April 2015

ClinicalLaboratory

News

An AACC Publication | Volume 41, Number 4

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1CONTENTS

EDITORIAL STAFFManaging Editor Bill MaloneSenior Editor Genna RollinsCommunications Manager Christine DeLongContributor Elizabeth Palavecino, MD

BUSINESS STAFFManager of Business & Publications Marketing Camille Walker

Board of EditorsChair Lorin M. Bachmann, PhD, DABCCVCU Health System, Richmond, Va.MembersLinnea M. Baudhuin, PhD, DABMG

Mayo Clinic, Rochester, Minn.Joshua Bornhorst, PhD, DABCC, FACB

University of Arkansas, Little Rock, Ark.Elizabeth Palavecino, MD

Wake Forest Baptist Medical Center, Winston-Salem, N.C.

Pamela Steele, PhD, FACBRoche Diagnostics, Indianapolis, Ind.

Joely Straseski, PhD, DABCC, FACBARUP Laboratories, Salt Lake City, Utah

AACC OfficersPresident David Koch, PhD, DABCC, FACBPresident-Elect Patricia M. Jones, PhD, DABCC, FACBTreasurer Michael J. Bennett, PhD, DABCC, FACBSecretary David Grenache, PhD, DABCC, FACBPast President Steven H. Wong, 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 © 2015 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 Reimbursement Outlook for Molecular Diagnostics

Shifting Policies, Market Demands Trace Uncertain Path

10 Personalized Cardiovascular MedicineDiagnostics Offer New Insights and New Possibilities

16 One Sample, Multiple ResultsThe Use of Multiplex PCR for Diagnosis of Infectious Syndromes

Departments 2 Federal Insider 4 Bench Matters 6 The Sample 20 Regulatory Roundup 22 Special Section: Patient Safety Focus 26 Industry Playbook 28 Ask the Expert

2 APRIL 2015

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EHR Incentive Program Updates Respond to Hospital WorriesThe Centers for Medicare and Medicaid Services (CMS) is using the rulemaking process to update the Medicare and Medicaid Electronic Health Record (EHR) Incentive Programs. According to Patrick Conway, MD, the CMS deputy administrator for innovation and quality and CMS chief medical offi cer, these changes will reduce the reporting burden on providers, while supporting the long term goals of the program. So far, more than 400,000 eligible providers are considered by CMS to be meaningful users of EHRs.

Changes to the incentive program will include realigning hospital EHR reporting periods to the calendar year to allow eligible hospitals more time to incorporate 2014 edition software into their workfl ows and to better align with other CMS quality programs; modifi cations to other aspects of the program to match long-term goals, reduce complexity, and lessen providers’ reporting

burdens; and shortening the EHR reporting period in 2015 to 90 days to accommodate these changes. CMS is “working on multiple tracks right now” to be responsive to hospital and other providers’ concerns, Conway said.

In a separate announcement, the Department of Health and Human Services’ Offi ce of the National Coordinator for Health Information Technology (ONC) released a plan to tackle interoperability of health IT software—an issue that has long been a major problem for providers

attempting to securely exchange health information across platforms. In the plan, ONC lays out a strategy to create clear and enforceable

interoperability standards, the lack of which has made most health information exchanges unworkable.

■BIG BOOST IN DEMAND NOT LIKELY UNDER ACA

Even though some 11 million people have gained health

insurance under the Affordable Care Act (ACA), this infl ux of newly insured is unlikely to overwhelm healthcare providers or signifi cantly increase healthcare utilization, concludes a Commonwealth Fund issue brief. The authors project that primary care providers will see, on average, 1.34 additional offi ce visits per week, or about a 3.8% increase in visits nationally. Hospital outpatient departments will see, on average, 1.2–11.0 additional visits per week, or about 2.6% nationally.

The report predicts that emer-gency department visits will increase by 1.1 million, or 2.2%, with those gaining Medicaid coverage account-ing for more than two-thirds of the increase. Overall, only 17 states are

expected to experience increases in primary care visits that exceed 4%, and only seven states are expected to see increases of greater than 5%. The majority of states are also expected to experience increases in outpatient care utilization of 4% or less.

■ICD-10 TESTING GOING WELL, CMS SAYS

As providers get ready for the October 1, 2015 deadline for

using the ICD-10 claims coding system, CMS has released results from its end-to-end testing that ran from January 30, 2014 to February 3, 2015. Some 660 providers, clearinghouses, and billing agencies participated. During the test, CMS received 14,929 claims with an 81% acceptance rate. According to CMS, 13% of the rejections were due to non-ICD-10 related errors.

CMS Administrator Marilyn Tavenner emphasized that ICD-9 codes must be used for services provided before the October 1 deadline, and ICD-10 for services provided after October 1, a point that she said has caused confu-sion among providers. The rule applies no matter when a claim is submitted: claims submitted after October 1, 2015, for services provided before that date must use ICD-9 codes.

During a February 11 hearing of the House Energy and Commerce Committee, the American Hospital Association submitted testimony that the association did not support any further delay and that more than 90% of hospitals surveyed by the association in January and February were either moderately confi dent or very confi dent in their ability to transition to ICD-10.

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Bench Matters

Timothy Hanley, MD, PhD

Hemoglobin A1c (A1c) is an essential component to both the diagnosis and management of patients with

diabetes mellitus. A1c is a specifi c glycated hemoglobin (Hb) that is modifi ed at the N-terminal valine residue of each ß-chain of Hb A. A1c levels refl ect not only average blood glucose concentrations during the previous 8 to 12 weeks but also long-term glycemic control. The landmark Diabetes Control and Complications Trial showed that A1c is directly related to risks for diabetic complications, and as a result, clinical guidelines recommend specifi c treatment goals related to A1c levels.

Measuring A1c is an integral component of the standard of care for diabetic patients, and there are a variety of meth-ods to do so. A1c methods fall into two broad categories: those that use molecular charge (ion-exchange high perfor-mance liquid chromatography [HPLC], and electrophoresis) and those that use molecular structure (immunoassay and affi nity chromatography). Nearly all A1c measurements in the U.S. are performed with these methods, though point-of-care (POC) devices also are used widely.

A clinical laboratory’s choice of A1c methods depends on factors such as cost, patient population, existing instru-mentation, performance, and available resources. When selecting an A1c method labs should fi rst determine if the method is National Glycohemoglobin Standardization Program (NGSP)-certifi ed—better than 99% in the U.S. are—and evaluate College of American Pathologists (CAP) data to assess how well the method actually performs. With any method, if A1c concentrations do not match the clini-cal picture, then biologic factors—such as altered erythro-cyte lifespan—should be considered. Additionally, labora-tories should be aware of the limitations their method has with respect to Hb variants and communicate this with their clinical colleagues. Efforts should be made to identify Hb variants whenever possible. And if necessary, alternative methods, such as fructosamine, should be selected to moni-tor these patients with diabetes.

Hb VARIANT DETECTION VARIES ACROSS METHODSCation-exchange HPLC separates glycated from non-glycated Hb components based on differences in their charges, as glycation of the N-terminal residue decreases its positive charge. Several fully automated systems are available for the clinical laboratory and analysis time is typically less than 5 minutes. According to a 2014 CAP survey, the coeffi cient of variation (CV) for this method was 1.6–2.7%. More common Hb variants can usually be detected by examining the chromatogram, but if the variant can’t be separated from Hb A or A1c, incorrect levels will be reported. Even though ion-exchange HPLC allows for Hb variant detection and has good precision,

implementing this platform into the clinical laboratory can be demanding in terms of necessary operator skills and the fi nancial burden of equip-ment purchase.

Immunoassays exploit structural variations and use antibodies that target N-terminal glycated amino acids on the ß chain to quantify A1c. Immunoassays are commercially avail-able and, according to the 2014 CAP survey, have variable CVs between 1.6–6.1%. Interferences from Hb vari-ants depend on where the antibody is targeted and whether a patient’s mutation is in the fi rst few amino acids of the ß chain.

Patients with Hb F levels above 10% will have a falsely low A1c because the gamma chain of Hb F shares only four of the 10 fi rst amino acids with the ß chain of Hb A, and therefore has little to no immuno-reactivity with most antibodies. On the plus side, immunoassays are affordable, easy to operate, and also easy to add to existing platforms in the laboratory. However, labs need to look carefully at the antibodies any particular assay targets and the patient population served to ensure the method will yield reliable results, or be prepared to investigate when test results don’t match the patient’s clinical picture.

Boronate affi nity chromatography also relies on structural variations to detect and quantify Hb with attached glucose residues. m-amino-phenylboronic acid reacts with the glucose bound to Hb to selectively hold the glycated hemoglobin (GHb) on the column. Commercial assays are available, and according to the CAP 2014 survey this technique has reasonably good precision with a reported CV of 2.1–3.1%. This method has less interference from common Hb variants, but like immu-noassays, it cannot detect the pres-ence of variants and is affected by

Considerations in Choosing Hemoglobin A1c Methods

Heather Signorelli, DO

APRIL 2015

elevated Hb F levels above 10–15%. This is thought to result from a lower glycation rate for Hb F compared with Hb A. Therefore, like HPLC, affi nity chromatography benefi ts from good precision and less inter-ference from Hb variants. However, the method may require additional equipment and technical staff that may be cost prohibitive.

POINT-OF-CARE POC devices that measure A1c pro-vide clear benefi t in certain clinical situations. For example, during an in-offi ce visit with clinicians, imme-diate test results allow for immediate therapy decisions and potentially better adherence to therapy. In the past, POC instruments fell short of the accepted analytic performance and NGSP certifi cation. However, in recent years new instruments have come on the market with improved analytic performance. Even so, the American Diabetes Association con-cluded in 2014 that while POC A1c assays may be NGSP-certifi ed they should not be used for diagnostic purposes.

Although a powerful clinical tool, A1c analysis has limitations. For example, A1c is altered by red blood cell lifespan. Hb variants may also interfere with A1c measurement, inde-pendent of their effects on erythrocyte survival. Pathologic variants of Hb such as Hb S or Hb E, elevated Hb F, and chemically modifi ed derivatives of Hb (carbamylated Hb) seen in patients with renal failure can affect the accuracy of measurements from some methods. However, less informa-tion is available on interferences from patients with common Hb variants present in the homozygous state. The NGSP provides details on the effect of common Hb variants on a number of different methods in clinical use and is a useful resource when choosing an A1c method.

Timothy Hanley, MD, PhD, is a pathology resident and Heather Signorelli, DO, is a clinical chemistry fellow at ARUP Laboratories in Salt Lake City, Utah. +EMAIL: timothy.hanley@aruplab.com+EMAIL: heather.signorelli@aruplab.com

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Sex-Specifi c hs-cTn Thresholds Could Lead to More MI Diagnoses in WomenSex-specifi c thresholds used with a high-sensitivity cardiac troponin I (hs-cTn) assay could double the diagnosis of myocardial infarction (MI) in women, putting the percentage of women diagnosed with MI on par with that of men,

new research indicates (BMJ 2015;350:g7873I doi:101036/bmj.g7873). The study also showed “major sex differences” in the management of MI, with less than half of women with an adjudicated MI diagnosis receiving optimal treatment, compared with most men.

