December 2014

ClinicalLaboratory

News

An AACC Publication | Volume 40, Number 12

Troponin Q&A

Pancreatic Cancer Clues

TACKLING EBOLA

HOW LABS ARE COPING

+ Resources from AACC

include an on-demand webinar with laboratory experts.

TACKLING EBOLA

PAGE 11

LABAUTOMATION:FROM BLOOD DRAWS TO DRONES

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1CONTENTSDECEMBER 2014

EDITORIAL STAFFManaging Editor Bill MaloneSenior Editor Genna RollinsCommunications CoordinatorChristine DeLongContributors Robin A. Felder, PhD

BUSINESS STAFFManager of Business & Publications Marketing Camille Walker

Board of EditorsChair Lorin M. Bachmann, PhD, DABCCVCU Health System, Richmond, Va.MembersJoshua Bornhorst, PhD

University of Arkansas, Little Rock, Ark.Andrew Don-Wauchope, MD

Juravinski Hospital and Cancer Center, Hamilton, Ontario

Elizabeth Palavecino, MDWake Forest Baptist Medical Center, Winston-Salem, N.C.

Steven Goss, PhDSiemens Healthcare Diagnostics, Newark, Del.

Pamela Steele, PhDCovance, Inc., Indianapolis, Ind.

AACC OfficersPresident Steven H. Wong, PhD, DABCC, FACBPresident-Elect David Koch, PhD, DABCC, FACBTreasurer Michael J. Bennett, PhD, DABCC, FACBSecretary David Grenache, PhD, DABCC, FACBPast President Robert H. Christenson, PhD, DABCC, FACB

Advertising SalesCunningham Associates180 Old Tappan Rd., Old Tappan, NJ 07675Phone: +1 201.767.4170Fax: +1 201.767.8065E-mail: info@cunnasso.comwww.cunninghamassociates.comPresident Jim CunninghamSenior Vice President James G. PattisNational Accounts Manager Charlie MeitnerTraffi c Manager Kathy Tamalonis

SubscriptionsAACC1850 K Street, NW, Suite 625Washington, DC 20006Phone: +1 202.857.0717 or +1 800.892.1400Fax: +1 202.887.5093E-mail: custserv@aacc.org

Editorial CorrespondenceBill Malone, Managing EditorClinical Laboratory News1850 K Street, NW, Suite 625Washington, DC 20006 USAPhone: +1 202.835.8756 or +1 800.892.1400Fax: +1 202.833.4568E-mail: bmalone@aacc.org

Contents copyright © 2014 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 the clinical laboratorian.

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Features 8 The Hunt for Early Pancreatic Cancer Diagnostics Promising 4-Marker Panel Illustrates Hopes, Limitations of Current Research

10 Confronting Ebola in the U.S.Labs Race to Plan With Evolving Guidance and Missing Details

14 Advances in Clinical Laboratory Automation

Departments 2 Federal Insider 4 Bench Matters 6 The Sample 20 Regulatory Roundup 22 Industry Playbook 24 Ask the Expert

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Federal Panel Issues Draft Diabetes, Thyroid Screening RecommendationsThe U.S. Preventive Services Task Force (USPSTF) issued two draft recommendations, one that could boost diabetes screening and another that questions screening for thyroid dysfunction in those without symptoms.

In the fi rst statement, USPSTF said people with risk factors should be screened for diabetes, even if they do not have high blood pressure. The panel signaled it is moving to align with recommendations from the American Diabetes Association, the American Association of Endocrinologists, and others. The draft “B” recommendation suggests screening all adults with risk factors, including being age 45 or older, obesity, a fi rst-degree relative with diabetes, and certain racial and ethnic minorities. Women with a history of gestational diabetes or polycystic ovarian syndrome are also at increased risk. Evidence on the frequency of screening is limited, but the panel suggested that annual screening for those with risk factors may be appropriate. The panel’s previous position from 2008 only recommended screening asymptomatic adults if they had high blood pressure.

The draft recommendation mentions three acceptable screening tests: HbA1c, fasting plasma glucose, and 2-hour oral glucose tolerance testing. It also notes that HbA1c is most convenient for patients, while on the other hand, random blood glucose should not be used.

In the draft recommendation on thyroid screening, USPSTF concluded that current evidence is insuffi cient to make a recommendation for or against screening for thyroid dysfunction in adults who are not pregnant and show no signs or symptoms of a thyroid problem. This “I” statement indicates the panel believes more research is needed before acting. “People can have mild abnormalities in their thyroid tests and not have symptoms,” said Task Force Co-vice Chair Kirsten Bibbins-Domingo, MD, PhD. “We don’t know enough about the health consequences of fi nding these individuals and treating them. We need more research in this area.”

■WITH CONTROL OF CONGRESS, REPUBLICANS SIGNAL PUSH FOR DEVICE TAX REPEAL

After the midterm elections in November, Republicans will

control the Senate and have an increased majority in the House of Representatives in 2015. The day after the election, the Washington Post

reported that Senate Republican Leader Mitch McConnell (Kentucky) and House Speaker John Boehner (Ohio) already had drafted a short list of legislation to tackle early in the new year, including a repeal of the medical device tax included in the Affordable Care Act. The medical device tax was levied on diagnostics manufacturers beginning in 2013 and is estimated to cost the industry upwards of $30 billion over 10 years.

Even with their gains, Republicans will not have enough votes to sur-mount a veto from President Obama. While this makes an outright repeal of the Affordable Care Act that many Republicans have called for unlikely, the Post reported that the two lead-ers still plan to make changes to the law they think Obama might accept, such as eliminating the Independent Payment Advisory Board (IPAB).

In addition to pushing through changes to the Affordable Care Act, Republicans will also in 2015 chair key committees and subcommittees where the details of healthcare-related legislation get hashed out.

■OIG PLANS HARD LOOK AT INDEPENDENT LAB BILLING IN 2015

Independent labs will be under the microscope for compliance

issues in 2015, with a new plan to review Medicare payments, according to the U.S. Department of Health and Human Services (HHS) Offi ce of Inspector General (OIG) Fiscal Year 2015 Work Plan. The plan does not explain in detail which billing practices in particu-lar OIG will target, but notes that OIG will use the results of their reviews to identify clinical labora-tories that routinely submit improper claims, and recommend ways for the government to recover any overpayments.

Some clues may come from an OIG report released in July, “Questionable Billing for Medicare Part B Clinical Laboratory Services.” In this report, OIG found that more than 1,000 labs had claims that OIG considered irregular.

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Raffi ck Bowen, PhD, MHA, MT(CSMLS), DClChem, FCACB, DABCC, FACB

Labs naturally would like to minimize pre-analytical errors as much as possible, to improve the quality of

blood test results, reduce the number of specimens requiring re-collection, reduce turnaround time, and improve patient management. Blood collection tubes (BCTs) typically have been regarded as inert specimen carriers; however, studies have shown that BCTs can contribute to pre-analytical errors.

We don’t fully understand how these devices affect blood samples, but they may have a greater infl uence on test results than many health professionals realize. BCT components, including tube walls, rubber stoppers, lubri-cants, anticoagulants, separator gels, clot activators, and sur-factants, can affect the quality of specimens and accuracy of laboratory tests. These components and additives have the potential to alter the composition of serum and plasma fractions by adding constituents to blood, adsorbing ele-ments, interacting with protein and cellular components, or altering the stability of analytes in blood specimens.

Other than increasing vigilance when inspecting labora-tory test results and improving communication between the clinical laboratory and clinicians, laboratorians can’t do much to detect BCT problems readily without look-ing at population means (moving averages) of their assays. Following population means at regular timed intervals can alert the laboratory of potential problems with BCTs.

