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of General Medical Sciences
There are significant challenges to overcome before whole-genome sequencing can be routinely used in the clinic, researchers have reported in JAMA.
In sequencing the entire genome of 12 healthy individuals, the team found they sometimes had difficulty identifying
variants in disease-associated genes, disagreed about which variants were particularly important for disease, and were uncertain about clinically reportable findings.
The research also revealed that detailed genome analysis required up to 100 hours of manual assessment per person, and the total cost of this process (including follow-up tests) could exceed $15,000 per person.
This is more expensive and labor-intensive than previous estimates, the researchers noted.
“We need to be very honest about what we can and cannot do at this point in time,” said study author Euan Ashley, MB ChB, DPhil, of Stanford University in California.
“Our hope is that the identification of specific hurdles will allow researchers in this field to focus their efforts on overcoming them to make this technique clinically useful.”
To identify these hurdles, Dr Ashley and his colleagues evaluated whole-genome sequencing in 12 healthy individuals. The team took note of the degree of sequencing accuracy necessary to make clinical decisions, the time it took to manually analyze each person’s results, and the costs involved.
The researchers discovered that sequencing could not provide reliable results regarding all inherited disease genes or consistently detect variants with the highest potential clinical effects.
Depending on the sequencing platform used, 10% to 19% of inherited disease genes were not covered to accepted standards for single-nucleotide variant discovery.
And although genotype concordance was high for previously described single-nucleotide variants—99% to 100%—it was low for small insertions and deletions—53% to 59%.
“It’s ironic, and slightly sobering, that we struggle the most in identifying insertions and deletions—those changes in the genome that are most impactful,” Dr Ashley said.
Nevertheless, he and his colleagues were able to identify an average of about 100 variants per person that were considered important enough for follow-up. Each variant required about an hour of investigation to assess the relevant scientific literature and determine whether the change was likely to modify disease risk in the individual.
After this process, the researchers were left with approximately 2 to 6 results they felt could be clinically important.
The variants expected to have potential health consequences were shared with 3 primary care physicians and 2 medical geneticists, who independently studied the results and recommended possible follow-up tests for each person.
The researchers estimated that the median cost for sequencing and variant interpretation was $14,815 (range, $14,050 to $15,715), plus the costs of computing infrastructure and data storage. And the projected costs for follow-up tests ranged from $351 to $776.
Despite the challenges they identified, the team said they are confident that whole-genome sequencing is worth pursuing.
“Our intention in doing this analysis was to draw a line describing where we are with this technology at this point in time and identify how best to move forward,” Dr Ashley said. “Things are becoming more clear, and the challenges to bringing this technique to the clinic are becoming crystallized.” 
of General Medical Sciences
There are significant challenges to overcome before whole-genome sequencing can be routinely used in the clinic, researchers have reported in JAMA.
In sequencing the entire genome of 12 healthy individuals, the team found they sometimes had difficulty identifying
variants in disease-associated genes, disagreed about which variants were particularly important for disease, and were uncertain about clinically reportable findings.
The research also revealed that detailed genome analysis required up to 100 hours of manual assessment per person, and the total cost of this process (including follow-up tests) could exceed $15,000 per person.
This is more expensive and labor-intensive than previous estimates, the researchers noted.
“We need to be very honest about what we can and cannot do at this point in time,” said study author Euan Ashley, MB ChB, DPhil, of Stanford University in California.
“Our hope is that the identification of specific hurdles will allow researchers in this field to focus their efforts on overcoming them to make this technique clinically useful.”
To identify these hurdles, Dr Ashley and his colleagues evaluated whole-genome sequencing in 12 healthy individuals. The team took note of the degree of sequencing accuracy necessary to make clinical decisions, the time it took to manually analyze each person’s results, and the costs involved.
The researchers discovered that sequencing could not provide reliable results regarding all inherited disease genes or consistently detect variants with the highest potential clinical effects.
Depending on the sequencing platform used, 10% to 19% of inherited disease genes were not covered to accepted standards for single-nucleotide variant discovery.