The study involved 1,126 consecutive patients presenting with suspected acute coronary syndrome (ACS). Patients had troponin

measurements taken at baseline and 6 or 12 hours after symptom onset with both a contemporary sensitivity assay (cTn) and hs-cTn. The limit of detection for cTn is 10 ng/L, and the upper limit for a normal reference population is 28 ng/L. In contrast, the hs-cTn assay has a limit of detection of 1.2 ng/L and an upper limit for a normal reference

population of 26 ng/L. cTn has a coeffi cient of variation <10% at 50 ng/L, whereas hs-cTn has a coeffi cient of variation <10% at 6 ng/L.

Actual patient care was based solely on cTn results; researchers used hs-cTn in an independent review by two cardiologists, who considered all clinical information to classify patients as having type 1 MI, type 2 MI, myocardial injury, or unstable angina. These researchers also classifi ed or reclassifi ed patients using hs-cTn results with both a generic threshold (26 ng/L) and sex-specifi c thresholds of 34 ng/L for men and 16 ng/L for women.

Women with ACS were slightly older on average than men with ACS and had similar cardiovascular risk factors but had higher mortality risk and were less likely to have already undergone coronary revascularization.

With cTn results and a 50 ng/L threshold, 11% of women and 19% of men were classifi ed with type 1 MI. However, with hs-cTn and a generic 26 ng/L threshold, 16% of women and 23% of men were classifi ed with type 1 MI. When researchers used sex-specifi c hs-cTn thresholds, 22% of women versus 21% of men were classifi ed as having a type 1 MI. Use of hs-cTn and an age-specifi c threshold also resulted in a small but signifi cant increase in the number of women diagnosed with type 2 MI or myocardial injury.

The researchers also found that women diagnosed with MI were less likely than men to be referred to a cardiologist (80% versus 95%), receive coronary angiography (47% versus 74%), undergo coronary revascularization (29% versus 64%), or be prescribed statins at discharge (60% versus 85%). These inequalities were most pronounced in women diagnosed with MI only using hs-cTn.

While prior research also has noted sex-related differences in MI diagnosis, this dif-ference in the past has been attributed to

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differences in the symptoms women and men present with. However, the authors found equal proportions of women and men exhibiting chest pain and electrocardiographic changes.

■NEW METHOD DESCRIBED TO DETECT ß CELL DEATH

R esearchers reported a novel method for assessing β cell

death in individuals at risk for type 1 diabetes who subsequently developed the disease (J Clin Invest 2015; doi:10.1172/JCI78142). The method, a blood test that measures unmethyl-ated insulin DNA, can be used as a marker for β cell death, according to the authors.

The researchers developed the method as a way to measure β cell death directly in type 1 diabetes, which up until now has been assessed indirectly by measuring autoantibodies and glucose tolerance. However, auto-antibodies don’t correspond exactly with β cell death and don’t provide information about the pace of disease progression, according to the authors.

This led the investigators to pioneer a method to measure the amount of β cell-derived insulin DNA in circulation. Insulin DNA is methyl-ated in most cell types, and the only signifi cant source of unmethylated insulin DNA is β cells, according to the authors. The new method involves droplet digital PCR.

In an observational study of 50 participants from two cohorts at risk of developing type 1 diabetes, the authors found that those who progressed to type 1 diabetes had modestly elevated average levels of unmethylated insulin DNA in com-parison to healthy control subjects. These increases in unmethylated insulin DNA were associated with decreased insulin secretion, suggesting that unmethylated insulin DNA is a marker of β cell death.

■GENETIC TESTING BEFORE LUNG CANCER TREATMENT OPTIMIZES OUTCOMES

An economic analysis found that waiting for genetic testing

results before starting treatment for

non-small cell lung cancer (NSCLC) optimizes outcomes, and that multiplexed screening for epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements with test-guided chemotherapy is cost-effective in comparison to both empiric therapy and empiric switch therapy (J Thorac Oncol 2015; doi:10.1097/JTO.0000000000000474).

The investigators used a micro-simulation model to compare life expectancy and costs of multiplexed EGFR and ALK testing with: guided chemotherapy versus empiric che-motherapy with no testing; initial empiric chemotherapy switched to targeted therapy based on molecu-lar test results; or a total course of empiric chemotherapy followed by targeted therapy as indicated.

EGFR mutations and ALK rear-rangements occur in approximately 9.5% and 3.9% of all NSCLC, respec-tively. Guidelines recommend testing for EGFR and ALK to guide fi rst-line chemotherapy, but uptake of this recommendation appears underuti-lized in clinical care, according to the authors. At the same time, recent evidence has questioned the cost-effectiveness of this screening.

The authors found that the incre-mental cost-effectiveness ratio for testing and waiting for results com-pared to empiric chemotherapy was $136,000 per quality-adjusted life year gained, a metric considered a good value from a societal perspective.

■WOMEN WITH TYPE 1 DIABETES AT HIGHER RISK FOR DEATH THAN MEN WITH THE DISEASE

Arecent meta-analysis found that in comparison to men with

type 1 diabetes, women with the disease have nearly 40% excess risk of all-cause mortality and twice the excess risk of fatal and nonfatal vascular events (Lancet 2015; dx.doi.org/10.1016/S2213-8587(14)70248-7). The fi ndings support the need for further research to understand the basis for these differences, which could have “profound clinical implications for how women with type 1 diabetes are treated and

managed throughout their life course,” according to the investigators.

The authors evaluated 26 studies which involved 214,114 individuals.

The primary endpoint for the meta-analysis was all-cause mortality; secondary endpoints were mortality or incident coronary heart disease, stroke, cardiovascular disease, renal disease, cancer, and the combined outcome of accident and suicide.

The authors found the pooled women-to-men ratio of the standard-ized mortality ratio for all-cause mortality was 1.37 for incident stroke, 1.44 for renal disease, and 1.86 for cardiovascular disease. The “specifi c-ity of the observed sex difference for vascular-related outcomes in patients with type 1 diabetes adds to the accumulating evidence suggesting a greater adverse effect of hyperglyce-mia and diabetes on vascular risk in women than in men,” according to the authors.

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BY BILL MALONE

Molecular testing remains a hot spot for invest-ment in the global in vitro diagnostics (IVD) market that has seen

stretches of achingly slow progress over the last decade. With the number of research and development (R&D) dollars dedicated to molecular testing—and the returns for market leaders—clinical laboratories might expect to fi nd a parallel, positive trajectory for reimbursement and coverage from payers.

However, not only have pub-lic payers, such as the Centers for Medicare and Medicaid Services (CMS), and private payers lagged behind scientists’ innovation in this area, new warning signs are appearing that point to an even more complex and uncertain fi ght for reimburse-ment and coverage.

As Congress and President Obama tout the power of precision medi-cine, payers are requiring defi nitive evidence of a test’s value to patient care—a moving target that is getting more diffi cult for diagnostics to reach, according to Genevieve Tang, direc-tor of strategic product planning at Quorum Consulting.

“The reimbursement environment for molecular diagnostics is rapidly evolving, and you need to be able to adapt on the fl y in order to survive,” Tang said. “The trend for regulators

and payers is to place increased value and emphasis on proprietary, single-source tests with strong evidence of clinical utility. This is in contrast to commodity testing, where the per-ceived value and reimbursement rates are decreasing.” Tang spoke during a January 29 AACC webinar, Molecular Diagnostics: 2015 Market Trends and Reimbursement Outlook.

Market Investment, Despite HeadwindsEven with the high risks and regula-tory uncertainties, IVD companies continue to bet on the molecular space as a key driver for their busi-nesses. Tests for infectious diseases and cancer dominate, and will likely sustain the estimated 5% compound annual growth for the molecular sector this year, according to Kerri Weinert, CEO of Boston Biomedical Consultants (BBC), who also spoke during the AACC webinar.

Roche still leads the market, but has lost some ground due to the “enormous” amount of investment by competitors, Weinert said. “The investment in R&D for molecular diagnostics is very costly, and compa-nies that are willing to develop auto-mation and ongoing assay improve-ments will also have to invest heavily in customer education, physician education, and deal with regulatory and reimbursement challenges.”

A key to success for IVD com-panies will be reliable automation, an area with impressive innovation, according to Weinert. “When you consider that the fi rst moderately complex molecular test was intro-duced in 2006, and we just had the fi rst CLIA-waived molecular test approved this month, I think the industry is capable of anything in terms of innovation,” she said. The Alere i Infl uenza A&B assay received CLIA-waived status from the Food and Drug Administration (FDA) in January.

As companies continue to invest in automation, they will confront price erosion as competition among manufacturers stays strong, Weinert added. To fi nd success in the molecu-lar space, IVD businesses will have to meet clinical laboratories’ needs. That means offering a strong test menu that is consolidated on a single, automated platform.

SHIFTING POLICIES, MARKET DEMANDS TRACE UNCERTAIN PATH

The Reimbursement Outlook for

MOLECULAR DIAGNOSTICS

9APRIL 2015

Innovation vs. CommoditizationFor many years, the most signifi -cant economic challenge facing the clinical laboratory arena has been the intense, downward pressure on reimbursement to labs, and in turn, on pricing for IVD manufacturers. As traditional laboratory tests have moved to an automated, high-volume model, payers now see any ven-dor’s—or any laboratory’s—test as essentially the same. As tests have become commoditized, payers shop by price alone, choosing a lower-cost alternative whenever possible. Commoditization has led to private payers cutting deals for prices as low as half the Medicare rates.

Until last year, it appeared that CMS at least would remain a reliable anchor of decent—though nowhere near generous—payment. Now, with Congress’s overhaul of the lab fee schedule under the Protecting Access to Medicare Act of 2014 (PAMA),

Medicare rates will reset to the median of private payer rates beginning in 2017. CMS has a deadline of June 20, 2015 to publish rules for how labs will report private payer payment infor-mation to the agency. This reporting phase begins January 2016.

The bright spot for molecular tests under PAMA will be the law’s provi-sion for advanced diagnostic labora-tory tests (ADLT). CMS will reim-burse ADLTs at their list price for the fi rst 9 months beginning January 2017. PAMA defi nes ADLTs as tests provided by a single laboratory and involving the analysis of multiple biomarkers or unique algorithms, but CMS has wide latitude to include other “advanced” tests as well.

Especially now that FDA is tak-ing steps toward a plan to regulate laboratory-developed tests (LDTs), ADLTs may have a signifi cant advan-tage compared to “commodity tests,” Tang noted.

“For ADLTs, the fact that the lab performing the test will be the only contributor of private payer pay-ment data means that it will have the opportunity to maintain excellent pricing,” Tang said. “In contrast, we expect that under PAMA, commodity tests will most likely continue to see decreases in payment.”

Furthermore, if FDA begins regu-lating LDTs, those tests that make it through FDA clearance may be perceived as having more value than non-FDA approved tests, leading to more favorable reimbursement and coverage determinations.

Payers Demand Link to Improved Patient CareWhile some new, innovative tests will receive special treatment under the PAMA reimbursement scheme, another hurdle still awaits, Tang emphasized: how much an insurer might pay for a test doesn’t matter if it won’t pay at all. In fact, her experi-ence shows that coverage determina-tions are becoming more and more diffi cult to obtain.

Payers look for three levels of evidence when they decide whether or not to cover a test, Tang explained. “The fi rst is analytical validity, which refers to the accuracy, precision, and

reproducibility of the test results. The second is clinical validity, which is the correlation of the test results with the clinical outcomes of interest,” Tang said. “Third is clinical utility, which may seem an abstract concept, but essentially refers to how use of the test infl uences clinical decision-making and/or improving patient outcomes. This third level of evidence is what payers are really looking for.” For example, Palmetto GBA, a CMS contractor, now requires prospective clinical utility studies before evalu-ating a test for coverage under its MolDx program.

