Companion DiagnostiCs sales to ReaCh $5.8BSpurred by a focus on cost reduction by pharmaceutical companies and the rising demand for targeted therapies, the global market for companion diagnostics is expected to grow 18% each year from 2013–2019, reaching an estimated value of $5.8 billion by 2019, according to a new report from Transparency Market Research.

Companion diagnostics for breast cancer and lung cancer will lead the way. In 2012, breast cancer was already the most prominent segment of the market, and extensive research on breast cancer biomarkers will continue to propel the adoption of breast cancer companion diagnostics. There are also more FDA-approved companion tests for breast cancer than for any other indication.

In lung cancer, the report notes an “elaborate pipeline” of related companion diagnostics, estimating that the global market for lung cancer companion diagnostics will grow at a rate of more than 20% from 2013 to 2019. Other cancers driving the market include colorectal, gastric, and melanoma.

By region, North America will likely continue to be the largest market for companion diagnostics, followed by Europe. A large consumer base, higher disposable incomes, increased aware-ness, presence of suitable infrastructure facilities, and acceptance of novel ap-proaches in medicine will propel rapid development of companion diagnos-tics in the North American market, analysts predict. By company, Roche and Qiagen look to remain leaders. Other companies to watch include Abbott , Agilent Technologies, Ventana Medical Systems, and Genomic Health.

On the business side, the report forecasts more strategic collaborations among diagnostics companies and pharmaceutical manufacturers—such as Dako’s collaboration with Astra-Zeneca—as well as more mergers and acquisitions, such as GE Healthcare’s acquisition of Clarient to focus on can-cer diagnostics. Limits on the market include problems with reimbursement, as well as long developmental and ap-proval phases due to the complexities of targeted therapies.

ClinicalLaboratoryNews

n e w s b r i e fThe auThoriTaTive

source for The clinical laboraTorian

ocTober 2013volume 39, number 10

w w w . a a c c . o r g

The 2013 AACC Annual Meeting and Clinical Lab ExpoThousands Come for Cutting-Edge Laboratory Medicine Sessions, New Products

aACC welcomed more than 17,500 labo-ratory professionals to its 2013 Annual Meeting and Clinical Lab Expo from July 28–August 1, in Houston. During the 5-day event, attendees from around

the world gained new insights into the future of labora-tory medicine on a wide range of topics. Topping off the event was the world’s largest exposition of products for clinical laboratories, featuring more than 700 exhibitors.

In this issue of Clinical Laboratory News, we present highlights from some of the 200 scientific sessions and a look at product introductions from the show.

Nancy Sasavage, PhDEditor

A New Look at the Metabolic SyndromeKahn Says Gut Microbiome Could Be Key PlayerBy Genna Rollins

The 2013 Annual Meeting and Clinical Lab Expo opened with a fascinating lecture by C. Ronald Kahn, MD, on the complicated molecular pathology underlying the metabolic syndrome. Chief academic officer at the Joslin Diabetes Center in Boston and Mary K. Iacocca professor of medicine at Harvard Medical School, Kahn is internationally recognized for his pioneering research involv-ing insulin signal transduction and the mechanisms of altered insulin signaling in disease. He was

honored with the 2013 Wallace H. Coulter Lectureship Award, given annually at the AACC Annual Meeting to recognize individuals who have made lifetime commitments to laboratory medicine or patient care, and significantly advanced education, practice, or research.

Kahn made a compelling argument for unlocking the mysteries of the metabolic syndrome, owing to its link with obesity and type 2 diabetes, both of which are at epidemic levels, not only in the United States but also internationally. To the frustration of researchers, genomics has not proven to be particularly enlightening

in understanding these conditions. Of more than 40 genetic loci associated with type 2 diabetes, only five polymorphisms cause a change in gene coding. “Most are in introns [non-coding] or intragenic regions and we don’t know if they have any function at all,” he noted. Even more confounding, 85% of individuals carry the gene known to convey the largest risk for type 2 diabetes.

Insulin signaling and resistance pathways also are important in understanding the pathology of the metabolic syndrome, and like the genetics of this disorder, they are notably complex. “Once insulin binds to the cell, it creates a cascade of events, probably activating more than 100 different processes. One of our chal-lenges in understanding insulin resistance is to understand which of these processes are resistant and which are not,” Kahn

See metabolic syndrome, continued on page 3

2 0 1 3 a a C C a n n u a l M e e t i n G H i G H l i G H t s

in This issue

4 AACC CEO Kreizman— Strategic Plan Progress

2013 ANNuAL MEETiNg

5 Allergy Testing Standardization

6 Alzheimer’s Disease Advances

8 New QC Option from CMS

8 Future of Gene Patents

10 FDA on LTDs

12 Innovations at the Expo

LAb 2013

14 EGFR Testing Strategies

18 Patient Safety Focus

24 Regulatory, Industry, & Diagnostic Profiles

27 News From the FDA

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CliniCal laboratory news oCtoBeR 2013 3

explained. “Are different processes resistant to different cells of the body? Is the insulin resistance of obesity the same as the insulin re-sistance of type 2 diabetes? A lot of proteins and enzymes turn off the insulin signal, and we know very lit-tle about what regulates these turn-ing off signals.”

Evolving EvidenceKahn went on to reflect how dur-ing his professional career the un-derstanding about insulin action and insulin resistance has evolved considerably. Whereas decades ago, only three tissues—the liver, muscle, and fat—were thought to be insulin-resistant, research subsequently has demonstrated that insulin action takes place in virtually every tissue. “Even the pancreatic beta cell that makes insulin itself responds to in-sulin,” he said. “So we have to put this complex pathway of insulin action on a complex whole body where ev-ery tissue can be responding to insu-lin in different ways and have differ-ent levels of insulin resistance.”

By secreting hormones and re-leasing other actions that have both positive and negative signals, fat cells and adipose tissue-related macrophages also affect insulin ac-tion, Kahn explained. His investiga-tion of these mechanisms in mouse models led to one of the most in-triguing aspects of his presentation.

Kahn’s team found that obesity-prone mice have several distinct

metabolic features, including higher expression of PKCδ, an enzyme in-volved in turning off insulin signal-ing. These mice also have more in-flammation in their adipose tissue, and less brown and beige, energy-burning fat.

As they sought to better under-stand these differences, Kahn’s lab found another potential factor: dif-ferences in the gut microbiome of the two substrains of mice. Experiments in normalizing the differences in the mice—including manipulating their gut flora—showed that the obesity-prone strain could become obesity-resistant. These findings, Kahn sug-gested, have opened a promising new avenue for understanding the meta-bolic syndrome and devising more effective ways to prevent and treat obesity, diabetes, and the metabolic syndrome. CLN

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click on publications, then Clinical Laboratory News.

2 0 1 3 A A C C A n n u A l M e e t i n g H i g H l i g H t s

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Clinical LaboratoryNews

ediTorial sTaff

editor—Nancy Sasavage, PhDsenior editor—Genna Rollins senior editor—Bill Malone communications coordinator —Christine DeLongcontributors—Janet B. Kreizman and Honey V. Reddi, PhD

board of ediTors

chair—Lorin M. Bachmann, PhD, DABCC VCU Health System, Richmond, Va. members—Joshua Bornhorst, PhD University of Arkansas, Little Rock, Ark.Andrew Don-Wauchope, MD Juravinski Hospital and Cancer Center, Hamilton, OntarioJacqueline Fisher, MS, C(ASCP) Abbott Diagnostics Division, Boston, Mass.Steven Goss, PhD Siemens Healthcare Diagnostics, Newark, Del.Pamela Steele, PhD Covance, Inc., Indianapolis, Ind.

aacc officers

president—Robert H. Christenson, PhD, DABCC, FACB president-elect—Steven H. Wong, PhD, DABCC, FACB Treasurer—Michael J. Bennett, PhD, DABCC, FACBsecretary—Elizabeth L. Frank, PhD, DABCC, FACBpast president—Greg Miller, PhD, DABCC, FACB

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subscripTions

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Subscriptions to Clinical Laboratory News are free to qualified laboratory professionals in the United States. AACC members outside the U.S. pay $87 for postage. The subscription price for those who do not qualify for a free subscription is $87/year in the U.S. and $130/year outside the U.S. For more information, contact the AACC Customer Service Depart-ment at (800) 892-1400 or (202) 857-0717 or custserv@aacc.org.

ediTorial correspondence

Nancy Sasavage, PhD, Editor Clinical Laboratory News 1850 K Street, NW, Suite 625 Washington, DC 20006 Phone: (202) 835-8725 or (800) 892-1400 Fax: (202) 835-8725 E-mail: nsasavage@aacc.org

Contents copyright © 2013 by the American Association for Clinical Chemistry, Inc., except as noted. Printed in the U.S.A.

Clinical Laboratory news (issn 0161-9640) is the authoritative source for timely anal-ysis of issues and trends affecting clinical laboratories, clinical laboratorians, and the practice of clinical laboratory science.

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2 0 1 3 A A C C A n n u A l M e e t i n g H i g H l i g H t sCommitted to Science and the Public interestAACC CEO Reflects on Strategic Plan Goals, Progress

AACC’s new strategic plan—approved in December 2012 by the Board of Direc-tors—set 19 strategic priorities under five broad areas of focus. We’re well on our way to implementing these priorities, and I would like to point out some of our specific activities involving best practices, science and innovation, and global influence.

This year has been quite active for our International Consortium for Harmoniza-tion of Clinical Laboratory Results, an effort to make lab test results comparable around the world, regardless of where, when, and by which method the testing occurs. We al-ready have been joined in this initiative by the Chinese Association for Clinical Labo-ratory Management, the College of Ameri-can Pathologists, and the Korean Society of Clinical Chemistry, and we look forward to

the collaboration of colleagues from other laboratory medicine associations, stan-dards and metrology organizations, and others. In June, we hosted a well-attended forum to address communication barriers that in vitro diagnostic manufacturers and regulators face when the former recalibrate their assays to achieve harmonization.

Even as we seek partners in harmoni-zation, AACC is reaching out to other or-ganizations so that the voice and expertise of laboratory medicine professionals make their way into practice guidelines of those groups. An example is a recent collabora-tion we forged with The Endocrine Soci-ety that gave AACC a seat on Endocrine Society clinical practice guideline writing groups for guidelines that would benefit from the laboratory medicine perspective.

Already, this has taken root: an AACC member has joined The Endocrine Soci-ety’s guideline committee on pheochro-mocytoma/paraganglioma. We expect to establish similar collaborations with many other medical associations.

AACC also will have more of a voice on issues involving scientific policy and prom-inent public health concerns. Our goal in these efforts is to highlight, through posi-tion statements and other communica-tions vehicles, laboratory medicine’s essen-tial role in healthcare and its importance to the health of individual patients. We will is-sue position statements designed to concise-ly communicate to Congress, regulators, and the news media AACC’s positions on policy issues that directly affect our members and make the connection between laboratory medicine and important healthcare issues of the day. The first of these statements, due for release shortly, will communicate AACC’s position on harmonization of lab results.

As a membership association, AACC ob-viously is concerned about the professional lives of our members. We want to make their lives better in a number of ways, by offering top-quality educational programs, addressing the economics of laboratory medicine in terms of both reimbursement and quality, highlighting the innovations and outstanding science of our members, and ensuring that laboratorians are seen as key members of the healthcare team.

Look for further updates from me as we make headway with our strategic priorities. In the meantime, I invite you to contact me with your concerns, questions, and sugges-tions. We value our members and indus-try partners and look forward to a bright future of better health through laboratory medicine.Janet B. Kreizmanjkreizman@aacc.org202-835-8715

while attending my first aaCC annual Meeting and Clinical Lab expo this past July in Hous-ton, i was struck by the energy of the event. it was undoubt-edly an enthusiastic gather-ing of the best and brightest people, ideas, and technologies in our industry. attendees and exhibitors consistently shared with me positive comments about the excellent educational programming, the depth and breadth of the expo, and the myriad opportunities to net-

work with colleagues and global leaders in the field. this certainly was one of the highlights of my 6-month tenure at aaCC, but it is just one of many activities we’re engaged in to advance the laboratory medicine field, serve and support our members, and improve health and healthcare for patients worldwide.

The excitement of attendees at the 2013 AACC Annual Meeting and Clinical Lab Expo was evident throughout the George R. Brown Convention Center in Houston.

CliniCal laboratory news oCtoBeR 2013 5

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The complex and confusing world of allergy testing can be made better by laboratorian-led standardization efforts, ac-cording to Kareena Schnabl,

PhD, FCACB, a clinical biochemist in the department of laboratory medicine and pathology at Alberta Health Services and the University of Alberta Hospital in Ed-monton, who spoke at the 2013 AACC Annual Meeting, along with Harissios Vliagoftis, MD, an associate professor and director of pulmonary medicine at the University of Alberta. Their presentation on the utilization and standardization of laboratory allergy testing was part of the quadrennial joint Annual Meeting of AACC and the Canadian Society of Clini-cal Chemists.

Schnabl described an extensive Alberta-wide overhaul of allergy testing practices and protocols, which the participants now plan to extend to all of Canada. If only al-lergists and immunologists ordered allergy tests, the initiative in Alberta might not have been necessary, she suggested. How-ever primary care practitioners with less knowledge of the ins and outs of lab-based allergy tests are responsible for a sizable amount of this testing, owing to a shortage of specialists in Canada. As CLN has re-ported previously, there is confusion about this area of testing in the United States as well (CLN Dec 2010).

“We have a very dramatic shortage of allergists across all of Canada, so the load is resting on pediatricians and primary care doctors. Often, they don’t get as much education in allergy testing as clinical aller-gists or immunologists, so when they get into this area it can be a real challenge,” said Schnabl. “We frequently were getting calls from them, asking what test results meant. We also found that some of the testing was really inappropriate.”

Team Work and CommunicationConcerned about less-than-optimal test-ing patterns, Schnabl spearheaded the standardization effort, which started with a multidisciplinary working group. In ad-dition to a gap analysis comparing existing practices against guidelines, the working group contacted primary care physicians to learn what was confounding them about allergy testing.

The group also looked at test formular-ies and ordering practices and found that inconsistency was the name of the game. Considerable discussion focused on which tests to include on a proposed standard requisition form. In the end, the group de-cided to focus on tests for the top eight or so allergens responsible for about 90% of food allergies.

Another important step of the pro-cess was educating lab staff. “We needed something to guide them because we had so much confusion around lactose intoler-ance, celiac disease, and food allergies, and

which test to order for each condition,” said Schnabl. Other topics included explaining the differences among panel tests, screen-ing tests, and tests for individual allergens, as well as maintaining a problem requisi-tion folder for lab directors to review and resolve.

Schnabl personally tackled the thorny issue of referral testing and once again found a striking lack of consistency. This

analysis eventually led to proposed new reporting comments to help primary care practitioners better interpret allergy test results.