To evaluate interferences from collection device compo-nents in clinical tests, laboratorians should (1) test the same analyte with an alternative assay; (2) incubate the sample with the different parts of the collection device to identify the source of potential interferences; (3) contact both the col-lection device and assay manufacturers; (4) if necessary, fi le a medical device alert with the Food and Drug Administration; and (5) if possible, switch to a new BCT manufacturer.

For any new or substantially modifi ed BCTs introduced to the laboratory, a well-planned validation protocol should be written and reviewed for scientifi c validity by qualifi ed individuals. This protocol should describe the validation procedure in detail, include predefi ned acceptance criteria

and statistical methods, and follow the policies and procedures related to testing human subjects established by the institution’s review board or eth-ics committee. Blood specimens from both patients and apparently healthy individuals should be collected and included in the tube validation study. This study also should include the entire blood collection system (needles, holders, tubing, etc.) rather than a particular tube or component.

To determine the accuracy of assay results obtained from new or sub-stantially modifi ed BCTs, labs should conduct a tube comparison study similar to that described in the CLSI EP9-A (1992) guideline. Specimens that cover the reportable range for each analyte should be evaluated with an adequate number of samples. This will provide suffi cient power to con-duct statistical analyses of the data. Linear regression analysis or a similar type of regression method and Bland-Altman type plots should be used to analyze the tube comparison data.

To assess imprecision of assay results collected in new or substan-tially modifi ed BCTs, laboratorians can compare the variability of results for the samples collected in new tubes with the variability obtained from samples collected in their cur-rent BCTs. Another means to this end is replicate testing of quality control (QC) material and/or patient speci-mens, as described in the CLSI EP5-A (1992) guideline.

For analytes that are physiologically undetectable or those that exist in low concentrations in healthy individu-als, or to generate samples that cover the reportable range, samples should be spiked with the analyte of interest when feasible. The total number of assays for tube validation studies will depend on the intended use of the blood collection device. Laboratories can select for evaluation representative assays from different testing method-ologies, such as ion-specifi c electrode, immunoassay, and spectrophotometry.

Blood Collection Tubes: Reducing Pre-Analytical Errors

5DECEMBER 2014

CLSI GP-34A covers validation and verifi cation of BCTs.

BCT-related problems are diffi -cult to recognize in a timely manner because routine QC testing may not use the problematic collection devices. Likewise, profi ciency testing will not detect BCT-related problems because profi ciency specimens do not require collection with routinely used blood collection devices.

Comparing results for the con-trol sera exposed and unexposed to BCTs should reveal adverse effects from tube additives, but this testing is uncommon in most clinical labora-tories. It is also impractical for most because of the diversity of tubes used and frequent changes in tube lots. It may therefore be more appropriate for tube manufacturers to expose QC sera to BCTs on a lot-by-lot basis. Labs should implement a well-planned tube verifi cation protocol whenever they change the tubes they use.

Looking into the future, emerging technologies promise greater analytical sensitivities and lower specimen vol-umes. Yet they may be more suscepti-ble to analytical interference with even small amounts of interferents from BCT components, potentially altering assays and producing erroneous test results. BCT manufacturers, research-ers, and laboratorians alike will need to remain diligent about these challenges and develop products like a chemically modifi ed BCT wall to eliminate tube surfactant assay interference.

Since effective clinical decision-making depends on accurate and precise laboratory test results, BCTs should be manufactured according to an extremely high standard like other medical devices. And as medical

devices, BCTs should achieve the intended performance levels during defi ned conditions of use. Known and foreseeable risks as well as undesir-able effects should be eliminated and minimized. Tube manufacturers, in vitro diagnostic companies, and laboratorians should all remain alert in protecting against the potential adverse effects of BCTs.

Raffi ck Bowen, PhD, MHA, MT(CSMLS), DClChem, FCACB, DABCC, FACB, is a clinical associate professor of pathology at Stanford University and associate director of the clinical chemistry and immunology laboratory at Stanford Medicine in Stanford, California. +EMAIL: rbowen@stanfordhealthcare.org

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Consensus Document Cautions on Limitations of eGFR, Albuminuria in Monitoring Diabetic Kidney DiseaseA consensus conference of the American Diabetes Association (ADA), American Society of Nephrology, and the National Kidney Foundation (NKF) recently issued a report on diabetic kidney disease (DKD), one of the most frequent complications of diabetes and the leading cause of end-stage renal disease (Diabetes Care 2014;37:2864–83). The document summarizes the current state of DKD-related care and is intended to guide patient care and research.

The authors emphasized the importance of using estimated glomerular fi ltration rate (eGFR) to assess kidney function but noted that many clinicians and patients are unaware of how imprecise this estimate can be. eGFR has “at

best, a 90% chance of being within 30% of the measured GFR,” they wrote. Currently used eGFR equations also are “signifi cantly less precise” at

higher GFRs, a particular concern in early DKD when elevated GFR—also known as hyperfi ltration—may exist.

Although hyperfi ltration has been implicated in the development and progression of nephropathy, studies of this relationship have produced inconsistent results.

The report also underscored the importance and clinical utility of measuring albuminuria as a marker for kidney disease and cardiovascular disease risk. However, measurements for albuminuria have not been standardized and

have signifi cant imprecision, according to the authors. “The most common assays were compared with a recently developed

isotope dilution mass spectrometry assay and varied by approximately 40% across albumin concentrations from 13 mg/L to

1,084 mg/L,” they wrote. Compounding this imprecision, labs do not have a standardized way of reporting albuminuria and clinicians do not always understand how to interpret the results.

Still other issues with measuring and interpreting albuminuria include considerable intra-individual daily variation and “vagaries of study outcomes.” “A coeffi cient of variation of 40% has traditionally been reported for those with type 1 diabetes and an [albumin to creatinine ratio] of 30–300 mg/G creatinine,” according to the authors. Studies looking at albuminuria results have not taken a standard-ized approach, so some have used only a single urine sample, collected at various times of the day or at long periods between samples. The authors emphasize that ADA, NKF, and National Kidney Disease Education Program (NKDEP) recommendations all call for measuring albuminuria more than once, with two or three samples elevated during a 3-to-6 month period required to confi rm the diagno-sis of albuminuria.

The report notes that the NKDEP Laboratory Working Group and the National Institute of Standards and Technology already have stan-dardized creatinine measurements and are collaborating with the International Federation of Clinical Chemistry and Laboratory Medicine to standardize urine albumin measurements and reporting. Despite these efforts “residual impre-cision” in both biomarkers “makes it likely” that other biomarkers will be used in future, more precise predictive tools.

The authors cautioned clinicians about basing prognosis on a single biomarker measurement, yet they note that the American College of Physicians has challenged the concept of serial albuminuria monitoring in patients taking renin-angiotensin-aldosterone system antagonists. The report also suggests that it might be preferable to report urine albumin as a continuous variable.

7DECEMBER 2014

Finally, the authors cite eight issues ripe for future clinical research including reporting cutoffs to defi ne normal albuminuria, sex-specifi c cut-offs to identify patients at increased risk for cardiovascular disease, and whether albuminuria should be the primary endpoint in clinical trials to establish an evidence base for ongoing monitoring.

■SERIAL ANCA MEASUREMENT PREDICTS RELAPSE IN ANCA-ASSOCIATED VASCULITIS

Dutch researchers recently found that serial increases in anti-

neutrophil cytoplasmic antibody (ANCA) were associated with relapses in ANCA-associated vasculitis, particularly in patients with renal involvement (J Am Soc Nephrol 2014; doi:10.1681/ASN.2013111233). Although ANCAs play an important role in ANCA-associated vasculitis, measuring ANCA levels during follow-up to predict relapse is controversial.

The investigators followed 166 patients with ANCA-associated vasculitis for an average of 49 months and 18 ANCA measure-ments. In all, 74 patients relapsed. At the time of a major relapse, all 26 such patients were ANCA-positive, and in 24, the relapse was preceded by an ANCA rise.