But even when a company invests in expensive clinical utility studies, there still is no guarantee of cover-age. Tang offered the example of the Corus CAD test marketed by CardioDX. The test is a multi-analyte gene expression assay intended to aid physicians in identifying patients who are likely to have coronary artery stenosis of at least 50%. “The value proposition is that you can potentially avoid unnecessary and useless coro-nary angiography and other expensive or invasive tests, which then reduce the costs for the payer,” Tang said. CardioDX scientists published three clinical utility studies, ultimately win-ning Medicare coverage through the Palmetto MolDx program. However, only two Medicare administrative contractors followed Palmetto’s lead with defi nite coverage for the test. CardioDX faced even tougher odds with private payers: only one of the top 10 payers—Aetna Health—so far has decided to cover the test.

In what is likely a portent of prob-lems for other labs, the reason private payers did not cover the test was that the CardioDX studies did not link changes in clinical decision-making to patient outcomes.

“Securing payer coverage is increas-ingly going to require clinical util-ity studies that clearly demonstrate how use of the test improves patient outcomes,” Tang said. “I think it’s clear that in order to thrive in this new environment, labs must be prepared to invest in high-quality evidence. This is a very high bar to meet, but it is the reality of the new era of precision medicine that we’re now in.”

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10 APRIL 2015

BY JULIE KIRKWOOD

The death rate from cardiovascular disease has been falling steadily for years. Yet breakthrough discoveries that apply to general patient populations are becoming fewer and farther between. “We’ve made

enormous progress in the management of patients with cardiovascular disease in the last decade,” said Paulus Kirchhof, MD, chair in cardiovascular medicine at University of Birmingham, U.K. “It’s a remarkable success and I think we can be proud of it.”

Despite these advances, a new approach is needed to push medicine forward, according to experts. “The path of progress that we have followed so far has probably reached the end or is nearing its end,” Kirchhof said.

Jean-Claude Tardif, MD, director of the research center at the Montreal Heart Institute and professor of medicine at the University of Montreal, agreed. “Despite massive investments of pharma in drug development … the number of drugs that reach stage three and reach approval by [the Food and Drug Administration] FDA has actually gone down tremendously,” he said. “That may very well be because our view of the science and the world was probably too simplistic.”

Cardiology is increasingly turning toward a new approach: personalized medicine, the use of genetics and

CARDIOVA

DIAGNOSTICS OFFER NEW INSIGHTS AND NEW POSSIBILITIES

PERSO

11APRIL 2015

VASCULAR MEDICINE

coronary stent placement. Yet a study exploring genotype-based dosing of clopidogrel showed no effect.

Perhaps genetic tests will prove more useful in drug selection rather than dosing, Wu said. He is awaiting the results of the TAILOR-PCI trial, which asks if a different antiplatelet drug, ticagrelor (Brilinta), works bet-ter than clopidogrel in patients who have the liver enzyme abnormality, known as the *2 or *3 alleles.

New Drugs for Small PopulationsBeyond improving the use of existing drugs, personalized car-diovascular medicine offers the promise of developing new drugs specifi cally for certain subgroups of patients. Tardif and his col-leagues have just published a study of the drug dalcetrapib, developed by F. Hoffman-La Roche to raise high-density lipoprotein choles-terol (HDL-C) (Circ Cardiovasc Genet 2015; doi:10.1161/CIRCGENETICS.114.000663).

The drug failed a phase III clinical trial involving 15,871 patients who had been hospitalized for acute coro-nary syndrome. Dalcetrapib raised

biomarkers to understand and treat disease. Kirchhof was lead author of a position paper from the European Society of Cardiology exploring the promise and challenges of personal-ized medicine (Eur Heart J 2014; doi:10.093/eurheart/ehu312).

“The need is large,” said J. Wouter Jukema, MD, PhD, professor of car-diology at Leiden University Medical Center in the Netherlands, who was not involved in the study. “A lot of medication prescriptions, operations, and device implantations are done on the basis of the average patient. This is clearly suboptimal from many points of view.”

Improving Existing TherapiesSo far, much of the research in personalized cardiovascular medicine has explored biomarkers or pharma-cogenomics to personalize the dosing of existing drugs. For example, several studies have looked at B-type natri-uretic peptide (BNP) and NT-proBNP as markers to guide heart failure therapy in terms of choice and dosing of beta blockers and angiotensin-converting-enzyme (ACE) inhibitors (J Am Coll Cardiol 2009;55:61–4).

“These have had varying degrees of success,” said Alan H.B. Wu, PhD, pro-fessor of laboratory medicine at the University of California, San Francisco and section chief of clinical chemistry at San Francisco General Hospital. “Some studies have shown good suc-cess and others have shown success in only certain populations.”

Trials have also explored genotype-guided dosing of the anticoagulant warfarin. Polymorphisms in two genes, CYP2C9 and VKORC1, appeared to be associated with variations in dosage requirement. Despite high hopes, two large clinical trials found that geno-typing at the beginning of warfarin treatment did not help patients avoid bleeding and strokes (N Engl J Med 2013;369:2283–93 and N Engl J Med 2013;369:2294–303).

“This has led to a lot of questions about the value of pharmacogenom-ics, at least in regard to therapeutic dosing,” Wu said.

Likewise, researchers identifi ed a liver enzyme abnormality encoded in the CYP2C19 gene that appeared to make some patients unable to activate the antiplatelet drug clopidogrel (Plavix), which is administered after

ONALIZED

12 APRIL 2015

HDL-C levels but did not prevent future illness or death (N Engl J Med 2012;367:2089–9).

This sent Tardif and his co-authors back to conduct a genome-wide association study on more than 5,000 blood samples collected during that trial. They identifi ed single nucleotide polymorphisms on one particular gene, ADCY9, that were associated with the effect of the drug. When patients were stratifi ed by genotype, the drug appeared to protect some and harm others.

“This is really the fi rst time that the effect of a cardiovascular drug on heart events—meaning cardiovascular death, heart attack, stroke, and so forth—is determined by the genetic profi le,” Tardif said. “It could be the opening of a new way of looking at drug devel-opment and treating patients with cardiovascular disease, where it’s going to be much more personalized.”

His team is now meeting with regu-lators to plan a prospective study to fi nd out if dalcetrapib benefi ts patients screened for the appropriate genotype. If it does, the drug could be available in as little as 3–4 years, Tardif said.

“It begs the question, how many other drugs that have not been tested with pharmacogenomics and preci-sion diagnostics … are sitting on shelves in a drug company because in studies they appeared to have no effect?” Tardif said. “There might be other drugs that actually can be resur-rected by that kind of approach.”

Back to Basics?Aside from the immediate implica-tions, the dalcetrapib study also raises questions about the ADCY9gene and how it might be con-nected to cardiovascular disease mechanisms. It is just one example of how genomic testing and other

personalized medicine techniques are bringing new insight into fun-damental cardiovascular disease processes.

That return to basic science, with a new understanding of the genetic contributors or modifi ers of cardio-vascular disease, will hopefully lead to new drugs and therapies, Kirchhof said. “This is a vision, so it’s not something that will be implemented next year,” he cautioned. “But this is already happening.”

For example, researchers now know that heart failure and atrial fi brillation are caused by such a variety of mechanisms that eventually they will require a new taxonomy, and new tests to better classify and treat patients, Kirchhof noted.

A New Role forthe Clinical LaboratoryAs personalized medicine advances, the clinical laboratory will become even more indispensable in treating cardiovascular patients. “We’re going to see more specialty type laboratory tests that are linked to a particular disease,” Wu emphasized. “And more importantly—linked to a particular therapeutic or management posi-tion.” There may even be a role for the laboratory to work directly with patients on cardiovascular disease prevention, he said.

Biomarkers such as troponin could help a patient monitor whether exercise is decreasing their disease risk. Genetic tests could perhaps distinguish which smokers are at risk for disease or which sleep apnea suf-ferers have cardiac involvement. “So it becomes almost our job as laboratory professionals to educate the public as to the dangers of these behaviors,” Wu said.

We are just beginning to see the effects of advances in genome sequencing, bioinformatics, data pro-cessing, and statistics that enable per-sonalized medicine, noted Tardif. “The possibilities are almost infi nite right now,” he said. “I really think there will be a revolution in the personalization of therapies.”

Julie Kirkwood is a freelance writer who lives in Rochester, New York. +EMAIL: julkirkwood@gmail.com

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BY ELIZABETH PALAVECINO, MD

Once confi ned to research and reference laborato-ries, molecular test methods for the

diagnosis of infectious diseases have become part of routine testing algorithms in clinical laboratories of all sizes. Laboratory and clinical personnel have received this change with enthusiasm because molecular testing provides higher sensitivity and specifi city, and in most cases a shorter turnaround time than traditional methodology. Based on the increased acceptance of these tests in clinical practice, manufacturers have devel-oped a wide variety of options—both instruments and assays—from which laboratories can choose (1). The technology has evolved from manual to fully automated, closed systems that provide sample-to-result automation, enabling laboratories

encephalitis, and urinary tract, respiratory, or gastrointestinal (GI) infections, using a single specimen.

Advantages and Limitations of Multiplex PCR AssaysThis emergent technology is redefi n-ing the diagnosis of infectious diseases and can have a signifi cant impact on patient management while stream-lining the processing and testing of specimens in the clinical laboratory. The possibility of detecting multiple targets in a single sample is particu-larly important when clinical samples are diffi cult to collect or are limited in volume (e.g., spinal fl uid), or when multiple different pathogens can cause the same clinical presentation—making it diffi cult for clinicians to narrow down the causative pathogen.

Until now, widespread implementa-tion of multiplex molecular tests in

with limited prior experience to implement molecular testing.

Many studies have demonstrated the clinical effectiveness of molecu-lar testing to detect one particu-lar organism, such as Clostridium diffi cile or methicillin resistant Staphylococcus aureus (MRSA) (2). More recently, there has been a move toward developing molecular tests that detect multiple patho-gens associated with an infectious syndrome rather than one particular organism. Molecular technologies with multiplexing capabilities may use traditional polymerase chain reaction (PCR) or real-time PCR and reverse-transcription PCR to amplify targets. They are usually offered as a panel that simultaneously detects the pathogens most commonly associ-ated with a particular infectious syndrome, such as sepsis, meningitis/

ONE SAMPLE, MULTIPLE RESULTSTHE USE OF MULTIPLEX PCR FOR DIAGNOSIS OF INFECTIOUS SYNDROMES

17APRIL 2015

mechanisms is crucial in selecting appropriate therapy and is a decisive factor in patient survival.

While conventional culture and susceptibility testing may require 72 hours to produce results, multiplex PCR assays can do so in 1 to 3 hours after the blood culture is fl agged as positive by the blood culture instru-ment. The benefi t of such rapid testing will be seen if therapeutic decisions are made as soon as results are available; therefore, support from an antimicrobial stewardship team is paramount to achieve the goals of cost-effective testing and improved patient outcomes.

