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Kaiser Team Tracking Impact of WGS-based Preconception Carrier Testing under NHGRI CSER Grant


This is the second in a series of profiles of centers awarded grants this year under NHGRI's Clinical Sequencing Exploratory Research program. We previously profiled a project at the University of Michigan.

Researchers from Oregon's Kaiser Foundation Research Institute are embarking on a study to evaluate how best to communicate results from whole-genome sequencing to couples undergoing preconception carrier testing.

The effort is one of four new projects granted a total of $27 million over four years by the National Human Genome Research Institute last month under its Clinical Sequencing Exploratory Research, or CSER, program.

The project also joins six other CSER grantees, which have been operating since early 2012 (CSN 12/7/2011).

Recognizing that most of the other CSER studies are focused on cancer and other disease sequencing, Benjamin Wilfond, a bioethicist at the Seattle Children's Research Institute and the University of Washington and a co-principal investigator of the new project, said the Kaiser team decided to go in a different direction, opting to look at the logistics and impact of sequencing-based carrier status over standard single-disorder carrier testing.

Wilfond's co-PI Katrina Goddard spearheaded the design of the study, he told Clinical Sequencing News this week.

"Historically, genetics has often been focused on reproductive decision making, rather than on disease," he said. "So Katrina really thought that this was an opportunity to learn about something the other [CSER] groups aren’t looking at.

"And it's especially interesting because all the other groups will potentially have to deal with carrier status as an incidental finding," said Wilfond. "So this project really allows us to reverse what's considered incidental and what's the primary focus of sequencing to learn more about how people think about this in a way that may also be relevant to other programs."

In the study, the team plans to enroll about 380 people. Using the Kaiser Health system to track its members, the researchers will be alerted when someone seeks out or expresses interest in carrier testing for a particular disorder.

The group will then be able to contact these individuals and offer them enrollment in the study, Wilfond said.

As part of the investigation, these 380 participants will be randomized to either receive standard carrier testing for the disease of interest to them, or to undergo whole-genome sequencing with analysis focused on about 100 inherited disorders.

Wilfond said that sequencing for the trial will be conducted in two parts in collaboration with Oregon Health & Science University and the University of Washington using Illumina machines.

UW will perform initial whole-genome sequencing, he said, and if that yields results that the researchers intend to return to participants in the trial, they will be confirmed by additional sequencing through a CLIA-certified laboratory at OHSU.

The study hopes to answer questions about how patients choose which results they want to receive both in the context of carrier status and incidental findings, and how the process potentially impacts healthcare decision-making.

To do this, the researchers will survey participants after they are randomized to receive results of either a single-disorder test or the study's sequencing protocol. A smaller group of 50 subjects will be followed more deeply and will receive a more extensive interview, Wilfond said.

The researchers will also track what impact results have on healthcare utilization. "We want to know things like does [being in the sequencing group] generate more doctor visits, tests, and things like that," he said.

Rather than offering participants a full menu of every analyzed gene for which they might be a carrier, Wilfond said the group has decided to group all 100 disorders into about four or five categories ranging from the most severe to the least severe.

Participants will be able to choose which of these subgroups they would like to receive results about.

"In the most severe, you might have something like Tay-Sachs disease," Wilfond said. "And on the other side would be things like hearing loss and blindness. Some people might want to know about all of the categories and others might be more selective."

Participants will also be able to choose whether, and how much, they would like to learn about incidental findings, Wilfond said. The researchers will report results back to participants in two stages: first, carrier status findings, and then so-called incidental results a few months later.

While the team expects to learn a lot about the process of offering this kind of sequencing-based testing in the context of carrier screening, Wilfond said that because of the relatively small number of subjects, the study may not reveal much about how people use such testing to inform their reproductive decision-making.

"We are starting to appreciate that the number of positive results in terms of carrier status might be smaller than we thought," he said. "We might not find many carrier couples for particular diseases, so while we'll have some anecdotal evidence, it will be preliminary in terms of the larger question of how people use this to make reproductive decisions."

"The main thing we are going to learn about is the process of offering this: what people want, how they understand what they get, and what they think it means," he said.