Personal Genomes and Ethical Issues
02-223 How to Analyze Your Own Genome Declining Cost of Genome Sequencing
• The genome sequencing is expected to happen rou nely in the near future Schadt, MSB, 2012 The era of big data: the genome data are already being collected in a large scale and being mined for scien fic discovery to drive more accurate descrip ve and predic ve models that inform decision making for the best diagnosis and treatment choice for a given pa ent. Would you post your genome on the web? Genomes and Privacy
• DNA sequence data contain informa on that can be used to uniquely iden fy an individual (i.e., genome sequences are like fingerprints)
• Balancing the need for scien fic study and privacy Genomes and Privacy
• Privacy concerns – Genome sequence data and other related types of data (gene expressions, clinical records, epigene c data, etc.) are collected for a large number of pa ents for medical research – Most types of data are freely available through internet except for genotype data • NCBI GEO database for gene expression data • The cancer genome atlas data portals – Genotype data are available to scien sts through restricted access – Protec ng par cipants’ privacy through informed consent h ps://tcga-data.nci.nih.gov/tcga/tcgaHome2.jsp The Cancer Genome Atlas (TCGA) Data The Cancer Genome Atlas (TCGA) Data
h ps://tcga-data.nci.nih.gov/tcga/tcgaCancerDetails.jsp? diseaseType=LAML&diseaseName=Acute%20Myeloid%20Leukemia Access Control for TCGA Data
• Open access data er – De-iden fied clinical and demographic data – Gene expression data – Copy-number altera ons in regions of the genome – Epigene c data – Summaries of data, such as genotype frequencies, compiled across individuals
• Controlled-access data er – Individual germline variant data – DNA sequence data – One should apply for an access to the data through NIH (database of genotypes and phenotypes) Informed Consent for Scientific Research
• Standard prac ce for enrolling human subjects in a research study – fully informing poten al par cipants on all aspects of a study including the aims of the study, risks, benefits, costs, and protec on of personal privacy – The origins of modern day informed consent for medical research can be traced to the Nuremberg Code in 1947 in an effort to protect par cipants in research studies (Homan, 1991). Nuremberg Code
• Research ethics principles for human experimenta on • Established a er the Nuremberg Trials at the end of the Second World War
h p://www.hhs.gov/ohrp/archive/nurcode.html Nuremberg Code • On August 19, 1947, the judges of the American military tribunal in the case of the USA vs. Karl Brandt et. al. delivered their verdict. Before announcing the guilt or innocence of each defendant, they confronted the difficult ques on of medical experimenta on on human beings. Several German doctors had argued in their own defense that their experiments differed li le from previous American or German ones. Furthermore they showed that no interna onal law or informal statement differen ated between legal and illegal human experimenta on. This argument worried Drs. Andrew Ivy and Leo Alexander, American doctors who had worked with the prosecu on during the trial. On April 17, 1947, Dr. Alexander submi ed a memorandum to the United States Counsel for War Crimes which outlined six points defining legi mate research. The verdict of August 19 reiterated almost all of these points in a sec on en tled "Permissible Medical Experiments" and revised the original six points into ten. Subsequently, the ten points became known as the "Nuremberg Code." Although the code addressed the defense arguments in general, remarkably none of the specific findings against Brandt and his codefendants men oned the code. Thus the legal force of the document was not well established. The uncertain use of the code con nued in the half century following the trial when it informed numerous interna onal ethics statements but failed to find a place in either the American or German na onal law codes. Nevertheless, it remains a landmark document on medical ethics and one of the most las ng products of the "Doctors Trial." h p://www.ushmm.org/informa on/exhibi ons/online-features/special-focus/doctors-trial/ nuremberg-code Institutional Review Board (IRB)
• A commi ee that has been formally designated to approve, monitor, and review biomedical and behavioral research involving humans
• Title 45 Code of Federal Regula ons Part 46 – h p://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html Current Generation Informed Consents
• Single study focused • Top-down unidirec onal researcher-par cipant (research subject) rela onship. • Protec ng the par cipant is considered among the chief aims • Data genera on on study par cipants usually an integral part of the consent • Data ownership and terms of use driven by the inves gator and/or hos ng ins tu on • Study par cipants are counseled to ensure they understand all aspects of the study, although no evidence of understanding is sought or required • In most cases, anonymity, privacy, and confiden ality are guaranteed as a key condi on for a par cipant’s consent • Big data, more open data sharing mentality demand a new genera on of informed consents Genomes and Privacy
• How much should we be concerned about the privacy issues regarding personal genome data?