And although genotype concordance was high for previously described single-nucleotide variants—99% to 100%—it was low for small insertions and deletions—53% to 59%.
“It’s ironic, and slightly sobering, that we struggle the most in identifying insertions and deletions—those changes in the genome that are most impactful,” Dr Ashley said.
Nevertheless, he and his colleagues were able to identify an average of about 100 variants per person that were considered important enough for follow-up. Each variant required about an hour of investigation to assess the relevant scientific literature and determine whether the change was likely to modify disease risk in the individual.
After this process, the researchers were left with approximately 2 to 6 results they felt could be clinically important.
The variants expected to have potential health consequences were shared with 3 primary care physicians and 2 medical geneticists, who independently studied the results and recommended possible follow-up tests for each person.
The researchers estimated that the median cost for sequencing and variant interpretation was $14,815 (range, $14,050 to $15,715), plus the costs of computing infrastructure and data storage. And the projected costs for follow-up tests ranged from $351 to $776.
Despite the challenges they identified, the team said they are confident that whole-genome sequencing is worth pursuing.
“Our intention in doing this analysis was to draw a line describing where we are with this technology at this point in time and identify how best to move forward,” Dr Ashley said. “Things are becoming more clear, and the challenges to bringing this technique to the clinic are becoming crystallized.”
of General Medical Sciences
There are significant challenges to overcome before whole-genome sequencing can be routinely used in the clinic, researchers have reported in JAMA.
In sequencing the entire genome of 12 healthy individuals, the team found they sometimes had difficulty identifying
variants in disease-associated genes, disagreed about which variants were particularly important for disease, and were uncertain about clinically reportable findings.
The research also revealed that detailed genome analysis required up to 100 hours of manual assessment per person, and the total cost of this process (including follow-up tests) could exceed $15,000 per person.
This is more expensive and labor-intensive than previous estimates, the researchers noted.
“We need to be very honest about what we can and cannot do at this point in time,” said study author Euan Ashley, MB ChB, DPhil, of Stanford University in California.
“Our hope is that the identification of specific hurdles will allow researchers in this field to focus their efforts on overcoming them to make this technique clinically useful.”
To identify these hurdles, Dr Ashley and his colleagues evaluated whole-genome sequencing in 12 healthy individuals. The team took note of the degree of sequencing accuracy necessary to make clinical decisions, the time it took to manually analyze each person’s results, and the costs involved.
The researchers discovered that sequencing could not provide reliable results regarding all inherited disease genes or consistently detect variants with the highest potential clinical effects.
Depending on the sequencing platform used, 10% to 19% of inherited disease genes were not covered to accepted standards for single-nucleotide variant discovery.
And although genotype concordance was high for previously described single-nucleotide variants—99% to 100%—it was low for small insertions and deletions—53% to 59%.
“It’s ironic, and slightly sobering, that we struggle the most in identifying insertions and deletions—those changes in the genome that are most impactful,” Dr Ashley said.
Nevertheless, he and his colleagues were able to identify an average of about 100 variants per person that were considered important enough for follow-up. Each variant required about an hour of investigation to assess the relevant scientific literature and determine whether the change was likely to modify disease risk in the individual.
After this process, the researchers were left with approximately 2 to 6 results they felt could be clinically important.
The variants expected to have potential health consequences were shared with 3 primary care physicians and 2 medical geneticists, who independently studied the results and recommended possible follow-up tests for each person.
The researchers estimated that the median cost for sequencing and variant interpretation was $14,815 (range, $14,050 to $15,715), plus the costs of computing infrastructure and data storage. And the projected costs for follow-up tests ranged from $351 to $776.
Despite the challenges they identified, the team said they are confident that whole-genome sequencing is worth pursuing.
“Our intention in doing this analysis was to draw a line describing where we are with this technology at this point in time and identify how best to move forward,” Dr Ashley said. “Things are becoming more clear, and the challenges to bringing this technique to the clinic are becoming crystallized.”