The future clinical applications of whole genome sequencing come with speculation and enthusiasm but require careful consideration of the true system costs and health benefits of the clinical uses of this exciting technology.
The cost of whole genome sequencing is dropping rapidly. There has been a great deal of enthusiasm about the potential for this technological advance to transform clinical care. Given the interest and significant investment in genomics, this seems an ideal time to consider what the evidence tells us about potential benefits and harms, particularly in the context of health care policy. The scale and pace of adoption of this powerful new technology should be driven by clinical need, clinical evidence, and a commitment to put patients at the centre of health care policy.
The return of individual genetic research results has been identified as one of the most pressing ethical challenges warranting immediate policy attention. We explored the practices and perspectives of genome-wide association studies (GWAS) investigators on this topic.
Materials & methods
Corresponding authors of published GWAS were invited to participate in a semistructured interview. Interviews (n = 35) were transcribed and analyzed using conventional content analysis.
Most investigators had not returned GWAS results. Several had experience returning results in the context of linkage/family studies, and many felt that it will become a larger issue in whole-genome/-exome sequencing.
Research context and nature of the study are important considerations in the decision to return results. More nuanced ethical guidelines should take these contextual factors into account.
ethics; genome-wide association; genomics; policy; return of results; whole-genome sequencing
Published guidelines suggest that research results and incidental findings should be offered to study participants under some circumstances. Although some have argued against the return of results in research, many cite an emerging consensus that there is an ethical obligation to return at least some results; the debate quickly turns to issues of mechanics (e.g., which results? who discloses? for how long does the obligation exist?). Although commentators are careful to distinguish this as an ethical rather than legal obligation, we worry that return of results may unjustifiably become standard of care based on this growing “consensus,” which could quickly lead to a legal (negligence-based) duty to offer and return individualized genetic research results. We caution against this and argue in this essay that the debate to date has failed to give adequate weight to a number of fundamental ethical and policy issues that should undergird policy on return of research results in the first instance, many of which go to the fundamental differences between research and clinical care. We confine our comments to research using data from large biobanks, the topic of the guidelines proposed in this symposium issue.
biobanking; ethics; genetics; law; policy; return of results
To explore specific conditions and types of genetic variants that specialists in genetics recommend should be returned as incidental findings in clinical sequencing.
Sixteen specialists in clinical genetics and/or molecular medicine selected variants in 99 common conditions to return to the ordering physician if discovered incidentally through whole genome sequencing. For most conditions, the specialists independently considered 3 molecular scenarios for both adults and minor children: a known pathogenic mutation, a truncating variant presumed pathogenic (where other truncating variants were known to be pathogenic), or a missense variant predicted in silico to be pathogenic.
On average, for adults and children respectively, each specialist selected 83.5 and 79.0 conditions or genes out of 99 in the known pathogenic mutation categories, 57.0 and 53.5 out of 72 in the truncating variant categories, and 33.4 and 29.7 out of 72 in the missense variant categories. Concordance in favor of disclosure within the adult/known pathogenic mutation category was 100% for 21 conditions or genes and 80% or higher for 64 conditions or genes.
Specialists were highly concordant for the return of findings in 64 conditions or genes if discovered incidentally during whole exome or whole genome sequencing.
whole genome sequencing; incidental findings
Return of individual genetic results to research participants, including participants in archives and biorepositories, is receiving increased attention. However, few groups have deliberated on specific results or weighed deliberations against relevant local contextual factors.
The Electronic Medical Records and GEnomics (eMERGE) network, which includes five biorepositories conducting genome-wide association studies, convened a Return of Results Oversight Committee (RROC) to identify potentially returnable results. Network-wide deliberations were then brought to local constituencies for final decision-making.
Defining results that should be considered for return required input from clinicians with relevant expertise and much deliberation. The RROC identified two sex chromosomal anomalies, Klinefelter Syndrome and Turner Syndrome, as well as homozygosity for Factor V Leiden, as findings that could warrant reporting. Views about returning HFE gene mutations associated with hemochromatosis were mixed due to low penetrance. Review of EMRs suggested that most participants with detected abnormalities were unaware of these findings. Local considerations relevant to return varied and, to date, four sites have elected not to return findings (return was not possible at one site).
The eMERGE experience reveals the complexity of return of results decision-making and provides a potential deliberative model for adoption in other collaborative contexts.
