Genomic Research: Issues to Consider. IRB Brown Bag August 28, 2014 Sharon Aufox, MS, LGC

Transcription

1 Genomic Research: Issues to Consider IRB Brown Bag August 28, 2014 Sharon Aufox, MS, LGC

2 Outline Key genomic terms and concepts Issues in genomic research Consent models Types of findings Returning results Privacy

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4 Differences Between Genetic and Genomic Research Understanding the Genetic Basis of Disease Past Genetic Research Research involving genetic material (DNA, RNA, etc.) Focus on rare, single gene disorders Individual genes had large effects Minimal environmental component Family studies were vehicle for research Facilitated candidate gene approach Many genetic counselors involved in these types of studies Hypothesis driven

5 Differences Between Genetic and Genomic Research Understanding the Genetic Basis of Disease Today and Future Genomic Research Focus on common complex disorders of adulthood Multiple genes with small effects are studied Environmental component critical Gene gene interaction Genes with multiple effects Large population studies/biobanks supply patient samples and clinical information International Hap Map Project dbgap

6 Multifactorial Inheritance 2014

7 Differences Between Genetic and Genomic Research Understanding the Genetic Basis of Disease Today and Future Genomic Research Focus on common complex disorders of adulthood Multiple genes with small effects are studied Environmental component critical Gene gene interaction Genes with multiple effects Large population studies/biobanks supply patient samples and clinical information International Hap Map Project dbgap

8 Drug Response 2014

9 Pharmacogenomics 2014

10 Predicting Drug Response with Genomic Testing

11 Differences Between Genetic and Genomic Research New technologies are being used to identify some of the genetic factors involved in common disease Genome Wide Association Studies (GWAS) Whole Genome Sequencing (WGS) Gene Expression Profiling Whole exome sequencing (WES) Epigenetics Copy number variants (CNVs) Not necessarily hypothesis driven

12 Whole Genome Sequencing vs. Whole Exome Sequencing 2014

13 Whole Genome Sequencing Provides the most comprehensive collection of an individual s genetic variations but not all Does not look at variations in the entire genome Does not pick up 100% of known inherited genes (misses ~20%) Concerns about false negatives Better at detecting well known SNPs than copy number variants (regions of repeated sequence) Not always consensus on the implications of novel and rare genetic variant

14 Whole Exome Sequencing The exome is the part of the genome that mainly encodes proteins ~1% of the genome Whole exome sequencing (WES) can determine the DNA sequence of most protein encoding exons May include some DNA regions that encode RNA molecules that are not involved in protein synthesis Can be targeted to particular genes of a clinical interest.

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16 Biobanks A collection of biological material and the associated data and information stored in an organized system, for a population or a large subset of a population

17 Biobanks Numerous biobanks throughout institutions in US, Canada, Europe, and Asia Many different models for recruiting, consenting and obtaining specimens Many biobanks in Europe and Asia are conducted country or region wide Large research studies to evaluate genetic factors and the environmental components of specific diseases Similar to biobanks but are usually disease specific Usually grant supported

18 DNA Biobanks Designed to facilitate population based research Often no single disease focus Samples may be deidentified or associated with a limited data set of PHI No direct benefit to participation No individual results Seek to provide general results Some biobanks provide biometrics Longevity of study/biobank Data sharing regulations for NIH funded projects Sharing genetic results and clinical data with other investigators to facilitate and speed discovery

19 Storage of Samples for Future Genomic Research to store unused, left over blood for future research or.an additional tube of blood to be stored for future research Incorporating storage of samples (biobanking) in consent can be a separate consent form, optional element, or requirement for participation

20 Consent Models Opt in Opt out Broad Consent Categorical Consent Specific Consent

21 Some Issues to Consider When Conducting Genomic Research Consenting Ensuring participant comprehension Interpretation of data/classification of variants Privacy of information How to handle VUS How to handle variants with clinical implications Returning results? CLIA How to handle new knowledge/information Data sharing Implication of results Family members Stigmatization Inclusion of children (< 18) Downstream effects of results

22 Genes Associated with More Than One Condition Example: ApoE Key role in transporting cholesterol and other lipids in blood circulation and central nervous system 3 variants (ApoE2, ApoE3, & ApoE4) ApoE4 is associated with risks for: Cardiovascular disease Alzheimer disease Blood brain barrier dysfunction ApoE4 may be associated with susceptibility to: Malaria Viral infections (HIV, HSV) Cancer

23 Incidental Findings Genetic variants identified that were not related to the condition being investigated. Problem: Our current ability to interpret many of these variants is inadequate

24 Interpreting Findings Classifying Variants Phenotypic implications? Clinically actionable? Dewey F. et al. JAMA, 2014;311 (10):1035