While this successful improvement process was focused on allergy testing, it could be used for any type of diagnostic testing, according to Schnabl. “Commu-nication was the problem initially, and it’s what helped us solve the issue. Clinical

immunologists and allergists knew these problems existed but they didn’t have the time to deal with them or they needed help bringing all the parties together,” she said. “After we started this project I learned a lot by speaking with primary care practitio-ners and other laboratorians and finding out what worked or didn’t work for them. So our success came from taking those best practices and putting them all together.” CLN

2 0 1 3 A A C C A n n u A l M e e t i n g H i g H l i g H t s

The Confusing World of Lab-based Allergy TestingSpeakers Say Standardization Process Yields Better Test UtilizationBy Genna Rollins

6 CliniCal laboratory news oCtoBeR 2013

Though clinicians right now have little to offer Alzheimer’s disease patients, considerable progress has been made in understanding this devastat-

ing chronic disease of aging, and in devel-oping a diagnostic testing infrastructure that will be important when Alzheimer’s-related biomarkers come into common use clinically. Those were key points from

the symposium, “The Use of Biomarkers in Detection of Alzheimer’s Disease,” pre-sented at the 2013 AACC Annual Meet-ing by two highly respected researchers in the field, Joy Snider, MD, PhD, and Leslie Shaw, PhD.

“The bottom line for laboratorians is that more patients and diagnostic tests are on the way, so you need to be aware of the latest science in this field. I hope that labo-

ratories can serve as the front line in help-ing clinicians understand and interpret these tests, because we have a lot of patients coming,” said Snider, an associate professor of neurology at the Washington University School of Medicine in St. Louis.

She reminded the audience that physi-cians can only make a presumptive diagno-sis of Alzheimer’s disease based on clinical history.

Snider explained that while commercial tests for Alzheimer’s biomarkers are avail-able, proper use and interpretation of them remains challenging. “When they’re elevated they could tell you Alzheimer’s is a likely cause if the person has cognitive changes, but if the patient is normal, they don’t tell you for sure the person will develop symp-toms,” she said. The field lacks enough infor-mation about these markers to give clinically meaningful interpretation in cognitively normal people, so testing in this population is not recommended, Snider added.

Charting the Natural HistoryBoth she and Shaw reviewed what is known about the natural history of Alzheimer’s. Long before patients experience any symp-toms, the protein tau hyperphosphorylates, leading to neuronal cell death and charac-teristic tangles in the brain. Later on, amy-loid beta protein builds in the brain, form-ing plaques.

“It’s thought that these two primary processes are relatively independent of one another, at least at their onset. However, at some point in time they intersect,” Shaw explained. “Then one can ask, does one type of pathology exacerbate the other? That’s a current hypothesis that needs to be tested.” He is a professor of pathology and laboratory medicine at the University of Pennsylvania Perelman School of Medi-cine in Philadelphia, and was honored at the 2013 AACC Annual Meeting and Clini-cal Lab Expo with the outstanding lifetime achievement award in clinical chemistry and laboratory medicine.

Shaw went on to outline numerous tech-nical and analytical advancements from the landmark Alzheimer’s Disease Neuroim-aging Initiative (ADNI) clinical trial and several follow-on studies. ADNI research-ers standardized a process for performing lumbar puncture (LP) and processing cere-brospinal fluid specimens (CSF), so that LP participation rates—initially planned to be 20%—are as high as 90% in certain ADNI studies. Similarly, ADNI investigators took pains to standardize pre-analytical CSF preparation as well as CSF analysis. The research team has conducted several ana-lytical studies, including comparing inter-lab performance and immunoassay versus mass spectrometry methods in measuring Alzheimer’s-related biomarkers. Profi-ciency testing for these biomarkers, spon-sored by the Alzheimer’s Association, also has been developed. In addition, Shaw’s lab and others have been involved in research to establish cutpoints for amyloid beta and tau indicative of progression to Alzheimer’s disease, parameters of importance to phar-maceutical manufacturers running clinical trials of potential treatments for the disease.

“Looking at the future of this area, the infrastructure is being built step-by-step to the point where providing high-quality CSF specimens and processing will be very much an expectation of those following these patients,” said Shaw. CLN

2 0 1 3 A A C C A n n u A l M e e t i n g H i g H l i g H t s

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labs should get ready now for a new quality control (QC) mod-el from regulators that is slated to launch next year, according to officials at the Centers for

Medicare and Medicaid Services (CMS). Called the Individualized Quality Con-trol Plan (IQCP), this optional program will allow labs to customize QC based on risk management principles, and in certain cases may allow them to run fewer external liquid controls as long as they follow an in-strument manufacturer’s instructions. Ann Snyder, MT(ASCP), a medical technologist with the CMS Division of Laboratory Ser-vices, introduced the new program at the 2013 AACC Annual Meeting during a short course on hot topics in point-of-care testing.

As clinical laboratory instruments have become more sophisticated, regulators have struggled to find a way to account for inno-vations in internal, electronic QC systems that manufacturers employ in new instru-

ments. CMS first allowed labs to use what the agency termed equivalent QC in 2003, a controversial provision where labs could reduce the frequency of their external QC runs—down from the CLIA default stan-dard of two levels per day to as infrequently as once per month—after a 10-day trial.

Now CMS is ready to roll out a more refined alternative, this time based on the new EP-23 guideline from the Clinical and Laboratory Standards Institute (CLSI). The IQCP protocol borrows risk management principles from the CLSI guideline, but is not identical to it, Snyder noted.

Snyder emphasized the holistic ap-proach of IQCP. It requires labs to carefully review all phases of the testing process and perform a thorough risk assessment, the results of which may not necessarily lead to fewer external QC runs. “This plan can be customized based on patient population, environment, test system, personnel, and test uses. It’s for your unique laboratory.

You’ll look at the entire testing process,” she said. “It also allows you to adapt to future technology, as manufacturers continually improve their instruments.”

The essence of IQCP, according to Sny-der, is balancing manufacturers’ instruc-tions for an instrument while still meeting regulatory requirements. “At a minimum, labs must follow manufacturers’ instruc-tions. The whole reason we’re doing IQCP in the first place is that we have manufac-turers who have developed processes for external QC that are less stringent than the QC regulation requirement of two levels per day,” Snyder explained.

IQCP will be voluntary—labs can still abide by the default two levels per day orig-

inally required by CLIA. However, if labs wish to reduce external QC runs based on a manufacturer’s instructions, they must use IQCP. “I want to be very careful to say to you, that if, for example, the manufacturer says the QC frequency is once a week, and you want to employ that QC frequency of once a week, you have to use IQCP,” Snyder said. “If you run QC at a frequency that is below what CLIA normally requires, you must use IQCP.”

Labs can’t begin using IQCP until Janu-ary 1, 2014. However, an updated section of the CLIA Interpretive Guidelines that lays out the program is now available on the CMS CLIA website, along with other educational material. CLN

Patent WarsACLU Attorney Warns of New Clashes Over Diagnostics By Bill Malone

in a special session at the 2013 AACC Annual Meeting about the Supreme Court ruling on gene patents, the American Civil Liberties Union (ACLU) lead counsel in the case,

Sandra Park, JD, told attendees that the sto-ry of gene patents isn’t over. While ACLU won a big victory when the court unani-mously struck down Myriad Genetics’ pat-ents on the BRCA gene, Park predicted that the landmark ruling would lead to further battles over human gene-related patents. In particular, she focused on the somewhat confusing issue of patents on complemen-tary DNA (cDNA), which the Supreme Court left standing.

In leaving these patents untouched, the court relied on the fact that cDNA is the product of a process that retains only the exons needed to translate the DNA into proteins. As such, the court decided that cDNA is patentable because it is synthetic and not “naturally occurring” in the way other isolated DNA sequences are. After the court ruled, many companies—Myriad included—saw a victory in this part of the ruling. Patents for cDNA were safe.

But according to Park, the story is about to change again, and it may be only a mat-ter of time before cDNA patents fall as well, affecting diagnostic firms that rely on these patents for their commercial success. “The court said that cDNA is not a product of nature, but clearly left open whether pat-ents on cDNA might be invalid based on other grounds under the patent act,” Park emphasized. “For example, the courts said that ‘we express no opinion on whether cDNA satisfies the other statutory require-ments of patentability.’”

One of the grounds of patentability that has been discussed as a possible way

to invalidate patents on cDNA is called obviousness, Park explained. In patent law, obviousness refers to whether something is obvious based on what has been previously invented or published, and whether some-one with ordinary skill in the relevant art or discipline would readily conceive of the innovation in question.

How obvious is cDNA? The fate of cDNA could depend on how the courts interpret an earlier, unrelated case that examined cDNA, according to Park. In this 2009 case, “In re Kubin,” the U.S. Court of Appeals for the Federal Cir-cuit invalidated a patent based on cDNA on the grounds of obviousness. The patent claim covered cDNA that encoded a pro-tein known as a Natural Killer Cell Activa-tion Inducing Ligand (NAIL). The court found that because the protein was already known, the cDNA sequence was obvious. Even though this particular NAIL DNA sequence had not yet been published, the court cited the fact that someone of ordi-nary skill in molecular biology could use existing methods to obtain that sequence without difficulty.

Park noted that the Supreme Court has taken three patent-related cases since 2010, an unusual move for the court. Both in the decisions it has handed down, and in the language it has used, the justices have worked to establish a clear precedent that raises the bar for patents in biology, medi-cine, and business. “The Supreme Court has signaled that they are really concerned that there are too many patents that are po-tentially inhibiting scientific innovation,” she said. “They clearly see both the appeals courts as well as the patent office as having been too loose in granting patents.” CLN

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10 CliniCal laboratory news oCtoBeR 2013

for more than 3 years, the lab community has endured an uncomfortable and uncertain limbo around potential U.S. Food and Drug Administration

(FDA) regulation of lab-developed tests (LDTs). Now, an unusually candid presen-tation by Alberto Gutierrez, PhD, director of FDA’s Office of In Vitro Diagnostics and Radiological Health at the 2013 AACC Annual Meeting in Houston is raising new questions about how—and if ever—FDA will move on LDTs and release a long-awaited draft guidance.

According to Gutierrez, an increase in lobbying by groups such as the Ameri-can Clinical Laboratory Association has stalled progress on the draft guidance and changed the tone of FDA’s previously open discussions with stakeholders. “At one time I thought the agency could put a proposal on the table, and we could have a discus-sion,” Gutierrez said. “Three years later, I can tell you only that I can’t tell you that it’s not going to happen; I can’t tell you that it’s going to happen—it’s out of my hands. I have no idea whether the agency will be able to put together a proposal for this or

not.” Gutierrez spoke during the AACC/ASCLS Healthcare Forum, an annual sym-posium at the AACC Annual Meeting.

When FDA announced its intention to begin regulating LDTs in 2010, many labo-ratorians feared a burdensome and costly new layer of regulation on essential tests they had developed or modified in-house for years.

In fact, the agency had intended to re-lease a draft guidance as early as 2011, but it got stalled after the issue became politi-cized, according to Gutierrez. In 2012, those opposed to LDT regulation convinced Congress to pass a law that requires FDA to give Congress 60 days’ notice before is-suing a draft guidance on LDTs. “It seems to me that the only reason Congress wants to know 60 days before is because they have lobbyists who want to prevent the guidance from coming out,” Gutierrez said. “There-fore, the discussion that we meant to have is not likely to happen. We’ve started a new era where the discussion has become political.”

Gutierrez also made the case that, de-spite a slow and politicized process, LDT regulation is still needed. He offered several recent examples of problems, including the ongoing use of the BD SurePath test for human papillomavirus (HPV) screen-ing. This test is FDA-approved only for Pap testing, and the agency warned labs in June that using SurePath for HPV screening could produce false-negative results.

He went on to highlight how the FDA and LDT regulatory pathways have been competing in the marketplace. In one case, not long after the agency in 2011 approved the Roche Diagnostics BRAF mutation test kit for labs, another company announced it would offer the test as an LDT, avoiding the FDA clearance or approval pathway.

At the same time that he lamented a process mired in politics, Gutierrez hinted that leaving the LDT issue up for grabs could be perilous, both for patients and for the lab community. He invoked the problems with compounding pharmacies in 2012 where unsterile conditions led to a fungal meningitis outbreak that killed 55 people and sickened hundreds. In the wake of that disaster, many in Congress advo-cated for greater FDA authority and over-sight. Gutierrez suggested something simi-lar could happen with LDTs. “Are we going to wait until there is a disaster? Remember, CLIA came about in the first place because there was a disaster in the laboratories,” he warned. CLN

Straight Talk on Lab-Developed Tests From FDAAgency’s Diagnostics Director Denounces Politicized DebateBy Bill Malone

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AACC Annual Meeting attendees came to the annual AACC/ASCLS Healthcare Forum to hear updates on regulatory and policy issues.