Rises in ANCA were most strongly correlated with relapses among patients who had renal involvement, defi ned as showing on biopsy pauci-immune necrotizing glomerulone-phritis. In these patients, longitudinal increases in ANCA were correlated with an 11.09 hazard ratio for relapse. Rises in ANCA overtime did not have as strong a correlation for relapse in patients without renal involvement, yielding a 2.79 hazard ratio.

The authors suggested that serial monitoring of ANCA levels could help better manage patients with ANCA-associated vasculitis. “By measuring ANCA levels in patients with kidney involvement, doctors can predict which patients are going to relapse. It is expected that by using ANCAs as a guideline, severe relapses necessitating dialysis can be

prevented,” said senior author, Jan Willem Cohen Tervaert, MD, PhD, in a prepared statement.

■PSA SCREENING STILL NOT IN LINE WITH CURRENT RECOMMENDATIONS

In recent years, medical associations and other healthcare groups have

revised their guidelines on prostate-specifi c antigen (PSA)-based screening for prostate cancer, recommending more restrictive use of PSA than in prior guidelines. However, the effects of these changes, such as not routinely screening elderly men, have been “minimal at best,” according to new research (JAMA Intern Med 2014; doi:10.1001/jamainternmed.2014. 4117).

The authors analyzed data from the 2012 Behavioral Risk Factor Surveillance System to gauge current

nation-wide patterns of PSA screen-ing. Of 114,544 men 50 years and older, 37.1% reported having under-gone PSA screening within the past year. Factors associated with the highest rates of screening included: having access to regular healthcare; income greater than $75,000; college education; health insurance; and being age 70 to 74. After adjustment for covariates, the highest self-reported rate of screening was among men in Hawaii (59.4%) versus the lowest in New Hampshire (24.5%).

Contrary to current guidelines advising against the practice, 45.7% of men ages 75 to 79 reported undergoing PSA screening within the preceding year. The researchers also noted wide state-by-state variances in screening rates. “It is alarming that the prevalence of PSA screening can double from one state to the next,” they wrote.

■

GUIDELINE ENDORSES EGFR AND ALK MUTATION TESTING

IN ALL PATIENTS WITH LUNG ADENOCARCINOMA

The American Society of Clinical Oncologists (ASCO) recently endorsed a previously published guideline on molecular testing for

selecting patients with lung cancer for therapies targeting epidermal

growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) (J

Clin Oncol 2014; doi:10.1200/JCO.2014.57.3055). The guideline, originally

developed by the College of American Pathologists (CAP), International

Association for the Study of Lung Cancer (IASLC), and Association of

Molecular Pathologists (AMP), was fi rst published in 2013 (Arch Pathol Lab

Med 2013;137:828–60).

In endorsing the CAP/IASLC/AMP guideline, ASCO noted that the

document represents an important advance towards standardizing EGFR

and ALK testing practices. Up to 20% of patients with lung adenocarcinoma

will test positive for either EGFR or ALK mutations.

The guideline recommends testing for EGFR and ALK in all patients with

lung adenocarcinoma or mixed lung cancers with adenocarcinoma

component. Labs should validate their EGFR testing method to ensure that

EGFR testing detects mutations in samples with as few as 50% tumor cells.

However, the guideline encourages sensitivity to detect mutations in samples

containing >10% tumor cells. Labs should turn around EGFR and ALK

mutation test results within 5 to 10 working days. Immunohisto-chemistry for

total EGFR, EGFR copy number, and ALK real-time polymerase chain reaction

testing are not helpful as predictive assays for treatment selection.

8 DECEMBER 2014

The Hunt for Early Pancreatic Cancer DiagnosticsPROMISING 4-MARKER PANEL ILLUSTRATES HOPES, LIMITATIONS OF CURRENT RESEARCH

BY GENNA ROLLINS

Inroads in treating many cancers have largely bypassed pancreatic cancer, which remains one of the most lethal: in the United States about 46,000 people are diagnosed each year

and about 40,000 die from it. The challenge in changing this discouraging track record has been that nearly all patients are diagnosed well into the disease process, now thought to progress for up to 2 decades. Despite rigorous research efforts, so far no validated biomarker with suffi cient sensitivity or specifi city has surfaced to make it a serious screening or diagnostic contender.

9DECEMBER 2014St

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cancer really has to have very strong operating characteristics, with very high positive- and negative-predictive values. We’re talking percentages in the high 90s, even 100, to really make this both clinically effective and cost-effective,” said James Farrell, MD, director of the Yale University Center for Pancreatic Diseases in New Haven, Connecticut.

“The challenge really rotates around the fact that this is not a high-prevalence cancer. So if you start getting false-positives, you’re basically going to put a lot of patients through unnecessary anxiety and testing. On the other hand, you don’t want to miss any patients who actually have the disease,” he added. A population-based screening test with even an impeccably high specifi city like 99% still could lead to an abundance of false-positives, with all the attendant follow-up testing to rule-out disease.

The other issue is how early in the disease process any biomarker would accurately distinguish pancreatic cancer, when it might be surgically resectable. Taguchi emphasized that a strength of his fi ndings is that samples were from patients with early-stage disease, whereas most studies looking at CA 19-9 have been from individu-als in later stages.

Whom to Screen?Some researchers place narrowing the potential screening population on equal footing with fi nding robust diagnostics. “Unless we can identify appropriate groups for screening, the predictive value of any test is not likely to be adequate for wide-spread population-based screening,” said Steven Leach, MD, director of the David M. Rubenstein Center for Pancreatic Cancer Research at Memorial Sloan-Kettering Cancer Center in New York City.

Others argue that merely detecting early stage disease among high-risk patients is not the only hurdle any clinically useful marker will need to clear. “Identifying patients who have favorable tumor biology would be fairly important so we would know who would benefi t most from

aggressive treatment,” explained Jashodeep Datta, MD, Harrison post-doctoral research fellow at the University of Pennsylvania Perelman School of Medicine in Philadelphia.

On the HorizonWith these stringently high standards against the backdrop of a relentless disease, is there reason to expect that a biomarker or biomarker panel will be useful anytime soon in detecting pancreatic cancer when it is treat-able? Despite the seemingly long odds, researchers still have high hopes. “There has been a tremendous amount of work over the last 10 years that has inspired a lot of smart people to get into the fi eld. It’s one of the most intensely researched cancers now. That’s where the optimism comes from,” says Farrell.

He was not alone in suggesting that it will be key to keep an open mind not only about candidate pro-teins but also markers refl ecting other aspects of pancreatic cancer patho-physiology. “Protein-based markers potentially are easier to translate into the clinical setting. But we also know that there are about four to fi ve canonical genetic mutations in the progression from normal pancreas to cancer, so exploiting that knowledge and the associated pathways, whether at the DNA or RNA levels, certainly would be helpful,” explained Anil Rustgi, MD, chief of gastroenterology at the Perelman School of Medicine. He also cited as potentially useful any biomarkers that could capture the robust fi brotic response that takes place once pancreatic tumors begin spreading into surrounding tissue, as well as those that might catch tumor cells as they disseminate rapidly throughout the body.

Leach added that while proteins might have an edge right now, “this may be more a function of cost and technology rather than biology, and cost and technology can obviously change rapidly.” Indeed, Taguchi’s team already is collaborating with other researchers at MD Anderson, exploring the diagnostic power of microRNAs and autoantibodies.

Carbohydrate antigen (CA) 19-9—the only biomarker cleared by the Food and Drug Administration to monitor pancreatic cancer progress—is a problematic tool for screening or diagnosis because it also is elevated in other diseases such as diabetes and chronic pancreatitis, and up to 15% of people don’t produce this glycopro-tein. Given all these factors, the pancreatic cancer scientifi c community took note of research presented earlier this year at an American Association for Cancer Research conference on pancreatic cancer.