To date, there are two FDA-cleared molecular blood culture panels: the FilmArray Blood Culture Identifi cation panel manufactured by Biofi re Diagnostics and the Verigene blood culture test manufactured by Nanosphere. A sample from a positive blood culture bottle is tested on the corresponding system and all three reactions—sample preparation, ampli-fi cation, and detection—are performed automatically by the instrument. The FilmArray assay is offered as a panel that detects gram negative, gram posi-tive, and yeasts. The Verigene assay uses a separate detection panel for gram positive and gram negative, with the panel selected based on Gram stain results. Table 2 summarizes the details on the time to result for each of these blood culture panels and the group of organisms detected by each.

Evaluation of both of these panels has shown that they accurately identify most leading causes of blood stream infections and provide results signifi cantly faster than traditional methodologies, enabling clinicians to prescribe appropriate therapy much earlier (5).

Viral Respiratory PanelsOne area that has experienced a dramatic change from conventional to molecular methodologies is virology testing. Respiratory tract infections are one of the most common causes of morbidity and mortality in all age groups, and the clinical presentation of different organisms can be simi-lar, making it impossible to reliably predict the causative pathogen based solely on clinical symptoms.

T1 Potential advantages and disadvantages of multiplex PCR tests for diagnosis of infectious syndromes.

POTENTIAL ADVANTAGES

Increase diagnostic yield as multiple targets are tested in one sample

Conserve and optimize analysis of samples diffi cult to obtain (spinal fl uid, vitreous fl uids, synovial fl uids)

Simplify ordering algorithm as only one test needs to be requested

Streamline workfl ow in the laboratory and reduce hands-on time

Potential saving in reagents by testing multiple organisms at once compared to testing each pathogen separately

Standardize testing

POTENTIAL DISADVANTAGES

False positive results due to cross reactivity or unspecifi c amplifi cation caused by multiple primers/targets present in the reaction

False-negative results due to use of preferential amplifi cation of one target over another

Negative internal control due to exhaustion of reagents in samples with a high amount of one particular target

Added cost of testing targets that may not be necessary in some patient populations

High cost of commercial kits and instruments

clinical laboratories has been hindered by the high cost of the kits and by the need to acquire multiple instruments to cover the testing needs of different infectious syndromes. These assays also have some shortcomings. Table 1 sum-marizes the possible advantages and disadvantages of multiplex PCR assays.

However, even with their possible limitations, multiplex PCR assays are being adopted rapidly in clinical practice. I am hopeful that competi-tion triggered by rapid market growth along with a reasonable reimburse-ment plan will lead to these tests being available at signifi cantly lower cost and with an increased number of targets and improved automa-tion. The paradigm shift from single to multiplex molecular assays will continue to occur as long as clinical benefi ts are observed.

The remainder of this review will focus on the use of multiplex PCR tests in the following infectious syndromes: blood stream, respira-tory, and GI infections. The need for rapid molecular testing with each type of infectious syndrome will be discussed, along with advantages of multiplex tests over conventional methods, and any possible disad-vantages. In addition, the multiplex PCR assays that are commercially available and cleared by the Food and Drug Administration (FDA) for the diagnosis of these infections will be described and compared.

Commercial Panels—Multiplex PCR Tests for Specifi c Infectious Syndromes Blood Culture PanelsBlood stream infection—the presence of organisms in the blood—can trigger a systemic infl ammatory response syndrome that can progress to severe sepsis and septic shock. Two fac-tors drastically increase mortality in patients with bloodstream infections: progression of the infection to sepsis or septic shock, and delayed imple-mentation of appropriate antimi-crobial therapy (3,4). In addition, to prevent the emergence of antibiotic resistance, clinicians must start effec-tive therapy early and avoid having patients unduly exposed to broad-spectrum antibiotics. For all these reasons, rapid laboratory identifi cation of the pathogen and its resistance

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The Infl uenza A H1N1 epidemic in 2009 clearly demonstrated that rapid and specifi c diagnosis of viral respiratory infections is important for patient and public health manage-ment. Clinicians are becoming more aware that viral respiratory infections other than infl uenza can be very severe, driving interest in a rapid and comprehensive multiplex PCR test that can detect the most common pathogens—both for patient manage-ment as well as surveillance moni-toring of respiratory viral infections. Nevertheless, the variable sensitivity observed with rapid antigen infl uenza tests limit their clinical utility.

Currently, there are many molecular testing options for infl u-enza, including one assay recently FDA-cleared as a point-of-care test (6). In addition to the widely available molecular assays designed to detect infl uenza A (with and

without subtyping), infl uenza B, and/or respiratory syncytial virus from nasopharyngeal swabs, multiplex PCR assays that detect multiple respiratory viruses are being used more fre-quently by clinical laboratories. At the time of this review, there were four FDA-cleared multiplex molecular respiratory viral panels (RVP). Table 3 lists the capabilities of these assays.

Sensitivity varies by assay and by target, but all show high specifi city for all targets included in the panels (7). Each laboratory should determine which system is appropriate for its specifi c needs, based on instrumenta-tion available, experience and com-petency of personnel, and the patient population served.

GI PanelsInfectious diarrhea can be caused by bacterial, viral, or parasitic pathogens and remains a signifi cant healthcare burden worldwide (8). Although most GI infections are self-limiting, they can be severe and even fatal in young children, the elderly, and other immunocompromised individ-uals. Because the pathogen cannot be ascertained by clinical presentation, clinicians often order a bacterial culture and also an ova and parasite (O&P) exam in stool samples from patients with diarrhea.

However, this conventional testing approach has at least three signifi cant diagnostic limitations. First, culture and identifi cation of bacterial patho-gens in stool is labor intensive and can take 3–5 or more days for results. In addition, the CDC recommenda-tion of simultaneous testing for Shiga toxin and culture has increased the cost of bacterial cultures in stool with little benefi t in those areas with low prevalence of Shiga toxin-producing Escherichia coli (9). Second, the O&P exam lacks sensitivity, is time con-suming, and requires highly trained personnel for meaningful interpreta-tion and detection of parasites causing diarrhea (10). Third, although viral infections are an important cause of GI illness outbreaks, the majority of laboratories do not perform viral culture or antigen testing—except for rotavirus—so the infection goes unno-ticed and potentially spreads.

There are two FDA-cleared multiplex PCR assays that can

detect bacterial pathogens in stool—Hologic’s ProGastro SSCS and the BD MAX Enteric Bacterial Panel. However, a more comprehensive, rapid, sensitive, and specifi c assay for the diagnosis of infectious diarrhea caused not only by bacterial but also viral or parasitic pathogens may be desirable for several reasons, including minimizing additional testing, quickly implementing infection control prac-tices to decrease spread, and poten-tially avoiding unnecessary antibiotics. Table 4 lists three such FDA-cleared GI assays and the target organisms included in each of these panels.

These assays have high sensitivity and specifi city, and they allow the detection of viral pathogens which are usually not detected by routine work up of stool samples. The clinical and fi nancial impact of GI panels has not yet been fully evaluated, and there are some concerns that molecular testing may be detecting colonization rather than infection in some cases, making it diffi cult for clinicians to interpret the results. With more laboratories using GI panels, I am hopeful that the clinical effi cacy and cost effectiveness of these panels will be revealed in the near future.

ConclusionMolecular testing is replacing conven-tional methodologies for the diagnosis of infectious diseases. The improved instrumentation and the availability of fully automated systems with sample-to-answer design have helped clinical laboratories implement these assays. More recently, the availability of multiplex PCR assays that can detect a large number of targets in a single sample has shifted the paradigm from ordering a series of individual tests to detect many different pathogens to using one sample and one test to make a diagnosis of infectious syndromes.

Multiplex PCR assays are even more useful clinically when there is support from an antimicrobial stewardship team that can act on results in real time. The high cost of these molecular panels compared to conventional methodology is still hin-dering them from being implemented widely, but the rapid turnaround time and higher sensitivity and specifi c-ity are factors that could make these

T2 Commercial molecular assays for detection of organisms in positive blood cultures of patients with bloodstream infection

ASSAY ORGANISM GROUP DETECTED (SPECIES)FilmArray BCID1

The Biofi re Diagnostics FilmArray InstrumentTime to result: 1 hour

Staphylococus/S aureus

Streptococcus (3)

Enterococcus

Listeria monocytogenes

Enterobacteriaceae (6)

Acinetobacter baumanii

Pseudomonas aeruginosa

Haemophilus infl uenzae

Neisseria meningitidis

Candida (4)Resistance mechanisms (mecA, ESBL, KPC, Van A/B)

BC-GP2

The Nanosphere, Inc. Verigine Reader and Processor SPTime to result: 2.5 hours

Staphylococus (3)

Streptococcus (4)

Enterococcus (2)

Listeria spp.

Resistance mechanisms (mecA, VanA, and VanB)

BC-GN3

The Nanosphere, Inc. Verigine Reader and ProcessorTime to result: 2 hours

Enterobacteriaceae (6)

Acinetobacter spp

Pseudomonas aeruginosa

Resistance mechanisms ESBL (CTX-M), Carbapenamases (IMP, KPC, NDM, OXA, VIM)

19APRIL 2015

tests a powerful tool. The cost savings of implementing multiplex PCR assays may not be seen directly in the clinical laboratory, but rapid diagnosis can be translated into savings for the institution due to decreased length of stay and better clinical outcomes for patients.

Acknowledgments: I thank Carlos A. Fasola for helpful editorial suggestions to the manuscript.

Elizabeth Palavecino, MD, is an associate professor of pathology, director of the clinical microbiology laboratory, and co-director of the Mass Spectrometry Translational Center at Wake Forest School of Medicine in Winston-Salem, North Carolina.+EMAIL: epalave@wakehealth.edu

References 1. Emmadi R, Boonyaratanakomkit

JB, Selvarangan R, et al. Molecular methods and platforms for infectious disease testing. A review of FDA-approved and cleared assays. J Mol Diagn 2011;13:583–604.

2. Palavecino E. Rapid methods for detection of MRSA in clinical speci-mens. In: Yinduo J, editor. Methicillin-resistant Staphylococcus aureusprotocols. 2nd Ed. Humana Press Inc. 2013:71-83.

3. Kumar A, Ellis P, Arabi Y, et al. Initiation of inappropriate antimicro-bial therapy results in a fi vefold reduc-tion of survival in human septic shock. CHEST 2009;136:1237–48.

4. Mancini N, Carletti S, Ghidoli N, et al. The era of molecular and other non-culture-based methods in diag-nosis of sepsis. Clin Microbiol Rev 2010;23:235–51.

5. Ward C, Stocker K, Begum J, et al. Performance evaluation of the Verigene (Nanosphere) and FilmArray (BioFire) molecular assays for identifi -cation of causative organisms in bac-terial bloodstream infections. [Epub ahead of print] Eur J Clin Microbiol Infect Dis October 14, 2014.

6. Bell J, Bonner A, Cohen DM, et al. Multicenter clinical evaluation of the novel Alere™ i Infl uenza A&B isother-mal nucleic acid amplifi cation test. J Clin Virol 2014;61:81–6.

7. Papowitch EB, O’Neill S, Miller M. Comparison of the Biofi re Film Array RP, Genmark eSensor RVP, Luminex

xTAG RVPv1, and Luminex xTAG RVP fast multiplex assays for detection of respiratory viruses. J Clin Microbiol 2013;51:1528–33.

8. Scallan E, Hoekstra RM, Angulo FJ, et al. Foodborne illness acquired in the United States—major pathogens. Emerg Infect Dis 2011;17:7–15.

9. Woo JS, Palavecino EL. Four-year

experience with simultaneous culture and shiga toxin testing for detection of shiga toxin-producing Escherichia coli in stool samples. J Clin Microbiol 2013;51:985–7.

