Sample and Data sharing in the era of "big data" in biology

1. Sample and Data sharing in the era of "big data" in biology Dr. Anne Cambon-Thomsen, MD, DR CNRS Inserm and University of Toulouse III Paul Sabatier, UMR 1027: Epidemiology and public health analyses Societalplatform « Genetics and society » www.u1027.inserm.fr ; http://societal.genotoul.fr/ EUCCONET seminar, 8/7/2013, INED, Paris « International access to cohort data »

2. Outline • Large scale biology and bioresources/data sharing • The ethical dimensions and legal framework of bioresources/ data sharing • Revision of data protection Directive • ELSI aspects, international coordination: ELSI 2.0 • Towards incentives; example of BRIF initiative • Conclusion EUCCONET seminar 8/7/13, Paris

3. International collaboration “…The full benefits for which the subjects gave their samples will be realized through maximizing collaborative high quality research. Therefore there is an ethical imperative to promote access and exchange of information.” Data Storage and DNA Banking for Biomedical Research: Technical, Social and Ethical Issues, ESHG, 2001, art. 17. What does prevent sharing of bioresources ? Technical aspects? Protection of individuals? Intellectual / institutional protection? Lack of rewarding mechanisms? EUCCONET seminar 8/7/13, Paris

4. Why is sharing cohort samples and data important? • Enable research • Build on existing resources • Construct communities • Optimise fund investment in research • Ethical imperative • Policies in place (in light of open access) • But… EUCCONET seminar 8/7/13, Paris

5. Why are such resource sharing important…. and poorly done? • Much biomedical/epidemiological research is based on using bioresources • Their access to all relevant researchers is essential • Promoting their sharing is crucial • There are today ~ no incentive to that. EUCCONET seminar 8/7/13, Paris

6. What to share and when? In Research, Data Sharing = set of practices aiming at allowing and facilitating the re-use of data gathered or produced in the context of (publicly funded) research by other researchers (does not imply necessarily free access) « One of the lessons from the Human Genome Project (HGP) was the recognition that making data broadly available before publication can be profoundly valuable to the scientific enterprise and lead to public benefits. This is particularly the case when there is a community of scientists that can productively use the data quickly — beyond what the data producers could do themselves in a similar time period, and sometimes for scientific purposes outside the original goals of the project.” NATURE|Vol 461|10 September 2009, 168-170 éminaire Data sharing-BRIF 6/6/2013 6

7. An OECD text of reference In 2004, the ministries of science and technology asked OECD to define guidelines based on agreed principles in order to facilitate access to digitalised data issued from publicly funded research. OECD Principles and guidelines for access to data from publicly funded research (2007) http://www.oecd.org/dataoecd/9/60/38500823.pdf Séminaire Data sharing-BRIF 6/6/2013

8. Landscape of data sharing (1) • Principles for rapid release of genome sequence data from the HGP formulated at a meeting in Bermuda 1996; • Bermuda meetings (1996, 1997 and 1998) • 2003 Fort Lauderdale meeting, • rapid prepublication release (resource for scientific community) • responsibilities of the resource producers, resource users, and the funding agencies. • OECD 2004 • 2008 Amsterdam meeting extended to proteomics • 2009 Toronto statement on pre-publication data release • 2010 : Oxford IntConf on data sharing (+P3G) Séminaire Data sharing-BRIF 6/6/2013

9. The landscape of data sharing (2) • 2011: Sharing research data to improve public health: joint statement of purpose (+ Comment in Lancet, 10/1/11) • 2011: A data sharing Code of Conduct for international genomic research • 2012: The tension between data sharing and the protection of privacy in genomics research.Annu Rev Genomics Hum Genet 13, 415 (2012) EUCCONET seminar 8/7/13, Paris

10. The landscape of data sharing (3) • June 2013: Global alliance; Geneticists push for global data-sharing • International organization aims to promote exchange and linking of DNA sequences and clinical information: 69 institutions in 13 countries • Nature 498, 16–17 (05 June 2013) | doi:10.1038/498017a http://www.nature.com/news/geneticists-push-for-global-data-sharing-1.13133 • A projectbetween Indiana University (E Meslin) - UMR 1027 - Consortium GEN2PHEN “Big Data Sharing by Genomics and Health Informatics Researchers: Identifying the “Top Ten” Impediments and Solutions” EUCCONET seminar 8/7/13, Paris

11. Guiding principles • Human dignity • Human rights and fundamental freedoms • Autonomy • Privacy • Non-discrimination and non-stigmatization But also • Solidarity • Common good Duty to explicit, Duty to use, Duty to share : transparency EUCCONET seminar 8/7/13, Paris

