Carol H. Kasten, M.D. Geneticist and Lead for Genomic Studies US National Children’s Study National Institutes of Health International Childhood Cancer Cohort Consortium September 2011 Meeting Barcelona, Spain

7-8 MARCH 2011 GENEVA, SWITZERLAND BROCHER FONDATION SYMPOSIUM RECOMMENDATIONS

BROCHER FONDATION SYMPOSIUM “Ethical Issues in the Use of Neonatal Screening Bloodspots in International Population - Based Studies of Childhood Cancer”

BROCHER SYMPOSIUM What brought us here? What do we hope to accomplish? Next Steps

BROCHER SYMPOSIUM What brought us here? Possible Venue for Conference on Ethical Issues 2011

What brought us here?

FONDATION BROCHER

BROCHER SYMPOSIUM What bought us here? NEONATAL BLOOD SPOTS RESEARCH We know DNA can be extracted and used for genetic studies Environmental exposures may be measured What’s the delay? Ethical issues

BROCHER SYMPOSIUM What brought us here? SCIENCE April 2009 – J. Couzin-Frankel

BROCHER SYMPOSIUM What brought us here? SCIENCE August 14, 2009

Two related issues considered Context limited to international childhood cancer research Secondary use of DBS AIMS – Ancestry Informative Markers Data pooling across countries, continents, the equator required to study the antecedents of this rare disease Molecular ancestry will be a confounder

BROCHER SYMPOSIUM DBS Issues What are ethical concerns regarding use of NBS for research? Childhood cancer research? How have some countries responded to these concerns? Successes? How can we assure that newborn screening programs are not adversely affected by research using NBS? What appears to be the best approach to use extant repositories for this research? How could future collection of NBS be changed to address ethical concerns for their use in this research?

BROCHER SYMPOSIUM AIMs Issues Use of AIMs in research When should AIMs be used (in what sort of research)? Should their use be restricted to multi-ethnic, multi-racial population–based studies? Which AIMS should be used and who decides? Which Reference Populations? What safeguards are needed to protect all ethnicities and races? How can AIMs be used while still protecting the participants from racial/ethnic discrimination? Should there be public engagement?

BROCHER SYMPOSIUM What do we hope to accomplish? CHARGE TO SYMPOSIUM Summarize the comments and opinions of speakers and participants regarding use of DBS for international epidemiological childhood cancer research and the role of AIMs in that research. DBS: Dried (Newborn)Blood Spots AIMs: Ancestry Informative Markers

Brocher Recommendations DBS Use for Research DBS are unique Differences in public engagement, ethical perspectives, and policies on DBS use and storage were identified to be major challenges in using DBS collaboratively. Because of the value of DBS for research, Brocher Contributors strongly supported their use for this purpose. They recommended that DBS be stored for decades after initial screening has been performed.

Brocher Recommendations DBS Use for Research DBS collection and storage should be carried out according to local laws and stringent authorized procedures to ensure safety and security. Recommendations for national guidance regarding retention and use of DBS specimens after newborn screening have been recently drafted in Denmark and the US.

Brocher Recommendations DBS Use for Research Brocher Contributors will work as a group to prepare international guidelines on parental consent and the secondary use of de-identified DBS, using these guidance recommendations as templates.

Brocher Recommendations AIMs in Data Pooling In international data-pooling studies of childhood cancer using DBS for genetic and environmental analyses, it may be important to consider using Ancestry Informative Markers (AIMs) to control for confounding by genetic ancestry. As Yang et al reported recently in a large case- only cohort study of children with acute lymphocytic leukemia, the single most important determinant of relapse after induction completion was a 10% or greater component of genomic ancestry variation co- segregating with Native American ancestry [10]. Moreover, children with an elevated ancestry- related relapse risk who received an additional phase of chemotherapy after induction had their relapse rate fall to that of non-at risk children.

Brocher Recommendations AIMs in Data Pooling As Yang et al reported recently in a large case- only cohort study of children with acute lymphocytic leukemia, the single most important determinant of relapse after induction completion was a 10% or greater component of genomic ancestry variation co- segregating with Native American ancestry.

Brocher Recommendations AIMs in Data Pooling Despite their utility the Symposium participants presented many ethical issues inherent to identification of ethnicity, such as discrimination based on one’s genetic and geographic ancestry. The participants agreed that their use is appropriate in international data pooling studies of childhood cancer; and, robust discussion of this opinion in scientific communities and the lay public must be promoted.

Brocher Recommendations Symposium participants emphasized that DBS must first and foremost serve their primary function as a screening tool for treatable congenital disorders, including infectious diseases in some countries. Low and middle income countries may broaden their screening programs to include DBS for research as sustainability and resource allocation permits.

Brocher Recommendations As a result of new research and policy documents presented at the Symposium, contributors have initiated development of internationally accepted guidelines to facilitate the use of DBS -and AIMs where appropriate - in data pooling research. Contributors emphasized the importance of engaging the public in this process.

Brocher Recommendations Consensus from the March 2011 Brocher Symposium: There is an urgent need for internationally-accepted ethics policies for large data pooling studies on childhood cancer using DBS and AIMs.

A Symposium with a View

Contributors and Co-Organizer

Another Contributor

The AIMs Group

Brocher Symposium 7-8 March 2011 “…on the shores of Lake Geneva…”

2011 Brocher Symposium Just Some of the Contributors…

POST BROCHER SYMPOSIUM What’s changed? Wiemels’ data published in CEBP August 2011 These data presented at Brocher solidified group’s unanimous support for publication of recommendations Nature editorial…

Nature Editorial July 2011 Nature 2011;475:139

Brocher Letter Submitted to Editor - Nature We thoroughly support the view expressed in the editorial “There will be blood.” 1 The issue raised has become urgent with the June 2011 publication of Chang et al’s "Profound Deficit of IL10 at Birth in Children Who Develop Childhood Acute Lymphoblastic Leukemia” which reported that IL10 levels measured in archived dried blood spots (DBS) were profoundly lower in cases of children who went on to develop childhood acute lymphocytic leukemia than in controls. 2 If validated, this research will have provided us with the first biomarker for later onset of childhood cancer. The potential of this research should not be underestimated nor should the ethical hurdles which may be constructed if countries around the globe do not heed the editorial warning. At the March International Brocher Symposium “Ethical, Legal, and Social Issues in the Use of Neonatal Blood Spots for Population-Based Research on Childhood Cancer,” experts emphasized the urgent need for internationally accepted ethics policies for use of archived DBS in research. 3 Without these changes to collection and DBS storage policies, data pooling across countries which is essential for finding the causes of childhood cancer, will not be possible. 4 As a result of new research and policy documents presented at the Symposium, participants have initiated development of guidelines to facilitate the use of DBS in international data-pooling research. As emphasized in the editorial, there was a strong consensus at the Symposium that the public, parents, and policymakers must be engaged in this process. The international implementation of newly issued or extant policies on consent for collection, storage, and secondary research using DBS was uniformly endorsed. 4,5 We echo the call for action in “There Will Be Blood.” It is imperative for parents, researchers, and policy experts to work together to craft policies which fundamentally improve the consent process including permission to use archived DBS in research. Surely the glimmer of pre-symptomatic diagnosis of childhood cancer should bring all groups together quickly to address the ethical gaps identified in “There will be Blood.”