AACC3M - Medical Device ComponentsA/C Diagnostics LLCA2LA American Association for LaboratoryAAFP- Profi ciency TestingAalto Scientifi c, Ltd.AB SCIEXAbbott DiagnosticsAbD SerotecAccess Biologicals, LLCAccuBioTech Co., Ltd.Accudynamics LLCAccuMed BiologyAccumetrics, IncAcon Laboratories, Inc.Adaptive Mfg. Technologies, Inc.Adhesives Research, Inc.Advanced Instruments, Inc.Advanced Microdevices Pvt. Ltd.Aesku DiagnosticsAggredyne, Inc.Agilent TechnologiesAhlstrom Filtration LLCAhram Biosystems, Inc.Aim Lab Automation Technologies Pty Ltd.ALIFAX SPAALPCOAmerican Medical TechnologistsAmerican Profi ciency InstituteAnalyticon Biotechnologies AGAni Labsystems Ltd. OyAnteo DiagnosticsApplied Biocode, Inc.Aries FilterworksArista Biologicals Inc.ARK Diagnostics, Inc.ARKRAYArlington Scientifi c Inc.ArtelARUP LaboratoriesASCLSASCO NumaticsAssociates of Cape Cod, Inc.Audit MicroControls, Inc.Auer Precision Co.Autobio Diagnostics Co. Ltd.AutoGenomics, Inc.AVE Science & Technology Industrial Co.Awareness Technology, Inc.AWEXAxxinB&E Scientifi c Inc.Bangs Laboratories/PolysciencesBBInternationalBDBeckman CoulterBeijing Chemclin Biotech Co., Ltd.Beijing Golden Bridge TechnologyBERTHOLD TECHNOLOGIES GmbHBethyl LaboratoriesBig C: Dino-lite ScopesBinding Site Inc., TheBIOANALYSE Tibbi Malz. San.ve.Tic. Ltd.BioAssay Works, LLCBio-Chem Fluidics Inc.BIOCLINBioDot, Inc.BioFire DiagnosticsBIOLYPH, LLCBioMedica Diagnostics Inc.BIOMERICABioneer CorporationBioPorto Diagnostics A/SBio-Rad LaboratoriesBio-Rad LaboratoriesBioresource Technology, Inc.BioScience Writers, LLCBiosearch TechnologiesBiosensiaBioSero, LLCBiosino Bio-Technology & Science Inc.BiosPacifi cBiotixBIT CompaniesBroadmaster Biotech Corp.Bruker DaltonicsBUHLMANN Laboratories AGBurkert Fluid Control Systems

C & A Scientifi c Co., Inc.CalBioreagentsCalbiotech, IncCalzyme Laboratories, Inc.Cambridge ConsultantsCapitalBio CorporationCapralogics IncCardinal Biologicals, Inc.CARE diagnostica InternationalCarolina Liquid ChemistriesCedarlaneCellaVisionCenters for Medicare & Medicaid ServicesCepheidCeragem Medisys, Inc.CerilliantCETAC TechnologiesChembio Diagnostic Systems, Inc.Chongqing Tianhai Medical Equipment Co.Chromsystems GmbHChrono-log CorporationCleveland Clinic LaboratoriesClinical Diagnostic Solutions, Inc.CLINIQA CorporationCLTech International Corp.COLACollege of American PathologistsCompuGroup MedicalConductive Technologies Inc.Constitution MedicalCopan Diagnostics, Inc.CorgenixCorvalent CorporationCSCCCyVekDaan Diagnostics Ltd./DAAN Gene Co. Ltd.DakoData Innovations, LLC.Data Unlimited International, Inc.Dawning Technologies, Inc.Denka Sieken Co., Ltd.DenLine Uniforms, Inc.Desert Biologicals/Omega BiologicalsDetekt BiomedicalDiagnostic Biochem Canada Inc.Diagnostic Consulting NetworkDiagnostic NetDiagnostica Stago, Inc.DIALAB GmbHDiametraDiamond Diagnostics Inc.DIARECT AGDiaSys Diagnostic SystemsDiatronDiazyme LaboratoriesDIBA Industries, Inc.DIESSE Diagnostica Senese S.p.ADiruiDOCRO, Inc.Douglas Scientifi cDRG International, Inc.Drummond Scientifi cDynex Technologies Inc.EastCoast Bio, Inc.Edan Instruments, Inc.Egemin Automation, Inc.Elitech Group CompanyEmergo Group, Inc.Entrocomponent Solutions (ECS)Epitomics, Inc.EppendorfEquitech - Bio Inc.Erba Diagnostics Manneim GmbHEuroimmun USEurospitalEurotrol, Inc.EVERGREEN SCIENTIFICExcel Scientifi c, Inc.Express DiagnosticsFapon Biotech Inc.Fitzgerald Industries Int’lFlexLink Systems, Inc.Fluid Metering, Inc.Focus DiagnosticsFreezerworksFujirebio Diagnostics, Inc.Gems Medical SciencesGeneral Biologicals Corp.Genisphere, LLC

GenMark Diagnostics, Inc.GenWay Biotech, Inc.GG&B CompanyGilson, Inc.Globe Scientifi c Inc.Gold Standard DiagnosticsGolden West Biologicals, Inc.Greiner Bio-One North AmericaGRIFOLSHamamatsu CorporationHamilton CompanyHanlab CorporationHB OpticalHeathrow Scientifi cHedwin CorporationHelena LaboratoriesHELMERHemo bioscienceHettichHologicHoover Precision Products, LLCHORIBA MedicalHycor BiomedicalHyTest Ltd.IDEX Health & ScienceIFCC-Intl Federation of Clinical Chemistry & Laboratory MedicineIline MicrosystemsIMMCO DiagnosticsImmucor, Inc.Immundiagnostik AGImmuno ConceptsImmunodiagnostic Systems Inc.Immunology Consultants Laboratory, Inc.ImmunoReagents, Inc.Improve MedicalInBios International, Inc.InnovizeInstrumentation Laboratory (IL)InTec Products, Inc.Integra Biosciences (ViaFlo)Inter Bio-Lab, Inc.International Immunology CorporationInvetechIonics Mass Spectrometry GroupIQuum, Inc.ITC Nexus DXIwaki America Inc.Jackson ImmunoResearch Laboratories, IncJadak, LLCJiangsu Kangjian Medical Apparatus Co.Jiangsu Zhengji Instruments Co. LtdJSR CorporationKamiya Biomedical CompanyKem-En-Tec DiagnosticsKey TechKinematic Automation Inc.KMC Systems, Inc.KNF Neuberger Inc.KRONUS, Inc.LabCorp - EsoterixLABiTec GmbHLabnovation Technologies, IncLaboratory Desk Reference™Labotix Automation, Inc.Labroots, Inc.LabtestLampire Biological Laboratories, Inc.Landwind MedicalLathrop Engineering Inc.Lee Company, TheLife TechnologiesLifeSign LLCLipoScienceLiuyang Medical Instrument FactoryLohmann Precision Die CuttingLRE Medical, an Esterline CompanyLuminex CorporationMagnaBioSciencesMagnaMedicsMagneMotionMagsphere Inc.Maine Biotechnology ServicesMaine Manufacturing, LLCMaine Standards Co. LLC.MAKER BiotechnologyMarket Diagnostics InternationalMBL International

McKessonMediaLab, Inc.Medica 2013/Messe DuesseldorfMedica CorporationMedical Device Safety Service GmbHMedical Electronic SystemsMedical Laboratory EvaluationMedicalLab Management MagazineMediSensor, Inc.Medix BiochemicaMedTest DX, Inc.Megatone Electronics Corp.Meizhou Cornely Hi-Tech Co. Ltd.Mercodia Inc.Mercy ShipsMeridian Bioscience, Inc.Meridian Life Science, Inc.Micro Digital Co., Ltd.Microbix Biosystems Inc.Micronics, Inc.Micropoint Bioscience, Inc.Midland BioProducts CorpMinitubesMiracle Electronic Devices Pvt. Ltd.Mitsubishi Chemical USAMoeller Medical GmbHMonobind Inc.Moss, Inc.Motoman YaskawaMultisorb Technologiesm-u-t AGNeogen CorporationNew England Biolabs, Inc.New England Small TubeNICHIREI BIOSCIENCES, INC.Nikon Instruments Inc.NOF America CorporationNor-Lake Scientifi cNova Biologics, Inc.Nova BiomedicalNovatec Immundiagnostica GmbHNuAire IncOAPI Medical DevicesOmega Bio-tekOmega Diagnostics Group PLCOraSure Technologies, Inc.Orchard So� ware CorpOrtho Clinical DiagnosticsPath - TecPel-Freez BiologicalsPevcoPointe Scientifi c, Inc.Polymed Therapeutics, Inc.Polymedco Cancer Diagnostic Products LLCPolymedco, Inc.Precision Dynamics - St. JohnPrecision Systems Inc.Primer Design Ltd.Prior Scientifi c, Inc.Proliant Health and BiologicalsPuritan Medical ProductsPZ CORMAY S.A.QBC DiagnosticsQingdao Hightop Biotech Co., Ltd.QuanterixQuantimetrix CorporationQuest DiagnosticsQuidel CorporationR D Plastics CompanyRadiometer AmericaRainin Instrument, LLCRandox Laboratories US LtdRayto Life & Analytical Sciences Co, LtdR-Biopharm AGRheonix, Inc.RND Group, Inc., TheRoche Diagnostics CorporationRockland Immunochemicals, Inc.ROHM CO., Ltd.Rotek IndustriesRUI Bio-Technology Co., Ltd.Runlab Labware Mfg. Co., LtdSA Scientifi c LTDSamsung ElectronicsSarstedt, Inc.Sartorius Stedim BiotechScantibodies Laboratory Inc.SCC So� ComputerScienion US, Inc.

Scimedx CorporationSclavo Diagnostics International SrlScripps LaboratoriesSDIXSebia ElectrophoresisSeegene, Inc.Sekisui DiagnosticsSeparation Technology, Inc. (STI)SeraCare Life SciencesShanghai Kehua Bioengineering Shanghai Chemtron Biotech Co., Shanghai Fosun Long March Medical & Shanghai Upper BiotechShel Lab (Sheldon Manufacturing Shenzhen Emperor Electronic TechnologyShenzhen Mindray Bio-Medical ElectronicsShenzhen Xilaiheng Medical ElectronicsSIAS AGSiemens HealthcareSiloam BiosciencesSimPort Scientifi cSLR Research CorporationSMC Corporation of AmericaSNIBE CO., LTDSo� tech HealthSpark Holland B.V.Sparton MedicalSpherotech, Inc.Stanbio LaboratorySTRATEC Biomedical Systems AGStratos Product DevelopmentStreck, Inc.Sunostik Medical Technology Co., Ltd.Sunquest Information SystemsSurModics IVDSwisslogSyntron Bioresearch, Inc.Sysmex America, Inc.Taigen Bioscience CorporationTecanTechnidataTeco DiagnosticsTELCORTherapak CorporationThermo Scientifi cTianjin Era Biology Engineering Co.,LtdTopscien Instrument (Ningbo) Co., Ltd.Tosoh BioscienceToyobo Co. LtdTRINA BIOREACTIVES AGTrinity BiotechUCLA Health SystemUCSF Medical CenterUNICO/United Products & InstrumentsUTAK Laboratories, Inc.ValuMax InternationalVEDA.LABViroStat, Inc.Vital DiagnosticsViva ProductsVonco ProductsWako DiagnosticsWarde Medical LaboratoryWaters CorporationWeidmann Plastics Technology AGWest Medica Produktins-GmbHWesTgard QC, Inc.WheatonWiener Laboratorios SAICWisepac Active Packaging Components Co.Wondfo USAWorthington Biochemical CorporationXEMA GroupYantai Addcare Biotech Co., Ltd.YD Diagnostics CorporationZeptoMetrix CorporationZeus Scientifi c, Inc.Zhejiang Aicor Medical Technology Co.Zhejiang Gongdong Medical TechnologyZhongshan Chuangyi Biochemical

Ahlstrom Filtration LLCAhram Biosystems, Inc.

Chromsystems GmbHChrono-log CorporationCleveland Clinic LaboratoriesClinical Diagnostic Solutions, Inc.CLINIQA Corporation

HORIBA MedicalHycor BiomedicalHyTest Ltd.IDEX Health & ScienceIFCC-Intl Federation of Clinical

Micronics, Inc.Micropoint Bioscience, Inc.Midland BioProducts CorpMinitubesMiracle Electronic Devices Pvt.

Mitsubishi Chemical USAMoeller Medical GmbHMonobind Inc.Moss, Inc.Motoman YaskawaMultisorb Technologies

SimPort Scientifi cSLR Research CorporationSMC Corporation of AmericaSNIBE CO., LTDSo� tech HealthSpark Holland B.V.Sparton MedicalSpherotech, Inc.

Ahram Biosystems, Inc.Aim Lab Automation Technologies Pty Ltd.ALIFAX SPAALPCOAmerican Medical TechnologistsAmerican Profi ciency InstituteAnalyticon Biotechnologies AGAni Labsystems Ltd. OyAnteo DiagnosticsApplied Biocode, Inc.

CLINIQA CorporationCLTech International Corp.COLACollege of American PathologistsCompuGroup MedicalConductive Technologies Inc.Constitution MedicalCopan Diagnostics, Inc.CorgenixCorvalent Corporation

IFCC-Intl Federation of Clinical Chemistry & Laboratory MedicineIline MicrosystemsIMMCO DiagnosticsImmucor, Inc.Immundiagnostik AGImmuno ConceptsImmunodiagnostic Systems Inc.Immunology Consultants Laboratory, Inc.

Miracle Electronic Devices Pvt. Ltd.Mitsubishi Chemical USAMoeller Medical GmbHMonobind Inc.Moss, Inc.Motoman YaskawaMultisorb Technologiesm-u-t AGNeogen CorporationNew England Biolabs, Inc.

Meizhou Cornely Hi-Tech Co. Ltd.Mercodia Inc.Mercy ShipsMeridian Bioscience, Inc.Meridian Life Science, Inc.Micro Digital Co., Ltd.Microbix Biosystems Inc.Micronics, Inc.Micropoint Bioscience, Inc.Midland BioProducts Corp

Miracle Electronic Devices Pvt.

BiotechShel Lab (Sheldon Manufacturing Shenzhen Emperor Electronic TechnologyShenzhen Mindray Bio-Medical ElectronicsShenzhen Xilaiheng Medical ElectronicsSIAS AGSiemens HealthcareSiloam BiosciencesSimPort Scientifi c

Shanghai Chemtron Biotech Co., Shanghai Fosun Long March Medical & Shanghai Upper

Shel Lab (Sheldon Manufacturing Shenzhen Emperor Electronic

Access Biologicals, LLCAccuBioTech Co., Ltd.Accudynamics LLCAccuMed BiologyAccumetrics, IncAcon Laboratories, Inc.Adaptive Mfg. Technologies, Inc.Adhesives Research, Inc.Advanced Instruments, Inc.Advanced Microdevices Pvt. Ltd.Aesku DiagnosticsAggredyne, Inc.Agilent TechnologiesAhlstrom Filtration LLCAhram Biosystems, Inc.Aim Lab Automation

AccuMed BiologyAccumetrics, IncAcon Laboratories, Inc.Adaptive Mfg. Technologies, Inc.Adhesives Research, Inc.Advanced Instruments, Inc.Advanced Microdevices Pvt. Ltd.Aesku DiagnosticsAggredyne, Inc.Agilent TechnologiesAhlstrom Filtration LLCAhram Biosystems, Inc.Aim Lab Automation Technologies Pty Ltd.

AACC AND CSCC

THANKTHE EXHIBITORS AND 17,000+

ATTENDEES WHO MADE THE 2013

AACC/CSCC ANNUAL MEETING AND

CLINICAL LAB EXPO A SUCCESS.

SEE YOU NEXT YEAR IN CHICAGO!