12. Balancing values evolve “Ethics does not consist of a static set of theories or principles that can unproblematically be ‘applied’ to new situations.” Knoppers and Chadwick, Nat Rev Genet, 2005 “However, informed consent is far from being a magical solution to ethical preoccupations,…” Cambon-Thomsen, Nat Rev Genet, 2004 “A focus on informed consent is also highly convenient for researchers and their institutions, and above all commercial enterprises. The reason is simple: insofar as individual rights delimit the domain of ethics, they shield other substantive issues from critical scrutiny.” Garrath, Genomics, Society, Policy, 2005 EUCCONET seminar 8/7/13, Paris

13. Specific questions • What are the ethical challenges in sharing internationally children cohort data? • Is large scale biobanking, cohort and genome analysis methods modifying the picture of privacy protection and non discrimination from the ethical point of view ? • What is the evolution of the EU legal framework ? EUCCONET seminar 8/7/13, Paris

14. Ethical issues • Numerous studies/markers might immediately or later on, in case of long term analyses, reveal predictive information : issue of incidental findings and issue of public release. • How to handle such potential information must be foreseen (duty to inform?). • Issues of re-identification (cross of databases) • Sharing of data and samples • Growing maturity of child to take into account • Right to know/right not to know for parents EUCCONET seminar 8/7/13, Paris

15. The present debate on unsolicited findings • Huge debate about sequencing becoming a usual practice • ACMG recommendations • ESHG recommendations • Debates in « Science • Consultation on the topic (in general) by the USA   “Presidential Commission for the Study of Bioethical Issues”. [ended July 5] EUCCONET seminar 8/7/13, Paris

16. Patient Autonomy and Incidental Findings (IF) in Clinical Genomics • This paper (S Wolf et al. in Science, Policy Forum, May 16) • pushes back against these recommendations, and offer compelling reasons why patient autonomy must remain firmly in place as science advances, • urges ACMG to reconsider their recommendations. “Returning genetic IF without patient consent is misguided.” • Another paper • same issue (Mc Guire et al.) supports ACHG views “Laboratories have an obligation to report clinically beneficial IF” So the debate goes on. What do you think? The 10th International Workshop on Advanced Genomics Tokyo, May 21-23, 2013

17. Science 18 January 2013: Vol. 339 no. 6117 pp. 321-324 - Report + Interview + 39 p Supp. Material.IdentifyingPersonalGenomes by SurnameInference Melissa Gymrek1,2,3,4, Amy L. McGuire5, David Golan6, Eran Halperin7,8,9,Yaniv Erlich1 1Whitehead Institute for BiomedicalResearch, Cambridge, MA , USA. 2Harvard–Massachusetts Institute of Technology (MIT) Cambridge, MA , USA. 3Program in Medical and Population Genetics, MIT and Harvard, Cambridge, MA , USA. 4Dept MolecularBiology &Diabetes Unit, Massachusetts General Hosp, Boston, MA , USA. 5Center for MedicalEthics and Health Policy, BaylorCollege of Medicine, Houston, TX , USA. 6Department of Statisticsand Operations Research, Tel AvivUniversity, Tel Aviv, Israel. 7School of Computer Science, Tel AvivUniversity, Tel Aviv, Israel. 8Department of MolecularMicrobiology and Biotechnology, Tel-AvivUniversity, Israel. 9The International Computer Science Institute, Berkeley, CA , USA. Science 18 January 2013: Vol. 339 no. 6117 p. 262 - News & Analysis Genetics Genealogy Databases Enable Naming of Anonymous DNA Donors John Bohannon Science 18 January 2013: Vol. 339 no. 6117 pp. 275-276 - Policy Forum - ResearchEthics The Complexities of GenomicIdentifiability Laura L. Rodriguez1, Lisa D. Brooks1, Judith H. Greenberg2, Eric D. Green1 1National Human Genome Research Institute,National Institutes of Health (NIH), Bethesda, MD, USA. 2National Institute of General Medical Sciences, NIH, Bethesda, MD , USA.

