Kristien Hens

The return of individual research findings in paediatric genetic research

The combination of the issue of return of individual genetic results/incidental findings and paediatric biobanks is not much discussed in ethical literature. The traditional arguments pro and con return of such findings focus on principles such as respect for persons, autonomy and solidarity. Two dimensions have been distilled from the discussion on return of individual results in a genetic research context: the respect for a participant’s autonomy and the duty of the researcher. Concepts such as autonomy and solidarity do not fit easily in the discussion when paediatric biobanks are concerned. Although parents may be allowed to enrol children in minimal risk genetic research on stored tissue samples, they should not be given the option to opt out of receiving important health information. Also, children have a right to an open future: parents do not have the right to access any genetic data that a biobank holds on their children. In this respect, the guidelines on genetic testing of minors are applicable. With regard to the duty of the researcher the question of whether researchers have a more stringent duty to return important health information when their research subjects are children is more difficult to answer. A researcher’s primary duty is to perform useful research, a policy to return individual results must not hamper this task. The fact that vulnerable children are concerned, is an additional factor that should be considered when a policy of returning results is laid down for a specific collection or research project.

Developing a policy for paediatric biobanks: principles for good practice.

The participation of minors in biobank research can offer great benefits for science and health care. However, as minors are a vulnerable population they are also in need of adequate protective measures when they are enrolled in research. Research using biobanked biological samples from children poses additional ethical issues to those raised by research using adult biobanks. For example, small children have only limited capacity, if any, to understand the meaning and implications of the research and to give a documented agreement to it. Older minors are gradually acquiring this capacity. We describe principles for good practice related to the inclusion of minors in biobank research, focusing on issues related to benefits and subsidiarity, consent, proportionality and return of results. Some of these issues are currently heavily debated, and we conclude by providing principles for good practice for policy makers of biobanks, researchers and anyone involved in dealing with stored tissue samples from children. Actual implementation of the principles will vary according to different jurisdictions.

Biological sample collections from minors for genetic research: a systematic review of guidelines and position papers

Stored tissue samples are an important resource for epidemiological genetic research. Genetic research on biological material from minors can yield valuable information on the development and genesis of early-onset genetic disorders and the early interaction of environmental and genetic factors. The use of such tissue raises some specific ethical and governance questions, which are not completely covered by the discussion on biological materials from adults. We have retrieved 29 guidelines and position papers pertaining to the storage and use of biological tissue samples for genetic research, originating from 27 different organizations. Five documents have an international scope, three have an European scope and 21 have a national scope. We discovered that 11 of these documents did not contain a section on biological materials from minors. The content of the remaining 18 documents was categorized according to four themes: consent, principles of non-therapeutic research on vulnerable populations, ethics committee approval and difference between anonymous and identifiable samples. We found out that these themes are not consistently mentioned by each document, but that documents discussing the same themes were mostly in agreement with their recommendations. However, a systematic reflection on the ethical and policy issues arising from the participation of minors in biobank research is missing.

Genetic research on stored tissue samples from minors: a systematic review of the ethical literature.

The potential benefits of biobank research are well known. Also, the ethical implications of genetic research on stored tissue samples are well discussed in existing literature. The inclusion of tissue samples from minors may have significant scientific value. However, this inclusion raises specific ethical questions. We have performed a systematic search of the literature and found 21 theoretical and empirical articles dealing with the issue. After review, we distilled five clusters of themes: consent, risks, benefits, return of results, and ownership. We have described the different components of these themes, as they occurred in the literature and have provided a discourse on the topic.

The Storage and Use of Biological Tissue Samples from Minors for Research: A Focus Group Study

Genetic research on pediatric stored tissue samples raises specific ethical questions that differ from those raised when adults are the donors. To investigate opinions on this matter, we conducted 10 focus group discussions. Five focus groups were conducted with adult participants and 5 had teenage participants between 15 and 19 years old. The discussions were analyzed with NVIVO 8 (qualitative research software). We found the following recurrent categories: the requirement that research should not pose any burden on children and that it should benefit other children, the trust people had in the role of parents, the need for information and the growth towards autonomy. Both the adults and teenagers we interviewed thought that the inclusion of tissue samples from minors in research had ethical implications. A major concern was that nontherapeutic research would pose no extra burden on children, which would assume the use of nonintrusive methods of gathering samples and the use of samples that were gathered in a diagnostic context. Participants, however, also understood the necessity of such research. The overall impression was that parents would be the best persons to make decisions on behalf of a small child and that the same parents would engage their children in the decision-making when they grew older. People thought that there was a duty to recontact minors when they reached the age of competence but on a best-effort basis.

Children, biobanks and the scope of parental consent

The use of stored tissue samples from children for genetic research raises specific ethical questions that are not all analogous to those raised when adult participants are concerned. These include issues with regard to consent, as it is typically a parent who consents to the use of samples from children. In this paper, we discuss the scope of parental consent. This scope has a temporal dimension and one related to the content of consent. It is not questioned that the temporal scope of parental consent is limited and that young adults have the right to decide on the fate of their samples when they reach the age of maturity. With regard to the content of consent, the question remains whether parents are allowed to give full broad consent to any possible future research on the samples of their children. We argue that they should not be allowed to do so, based on two premises. First, it is generally acknowledged that children have a right to express their own values and that they should be given the opportunity to develop their own autonomy as they grow older. Second, research and science are not completely value-free and some types of research may be more sensitive than other types. Children should be given the opportunity to express their values also in this respect.

