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April 2013

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ACMG issues guidance on incidental findings

The American College of Medical Genetics and Genomics released last month its recommendations for reporting incidental findings in clinical exome and genome sequencing. An ACMG working group, working with 15 experts who served as external reviewers, specifies a set of disorders, the relevant associated genes, and certain categories of variants that should be reported, based on a consensus-driven assessment of clinical validity and utility.

On the list are, among many other conditions and genes, hereditary breast and ovarian cancer (BRCA1 and 2), Lynch syndrome (MLH1, MSH2, MSH6, and PMS2), familial adenomatous polyposis (APC), Von Hippel Lindau syndrome (VHL), retinoblastoma (RB1), Multiple Endocrine Neoplasia types 1 (MEN1) and 2 (RET), and Tuberous Sclerosis Complex (TSC1 and 2).

“While some definitions of incidental findings allude to findings that are discovered without actually searching for results, this was not the basis for our recommendations,” write the 14 authors of the report. “The Working Group recommended that the laboratory actively search for the specified types of mutations in the specified genes listed in these recommendations.”

It is expected that the clinician who ordered the sequencing will manage the information with the patient in the context of medical and family history, physical exam, and other lab testing.

The working group recognized that when a lab evaluates genes for the specified categories of variants recommended in the report as incidental findings, the analysis may not be equivalent to examining these genes as a primary finding. “For example,” the authors write, “sequencing could have areas of diminished or absent coverage in the genes examined for incidental findings that would be filled in by Sanger sequencing or other supplementary approaches if the gene were being evaluated for a primary indication.” Given the group’s concern that clinicians or patients could misconstrue a negative incidental findings report as assurance that a pathogenic variant is absent, they recommend that the lab’s report of incidental findings “include distinct language differentiating the quality of the incidental findings report from the quality of molecular testing that would be conducted for a primary indication.”

The group estimates “from limited amount of published data that approximately 1% of sequencing reports will include an incidental variant” from the list it sets forth.

ACMG president Wayne Grody, MD, PhD, who was a member of the working group and is a coauthor of the report, told CAP TODAY that the patient can opt out but only early in the process, at the time he or she is first offered the test. “At that point, we hope the ordering physician will explain to the patient that since this is a genomewide test, it will pick up other things besides what we may be looking for,” says Dr. Grody, professor of pathology and laboratory medicine, pediatrics, and human genetics at UCLA School of Medicine. “‘And if it does pick up any that are in this subset of important genes, we are going to tell you about them. If that bothers you and you don’t think you want to hear those, tell us now and we won’t do the whole exome test in the first place. We’ll just do some other targeted test for whatever your disorder is.’ So, that’s a big departure from things that have gone before.”

He expects the recommendations to be updated at least every year, if not more often. “Clearly the recommendations say this is just a first attempt at some guidance for the labs, which up until now have been working on this with no guidance at all—including my own lab at UCLA. So at least it’s a start to open the discussion. This list of diseases, and even the whole procedure, will certainly be modified in future revisions,” Dr. Grody says

Stressing that the recommendations are not mandatory and labs will set their own policies, Dr. Grody says, “No one is expected to institute these changes overnight. We’ve given the labs a lot of flexibility, even a year or two, to bring this on board.”

Robert C. Green, MD, MPH, a medical geneticist at Brigham and Women’s Hospital and Harvard Medical School, co-chaired the group and is lead author of the report, which can be found online at and in a forthcoming issue of Genetics in Medicine.

FDA OKs Quidel C. diff assay with Life Tech PCR

Quidel and Life Technologies received FDA 510(k) clearances to market the Quidel Molecular Direct C. difficile assay with Life Tech’ QuantStudio Dx and 7500 Fast Dx Applied Biosystems real-time PCR instruments.

The Molecular Direct C. difficile assay kit includes an extraction-free, three-step sample preparation process that requires no heat step, no timed step, and no centrifugation. This direct-to-amplification procedure allows the assay to generate a result in less than 70 minutes.

The QuantStudio Dx real-time PCR instrument’s touchscreen, reagent and sample tracking, and LIMS interface are designed for ease of use, and the six-color feature allows for a multiplex of six targets in one reaction.

The 7500 Fast Dx system is a five-color real-time PCR instrument. It is also FDA cleared for diagnostic use with the CDC’s H1N1 assay and with the Quidel Molecular assays for influenza A/B and human metapneumovirus.

SASCP, API forge alliance

The American Society for Clinical Pathology and the Association for Pathology Informatics signed a Memorandum of Understanding effective March 8 to collaborate on education, advocacy, and membership strategies to the mutual benefit of members of both organizations.

“The future of diagnostics is the future of informatics,” John Tomaszew-ski, MD, a former ASCP president and a member of API since the 1990s, said in a statement.

Liron Pantanowitz, MD, API president, said in the statement that API is “at a crossroads in its infrastructure.”

“That requires us to change how we do things. The alliance with ASCP comes at the right time for us and brings us different expertise and additional resources that will help us reach the next level.”