July 27–312014 chicago, il·usa

save the date

ANNUAL MEETING 2014& CLINICAL LAB EXPO

AACC

2013 ANNUAL MEETING ORGANIZING COMMITTEE

Dennis Dietzen, PhD, Washington University School of Medicine

David Grenache, PhD, University of Utah & ARUP Laboratories

Larry Broussard, PhD, Louisiana State University, Health Sciences Center

David Sacks, MD, PhD, National Institutes of Health

Barbara Zehnbauer, PhD, Centers for Disease Control and Prevention

Stacy Melanson, MD, PhD, Brigham and Women’s Hospital

Nathalie LePage, PhD, Children’s Hospital of E. Ontario

David Armbruster, PhD, Abbott Laboratories

Peter Kavsak, PhD, Juravinski Hospital and Cancer Centre

Ross J. Molinaro, PhD, MT (ASCP), DABCC, FACB, Emory University Hospital Midtown

Chris McCudden, PhD, The Ottawa Hospital, General Campus

Danyel Tacker, PhD, West Virginia University Hospital

2013 BOARD OF DIRECTORS

AACC OFFICERSPresidentRobert H. Christenson, PhD, DABCC, FACB

President-ElectSteven H. Wong, PhD, DABCC, FACB

Past PresidentGreg Miller, PhD, DABCC, FACB

SecretaryElizabeth L. Frank, PhD, DABCC, FACB

TreasurerMichael Bennett, PhD, DABCC, FACB

BOARD OF DIRECTORSDennis J. Dietzen, PhD, DABCC, FACBCorinne Fantz, PhD, DABCC, FACBDavid G. Grenache, PhD, DABCC, FACBPatricia M. Jones, PhD, DABCC, FACBSteven C. Kazmierczak, PhD, DABCC, FACBLori J. Sokoll, PhD, FACB

HOUSE OF REPRESENTATIVESChair, House of DelegatesJack Zakowski, PhD, FACB

Chair-Elect, House of DelegatesStephen R. Master, MD, PhD

PROGRAM COORDINATING COMMISSIONChairAnthony A. Killeen, MD, PhD, DABCC, FACB

12 CliniCal laboratory news oCtoBeR 2013

Ab Sciex Announces First CE Marked Kit for MS Analysisthe first food and Drug adminis-tration (fDa)-cleared kits for mass spectrometry (Ms) analysis may be coming soon to u.s. laboratories. ab sciex announced a new family of iVD reagent kits Ce-marked for eu-rope, which it hopes to bring to the united states. sCieX iVD-Ms kits are specifically designed for diagnostic analysis by Ms. the first kit, avail-able in most eu countries, targets high-demand vitamin D analysis. us-ing the company’s 3200MD Ce-iVD series of Ms systems, labs can quan-titate both 25-oH-vitamin D2 and 25-oH-vitamin D3 in a single run.

Abbott Launches Next gen Lab Automation, HCV genotyping Testwith labs feeling the pinch of staff-ing shortages, automation solutions continue to help meet the demand to process tests faster and handle increased volume. the new abbott aCCeLerator a3600 track system meets those needs by process-ing up to 3,600 samples/hour and handling multiple tube sizes and types simultaneously. to see how it could work in their practice settings, attendees had the opportunity to lay out their ideal lab with realistic replica instruments and tracks. abbott also debuted the first fDa-approved hepatitis C virus (HCV) genotyping test, now avail-able on the m2000 platform. the test helps clinicians personalize

treatments to a patient’s HCV geno-type, leading to improved clinical outcomes.

Sysmex Marks Milestones of Progress With New introductionsCelebrating its 10th anniversary in the u.s. market, sysmex america showcased its two new hematol-ogy offerings: the sysmex Xp-300, a big update for smaller labs, and the sysmex Di-60 integrated slide processing system, an automated slide making/staining and digital cell image pre-classification system. the sysmex Xp-300 automated Hematology analyzer is the newest member of the company’s three-part differential analyzer portfolio, and features updated, user-friendly software. the Xp-300 provides the convenience of a color touch panel for ease-of-use operation and time- saving barcode scanning, and is capable of storing up to 40,000 samples. the sysmex Di-60 integrated slide processing system is a com-pact platform that provides inte-grated, scalable automation of the manual blood film preparation and wbC differential process. it inte-grates in a single work cell slide preparation, slide staining, and digi-tal image pre-classification of cells. a more standardized differential result and extensive collaboration via network connectivity enhances the level of service laboratories can provide to clinicians and patients.

EKF Displays Novel End-Stage Renal Disease, ß-Hb TestseKf Diagnostics showcased a novel test to accurately identify diabetic patients at high risk of progression to end stage renal disease (esrD) up to 10 years in advance of currently available tests. eKf’s new soluble tumor necrosis factor receptor 1 (stnfr1) test is an eLisa assay that has the potential to significantly im-prove diabetic patient management and outcomes. recent research has demonstrated that high circulating levels of stnfr1 are strongly as-sociated with progression to esrD in patients both with and without overt nephropathy. the company also announced the worldwide launch of the stat-site M ß-Hb following the test’s recent Ce marking in europe. the quantitative strip-based test for ß-hydroxybutyrate provides a quick and easy assessment of diabetic ketoacidosis in less than 80 seconds.

Tacrolimus immunoassay, Cardiac Controls Among New Products From Thermo Fisherthermo fisher scientific inc. fea-tured specialty diagnostics products and analytical instruments designed to improve accuracy and productiv-ity in clinical applications, including the QMs tacrolimus immunoassay that recently received fDa 510(k) clearance. the liquid, ready-to-use immunoassay measures levels of

tacrolimus on automated clinical chemistry analyzers, including the bench-top thermo scientific indiko analyzer, to improve monitoring of kidney, liver, and heart transplant patients. the company also debuted another fDa-cleared prod-uct, the thermo scientific Mas Omni•CARDIO controls, an assayed control serum comprising a com-bination of cardiac and associated critical markers to monitor assay conditions. this single test elimi-nates the need for separate quality control measures between tests and provides rapid results.

beckman Coulter Moves Forward With Array of New Productsfeaturing in its booth for the first time products from iris Diagnostics, beckman Coulter and iris launched the alifax automated erythrocyte sedimentation rate analysis sys-tem, a product available through a distribution agreement with alifax. the system fits both large and small workloads, and automation delivers increased productivity and reduced turnaround times. the patented technology generates results in 35 seconds or less. iris’s automated urinalysis system was also featured. other products showcased in-cluded the newest, most advanced version of reMisoL advance, a data management system that connects to a single server not only beckman Coulter instruments but also up to

Exhibitors dazzled visitors at the 2013 AACC Clinical Lab Expo at Houston’s George R. Brown Convention Center, July 29–August 1, with hundreds of new and innovative products for clinical laboratories. Everything from molecular tests for genetic mutations to large automated systems capable of processing thousands of samples per hour was on display. Presented here are snapshots of some of the product introductions.

Expo Attendees Get First-Hand Look at the Future of Lab Medicine in Houston

The latest innovations in laboratory automation attracted lots of interest from attendees.

AACC’s booth was a popular spot for checking out membership benefits.

CliniCal laboratory news oCtoBeR 2013 13

Expo Attendees Get First-Hand Look at the Future of Lab Medicine in Houston

128 other instruments. the uniCel DxH600 Coulter cellular analysis system with advanced software provides improved first-pass accu-racy and automatic rerun and reflex testing, thereby reducing overall manual review rates and processes in mid- to high-volume labs. assays making their debut were the ac-cutni+3 on access 2 immunoassay systems and the Hba1c- assay on uniCel DxC systems, both of which recently received fDa clearance.

Siemens introduces VersaCell X3 Solutionsiemens further expanded its automation portfolio with the new VersaCell X3. this platform features a small footprint and upright design to fit the needs of low- and mid-volume laboratories for which track-based automation is out of reach. it can connect up to three siemens analyzers though a single robotic sample interface to help reduce operator sample handling, better prioritize work flow, and eliminate pre- and post-analytical processing. a new priority drawer above the routine sample drawer provides eight stat positions and frees up to 50 sample positions for routine pro-cessing. a centralized screen gives

the operator access to all connected analyzers for greater efficiency.

intelligent Automation Manage-ment Featured in Roche’s boothroche announced plans for the u.s. introduction of the cobas 8100 automated workflow series, an advanced system designed to automate many routine tasks and increase efficiency. the new system uses intelligent robotics to prepare blood samples from immediate testing and post-analytical process-ing, providing up to 1,100 samples per hour. other products displayed included the aCCu-CHeK inform ii system, the first point-of-care blood glucose device to offer meter-level wireless technology; the Coagu-Check Xs plus system, a handheld pt/inr meter that recently earned a CLia waiver; and the cobas 48000 system, a walk-away system that offers molecular tests such as braf V600 and egfr. roche also announced that the fDa has approved a new, more efficient workflow process for roche’s HpV test, for the first time allowing sample processing from the primary sample collection vial after it has been used for pap testing.

bioMérieux Displays ViTEK MS System for bacterial iDrecently named by the Cleveland Clinic as one of the top 10 break-through medical technologies of 2013, a new system for Ms-based bacterial identification was one of the featured instruments in bioMérieux’s booth. the ViteK Ms is a matrix-assisted laser desorp-tion ionization time of flight mass spectrometer that can identify in minutes almost 200 disease-causing bacteria and yeast from plated colonies, a game-changing technol-

ogy in patient care. the instrument analyzes material from microbial cultures and identifies anaerobic bacteria, enterobacteriaceae, gram-positive aerobes, fastidious gram-negative bacteria, gram-negative non-enterobacteriaceae, and yeast.following the expo, bioMérieux announced that it has been granted fDa 510(k) de novo clearance for the ViteK Ms, which in a clinical trial pro-duced an overall accuracy for bacte-rial identification of 93.6% compared to nucleic acid sequencing.

more new productsYou can find more new products in CLN’s 2013 new products review.

visit www.aacc.org, and go to the July issue of CLN under publications.

14 CliniCal laboratory news oCtoBeR 2013

EgFR Signaling PathwayFollowing ligand binding at the extracel-lular domain, EGFR forms functionally ac-tive homo- or hetero-dimers. Dimerization induces the activation of the tyrosine kinase domain, leading to autophosphorylation of the receptor on multiple tyrosine residues. This phosphorylation triggers recruitment of a range of adaptor proteins, such as Src

homology 2 domain containing (SHC) protein and growth factor receptor-bound protein 2 (GRB2), followed by activation of a series of intracellular signaling cascades that affect cell proliferation, apoptosis, in-vasion, metastasis, and angiogenesis.

Downstream effects of EGFR activation include modulation of three major pathways that have been well characterized (Figure 1). Induction of the RAS-RAF-MAPK pathway

occurs when phosphorylated EGFR recruits the guanine-nucleotide exchange factor via the GRB2 and SHC adapter proteins, which activates RAS. This step subsequently stim-ulates RAF and the MAP kinase pathway, ultimately affecting cell proliferation, tumor invasion, and metastasis.

Following activation of the EGFR path-way, the phosphatidylinositol 3-kinase

(PI3K/AKT) pathway induces the major cellular survival and anti-apoptosis sig-nals by stimulating nuclear transcription factors such as NFKB. Involvement of the Janus kinase/signal transducer and activa-tor of transcription (JAK/STAT) pathway also is implicated in activating transcrip-tion of genes associated with cell survival.

EGFR activation affects other not so commonly known pathways as well. These

include phosphorylation of phospholi-pase C gamma 1(PLCG) and subsequent hydrolysis of phosphatidylinositol 4,5 bi-phosphate (PIP2) into inositol 1,4,5-tri-phosphate (IP3) and diacylglycerol (DAG), which results in activation of protein kinase C (PRKC). Activation of this kinase turns on the MAPK and c-Jun kinase pathways.

Today we know that EGFR signaling plays an essential role in cell proliferation, survival, and migration. Activating mu-tations of the EGFR gene are found pre-dominantly in females, individuals who have never smoked, and individuals with Asian ethnicity. Though its altered activity has been studied primarily in development and growth of non-small cell lung cancer (NSCLC), many other tumors, includ-ing head and neck, ovary, cervix, bladder, esophagus, stomach, brain, endometrium, colon, breast, and liver are also known to exhibit deregulation of EGFR.

Therapeutic Strategies Targeting EgFRGene amplification and over-expression of the Erb family of receptors (EGFR and ErbB2) has been observed in breast, lung, and colorectal cancers, while the deregulat-ed activation of intracellular mitogenic sig-naling has been implicated in many other cancers. These two pathways make protein target-based therapies very promising tools for treatment.

In fact, pharmaceutical companies have developed several potential therapies that use anti-EGFR monoclonal antibodies (mAbs) and small-molecule tyrosine kinase inhibitors (TKIs) that target distinct do-mains of EGFR. Anti-EGFR monoclonal an-tibodies, such as cetuximab, panitumumab, and nimotuzumab, bind to the extracellular domain of the EGFR monomer and com-pete for receptor binding by the endogenous ligands, triggering receptor internalization and blocking ligand-induced receptor ac-tivation. Cetuximab, which binds to the L2 domain of EGFR, is a chimeric protein an-tibody composed of variable and constant regions from mouse and human sources,

Mutations in the EGFR PathwayClinical Utility and Testing StrategiesBy Honey V. Reddi, PHd

epidermal growth factor receptor (egfr) is a transmembrane tyrosine kinase receptor that plays a

central role in regulating cell division and death. it belongs to the Her family of receptors, which

includes egfr (Her1/erbb1), erbb2 (Her2/neu), erbb3 (Her3), and erbb4 (Her4). these receptors

are characterized by an extracellular ligand-binding domain, a transmembrane domain, and a cy-

toplasmic domain containing the tyrosine kinase region followed by a carboxy-terminal tail with

tyrosine autophosphorylation sites. several growth factors, including egf, transforming growth factor-α (tgf-α),

amphiregulin (ar), epiregulin (ereg), heparin-binding egf (Hb-egf), betacellulin (btC), and epigen (epg) bind to

the erbb receptors.

Mutations in the gene encoding egfr that lead to overexpression of the protein have been associated with

a number of different cancers. furthermore, this upregulation appears to be frequently associated with adverse

prognosis. these discoveries have stimulated researchers to identify novel biomarkers that can be used to deter-

mine which patients have the mutations so that they can receive therapeutics targeted to their cancer.

Here i present an overview of the egfr signaling pathway, as well as testing and therapeutic strategies for

patients who test positive for various mutations in the signaling pathway.

CLN’s

improviNgheaLthCare through LaboratorymediCiNe

series

CliniCal laboratory news oCtoBeR 2013 15

respectively, while panitumumab and ni-motuzumab are fully humanized EGFR antibodies. To date, the Food and Drug Ad-ministration has approved EGFR-targeted mAbs for use in advanced colorectal cancer, gliomas, and head and neck tumors. Patients receive the drugs intravenously.

On the other hand, EGFR-specific small molecule inhibitors such as erlotinib (Tarceva) and gefitinib (Iressa), which are taken orally, translocate across the plasma membrane and interact with the cytoplas-mic domain of EGFR. Small molecule in-hibitors belong to a class of therapeutics called tyrosine kinase inhibitors or TKIs. In the cell, TKIs compete with ATP to bind the catalytic domain of the kinase, which in turn inhibits EGFR autophosphoryla-tion and downstream signaling, including cell proliferation and survival. TKIs have been approved for treatment of advanced NSCLC and pancreatic carcinoma.

Small molecule inhibitors are thought to be less specific than mAbs since they can po-tentially target any tyrosine kinase, diluting the therapeutic effect on the target of inter-est. To increase the specificity and improve clinical effectiveness of TKIs, researchers have also developed bi-specific inhibitors such as lapatinib that target EGFR/ErbB2. However, the overall clinical effectiveness of these therapies and their correlation to EGFR expression is not clear. EGFR inhibi-tors are effective in only a small subset of patients, despite high levels of EGFR ex-pression. Some cancers appear to acquire resistance to EGFR inhibitors, and multiple mechanisms seem to underlie the lack of sensitivity to the targeted therapies, includ-ing mutations in the EGFR gene itself, as well as in down-stream effectors such as RAS, RAF, and AKT that appear to be as-sociated with differential clinical outcomes.

impact of Mutations in EgFR and Downstream Signaling PathwaysThe EGFR gene is present on chromo-some 7p11.2 and has 28 exons coding for a transmembrane receptor protein of 464 amino acids. Within EGFR, exons 5–7 and 13–16 code for the ligand binding domain while exons 18–24 code for the TK domain. Autophosphorylation occurs in the region encoded by exons 25–28.