Ayumu Taguchi, PhD, MD, and his colleagues at The University of Texas MD Anderson Cancer Center in Houston reported that a panel of four biomarkers proved better than CA 19-9 alone in distinguishing samples from subjects with pancreatic cancer from those of healthy individuals, those with chronic pancreatitis, and those who had pancreatic cysts, correctly identifying 92%, 85%, and 92%, respectively. In a logistic regression model, the area under the curve of the four biomarker panel—comprised of CA 19-9 and three other not publicly named markers—was 0.80, compared with 0.76 for CA 19-9 alone.

The four-analyte panel also correctly identifi ed as negative for pancreatic can-cer 94%, 90%, and 91% of samples from healthy individuals, those with chronic pancreatitis, and those with pancreatic cysts, respectively.

“In our training set, CA 19-9 showed high specifi city; however it still failed to identify 40 percent of pancreatic cancer samples. We then developed a decision tree model which included CA 19-9. The performance in the fi nal training set was signifi cantly improved over CA 19-9 alone, identifying 22 out of 23 pancreatic cancer patients,” recalled Taguchi, an assistant professor of translational molecular pathology at MD Anderson. “Even so, I think our biomarker panel is still preliminary.”

Beyond RobustThough heartened by Taguchi’s fi nd-ings, other pancreatic cancer specialists agreed that this line of research needs to be fl eshed out more. “Any sort of blood marker that is identifi ed for pancreatic

Any sort of blood marker that

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10 DECEMBER 2014

BY BILL MALONE

After concern over the spread of Ebola grew in the U.S. this fall, many laboratorians spent hours online dutifully

clicking through the Centers for Disease Control and Prevention (CDC) website, as well as reviewing guidance from other organizations, such as the World Health Organi-zation (WHO), American Society for

Microbiology (ASM), and others. What greeted laboratorians’ tired eyes was a patchwork of sometimes vague or even confl icting advice, leaving them with nagging questions about what was safe.

As the number of U.S. cases increased—from 2 in early August, to 9 by the beginning of November—CDC moved swiftly to offer extra help to hospitals and reassure the

public. On October 20, the agency issued stricter guidelines for the personal protective equipment (PPE) that healthcare workers who treat patients with Ebola should wear. But for clinical labs, CDC has left the practical, detailed planning up to hospitals. Pressing laboratory-specifi c problems—such as which instruments to use, or how to decontaminate them—remain in the do-it-yourself category. At CLN press time, CDC’s recommendations for labs receiving samples from patients suspected of Ebola infection boiled down to fol-lowing standard precautions, and as an added provision, using a certifi ed class II biosafety cabinet or splash guard with PPE that protects skin and mucous membranes.

With the exception of phlebotomy, laboratorians are not exposed directly to patients; however, the laboratory’s instruments and environment create distinctive risks that are still not fully understood, noted Lance Peterson, MD, a clinical professor of pathology at the University of Chicago Pritzker School of Medicine. “The labora-tory is unique in that we may need to be even more cautious in certain ways because we have the potential to create hazards that the patients themselves would not create,” he said. “There is every reason to believe that if you had a tube rupture in a centrifuge or other kind of aerosoliza-tion, such an exposure could lead to infection. So even though the virus is not aerosolized from the same stand-point as tuberculosis, if you create an aerosol in the laboratory, that risk is quite real.” A leading expert on infec-tion control, Peterson is also director of the microbiology and infectious disease research program for the NorthShore University HealthSystem in Evanston, Illinois.

LABS RACE TO PLAN WITH EVOLVING GUIDANCE AND MISSING DETAILS

CONFRONTINGEBOLA IN THE U.S.

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11DECEMBER 2014

Looking for AnswersAfter Liberian national Thomas Eric Duncan became the fi rst person in the U.S. diagnosed with the Ebola virus on September 30, anxiety soared in hospitals. AACC on October 7 held a webinar about laboratory practices for manag-ing suspected Ebola specimens with CDC Medical Offi cer Nancy Cornish, MD. During the webinar, which attracted some 1,600 partici-pants, Cornish enumerated the CDC resources that explain in great detail how laboratories should carry out precautions against infectious agents.

A number of agencies and offi ces in the federal government have promul-gated standards related to infectious agents over the years, including CDC’s National Institute for Occupational Safety and Health (NIOSH) and Healthcare Infection Control Practices Advisory Committee (HICPAC), as well as the Occupational Safety and Health Administration (OSHA) (See Box, below). However, Cornish advised that labs not depend solely on the government’s infection control library, but confer as well with experts about their specifi c circumstances. She warned that some of those answers could be surprising. “Laboratories should consult with an industrial hygienist, as well as instrument manufacturers,” Cornish said. “In one case, we asked a manufacturer how an instrument could be decontaminated, and the representative responded: incinerate it.”

Also speaking during the webinar, Yale University Laboratory Medicine Professor Sheldon Campbell, MD, emphasized that labs would face con-tinued uncertainty and the need for ongoing risk assessment. “Laboratories should plan for what’s reasonable right now, then reassess risk periodi-cally,” he said. “To reconcile confl icts among guidance documents, you have to assess risk in your own setting and patient population, and recognize that zero risk is unattainable.”

Early Lessons Learned From EmoryStaffed by physicians, nurses, and laboratory technologists who

volunteered for special duty, Emory University Hospital’s Serious Communicable Disease Unit in Atlanta has become known for treating the fi rst two patients with Ebola in the U.S. Emory in 2002 established this specialized isolation unit in collaboration with CDC to care for patients with unidentifi ed or highly contagious infectious diseases. In a Lab Medicine paper published in September, nine members of Emory’s laboratory medicine department out-lined the laboratory testing protocols used to treat these patients (Lab Med 2014;45:e109–11).

According to a co-author of the article, Colleen Kraft, MD, medi-cal director of the Emory Medical Laboratories microbiology section, the challenges the team faced can translate to other labs. Kraft advised a high level of caution and prepared-ness for any laboratory handling specimens from patients suspected of Ebola infection. “Based on our expe-rience, I do not think that testing for patients with Ebola should be done in a central lab. There are enough guidelines, such as from WHO and the Australian Department of Health, that state that if you have Ebola virus in a line where you’re running other samples, you need to decontaminate that line. So a separate, enclosed lab is safest,” Kraft said. “I know that this could be an unpopular opinion, but patients with Ebola have extremely high viral loads and the handling of these specimens is critical.”

As part of the team caring for patients with Ebola at Emory, Kraft worked 60 hours per week in the unit, in addition to her regular full-time job. Her main message for labs: expect the unexpected. “Our team performed drills for 12 years, and we still didn’t really grasp how much work it would be until we were dealing with the real thing,” she said. “Caring for these patients takes an immense amount of personnel, containment practices, and training. And we’re also always watching each other to make sure that there is no safety protocol breach. This isn’t a casual investment.”

The Rush to Point-of-Care TestingBased on reports from laborato-ries around the country posted on AACC listervs and from telephone interviews with CLN, it appears that many have already drawn up plans for treating patients suspected of having Ebola using only point-of-care (POC) instruments, both to limit transporting infectious samples and to avoid dealing with decontamina-tion of complex and expensive central laboratory analyzers. Both ASM and New York State Department of Health guidelines suggest considering this option. CDC does not recommend limiting testing to POC, but assures labs that they can handle specimens safely following standard OSHA guidelines and using proper PPE.

Peterson recommended the New York State guide-line as a practical start-ing point for labs. “Each laboratory will have to modify this and determine whether they will perform point-of-care testing at the patient bedside or carefully transfer specimens to one or two contained areas in the laboratory. We’re going to do the second,” he said. “But we are not going to put these specimens on the line. We will use several bench-top instruments that are locked shut so there is no potential aerosolization.” A key issue is how much the lab realisti-cally can decontaminate, he added.