Children and biobanks: a review of the ethical and legal discussion

The use of tissue samples from children is vital to genetic research. Collections of such tissue, in so-called biobanks, can take the form of large-scale prospective cohort studies or disease-specific studies using tissue of children with that specific disease. Collections of samples gathered in a diagnostics context, such as blood spot cards, can also be used for genetic research. Research on stored tissue samples from children poses ethical questions that are different from those posed by the use of samples from adults. Also, the ethical questions raised by the participation of children in biobanks are not analogous to those raised by the participation of children in clinical trials. In this review we first give an overview of the international ethical guidelines and legal regulations concerning biobanking and minors. Next, we review the different themes that occur in the ethical literature on this subject. Specifically we focus on questions of risk and benefit, consent and assent and the return of individual results. We also discuss the concept of solidarity, which is a relatively new concept in the context of children and biomedical research. To conclude, we discuss the gaps and questions raised by the review.

Risks, Benefits, Solidarity: A Framework for the Participation of Children in Genetic Biobank Research

Research on biological samples from children and pediatric biobanks can be useful for the progress of medical science. For example, genetic cohort studies can shed an important light on the interaction between genes and environment and help understand diseases such as asthma, food intolerances, autism, and attention-deficit/ hyperactivity disorder. Also, disease-specific collections can help in the understanding of the importance of gene variations in the development of the disease in question. Collections of samples and extracted DNA can typically be stored in a longer period, and research on them can change with time. Collections can be gathered primarily for research purposes, or collections originally gathered for diagnostic purposes could be re-used for genetic research. Although useful, such collections also pose specific ethical problems that are not covered by the discussion on stored tissue samples from adults. Existing discussions often link the question whether children should and can participate to the question of minimal risk and benefit. In this paper, we explore these topics further in the context of pediatric biobanks and provide some suggestions on the ethical inclusion of children in biobank research. We shall use the term ‘‘children’’ rather broadly, from birth until the legal age of competence, although we admit that each phase in growing up has specific issues and therefore requires a slightly different approach. We assume that the children in question will become independent adults. The issue of mentally retarded children who will never become independent adults is an interesting topic in itself. These children will stay in the custody of parents or family members or, when deceased or otherwise unavailable, in the custody of the state when they become adults. This raises special issues about who can consent for research on samples of these children or adults. Although we do not question the rights of parents to consent for research on biological samples also in this case, the right of the state to consent to genetic research on samples from individualsin itscustody ismoreproblematic. Thisissue merits further reflection, but is beyond the scope of this paper. We also admit that there is a difference between the use of collections of samples that were gathered for diagnosis and the gathering of new samples from children with the sole purpose of therapeutic research. This difference has ethical implications to which we shall come back in due course. In the context of biobanks, some have argued thatthe traditional autonomy paradigm in bioethics has failed. 1,2 In this

In vitro screening of embryos by whole-genome sequencing: now, in the future or never?

STUDY QUESTION What are the analytical and clinical validity and the clinical utility of in vitro screening of embryos by whole-genome sequencing? SUMMARY ANSWER At present there are still many limitations in terms of analytical and clinical validity and utility and many ethical questions remain. WHAT IS KNOWN ALREADY Whole-genome sequencing of IVF/ICSI embryos is technically possible. Many loss-of-function mutations exist in the general population without serious effects on the phenotype of the individual. Moreover, annotations of genes and the reference genome are still not 100% correct. STUDY DESIGN, SIZE, DURATION We used publicly available samples from the 1000 Genomes project and Complete Genomics, together with 42 samples from in-house research samples of parents from trios to investigate the presence of loss-of-function mutations in healthy individuals. PARTICIPANTS/MATERIALS, SETTING, METHODS In the samples, we looked for mutations in genes that are associated with a selection of severe Mendelian disorders with a known molecular basis. We looked for mutations predicted to be damaging by PolyPhen and SIFT and for mutations annotated as disease causing in Human Genome Mutation Database (HGMD). MAIN RESULTS AND THE ROLE OF CHANCE More than 40% of individuals who can be considered healthy have mutations that are predicted to be damaging in genes associated with severe Mendelian disorders or are annotated as disease causing. LIMITATIONS, REASONS FOR CAUTION The analysis relies on current knowledge and databases are continuously updated to reflect our increasing knowledge about the genome. In the process of our analysis several updates were already made. WIDER IMPLICATIONS OF THE FINDINGS At this moment it is not advisable to use whole-genome sequencing as a tool to set up health profiles to select embryos for transfer. We also raise some ethical questions that have to be addressed before this technology can be used for embryo selection. TRIAL REGISTRATION NUMBER N/A.

Biobanks: oversight offers protection.

D. Gurwitz et al. (“Children and population biobanks,” Policy Forum, 14 August, p. [818][1]) are right to argue that the storage and use of tissue samples and extracted DNA from children for genetic research pose specific ethical questions, which are different from those posed by adult samples.