25 Variants of Uncertain Significance Example: KCNH2 Can cause drug induced QT prolongation Mutations cause LQT2

26 Considerations in Returning Results Does the researcher have a duty to return results? Blurs the distinction between the roles of the researcher versus the clinician Clinical significance / Clinically actionable Actionable genes Those with deleterious mutation(s) whose penetrance would result in specific, defined, medical recommendations both supported by evidence and, when implemented, expected to improve an outcome(s) in terms of mortality or the avoidance of significant morbidity 1 ACMG variant list CLIA Downstream effects How long to update information 1 A. Haukkala et al Public Health Genomics 2013;

27 Clinical Laboratory Improvement Amendments (CLIA) Regulates laboratory testing Multiple types of CLIA certificates based on the type of diagnostic tests performed Test results used in the diagnosis, prevention, or treatment of any disease or impairment of, or the assessment of the health, of human beings 1 Research laboratories that test human specimens, but no report patient specific results for the diagnosis, prevention, or treatment of any disease or impairment of, or the assessment of the health of individual patients are exempt from CLIA U. S.C. 263a 2 42 CFR 493.3(2)

28 GINA and HIPAA Genetic Information Nondiscrimination Act Protects against the use of genetic information to discriminate in health insurance and employment Health Insurance Portability and Accountability Act Protects the privacy of healthrelated information 28

29 Summary of GINA Under GINA, group and individual health insurers cannot Use a person s genetic information to set eligibility requirements or establish premium or contribution amounts Request or require that a person undergo a genetic test Under GINA, employers cannot Use a person s genetic information in decisions about hiring, firing, job assignments, or promotions Request, require, or purchase genetic information about an employee or family member 29

30 What is Protected Under GINA Family medical history Carrier testing Prenatal genetic testing Susceptibility testing e.g., BRCA testing for breast cancer risk, testing for Huntington disease, or testing for HNPCC for colon cancer risk Analysis of tumors or other assessments of genes, mutations, or chromosomal changes 30

31 2010 Patient Protection and Affordable Care Act (ACA) Outlaws discrimination by health insurers on the basis of signs and symptoms of genetic disease Group or individual health insurance cannot establish rules for eligibility on the basis of health status, medical condition, claims experience, receipt of health care, medical history, genetic information, evidence of insurability or disability. (Patient Protection and Affordable Care Act, Pub. L. No (2010)) Beginning in 2014, the ACA will prohibit variations in premiums according to health status and genetic information

32 Certificates of Confidentiality Helps researchers protect the privacy of human subject research participants enrolled in biomedical, behavioral, clinical, and other forms of sensitive research Protects against compulsory legal demands for identifying information/characteristics of a research participant

33 Possible Future American College of Medical Genetics (ACMG) Advanced Notice of Proposed Rule Making (ANPR)

34 American College of Medical Genetics Recommendations Mutations found in 56 genes should be reported by the laboratory regardless of indication Responsibility of ordering clinician/team to provide comprehensive preand posttest counseling to the patient ~3.4% of European descent and ~1.2% of African decent adults can be expected to have actionable highly penetrant pathogenic or likely pathogenic mutations 1 Genet Med 2013:15(7): Dorschner et al. AJHG 2013:93:

35 Advanced Notice of Proposed Rulemaking (ANPR) Concerns about data protections and minimizing information risks: The nature of risk and benefits for research participants has changed with the increased use of genetic information, existing (stored) biospecimens, and medical records in research What data constitutes as identifiable and deidentified is fluid

36 Advanced Notice of Proposed Rulemaking (ANPR) Pre existing data or biospecimens: Currently research with de identified data is exempt Proposes that general (broad) consent would be required for research use of biospecimens regardless if it is associated with identifiers or not Consent for using stored samples is treated differently from other types of research

37 Summary Careful consideration and planning needs to go into any protocol involving genomic research Unanticipated issues and changing policies Thorough consenting is necessary Consult/include a genetics professional

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39 Translating Genomic Information into Clinical Practice Why this is so challenging right now Lack of comparative effectiveness data for genomic applications Market access to genomic tests makes lack of evidence more problematic Lack of consensus on evidence requirements or thresholds for genomic test evaluation Several alternative models are have been proposed in absence of definitive data Need for alternative models for evaluating risk and benefit trade offs Traditional medical genetics models won t work Not scaleable Current consent processes and patient interactions based on one gene at atime Time needed Large amounts of data

40 DNA Microarray Analysis Most common use is for gene expression analysis A technique used to determine whether genes are turned on or off A gene is turned on if RNA is present A technique to detect sequence variations in SNPs (single nucleotide polymorphisms) Allows thousands of genes to be tested at the same time

41 Gene Expression

42 SNP Genotyping