So far, manufacturers have been cautious when it comes to Ebola. One company circulated a letter to customers stating that while its

AACC has curated a list of Ebola resources online, including

guidance documents, fact sheets, an on-demand webinar, and a members-only Ebola listserv.www.aacc.org/health-and-science-policy/ebola

To reconcile confl icts among guidance documents, you have to assess risk in your own setting.

12 DECEMBER 2014

“diagnostic instruments are gener-ally designed to prevent formation of sample aerosols during testing, [the manufacturer] cannot provide assurance that dispersion of infec-tious disease agents, including Ebola virus, is completely prevented during specimen testing or if an instrument malfunctions or is misused.”

Patti Jones, PhD, clinical direc-tor of the chemistry and metabolic disease labs at Children’s Medical Center of Dallas and professor of pathology and medical laboratory science at UT Southwestern Medical Center, explained her lab’s plans as follows. Staff will use handheld POC instruments in patient rooms. However, healthcare workers work-ing in a buddy system will use full isolation PPE—including powered air purifying respirators—with a

multi-step system for donning and doffi ng. The POC instrument will be used for electrolytes, blood urea nitrogen, creatinine, ionized calcium, and blood gases. Other testing will be performed on a benchtop instrument in a special mini-lab.

Children’s Medical Center was designated as the hospital in Dallas where any infected children would be cared for after CDC discovered that eight had been in contact with

Thomas Eric Duncan. The hospital created an isolation zone by clearing an intensive care unit wing with two negative-pressure patient rooms and a room two doors away to serve as the mini-lab.

Jones also noted that the primary handheld POC instrument the hos-pital chose was not FDA-cleared for performing prothrombin time testing outside of Coumadin monitoring, so her laboratory performed an exten-sive validation in order to be able to use it for patients with Ebola. “Doing this causes the test to be designated as high-complexity under CLIA,” Jones explained. “Therefore, only those individuals with appropriate licen-sure, training, and competency will be performing the test.”

Practice Your PlanExperts agreed that laboratories should not be working alone, and that simply getting a plan on paper is not enough. “My advice is to get ahold of New York state guidance and then work with your emergency and infec-tion control departments to identify two or three core people who will make the decision on who is a high-risk person,” Peterson said.

Practice is also essential, Peterson emphasized, especially to pick up on any roadblocks not specifi ed in the plan. For example, Emory and other hospitals were surprised when waste disposal vendors balked at offering service. “You must practice your plan because those specimens are going to show up in the laboratory. It’s going to happen,” Peterson said.

A realistic and straightforward plan is also key, Campbell emphasized during the AACC webinar. “A simple plan that’s well-implemented by trained staff is better than a complex plan that’s badly implemented.”

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The use of automation and robotics has become pervasive in clinical laboratories around the world. Laboratories face unrelenting pressure to produce faster turnaround times and reduce errors to improve patient care. Since the development of the continuous fl ow analyzer in the 1950s, laboratory automation has continued

to evolve and expand its capabilities to become an indispensable necessity. Current technologies can automate specimen transportation, sorting, accession-ing, and inspection.

As pressure has increased to cut healthcare costs over the last decade, labo-ratories have relied on automation to maintain profi tability as well. Laboratory automation is designed to maximize effi ciency and minimize errors by integrat-ing mechanical, electronic, and informatics tools to perform an ever expanding variety of laboratory tasks. Following the installation of automation error reduc-tion rates exceed 70%, while staff time per specimen collection is reduced by over 10%. Patient safety is increased by an average 50% reduction in specimen turnaround time directly attributable to automation.

Currently, more than 30% of laboratories in Japan, Europe, and North America have implemented a signifi cant degree of central laboratory automa-tion. In addition, many laboratories report that automation creates excess capac-ity to expand testing without the need to increase their workforce. As a result, the proper sizing of laboratory automation systems with current and anticipated testing volume is important.

ADVANCES IN CLINICAL LABORATORY AUTOMATION

Defi ning the STATE OF THE ARTThere is virtually no limit to the number and complexity of tasks that can be automated. For example, at least one company is currently working to automate phlebotomy(1). Called the Veebot, this instrument would locate forearm veins and then chart the trajectory for a needle-wielding venipuncture robot. Failed venipunc-ture procedures can injure patients due to so-called bad veins. In fact, nearly 25% of procedures fail to draw blood on the fi rst attempt, and almost a million needle stick injuries are reported each year (2).

Modern laboratory automation resembles a traditional assembly line, termed total laboratory automation (TLA). TLA consists of a specimen sorter that can sort specimens by ana-lytical needs and transport specimens requiring serum or plasma testing to an automated centrifugation station

BY ROBIN A. FELDER, PHD

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15DECEMBER 2014

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• Specimen TransportationDespite the variety of methods of transportation currently available, all have considerable fl aws. Human and robotic courier services have infl ex-ible pickup times and delays, while pneumatic tube systems have poten-tial for specimen damage and limited carrying capacity (4). Electric track vehicles reduce the damage risks of tube systems and the lack of fl exibil-ity from the courier service, but they take up large amounts of space.

One alternative is automated specimen delivery using mobile robots that can negotiate the halls of a hospital (5, 6). Once in the laboratory, the robot can automati-cally deliver its payload and continue service without having to interrupt a laboratory technologist (7).

In the near future, drones may provide both extra-laboratory as well as inter-laboratory delivery. A drone’s ability to rapidly move small numbers of specimens from a clinic to a laboratory can avoid automobile traffi c delays. Inside a laboratory, drone deliveries can make a 200 foot journey in less than 2 seconds, according to Donald Nagy, CEO of California Computer Research and member of the Society for Laboratory Automation and Screening.

• Pre-Analytical AutomationOnce specimens arrive in the labora-tory there are new pre-accession processors that can start with a bucket of randomly oriented speci-mens and fi nish with racked and processed specimens for downstream analytical processing. Researchers at the University of Utah are develop-ing an automated specimen inspec-tor that examines critical specimen quality issues such as proper labeling, suffi cient volume, and correct vial additive. In the future, the inspector will also determine the presence of lipemia, icterus, or hemolysis through several overlaid labels (8).

From the inspector, next-generation linear motor conveyors will transport the tubes very rapidly: 3,000–18,000 tubes an hour moving at a rate of 20–120 meters a second.

The system will also employ an auto-mated sorting area where specimens can be automatically centrifuged or passed on directly to the hematology/coagulation robotic area, according to Charles D. Hawker, PhD, MBA, FACB, scientifi c director of automa-tion and special projects at ARUP Laboratories. Essentially the entire accessioning process will be auto-mated so that time from phlebotomy to result will be 30 minutes or less.

• Sample LabelingMistakes in sample labeling can lead to sample misplacement and mislabel-ing, resulting in a loss of samples and

inaccurate results. The progression from manual labeling to 2- and 3-D barcodes has dealt with many labeling problems and signifi cantly cut down on sample misplacement and misla-beling. However, the development affordable radio-frequency identifi ca-tion (RFID) is poised to allow positive passive specimen tracking as samples are moved from patient bedside to analysis. While barcodes often require manual scans, RFID completely eliminates human involvement. Reduced costs for the technology, and advantages such as error reduction and reduced labor demand, have put RFID in the spotlight at the Mayo Clinic and other organizations (9).

DISRUPTIVE Analytical Methods and TrendsSeveral emerging methods closely related to laboratory automation are poised to shift the landscape of

for processing. Following sample separation the serum or plasma is then transported for sampling to various chemistry and immuno-assay analyzers. The sorter can also identify whole blood specimens and convey them to automated instruments for complete blood counts and other hematology testing. Remaining specimens are automatically sent to racks that are specifi c for each analytical platform. These specimens can then be manually transported and inserted into the instrument of choice.

