Recommendations for ethical approaches to genotype-driven research recruitment

Recruiting research participants based on genetic information generated about them in a prior study is a potentially powerful way to study the functional significance of human genetic variation. However, it also presents significant ethical challenges that, to date, have received only minimal consideration. We convened a multi-disciplinary workshop to discuss key issues relevant to the conduct and oversight of genotype-driven recruitment and to translate those considerations into practical policy recommendations. Workshop participants were invited from around the US, and included genomic researchers and study coordinators, research participants, clinicians, bioethics scholars, experts in human research protections, and government representatives. Discussion was directed by experienced facilitators and informed by empirical data collected in a national survey of IRB chairs and in-depth interviews with research participants in studies where genotype-driven recontact occurred. A high degree of consensus was attained on the resulting seven recommendations, which cover informed consent disclosures and choices, the process for how and by whom participants are recontacted, the disclosure of individual genetic research results, and the importance of tailoring approaches based on specific contextual factors. These recommendations are intended to represent a balanced approach-protecting research participants, yet avoiding overly restrictive policies that hinder advancement on important scientific questions.     

Parent perspectives on pediatric genetic research and implications for genotype-driven research recruitment

As genetic research is increasingly conducted in children, it is important to understand how parents make decisions about enrolling their children and what they think about receiving their children's genetic research results. We conducted semi-structured phone interviews with 23 parents of children enrolled in genetic studies of autism or diabetes. Qualitative thematic analysis focused on two important components of genetic research and genotype-driven recruitment: participation in genetic research and return of results. Our findings suggest that parents' preferences and perspectives may be specific to their child's disease and the needs of the family as a whole. Assessing the expectations of target research populations will be beneficial for developing best practices for pediatric genetic research, return of results, and genotype-driven recruitment.     

Epilepsy patient-participants and genetic research results as "answers"

Better understanding of how research participants with a known condition ascribe meaning to individual genetic results is important to help researchers and institutional review boards evaluate the potential benefits and harms of disclosing results in the context of genotype-driven research recruitment. Based on 29 in-depth interviews with epilepsy patients participating in a genetic study, we found that this population of research subjects anticipated that genetic research results would provide answers to a range of questions about the research process and their condition. Their multi-layered interpretations underscore the need for clear communication about the nature and limitations of results if individual or aggregate genetic results are returned in the process of recruitment for additional research.     

The meaning of genetic research results: reflections from individuals with and without a known genetic disorder

In the debate about whether to return individual genetic results to research participants, consideration of the nature of results has taken precedence over contextual factors associated with different study designs and populations. We conducted in-depth interviews with 24 individuals who participated in a genotype-driven study of cystic fibrosis: 9 of the individuals had cystic fibrosis, 15 had participated as healthy volunteers, and all had gene variants of interest to the researchers. These interviews revealed that the two groups had different ideas about the meaningfulness of genetic results. Our findings point to the importance of understanding research context, such as participants' relationship with the researcher and whether they have the disease condition under study, when considering whether to return individual results.     

What research participants want to know about genetic research results: the impact of "genetic exceptionalism"

The disclosure of individual genetic results has generated an ongoing debate about which rules should be followed. We aimed to identify factors related to research participants' preferences about learning the results of genomic studies using their donated tissue samples. We conducted a cross-sectional survey of 279 patients from the United States and Spain who had volunteered to donate a sample for genomic research. Our results show that 48% of research participants would like to be informed about all individual results from future genomic studies using their donated tissue, especially those from the U.S. (71.4%) and those believing that genetic information poses special risks (69.7%). In addition, 16% of research participants considered genetic information to be riskier than other types of personal medical data. In conclusion, our study demonstrates that a high proportion of participants prefer to be informed about their individual results and that there is a higher preference among those research subjects who perceive their genetic information as riskier than other types of personal medical data.     

Disclosure of individual genetic data to research participants: the debate reconsidered

Despite extensive debate, there is no consensus on whether individual genetic data should be disclosed to research participants. The emergence of whole-genome sequencing methods is increasingly generating unequalled amounts of genetic data, making the need for a clear feedback policy even more urgent. In this debate two positions can be broadly discerned: a restrictive disclosure policy ('no feedback except life-saving data') and an intermediate policy of qualified disclosure ('feedback if the results meet certain conditions'). We explain both positions and present the principal underlying arguments. We suggest that the debate should no longer address whether genetic research results should be returned, but instead how best to make an appropriate selection and how to strike a balance between the possible benefits of disclosure and the harms of unduly hindering biomedical research.     

