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The decreasing cost of data collection increases medical use, but analysis and reimbursement remain challenging
After the completion of the Human Genome Project, it was expected that medicine would change, indeed, our lives would change. By knowing the human genetic code, it would be possible to battle disease by having better characterized targets and medicines as accurate as smart bombs. While medical practice has not been completely transformed, big changes are underway in genome sequencing in clinical situations. “There’ve been huge innovations and improvements in the past three to four years, in particular,” says Wendy Chung, a pediatrician at Columbia University (New York, N.Y.) and an expert in the applications of clinical sequencing. “You can look at a single gene or the entire whole genome sequence.”
George Asimenos, director of strategic projects at DNAnexus (Mountain View, Calif.), says, “From our perspective, clinical sequencing is increasingly applied in oncology to advance personalized treatment of cancer, identification and treatment of Mendelian diseases, and in prenatal genetic testing.”
Despite the growing list of clinical applications of sequencing, Jonathan Arnold, senior director of marketing for next-generation sequencing (NGS) at QIAGEN (Hilden, Germany), says, “We’re still in the early days.” For oncology, he notes, “NGS…[allows] clinicians to make a much more comprehensive evaluation of cancer samples.”
Clinical sequencing is being used increasingly, partially because of its decreasing price. In 2001, it cost nearly $10,000 to sequence a million bases of DNA, and now it’s about a penny, according to U.S. National Institutes of Health’s National Human Genome Research Institute. With sequencing so inexpensive, analysis creates the real cost now. As Chung says, “The challenge now is more the data interpretation.”
With all of the hubbub surrounding next-generation sequencing, which is basically just faster and more complete than previous methods like Sanger sequencing, scientists might think that only NGS is being used in clinical sequencing, but it’s not. In targeted applications, where a clinician knows just what to look for, Sanger sequencing is still used. “If you had to say what technology is used most, measured as the number of base pairs produced by the industry,” Chung explains, “more than 99.9% is from NGS because you get so much more from one run.”
Whole or part?
Some clinical situations call for a whole-genome screen, while others can be done with screening for limited panels. Panels are fine for some forms of inherited cancer; in other cases, the targets are not clear enough to make an effective panel. “For childhood intellectual disabilities,” Chung says, “no panels give a high enough clinical yield, so you have to sequence the exome”—the entire protein-coding part of the genome.
Illumina’s MiSeqDx is cleared for clinical use by the FDA and can also run a variety of research applications. (Image courtesy of Illumina.)Clinicians need platforms made specifically for NGS. “Illumina’s MiSeqDx is the world’s first FDA-cleared NGS instrument,” says Raj Kapadia, director of clinical marketing at Illumina (San Diego, Calif.). “It was designed with clinical laboratories in mind.” This platform can be used for the growing list of FDA-cleared assays and research-use-only (RUO) applications available for Illumina’s MiSeq sequencer. “This ‘dual mode’ capability gives clinicians the ability to develop diagnostics, and provides researchers with the flexibility to pursue RUO experiments on the same instrument,” Kapadia says.
QIAGEN’s GeneReader NGS provides sample preparation, sequencing and data analysis, which simplifies the use of sequencing in clinical research. (Image courtesy of QIAGEN.)To make more sequencing tests available clinically, they need to be validated, verified and approved. “Illumina is working on developing clinical products, inclusive of informatics solutions, in the areas of reproductive and genetic health and oncology,” Kapadia says. “We also look for opportunities to partner with regulatory agencies, associations and other industry players to set standards.”
QIAGEN’s GeneReader NGS is RUO; Arnold points out that having a complete solution—sample preparation, sequencing and data analysis—in one platform makes it easier for clinical researchers to move to NGS. “This system goes from nucleic-acid extraction to data analysis and interpretation and solves the NGS adoption hurdles that laboratorians have struggled to overcome,” he says.
Dealing with more data
“As sequencing costs have gone down, data challenges have become more severe,” says Asimenos. “Data that once came into a lab as a trickle has turned into a flood.” He adds, “A major challenge in realizing the true potential of clinical sequencing is managing, securing and ascertaining results from these large stockpiles of genomic datasets.
“Once the results have been acquired from genomic analysis, then researchers need to make biological sense of all the genomic variation in the context of disease.” Doing that requires sequencing and analyzing thousands, maybe millions, of patients to reach the needed statistical correlation and validation.
To handle these challenges, DNAnexus created a cloud-based solution, described by Asimenos as a “genome informatics and data-management platform that is used by organizations that are pursuing genomic approaches to health, in the clinic and in the research lab.” He adds, “Cloud computing not only mitigates the data deluge issue; it also fosters collaboration across geographic, academic and commercial boundaries.”
This platform is already in use by genome centers like the Baylor College of Medicine (Houston, Texas), and diagnostic-test providers, including Natera (San Carlos, Calif.) and CareDx (Brisbane, Calif.). Users also include clinical and research sequencing service providers, such as the Garvan Institute of Medical Research (Darlinghurst, Australia).
Reimbursement obstacle
In the past, the technology for clinical sequencing created the bottleneck. Today, it’s knowledge and payment. “It’s possible for any licensed clinician to order any of these tests,” Chung explains. “The barrier at this point is that some clinicians still don’t know the utility of this testing, so they don’t all feel comfortable ordering it.” Clinicians who do order sequencing tests face a different obstacle: getting reimbursed from insurance companies. As Chung says, “Insurance companies are struggling to understand the clinical utility and for which indications there is clinical utility.”
Luckily, the reimbursement part is changing. On January 11, 2016, Independence Blue Cross and NantHealth announced coverage for whole genome and proteome screening. Others will likely follow suit over time.
“The real promise of clinical sequencing is that it is becoming very easy to get to the diagnosis quickly and cost-effectively,” says Chung, “and that gets patients to the best treatments.”
Mike May is a freelance writer and editor living in Ohio. He can be reached at [email protected]