Currently, approximately 80% of the testing and only about 50% of the manual labor performed in a clinical laboratory is impacted by automation, leaving many opportunities for novel automation technologies in sample collec-tion, centrifugation, accessioning, sample inspection, transportation, and more.

A Look at the FUTUREGiven that automation is becoming a commodity in larger laboratories, laboratorians need to stay up-to-date on new opportunities. For each area below, I forecast what form laboratory automation may take in the future, perhaps in the next decade or two.

• Automated Specimen SeparationBlood separation into serum or plasma has been an insuperable bottleneck in all clinical laboratories. Ideally, sample separation should be done at the point of sample collection and incorporate automated labeling. An elegant point-of-care separa-tion solution, the Axial Separation Module, was developed for separating formed elements from plasma in a whole blood specimen in under one minute immediately after phlebot-omy (3). Unfortunately, this technol-ogy failed to gain market acceptance. Similar technologies are under devel-opment that uses creative means to impart increased centrifugal forces on the blood specimen. Hopefully, some of these will be commercialized in the near future.

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17DECEMBER 2014

laboratory testing. In addition, the push for expanding biobanking and home monitoring cannot be ignored.

• MicrobiologyThe most disruptive use of automa-tion in the laboratory will come in the form of rapid sequencing of entire microbe DNA/RNA. Advanced computer software can identify each individual organism in an infection, as well as the organism’s suscep-tibility to specifi c antimicrobials. Technologies such as Ion Torrent, Myseq, ionPGM, and PackBio are already demonstrating improved turnaround time and positive microbe identifi cation in clinical settings. Coupled with software algorithms that can match DNA/RNA sequences with those from known pathogens, these technologies might one day replace much of today’s conventional microbiological laboratory procedures similar to the Lawrence Livermore Microbial Detection Array (10).

• Cell Based AssaysAnother disruptive technology will be the use of living cells from patients as diagnostic tools. Cell-based assays are being used for diagnosis, as well as predicting clinical outcomes and response to therapy in an increasing number of diseases including cancer, organ rejection, and diabetes (11). Exfoliated organ cells have the poten-tial to supplement current biomarker-based analyses since cell-based assays can measure aberrations in cell activ-ity that may be present in complex chronic diseases. For example, salt sensitivity of blood pressure is a major public health challenge and a disease for which there is no convenient diag-nostic test. We demonstrated that cells isolated from urine in normal subjects not only provided a personalized cell-based diagnostic test for salt sensitiv-ity, but also provided a personal salt index, which is the amount of sodium each person should safely consume in a day (12). Like conventional analyti-cal techniques, cell based assays will be readily automated when suffi cient volume justifi es the investment.

• BiobankingBiobanking is the process of storing left over medical specimens along with data describing the phenotype and

genotype of the patient from which the specimen was obtained. This material is valuable to diagnostic and pharmaceutical companies for research and development. Most of the steps in biobanking have been automated, such as specimen aliquoting, labeling, freez-ing, and storing. Even the retrieval of selected specimens in order to prepare a disease representative cohort can be

automated using “cherry pickers” that operate at freezing temperatures. Thus, automation can turn medical waste (i.e. leftover medical specimens) into profi t for the laboratory and tools for researchers.

• The Final Frontier: Home-Based MonitoringMonitoring is pervasive with the

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advent of wearable sensors that communicate with smartphones. The hope is that individuals will use this medical data to adopt healthier lifestyles. Increasingly, biomarkers in body fl uids will also be the target of ubiquitous personal sensors. For example, Google recently announced that it was developing a contact lens that would measure glucose secreted in tear fl uid in order to provide pas-sive sensing for diabetic patients. Similar technology is being developed in a more convenient “insertable” and therefore body resident format (13). The future will provide an ever broadening number of biomarkers—such as cortisol for stress monitor-ing—and physiologic parameters that will guide lifestyle choices.

ConclusionLaboratory automation has become a well-accepted technology that allows high quality, effi cient, and patient-centric operation with low operating costs. Automation should also be the foundation on which a Six Sigma program can be built and maintained. Technological advances will increase the number of labora-tory unit operations that can be either partially or fully automated. Near patient or personal wellness test-ing should be considered an exten-sion of the laboratory automation enterprise.

References 1. Boyd JC, Hawker CD. Automation

in the clinical laboratory. In: Burtis CA, Ashwood ER, Bruns DE, eds. Tietz textbook of clinical chemis-try and molecular diagnostics. 5th Ed. Phildelphia: W.B. Saunders 2012:469–85.

2. Occupational Safety & Health Administration. Healthcare wide hazards: Needlestick/sharps injuries. http://www.osha.gov/SLTC/etools/hospital/hazards/sharps/sharps.html (Accessed October 2014).

3. Estey CA, Felder RA. Clinical trials of a novel centrifugation tech-nique: Axial separation. Clin Chem 1996;42:402–9.

4. Felder RA. Preanalytical errors introduced by sample-transportation systems: A means to assess them. Clin Chem 2011;57:1349–50.

5. Rosetti MD, Kumar A, Felder RA. Simulation of robotic courier deliveries in hospital distribution services. Health Care Man Science 2000;3:201–13.

6. Felder RA. Laboratory systems integration: Robotics and automation. Ann Biol Clin 1991;49:298–300.

7. Patent US6543983 B1 - Robotic pickup and delivery system. http://www.google.com.ar/patents/US6543983 (Accessed October 2014).

8. Hawker CD, McCarthy W, Cleveland D, et al. Invention and validation of an automated camera system that uses optical character recognition to identify patient name mislabeled samples. Clin Chem 2014;60:463–70.

9. ODIN. ODIN introduces EasySpecime RFID-based lab tracking solution. http://odinrfi d.com/odin-introduces-easyspecimen-rfi d-based-lab-tracking-solution (Accessed September 1, 2014).

10. Dark Daily. http://www.darkdaily.com/researchers-at-livermore-national-laboratory-develop-microbial-detection-array-capable-of-detecting-thousands-of-known-and-unknown-pathogens-in-a-single-rapid-test#axzz3HTavrFO5 (Accessed October 28, 2014).

11. Rahmoune H, Thompson PW, Ward JM, et al. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes 2005;54:3427–34.

12. Gildea JJ, Lahiff DT, Van Sciver RE, et al. A linear relationship between the ex-vivo sodium mediated expression of two sodium regula-tory pathways as a surrogate marker of salt sensitivity of blood pressure in exfoliated human renal proximal tubule cells: The virtual renal biopsy. Clin Chim Acta 2013;421:236–42.

13. Patent US8090426 B2 - Micro elec-tronic biosensor plug. http://www.google.com/patents/US8090426 (Accessed October 2014).

Robin Felder, PhD, is a professor of pathology and associate director of clinical chemistry at the University of Virginia Health System in Charlottesville, Virginia and chair of MedicalAutomation.org. +EMAIL: rfelder@virginia.edu

THE IDEAL AUTOMATION BLUEPRINTWhen fi rst considering the purchase of a fully automated laboratory, the layout of the laboratory and shape of the room is critical for maximizing the return on investment. The ideal physical plant and layout for an automated clinical laboratory is a linear “bowling alley” design.

• Specimen arrivals should take place at the proximal end of the laboratory where accessioning can occur immediately after unpacking, and the automated sorter should be readily accessible at the end of the accessioning line.

• Each analytical automation line should run in parallel so that bench scientists can service several analytical areas with as few steps as possible.

• Completed specimens should be automatically stored at the distal end of the laboratory conveyor belt so that they may participate in refl ex, repeat, or add-on testing without human intervention. Automated specimen refrigerators (4°C) and freezers (either -20°C or -80°C) are available that are capable of performing these tasks.

• Laboratories that anticipate making their medical waste available for research may install automated aliquoting and labeling systems, as well as biorepository-sized automated storage systems.