10. McHardy IH, Wu M, Shimizu-Cohen R, et al. Detection of intestinal proto-zoa in the clinical laboratory. J Clin Microbiol 2014;52:712–20.

T3 Characteristics of multiplex PCR panels for detecting respiratory pathogens in nasopharyngeal swab samples.

ASSAY NAME (MANUFACTURER)

ANALYSISPLATFORM

DETECTION METHODOLOGY

NO. OF TARGETS

TIME TO RESULT* BATCHING

FilmArray Respiratory Panel (Biofi re Diagnostics)

Film Array System

Endpoint melt curve analysis

17 viral targets3 bacterial targets

1 hour No. One sample in 1 hour per instrument

eSensor Respiratory Viral Panel (GenMark Dx)

eSensor Electrochemical 14 viral targets 7 hours Yes. 21 samples in 8 hours per instrument

xTAG Respiratory Panel v1 (Luminex Molecular Diagnostics)

Luminex 100/200 Fluorescence-labeled bead array

12 viral targets 8 hours Yes. 21 samples in 8 hours per instrument

xTAG Respiratory Panel Fast (Luminex Molecular Diagnostics)

Luminex 100/200 Fluorescence-labeled bead array

8 viral targets 5 hours Yes. 21 samples in 8 hours per instrument

*The time to result listed includes the time required for pre-extraction of nucleic acids using the NucleiSENS easyMAG instrument (BioMerieux) for the eSensor and xTAG assays.

ASSAY ORGANISMS DETECTEDFilmArray GI(BioFire Diagnostics)

Bacteria Campylobacter (yeyuni, coli, and upsaliensis), Clostridium diffi cilePlesiomonas shigelloides, Salmonella, Yersinia enterocolitica. Vibrio (parahemolyticus, vulnifi cus, and cholera), Diarrheagenic E. coli/Shigella (EAEC, EPEC, ETEC, STEC, EIEC), Shiga-producing E. coli, E. coli O157.

Viruses Adenovirus F40/41, Astrovirus, Norovirus GI/GII, Rotavirus A, Sapovirus.

Parasites Cryptosporidium, Cyclospora cayetanensis, Entamoeba histolytica, Giardia lamblia.

xTAG GPP*(Luminex Molecular Diagnostics)

Bacteria Campylobacter, Clostridium diffi cile, Salmonella, Yersinia enterocolitica. Vibrio cholera, Enterotoxigenic E. coli (ETEC), Shigella, Shiga-producing E. coli, E. coli O157.

Viruses Adenovirus F40/41, Norovirus GI/GII, Rotavirus A.

Parasites Cryptosporidium, Entamoeba histolytica, Giardia lamblia.

Verigene EP(Nanosphere Inc.)

Bacteria Campylobacter group, Salmonella, Shigella, Vibrio group, Yersinia enterocolitica, Shiga-toxin 1 and 2.

Viruses Norovirus GI/GII, Rotavirus A.

Parasites None

EAEC: Enteroaggregative E. coli; EPEC: Enteropathogenic E. coli; ETEC: Enterotoxigenic E. coli; STEC: Shiga-toxin–producing E. coli; EIEC: Shigella/Enteroinvasive E. coli.*This assay requires pre-extraction of nucleic acids using the NucleiSENS easyMAG instrument (BioMerieux).

T4 Pathogens detected by gastrointestinal panels FDA-cleared for testing stool samples in patients with infectious diarrhea.

20 APRIL 2015

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Premaitha Health’s Iona Test Becomes First CE-Marked Diagnostic for NIPTPremaitha Health has received the CE mark for the Iona test, making the Iona the fi rst in vitro diagnostic for non-invasive prenatal t esting (NIPT) to meet the quality standards set down by Europe’s In Vitro Diagnostic Medical Device Directive. The Iona test uses next-generation sequencing technology to estimate the risk of a fetus having trisomies 21, 18, and 13 by analyzing cell-free fetal DNA from a sample of maternal blood. It provides a complete system to clinical laboratories that includes DNA extraction through to data analysis with a standardized workfl ow.

Presently, pregnant women in Europe and the U.K. can only access NIPT via the private testing market provided by service laboratories. According to Premaitha Health, this means that their blood samples are sent to labs in the

U.S. or China, which can lead to a wait time for results of up to 2 weeks. Now that the European regulatory agencies have authorized the Iona test, hospitals across Europe and the U.K. will have the option of providing pregnant women with a local non-invasive prenatal test with a turnaround time of 3 days. Premaitha Health believes this could speed the dissemination of NIPT throughout Europe, potentially reducing the number of women who undergo unnecessary confi rmatory invasive prenatal testing due to false-positive results from current prenatal screens.

■BLOOM SYNDROME TEST BECOMES FIRST 23ANDME TEST TO RECEIVE FDA CLEARANCE

The Food and Drug Administration (FDA) has

granted 23andMe 510(k) clearance for its Bloom syndrome carrier test, a direct-to-consumer (DTC) genetic test that determines whether healthy individuals have a genetic variant that could lead to their children inheriting this disorder. This marks a major milestone for 23andMe after FDA ordered the company in 2013 to stop selling its DTC genetic testing service.

Just as it has for other home-use medical tests, such as those for pregnancy and HIV, FDA will require the Bloom syndrome test’s results to be conveyed in a way that consumers can understand and use. To address concerns that DTC genetic test results may mislead consumers, the agency is also requiring that 23andMe explain in the test’s labeling what the results

might mean for prospective parents interested in seeing if they are Bloom syndrome carriers. Additionally, if 23andMe sells this test over the coun-ter, it must include information about how consumers can access a board-certifi ed clinical molecular geneticist or equivalent to assist in pre- and post-test counseling.

Along with this clearance, FDA has also decided to classify carrier screen-ing tests as class II and has stated that it eventually aims to exempt these tests from premarket review.

Given the probability of erroneous results, professional societies typically recommend that only prospective par-ents with a family history of a genetic disorder undergo carrier screening.

■WHO AUTHORIZES USE OF FIRST RAPID TEST FOR EBOLA

The World Health Organization (WHO) has assessed and listed

Corgenix’s ReEBOV Antigen Rapid Test Kit as eligible for use in Ebola-affected countries. The test was evaluated under WHO’s Emergency Assessment and Use, a procedure established to provide minimum quality, safety, and performance assurance for diagnostic products used in the current Ebola outbreak.

The nucleic acid tests (NATs) pres-ently used to diagnose Ebola require well-established laboratories and fully trained personnel, with a turnaround time that can vary between 12 and 24 hours. In comparison, Corgenix’s test can provide results within 15 minutes by detecting Ebola protein in the blood rather than nucleic acid. While less accurate than NATs, the ReEBOV Antigen Rapid Test Kit is also easy to perform and does not require electric-ity, making it possible for healthcare workers to use it at less sophisticated healthcare facilities or in mobile units for patients in remote settings.

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Covert, Cognitive Biases May Affect Your Decisions

The extremely complex human brain is like a powerful com-puter, storing memories and

controlling how we think, feel, and react. Yet, there are limitations to how the brain processes information. For decision-making to be less taxing on our minds, we have evolved short-cuts in our thinking called heuristics, which include common sense judg-ments, educated guesses, and the use of intuition.

In dangerous situations, this kind of quick thinking comes in handy; how-ever, when we settle for quick heuris-tics in our everyday decisions, we can be led astray. Our personal lens creates errors of social attribution, memory, and miscalculations—for example misjudging risk—all of which affect how we assimilate information. These mental mistakes or cognitive biases interfere with our desire to appreciate others and treat people equally, and

they greatly compromise our ability to make sound decisions.

There are many ways in which humans can be infl uenced or biased. Companies and universities require overt biases to be disclosed when reporting fi ndings for studies or even when providing education. However, we also need to be cognizant of the covert, cognitive biases that infl uence our daily decisions. Even though most errors in our thinking occur uncon-sciously, we can learn behaviors that de-bias our decisions.

The Top Three Cognitive BiasesConfi rmation biasWho doesn’t want the best person for the job? The fact is we pass most of our judgment about a candidate in the fi rst few seconds of meeting the person. Confi rmation bias occurs when we make assumptions about people, essentially confi rming our belief when linking candidates’ traits or actions with our preconceived ideas about those traits and actions. Confi rmation bias can lead quickly to hiring the wrong person for the job and create an unfair playing fi eld for other applicants. The strength of a handshake, where the candidate went to college, whether or not the person smiles, how he or she dresses, his or her sex, and race are all factors that can infl uence who gets a job even before considering the individual’s qualifi cations.

Interviews are a time to recognize subtle, unconscious judgments that our minds might make. Is it possible that the candidate with the weak handshake has a disability affecting his hand? Why would graduation from your rival college make this

candidate unsuitable for any particu-lar position? We owe it to our patients to ensure we acknowledge our own reactions as well as the reactions of others, and to listen for clues that the candidates possess the expertise and experience that make them the best fi t for the job.

Bandwagon biasBandwagon bias, also known as herd behavior, is a common bias that can impact labs in many ways. For example, consider requests from mul-tiple departments to have all samples prioritized as stat. A surgeon hears that the emergency department (ED) is sending all of its samples in red bags so that lab staff can prioritize and process those samples more quickly. Well, what is good for the ED must be good for the operating room and intensive care unit, and pretty soon the laboratory ends up with a stat priority determination for the major-ity of in house samples. Stat becomes the routine, and patients truly in need of stat priority are now at higher risk of being overlooked. While these departments had good intentions of getting their samples prioritized and processed quickly, their herd behavior overloaded the system.

We love to follow the crowd—it satisfi es our desire to fi t in. Yet the crowd doesn’t have to be a large department. It can be a small group of co-workers, banding together to make changes without careful consideration of the consequences.

Framing effectThe framing effect occurs when people react to a choice differently depending on whether it is presented

BY CORINNE R. FANTZ, PHD, DABCC, AND MICHAEL ASTION, MD, PHD

EXAMPLES OF COMMON HEURISTICS IN THE CLINICAL LABORATORY AND HOW THEY CAN CAUSE PATIENT SAFETY PROBLEMS.• Assuming that a coworker has completed a

task, such as communicating a lab result, because that coworker is usually reliable.

• Taking a work break at a time when the Emergency Department is usually not busy, but without confi rming.

• Hiring a person who has many similarities to the group, but who turns out to be disruptive to the lab’s workfl ow.

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as a loss or a gain. Political ads, opinion polls, and advertisements are often framed to elicit a desired response. Sales teams are constantly bombard-ing labs with framed solutions to their problems. Later, labs may realize the framing effect when these solutions turn out to cause problems.

For example, healthcare administra-tors considering budget requests may be subject to framing effect biases. The administrator may react more or less favorably depending on how it is justifi ed (framed) and the project’s perceived importance. A large percent-age reduction in errors or costs is more likely to be viewed as favorable versus presenting a low absolute number of errors or costs—even though the two choices are identical.

Laboratory leaders asking for budget justifi cations should expect to be presented with biased views for the requests. Leaders need to consider what may be missing to get an accu-rate understanding of the proposed sale or request.

Overcoming BiasMany situations facing laboratorians are likely to involve bias. Consider the following fi ve tips for reducing the effect of bias on decision making:

• Recognize that bias is a factor in decision making. Remind yourself of a bias-based error that you have made in the past.