The duty to recontact: attitudes of genetics service providers

The term "duty to recontact" refers to the possible ethical and/or legal obligation of genetics service providers (GSPs) to recontact former patients about advances in research that might be relevant to them. Although currently this practice is not part of standard care, some argue that such an obligation may be established in the future. Little information is available, however, on the implications of this requirement, from the point of view of GSPs. To explore the opinions of genetics professionals on this issue, we sent a self-administered questionnaire to 1,000 randomly selected U.S. and Canadian members of the American Society of Human Genetics. We received 252 completed questionnaires. The major categories of respondents were physician geneticist (41%), Ph.D. geneticist (30%), and genetic counselor (18%); 72% of the total stated that they see patients. Respondents indicated that responsibility for staying in contact should be shared between health professionals and patients. Respondents were divided about whether recontacting patients should be the standard of care: 46% answered yes, 43% answered no, and 11% did not know. Those answering yes included 44% of physician geneticists, 53% of Ph.D. geneticists, and 31% of genetic counselors; answers were statistically independent of position or country of practice but were dependent on whether the respondent sees patients (43% answered yes) or not (54% answered yes). There also was a lack of consensus about the possible benefits and burdens of recontacting patients and about various alternative methods of informing patients about research advances. Analysis of qualitative data suggested that most respondents consider recontacting patients an ethically desirable, but not feasible, goal. Points to consider in the future development of guidelines for practice are presented.     

Disclosure of genetic information obtained through research

The rapid expansion of information and knowledge of genetics has implications for the question of whether, and under what circumstances, information discovered in the course of genetic research should be conveyed to research participants and/or their relatives. The aim of this paper is to propose an ethically defensible solution to a specific case example illustrating this problem. To do this we reviewed the literature to find answers to the following three questions: (1) What do current regulations, guidelines, and commentary say about the disclosure of genetic risk information obtained through research to research participants? (2) What do current regulations, guidelines, and commentary say about the disclosure of genetic risk information obtained through research to the relatives of research subjects? and (3) What do current regulations, guidelines, and commentary say about the disclosure of genetic risk information obtained through research about former research participants who are now deceased? Our conclusion is that current U.S. federal guidelines governing the use of human subjects in research, as well as much of the current literature, do not adequately address the familial dimension inherent in genetic research, are virtually silent on the issue of sharing information of relevance to family members, and do not protect the deceased. It is our belief that this omission needs to be corrected and that explicit guidance on this issue needs to be provided to institutional review boards and researchers alike.     

Experiences of Genetic Risk: Disclosure and the Gendering of Responsibility

The question of ‘who owns genetic information‘ is increasingly a focus of ethical inquiry. Applied to predictive testing, several recent critiques suggest that persons with a genetic disorder have a moral duty to disclose that information to other family members. The justification for this obligation is that genetic information belongs to and may benefit not only a single individual, but also members of a biological kinship. This paper considers this issue from a different vantage point: How does gender intersect with the moral duty to disclose genetic information? Scholars have argued that gender is partly comprised of distinct assignments and assumptions of responsibility. Thus, there is a danger that gendered patterns of socialization will make women feel that they should take primary responsibility for disclosing genetic information to others. This article explores issues of responsibility and disclosure of risk information by drawing on an empirical study of women and men who have undergone genetic testing for hereditary breast/ovarian cancer. The research study suggests that disclosure of genetic information is a gendered activity, with both the benefits and burdens of this task falling primarily on women. It also illustrates that when disclosure is understood contextually, it is a far more complicated matter than when viewed through a theoretical lens. The article considers the relevance of these findings on ethical debate and genetic counselling practices.     

Genetic diversity at neutral and adaptive loci determines individual fitness in a long-lived territorial bird

There is compelling evidence about the manifest effects of inbreeding depression on individual fitness and populations' risk of extinction. The majority of studies addressing inbreeding depression on wild populations are generally based on indirect measures of inbreeding using neutral markers. However, the study of functional loci, such as genes of the major histocompatibility complex (MHC), is highly recommended. MHC genes constitute an essential component of the immune system of individuals, which is directly related to individual fitness and survival. In this study, we analyse heterozygosity fitness correlations of neutral and adaptive genetic variation (22 microsatellite loci and two loci of the MHC class II, respectively) with the age of recruitment and breeding success of a decimated and geographically isolated population of a long-lived territorial vulture. Our results indicate a negative correlation between neutral genetic diversity and age of recruitment, suggesting that inbreeding may be delaying reproduction. We also found a positive correlation between functional (MHC) genetic diversity and breeding success, together with a specific positive effect of the most frequent pair of cosegregating MHC alleles in the population. Globally, our findings demonstrate that genetic depauperation in small populations has a negative impact on the individual fitness, thus increasing the populations' extinction risk.     