Although mutations can occur any-where within the TK domain, a significant set of EGFR mutations in lung cancer that are associated with objective response to single agent TKI therapy are observed in exons 18–21. The most frequent of these are in-frame deletions in exon 19 that oc-cur in approximately 45% of cases, fol-lowed by point mutations in exon 21, in 40–45% of cases. While more than 20 dif-ferent deletions are observed in exon 19, L858R in exon 21 is the most common point mutation detected (Figure 2). Greater response to TKIs also correlates with EGFR amplification that frequently coexists with EGFR mutations and is more common in gefitinib-sensitive NSCLC with increased expression of ErbB3.

Researchers have also observed re-sistance to anti-EGFR therapies in a sig-nificant number of cancers, altering the clinical impact of anti-EGFR treatments. De novo mutations are known to occur within EGFR that constitutively turn on the receptor, allowing the tyrosine kinase to work much better than normal and

overcoming the effects of the TKI. While the most important of these is T790M, a point mutation in exon 20 that accounts for about 50% of cases, insertional muta-tions in exon 20, which occur in about 5% of cases, have also been associated with TKI resistance.

Primary resistance to EGFR TKIs is mostly due to the presence of wild-type EGFR, since these tumors harbor muta-tions in other genes downstream of EGFR such as KRAS and BRAF that may play a role in predicting clinical response to anti-EGFR therapies. Mutations in KRAS at co-dons 12 and 13 occur in about 15–50% of NSCLC patients, while BRAF mutations are

detected in 1–2% of lung cancer patients. KRAS and EGFR mutations appear to be mutually exclusive in NSCLC, with EGFR mutations occurring in non-smokers and KRAS mutations in smokers. Exclusivity is also observed in the case of BRAF and EGFR mutations. This makes it difficult to evaluate whether the observed resistance to EGFR-targeted TKIs is due to the presence of mutated KRAS or BRAF or the absence of mutated EGFR.

Inactivation of PTEN is observed in sev-eral cancers, including colon, breast, brain, gastric, and lung, which results in activation of the PI3K/AKT pathway and subsequent degradation of EGFR that generates insen-

sitivity to anti-EGFR therapies. EML4-ALK fusions are a rarer abnormality only de-tected in 3–13% of lung adenocarcinomas, mutually exclusive of EGFR status. Lung cancers positive for these fusions are resis-tant to EGFR-targeted TKIs but sensitive to ALK TKIs such as crizotinib (also known as Xalkori).

Acquired or secondary resistance to EGFR-targeted TKI therapies also includes secondary mutations in EGFR, particularly the T790M that is observed post gefitinib treatment and is thought to occur due to selection pressure. Similarly, mutations in PIK3CA and MET are also believed to be as-sociated with acquired resistance. PIK3CA

figure 1

egfr signaling pathway

egfr is activated either as a homo- or heterodimer resulting in regulation of multiple pathways. in particular the ras/raf/MapK, aKt, and JaK/stat pathways downstream of egfr play integral roles in cell migration, pro-liferation, and survival, respectively. anti-egfr antibodies are targeted to the external ligand binding domains while the small molecule inhibitors or tyrosine kinase inhibitors (tKis) target its cytoplasmic kinase domains.

16 CliniCal laboratory news oCtoBeR 2013

mutations occur in approximately 5% of EGFR mutant lung cancers, while ampli-fication of MET is detected in up to 20% of lung cancer specimens that developed acquired resistance to gefitinib or erlotinib. The data suggests that EGFR TKI treat-ment may select for preexisting cells with MET amplification during the acquisition of EGFR TKI resistance.

Testing for Mutations in the EgFR Pathway Clearly, the therapeutic implications of EGFR pathway mutations are substantial. Laboratory studies to identify the muta-tions are therefore integral to evaluating the efficacy of anti-EGFR therapies designed to manage and treat patients with positive test results.

Traditional methods for detecting EGFR mutations involved screening by direct DNA sequencing of the tumor tissue. Sanger sequencing technology is available in most molecular diagnostic laboratories, and it has the singular advantage of detect-ing alterations across a gene, including novel variants. However, the sensitivity of this method is low. In a heterogeneous tumor, there must be at least 10–30% mutant DNA in the background of normal DNA. Muta-tion screening by sequencing is also time- and labor-intensive, making the test costly.

Recent methodologies have therefore focused on targeted screening of muta-tions to achieve more rapid, robust, and sensitive tests. Molecular diagnostic labo-ratories currently use a variety of meth-ods, including amplification refractory mutation system, pyrosequencing, smart amplification process, high-resolution melting analysis, and restriction fragment length polymorphism, to name a few. These methods all distinguish between mutant and wild-type DNA within the region of interest. In contrast to direct sequencing, the limit of detection for targeted analysis is ~1–5% mutant DNA in the background of normal DNA. The disadvantage, of course, is that the assay will only detect those specific mutations targeted by the assay.

Laboratories would be well advised to choose a method after considering a number of factors, including availabil-ity of instrumentation, reagents required, and other preferences and practices in the lab. However, by far the most important

consideration in choice of methodology is the amount of sample available for testing. More often than not, a very small amount of tumor is available. Furthermore, clini-cians need the test results quickly to evalu-ate drug sensitivity or resistance, so the turnaround time must be as short as pos-sible. In many cases, depending upon the technology and platform used, establish-ing a viable cost-benefit ratio also becomes a challenge. In sum, these considerations generally point to targeted screening of EGFR mutations.

Today, most laboratories use formalin-fixed, paraffin-embedded (FFPE) tissue to test for EGFR mutations. A few also use frozen tumor tissue. However, screening FFPE samples poses significant challenges, including successfully extracting the DNA, interferences from the fixatives used for embedding tissue, and most importantly, obtaining shorter amplicons for effective analysis, particularly if a PCR-based meth-odology is used.

Alternate sample types such as fine needle aspirates and pleural effusions are currently being evaluated as viable options to enable quicker, easier diagnosis of malignancy. Micro-dissection of the tumor prior to test-ing is also helpful as it effectively enriches the sample, thereby increasing sensitivity.

Strategies for TherapyUnderstanding the efficacy of anti-EGFR treatments, as well as how efficacy corre-lates to mutations within the EGFR, RAS, BRAF, and other pathways, as well as with crosstalk to the EGFR pathway, has proven to be challenging. In a majority of cancers, single therapies are either short-lived or completely ineffective. Some of the factors that may contribute to these observations are the presence of mutations in multiple pathways and the induction of mutations in non-targeted pathways that have a dom-ino effect, impacting efficacy of the targeted therapy by feedback inhibition (acquired resistance).

Given these shortcomings in targeted therapies, researchers are also evaluating combinatorial therapies, such as sorafenib (targets RAF) with erlotinib, for EGFR mutations and the downstream signal-ing pathways in NSCLC and glioblastoma. Similarly in patients with both EGFR and PIK3CA mutations, clinicians might con-sider combination therapy with an EGFR TKI and a PI3K inhibitor. Solving this problem will require algorithms that fa-cilitate testing for mutations, not just in EGFR, but also in molecules downstream (RAS, RAF, AKT, and PIK3CA, etc.). This information might allow clinicians to pre-dict patients’ clinical response to standard therapies, particularly for combinatorial approaches that in theory appear to be the most effective.

Many questions need to be answered in order to effectively treat patients with defects in the EGFR family of pathways. Should patients be tested for de novo mu-tations sequentially or simultaneously in EGFR/RAS/RAF? Assuming they present with the same mutation profile, should patients’ metastatic tumors be treated similarly to their primary tumor, or should the metastatic tumor be tested pri-or to treatment? Should patients receive personalized treatment based on the mu-tation profile that involves combinatorial therapies not evaluated before? Should pharmaceutical companies actively evalu-ate multi-arm combinatorial therapy clinical trials targeting EGFR pathways similar to those in triple-negative/triple-positive breast cancer?

To determine the most appropriate treatment for an individual, the American

Society for Clinical Oncology recommends that patients with advanced NSCLC who have not previously had chemotherapy or an EGFR TKI drug have their tumors tested for EGFR mutations before therapy is ad-ministered. Given the acquired resistance to anti-EGFR therapies observed in tumors, ideally laboratories would test the primary, as well as recurrent metastatic tumors to ensure effective clinical response.

Clinicians and molecular testing labora-tories will need to keep up-to-date with the growing body of literature on the mecha-nisms involved in modulation of signaling pathways such as EGFR in cancer, as well as its sensitivity and resistance to currently available treatments. Currently, there is no right or wrong strategy, only an appropri-ate one that can be personalized to benefit the patient. CLN

SuggESTED READiNgCheng L, Alexander RE, Maclennan GT,

et al. Molecular pathology of lung can-cer: Key to personalized medicine. Mod Pathol 2012;25:347–69.

Ellison G, Zhu G, Moulis A, et al. EGFR mutation testing in lung cancer: A re-view of available methods and their use for analysis of tumour tissue and cytolo-gy samples. J Clin Pathol 2013;66:79–89.

Lin L, Bivona TG. Mechanisms of resis-tance to epidermal growth factor re-ceptor inhibitors and novel therapeutic strategies to overcome resistance in NSCLC patients. Chemother Res Pract 2012;2012:817297.

Scaltriti M, Baselga J. The epidermal growth factor receptor pathway: A model for targeted therapy. Clin Cancer Res 2006;12:5268–72.

Sharma SV, Bell DW, Settleman J, et al. Epidermal growth factor receptor mu-tations in lung cancer. Nat Rev Cancer 2007;7:169–81.

Honey V. Reddi, PhD, is laboratory director of mo-lecular genetics at Prevention Genetics, Marshfield, Wisc.

Email: honeyreddi@gmail.com

Disclosure: The author has nothing to disclose.

figure 2

spectrum of egfr mutations

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for clinical laboratory scientists, keeping up with what’s new in science, technology, manage-ment, and regulatory affairs comes with the territory. That’s

why AACC continues to add new educa-tional programming to its calendar all year long! Here’s what we’ve just added to our fall lineup of webinars.

iQCP and ReimbursementThroughout 2013, Clinical Laboratory News has featured stories on the Individual-ized Quality Control Plan (IQCP), a new QC alternative based on risk management principles that was recently launched by the Centers for Medicare and Medicaid Services (CMS). On November 14, during the webinar, “CMS, Customized QC, and the Clinical Lab,” CLIA Administrator Judy Yost, MA, MT(ASCP), will discuss the ad-vantages of using the IQCP and provide in-formation on how CMS plans to survey labs that choose to use the new QC alternative.

Reimbursement for laboratory test-ing has also been in the news lately. To provide the most recent information on this issue, and to examine what other fac-tors are likely to affect laboratory test re-imbursement next year, AACC has added “Reimbursement 2014: Survival Strategies for Today’s Lab” to its fall webinar lineup. The program, featuring reimbursement experts Charles Root, PhD, and Peter Kazon, is slated for December 4.

Managing Costs, QC, and POCT With laboratory test reimbursement a constant target for payers who want to cut their costs, the challenge of manag-ing shrinking budgets continues to plague laboratory managers. The December 12 webinar, “Curbing the Cost of Reference Lab Testing,” will help labs make the most of their send-out test budgets. Yan Zhang, PhD, is the featured presenter.

Reducing pre-analytical errors is also a good way for labs to control costs, and Ken Blick, PhD, will provide advice on “Get-ting Specimens Labeled Correctly…Every Time” during his November 5 webinar.

Another fall webinar, “Achieving Con-cordance Between POC Test Results and Central Lab Test Results,” focuses on quality assurance issues and features Brad Karon, MD, PhD. Clinicians expect laboratory test results to be reliable, regardless of whether the test is performed in the central labora-tory or at the point of care (POC). During this webinar, Karon will discuss common sources of error affecting POC test results and how these contribute to discordance between central laboratory and POC meth-ods. He will also provide guidance on when it is clinically important to achieve concor-dance between the results of a POC assay and its central laboratory counterpart (and when it is not), and will identify strategies for overcoming the challenges labs face when attempting to achieve concordance between test methods. The webinar, which is co-sponsored by AACC and Seattle Chil-dren’s Hospital, takes place November 21, and will be moderated by Michael Astion, MD, PhD.

Astion will also be moderating an October 15 webinar, “Modern Approaches to Quality Control: Moving Averages and Beyond.” The speaker, Mark Cervinski, PhD, will describe how labs can use patient samples to improve their QC processes and is also co-sponsored by AACC and Se-attle Children’s Hospital. Educational grants from Randox Laboratories U.S. Limited and Bio-Rad Laboratories fund the program.

The Latest in Lab ScienceAACC’s fall lineup of webinars provides access to newsmakers in several areas of lab science. Our new Biomarkers of Acute

Cardiovascular Diseases Division is co-sponsoring a November 19th webinar, “hs-cTn and the Changing Algorithm for Rapid Rule-Out of AMI,” that explores whether absolute high-sensitivity troponin measurements can be used to streamline the assessment of chest pain patients in the emergency department. The division lead-ership selected world-renowned cardiolo-gist Tobias Reichlin, MD, as the speaker for the program.

On November 26, AACC is offering the webinar, “Current Issues in Prenatal Screen-ing.” During the webinar, Christopher Rob-inson, PhD, will provide information on

current best practices in prenatal screening, and will also explore exciting new tests that are quickly coming into clinical use.

Other new technologies to be explored in upcoming webinars include multiplex testing for respiratory viruses, new sep-sis diagnostics testing algorithms, and the changing role of hepatitis C virus testing (supported by a grant from Roche Diag-nostics).

Register Today!For a comprehensive list of AACC’s fall webinars and to register, please visit www.aacc.org/events/webinars. CLN

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The Surviving Sepsis Campaign (SSC) has produced new recommendations titled International Guidelines for Management of Severe Sepsis and Septic Shock: 2012. These new updated guidelines call for lactate assays to direct therapy for septic shock. For patients with lactate greater than 4 mmol/L, SSC recommends quantitative resuscitation targeting normalization of lactate levels.

StatStrip Lactate provides a 13 second assay on a fingerstick capillary sample to allow rapid, early, goal directed therapy in septic patients. Testing is as fast and easy as bedside glucose testing. The single use StatStrip Lactate biosensor is pre-calibrated, fast and uses a very small whole blood sample (0.7 microliters) yet provides lab equivalent accuracy.