• Make key decisions—such as hiring, technology selection, and budget approvals—deliberately. Include a pause period to see if a decision marinates well over time before proceeding with it. Many times, a colleague will come in your offi ce expecting you to make a decision immediately, but the situation is not urgent. Have the courage to take some time to refl ect before making a fi nal deci-sion. Let people know that your

pause is not a delaying maneuver, but rather a tactic to make a good decision.

• Use people outside your herd to help with your decision process. They can bring fresh eyes and ears to it, and may not be so easily led by the herd.

• Ask an outsider to look critically at your decision, with an eye for bias-based weaknesses in the decision.

In summary, whether we admit it or not, bias lives in all of us. Overcoming bias involves acknowledging its pres-ence and then practicing some simple interventions to overcome it.

EDITOR-IN-CHIEF

Michael Astion, MD, PhD Seattle Children’s HospitalSeattle, Wash.

Nikola Baumann, PhDMayo ClinicRochester, Minn.

Sharon Geaghan, MDStanford University School of Medicine, Stanford, Calif.

PATIENT SAFETY FOCUS EDITORIAL BOARD

James S. Hernandez, MD, MSMayo Clinic ArizonaScottsdale and Phoenix, Ariz.

Brian R. Jackson, MD, MSARUP LaboratoriesSalt Lake City, Utah

Jaime Noguez, PhDUniversity Hospitals Case Medical Center, Cleveland, Ohio

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US Different Roles, Same Goals: Improving Patient Safety

Through Laboratory–Pharmacy Partnerships

Healthcare often suffers from the silo effect—the lack of shar-ing vital information across

disciplines—which impedes patient care coordination. Operating with a silo mentality not only reduces effi ciency and the quality of care but also can have serious patient safety implications (1).

Efforts to enhance patient safety nationwide are underway as health-care transitions from a fragmented model to an integrated system that fosters a multidisciplinary approach. Connecting healthcare silos through teamwork, collaboration, and com-munication has contributed to improved patient safety across vari-ous disciplines (2). However, litera-ture reports of collaborative efforts between laboratory and pharmacy remain relatively scarce. The paucity of reports on such collaborations is surprising considering that both disciplines are integral to the care of all patients, and that cultivating such partnerships can signifi cantly impact the value of lab tests and drug therapies.

This article highlights examples of laboratory–pharmacy partnerships at University Hospitals Case Medical Center (UHCMC) and the Cleveland Clinic Health System that are pro-viding safer and more coordinated patient care.

Collaborative Therapeutic Drug Monitoring Monitoring levels of high-risk drugs in the bloodstream can minimize the risks of adverse events due to toxicity and maximize effectiveness by facilitating a constant therapeu-tic concentration. The timing of

specimen collection is crucial because an incorrect draw time relative to the last dose may lead to inaccurate interpretation of test results. Timely result reporting is also important to facilitate prompt dose adjustments when necessary. The success of therapeutic drug monitoring (TDM), therefore, relies heavily on input from both the laboratory and pharmacy and benefi ts greatly when these two professions collaborate to streamline processes and provide more effective patient care.

At UHCMC, we initiated a laboratory–pharmacy collaboration to optimize TDM of immunosup-pressant medications in transplant patients. We found that many patients were having blood drawn at inconsistent times in relation to their previous dose due to variations in the dosing times and in phlebotomy workfl ow. These variations led to many instances when the blood drug levels did not refl ect true trough levels. In addition, results were not always reported in time to make an adjustment prior to the next dose.

The laboratory–pharmacy team tackled this problem by defi ning con-sistent draw times (5:30–6 a.m.) and dosing times (6:30 a.m. and 6:30 p.m.) for transplant patients. This improved the frequency with which patients have true trough levels drawn. Under our new process, phlebotomists go to the transplant fl oors fi rst for morning blood draws and a nurse further expe-dites collection by fl agging the charts of patients who need therapeutic drug levels determined.

Defi ning the morning run times for immunosuppressant levels in the lab enables results to be available by

early afternoon and increases the fre-quency of drug doses being changed pre- versus post-evening dose. The improvements made by this collabo-ration also resulted in fewer redraws to assess drug levels, which conserves resources and prevents additional patient discomfort.

Antimicrobial StewardshipMultiple organizations, including the Centers for Disease Control and Prevention and the World Health Organization, have recently voiced concerns regarding the increasing incidence of multi-drug resistant organisms. Health systems are now focusing efforts in antimicrobial stewardship, which seeks to achieve optimal clinical outcomes related to antimicrobial use, including mini-mizing toxicity and other adverse events, reducing infection-related healthcare costs, and limiting selection for antimicrobial resistant strains (3). Increased laboratorian–pharmacist collaboration can achieve these goals by accelerating the noti-fi cation of actionable microbiology results and subsequent adjustment of antimicrobial therapy.

The microbiology laboratory and infectious diseases pharmacists at Cleveland Clinic are collaborating on a stewardship intervention involving rapid diagnostic tests for blood cul-tures. Pharmacists are notifi ed imme-diately of positive results and they review patient histories promptly. The pharmacist then notifi es the primary medical team of the positive result and any recommended changes in antimicrobial therapy. Verbal commu-nication of positive laboratory results to the pharmacist allows patients to

BY ROSEMARY PERSAUD, PHARMD, AND JAIME NOGUEZ, PHD

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receive targeted antimicrobial treat-ment sooner. Direct interaction and feedback between the pharmacist and ordering prescriber helps reduce inap-propriate use of antimicrobials.

PharmacogenomicsPharmacogenomics is an emerg-ing area in medicine that takes into consideration the contribution of genetic variability on drug response. Certain medications administered at recommended doses may yield sub-therapeutic drug levels or cause toxicity due to variations in patients’ genetics. Because pharmacogenomic testing is based on genetic charac-teristics, the results will not change and can be used to guide medication therapy throughout a patient’s life. Laboratory–pharmacy collaborations are useful in this area to facilitate appropriate test utilization, selection, and interpretation so patients receive suitable drug therapy.

At Cleveland Clinic, our labora-tory and pharmacy departments are collaborating on test utilization efforts to ensure that we interrogate appropriate genetic variants for select pharmacogenomic test orders, and that we place the results in the elec-tronic medical record (EMR) for easy accessibility. When the laboratory receives these test results, we enter them into discrete fi elds in the EMR that are displayed differently than other laboratory results. This makes pharmacogenomic results easily accessible over an extended period of time and ensures they are not buried behind other test results. Additionally, our EMR has clinical decision support functionalities that notify physicians of relevant pharmacogenomic test results when particular medications are prescribed.

Collaborative Approach to Quality ManagementHospital pharmacies perform sterile compounding of parenteral medications and nutritional prod-ucts. However, both automated

compounding devices and manual preparation techniques carry risks for errors that can lead to patient harm. Laboratorians and pharma-cists working together can mini-mize medication-related errors and improve patient safety by ensuring that medication solutions are mixed accurately.

The UHCMC laboratory and pharmacy have collaborated to imple-ment an additional quality check for the total parenteral nutrition (TPN) batches formulated daily for our pediatric and adult patients. We prepare daily two batches of each formulation and send samples from each batch to the laboratory for test-ing to ensure that the components are within acceptable limits. The lab calls the results to a pharmacist who signs off on the acceptability of each batch before it is released for patient use. This check ensures that we detect any large variations in either the TPN content or our preparation practice.

Laboratory and pharmacy have successfully collaborated on multiple projects to improve patient care at our institutions. Working toward a shared goal helped each department gain a better understanding of what they contribute to a process and enabled all parties to provide input on

how to improve it. Although initiat-ing projects between departments may be challenging, the potential benefi ts of collaboration are well worth the efforts.

Starting with small interdisciplin-ary projects to improve patient safety issues helps break down organiza-tional barriers and leads to small victories, creating momentum for larger-scale efforts in the future. By moving away from the silo mentality, our institutions have been able to uti-lize the expertise of both laboratori-ans and pharmacists to have a greater impact on patient care.

References1. Institute of Medicine. Crossing the

Quality Chasm: A New Health System for the 21st Century. Washington, D.C.: National Academy Press; 2001.

2. Epstein NE. Multidisciplinary in-hospital teams improve patient outcomes: A review. Surg Neurol In 2014;5:S295–303.

3. Dellit TH, Owens RC, McGowan JE, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institu-tional program to enhance antimi-crobial stewardship. Clin Infect Dis 2007;44:159–77.

START FROM THE TOPA culture of collaboration begins by establishing a leadership team. Select individuals from your department to serve as leaders who will oversee collaborative efforts and drive progress.

GET ON THE SAME PAGEWorking toward a shared goal is a key component of successful collaboration. Establish clear goals and expectations that are aligned so everyone understands the objective.

KNOW YOUR ROLEFor effective partnerships, defi ne the roles and responsibilities of each team member and each department to promote accountability and effi ciency.

MAP THE PROCESSMapping the process together—taking current departmental workfl ows and needs into consider-ation—is the best way to avoid ineffi cient and non-sustainable processes. Encourage input from front-line team members to contribute to long-term solutions.

Tips for Effective Multi-Disciplinary Collaboration

26 APRIL 2015

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EKF Molecular Diagnostics, Angle Partner on Liquid Biopsy for Colon, Other CancersEKF Molecular Diagnostics has entered a collaboration with the specialist medtech company Angle to develop a liquid biopsy combining Angle’s Parsortix circulating tumor cell (CTC) harvesting platform with EKF’s PointMan DNA enrichment technology. The collaboration will initially focus on colorectal cancer before expanding to other cancer types, and will start by harvesting CTCs from cancer patients’ blood using Angle’s Parsortix system. These CTCs will then be analyzed using PointMan DNA enrichment technology to identify genetic variation in the cancer.

The PointMan system preferentially amplifi es variant sequences of interest while suppressing amplifi cation of wild type DNA, giving it the potential to identify all mutations associated with the clinical utility of targeted cancer therapies. Both EKF and Angle believe this may give PointMan an advantage

over existing genetic analysis systems, which generally only amplify those areas predicted to contain a mutation, potentially missing unexpected

variants. The PointMan system also works with levels of target material potentially as low as one CTC, while the Parsortix system harvests rare CTCs in cancer patient blood even when there is less than one CTC in one billion healthy cells. These capabilities could enable the combined Parsortix-PointMan system to be used in the diagnosis of a wide variety of cancer types and stages of disease.

Through Angle’s existing research collaboration with the University of Surrey and the Royal Surrey County Hospital, the University of

Surrey Oncology Department has already processed 20 colorectal cancer patient samples with the Parsortix system and stored the harvested cells

for analysis. This bank of samples should enable the collaboration to make rapid progress toward initial proof-of-principle.

■ ORTHO INKS AGREEMENT TO DISTRIBUTE TRANSFUSION DIAGNOSTICS PLATFORM

O rtho-Clinical Diagnostics has entered an agreement with

commercial-stage diagnostics com-pany Quotient Limited to distribute and sell Quotient’s transfusion diagnostics platform MosaiQ. MosaiQ, which is currently in development, is being designed with Quotient’s proprietary technology platform with the aim of providing improved time to results and more comprehensive matching of donor and patient blood.

Under the terms of the agreement, Quotient is responsible for developing and launching MosaiQ, while Ortho will have exclusive rights to distribute

MosaiQ to the global patient testing market for blood grouping, and to the donor testing market in the develop-ing world and Japan for blood group-ing and serological disease screening.