• Delivery and storage of analytical reagents is ideally accomplished in a bank of refrigerators/freezers with doors on both sides of the laboratory installed parallel to the analytical systems they serve. Stocking occurs from the back of each unit and retrieval of reagents from the front.

• Finally, medical and reagent packag-ing waste should exit the laboratory at the distal end, accessible to automated pickup carts and vehicles.

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20 DECEMBER 2014

RegulatoryRoundup

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Medicare Awards Coverage to Molecular Breast Cancer Test From BioTheranosticsBioTheranostics’s Breast Cancer Index test has received Medicare coverage, making it the only molecular test covered by Medicare that assesses a patient’s risk of late distant breast cancer recurrence and identifi es which patients will benefi t from extended hormone therapy. The Centers for Medicare and Medicaid Services posted a positive coverage and reimbursement policy after evaluation by Palmetto GBA, the Medicare administrator responsible for the MolDx molecular diagnostic technology assessment program. This policy covers use of the test to predict risk of breast cancer recurrence after 5–10 years in women with early stage, estrogen receptor-positive breast cancer who are considering extended endocrine therapy but are concerned about its documented toxicity or possible

patient-specifi c side effects. About two-thirds of breast cancer patients are estrogen receptor-positive, and the risk of late distant recurrence in these women is a substantial concern, with more than 50% of recurrences arising after 5 years.

In addition to new claims, Medicare coverage and payment for the Breast Cancer Index test will be made retroactively for previously submitted claims. The Medicare coverage decision was based on a review of the scientifi c evidence supporting the analytical validity, clinical validity, and clinical utility of the test. It is one of the fi rst coverage

determinations for a molecular cancer diagnostic technology handed down by the rigorous evaluative process implemented by Palmetto GBA since the inception of MolDx in 2011.

■TWO BIOFIRE EBOLA TESTS RECEIVE EMERGENCY USE AUTHORIZATION FROM FDA

The Food and Drug Adminis-tration (FDA) has granted

Emergency Use Authorization to BioFire Defense for its commercial FilmArray Ebola test—the BioThreat-E test—as well as for a second Ebola test to be used by laboratories designated by the Department of Defense. The FilmArray BioThreat-E is the fi rst commercial Ebola test to be authorized for emergency use on patients with signs and symptoms of Ebola Zaire virus infection in conjunction with epidemiological risk factors. It is available to high and moderate complexity clinical laboratories in the U.S. and can be run on any existing BioFire

FilmArray system, which is in routine use in more than 300 hospitals. Previously cleared by FDA, the FilmArray system is a PCR-based diagnostic device that can identify pathogens in 1 hour, enabling health professionals to make rapid treat-ment decisions.

The BioThreat-E test has not received FDA clearance or approval, and is only authorized for the duration of the declaration that circumstances exist justifying emergency use tests for the detection of Ebola Zaire virus.

■ABBOTT GRANTED CE MARK FOR MOLECULAR TUBERCULOSIS TEST

Abbott has received CE mark approval for a molecular

diagnostic test for the detection of

Mycobacterium tuberculosis (MTB), which causes tuberculosis. Tuberculosis continues to be a major public health threat, with the World Health Organization estimating that 8.6 million people developed the disease in 2012. Of these, an estimated 1.1 million are also HIV-positive, due to the fact that individuals with compromised immune systems are at a higher risk of developing TB. Abbott’s MTB test is performed on the automated m2000 molecular diagnostic testing system and consolidates HIV-1 and MTB tests on the same platform. Abbott intends for this test to help reduce the global burden of infec-tious diseases in high prevalence areas like Africa, where 75% of TB-HIV co-infections occur.

21DECEMBER 2014

Additionally, an MTB inactivation step is included with the test procedure to reduce the risk of infection caused by airborne exposure to MTB during handling of sample material.

■FDA CLEARS QUIDEL ADENOVIRUS ASSAY

Quidel Corporation has received FDA clearance for its Lyra

Adenovirus assay, a real-time PCR test for the qualitative detection of human adenovirus DNA isolated from nasal swab and nasopharyngeal swab specimens. Adenovirus infections can cause several illneseses and symptoms, such as colds, sore throat, bronchitis, pneumonia, diarrhea, pink eye, and fever.

Quidel’s Lyra Adenovirus assay is part of the company’s new Lyra brand of ready-to-use, molecular PCR reagent kits that are designed to be compatible with a laboratory’s existing thermocycler. These kits provide ready-to-use master mix and refrigerated storage of key reagents, in addition to yielding quantitative PCR results within 75 minutes.

■NANOSPHERE ENTERIC PATHOGENS TEST RECEIVES FDA CLEARANCE FOR NEW VIRAL TARGETS

FDA has cleared new viral targets for Nanosphere’s Verigene

Enteric Pathogens Nucleic Acid test (EP) in addition to the bacterial and toxigenic targets the agency cleared earlier this summer. Verigene EP is a rapid alternative to traditional stool diagnostics that has the potential to reduce the use of unnecessary or inappropriate antibiotics by enabling clinicians to make informed patient treatment decisions earlier. Designed on the Verigene system, it uses Nanosphere’s core proprietary gold nanoparticle chemistry to offer highly sensitive, highly specifi c molecular diagnostic results through multiplexing, and detects infectious pathogens and drug resistance markers by targeting conserved genetic regions of a bacterium or virus.

■BECKMAN COULTER GETS FDA NOD FOR AUTOMATED SAMPLE PROCESSING SYSTEM

FDA has granted Beckman Coulter 510(k) clearance for its

Power Express high-speed automated sample processing system, which processes samples for all core disci-plines: chemistry, immunoassay,

hematology, and coagulation. The Power Express provides connected automation by combining Beckman Coulter’s AU clinical chemistry system, the UniCel Dxl 800 immuno-assay system, and third-party connec-tion capabilities, including coagula-tion. The company also plans to include hematology solutions in the system later this year.

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22 DECEMBER 2014

Industry Playbook

New Kalorama Report Finds Proteomics a Booming Segment of the Diagnostic MarketThe market for proteomics instruments, reagents, and testing for research and diagnostic applications topped $5 billion in 2013, and should continue to see rapid revenue growth, according to Kalorama Information. Demand for a better understanding of proteins and a desire for new therapies is expected to drive this growth, despite the cost pressures that research is facing in general. This fi nding was discussed in Kalorama’s latest report, “Proteomics Markets for Research and IVD Applications.”

As part of the Human Genome Project, researchers identifi ed and mapped more than 20,000 genes in the human genome. However, the proteins encoded

by these genes were not all identifi ed and characterized. Kalorama notes that this is an enormous undertaking. While the genome is fi xed, the proteome changes in response to various factors, such as those that affect which genes are expressed. “It’s enormously diffi cult to study proteins, but hard-fought discoveries made in the research enable biomarker discovery, drug discovery, new IVDs, and personalized solutions,” said Bruce Carlson, publisher of Kalorama Information.

Many different types of technologies are being used to study proteins, with mass spectrometry, antibodies (or antibody capture), and knowledge bases serving as the three technological pillars of the Human Proteome Project. Kalorama predicts a bull market for these technologies in the future. The

report also foresees that technological advances in proteomics will continue to move gradually into the clinical laboratory. This will include advances in technologies for the detection and identifi cation of proteins, as well as the use of novel biomarkers in diagnostic assays.