The consent problem within DNA biobanks

Large prospective biobanks are being established containing DNA, lifestyle and health information in order to study the relationship between diseases, genes and environment. Informed consent is a central component of research ethics protection. Disclosure of information about the research is an essential element of seeking informed consent. Within biobanks, it is not possible at recruitment to describe in detail the information that will subsequently be collected because people will not know which disease they will develop. It will also be difficult to describe the specific research that will be performed using the biobank, other than to stipulate categories of research or diseases that are not included. Potential subjects can only be given information about the sorts of research that will be performed and by whom. Organisations responsible for biobanks usually argue that this disclosure of information is adequate when seeking informed consent, especially if coupled with a right to withdraw, as it would not be feasible or it would be too expensive to seek consent renewal on a regular basis. However, there are concerns about this 'blanket consent' approach'. Consent waivers have also been proposed in which research subjects entrust their consent with an independent third party to decide whether subsequent research using the biobank is consistent with the original consent provided by the subject.     

The role of community review in evaluating the risks of human genetic variation research.

The practicality and moral value of community review of human genetic research has become a focus of debate. Examples from two Native American communities are used to address four aspects of that debate: (1) the value of community review in larger, geographically dispersed populations; (2) the identification of culturally specific risks; (3) the potential conflict between individual and group assessments of research-related risks; and (4) the confusion of social categories with biological categories. Our experiences working with these two communities suggest that: (1) successful community review may require the involvement of private social units (e.g., families); (2) culturally specific implications of genetic research may be identifiable only by community members and are of valid concern in their moral universes; (3) community concerns can be incorporated into existing review mechanisms without necessarily giving communities the power to veto research proposals; and (4) the conflation of social and biological categories presents recruitment problems for genetic studies. These conclusions argue for the use of community review to identify and minimize research-related risks posed by genetic studies. Community review also can assist in facilitating participant recruitment and retention, as well as in developing partnerships between researchers and communities.     

Disclosure is Inadequate as a Solution to Managing Conflicts of Interest in Human Research

Disclosure is a common response to conflicts of interest; it is intended to expose the conflict to scrutiny and enable it to be appropriately managed. For disclosure to be effective the receiver of the disclosure needs to be able to use the information to assess how the conflict may impact on their interests and then implement a suitable response. The act of disclosure also creates an expectation of self-regulation, as the person with the conflicting interests will be mindful of their own potential biases and aware that their decisions may be monitored. This article discusses some of the problems of relying on disclosure as a solution to address conflicts of interest in research, including the added complexities around institutional conflicts of interest. The case of Dan Markingson illustrates these issues and highlights the vulnerable position relying on disclosure as a solution leaves research participants in.     

The Double Helix: Applying an Ethic of Care to the Duty to Warn Genetic Relatives of Genetic Information

Genetic testing reveals information about a patient's health status and predictions about the patient's future wellness, while also potentially disclosing health information relevant to other family members. With the increasing availability and affordability of genetic testing and the integration of genetics into mainstream medicine, the importance of clarifying the scope of confidentiality and the rules regarding disclosure of genetic findings to genetic relatives is prime. The United Nations International Declaration on Human Genetic Data urges an appreciation for principles of equality, justice, solidarity and responsibility in the context of genetic testing, including a commitment to honoring the privacy and security of the person tested. Considering this global mandate and recent professional statements in the context of a legal amendment to patient privacy policies in Australia, a fresh scrutiny of the legal history of a physician's duty to warn is warranted. This article inquiries whether there may be anything ethically or socially amiss with a potential future recommendation for health professionals or patients to universally disclose particular cancer predisposition genetic diagnosis to genetic family members. While much of the discussion remains applicable to all genetic diagnosis, the article focuses on the practice of disclosure within the context of BRCA1/2 diagnosis. An ‘ethic of care’ interpretation of legal tradition and current practice will serve to reconcile law and medical policy on the issue of physician disclosure of genetic results to family members without patient consent.     

Professional and personal attitudes about access and confidentiality in the genetic testing of children: a pilot study

The ability to perform predictive genetic testing of children raises ethical concerns regarding whether and when to test and the disclosure of results. Semi-structured interviews with a convenience sample of pediatricians (12) and geneticists (13) were conducted to see how they would react to parental requests for predictive genetic testing of their children, and their attitudes about testing their own children. We also asked about disclosure attitudes and practices for their patients' relatives and within their own families. Respondents would provide predictive genetic testing for most conditions, yet were less likely to seek this information about their own children. Respondents believed it was very important for patients to share some types of genetic information with relatives, and were directive in their counseling about intrafamilial disclosure, especially within their own families. Although respondents would almost never breach patient confidentiality, many would breach confidentiality within their own families. Health care professionals distinguish between their professional and personal roles with regard to issues of access and confidentiality in predictive testing of children. They are willing to provide greater access and more confidentiality for their patients than within their own families.     

