1. Canada Research Chair in Neuroethics Professor of Neurology National Core for Neuroethics University of British Columbia Presidential Commission for the Study of Bioethical Issues February 2011 Frontiers in Incidental Findings Judy Illes, Ph.D.

2. Agenda Background Current landscape Ongoing discovery Uncharted territory

3. Agenda Background Current landscape Ongoing discovery Uncharted territory

4. Incidental Findings Findings unrelated to the purpose of a research study or clinical examination

5. Case Study in Neuroimaging MK is a medical student conducting functional MRI research for his PhD on memory. He has been a mentor to the incoming medical student class. Two weeks into the program SH, a new medical student, enthusiastically enrolls in MK’s study. On the anatomy pre-scan, MK notices an anomaly in SH’s prefrontal cortex. There is no institutional protocol in place. What should he do?

6. Real people, real problems Potentially significant disorders of the CNS Psychological and financial cost Risk to personal health care security Relevance to third parties Trust and reciprocity Cost to the research enterprise Increasing applications of neuroimaging Expanding requirements for biobanks and data sharing Fundamental Issues

7. Agenda Background Current landscape Ongoing discovery Uncharted territory

8. Cavernous hemangioma AVM Mucous plug Meningioma Structural Anomalies

9. Frequency Overall occurrence of anomalies in adults and children: 18%-20% (one in every five people scanned) vascular and tumours Clinically significant findings requiring follow- up: 2%-8%

10. Age youngold Frequency low high Routine Urgent Associations with Age Illes et al., Neurology, 2008

11. Personnel conducting scans Management Strategies Neuroradiological review Illes et al., JMRI, 2004 Racine et al., BMC Ethics, 2010

12. Significance of Finding Would Want to be Informed Would Seek Evaluation Benign91%77% Malignant, but curable 100%97% Malignant and not curable 96%99% Life-threatening medical emergency 100%98% Subjects’ Expectations Kirschen et al., JMRI, 2006

13. Illes, Nature Clinical Neurology, 2006; Illes et al., Neurology, 2008 The Challenge

14. Illes et al., based on Science 2006, Neurology 2008 Research Study Principal investigator or designate Physician qualified to read scans Incidental finding is detected All scans reviewed C IRB protocol & informed consent articulate plan for managing incidental findings Incidental findings are managed Subject option to decline to be informed Incidental findings are not managed B Principal investigator or designate Research subject or surrogate is encouraged to initiate clinical follow-up Incidental finding is evaluated Incidental finding is communicated No action taken D Research protocol anticipates incidental findings A

15. Agenda Background Current landscape Ongoing discovery Uncharted territory

16. Economic Analysis Cost implications of managing incidentally found intracranial aneurysms Mathematical modeling of four strategies for different populations of human subjects Sadatsafavi et al., Value in Health, 2010

17. Four Different Strategies 1. No screening, no further workup 2. MRI read by researcher not trained in clinical neuroimaging If suspicious: read by specialist If suspicious: MR Angiography (MRA) 3. MRI read by specialist If suspicious: MRA 4. Full clinical-grade work-up in all participants

18. Best Economic Strategy per Subgroup AgeGender Family History No screening Screening by researcher Screening by specialist Full, clinical grade screening 18-40M- ● 40-60M- ● >60M- ● 18-40F- ● 40-60F- ● >60F- ● 18-40M+ ● 40-60M+ ● >60M+ ● 18-40F+ ● 40-60F+ ● >60F+ ●

19. Implications for Management A shift from researcher-focused to participant-focused decision-making for incidental findings Initial screening by a non-trained researcher is not cost-effective for any subgroup A customized strategy is essential Optimal strategy is affected by variables at time of screening: age group, gender, family history Exclusion of certain participant groups may be justified when weighing risk and cost of screening

20. Imaging Genetics An emerging approach to the study of genetic variations and functional brain responses Brain activation patterns and the course of cognitive decline in people with AD susceptibility genes COMT gene polymorphism and prefrontal dopamine regulation with genetic risk of schizophrenia 5-HTT serotonin transporter gene and amygdala activation in response to fearful stimuli

21. Discriminative Power Cumulative Power Cumulative Power Imaging Genetics Science and Society Disease Differentiation Incidental Findings TranslationStigmaResponse Sensitivity Privacy/ Autonomy Resources Commercialization Ethical Considerations Neuroimaging Clinical Features Genes Neurochemical (MRS, SPECT, PET) Neurochemical (MRS, SPECT, PET) Structural (CT, MRI, DTI) Structural (CT, MRI, DTI) Functional (MRI, SPECT, PET) Functional (MRI, SPECT, PET) Gene expression ProteinCellsSystemsBehaviour Roffman et al., 2005 Tairyan et al., Neuroscience, 2009

22. Functional Frontier: Resting State fMRI The brain is highly active at rest Connectivity analyses suggest distributed, large-scale functional networks Detection of changes in functional connectivity within individuals from a single scan Disruptions of the networks have been observed in Alzheimer’s, schizophrenia and other disorders of the CNS Will task-dependent or task-independent resting state fMRI be the first functional frontier for incidental findings?

23. Uncertainty in current understanding of the resting state Heritability of networks Anonymization in offline processing Implications of findings for perception of self and social categories Frontier Challenges

24. Agenda Background Current landscape Ongoing discovery Uncharted territory

25. Uncharted Territory Economic analyses beyond aneurysms Incidental findings in children Evolving processes for recruitment and consent Responsibilities and policies in the unregulated non-clinical for-profit sector Management of incidental findings in cultures in which ownership of health data and consent are shared by communities Evidence-based policies in a changing health care climate