18. Science 8 February 2013: Vol. 339 no. 6120 p. 647 - Letter Legal Limits to Data Re-Identification Stephen Wilson Lockstep Consulting Pty Ltd, Five Dock (Sydney) NSW 2046, Australia. Science 1 March 2013: Vol. 339 no. 6123 p. 1032 - Letter Data Re-Identification: Prioritize Privacy Amy Gutmann. Chair, Presidential Commission for the Study of Bioethical Issues and President, University of Pennsylvania, Philadelphia, PA, USA Hastings Cent Rep.2013 May-Jun;43(3):15-8. Found your DNA on the web: reconciling privacy and progress. Gutmann A, Wagner JW. Science 1 March 2013: Vol. 339 no. 6123 p. 1033 - Letter Data Re-Identification: Protect the Children David GurwitzHuman Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Israel Science 1 March 2013: 1032-1033 - Letter Data Re-Identification: SocietalSafeguards Russ B. Altman, Ellen Wright Clayton, Isaac S. Kohane, Bradley A. Malin, and Dan M. Roden 1Department of Bioengineering, StanfordUniversity, Stanford, CA, USA. 2Center for BiomedicalEthicsand Society, Vanderbilt University, Nashville, TN, USA. 3Department of Pediatrics, Children'sHospital Boston, Boston, MA, USA. 4Department of BiomedicalInformatics, Vanderbilt University, Nashville, TN, USA. 5Department of Medicine, Vanderbilt University, Nashville, TN, USA..

19. EU Data protection revision: potential implications for health research Slidesprepared in collaboration withwith V. Anastasova, A. Mahalatchimy, E. Rial-SebbagUMR 1027 Inserm-Université de Toulouse III Paul Sabatier, Toulouse MeDALL-Annual meeting 14th and 15th January 2013, Berlin, Germany

20. Introduction • The main instrument for the legal protection of personal data in the EU: Directive 95/46/EC on the protection of individuals with regard to the processing of personal data and on the free movement of such data. • Purpose: To find the right balance between a high level of protection for the privacy of individuals and the free movement of personal data within the EU. • The Directive is currently under revision  Proposalfor a Regulation on the protection of individuals with regard to the processing of personal data and on the free movement of such data (General Data Protection Regulation) , 25/01/2012, then various comments and amendments proposals. MeDALL-Annual meeting 14th and 15th January 2013, Berlin, Germany

21. MeDALL-Annual meeting 14th and 15th January 2013, Berlin, Germany

22. Objectives of the revision • To modernizethe EU legal system regarding technological developments; • To improve the clarity and coherence of the EU legal framework ; • To achieve effective legal implementationof data protection and of the rules allowing their lawful free movement; • To continue guaranteeing a high level of individuals’ protection (personal rights) in the processing of personal data in all areas of the EU’s activities. MeDALL-Annual meeting 14th and 15th January 2013, Berlin, Germany

23. Agenda I/ Health data protection in the proposal of regulation: 1/ From “Directive” to “Regulation” 2/ New category of sensitive data: genetic data 3/ Enhancement of fundamental rights 4/Reinforcement of international collaboration: transfer to Third Countries 5/Data protection impact assessment 6/New mechanisms of data protection 7/ Data protection authorities : EC and supervisory authorities II/ Emergence of legal regime for the processing of data of a child in the proposal of regulation MeDALL-Annual meeting 14th and 15th January 2013, Berlin, Germany

24. II/ Emergence of legal regime for the processing of data of child in the proposal of regulation (1) • Directive: No particular mention regarding children. • Proposal of Regulation: General provisions dedicated to processing of personal data of a child • Purpose: balance between appropriate protection and special attention to the opinion of the child; • Initiative also supported by the Data Protection Working Party and the Council of Europe;  Potential Implications for research studies involving children . MeDALL-Annual meeting 14th and 15th January 2013, Berlin, Germany

25. II/ Emergence of legal regime for the processing of data of child in the proposal of regulation (2) • Regarding definition of child: • uniformed definition for more clarity: any person below the age of 18 years (reference to UN Convention on the Rights of the Child, 1989); • Regarding fundamental rights of children: • Information in the decision making process : clear and simple, adapted to comprehension of a child able to express his/her opinion; • Consent/Assent: processing of data of a child below the ageof 13 years is lawful if and to the extent that consent is given orauthorisedby the child's parent or custodian; • Special attention to the right to be forgotten and erasure of personal data : respect of child’s wish when he/she reaches the legal majority; • EC may lay down standard forms for specific methods to obtain verifiable consent (potential establishment of European methods about the assent of the child which data are used in research study); MeDALL-Annual meeting 14th and 15th January 2013, Berlin, Germany

26. II/ Emergence of legal regime for the processing of data of child in the proposal of regulation (3) • Regarding the concept of transparency : any information about the research and the way of communication should be in such a clear and plain language that the child can easily understand; • Regarding the transfer to third countries: clearly explained during the decision making process and expressly mentioned in the informed consent form (assent of mature child); • Regarding the data protection impact assessment: duties in research to conduct privacy impact assessment when the study could potentially impact personal privacy of the child; • Regarding code of conduct and certification: incitation to set up codes of conduct concerning information and protection of children, including in paediatric research. MeDALL-Annual meeting 14th and 15th January 2013, Berlin, Germany

