allow for accountability and progress. • In person meetings are invaluable. • Importance of flexibility.

10. CLIC Working Groups – Pooled Analyses

11. How CLIC and I4C can interact fruitfully Produce parrallel papers on data relating to the same hypothesis Hypotheses related working groups eg, birth weight, pesticides, infection Hypotheses related working groups eg, birth weight, pesticides, infection Look at specific Questions that arise From analyses that each Conduct – eg recall or Selection bias, or details Of exposure measurement Or of childhood cancer subtype

12. However in research on childhood cancer additional evidence from prospective cohort studies is highly desirable • to address concerns regarding recall bias and • to permit collection of biological specimens prior to disease onset Environmental chemicals Infections in childhood Birth weight

13. The ClIC consortium of case-controls studies and 14C are highly complementary to each other and have begun working together

14. In childhood cancer, cohort studies have been difficult to mount because they need to be very large ( hence the development of I4C) and the principal epidemiological approach has been the case-control study

15. Outstanding Research Questions • What are the critical windows of exposure? • What are the “environmental” (or non-genetic) risk factors for rarer childhood leukemia subtypes like AML, APL, T-cell ALL? • What risk factors are specific to childhood leukemia cytogenetic/molecular subtypes of ALL and AML, or other tumor characteristics? • What role does genetics play in CL etiology? • What is the contribution of gene-environment (GxE) interaction?

16. Organization of the CLIC

17. CLIC Core Logistics Groups Core Logistics Groups advise and facilitate cross-cutting issues within the consortium. There are four groups.

18. CLIC Interest Groups The Interest Groups will promote collaborative projects in specific areas of childhood leukemia research. There are nine Interest Groups in CLIC.

19. CLIC Procedures

20. Challenges • Specificity of studies regarding prevalence of exposure, design, confounders (e.g. socio-economic status, ethnicity, etc.) • Meta-data analyses vs. pooling of raw data • Recognize potential for selection bias in observational studies that require data access, subject consent, and importance of assessing the representativeness of study participants • Data harmonization

21. Opportunities of Collaborations with the International Childhood Cancer Cohort Consortium (I4C) • Exchanges of ideas • Genetic, epigenetic and tumor biology studies • Exposure assessment • Ethical issues • Emerging hypotheses • Exchanges of procedures • Standardize data • Develop background information on exposure by country, time and activity patterns.

22. Acknowledgements • Families of CLIC Member Studies • CLIC Coordination Group (Principal Investigators) and Management Group • Other CLIC Collaborators (Researchers, Clinicians, Advisors) • Our sponsors at the National Cancer Institute US, Children with Cancer UK, National Institute of Environmental Health Sciences (NIEHS) US, Environmental Protection Agency (EPA) US, Telethon Institute for Child Health Research, Australia

23. Thank you! CLIC is an open consortium and welcomes individuals interested in childhood leukemia research. Membership applications and other CLIC guidelines can be found online at the CLIC website, https: clic.berkeley.edu. If you have any questions regarding the Consortium and/or difficulty accessing any of the documents, please contact Alice Kang at clic_centraloffice@berkeley.edu.

24. Additional Slides

25. CLIC Website – clic.berkeley.edu

26. CLIC Coordination Group • The Coordination Group includes the Principal Investigator (PI) of each childhood leukemia study that will contribute data (and possibly additional co-PI for large studies). In the event the PI cannot be in the Coordination Group, s/he will nominate an authorized designate to represent her/his study.

27. Active Members of the CLIC Coordination Group

28. Active Members of the CLIC Coordination Group (continued)

29. Active Members of the CLIC Coordination Group (continued)

30. Active Members of the CLIC Coordination Group (continued)

31. Proposed Childhood Leukemia Studies

32. Proposed CLIC Papers • Introductory Paper on CLIC • Fetal growth and risk of childhood acute lymphoblastic leukemia (ALL) • Vitamin/folate supplementation before and during pregnancy, MTHFR variants and risk of childhood ALL and acute myeloid leukemia (AML) • Parental smoking and xenobiotic-metabolizing gene variants

33. Biospecimens in CLIC Studies

34. CLIC Database • Web-based inventory under development • Surveys for availability of biospecimen, genetic, and cytogenetic data • Seek additional funding to complete and maintain CLIC data harmonization

35. CLIC Pooled Analyses (continued)

36. CLIC Pooled Analyses

37. Case-controlstudies • Compare a group of patients or ‘cases’ with ‘controls’ free of disease cases controls exposed Exposed

38. The importance of both case-control studies and prospective cohort studies rests on the assumption that Data on human subjects is essential for gaining an understanding of the environmental causes of childhood cancer and adds great value to the genetic research

39. Case-control studies - of the kind involved in the CLIC consortium- are a central component of this work because they allow us to conduct studies with substantial power and focused measurement of exposures – cost-effectively