Canada Research Chair in Neuroethics Professor of Neurology National Core for Neuroethics University of British Columbia Presidential Commission for the.

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 FindingsJudy Illes, Ph.D.

Agenda• Background• Current landscape• Ongoing discovery• Uncharted territory

Agenda• Background• Current landscape• Ongoing discovery• Uncharted territory

Incidental Findings

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

Case Study in NeuroimagingMK 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?

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

Agenda• Background• Current landscape• Ongoing discovery• Uncharted territory

Cavernous hemangioma AVM

Mucous plug

Meningioma

Structural Anomalies

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%

Ageyoung old

Fre

qu

ency

low

high Routine

Urgent

Associations with Age

Illes et al., Neurology, 2008

Personnel conducting scans

Management StrategiesNeuroradiological review

Illes et al., JMRI, 2004Racine et al., BMC Ethics, 2010

Significance of FindingWould Want to be

InformedWould Seek Evaluation

Benign 91% 77%

Malignant,but curable

100% 97%

Malignantand not curable

96% 99%

Life-threatening medical emergency

100% 98%

Subjects’ Expectations

Kirschen et al., JMRI, 2006

Illes, Nature Clinical Neurology, 2006; Illes et al., Neurology, 2008

The Challenge

Illes et al., based on Science 2006, Neurology 2008

Research Study

Principal investigator or designate

Physician qualified to read scans

Incidental finding is detectedAll scansreviewed

C

IRB protocol & informed consent articulate plan for managing incidental findings

Incidental findings are managed

Subjectoption 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

QuickTime™ and a decompressor

are needed to see this picture.

Agenda• Background• Current landscape• Ongoing discovery• Uncharted territory

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

Four Different Strategies

1. No screening, no further workup

2. MRI read by researcher not trained in clinical neuroimagingIf suspicious: read by specialistIf suspicious: MR Angiography (MRA)

3. MRI read by specialistIf suspicious: MRA

4. Full clinical-grade work-up in all participants

Best Economic Strategy per SubgroupAge Gender

Family History

No screeningScreening by

researcherScreening by

specialist

Full, clinical grade

screening

18-40 M - ●

40-60 M - ●

>60 M - ●

18-40 F - ●

40-60 F - ●

>60 F - ●

18-40 M + ●

40-60 M + ●

>60 M + ●

18-40 F + ●

40-60 F + ●

>60 F + ●

Implications for ManagementA 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

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

Discriminative Power

Discriminative Power

CumulativePower

CumulativePower

Imaging Genetics

Science and Society

Disease Differentiation

Incidental Findings

Translation Stigma Response Sensitivity Privacy/

Autonomy Resources

Commercialization

Ethical Considerations

Neuroimaging

Clinical FeaturesGenes

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

Protein Cells Systems Behaviour

Roffman et al., 2005

Tairyan et al., Neuroscience, 2009

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?

•  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

Agenda• Background• Current landscape• Ongoing discovery• Uncharted territory

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