27. Conclusion (1) • The provisions exposed above are proposals: necessity to wait for the final version of the Regulation; • More clarification regarding the data processing for scientific research purposes (definition) and their legal regime (consent/assent and exemption); • Necessity to integrate specific provisions on processing of data of children in research studies; • Respect of other relevant legislation forthe processing of personal data for the purposes of historical, statistical or scientific research: article 4 (Clinical trials on minors) of Clinical trials Directive; MeDALL-Annual meeting 14th and 15th January 2013, Berlin, Germany

28. Some proposed amendments to the Regulation proposal for « Data protection » • Deleted exception “or for historical, statistical and scientific research purposes.” • Justification: “Processing of sensitive data for historical, statistical and scientific research purposes is not as urgent or compelling as public health or social protection. Consequently, there is no need to introduce an exception which would put them on the same level as the other listed justifications.” Inauguration CONSTANCES, Paris 7/3/13

29. Some elements to discuss in Regulation proposal: consent (1) 1/ Initial proposal (January, 2012): “Consent should be given explicitly by any appropriate method enabling a freely given specific and informed indication of the data subject's wishes, either by a statement or by a clear affirmative action by the data subject, ensuring that individuals are aware that they give their consent to the processing of personal data.” - For all Sensitive Data - For Data processingconcerning…scientificresearchconsent couldbe one condition but not the only one

30. Some elements to discuss in Regulation proposal: consent (2) 2/ EU Parliamentamendments on the legalregime (Dec., 2012) “The amendments to paragraphs (…) ensure that health data, which is extremely sensitive, may only be used without the consent of the data subject if it serves an exceptionally high public interest and in this case must be anonymised or at least pseudonymised using the highest technical standards.” • For processing of personal data concerning health which is necessary for … scientific research purposes, shall be permitted only with the consent of the data subject (…)

31. Currrent actions • Protestations (Scientificsocieties, consortia, institutions…) • Things are not « frozen » yet • Example of ethicalwith a legal dimension : • tension betweenlegitimity of research and certain aspects of persons ’ protection • whentoolsbecomerules • Wordscounts: • persons’ protection regardingtheir data use vs data protection Inauguration CONSTANCES, Paris 7/3/13

32. Nextsteps • Input of the EC on paediatric research:establishment of a uniform practice; • National regulations remain necessary for research including paediatric research (collaboration EC and national supervisory authorities); • Provisions to be followed up: • Data protection by design; • Data protection and privacy. • Discussion at the EU parliament soon • Vote end of year? MeDALL-Annual meeting 14th and 15th January 2013, Berlin, Germany

33. THANKS TO: My colleagues jurists Velizara Anastasova Gauthier Chassang Aurélie Mahalatchimy Emmanuelle Rial-Sebbag MeDALL-Annual meeting 14th and 15th January 2013, Berlin, Germany

34. Summary (1) • The evolving status of genetic information available • Data versus results; raw data versus interpretated data • Changing of degree of identifiability over time • Changing in capacity of interpretation • Mixture of health related/non health related information • Production of genetic information “unuseful at least presently” routinely • Issue of what is done with this “extra information” (notion of filter) • Perception of genetic information changing • Source and access to genetic information changing (ex: direct to consumer, internet sharing of information) EUCCONET seminar 8/7/13, Paris

35. Summary (2) 2. How data and biological sample sharing policies in science deal with discrimination risk • Lots of information (also in consent) • Not promising full anonymity, but access policy and defined categories of uses • Rely on technology • Responsibility of researchers and their institutions • Transparency of procedures EUCCONET seminar 8/7/13, Paris

36. Summary (3) 3. Empowering versus protecting: what is most efficient? - when you cannot guarantee full anonymity - when privacy concept/practice is changing What to do? - Define responsibilities and make them publicly known - Define professional/community relevant “sanctions” • Empower individuals and groups through information • Organise observatories of practices EUCCONET seminar 8/7/13, Paris

37. Outline • Large scale biology and bioresources/data sharing • The ethical dimensions and legal framework of bioresources/ data sharing • Revision of data protection Directive • ELSI aspects, international coordination: ELSI 2.0 • Towards incentives; example of BRIF initiative • Conclusion EUCCONET seminar 8/7/13, Paris

38. ELSI research and policy jungle • Important questions debated • in many settings • In many countries • In many ways • Resulting in non harmonised policies, that reflect in difficulties to share data/resources EUCCONET seminar 8/7/13, Paris