■T2 BIOSYSTEMS, CANON COLLABORATE ON LYME DISEASE TEST

T2 Biosystems and Canon U.S. Life Sciences have formed a

strategic agreement to develop a novel diagnostic test panel for the rapid detection of Lyme disease. The current gold standard for Lyme disease diagnosis is blood culture, but this technique has low sensitivity and takes approximately 2 to 3 weeks to

provide results. The Centers for Disease Control and Prevention estimates that Lyme disease affects close to 360,000 people in the U.S. each year, but that only 30,000 of these cases are reported due to poor diagnostic testing. This partnership hopes to leverage the T2 Biosystems T2MR technology platform—which uses magnetic resonance to detect molecular and immunodiagnostic targets—to develop an accurate test that can provide results within hours. Under the terms of the agreement, T2 Biosystems will receive an upfront payment of $2 million from Canon U.S. Life Sciences, and additional milestone payments that will add up to $8.5 million.

27APRIL 2015C

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■WAFERGEN, U TORONTO TO DEVELOP TEST FOR POPULATION-WIDE BRCA1, BRCA2 SCREENING

WaferGen Biosystems has formed a research partner-

ship with the Familial Breast Cancer Research Unit of the Women’s College Research Institute at the University of Toronto to develop a cheaper test for BRCA-related cancer. With a focus on breast and ovarian cancers, the Familial Breast Cancer Research Unit studies genetic mutations that are known to increase the risk of many cancers, most notably the BRCA1 and BRCA2 mutations. The collaboration will use WaferGen’s Seq-Ready TE System—a one-step target enrichment and library preparation solution—with the goal of enabling affordable, large-scale BRCA1 and BRCA2 screening for the general population. The research conducted around the collaboration will be led by Steven Narod, MD, director of the Familial Breast Cancer Research Unit and co-discoverer of the BRCA1 and BRCA2 genes.

“We believe that there is a sig-nifi cant medical benefi t to providing BRCA1 and BRCA2 genetic testing for the general population,” said Narod. “However, in order to offer large-scale genetic screening, an accurate, low-cost test will need to be developed. Based on our experience, we think WaferGen’s Seq-Ready TE System has the potential to enable the develop-ment of such a test.”

■ROCHE BUYS COMPANY SPECIALIZING IN CANCER BIOBANKS, NEXT-GENERATION SEQUENCING

Roche has acquired Signature Diagnostics, a translational

oncology and genomics company that develops large blood plasma and tissue biobanks in multiple cancers—including colorectal and lung—from multicenter prospective clinical studies. Signature uses the samples from its biobanks along with

accompanying clinical progression and genetic data to develop and validate next-generation sequencing (NGS)–based cell-free DNA tests for non-invasive monitoring of treatment response for cancer patients. “Biobanks play an important role in uncovering the cause or origin of disease such as cancer, which is important in translational research and the development of personalized therapies for patients,” said Roland Diggelmann, chief operating offi cer of Roche Diagnostics. “Signature represents a unique bridge between high value cancer biobanks and NGS assay development. Roche plans to leverage Signature’s expertise in both of these areas to accelerate the development of targeted NGS-based diagnostics in the future.”

■BAYLOR COLLEGE OF MEDICINE, MIRACA TO START NEW CLINICAL GENETICS LAB

Under the terms of a new partnership, Baylor College of

Medicine in Houston, Texas plans to share ownership and governance of its clinical genetics diagnostic laborato-ries with Miraca Holdings. Baylor is home to one of three U.S.-based large-scale genome sequencing centers funded by the National Institutes of Health, and Miraca is a Japan-based international healthcare company with a focus on clinical laboratory testing. Together, the two plan to start Baylor Miraca Genetics Laboratories, a jointly-owned clinical diagnostic venture that will be headquartered in Houston. The new laboratories will be built on Baylor’s existing Medical Genetics Laboratories. “Academic medical centers and teaching hospitals in Houston have lagged behind other areas of the country in commercial-izing medical inventions developed in their laboratories,” said Paul Klotman, MD, president, CEO, and executive dean of Baylor. “With partnerships such as this, the potential for growing biotech into a major economic driver for Houston and the Texas Medical Center is tremendous.”

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NEW DATES FOR 2016 AACC ANNUAL MEETING & CLINICAL LAB EXPOAACC announced a date change for the 2016 AACC Annual Meeting & Clinical Lab Expo in Philadelphia, due to the scheduling of the Democratic National Convention. The new dates for AACC’s 2016 meeting are July 31–August 4, 2016—one week later than the original planned dates. This year, AACC’s meeting is in Atlanta, Georgia, July 26–30.

28 APRIL 2015

QAsk The Expert

Tackling Profi ciency Testing Failures

EXPERT

Rex Astles, PhD, DABCC, FACB

required by CLIA regulations, then a miss causing an unsatisfactory PT event (<80% correct) is likely to have regulatory implications. CLIA requires that the root causes for any PT miss be investigated and fi xed, and the outcomes documented.

The consequences of a PT miss depend upon how many challenges were missed and the frequency of errors. PT events usually occur three times per year and most events involve fi ve challenges. For most required analytes, missing only one of fi ve challenges (80% score) is passing and the event is “satisfac-tory.” An “unsatisfactory” score will involve scrutiny by CLIA survey-ors or accreditation organizations. Fortunately, by carefully reviewing PT results from every event, a laboratory can frequently detect and deal with analytical problems before they result in inaccurate patient testing.

What are the odds that a given PT result may be outside the CLIA acceptance limits (ALs)?Typically, PT results are judged against results from other laboratories that use the same test method; the target value is the mean of equivalent test methods in the peer group. Some ALs are based on percentages and/or concentrations around the peer group mean. In other cases, ALs are three standard deviations, in which case the miss rate per challenge will typically be about 1%—or greater due to non-Gaussian distribution—regardless of the peer group’s overall precision. The risk of a specifi c PT result failing a challenge depends upon not only the laboratory’s accuracy relative to its peer group, but also the stringency of the analyte’s AL. Analytical perfor-mance goals should be tight enough to minimize the risk of missing a PT challenge, but perhaps even tighter to meet clinical needs based on the laboratory director’s judgment.

What should one do after a PT miss?The response should begin with reviewing all the recorded data sur-rounding the PT event. Look for obvious transcription errors, including transposed results, miscalculations,

I missed a PT challenge. What now?

A:When profi ciency testing (PT) challenges are missed, the labo-

ratory is presumed to have a problem with the test method, and this is an opportunity to identify and fi x problems in the total testing process. If the challenge involves one of the approximately 100 analytes explicitly

and so on. Question the technologist who performed the analysis to assure the PT samples were handled cor-rectly. Barring obvious pre- or post-analytic explanations, focus should include analytic causes, which would include systematic errors (bias) and random errors (imprecision).

To look for bias relative to the peer group, examine results for all chal-lenges for the past few events. Are results consistently running below or above the peer group mean? Review the calibration and calibration verifi ca-tion records looking for shifts in qual-ity control (QC), internal standards, and, if possible, the mean or median of patient results. Review maintenance records and compare reagent lot records against calibration records.

While sources of systematic error are more likely to cause misses for several PT challenges, sources of random error are likely to pres-ent as a relatively rare aberration. Reviewing QC results and previous PT results also helps to detect sources of random error. It may be helpful to review training records and compe-tency assessment records. Of course, sometimes both systemic and random errors may simultaneously underlie PT misses.

In short, PT misses and unsat-isfactory events help identify and correct underlying problems, as PT is designed to do. It is helpful to know the PT ALs and actively review all PT results, especially when they are approaching ALs. Even when there aren’t any misses, staff can keep ahead of sources of error. CLSI GP27-A2, “Using Profi ciency Testing to Improve the Clinical Laboratory,” is especially helpful for interpreting patterns in PT results. PT programs and accreditation organizations can provide helpful advice, too.

Rex Astles, PhD, DABCC, FACB, is a health scientist at the Centers for Disease Control and Prevention (CDC) Division of Laboratory Programs, Standards, and Services. He leads a CDC team that is working with the Centers for Medicare and Medicaid Services to update the CLIA regulations for PT. +EMAIL: jda4@cdc.gov

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from 14 high-risk types of human papilloma virus (HPV) that together cause 90% of cervical cancers. In January 2015, the American Society for Colposcopy and Cervical Pathology (ASCCP), and the Society of Gynecologic Oncology (SGO) issued interim guidance that newly suggests HPV primary (HPVpr) testing as a possible screening strategy, in addition to cytology and use of both tests, also known as co-testing.

The interim guidance recommends that clinicians con-sider HPVpr testing for women starting at age 25. Those with negative results should not be retested again for at least 3 years, while women who test positive for HPV 16 and 18 should have colposcopy. Women positive for the 12 other high-risk HPV genotypes should have refl ex cytology (Obster Gynecol 2015; 125: 330-7).

Among HPVpr’s advantages over cytology and co-test-ing is a single FDA-approved algorithm for handling abnor-mal results, the interim guidance notes. HPVpr also offers better sensitivity and negative-predictive value (NPV) for cervical intraepithelial neoplasia grade 3 (CIN3) or higher, as demonstrated by recently published fi nal data from the ATHENA (Addressing THE Need for Advanced HPV Diagnostics) trial (Gynecol Oncol 2015; doi:10.1016/j.ygyno.2014.11.076). However, HPVpr’s increased sensitiv-ity results in more colposcopies than co-testing or cytology, although the number of colposcopies needed to detect a single case of CIN3 after HPVpr is roughly equal, the study says.

“The new guidelines support the well-researched premise that HPV causes cervical dysplasia and malignancies,” said interim guidance fi rst author Warner K. Huh, MD, associate professor of gynecologic oncology and associate scientist at the University of Alabama Comprehensive Cancer Center in Birmingham. “When women get negative HPV results, there’s an extraordinarily low risk of their developing cancer. You don’t get the same reassurance with the Pap.”

Authors of the interim guidance and others in the fi eld have expressed concern about the increased use of col-poscopies that will occur with HPVpr, while others have urged continued caution about its use in women ages 25 to 29. But experts agree: clinician education about HPV, the

April 2015

ClinicalLaboratory

News

An AACC Publication | Special Supplement

New Guidance on Cervical Cancer Screening THREE MEDICAL SOCIETIES RECOMMEND HPV PRIMARY TESTING

BY DEBORAH LEVENSON

Since the Food and Drug Administration’s (FDA) April 2014 approval of the Roche Molecular Systems cobas HPV test, clinicians and laboratorians have been waiting for

guidance on how to use the assay, which detects DNA continues on next page

SPONSORED BY ROCHE DIAGNOSTICS

CERVICAL CANCER SCREENING SENSITIVITY

Sensitivity for cervical intraepithelial neoplasia grade 3 or higher. Source: ATHENA trial.

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interim guidance, and relevant data is crucial.

Recommendations and DataIn developing the interim guidance, its authors reviewed 11 studies, includ-ing ATHENA. This trial followed 47,000 women ages 21 or older for 3 years to compare cytology, co-testing, and HPVpr for detecting high-grade lesions. For women who had HPVpr screening, researchers handled abnormal results according to the FDA-approved algorithm also recom-mended in the interim guidance.

For women in all age groups, HPVpr had the highest sensitivity for CIN3, 76.1%, versus 47.8% for cytology and 61.7% for co-testing. The specifi city for CIN3+ was 97.1%, 94.6%, and 93.5% for cytology, co-testing, and HPVpr, respectively.

