Seek and ye shall find: the challenge of genome sequencing

The 100,000 Genomes Project, launched by the Prime Minister in late 2012 (see BioNews 685), aims to bring the benefits of genomic science and medicine to NHS patients. As well as offering direct benefits to participants, the project also offers the potential of wider benefits by furthering the understanding of the complex relationship between genetics and health, and exploiting this knowledge to develop new therapies.

Genome sequencing has the potential to create unprecedented quantities of data, yet this project goes beyond genomic data by seeking to link genomic and other health data. Given this heady mixture, combining different forms of highly sensitive personal data, the ethical issues will be abundant. From the outset, the project has established an independent Ethics Advisory Committee to steer the project through these issues.

One of the thorniest ethical issues concerns the management of 'findings' from the project and whether, what, and how research participants should receive feedback. These questions are not new ones but they are now being brought to the fore.

Should participants be permitted to opt-out of any feedback? The Universal Declaration on the Human Genome and Human Rights states: 'The right of each individual to decide whether or not to be informed about the results of genetic examination ... should be respected'.

The WHO and the Council of Europe also recognise the right to remain in ignorance, saying: 'The wish of individuals and families not to know genetic information, including test results, should be respected'. Human Rights legislation could also be read as including the right to remain in ignorance within the principle of respect for private and family life.

Some have argued that to remain in ignorance is to be morally irresponsible, especially in the context of genetics, which has implications for family members. Consider the analogy of taking the family car to a mechanic for a service and ordering him not to inform you if there is expensive bad news (like the brakes or tyres are worn out). If we find this ridiculous in the case of a car, then why should it be different for a potentially serious health condition?

A project like 100,000 Genomes has to develop a strategy which can withstand scrutiny even though there are many ethical nuances. Should acceptance of feedback be mandatory to participate in genome sequencing research? If so, what should be fed back?

Perhaps an obvious place is to start with the opinions and views of potential participants. There have been several studies of potential participants' views on feedback: one study showed that there was overwhelming support for the return of health-related findings to research participants, and another showed that families undergoing exome sequencing had a strong preference for disclosure of secondary findings.

The opinion of professionals is also important and the American College of Medical Genetics published a position statement requiring feedback on a list of known pathogenic gene defects. This requirement has been disputed because not all sequencing projects will have the capacity to report on these genes to an appropriate clinical standard.

The 100,000 Genomes project will need to develop a prudent, manageable, and above all ethical approach. Set out below are the common categories of research findings and some of the critical questions a policy on findings must address.

1. Primary or 'pertinent' findings are the most likely category of finding since they are closely related to the condition under consideration and are also the most likely to be pathogenic. It might be reasonable to presume that most participants would wish to receive information about such findings, but will this be mandatory for participants in the study? How will the feedback be handled, for example, in the case of family-relevant findings, or where the subject is a child or an adult who lacks capacity to consent?
2. Secondary or 'additional' findings may be unrelated to the condition under scrutiny but may nevertheless be serious in nature. While it may not be possible or practical to include the entire list of gene variants identified by the ACMG it will be necessary to consider whether the BRCA1/2 (genes causing breast and ovarian cancer) or the genes responsible for familial bowel cancer and similar pathogenic genes ought to be on 'the list'. The crucial question is: will feedback of such findings be mandatory or optional?
3. Incidental findings are findings that, although not directly sought out, may nevertheless be discovered. Such findings may have known or unknown implications for the participant. Some academic ethical discussions about incidental findings have concluded that there is no obligation to seek or to report on them. However, a project like the 100,000 Genomes is actively seeking to expand knowledge about the role of genes in health and disease and it surely must be responsive to changes in knowledge and be prepared to expand its list of candidate secondary findings from knowledge gained incidentally. This calls for an ethically reflective and responsive approach to managing findings across the lifetime of the project.

In its ambition to set the standard for genomic medicine and research, the 100,000 Genomes Project must not neglect the opportunity to set the highest possible ethical standards for the field.