18 CliniCal laboratory news oCtoBeR 2013

PATIENT SAFETY FOCUST A K i N g A i M A T R E D u C i N g L A b E R R O R S

guiding Providers to improve Their Test Orders Tips and Tricks for Improving Utilization of Genetic TestsBy daRCi l. steRnen, Ms, lGC, and Jessie Conta, Ms, lGC

Unfortunately, physicians are some-times uncomfortable with genetic testing consults as they may feel asking for help shows a lack of competence on their part. To overcome such obstacles, consultants need to gain the trust of the ordering phy-sician.

Organize and Prepare In our experience as genetic counselors, two important elements of successful consultations with physicians are orga-nizing the facts of the case and preparing for the interaction. Reviewing the facts of the case before talking to the physician in-volves taking a couple of minutes to read the provider’s recent clinic notes and the patient’s relevant studies, both completed and pending.

Once the facts are organized, the second task is preparing a list of what you want to achieve during the consult. One frequently-neglected, but essential, aspect of preparing is having a plan that avoids recollecting a specimen. Alternatively, when specimen recollection is necessary, making it easy to do so improves the chances that the physi-cian will agree to the recommended order change.

A Case Study The following sample dialogs illustrate the difference between a genetic test utilization consultant who is prepared and one who is unprepared. In the case being discussed, changing the test order would provide the physician with the information needed to make a diagnosis and avoid additional test-ing.

The Prepared CallConsultant: “Hello, Dr. Big. We received a blood sample for your patient, John Doe,

medical record number 123456, who has multiple congenital anomalies and devel-opmental delay. A blood karyotype was ordered. A single nucleotide polymor-phism test, also called a SNP chromosome microarray test, has a higher sensitivity for detecting chromosome deletions and du-plications. The SNP microarray requires an EDTA blood sample, but this sample type was not collected for the karyotype. I see in the patient’s chart, however, that an EDTA blood sample was collected for the Fragile X DNA test you also ordered. We can use some of that EDTA sample for the SNP microarray. Would you like to consider changing this order?”Dr. Big: “Yes, please. I will change the karyotype order to a SNP microarray. Thank you for your call.”

The Unprepared CallConsultant: “Hello, Dr. Big. We received a blood sample for your patient, John Doe, medical record number 123456, who has multiple congenital anomalies and devel-opmental delay. A blood karyotype was or-dered. A single nucleotide polymorphism test, also called a SNP chromosome micro-array test, has a higher sensitivity for detect-ing chromosome deletions and duplications. Would you like to consider changing the or-der from a karyotype to a SNP microarray?”Dr. Big: “Yes, I can consider it: however, the patient has already gone home. Would we need to collect a new blood sample?”Consultant: “Good question. I will find out and call you back.”

The consultant obtains the answer and calls back 5 minutes later. Dr. Big is now busy with another patient. The consultant finally reaches Dr. Big 3 hours later. Consultant: “Hello, Dr. Big. I am calling you back regarding your patient, John Doe,

medical record number 123456, who had a blood draw for a karyotype.”Dr. Big: “I’m sorry; it’s been a busy day. Can you remind me about your question regarding this order? ”Consultant: “Yes, of course. This patient has multiple congenital anomalies and developmental delay. A blood karyotype was ordered. A single nucleotide poly-morphism test or SNP chromosome mi-croarray test has a higher sensitivity for detecting chromosome deletions and du-plications. You were considering chang-ing the karyotype order to a SNP micro-array order. I checked to see if the blood sample collected can be used for the SNP microarray. Unfortunately, a sodium heparin tube was collected for the karyo-type, but a SNP array requires an EDTA tube. We will need a new blood sample to change the order.”Dr. Big: “Then I prefer to keep the karyo-type order. I wish you had told me this during the first call. I find these calls so annoying!”

Obtaining the best Result for the PatientThis case illustrates how a consultant who is organized and prepared is able to guide the physician to order the correct test. By keeping the conversation friendly, giv-ing the physician the power to make the change, and making it easy to make the change, the consultant is able to gain the physician’s approval.

The prepared consultant organized the facts based on the medical record and de-termined that a different test order could benefit the patient. She then prepared for

the phone call by choosing words that would project a positive relationship and by determining that a sample already col-lected could be used for the recommended test. In this example, knowing that a new sample was not needed helped sway the doctor in favor of an appropriate order change.

Using this style of interaction, which is patient-focused and emphasizes organiza-tion, preparation, and collegiality, we find that the majority of physicians are happy to modify test requests without complaining or getting frustrated.

REFERENCES1. Epner P, Astion M. Focusing on test or-dering practices to cut diagnostic errors. CLN 2012;38(7):17–8. Available at: www.aacc.org/publications/cln/2012/July/pag-es/ReducingDiagnosticErrors.aspx#

2. Gandhi TK, Kachalia A, Thomas EJ, et al. Missed and delayed diagnoses in the ambu-latory setting: A study of closed malpractice claims. Ann Intern Med 2006;145:488–96.

Darci L. Sternen, MS, LGC, is a licensed genetic counselor in the Department of Labora-tories at Seattle Children’s Hospital, Seattle.

Email: darci.sternen@seattlechildrens.org

Jessie Conta, MS, LGC, is a li-censed genetic counselor in the Department of Laboratories at Seattle Children’s Hospital, Seattle.

Email: jessie.conta@seattlechildrens.org

ordering the wrong test, misinterpreting a test result, and failing to retrieve a lab result are the three most common problems in laboratory services that lead to malpractice claims (1, 2). to help physicians order the right test, clinical laboratories have created a variety of strategies focused on test utilization.

one widely used strategy is providing physicians the oppor-tunity to consult with an expert regarding appropriate testing options. this approach has become particularly important in ge-netic testing, because it is difficult for physicians to remain knowl-edgeable about the ever-expanding list of new tests. in fact, it is becoming more common for large laboratories to have genetic counselors on staff to help physicians, especially those not versed in genetics, order the appropriate genetic test for their patients.

physician response to the unprepared test utilization consultant.

CliniCal laboratory news oCtoBeR 2013 19

improving Patient Safety Through inter-Departmental PartnershipsHow Phlebotomists Can Help Decrease the Risk of Hospital FallsBy eMily Ryan, PHd, and CoRinne R. Fantz, PHd, daBCC

impact of Hospital FallsFalls are the most common adverse event reported in hospitals, with more than one million hospital inpatients falling each year (1). Head trauma and fractures are among the most serious complications, often re-sulting in longer hospital stays, litigation, and increased healthcare costs. To bring attention to this problem, the federal gov-ernment in 2008 eliminated payments to hospitals for costs associated with treating fall-related injuries (2).

Yet, even with the intense governmen-tal pressure and concentrated local efforts, hospitals still struggle to develop effective strategies that decrease fall rates.

Assessing Patients’ Fall Risk Numerous factors have been associated with increased risk of falling, including ad-vanced patient age, a documented history of falling, certain medications, insecure bedrails, impaired balance and cognition, and even the unit where a patient is located. Consequently, a number of tools have been developed to assess a patient’s risk.

Our hospital assesses fall risk at the time of admission using the Morse Fall Scale. This scale accounts for recent fall history, gait, balance, and presence of an ambulatory aid such as crutches or a walker. Interestingly, when reviewing 2012 fall data, staff noticed an increase in patient fall rates that coincided with early morning phlebotomy collections.

An analysis revealed that when patients were awakened for sample collection, they often stayed awake and attempted to use the restroom unassisted or wanted to watch television and fell reaching for the remote.

unlikely Partners Team upBased on this analysis, the nursing staff de-cided to enlist the help of the phlebotomy team to decrease fall rates. Working with the various clinical teams, the phleboto-mists developed unit-specific, phlebotomy-

driven interventions for units deemed high-risk for patient falls.

The teams quickly realized that it was important to develop unit-specific strat-egies because falls occur for a variety of different reasons. On some units, they de-cided that it was best for the phlebotomists to call ahead so that the nurses could offer the patient assistance, thereby minimizing the opportunity for a patient to get up in-dependently.

In other units, phlebotomists were trained to look for standard, institutional fall risk signs before entering patients’ rooms. For these high-risk individuals, phlebotomists developed a special routine that involved specifically asking patients if they needed to use the restroom after

collecting the specimen. For patients who do, the phlebotomist notifies a nurse and waits to ensure the patient gets the required assistance.

Driving Change and Adding Value Successfully implementing a program like this can be challenging and may require changes in measuring staff performance. For example, the extra time it takes to en-sure a patient is safe may decrease the pro-ductivity of an individual phlebotomist. Given how daily workload varies, some phlebotomists also may find it challenging to give the floor a phone call 10–15 minutes before arriving. Phlebotomists will need to display patience and flexibility when wait-ing for a nurse to arrive, which also can delay collecting other patient samples and finishing their rounds. In our experience, metrics designed to assess meaningful sys-tem goals, rather than optimizing individ-ual phlebotomy goals, have been key to the collaboration’s success.

The phlebotomy team has willingly em-braced this new role in our organization. Teaming up with patients and nursing staff to improve patient safety has brought real

value to the fall prevention program and initial results suggest a decreasing fall rate.

One phlebotomist said this new pro-cedure has given her greater ownership of the patient’s safety while she is in the room. She says she feels greater responsibility for the patient’s well-being and now double checks the bed height and railing as part of her routine. Another described how the ad-dition of the fall question to her process has led patients to ask for personal belongings such as a book or remote control, a request that could prevent a fall.

All agree that the new process has cer-tainly been successful in improving patient-phlebotomist interactions. We think this is a great example of how non-traditional, interdepartmental partnerships are adding value to patient safety initiatives.

REFERENCES1. Currie L. Fall and injury prevention. In: Hughes RG, ed. Patient safety and quality: An evidence-based handbook for nurses. Rockville, Md.: Agency for Healthcare Re-search and Quality 2008.

2. Inouye SK, Brown C, Tinetti M. Medicare nonpayment, hospital falls, and unintend-ed consequences. NEJM 2009;360:2390–3.

Emily Ryan, MD, is a clinical chemistry fellow in Pathology and Laboratory Medicine at Emory University School of Medicine, Atlanta.

Email: eryan2@emory.edu

Corinne R. Fantz, PhD, DABCC, is associate professor of Pathology and Laboratory Medicine at Emory University School of Medicine, Atlanta,

and a member of the Patient Safety Focus Editorial Advisory Board. Email: cfantz@emory.edu

fall prevention strategies used by phlebotomy

® ask if the patient needs to use the restroom.

® Check that bedrails and furniture on wheels are locked in position.

® place tV remote control, phone, eyeglasses, etc. within easy reach for the patient.

® Check that the bed is in the low position.

® Check the floor and clear pathway to restroom.

could a phlebotomist have prevented this fall? The surprising answer is yes!

phlebotomists are integral members of the laboratory team and often patients’ only contact with the laboratory. as such, their attitude and actions color patients’ feelings toward the labora-tory. not only do phlebotomists have a huge impact on patients’ perceptions of the laboratory, but they are the front line when it comes to patient safety issues such as sample quality and identi-fication.

but thinking outside the box when it comes to patient safety can lead to some surprising results. this is a story of how a non-traditional partnership between our phlebotomy team at emory university Hospital in atlanta and the nursing staff led to a de-crease in patient fall rates, a major safety problem in hospitals.

Falls are the most common adverse event reported in hospitals, with more than

one million hospital inpatients falling each year.

20 CliniCal laboratory news oCtoBeR 2013

How Is Burnout Measured?There are a number of validated tools for describing burnout, the most common be-ing the Maslach Burnout Inventory (3). A recent study of 7,288 U.S. physicians using this tool asked 22 questions that explored all three domains of burnout: emotional exhaustion, depersonalization, and per-sonal accomplishment (1).

How Burned Out Are Physicians? The researchers found that 46% of physi-cians in all major disciplines had at least one symptom of burnout, with the most practicing in emergency medicine, family medicine, and critical care. In contrast, only 32% of pathologists reported expe-riencing at least one symptom, ranking them in the bottom quartile along with psychiatrists and rheumatologists. The results are significant because overall physicians were more likely to experi-ence burnout than a population of non- physician controls.

Physicians reporting burnout were also graded on the severity of their symptoms using a rating of 1 for “does not interfere with my life” to 7, “thinking about leaving the field.” Of interest, burned out patholo-gists had one of the highest severity scores, with a mean of 4. This means that patholo-gists are less likely than other physicians to

burn out; but when they do, it tends to be more severe.

What’s the Impact on Patient Safety? A number of authors have strongly sug-gested that physician burnout represents a significant patient safety problem. For example, Shanafelt and colleagues (1) con-cluded from their own study, as well as similar ones, that physician burnout was “a highly prevalent and systemic problem threatening the foundation of the U.S. medical care system.” Robert Wachter, MD, of the University of California, San Fran-cisco, an influential figure in the patient safety movement, recently expressed an-other point of view. He hypothesized that

the many time-consuming patient safety initiatives in hospitals contribute signifi-cantly to physician burnout (4).

How to Approach Burnout on Patient Safety?To date, the impact of burnout on patient safety has not been thoroughly evaluated. One could make a reasonable argument, however, that the hallmarks of burnout—

loss of enthusiasm for work, depersonaliza-tion in dealing with patients and colleagues, and lack of concentration—impact more than patient safety. Burnout also likely de-tracts from the health, safety, satisfaction, and retention of healthcare workers.

Nevertheless, any conclusions about the effect of burnout on patient safety (and patient safety on burnout), especially in the laboratory where data is absent, remain speculative. Therefore, prudence, work-place support, and further study, rather than crisis intervention, is the calm and practical approach.

REFERENCES1. Shanafelt TD, Boone S, Tan L, et al. Burnout and satisfaction with work-life balance among U.S. physicians relative to the general U.S. population. Arch Intern Med 2012;172:1377–85.

2. Kaschka WP, Korczak D, Broich D. Burnout: A fashionable diagnosis. Dtsch Arztebl Int 2011;108:781–7.

3. Maslach C, Jackson SE, Leiter MP. Maslach burnout inventory manual, 3rd Ed. Palo Alto, Calif.: Consulting Psycholo-gists Press 1996.

4. Wachter’s World. Wachter RM. Is the pa-tient safety movement in danger of flicker-ing out? http://community.the-hospitalist.org/2013/02/18/is-the-patient-safety-movement-in-danger-of-flickering-out/ (Accessed February 2013).

Michael Astion, MD, PhD, is medical director of Department of Labora-tories, Seattle Children’s Hospital, Seattle, and chair of the Patient Safety Focus Editorial Advisory Board.

Email: Michael.astion@seattlechildrens.org

burnoutA New Frontier in Patient Safety?By MiCHael astion, Md, PHd

Most demanding careers like those in medical disciplines come with stress. but when medical professionals feel completely ex-hausted, unable to concentrate, or neglect their own well-being, they can potentially harm patients. Consequently, the subject of burnout is getting a lot of attention these days in discussions of patient safety.

burnout is a syndrome characterized by emotional exhaustion, depersonalization, and feelings of lack of personal accomplish-ment (1). Medically, however, it is controversial (2). burnout is not an accepted medical diagnosis, but rather a description of an emotional and behavioral state. there is some evidence that burnout is a risk factor for depression.

while more than 200 published studies describe burnout in medical professionals such as nurses, physicians, and medical students, to my knowledge, there are no peer-reviewed studies of clinical laboratory workers. only pathologists have been included in studies of physician burnout.

are patient safety initiatives burning out this lab manager?

five signs of burnoutYou may be on the road to burnout if:

® every day is a bad day.

