Members of the UK10K whole-genome sequencing project have published a detailed description of their strategy to manage the return of potentially clinically significant findings to subjects of the three-year sequencing effort.
Under the structure, described online in the European Journal of Human Genetics this month, findings have been and can be returned to UK10K research participants if they meet four conditions — explicit consent by the participant to receive results, significant clinical importance, analytical and clinical validation via an accredited lab, and communication by a trained profession able to provide genetic counseling.
If any one of these conditions is not met, findings are not fed back to a participant, regardless of their potential clinical import, according to the report.
Jane Kaye, the study's first author and a member of the UK10K Ethics Advisory Group, told Clinical Sequencing News that arriving on a structure under which potentially clinically useful findings could be returned in an ethically appropriate way was a significant undertaking for the UK10K project.
"It was a long process, and there was a lot of discussion about whether we should even address this, but because of the nature of [whole-genome and whole-exome] sequencing, we thought the only responsible thing to do was to take the issue head on," Kaye said.
As genome sequencing research projects expand and multiply both in the UK and globally, she said the UK10K group hopes sharing its example may help others streamline the creation of their own rules systems for how and when to return WGS results with potential clinical implications.
"We've done this thinking, which actually was a lot of thinking," she added. "So now, hopefully other people will be able to use it."
In the UK10K project, which took place between 2010 and 2013, approximately 4,000 participants were drawn from two existing cohort studies — TwinsUK and the Avon Longitudinal Study of Parents and Children — and another 6,000 participants were recruited within 11 disease- or condition-specific studies, including studies focused on neurodevelopment, obesity, and rare disease phenotypes.
The 4,000 participants from TwinsUK and ALSPAC had their whole genomes sequenced by the Wellcome Trust Sanger Institute to approximately six-fold coverage and those recruited for specific phenotype studies had their exomes sequenced to approximately 60-fold coverage.
Because the TwinsUK and ALSPAC subjects did not have an ongoing clinical relationship with researchers in the study, and their cohorts had their own internal rules for returning clinically relevant results, the return-of-results management plan described in the new paper mostly applies to the other 6,000 subjects in the project, the authors wrote.
In the EJHG report, Kaye and her colleagues described the framework they developed to guide UK10K researchers on when and how to return clinically significant findings — either related specifically to a disorder being studied within the effort, or for discoveries falling under the umbrella of so-called incidental findings.
According to Kaye, this distinction — between incidental results and what the group deemed "pertinent" findings — is an important aspect of the framework. Researchers working with the UK10K study have no obligation to pass on incidental findings, but if a researcher identifies a pertinent finding, the framework becomes the mechanism under which that finding can be transmitted to the participant in whose genome it was discovered.
"Something really important that we wanted to establish was that no one has an obligation to pass on incidental findings to participants," Kaye said. "There is not an obligation to go out and search for this stuff [in the sequencing data.]"
"So we tried to make the distinction between pertinent findings and incidental findings — in terms of obligations in regard to them — clear in the framework," she explained.
According to the group, under the management framework for UK10K, if a clinically significant and pertinent finding is identified, a four-stage path defines how that finding should be communicated to a participant, with a slightly different path for findings by researchers within the consortium versus those by the wider community studying the UK10K database.
Unaffiliated researchers are not obliged to share pertinent findings, but if they want to, they can pass the finding on to the UK10K management, which will feed it into the return-of-results process.
If a UK10K researcher discovers pertinent findings, they are passed on to a relevant sample custodian, and then to the clinician within the consortium who has a pre-existing relationship to the subject. Then the subject's consent is rechecked and the validity of the finding reconfirmed by a clinically accredited laboratory before the clinician can then move to share the result with the subject.
The clinician must also establish, on a case-by-case basis, that any finding to be returned is of "significant" clinical importance, according to the UK10K authors. "Benefit of informing participants of CSF's should considerably outweigh any potential harm that could be caused by reporting back," the group wrote.
Kaye said that it was important to the organizers to keep this decision making case-by-case, rather than outline distinct categories of results that should always, or never, be returned to participants.
This approach contrasts with more aggressive positions taken in the clinical genomics sphere, such as the American College of Medical Genetics recommendations last year that certain variants in 56 genes should be communicated to patients by clinical exome and whole-genome sequencing labs, regardless of the patient's preference.
"I think a case-by-case basis is really where we are right now, because it's early days yet," Kaye said. "But maybe as things start to become more routine we will move beyond that."
According to the UK10K authors, the framework they developed can only guide return of results through the end of the consortium project, as the management committee will no longer exist after the project's end to facilitate the communication of results through clinicians with direct, pre-existing relationships to participants.
However, it may be possible for some sort of data access committee to take on this role beyond the lifetime of UK10K, as researchers continue to study the data from the project stored in the European Genome-phenome Archive. According to the group, plans for this future management require further consideration by policy makers and funders.
In the meantime, Kaye said the group hopes its study can be a practical example, useful for other large sequencing research projects struggling with the same questions.
Kaye said that many unanswered questions also remain about how to integrate the management of genomic findings in the research sphere with the clinic.
"There are other research projects in the US doing this, and they have different pathways. But I think we've got to start generating these example before we can pull all the scattergun points together to get a real consensus on the way forward," she said.