Karen J. Maschke

Managing Incidental Findings and Research Results in Genomic Research Involving Biobanks and Archived Data Sets

Biobanks and archived data sets collecting samples and data have become crucial engines of genetic and genomic research. Unresolved, however, is what responsibilities biobanks should shoulder to manage incidental findings and individual research results of potential health, reproductive, or personal importance to individual contributors (using “biobank” here to refer both to collections of samples and collections of data). This article reports recommendations from a 2-year project funded by the National Institutes of Health. We analyze the responsibilities involved in managing the return of incidental findings and individual research results in a biobank research system (primary research or collection sites, the biobank itself, and secondary research sites). We suggest that biobanks shoulder significant responsibility for seeing that the biobank research system addresses the return question explicitly. When reidentification of individual contributors is possible, the biobank should work to enable the biobank research system to discharge four core responsibilities to (1) clarify the criteria for evaluating findings and the roster of returnable findings, (2) analyze a particular finding in relation to this, (3) reidentify the individual contributor, and (4) recontact the contributor to offer the finding. We suggest that findings that are analytically valid, reveal an established and substantial risk of a serious health condition, and are clinically actionable should generally be offered to consenting contributors. This article specifies 10 concrete recommendations, addressing new biobanks as well as those already in existence.Genet Med 2012:14(4):361–384

Preemptive genotyping for personalized medicine: design of the right drug, right dose, right time-using genomic data to individualize treatment protocol.

OBJECTIVE To report the design and implementation of the Right Drug, Right Dose, Right Time-Using Genomic Data to Individualize Treatment protocol that was developed to test the concept that prescribers can deliver genome-guided therapy at the point of care by using preemptive pharmacogenomics (PGx) data and clinical decision support (CDS) integrated into the electronic medical record (EMR). PATIENTS AND METHODS We used a multivariate prediction model to identify patients with a high risk of initiating statin therapy within 3 years. The model was used to target a study cohort most likely to benefit from preemptive PGx testing among the Mayo Clinic Biobank participants, with a recruitment goal of 1000 patients. We used a Cox proportional hazards model with variables selected through the Lasso shrinkage method. An operational CDS model was adapted to implement PGx rules within the EMR. RESULTS The prediction model included age, sex, race, and 6 chronic diseases categorized by the Clinical Classifications Software for International Classification of Diseases, Ninth Revision codes (dyslipidemia, diabetes, peripheral atherosclerosis, disease of the blood-forming organs, coronary atherosclerosis and other heart diseases, and hypertension). Of the 2000 Biobank participants invited, 1013 (51%) provided blood samples, 256 (13%) declined participation, 555 (28%) did not respond, and 176 (9%) consented but did not provide a blood sample within the recruitment window (October 4, 2012, through March 20, 2013). Preemptive PGx testing included CYP2D6 genotyping and targeted sequencing of 84 PGx genes. Synchronous real-time CDS was integrated into the EMR and flagged potential patient-specific drug-gene interactions and provided therapeutic guidance. CONCLUSION This translational project provides an opportunity to begin to evaluate the impact of preemptive sequencing and EMR-driven genome-guided therapy. These interventions will improve understanding and implementation of genomic data in clinical practice.

The Mayo Clinic Biobank: A Building Block for Individualized Medicine

OBJECTIVE To report the design and implementation of the first 3 years of enrollment of the Mayo Clinic Biobank. PATIENTS AND METHODS Preparations for this biobank began with a 4-day Deliberative Community Engagement with local residents to obtain community input into the design and governance of the biobank. Recruitment, which began in April 2009, is ongoing, with a target goal of 50,000. Any Mayo Clinic patient who is 18 years or older, able to consent, and a US resident is eligible to participate. Each participant completes a health history questionnaire, provides a blood sample, and allows access to existing tissue specimens and all data from their Mayo Clinic electronic medical record. A community advisory board provides ongoing advice and guidance on complex decisions. RESULTS After 3 years of recruitment, 21,736 individuals have enrolled. Fifty-eight percent (12,498) of participants are female and 95% (20,541) of European ancestry. Median participant age is 62 years. Seventy-four percent (16,171) live in Minnesota, with 42% (9157) from Olmsted County, where the Mayo Clinic in Rochester, Minnesota, is located. The 5 most commonly self-reported conditions are hyperlipidemia (8979, 41%), hypertension (8174, 38%), osteoarthritis (6448, 30%), any cancer (6224, 29%), and gastroesophageal reflux disease (5669, 26%). Among patients with self-reported cancer, the 5 most common types are nonmelanoma skin cancer (2950, 14%), prostate cancer (1107, 12% in men), breast cancer (941, 4%), melanoma (692, 3%), and cervical cancer (240, 2% in women). Fifty-six percent (12,115) of participants have at least 15 years of electronic medical record history. To date, more than 60 projects and more than 69,000 samples have been approved for use. CONCLUSION The Mayo Clinic Biobank has quickly been established as a valuable resource for researchers.

Navigating an ethical patchwork—human gene banks

Population genetics research collaborations are reaching increasingly across national boundaries to access human tissue repositories. Will discrepancies in national policies on informed consent and IP rights hinder progress?

IRB practices and policies regarding the secondary research use of biospecimens.