® Caring about your work or home life seems like a total waste of energy.

® You’re exhausted all the time.

® the majority of your day is spent on tasks you find either mind-numbingly dull or overwhelming.

® You feel like nothing you do makes a difference or is appreciated.

The researchers found that 46% of physicians in all major disciplines

had at least one symptom of burnout, with the most practicing in emergency medicine,

family medicine, and critical care.

Share Your Patient Safety Stories

Article submissions are welcome.

Contact Dr. Michael Astion at:

michael.astion@ seattlechildrens.org.

CliniCal laboratory news oCtoBeR 2013 21

editor’s notethe Clinical and Laboratory standards institute (CLsi) recently released an updated edition of its standard nbs01-a6, “blood Collection on filter paper for newborn screening programs,” which replaces standard La04-a5. this important document, revised for the first time since 2007, contains a substantial amount of new information on the essentials of correctly collecting a high-quality specimen, handling the specimen after it has been collected, transporting it to the testing facility, and sorting the residual specimen that remains after laboratory testing. for additional information, visit the CLsi website at www.clsi.org.

Please describe drawing blood by heel-stick sampling. The heel-stick method for drawing capil-lary blood is the most common way to draw newborns’ blood. It is used to collect blood for newborn screening tests, usually before the baby leaves the hospital. Heel sticks are the most commonly performed invasive procedure in neonatal intensive care units. When is the heel-stick method used to draw blood from infants? That is a frequently asked question. I like to think of this question in terms of de-velopmental milestones. While fingers are the site of choice after infancy, heel sticks are appropriate for most babies, includ-ing premature infants, neonates, and even babies 4 to 7 months old. The only caveat is that babies discover other parts of their bodies, such as their feet and toes, as they grow older.

A bandage placed on a baby’s heel can pose a safety risk when the child is able to place its feet in its mouth. By 8 to 12 months, babies are pulling themselves up, standing, and preparing to walk or walk-ing; so heel sticks are not recommended at this developmental stage because the heels are bearing weight to varying degrees. Pre-mies may not reach such milestones on the same schedule as full-term babies, so I rec-ommend that parents be questioned about their child’s development before perform-ing a heel stick.

What risks are particular to heel sticks?Improper heel-stick technique can dam-age the structures of the foot, including the calcaneus bone and soft tissues. In fact, some reports have documented difficulties walking later in life. It is safe to perform a heel stick if the puncture site is limited to the medial and lateral planter aspects of each heel pad, specifically medial to a visual line drawn from the middle of the big toe extending posterior to the heel or lateral to a line drawn from between the fourth and fifth toes and extending posterior to the heel. Repeated punctures, bruising, or erythema limit the available area for punc-tures, especially in premature infants who

may have blood drawn multiple times or very tiny heels.

How can heel-stick safety be assessed?Due to the special technical requirements of this procedure, it is ideal to have expe-rienced staff who perform heel sticks fre-quently. It is also important to have a pro-gram in place to maintain this special skill set. Periodic quality rounds to randomly

inspect neonatal heels are a good idea to evaluate staff performance and take correc-tive actions when necessary.

Are there other safety risks associated with heel sticks?Yes, there is also a risk of burning the baby’s skin while warming its heel before the blood is drawn. Heel warming is used

to increase blood flow in the capillaries. If the heel is to be warmed, using warm water submersion is risky unless you tightly con-trol the temperature.

Chemical heat packs are single-use, and offer a temperature-controlled, safer, but more expensive alternative. Though heel warming is commonly performed to increase blood flow, this protocol is actually based more on theoreti-cal grounds than on any solid evidence

that it works. Two studies have claimed that heel warming does not increase blood flow; however, the studies were not blinded (1, 2). It is costly in terms of time and consumables, so a well-designed study to resolve this question would be welcome.

Are finger sticks on infants safe?Yes, they can be performed with special safety measures. Special lancets less than 1.5-mm thick can be used once heel sticks are no longer an option and after 6 months of age. At that age, distance from the skin surface to bone and cartilage in the middle finger is only 2.5 mm (3).

REFERENCES1. Barker DB, Willets B, Cappendijk VC, et al. Capillary blood sampling: Should the heel be warmed? Arch Dis Child Fetal Neo-natal Ed. 1996;74:139–40.

2. Janus M, Pinelli J. Comparison of blood sampling using an automated incision de-vice with and without warming the heel. J Perinatol 2002;22:154–8.

3. Reiner CB, Meites S, Hayes JR. Optimal sites and depths for skin puncture of infants and children as assessed from anatomical measurements. Clin Chem 1990;36:547–9.

in the July issue of patient safety focus, Dr. geaghan described the risks associated with capillary blood sampling from a finger-stick puncture, a widely used method in point-of-care glucose testing. Here she expands on that interview, focusing on the heel-stick sampling method, a simple procedure in which a baby's heel is pricked with a lancet and then a small amount of the blood is collected in a narrow-gauge capillary glass tube or on a filter paper. Dr. geaghan is profes-

sor of pathology and pediatrics at stanford university school of Medicine in palo alto, Calif.

nanCy sasaVaGe, PHd, ConduCted tHis inteRView.

chairmichael astion, md, phdseattle Children’s Hospital

seattle, wash.

membersnikola baumann, phd

Mayo Clinicrochester, Minn.

corinne fantz, phdemory university

atlanta, ga.

James s. hernandez, md, ms Mayo Clinic arizona

scottsdale and phoenix, ariz.

brian r. Jackson, md, msarup Laboratories salt Lake City, utah

patient safety focus editorial board

Heel-Stick Sampling What Precautions Should Be Taken When Drawing Blood From Infants an inteRView witH sHaRon M. GeaGHan, Md

While fingers are the site of choice after infancy, heel sticks are appropriate for most babies, including premature infants,

neonates, and even babies 4 to 7 months old.

22 CliniCal laboratory news oCtoBeR 2013

With all the demands lab-oratory professionals face today, taking time out to learn new skills can be challenging.

AACC’s online certificates offer personal-ized, high-quality education on a variety of laboratory testing and management topics. Here’s a look at our newest and most popu-lar online certificate programs.

Patient Safety and OutcomesIn today’s clinical lab, patient safety and improving patient outcomes have become essential. AACC offers two certificate pro-

grams on complementary subjects. Improving Outcomes Through POCT is

an advanced exploration of point-of-care testing (POCT) applications, including best practices and POCT implementation in the emergency department, disaster medicine, and infectious diseases scenarios. The fac-ulty also provides in-depth knowledge on how POCT can improve patient outcomes in creatinine blood testing, heart condi-tions, diabetes management, and infectious diseases.

A new certificate program, Patient Safety Essentials for Laboratory Professionals, offers practical tips for laboratorians on identify-

ing patient safety hazards and employing resources at hand to improve patient care. Faculty experts provide step-by-step meth-ods for approaching error detection and response, risk management, and quality im-provement.

Both of these resources are offered as multi-course online certificate programs, each with lectures, recommended readings, and quizzes. Program materials are acces-sible online until July 15, 2014. A certificate of completion is awarded to those who suc-cessfully pass all courses, and continuing education credits are provided.

And this year only, our newest program

on patient safety is being offered to AACC members with an additional savings of 20% over the current member rate. Simply reg-ister online using promotional code 140 or mention this offer when registering by phone with our customer service department.

The Realm of Molecular TestingWith the evolution of personalized medi-cine in cancer treatment and the rise of genetically targeted therapies, the demand is increasing for skilled laboratory profes-sionals able to perform molecular diag-nostic tests and help physicians determine effective treatment plans.

You can take a first step toward this excit-ing trend in laboratory medicine by testing your knowledge using the certificate pro-gram, Fundamentals of Molecular Pathol-ogy, which features expert contributors in the field. This basic-to-intermediate-level program offers a comprehensive look at mo-lecular testing in nine different courses, span-ning techniques in genetics, cancer diagnosis, infectious diseases, and pharmacogenomics.

Education in Laboratory Management For clinical lab professionals interested in management subjects, there are five certifi-cate programs to choose from that include our newest program, Patient Safety Essen-tials for Laboratory Professionals.

Basic Principles and Architecture of Labo-ratory Information Systems features online lectures and resources to assist with labora-tory information system decisions, trouble-shooting, and matters related to patient safety.

In the Clinical Laboratory Leadership and Management certificate program, you can learn tools for managing time, person-nel, and enhancing your team development and leadership skills.

For those interested in regulatory affairs and compliance with state and federal reg-ulations, AACC offers a certificate program on Regulatory Affairs for Laboratory Com-pliance. This course outlines how CLIA ’88, OSHA, and HIPAA regulations affect op-erations, compliance, and reimbursement issues for the lab.

AACC also offers the Statistical Meth-ods for Clinical Laboratorians certificate program that reviews the essentials of lab statistics. This knowledge will not only help you better understand the quality of your results data, but it will also allow you to eval-uate the statistical methods in your lab.

As an added benefit of these laboratory management programs, students receive invitations to special educational events on related topics. Both current students and graduates of these certificate programs can participate in these events at no cost. For example, an upcoming event for these learners is a webinar on the impact of FDA regulation in today’s clinical lab on October 10, featuring expert Steve Binder from Bio-Rad Laboratories.

How to RegisterFor a comprehensive list of AACC’s certifi-cate programs and to register, please visit www.aacc.org/cert_prog or call 800-892-1400. CLN

What’s the best Way to Expand Your Skill Set in Laboratory Medicine?Take a Look at AACC’s Online Curriculum for Convenient, In-Depth Education

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Registration and program information is available at aacc.org/cert_prog.To enroll by phone, call Customer Service at (800) 892-1400 or (202) 857-0717.

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BECKMANCONFERENCE30 th November 5–6, 2013

AtlANtA, GA

Novel biomArkers of kidNey diseAse:f A l s e d A w N o r N e w h o r i z o N ?

Come to the 30th Beckman Conference to learn about and discuss with colleagues the new biomarkers that are about to revolutionize laboratory testing for kidney function and disease. You will gain new knowledge and insights that will help you advance in your role towards improving patient care and outcomes.

AACC is delighted to partner with the American Society of Nephrology (ASN) in presenting this conference in conjunction with ASN’s Kidney Week.

e A r ly- b i r d r e G i s t r At i o N e N d s o N s e p t e m b e r 18

Visit aacc.org/Beckman13 to register

This conference is funded, in part, by an endowment from the Arnold O. and Mabel Beckman Foundation.

the distinguished faculty, representing both laboratory and clinical perspectives, will present the impact these promising biomarkers are expected to have on medical care for patients with kidney diseases and related conditions.

Here’s a snapshot of the session topics: •biomarkers in Clinical practice•Chronic kidney disease: improving the

prediction of disease progression•Acute kidney injury biomarkers:

lessons from multicenter studies•kidney biomarkers: Applications in other diseases•kidney biomarkers in transplantation

and prevention of organ rejection•A debate on biomarkers in Acute kidney injury

Clinical trials — Are they ready or Not?•experimental methods•statistics and study design•measurement Questions

ACC-102 conference tabloid ad.indd 1 7/10/13 10:38 AM

24 CliniCal laboratory news oCtoBeR 2013

cola sounds alarm over Waived Testing Quality

cOLA, a lab accrediting organization, is warning the lab community about

growing quality problems at waived test-ing sites. The organization addressed the Clinical Laboratory Improvement Advi-sory Committee (CLIAC) at its August

21–22 meeting in Atlanta along with other accreditors, The Joint Commission (TJC), and the College of Pathologists (CAP).

Verlin Janzen, MD, a member of COLA’s board of directors, presented COLA’s ob-servations about the growing role of waived testing and COLA’s evidence of mounting quality problems. According to Janzen, these quality problems exist largely in un-

regulated labs that rely on waived tests, and have the potential to cause errors and even patient harm. He cited research showing that the number of waived tests has in-creased from just nine in 1993 to more than 5,400 tests and 110 analytes today. What’s more, the quality problems have been exac-erbated by technology advances that enable many tests to now be performed on mobile devices by personnel with limited experi-ence and training, Janzen added.

The most common quality challenges that COLA reported included: high staff turnover, failure to adequately train per-sonnel and maintain competency, failure to monitor and respond to quality control, lack of knowledgeable lab directors, failure to document lot numbers and expirations, failure to follow current instrument or kit instructions, pre- and post-analytic errors, waived sites performing non-waived test-ing, and failure to enter results into elec-tronic medical records.

Janzen recommended more education for Certificate of Waiver site directors and testing personnel. More information about COLA’s report is available from www.cola.org.

report calls for better oversight of racs

after 3 years of complaints about Medi-care’s controversial Recovery Audit

Contractor (RAC) program, a new report from the Department of Health and Hu-man Services’ (HHS) Office of the Inspec-tor General (OIG) has found that RACs may not be working as intended.

RACs are supposed to protect Medicare by identifying improper payments and re-ferring potential fraud to the Centers for Medicare and Medicaid Services (CMS). OIG noted in its report that previous Gov-ernment Accountability Office reports have found problems with CMS’s actions to deal with improper payment vulner-abilities. Similarly, prior OIG investigations discovered problems with CMS’s response to referrals of potential fraud from RACs, and OIG has in several other cases identi-fied vulnerabilities in CMS’s oversight of contractors.

Hospitals have been particularly vocal in their criticism of RACs, which they see as a burdensome and flawed government pro-gram. Last year the American Hospital As-sociation asked for an OIG review of RACs, while the association simultaneously joined with four health systems in suing HHS for denying payments.

Hospitals complain that RACs over-reach in their demands for large numbers of records from providers, through which they scrutinize for past overpayments. If successful in finding overpayments, RACs get to keep up to 10% of the money they force healthcare providers to give back to the government. But according to hospitals, RACs have been consistently inaccurate and aggressive in their audits.

However, the OIG report does less to bolster the claims of hospitals than it does undermine CMS’s credibility with RACs. The OIG report found that in fiscal years 2010 and 2011, RACs identified half of all claims they reviewed as having resulted in

improper payments totaling $1.3 billion. CMS took corrective actions to address the majority of these vulnerabilities, but it did not evaluate the effectiveness of these ac-tions, according to OIG. “As a result, high amounts of improper payments may con-tinue,” OIG warned. Additionally, CMS did not address referrals of potential fraud that it received from RACs, nor did the agency’s performance evaluations include metrics to evaluate RACs’ performance on all contract requirements.