A multi-locus assessment of connectivity and historical demography in the bluehead wrasse (Thalassoma bifasciatum)

The pelagic larval stage of most coral reef fishes might allow extensive dispersal or, alternatively, some level of local recruitment might be important. Molecular markers can be used to obtain indirect estimates of dispersal to evaluate these alternatives, yet the extent of gene flow among populations is known for only a small number of species. The use of such markers must take into account the properties of the markers and the demographic history of the population when making inferences about current gene flow. In the Caribbean bluehead wrasse, Thalassoma bifasciatum, previous studies have found both substantial levels of local recruitment, in studies interpreting otolith microchemistry and, conversely, a lack of genetic differentiation inferred from mitochondrial DNA (mtDNA) restriction-fragment length polymorphism (RFLP) data and allozymes. However, if subtle differentiation exists, larger sample sizes and highly variable markers may be required to discern it. Here we present results from mitochondrial control region sequence and microsatellite data that indicate a lack of genetic differentiation at both small and large spatial scales. However, historical processes, such as changes in population size, may have affected the current distribution of genetic variation.     

Video‐recording complex health interactions in a diverse setting: Ethical dilemmas,reflections and recommendations

Video‐recording healthcare interactions provides important opportunities for research and service improvement. However, this method brings about tensions, especially when recording sensitive topics. Subsequent reflection may compel the researcher to engage in ethical and moral deliberations. This paper presents experiences from a South African genetic counselling study which made use of video‐recordings to understand communicative processes in routine practice. Video‐recording as a research method, as well as contextual and process considerations are discussed, such as researching one's own field, issues of trust and anonymity, the challenge of providing true informed consent and capturing details which may cause psychological harm. Several recommendations for research practice in diverse healthcare settings are made. This includes the value of reflective pieces, the importance of retrospective consent, disclosure of the limitations to anonymity, as well as the collective responsibility of those involved to produce ethical research. These recommendations have value for genetic counselling and other healthcare fields.     

Inappropriate publication of trial results and potential for allegations of illegal share dealing.

There is increasing evidence of fraud in clinical research, and one aspect concerns trading in pharmaceutical company shares by people who may have confidential information about the results of clinical trials. Plainly this has implications for honest investigators, who may find themselves exposed to such allegations. In this paper Dr D S Freestone and Mr H Mitchell, QC, identify three interlinked issues which they think underlie the potential for these allegations. They are pressure for premature or inappropriate communication of research results; trading in pharmaceutical company shares by academic clinical investigators; and the possibility that clinical investigators might succumb to temptation. Dr Freestone and Mr Mitchell suggest that whenever possible results of clinical studies should be published in appropriate medical journals without prior public disclosure. This conflicts with Stock Exchange rules, which require that price sensitive information should be published at the earliest opportunity and preclude priority of publication in medical journals. Freestone and Mitchell believe that rarely rapid public disclosure is acceptable if it is to protect patients'' interests but that it must not prejudice publication in the medical or scientific press. When rapid public disclosure is needed, they say, every attempt should be made to inform prescribers before patients. Dr Freestone and Mr Mitchell warn that academic clinical investigators who have access to unpublished price sensitive information about pharmaceutical companies whose shares they trade in will almost certainly be in breach of the Company Securities (Insider Dealing) Act 1985. Furthermore, disclosing such information to third parties, they say, exposes those people also to potential criminal liability. Freestone and Mitchell advise that when potential for allegations of conflict of interest exists clinical investigators should consider declaring their position to ethics committees and any sponsoring organisations.     

Managing the Ethical Issues of Genomic Research using Pathology Specimens

Biobanks of human biospecimens involving tissue taken from surgery require close relationships with diagnostic pathology practices. As most of the tissue will be analysed using genetic or genomic technologies there is the possibility that new information is created that could be of relevance to the donors. Although attention has been recently focused on the responsibilities that may arise from researchers and biobanks in terms of giving back individual genetic research results (IGRRs) to research participants, little has been said in relation to the role of pathology services. In this Commentary, we summarise the issues with respect to pathology services and what guidelines and professional practice documents say about their responsibilities. We also provide points to consider in the development of an ethically defensible plan for giving back individual research results.     

Exploring Heterozygosity-Survival Correlations in a Wild Songbird Population: Contrasting Effects between Juvenile and Adult Stages

The relationship between genetic diversity and fitness, a major issue in evolutionary and conservation biology, is expected to be stronger in traits affected by many loci and those directly influencing fitness. Here we explore the influence of heterozygosity measured at 15 neutral markers on individual survival, one of the most important parameters determining individual fitness. We followed individual survival up to recruitment and during subsequent adult life of 863 fledgling pied flycatchers born in two consecutive breeding seasons. Mark-recapture analyses showed that individual heterozygosity did not influence juvenile or adult survival. In contrast, the genetic relatedness of parents was negatively associated with the offspring’s survival during the adult life, but this effect was not apparent in the juvenile (from fledgling to recruitment) stage. Stochastic factors experienced during the first year of life in this long-distance migratory species may have swamped a relationship between heterozygosity and survival up to recruitment.