3 new NGS Surveys on CAP 2016 PT launchpad

Over the long term, Dr. Voelkerding projects, “We think the solution—and this is part of our development efforts—is to essentially create customized bioinformatics challenges on individual laboratory tests.” They envision that individual laboratories will provide the CAP with their generated data sets, he says. “We would then use in-silico algorithms to create a series of specific mutations in specific genes in their provided data set, then return that data set to them, without altering the overall format. When the lab receives back the in-silico data set, they would be able to run it through their pipeline and identify what differences we introduced.”

That customized approach, still in the developmental stage, is a reflection of how diverse the technical methods and approaches developed and implemented by clinical laboratories have turned out to be. “In some specific testing areas, there has been more of a movement toward harmonization of methodologies, but overall, we’re continuing to see an expansion of diversity, and that reflects that more labs are performing NGS-based testing, and they are each working through their own approaches.” Secondarily, he adds, commercial vendors are offering more and more technological methods and options to support the various process steps needed to generate an NGS test.

Meanwhile, evaluation of the initial results of the first NGS proficiency test continues, Dr. Voelkerding reports. He expects the bioinformatics and other new NGS PT challenges to be available by the end of the first quarter of 2016. “We’re currently reviewing the A mailing for 2015, then results will be coming from the B mailing in December.”

The other two NGS Surveys to be added in 2016 are for solid tumors and hematologic cancers. “We’re finalizing these now and they will be sent out to labs in early 2016,” Dr. Merker says. The Molecular Oncology Committee he chairs has been collaborating with the NGS project team, the CAP Personalized Health Care Committee, and the CAP/ACMG Biochemical and Molecular Genetics Resource Committee to develop the new NGS Surveys.

Survey development is a process that takes time, says Dr. Merker, co-director of the Stanford Medicine Clinical Genomics Service and assistant professor of pathology at Stanford University School of Medicine. “We needed to identify well-characterized specimens that would be usable for a broad variety of assays, and, consequently, we had to design and manufacture those materials.” Members of the Molecular Oncology Committee tested the materials already available and found there were challenges with those materials for some assay types. “So we specifically redesigned materials to get around those issues.”

The growth in NGS has already been striking, and Dr. Merker expects it to continue. “We’ve seen a dramatic uptake of NGS for heritable disease testing, initially with panel-based testing and more recently with broader-based testing such as exome or genome testing.” Likewise, survey data from clinical laboratories that participate in other CAP molecular oncology PT challenges indicate “there has been and will continue to be a significant increase in the use of NGS-based methods for somatic variant detection, particularly for testing solid tumors,” he says. Factors at play are improvements in sequencing accuracy, decreases in cost, and the availability of smaller, easier to operate, and more affordable desktop sequencers.

The Molecular Oncology Committee has led the effort to design PT for NGS-based testing for detection of somatic variants observed in solid tumors and hematologic malignancies. Says Dr. Merker: “For each Survey mailing, the CAP will provide three engineered specimens, composed of genomic DNA that contains up to six somatic variants in the genes being examined in the respective Surveys. Based on questionnaires included in other molecular oncology Surveys, we selected those genes and variants such that the Survey will be useful for most laboratories performing this type of testing.”

The NGS Solid Tumor Survey will focus on the detection of somatic single nucleotide variants and small insertions or deletions observed in solid tumors. Twenty-eight genes are included in the NGS Solid Tumors Survey: AKT1, ALK, APC, ATM, BRAF, CDH1, CTNNB1, EGFR, ERBB2, FBXW7, FGFR2, GNAQ, GNAS, HRAS, IDH1, KIT, KRAS, MET, NRAS, PDGFRA, PIK3CA, PTEN, SMAD4, SMARCB1, SMO, SRC, STK11, and TP53.

The NGS Hematologic Malignancies Survey will focus on the detection of somatic single nucleotide variants and small insertions or deletions observed in hematologic malignancies. Twenty-four genes are included in that Survey: ASXL1, ATM, BRAF, CALR, CEBPA, CREBBP, CSF3R, DNMT3A, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KMT2D, MPL, MYD88, NOTCH1, NPM1, SF3B1, SRSF2, TET2, TP53, and U2AF1.

Although Dr. Merker is optimistic about the utility of the new NGS Surveys, he is confident the Surveys will confirm the high quality of laboratories’ performance in NGS. “Our PT experience to date indicates that labs are doing an exceptional job of testing in molecular oncology, and data generated during the piloting of these new Survey materials indicate high performance among pilot laboratories. We look forward to seeing a similar performance in our NGS Surveys next year.”

In the coming years, the CAP hopes to achieve a diversity of PT challenges, Dr. Voelkerding says, and that’s why the NGS project team he leads includes members of a variety of CAP resource committees. That cross-fertilization, or “cross-talk,” among project team members is important, he says. “In essence we’re creating a portfolio and infrastructure that can address not only the PT needed for germline and somatic variants for human diagnostic testing but also leveraged for the development of PT for NGS-based assays for infectious diseases and other clinical needs.”

Anne Paxton is a writer in Seattle. For more information about NGS Surveys, go to “PT Order Supplements” at http://j.mp/cap_catalogs.