More information on the OIG report is available from http://oig.hhs.gov.

nih project Tackles clinical, ethical Questions on sequencing newborn’s genomes

With genome sequencing speed in-creasing and cost plummeting, NIH

announced a new plan to deal with the medical and ethical quandaries that arise in sequencing babies’ genomes. Pilot projects to examine these questions are being fund-ed by the Eunice Kennedy Shriver National Institute of Child Health and Human De-velopment (NICHD) and the National Hu-man Genome Research Institute (NHGRI), both parts of the National Institutes of Health. Awards of $5 million to four grant-ees have been made in fiscal year 2013 un-der the Genomic Sequencing and Newborn Screening Disorders research program. The program will be funded at $25 million over 5 years.

“Genomic sequencing has potential to diagnose a vast array of disorders and con-ditions at the very start of life,” said Alan Guttmacher, MD, director of NICHD. “But the ability to decipher an individual’s ge-netic code rapidly also brings with it a host of clinical and ethical issues, which is why it is important that this program explores the trio of technical, clinical, and ethical as-pects of genomics research in the newborn period.”

The awards will fund studies on the po-tential for genome and exome sequencing to expand and improve newborn health-care, especially in how to use the massive amount of information produced through sequencing, according to NHGRI director Eric Green, MD, PhD. “We are at a point now where powerful new genome se-quencing technologies are making it faster and more affordable than ever to access genomic information about patients,” he said. “This initiative will help us better un-derstand how we can appropriately use this information to improve health and prevent disease in infants and children.”

Programs currently screen almost all of the more than 4 million infants born in the United States each year. Until now, the test-ing of DNA has not been a first-line new-born screening method, but has been used to confirm the screening results of some disorders, such as cystic fibrosis.

Each of the new awards will consist of three parts: genomic sequencing and analy-sis; research related to patient care; and the ethical, legal, and social implications of us-ing genomic information in the newborn period.

More information about the project is available from www.genome.gov.

p r o f i L e sp r o f i L e s

r e g u L at o r y

CliniCal laboratory news oCtoBeR 2013 25

biomérieux signs agreement to acquire biofire

bioMérieux has inked a deal to buy BioFire Diagnostics, Inc. for $450 mil-

lion plus BioFire’s net financial debt. A mo-lecular biology company that specializes in PCR technology, BioFire developed and produces the multiplex PCR FilmArray sys-tem. FilmArray takes a novel approach to diagnosing infectious diseases that involves analyzing a syndrome, or set of symptoms, and using a single reagent to identify the viruses or bacteria causing the syndrome. Its test menu currently includes respira-tory and sepsis panels, with gastrointestinal and meningitis panels under development. Within the next 3 years, company officials predict FilmArray will detect more than 70 disease agents.

“This new acquisition enables us to re-inforce our infectious diseases franchise, our main area of specialization,” said Jean-Luc Belingard, chairman and CEO of bioMérieux. “In all markets, we now have a complete portfolio of particularly inno-vative technologies with two key benefits: enhanced medical value of diagnostics and optimized workflows in medical laborato-ries.”

The acquisition is expected to wrap up by the end of bioMérieux’s fiscal year on December 31 or in early 2014.

gene by gene, arpeggi merger to focus on genetic Testing

gene by Gene, Ltd. has acquired Arpeggi, Inc. for an undisclosed sum

with the aim of making next-generation DNA sequencing and clinical genomics accessible and affordable to all. “We are on a mission to transform healthcare by dramatically speeding up the process, and reducing the costs, of genetic tests, which today are often far too expensive for the average consumer,” said Max Blankfeld, managing partner of Gene by Gene. Gene by Gene was the first company to develop consumer DNA testing products for ances-try and genealogy applications, while Ar-peggi specializes in solutions for genome sequencing, data management, and com-putational analysis.

inova, gns healthcare partner to reduce risk of preterm birth

The Inova Translational Medicine Insti-tute (ITMI) and GNS Healthcare have

entered a collaboration to develop comput-er models that predict the risk of preterm live birth using next generation sequencing and electronic medical record data. The two companies will use GNS’s data ana-lytics platform to construct these models from ITMI’s database, which includes nor-mal birth and preterm birth family cohorts. By linking genetic and molecular factors with clinical data and health outcomes, the

models will identify the underlying causes of preterm birth and allow for personalized prediction of preterm birth risk and gesta-tional length.

“We see this work in preterm birth as a first step toward building similar prediction models for other complex diseases, such as autism, diabetes, and obesity, supported by ITMI’s massive familial whole genome

sequence databases,” said Joe Vockley, PhD, chief operating officer and chief scientific officer of ITMI. “Prediction followed by prevention is a key component of transla-tional medicine.”

Once the models are developed, ITMI and GNS plan to commercialize them and corresponding software along with option-al access to the underlying ITMI data.

seracare buys Kpl

seraCare Life Sciences has acquired Kirkegaard & Perry Laboratories (KPL),

a provider of antibodies and related di-agnostic and life sciences reagents. KPL’s

portfolio includes immunochemicals for in vitro diagnostics, such as primary and secondary antibodies, as well as reagents and kits targeting enzyme-linked immu-nosorbent assay, western blotting, immu-nohistology, protein labeling, nucleic acid labeling, sample preparation, protein pu-rification, and recombinant protein detec-tion and analysis. According to SeraCare’s press release, this acquisition will help ex-pand the company’s selection of products designed to help researchers develop in vitro diagnostic assays through both off-the-shelf products and custom antibody design. The company did not disclose the terms of this transaction.

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26 CliniCal laboratory news oCtoBeR 2013

risk of hypoglycemia spans the range of hba1c levels

severe hypoglycemia is common in type 2 diabetics, regardless of their level of

glycemic control measured by HbA1c, and risk of hypoglycemia is higher in patients with either near-normal or poor glycemic control (Diabetes Care 2013; doi:10.2337/

dc13-0610). This finding, which runs con-trary to conventional wisdom that risk of hypoglycemia is highest in patients with the lowest HbA1c levels, suggests that strategies to improve the safety of glucose-lowering therapies need to be directed not only to patients with poorly controlled disease, but also those with near-normal glycemic control.

The researchers conducted the study because recent guidance from professional organizations has called for individualized decision-making in diabetes that takes into account patient goals and preferences, and the risks and benefits of glucose-lowering therapy to set glycemic targets. These rec-ommendations also suggest less intensive glucose control strategies for older individ-uals with limited life expectancy, advanced diabetes, cognitive impairment, or very poor health. While prior research has found an inverse relationship between HbA1c levels and severe hypoglycemia in type 1 diabetics, other analyses have shown conflicting as-sociations between diabetic treatment and control and risk of hypoglycemia.

The study involved a survey of 9,094 type 2 diabetics receiving care in a large, in-tegrated healthcare system who were 30–77 years and were being treated with glucose-lowering therapy. The survey asked about severe hypoglycemia requiring assistance and accessed respondents’ last recorded HbA1c level in the year prior to the study period.

Overall, 10.8% of respondents experi-enced hypoglycemia. Compared to those with HbA1c levels of 7–7.9%, the relative risk of hypoglycemia in a fully adjusted model was 1.25, 1.01, 0.99, and 1.16 in those with HbA1c <6, 6–6.9, 8–8.9, and ≥9%, respectively. Based on these findings, the authors called for further research to identify management strategies and treat-ment factors that might mitigate hypogly-cemia risk.

Timing of stool collection Key in reducing false-negative C. difficile results

empirical antimicrobial therapy for sus-pected Clostridium difficile infection

(CDI) might result in false-negative poly-merase chain reaction (PCR) test results if there are delays in stool specimen col-lection (Clin Infect Dis 2013;57:494–500). The findings suggest that in patients with suspected CDI and mild-to-moderate symptoms, it might be reasonable to stipu-late that empirical therapy start only after a stool specimen has been collected, accord-ing to the authors. In the case of patients with suspected severe CDI in which imme-diate empirical therapy is indicated, expe-dited specimen collection is imperative.

Guidelines call for empirical antimi-crobial treatment for patients suspected of having severe CDI, but in practice, clini-cians routinely prescribe empirical therapy even in patients with mild-to-moderate symptoms, especially when they anticipate delays in collecting specimens. However, little information is available about how likely empirical therapy is to cause false-negative CDI test results.

Over a 4-month period, the authors examined the effect of CDI treatment on CDI test results. They looked at the time for test results, including PCR, glutamate dehydrogenase, and toxigenic culture, to convert from positive to negative during CDI therapy. The authors found these tests all converted at similar rates. In the case of PCR, 14%, 35%, and 45% of positive CDI tests converted to negative after 1, 2, and

3 days of treatment, respectively. Overall, 44% of empirically treated CDI patients converted to negative PCR and toxigenic culture results, compared with none of the CDI patients who did not receive empiri-cal therapy. All the patients who converted to positive received at least 24 hours of CDI therapy prior to stool collection.

urinary cXcl9 early detector of acute Kidney Transplant rejection

urinary CXCL9 protein is a robust marker for ruling out acute kidney

transplant rejection, and for stratifying patients for low- and high-risk of allograft injury (Am J Transplant 2013; doi: 10.1111/ajt.12426). According to the authors, the findings lay the foundation for future re-search aimed at improving kidney trans-plant outcomes through biomarker-guided decision-making.

The researchers conducted a prospec-tive, multicenter observational study to validate biomarkers for diagnosing acute rejection and stratifying patients based on risk of developing acute rejection or pro-gressive renal dysfunction. Single-center studies had suggested several biomarkers might be useful for these purposes, but without validation in a multicenter popula-tion, they have not been adopted in clinical practice.

The study involved 280 kidney trans-plant recipients. Blood and urine samples were collected prior to transplant surgery, and on day 3, weeks 1–4, and months 2–6, 12, and 24 after transplant. The investiga-tors analyzed a number of biomarkers us-ing different methods, ranging from gene expression and urine protein profiling to enzyme-linked immunosorbent assays.

Of all the biomarkers investigated for diagnosing acute rejection, urinary CXCL9 mRNA and urinary CXCL9 protein were the most robust. Levels were significantly higher in patients with acute rejection, as determined by biopsy, and elevations were detectible up to 30 days before graft dys-function became evident clinically. The authors also found that absence of CXCL9 during acute graft dysfunction ruled out acute rejection with a negative predictive value of 92%. They also found that sus-tained low levels 6 months after transplan-tation uniquely identified patients at low risk for developing acute rejection over the next 18 months.

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CliniCal laboratory news oCtoBeR 2013 27

fda releases draft guidance clarifying good laboratory practice regulations

The Food and Drug Administration (FDA) has announced the availability

of the draft guidance, “The Applicability of Good Laboratory Practice in Premarket Device Submissions: Questions and An-swers.” The agency issued the good labora-tory practice (GLP) regulations to address concerns that poor research practices and laboratory misconduct had undermined the reliability of several important stud-ies supporting the safety of FDA-regulated products. This draft guidance responds to frequently asked questions about the ap-plicability of GLP to nonclinical laboratory studies conducted in support of research and marketing applications for medical devices. It also clarifies GLP terminology and, if applicable, the types of information related to GLP that should be provided to FDA. When finalized, it will represent FDA’s current thinking on GLP.

The agency is accepting comments on this draft guidance until November 26. Electronic comments may be submitted at www.regulations.gov.

magellan receives clearance for lead blood Test

fDA has cleared Magellan Diagnostic, Inc.’s LeadCare Ultra Blood Lead Test-

ing System for quantifying lead levels in blood. According to Magellan’s press re-lease, LeadCare Ultra is the first plug-and-play, bench-top system for laboratory lead analysis. It is based on technology devel-oped by Magellan that has been in use for nearly two decades.

fda approves alere Test for early hiv detection

alere Inc. has received FDA approval for the Alere Determine HIV 1/2 Ag/Ab

Combo for the detection of HIV-1 p24 an-tigen and antibodies to HIV-1/HIV-2. The new test, which is classified as a moderately complex medical device under CLIA, is the first and only FDA-approved, rapid point-of-care test that detects both HIV-1/2 an-tibodies and the HIV-1 p24 antigen. The HIV-1 p24 antigen can appear days after infection and prior to HIV-1/2 antibodies, allowing healthcare workers to detect HIV in patients earlier than with second- and third-generation antibody-only tests.

fda clears spartan bioscience drug metabolism Test

spartan Bioscience received FDA clear-ance for the Spartan RX CYP2C19

System, which provides genetic results in less than 60 minutes from a non-invasive cheek swab. This automated sample-to-result system identifies CYP2C19*2, *3, and *17 variations, providing clinicians with information that helps determine therapeutic strategy for drugs metabolized by the CYP450 2C19 genetic pathway. The CYP2C19 enzyme metabolizes approxi-mately 15% of all prescribed drugs.

cepheid Tuberculosis Test categorized as moderate complexity under clia

fDA has categorized Cepheid’s Xpert MTB/RIF test as moderate complexity

under CLIA, making it the first and only molecular tuberculosis (TB) test to receive this rating. Designed for Cepheid’s GeneX-pert Systems, the Xpert MTB/RIF test de-tects Mycobacterium tuberculosis complex (MTB-complex) DNA in approximately 2 hours, as well as rifampin-resistance as-sociated mutations of the rpoB gene. This latter capability can not only help clinicians identify patients with rifampin-resistant TB strains, but it can also indicate strains that may be multidrug-resistant.

biomérieux receives fda nod for rapid microbial identification Technology

fDA granted bioMérieux 510(k) clear-ance for VITEK MS, a clinical mass

spectrometry MALDI-TOF-based system for the rapid identification of disease- causing bacteria and yeast. The VITEK MS can detect nearly 200 different microorgan-isms that represent the majority of bacterial and fungal infections that afflict humans, yielding results in minutes. Its overall ac-curacy is 93.6% when compared to the accuracy of 16S Ribosomal RNA gene se-quencing, the gold standard for identify-ing anaerobic bacteria, Enterobacteriaceae, Gram-positive aerobes, fastidious Gram-negative bacteria, Gram-negative non- Enterobacteriaceae, and yeast.

bd gets fda clearance for Trichomoniasis assay

fDA has cleared BD Diagnostics’ BD ProbeTec Trichomonas vaginalis Qx

Amplified DNA Assay for the diagnosis of trichomoniasis on the BD Viper Sys-tem with XTR Technology. This platform performs direct qualitative detection of T. vaginalis DNA in endocervical and vaginal samples, as well as neat urine specimens. It offers automated DNA extraction and simultaneous amplification and detec-tion, improving accuracy and time to re-sults compared to wet mount microscopy and culture, according to BD. The BD Vi-per System also allows laboratories to test samples in panel mode for T. vaginalis, C. trachomatis, and N. gonorrhea, or in batch mode for chlamydia and gonorrhea, tricho-monas, and herpes on the same automated platform.

news from the fda

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Kamiya biomedical company . . . . . . . . . . . . . . . . . . . . . . . . . . . 3, 8, 27 www.k-assay.com

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pharmasan labs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 www.ispotlyme.com

roche diagnostics corp. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 www.mylabonline.com

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