Women ages 30-39 had the high-est rate of CIN3, 40.3%, compared to women 25-29 (34.3%), and 40 or older (25.3%). Among the young women who had co-testing, more

than half of CIN3 detected by HPV tests were not found by cytology, the researchers noted.

Among young women, HPVpr testing had both the highest sensitiv-ity for CIN3, 76.1%, and NPV, 99.7%, while its specifi city was 93.5% and its positive-predictive value (PPV) was 12.9%. In contrast, co-testing’s sensi-tivity for CIN3 was 61.7%, specifi city was slightly higher at 94.6%, and PPV and NPV were slightly lower at 12.6% and 99.5%, respectively. Both HPVpr testing and co-testing outperformed cytology, which for CIN3 had a sensi-tivity of 47.8%, specifi city of 97.1%, PPV of 17%, and NPV of 99.3%.

Among women age 30 or older, HPVpr also had the highest sensitiv-ity and NPV for CIN3, at 72.3% and 99.7%, respectively. HPVpr had speci-fi city of 94.9% and PPV of 12.1%. Meanwhile, for CIN3, co-testing had sensitivity of 69.3%, specifi city of 94.7%, PPV of 11.4%, and the same NPV, 99.7%. In this age group, for CIN3, cytology had a sensitivity of

48%, specifi city of 97.7%, as well as PPV and NPV of 16.7% and 99.5%, respectively.

The downside of primary screen-ing is a signifi cant increase in the number of colposcopies compared to either cytology or co-testing, the researchers wrote. Compared to cytology, HPV primary screen-ing almost doubled the number of colposcopies among women age 25 or older. Among the cytology group, there were 1,934 colposcopies, versus 3,769 in the HPVpr group. However, the number of colposcopies required to detect a single case of CIN3 was almost the same for HPVpr and co-testing—12.9 and 12.8, respectively.

Concerns About Young WomenPrior to release of the interim guid-ance, using HPVpr in women ages 25–29 had been a topic of debate. Some, including Attila Lorincz, PhD, worried about overuse of colposcopy in these younger women, whose infections might regress. Lorincz developed the fi rst HPV test and is professor of molecular epidemiology at the Wolfson Institute of Preventive Medicine at Queen Mary University of London.

Lorincz supports the interim guid-ance recommendations for HPVpr screening in women age 30 or older and in women ages 25–29, with carefully considered triage. However, he is still concerned about HPVpr in younger women and urges clini-cians to study the interim guidance in detail so they can clearly explain both risks and benefi ts. “The authors say these relatively common lesions in young women are important to detect and treat immediately, yet in the paper they state that up to 60% of CIN2 in young women regress,”said Lorincz. He pointed to a recent analysis that found more than 1% of women who have cervical treatment suffer serious obstetrical complica-tions such as miscarriage and ectopic pregnancy (BMJ 2014;349:g6192).

An ATHENA researcher defends the recommendation for HPVpr screening in younger women. “Screening is not about fi nding cancer, but about preventing it. After age 30, the cancer incidence goes up. So age 25 to 29 is the sweet spot for fi nding pre-cancer, and HPV primary

A New HPV Vaccine Shortly before three medical societies released interim guidance on use of a human papil-loma virus (HPV) test for primary screening, the Food and Drug Administration in December 2014 announced approval of a new vaccine that has the potential to protect against approxi-mately 90% of cervical, vulvar, vaginal, and anal cancers.

Gardasil 9, manufactured by Merck and approved for females ages 9 through 26 and males ages 9 through 15, protects against fi ve HPV types not covered by other HPV vaccines on the market. These types—31, 33, 45, 52, and 58—cause 20% of cervical cancers. As other FDA-approved HPV vaccines do, Gardasil 9 also protects HPV types 16 and 18, which cause 70% of cervical cancers, as well as types 6 and 11, which cause genital warts.

Increased use of the vaccine will eventually lead to changes in cervical cancer screening, said Mark H. Stoler, MD, who helped develop Gardasil 9 and is professor emeritus of pathology, cytology, and gynecology and associate director of surgical pathology and cytopathology at the University of Virginia School of Medicine in Charlottesville and past president of the American Society for Clinical Pathology. “Screening only works when there’s a certain prevalence. As vaccination increases and HPV prevalence drops, we will need more sensitive tests to fi nd residual disease in the population.”

In Australia, an 80% vaccination rate among young people led the nation’s Medical Services Advisory Committee to recommend that in 2016, cytology be phased out and replaced with HPV primary testing beginning at age 25, with a 5-year screening interval, Stoler noted.

Even with a relatively low vaccination rate of 30% to 40% among young people in the United States, incidence of HPV infection among U.S. teens is decreasing, noted Warner Huh, MD, author of recent interim guidance recommending HPV primary screening and associate professor of gynecologic oncology and associate scientist at the University of Alabama’s Comprehensive Cancer Center in Birmingham. A study by researchers at the Centers for Disease Control and Prevention shows that compared to the 4 year period prior to vaccine availability, infections with four HPV types targeted by the vaccine decreased by 56% among girls ages 14 to 19 in the 4 years after its introduction (J Infect Dis 2013;208:385–93).

3APRIL 2015 • SPECIAL SUPPLEMENT

screening in these women is a reason-able choice,” said Mark H. Stoler, MD, professor emeritus of pathology, cytology, and gynecology and associ-ate director of surgical pathology and cytopathology at the University of Virginia School of Medicine in Charlottesville and past president of the American Society for Clinical Pathology.

“The absolute numbers of colpos-copy [in the ATHENA data] look big, but not bigger than with co-testing. More colposcopy is what we have to contend with in order to fi nd more disease,” Huh added.

More Study NeededNoting a dearth of direct cost com-parisons of HPVpr, co-testing, and cytology, the interim guidance calls for more such research. A study by Huh compared costs of HPVpr with HPV 16 and 18 genotyping over 40 years and used preliminary ATHENA sensitivity and specifi city data. Huh found that the strategy reduced overall screening costs compared with cytol-ogy and co-testing, but it included only women ages 30 or older (Appl Health Econ Health Policy 2015;13:95–107). This analysis preceded Roche’s FDA application for primary screening, noted Huh, who hypothesized that the added colposcopies expected in younger women would likely make HPVpr less cost-effective.

While interim guidance directs clinicians to retest HPVpr-negative women no sooner than 3 years later, without specifying an optimum inter-val, it also calls for data to help deter-mine one. Studies conducted outside of the U.S. are poised to deliver that triage data. Lorincz is collaborating with Mexican researchers on FRIDA (Forwarding Research for Improved Detection and Access for Cervical Cancer Screening), which involves 100,000 women, but no HPV testing for those younger than 30. Other triage studies are ongoing at Vrije Universiteit Medical Center in the Netherlands, and in Canada, where researchers are fi nishing the HPV Testing for Cervical Cancer Screening (HPV FOCAL) study.

Educating CliniciansIn addition to the interim guid-ance, multiple screening guidelines

subject to more rigorous development processes still exist, notes Frederick Nolte, PhD, professor of pathology and laboratory medicine, vice chair of laboratory medicine, and director of clinical laboratories at the Medical University of South Carolina in Charleston. He urged laboratorians to help clinicians sort out the various recommendations.

Because the interim guidance considers cobas the only appropriate HPVpr test until FDA approves oth-ers, “there has to be dialogue between labs and clinicians about what HPV test the lab offers,” he added. Labs that do not use cobas should refer clinicians seeking HPVpr screening to labs that do. Nolte also urged labs to determine if clinicians are ordering HPV assays for primary screening, co-testing, or as refl ex tests.

Before discussing the most appro-priate HPV test, some laboratorians may fi rst need to dispel many clini-cians’ insistence on annual cytology, despite various guidelines’ recommen-dation for cytology screening every 3 years, said Lee Shulman, MD, chief of the Division of Obstetrics and Gynecology–Clinical Genetics and professor in obstetrics and gynecology and clinical genetics at Northwestern University in Chicago.

Shulman urged laboratorians to remind clinicians that although cytol-ogy is a powerful detector of cervi-cal cancer, it is not very effective at detecting changes that lead to cancer, which is the real goal of screening. Many clinicians forget that cervical surveillance is the main purpose of the annual gynecology visit, he added. Clinicians may cling to cytology screening because they fear patients won’t return for annual visits without it. Meanwhile, some clinicians have resisted use of HPV tests because insurance companies have balked at paying for them. “That’s changing now,” Shulman said.

As the state of knowledge about cervical cancer screening and practice evolves, laboratorians and clinicians should prepare for a future in which they will do more HPVpr tests and fol-low-up of HPV 16/18 positive results, and more young people receive HPV vaccinations, which could eventually alter the effectiveness of screening tests (see sidebar). “Labs will need to

keep on their toes due to the rapidly changing landscape in HPV testing, which is going to become an even big-ger and more important test over the next fi ve to ten years,” Lorincz said. “Keep your eyes on the many changes to come.”

Deborah Levenson is a freelance writer in College Park, Maryland.+EMAIL: dlwrites@verizon.net

Disclosures:

Dr. Huh is on the Scientifi c Advisory Board at Merck, which manufactures Gardasil.

Dr. Stoler is a consultant and speaker for Roche Molecular Systems and helped develop the Gardasil 9 vaccine.

Dr. Shulman is a speaker for Roche and has received honorarium from Qiagen.

Dr. Nolte is a member of the Gen-Probe scientifi c advisory board and has received grants from the company. His lab was a clinical trial site for the Hologic Cervista HPV assay.

Before discussing the most

appropriate HPV test,

some laboratorians

may fi rst need to

dispel many clinicians’ insistence on annual cytology, despite various

guidelines’ recommen-dation for cytology

screening every 3 years.

MORE EDUCATIONAL OPPORTUNITIES

WEBINARMark Stoler, MD, an ATHENA study principal, explains in a free, 60-minute webinar what new developments in cervical cancer screening mean for women’s healthcare. The webinar is supported by an educational grant from Roche Diagnostics. www.aacc.org > meetings and events > webinars

AACC ANNUAL MEETING & CLINICAL LAB EXPO EVENTA special event, Transforming Patient Care with Molecular Testing: Current and Future Impacts, will be held on Tuesday, July 28, 5:30–7:30 p.m. at the Hyatt Regency Atlanta, International Ballroom North. This educational activity has been made possible by an educational grant from Roche Diagnostics.www.aacc.org > meetings and events > conferences

4NOVEMBER 2014

For more information about the cobas® HPV Test, contact your Roche sales representative or visit www.hpv16and18.com.

Women ages 25-29 now have a better option for cervical cancer screening.

Recognizing that primary HPV screening delivers more accurate risk assessment than cytology alone, ASCCP and SGO screening guidance for women ages 25 and older now includes the option of primary HPV screening.2

But better risk assessment requires using the right HPV test. Roche’s cobas® HPV Test is the only test that has been approved by the FDA for primary HPV screening.

Are you prepared to give clinicians confidence and patients peace of mind? Be ready with Roche.

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References: 1. US Census Bureau. Age and Sex Composition: 2010 (C2010BR-03). Washington: GPO; 2011. 2. Huh WK, Ault KA, Chelmow D, et al. Use of primary high-risk human papillomavirus testing for cervical cancer screening: Interim clinical guidance. Gynecol Onc. 2015 Jan. doi: http://dx.doi.org/10.1016/j.ygyno.2014.12.022 [Epub ahead of print].

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