• Non-gene c data can be used to predict the genotypes of individuals (Bayesian method to predict individual SNP genotypes from gene expression data, Schadt et al. Nature Gene cs, 2012) – Uses gene expressions as non-gene c data and predicts the genotypes based on the gene expressions Predicting Genotypes with Non-Genetic Data (Schadt et al., 2012)
• Study design – Learn a predic ve model for predic ng genotypes given gene expression data from training set – Use the learned predic ve model to test whether genotype can be predicted correctly given gene expression from test set
• Two datasets from non-overlapping groups of individuals – the human liver cohort (HLC): liver gene expression and genotype data for 378 European- American individuals – Roux-en-Y gastric bypass cohort (RYGB): genotype data and expression data for liver and adipose ssue from 580 European-American subjects undergoing Roux-en-Y gastric bypass (RYGB)
• Learn model from HLC data (training set) and predict RYGB genotypes given RYGB expressions (test set) Predicting Genotypes from Gene Expressions
• Le semicircle: observed genotypes • Right semicircle: predicted genotype
• Blue line: correctly matched individuals • White line: incorrectly matched individuals
• Overall, we can resolve 99% of the iden es of individuals Personal Genome Project (www.personalgenomes.org)
• Volunteers from the general public working together with researchers to advance personal genomics
• Aims to sequence genomes of 100,000 individuals from the general public
• Volunteers should be willing to make their gene c and trait informa on publicly available The Evolving Informed Consent for Scientific Research I
• Open consents for public resources - the Personal Genome Project (PGP) Consent (Church, 2005; Lunshof et al, 2008) • Differs from classic informed consent in the following ways – Data ownership and terms of use of data no longer driven by study inves gator – Data are published to the web and made available without restric on – Single-study focused, but has broad and open-ended scope (data sharing as an aim) – Par cipants agree to reciprocal interac on with researchers – Par cipants must pass an exam to ensure they possess basic gene c literacy, are informed about the public nature of the study, understand the possibility of re-iden fica on, and that some risks are unknown and unpredictable. The Evolving Informed Consent for Scientific Research II
• Interoperable and Open Consents - The Portable Legal Consent (PLC) (h p://weconsent.us/) • Based upon the PGP consent, but altered in the following important ways – The PLC can be used across any number of studies – If varia ons of the same PLC form guarantee the same freedoms and creates no more than the same obliga ons, then it can be cer fied as interoperable across the PLC network – Fully digital, requires no input from a physician or other health/ research professional – Requires users sign terms of a contract to ensure compliance with data use terms – Intended for data already generated to enable open access of data across many studies Other Issues in Scientific Research
• Open personal data environment
• A greater par cipa on of informed pa ents
• Protec ng individuals from discrimina on – Gene c Informa on Nondiscrimina on Act (2008) • Law protec ng individuals from discrimina on based on their gene c informa on for health insurance and employment Other Social/Ethical Issues in Personal Genomes
• Consumer genomics services – 23andme, deCODE gene cs, Navigenics – Personal genomic services are offered in the private sectors more widely than by clinicians – Commercial genomic services may displace clinicians as the primary provider of health-related gene c informa on – Individuals may assume more responsibility for health-promo ng behavior Other Social/Ethical Issues in Personal Genomes
• P4 medicine (h p://p4mi.org) – Predic ve, preven ve, personalized, and par cipatory medicine – Apply systems biology to personalized disease preven on and maintenance of health Summary
• Ethical/Social/Legal issues in personal genomes – Protec ng privacy in terms of gene c informa on while enabling scien fic research – Protec ng individuals from discrimina on based on gene c informa on – Empowering individuals by keeping them informed of the various issues involved in personal genomes