NEW YORK (GenomeWeb) – Children's National Health System has begun a pediatric genomic initiative to move genetic testing in house, bringing on board next-generation sequencing capability to run its tests, which it will link with patients' electronic medical records.
Sean Hofherr, CNHS's director of molecular diagnostics, told GenomeWeb that the goal of the initiative is to improve diagnostic rates, speed up turnaround time, and be more cost efficient than the hospital's previous model of outsourcing genetic testing to reference laboratories.
The hospital's validated workflow includes Illumina's TruSight One panel, which focuses on 4,813 genes, and sequencing on Illumina's NextSeq 500 instrument, as well as GenomOncology's GO Clinical Workbench for analysis and report generation. The pipeline was implemented in February.
The hospital is taking somewhat of a unique approach to genomic testing. Clinicians can order the entire TruSight One panel, one of 29 fixed panels, or can customize their own panel based on suspected genes or the patient's phenotype. But, regardless of the order, the entire TruSight One panel will still be sequenced for every patient. Then using bioinformatics, the laboratory will focus analysis on only the ordered genes.
"Instead of ordering really general panels that sometimes have a lot of genes that are not relevant, physicians can go after their high-value target first," Hofherr said.
In addition, Hofherr said that the set-up favors the hospital's unique situation. The hospital is solely a pediatric hospital, he said, and it has "one of the largest clinical genetics programs in the nation," including 15 clinical geneticists and 15 genetic counselors on staff full time that see around 7,500 patients annually in the genetics clinic. In addition, the molecular diagnostics laboratory does not have a lot of space, so a huge genomics core was not a possibility, Hofherr said.
Previously, the hospital had outsourced all of its genetic testing to various reference laboratories, approximately 2,000 tests per year, Hofherr said. But under that model, "we were basically at the mercy of the reference labs as to how much the test was going to cost, turnaround time, [and] the content on the test," he said.
In addition, reference laboratories did not have the benefit of the rich clinical history stored within the patients' EMRs to help with interpreting sequence data, Hofherr said.
In 2013 the hospital moved array-based testing in house, which cut the number of outsourced tests by about half. Of the 800 to 1,000 tests sent out every year, over a quarter were ordered only one time.
The next year it decided to invest in NGS. "We needed to figure out a way to do [genetic testing] cost effectively and so that it would benefit our patients in the most valuable way possible," Hofherr said.
So, rather than design hundreds of individual panels, Hofherr said the lab validated one large panel, which could then be customized on the analysis side. The ordering physician has several options. The hospital has 29 fixed content panels for the most commonly ordered tests, for conditions like Noon syndrome, cardiomyopathies, and epilepsy, Hofherr said.
In addition, it also offers what it calls personalized sequence panels, or PSPs. There are two options for ordering PSPs. The physician can simply give the lab a list of genes, or the lab will design the PSP based on the clinical indication and phenotype of the patient.
For both options, before the test is run, the lab will verify that the target genes are covered by the panel at a high enough coverage to merit testing. For the second option, where a PSP is designed based on the phenotype, the lab will first produce a pre-test report, indicating the genes it recommends for testing and whether any are poorly covered by the TruSight One panel. Then the physician can discuss the test with a genetic counselor and decide whether or not to place the order.
Billing is based on the number of genes included in the panel, which "favors smart ordering by the physician," Hofherr said. A single gene costs $3,000, while the larger panels run around $7,500, Hofherr. On average, the per-test rate is about $5,000.
Turnaround times also vary depending on the size of the panel. For a single gene, it is three to four weeks, but larger panels are six to eight weeks, although Hofherr said that so far turnaround times have been "faster than we were anticipating," and much faster than the four- to six-month turnaround when testing was outsourced.
If the initial test is negative, physicians can expand the analysis to look at additional genes. The cost for that expansion will be the difference between the two panels. Panel prices are tiered, with a set price for a panel composed of two to five genes, six to 15 genes, 16 to 50 genes, 51 to 100 genes, 101 to 150, and so on.
"Prices are very comparable and oftentimes cheaper than what our patients were getting charged before," Hofherr said.
While the lab has tested around 50 patients so far, Hofherr said that with its one NextSeq system, it has an annual capacity of about 700 to 800 patients by multiplexing 24 patients in one run.
The data that is reported back to the clinician in the clinical report are entered into patients' electronic medical records. The remaining sequence data on the genes that were not analyzed on the initial test order are being kept indefinitely, at least for the time being, Hofherr said. That data is being stored both in the cloud using Illumina's BaseSpace, as well as stored locally, Hofherr said. The information is available if the initial test was negative for physicians to order the analysis of additional genes.
One benefit to the approach of doing one broad sequencing test but ordering targeted panels to be analyzed is that it cuts down on incidental findings, Hofherr said. The lab does not seek out information on genes unrelated to the patient's presentation in genes that can predict cancer risk or other adult onset diseases, Hofherr said, and so far, the families have not requested that information.
"We're a pediatric institution, and what people are interested in is getting a diagnosis for their children," he said. Nonetheless, he said that a physician could order a panel of such genes, for instance, the 56 genes that the American College of Medical Genetics and Genomics has recommended that labs screen for due to their actionability.
Children's National is not the only institution to take the approach of broad sequencing but focused analysis. Radboud University Medical Centre in the Netherlands also does exome sequencing but conducts a targeted analysis, which speeds up the process and cuts down on the number of incidental findings. Indeed, the center previously said that of 1,000 exomes sequenced, it had only identified one incidental finding.
In the next six months to one year, Hofherr said that he expects the laboratory to begin doing full exome sequencing. "We've been very conservative with exome testing because of the number of findings you get, including clinically relevant, incidental, and variants of uncertain significance," he said, calling it a "test of last resort."
However, he said, because of the rapid pace in which new disease-causing genes are being identified, exome sequencing "could improve our ability to test for any subset of genes that we want," he said. Eventually, he said that the test could be a "one-stop shop for all the genetic testing at our institution."
Aside from genetic testing, the hospital is looking to implement NGS in other capacities, Hofherr said. For instance, Joseph Campos, who directs the microbiology laboratory at the hospital, is interested in implementing whole-genome shotgun sequencing for infectious disease diagnostics and monitoring. For that application, Hofherr said the laboratory would likely look to bring a smaller NGS instrument on board, like the Illumina MiSeq.