39. Génétique et société La plateforme sociétale de la génopole Toulouse Midi-Pyrénées, GIS Genotoul – «  Une plateforme sur les enjeux sociétaux des biotechnologies » http://societal.genotoul.fr Responsable : Anne Cambon-Thomsen, anne.cambon-thomsen@univ-tlse3.fr Coordination /juridique: Emmanuelle Rial-Sebbag, emmanuelle.rial@univ-tlse3.fr Manager : Soraya Dauriac, soraya.dauriac@inserm.fr Contact général : societal.genotoul@toulouse.inra.fr Contact appui projets : appui-projets@genotoul.societal.fr

40. EXEMPLES DE REALISATIONS • Human Sample Exchange Regulation Navigator hSERN www.hsern.eu • Service « Ethique et réglementation » dans l’Infrastructure BIOBANQUES (http://www.biobanques.eu/) Gis GenoToul - Bureau 27 juin 2013

41. Obstacles to international ELSI research coordination • Fragmentation • Repetition/duplication • Cultural and legal aspects are national/ regional • Policy / Decision makers often have a national horizon • No easy « general portal » to address questions and search for experts EUCCONET seminar 8/7/13, Paris

42. ELSI 2.0 for genomics and society • Coordinate • Analyse • Exchange • Avoid replicate • Be prospective and responsive • Facilitate • Accelerate • Amplify policy impact An international initiative: « We need an international infrastructure for the ethical, legal social implications of genomic research » Kaye et al. Science, 2012, 336, 673-74 http://www.p3g.org/elsi-20 The 10th International Workshop on Advanced Genomics Tokyo, May 21-23, 2013

43. The notion of collaboratory for ELSI research on biobanks and genomics EUCCONET seminar 8/7/13, Paris ELSI 2.0 for Genomics and Society Science, 2012, 336, 673-674

44. What are the blockingfactors of the shared use of bioresources • Technical ones (quality etc.) • Institutional ones • No exchange, sharing or access policy • No practical help • Cost • Intellectual property ones • Information ones • No easily available information on content • Restricted use to pre-defined professional circles • No obvious positive spin off : incentives? EUCCONET seminar 8/7/13, Paris

45. What are the needs for assessing the use of Bioresources ? • For institutions: need to justify their use to • Patients • Funders • Users • For researchers/practitioners: need of documented long term recognition of the effort of quality biobanking • For individuals donating: need to be reassured that this is used, in reality • For the public: need to be sure that the major investment is justified and has an impact at society level EUCCONET seminar 8/7/13, Paris

46. The BRIF initiative is a workinprogress, currently developing a framework for: • - creating a tool for calculating research impact of bioresources based on a metric (algorithm) and a unique digital resource identifier (analogy Journal IF) • assessing requirements for citation/acknowledgement of bioresources in order to trace their use in research include both biological samples with associated data (medical/epidemiological, social), databases independent of physical samples and other biomolecular and bioinformatics research tools (BRIF group working definition). Online discussion forum/ GEN2PHEN knowledge centre: http://www.gen2phen.org/groups/brif-bio-resource-impact-factor Contacts:laurence.mabile@univ-tlse3.fr, anne.cambon-thomsen@univ-tlse3.fr BRIF Working Group Editors-Rome, 21/6/2013

47. Objective: increase sharing Purpose: recognition of the effort involved in establishing, maintaining and sharing resources Challenge: how to overcome the feeling of loss that may prevail Idea: Transforming a loss into an advantage. « The more it is shared, the more it contributes to science, the more it is recognised » Virtuous circle!

48. What is needed? Guidelines and tools are needed to maximise access by researchers to collections of biological materials and attached databases, and to recognise efforts involved in such and other bioresources. At publication level there is no standardized way to cite and acknowledge the bioresources used and their contributors BRIF Working Group Editors-Rome, 21/6/2013

49. International working group: steps - Jul/Sep 2010:launch of online BRIF discussion group (/Gen2phen Knowledge Centre) http://www.gen2phen.org/groups/brif-bio-resource-impact-factor • Documents on BRIF (original publications) • Discussion posts • Chart • Jan 2011:BRIF workshop,Toulouse, FR • Feb/Mar 2011:constitution of working subgroups • From June 2011:publications on behalf of the BRIF working group • Oct 2013: 2nd BRIF workshop, Toulouse, FR • From jan 2013:pilot studies BRIF Working Group Editors-Rome, 21/6/2013

50. Participants characteristics jul/10 - apr/12: 135members, 21countries, >95 institutions Legend: <5 5≤ >10 10≤ >20 20≤ >30 BRIF Working Group Editors-Rome, 21/6/2013