BackgroundAs sharing and secondary research use of biospecimens increases, IRBs and researchers face the challenge of protecting and respecting donors without comprehensive regulations addressing the human subject protection issues posed by biobanking. Variation in IRB biobanking policies about these issues has not been well documented.MethodsThis paper reports on data from a survey of IRB Administrative Directors from 60 institutions affiliated with the Clinical and Translation Science Awards (CTSAs) about their policies and practices regarding secondary use and sharing of biospecimens. Specifically, IRB ADs were asked about consent for future use of biospecimens, assignment of risk for studies using biobanked specimens, and sharing of biospecimens/data.ResultsOur data indicate that IRBs take varying approaches to protocol review, risk assessment, and data sharing, especially when specimens are not anonymized.ConclusionUnclear or divergent policies regarding biospecimen research among IRBs may constitute a barrier to advancing genetic studies and to inter-institutional collaboration, given different institutional requirements for human subjects protections.

The Ethical Imperative And Moral Challenges Of Engaging Patients And The Public With Evidence

Engaging patients and the public with evidence is an ethical imperative because engagement is central to respect for persons and will likely improve health outcomes, facilitate the stewardship of resources, enhance prospects for justice, and build public trust. However, patient and public engagement is also morally complex, because evidence alone is never definitive. As patients and the public engage with evidence, value conflicts will arise and must be managed to achieve trustworthy decision making. We outline value conflicts likely to emerge in the following five settings: clinical care, health care organizations, public health, the regulatory context, and among payers. Using a variety of examples, we offer suggestions about how such conflicts may be managed, including providing more opportunities for democratic deliberation and having more explicit community discussion of how to balance personal choice and community well-being, transparent discussions of cost and quality outcomes, and greater patient engagement in community-based participatory research and the governance of learning health systems.

Genomic data in the electronic medical record: perspectives from a biobank community advisory board.

A proof of principle pharmacogenomic translational study was used as a case example to explore Biobank Community Advisory Board (CAB) member views about placing genomic information into the medical record and to establish how CAB input could affect research design. CAB members expressed enthusiasm for the potential benefit of the research discussed, yet voiced concerns regarding the recruitment and consent materials. They discussed the value of genomic research and its clinical utility; the risk of genetic discrimination; and personal ownership of genomic data. Members distinguished between indirect benefits to future generations and individual risk to research participants. Feedback was used to revise the recruitment and consent materials. Results highlight tensions reported between the public’s support for genomic research and concerns with genomic information in the medical record and its use in medical decision-making.

US and UK policies governing research with humans

Human subjects research is on the rise in both the US and UK. It is estimated that 19 million people a year in the US (Shamoo 2001) participate in clinical trials, and that more than half a million people a year do so in the UK [Consumers for Ethics in Research (CERES): http:// www.ceres.org.uk/whatsnew.htm]. Researchers on both sides of the Atlantic are permitted to undertake research with humans only if they abide by national policies regarding the ethical conduct of research. This article examines the US and UK regulatory frameworks governing research with humans. The first part summarizes the main features of each nation’s regulatory policies. The article then describes the composition and responsibilities of ethics review committees in the US and UK, the panels from which researchers must obtain approval for their studies. Finally, the article describes each nation’s ethical standards for three areas of human subjects research: research with children, research with incapacitated adults, and research in emergency situations.

Proposed regulations for research with biospecimens: Responses from stakeholders at CTSA consortium institutions

Secondary research with biospecimens acquired through clinical care and through research is often conducted without the informed consent of individuals from whom the specimens were acquired. While such uses are consistent with the current federal regulations, surveys of the general public suggest that many individuals would prefer more information and choice regarding research use of biospecimens. The federal government issued an Advance Notice of Proposed Rulemaking (ANPRM) in 2011 that proposed a number of potential changes in the regulations governing human subjects. These proposed regulations are particularly pertinent to institutions committed to research involving human subjects—including institutions in the NIH‐funded Clinical and Translational Science Awards (CTSA) consortium. In this study, we reviewed public responses by CTSA‐funded institutions and CTSA‐affiliated organizations and groups regarding the proposed changes in the ANPRM with respect to research with biospecimens. Our results indicate that the majority of responses to the ANPRM from CTSA institutions were not supportive of the proposed changes. While many responses acknowledge a need to change current research practices regarding biospecimens, the proposed changes in the ANPRM received only limited support from this subgroup of academic research institutions.

Investigator Experiences and Attitudes About Research With Biospecimens.

To advance scientific knowledge about human diseases and effective therapeutic treatments, investigators need access to human biospecimens and associated data. However, regulatory and procedural requirements may impede investigators’ efforts to share biospecimens and data within and across institutions. Although a number of studies have explored experiences and attitudes of study participants and others about biospecimen and data sharing, less is known about investigators’ perspectives. We conducted an electronic survey to learn about investigators’ experiences and attitudes about research with biospecimens and associated data. A total of 114 practicing scientists from a pool of 60 university medical schools with Clinical and Translational Science Awards (CTSAs) funded by the National Institutes of Health (NIH) participated. We found a high degree of variability in investigators’ experiences with institutional review boards (IRBs) when seeking approval to conduct biospecimen research, as well as differences in approaches to informed consent for the collection of specimens. Participants also expressed concerns that the risks of biospecimen research may be overestimated by IRBs. This research suggests that the current regulatory environment for human research protections may require reconsideration with regard to standards for collection, use, and sharing of biospecimens and data.