Result return; biorepository; electronic medical records; deliberation; context
Improving the management of potential organ donors in the ICU could meet an important public health goal by increasing the number and quality of transplantable organs. However, randomized clinical trials (RCTs) are needed to quantify the extent to which specific interventions might enhance organ recovery and outcomes among transplant recipients. Among several barriers to conducting such studies are the absence of guidelines for obtaining informed consent for such studies, and the fact that deceased organ donors are not covered by extant federal regulations governing oversight of research with human subjects. This paper explores the underexamined ethical issues that arise in the context of donor management studies, and provides ethical guidelines and suggested regulatory oversight mechanisms to enable such studies to be conducted ethically. We conclude that both the respect that is traditionally accorded to the prior wishes of the dead and the possibility of post-mortem harm support a role for surrogate consent of donors in such RCTs. Furthermore, although recipients will often be considered human subjects under federal regulations, several ethical arguments support waiving requirements for recipient consent in donor management RCTs. Finally, we suggest that new regulatory mechanisms, perhaps linked to existing regional and national organ donation and transplantation infrastructures, must be established to protect patients in donor management studies while limiting unnecessary barriers to the conduct of this important research.
informed consent; organ donation; transplantation; research ethics
Mutational load of susceptibility variants has not been studied on a genomic scale in a clinical population, nor has the potential to identify these mutations as incidental findings during clinical testing been systematically ascertained.
Array comparative genomic hybridization, a method for genome-wide detection of DNA copy-number variants, was performed clinically on DNA from 9,005 individuals. Copy-number variants encompassing or disrupting single genes were identified and analyzed for their potential to confer predisposition to dominant, adult-onset disease. Multigene copy-number variants affecting dominant, adult-onset cancer syndrome genes were also assessed.
In our cohort, 83 single-gene copy-number variants affected 40 unique genes associated with dominant, adult-onset disorders and unrelated to the patients’ referring diagnoses (i.e., incidental) were found. Fourteen of these copy-number variants are likely disease-predisposing, 25 are likely benign, and 44 are of unknown clinical consequence. When incidental copy-number variants spanning up to 20 genes were considered, 27 copy-number variants affected 17 unique genes associated with dominant, adult-onset cancer predisposition.
Copy-number variants potentially conferring susceptibility to adult-onset disease can be identified as incidental findings during routine genome-wide testing. Some of these mutations may be medically actionable, enabling disease surveillance or prevention; however, most incidentally observed single-gene copy-number variants are currently of unclear significance to the patient.
copy-number variation; genetic load; genomic mutational load; incidentalome; structural variation; variants of unknown significance
During the last decade, the field of human genome research has gone through a phase of rapid discovery that has provided scientists and physicians with a wide variety of research tools that are applicable to important medical issues. We describe a case of familial Huntington disease (HD), where the proband at risk preferred not to know his disease status but wanted to know the status in his unborn child. Once we found the father to be negative, the case raised an important ethical question regarding the management of this as well as future pregnancies. This paper discusses the arguments for and against the right not to know of one’s carrier status, as well as professional obligations in the context of withholding unwanted information that may have direct implications not only for the patient himself but also for other family members. HD has been the gold standard for many other adult onset genetic diseases in terms of carrier testing guidelines. Hence, we feel it is time to revisit the issue of prenatal testing for HD and consider updating the current recommendations regarding the patient’s right to “genetic ignorance”, the right not to know genetic information.
Huntington Disease; prenatal testing; guidelines; ethics
Despite growing concerns toward maintaining participants’ privacy, individual investigators collecting tissue and other biological specimens for genomic analysis are encouraged to obtain informed consent for broad data sharing. To assess the effect on research enrollment and data sharing decisions of three different consent types (traditional, binary, or tiered) with varying levels of control and choices regarding data sharing.
A single blind, randomized controlled trial was conducted with 323 eligible adult participants being recruited into one of six genome studies at Baylor College of Medicine in Houston, Texas between January 2008 and August 2009. Participants were randomly assigned to one of three experimental consent documents (traditional, n=110; binary, n=103; tiered, n=110). Debriefing in follow-up visits provided participants a detailed review of all consent types and the chance to change data sharing choices or decline genome study participation.
Before debriefing, 83.9% of participants chose public data release. After debriefing, 53.1% chose public data release, 33.1% chose restricted (controlled access database) release, and 13.7% opted out of data sharing. Only one participant declined genome study participation due to data sharing concerns.
Our findings indicate that most participants are willing to publicly release their genomic data, however, a significant portion prefer restricted release. These results suggest discordance between existing data sharing policies and participants’ judgments and desires.
data sharing; genome research; ethical issues; participant perspectives; consent
Continued advances in human microbiome research and technologies raise a number of ethical, legal, and social challenges. These challenges are associated not only with the conduct of the research, but also with broader implications, such as the production and distribution of commercial products promising maintenance or restoration of good physical health and disease prevention. In this article, we document several ethical, legal, and social challenges associated with the commercialization of human microbiome research, focusing particularly on how this research is mobilized within economic markets for new public health uses.
