Clinical genomics, like an eagerly awaited computer application, has quite a few bugs. Several of them have been identified in an exploratory study conducted by Stanford researchers, who analyzed the whole genomes of 12 people who lacked any obvious hereditable diseases. Whole-genome sequencing (WGS), the researchers found, must overcome a number of significant challenges before it can be considered routinely clinically useful.
One particularly sobering observation was that WGS remains harder to use for disease prediction than for disease diagnosis. Yet even now, WGS can, in certain cases, identify clinically actionable genetic variants warranting early medical intervention.
Making use of the Stanford GenePool Biobank, researchers scrutinized data from adult participants who underwent WGS. The researchers took note of the degree of sequencing accuracy necessary to make clinical decisions in individuals, the time it took to manually analyze each person's results, and the projected costs of recommended follow-up medical tests.
As indicated in a paper (“Clinical Interpretation and Implications of Whole-Genome Sequencing”) that is to appear March 12 in the Journal of the American Medical Association, the researchers concluded that use of WGS “was associated with incomplete coverage of inherited-disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings.”
Commercially available WGS, the researchers determined, does not achieve the accuracy necessary to identify every nucleotide in 7–16% of genes known to be associated with increased disease risk. While a degree of uncertainty is allowable during studies of populations, which look for trends by comparing hundreds of genomes, a higher degree of accuracy is needed if clinicians are to make useful predictions about an individual’s health status.
“These off-the-shelf genome sequencing techniques were developed to provide generally good coverage of most of the genome,” said postdoctoral scholar and cardiology fellow Frederick Dewey, M.D. “But there are some regions that remain to be covered well that we care very deeply about. We still need to supplement this information with additional sequencing.”
The study also concluded that WGS currently imposes high curatorial costs. The amount of manual labor involved in sifting through the many variants in each individual approached 100 hours. With the exception of a few well-known mutations, the authors noted, there is still no standard way to assess the potential health impact of each change.
“We need to be very honest about what we can and cannot do at this point in time,” said Euan Ashley, M.D., associate professor of medicine and of genetics. “It's clear that if we sequence enough cases, we can change someone's life. But with this opportunity comes the responsibility to do this right. 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.”
The study did yield at least one highly positive outcome: One of the 12 participants, a woman with no family history of breast or ovarian cancer, learned she carried a potentially deadly deletion in her BRCA1 gene. After confirmation of the finding in a clinical cancer genetics setting, she was able to take action to reduce her future risk for breast and ovarian cancer.
Both the possibilities and the limitations of WGS are considered in an editorial that will accompany the main paper in JAMA. In this editorial, William G. Feero, M.D., Ph.D, of the Maine Dartmouth Family Medical Residency writes that, “Like the personal computer, Internet, smartphones, and electronic health records, turning back now from the use of genomic technologies in health care is inconceivable.”
Rather than concluding that clinical applications of WGS are too immature to be worth pursuing, Dr. Feero notes that while the Stanford researchers “demonstrate that much remains to be learned … before truly successful widespread integration can occur,” they also “provide a glimpse of what is possible.”
Dr. Feero’s assessment coincides with that of Dr. Ashley, who commented, “Our intention was to identify how best to move forward. Challenges to bringing this technique to the clinic are becoming crystallized. Whole-genome sequencing has the power to be absolutely transformative in the clinic.”