Education is at the forefront of this alliance. API will hold its fall annual meeting in conjunction with the 2013 ASCP annual meeting.

AACC names Kreizman CEO

Janet B. Kreizman on April 1 became chief executive officer of the American Association for Clinical Chemistry. She had been deputy executive director and chief policy officer of The Endocrine Society since 2009.

“I am honored to have been selected as AACC’s new CEO and am excited to drive its mission of providing global leadership in advancing the practice and profession of clinical laboratory science and medicine,” Kreizman said in a statement.

Whole-slide imaging via the cloud

Leica Biosystems announced on March 6 that Chinese physicians have access to U.S. health care organizations for real-time expert review of pathology cases via a scalable, secure medical cloud network made possible through Leica’s collaboration with Dell Healthcare and Life Sciences.

The cloud-based solution, powered by Dell’s Unified Clinical Archive, is a global, secure, and scalable IT platform.

The U.S. institutions providing pathology services are Johns Hopkins Hospital, Cleveland Clinic, Hospital of the University of Pennsylvania, Dianon/LabCorp, and ProPath.

“We are pleased to now have access to additional pathology resources,” Hongbo Li, MD, a GI pathologist and co-founder of Sinopath Diagnostics in Beijing, said in a statement.

Shiang Huang, MD, founder and CEO of Kindstar Globalgene Technology, said in the statement that with demand for pathology services in China growing rapidly, “we need easier access to experts both inside and outside of China to keep up with the demand.”

August Calhoun, PhD, VP and general manager of Dell Healthcare and Life Sciences, said in the statement: “This is a prime example of how a hybrid cloud solution with application-neutral data-management capabilities can break down traditional information silos and allow health care organizations to securely manage, store, and share data to advance patient care even across great distances.”

CPT, Z-Code identifiers to be mapped

The AMA and McKesson have entered into a licensing relationship to offer a way to identify and track molecular diagnostic tests. Under the deal, McKesson Z-Code identifiers—which are issued to each test and catalogued for reference by others—will be grouped and indexed with corresponding molecular pathology codes in the AMA’s Current Procedural Terminology code set.

The relationship will result in the creation of a new reference product that maps the Z-Code identifiers to CPT codes. The AMA will use the information that labs and manufacturers submit and then share in McKesson’s Diagnostics Exchange—a software-as-a-service catalog and shared workflow solution—to assign CPT code mappings where appropriate. Not all Z-Code identifiers will immediately map to a CPT code, and in many cases multiple Z-Code identifiers will map to a single CPT code. The new product will be available for licensing from the AMA early next year.

With the Z-Code identifiers connected to CPT codes, McKesson and the AMA say, labs will be able to identify more precisely which test was performed and then reported with the appropriate CPT code, potentially making the reimbursement process more efficient. Clinicians will be able to access the tool to help them accurately identify and select tests, and payers will have additional detailed test information to help identify the tests being performed, making it possible, McKesson and the AMA say, to track outcomes on specific tests and analyze the value of the tests.

Roche’s Kadcyla for breast cancer approved

The FDA has approved Roche’s Kadcyla (trastuzumab emtansine or T-DM1) for the treatment of HER2-positive metastatic breast cancer in those treated previously with Herceptin (trastuzumab) and a taxane chemotherapy.

Kadcyla, the first FDA-approved antibody-drug conjugate for treating patients with HER2-positive metastatic breast cancer, consists of the antibody, trastuzumab, and the chemotherapy, DM1, joined together using a stable linker. Kadcyla combines the mechanisms of action of trastuzumab and DM1.

Kadcyla represents a “completely new way to treat HER2-positive metastatic breast cancer, and it helped people in the EMILIA study live nearly six months longer,” Hal Barron, MD, Roche’s chief medical officer and head of global product development, said in a statement.

Roche has submitted a marketing authorization application to other regulatory authorities worldwide, including the European Medicines Agency.

The FDA approval of Kadcyla is based on results from EMILIA, an international phase three, randomized, open-label study comparing Kadcyla alone to lapatinib in combination with Xeloda (capecitabine) in 991 people with HER2-positive locally advanced breast cancer or metastatic breast cancer who had previously been treated with Herceptin and a taxane chemotherapy.Those who received Kadcyla lived a median of 5.8 months longer (overall survival) than those who received the combination of lapatinib and Xeloda. And those who received Kadcyla lived significantly longer without their disease getting worse compared with those who received lapatinib plus Xeloda (HR=0.65, 35 percent reduction in the risk of disease worsening or death, P<0.0001; median progression-free survival 9.6 months versus 6.4 months).

FDA clears urine analyzer

The Food and Drug Administration has cleared U.S. Arkray’s Aution Hybrid AU-4050 urine analyzer. The fully automated integrated urine analyzer combines in one 32-inch x 28-inch unit the company’s urinalysis strip technology with fluorescent flow cytometry sediment analysis.

The analyzer improves sample throughput capabilities with continuous sample loading averaging a rate of 150 samples per hour. The full reflex testing capabilities allow laboratories to complete urine analysis on the same platform with minimal interaction.


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