We conducted in-depth, semi-structured interviews (2009–2010) with 63 scientists, researchers, and National Institutes of Health project leaders (“investigators”) involved with human microbiome research. Interviews explored a range of ethical, legal, and social dimensions of human microbiome research, including investigators’ perspectives on commercialization. Using thematic content analysis, we identified and analyzed emergent themes and patterns.
Investigators discussed the commercialization of human microbiome research in terms of (1) commercialization, probiotics, and issues of safety, (2) public awareness of the benefits and risks of dietary supplements, and (3) regulation.
The prevailing theme of ethical, legal, social concern focused on the need to find a balance between the marketplace, scientific research, and the public’s health. The themes we identified are intended to serve as points for discussions about the relationship between scientific research and the manufacture and distribution of over-the-counter dietary supplements in the United States.
Commercialization; Human microbiome; Ethical legal and social implications (ELSI); Dietary supplements; Qualitative research
This manuscript describes the NIH Human Microbiome Project, including a brief review of human microbiome research, a history of the project, and a comprehensive overview of the consortium's recent collection of publications analyzing the human microbiome.
A report on the National Human Genome Research Institute's Ethical, Legal, and Social Implications Research Program 2011 Congress, 'Exploring the ELSI Universe', Chapel Hill, North Carolina, USA, 12-14 April 2011.
Empirical research; ethics; genomic research
Direct-to-consumer personal genome testing is now widely available to consumers. Proponents argue that knowledge is power but critics worry about consumer safety and potential harms resulting from misinterpretation of test information. In this article, we consider the health system implications of direct-to-consumer personal genome testing, focusing on issues of accountability, both corporate and professional.
Consumer safety; DNA test kit; Personal genome testing, direct-to-consumer
In January 2009 the National Heart, Lung, and Blood Institute (NHLBI) convened a 28-member multidisciplinary Working Group to update the recommendations of a 2004 NHLBI Working Group focused on Guidelines to the Return of Genetic Research Results. Changes in the genetic and societal landscape over the intervening five years raise multiple questions and challenges. The group noted the complex issues arising from the fact that the technologic and bioinformatic progress has made it possible to obtain considerable information on individuals which would not have been possible a decade ago. While unable to reach consensus on a number of issues, the Working Group produced five recommendations. The Working Group offers two recommendations addressing the criteria necessary to determine when genetic results should and may be returned to study participants, respectively. In addition, it suggests that a time limit be established to limit the duration of obligation of investigators to return genetic research results. The Group recommends the creation of a central body, or bodies, to provide guidance on when genetic research results are associated with sufficient risk and have established clinical utility to justify their return to study participants. The final Recommendation urges investigators to engage the broader community when dealing with identifiable communities to advise them on the return of aggregate and individual research results. Creation of an entity charged to provide guidance to IRBs, investigators, research institutions and research sponsors would provide rigorous review of available data, promote standardization of study policies regarding return of genetic research results, and enable investigators and study participants to clarify and share expectations for the handling of this increasingly valuable information with appropriate respect for the rights and needs of participants.
consent genetics; ethics; research genetics; risk rediction; single nucleotide polymorphism genetics
Should the results of whole genome sequencing research be disclosed to participants, in particular when the results have uncertain or indeterminate phenotypic consequences? This controversial question is considered in light of one author's (JL) experience as a geneticist who recently had his own genome sequenced.
No course in genetics can prepare the practicing physician to interpret whole-genome data. We argue that genetics is a microcosm of the changing dynamics of the practice of medicine. It illustrates the perfect storm of exponential increases in raw data with undetermined clinical relevance, ease of access to large amounts of data via the internet and shifting expectations of the doctor-patient relationship and the very mechanisms of health care delivery. Educational reform is needed across the continuum of medical education, from the student to the faculty training them, and requires a shift in focus from factual knowledge to data management and interpretation.
With recent advances in DNA sequencing technology, medicine is entering an era in which a personalized genomic approach to diagnosis and treatment of disease is now feasible. However, discovering the role of altered DNA sequences in various disease states will be a challenging task. The genomic approach offers great promise for diseases like pancreatic cancer in which the effect of current diagnostic and treatment modalities is disappointing. To facilitate the characterization of the genome of pancreatic cancer, high quality and well annotated tissue repositories are needed. This article summarizes basic principles guiding the creation of such a repository including sample processing and preservation techniques, sample size and composition, and collection of clinical data elements.
Pancreatic cancer; tissue bank; genomic analysis