■LABCORP INKS DEAL TO BUY COVANCE

Laboratory Corporation of America Holdings (LabCorp) and Covance have entered an

agreement under which LabCorp will acquire Covance for approximately $5.6 billion. LabCorp provides medical laboratory testing services through a national network of primary clinical laboratories and specialty testing laboratories, while Covance is a drug develop-ment company with an additional focus on nutritional analysis. This merger will join LabCorp’s clinical testing expertise with Covance’s experience in contract research and drug development. It will also leverage technolo-gies that improve patient recruitment for clinical trials, enhance effi ciency in the conduct of clinical trials, and deliver data faster to drug

sponsors, physicians, and patients. Additionally, Covance’s risk-based patient monitoring tools will enhance LabCorp’s existing capabilities in predictive analytics, benefi tting at-risk patients, risk-bearing physicians, and payors. With this range of offerings, the combined company aims to advance personalized medicine, improve the development of therapeutics, and drive greater research and development productivity for its pharmaceutical customers.

■CHEMBIO TO DEVELOP POINT-OF-CARE TESTS FOR EBOLA, DENGUE FEVER, CANCER

Under the terms of a collaboration with Integrated BioTherapeutics (IBT), B

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es

DECEMBER 2014 23

Chembio Diagnostics will combine its patented DPP technology with IBT’s proprietary Ebola reagents to develop a standalone point-of-care (POC) test for Ebola and to include an Ebola test in the company’s existing multiplex DPP Febrile Illness assay. Compared with traditional lateral fl ow technol-ogy, which some companies are already using to develop Ebola POC tests, DPP technology offers increased sensitivity and the ability to run multiple tests on a single patient sample. “We are facing a humanitarian crisis and global public health challenge. Development of a rapid point-of-care test for Ebola will be a critical step towards enabling early detection and quarantine that could help save countless lives,” said M. Javad Aman, president and chief scientifi c offi cer of IBT.

Chembio has also entered two separate agreements with undis-closed collaborators to develop other POC tests: one for dengue fever and another for a type of cancer. Both projects will also use the company’s DPP technology, and the cancer project represents the fi rst applica-tion of DPP technology outside of the infectious diseases fi eld.

■SIEMENS AND INPECO TO AUTOMATE NEW QUEST DIAGNOSTICS MEGA-LABORATORY

Siemens Healthcare, in agree-ment with Inpeco, has won an

exclusive contract to automate a new clinical laboratory of Quest Diag-nostics in Marlborough, Massa -chusetts. This will be the fi rst com prehensive automation solution Quest has deployed in one of its regional mega-laboratories in the United States. When fully opera-tional next year, the customized automation solution will transform the Marlborough lab into a continu-ously operating laboratory plant, enable Quest to process several thousand patient blood samples an hour, and feature one of the largest high-speed automation tracks ever built, according to a prepared

statement from Siemens. This track, which is expected to be 200 meters long, will be designed to facilitate sample fl ow through processing, testing, and storage.

“We will realize the fi rst step toward a laboratory medicine facility with a totally automated and trace-able solution,” said Andrea Pedrazzini, president of Inpeco. “This system is designed to achieve the utmost effi ciency and decrease testing turn-around times by optimizing the entire tube fl ow, resulting in state-of-the-art patient care.”

■MAYO CLINIC, SECOND GENOME COLLABORATE ON MICROBIOME-BASED THERAPEUTICS

Second Genome and the Mayo Clinic Center for Individualized

Medicine have formed a partnership to develop therapeutic products for multiple disease indications, starting with infl ammatory bowel disease, metabolic disorders, and colorectal cancer. Under the terms of the agreement, Second Genome will identify up to eight clinical indications in which the microbiome has a potential role in disease and will collaborate on microbiome research with Mayo Clinic investigators who specialize in each of the designated disease areas. Mayo Clinic will then provide human clinical samples from patients in targeted disease areas, while Second Genome will also deploy its proprietary microbiom e discovery platform to identify biological pathways implicated in disease. Furthermore, Second Genome will use its platform to discover novel therapies that target these microbiome-mediated pathways.

“The microbiome is an important area of medical research for Mayo Clinic, and this collaboration repre-sents a broad and signifi cant effort in our attempt to develop therapeutics targeting microbiome-mediated pathways,” said Heidi Nelson, MD, director of the Microbiome Program in the Mayo Clinic Center for Individualized Medicine.

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AACC launched a redesigned website on November 17. The modern redesign makes it easy to quickly fi nd news, education, meetings, and other information.

As part of this redesign, AACC also launched a col-laborative online social community, AACC Artery. Using the Artery, AACC members will access a rich, interactive experience in collaborating with other leaders in labora-tory medicine and working with AACC Divisions, Local Sections, and specialty groups.

GET MORE details about the AACC website redesign at www.aacc.org/newdesign

NEWAACC WEBSITE

24 DECEMBER 2014

QAsk The Expert

Flagging Troponin

EXPERT

Amy Saenger, PhD, DABCC, FACB

and Laboratory Standards Institute (CLSI) EP28-A3c guideline. This guideline recommends a minimum of 120 reference subjects for nonpara-metric statistics to estimate limits of a central 95% reference interval with limits at the 2.5th and 97.5th percentiles. However, determining the 99th percentile for cTn differs from the CLSI recommendations. Both the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Task Force and the European Society of Cardiology recommend a total of 300 normal subjects to prop-erly determine the 99th percentile.

Furthermore, when evaluating sex and age differences by decade, a minimum of 300 subjects per group are needed, for example 300 males and 300 females. Subjects included in a cTn reference interval study should be deemed healthy via use of health questionnaires along with biomark-ers such as NT-proBNP and eGFR to screen for subclinical disease and/or other co-morbidities.

In summary, while expert opinion leaders and guidelines will continue to advocate for more precise and sen-sitive cTn assays, we should continue to follow guideline recommendations and use the 99th percentile to defi ne abnormal cTn results, placing empha-sis on serial acute changes to aid in diagnosing MI from chronic myocar-dial disease.

Amy Saenger, PhD, DABCC, FACB, is the senior cardiac medical and scientifi c affairs manager at Roche Diagnostics and associate professor of laboratory medicine and pathology at Mayo Clinic. +EMAIL: amy.saenger@roche.com

What troponin concentration should I fl ag as an abnormal result?

A: The Global Task Force for the Universal Defi nition

of Myocardial Infarction defi ned a cardiac troponin (cTn) > 99th percentile—derived from a normal, healthy reference population—as the decision threshold for the diagnosis

WHILE PRECISION remains an important parameter, it is not the only metric that defi nes utility of cTn assays.

of myocardial infarction (MI). The 10% coeffi cient of variation (CV) is defi ned as the optimal total impre-cision of cTn assays at the 99th percentile, as most contemporary cTn assays lack the ability to deliver a 10% CV at or below the 99th percentile, or the ability to measure cardiac troponin below the 99th percentile. However, assays with a CV < 20% are considered clinically acceptable and will not cause false-positive acute MI diagnoses, provided serial samples are used to interpret acute changes (Clin Chem 2005;51:2198–200). Today, defi ning a high-sensitivity cTn assay requires an imprecision of < 10% CV at the 99th percentile. Therefore, abnormal should only be defi ned at the 99th percentile as long as the CV is < 20%.

What are the clinical ramifi cations for not using the 99th percentile? Using the 99th percentile to defi ne abnormal cTn optimizes the clinical diagnostic sensitivity of cTn assays and current data supports cTn assays with imprecision up to a 20% CV for both diagnosis and/or risk stratifi ca-tion use. While precision remains an important parameter, it is not the only metric that defi nes utility of cTn assays. Furthermore, we now know that a sensitive cTn assay with slightly more imprecision will correctly identify more patients at risk than an insensitive one with excellent impre-cision (Clin Chem 2010;56:941–3). While one could achieve the 10% CV metric simply by increasing the assay threshold to defi ne abnormal results, the consequence would be a decrease in clinical sensitivity. Ultimately, using the 10% CV identifi es fewer patients with disease and increases the time after myocardial injury when a fi rst positive result would be identifi ed, delaying diagnosis of a true MI and impeding appropriate treatment.

What is the 99th percentile and how is it established? Traditional reference intervals for clinical laboratory assays are most commonly established with an approach consistent with Clinical

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