January 2015

ClinicalLaboratory

News

An AACC Publication | Volume 41, Number 1

The Case for Anti-

Müllerian Hormone

Pushing Back on

FDA’s LDT Proposal

BIOMARKER BOOM

FOR COLON CANCER

SCREENING

CHOOSING AN AUTOMATED INSTRUMENT

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Focus Diagnostics, Simplexa and the associated logos are the trademarks of Quest Diagnostics. © 2014 Focus Diagnostics, Inc. All rights reserved. The use of Scorpions® probes for human in vitro diagnostic purposes is covered by a license to Focus Diagnostics, Inc., from DxS Ltd. Black Hole Quencher™, CAL Fluor™ and Quasar™ dyes are trademarks of Biosearch Technologies, Inc. ( ‘BTI’). Black Hole Quencher, CAL Fluor and Quasar dye technology is licensed pursuant to an agreement with BTI, and these products are sold exclusively for clinical, diagnostic, or research and development purposes.

1CONTENTSJANUARY 2015

EDITORIAL STAFFManaging Editor Bill MaloneSenior Editor Genna RollinsCommunications CoordinatorChristine DeLongContributors Geralyn Lambert-Messerlian, PhD, FACB

BUSINESS STAFFManager of Business & Publications Marketing Camille Walker

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

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

Juravinski Hospital and Cancer Center, Hamilton, Ontario

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

Steven Goss, PhDSiemens Healthcare Diagnostics, Newark, Del.

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

AACC OfficersPresident 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.

Design and Production Management

www.aacc.org

@ CLN_AACC

Features 8 AACC Urges FDA to Correct Course on Laboratory- Developed Test Proposal

10 The New Landscape for Colorectal Cancer ScreeningNoninvasive Tests Make Their Marks

14 The New Egg Timer Anti-Müllerian Hormone Levels for Assessing Ovarian Reserve

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

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CMS Expands Bundled Payments for 2015The Centers for Medicare and Medicaid Services (CMS) is moving forward with plans to add more laboratory services into ambulatory payment classifi cation (APC) codes for hospital outpatient care. CMS began including some clinical laboratory tests in these bundles in 2014, but in 2015, the agency will add codes for certain surgical pathology procedures, as well as immunohistochemistry, fl uorescence in situ hybridization, and fl ow cytometry. CMS is showing that, despite outcries from professional organizations, it is determined to remain on a course that will pull more and more services out of fee schedules and into single, capitated payments.

When CMS bundles laboratory codes, it essentially amounts to a reimbursement cut for the laboratory, as well as more complex accounting and administrative burdens for hospitals. Medicare’s complex APC system works very differently than a traditional fee schedule. APCs are small bundles of related services that group outpatient reimbursement based on the service provided to the patient. They package closely related items such as venipuncture, medical/surgical supplies and equipment, and some pharmaceuticals.

The change not only affects labs, but patients as well, according to AACC comments on CMS proposals. Bundling laboratory tests within APCs means laboratory tests are included as part of the APC deductibles and cost-sharing arrangements, increasing the fi nancial burden on consumers, particularly the elderly and the young, the association noted.

benchmarks more independent of the ACO’s past performance and more dependent on the ACO’s success in being cost-effi cient relative to its local market. The agency also wants to fi nd ways to reduce paperwork around claims data for ACOs. A 60-day com-ment period on the proposed rule ends February 3.

■REPORT: HEALTH INSURANCE MARKETPLACE REMAINS HIGHLY CONCENTRATED

An elite group of large health-care insurers dominate the

market in most states, setting the stage for reduced competition under the Affordable Care Act marketplace, according to a Government Accountability Offi ce (GAO) report. The report looked at data from 2010–2013, and is meant to lay the groundwork for future updates after full implementation of the Affordable Care Act.

Although at least two insurers participated in each state’s individual,

small group, and large group health insurance markets in 2013, enroll-ment was concentrated among the three largest insurers in most states, the report found. In each of the three market segments, the three larg-est insurers had at least 80% of the total enrollment in at least 37 states; in more than half of these states, a single insurer had more than half of the total enrollees; and in 5 of these states, the largest insurer had at least 90% of all enrollees in at least one market segment. In 14 states, mar-ket segments were considerably less concentrated.

The report found that certain states were outliers. In Alabama, for example , Blue Cross and Blue Shield in 2013 controlled 97% of the small-group health insurance market, 92% of the large-group market, and 90% of the individual health plan market. In contrast, the top three insurers in 2013 controlled 100% of markets in rural and small states, including Mississippi, Montana, South Dakota, Vermont, and Wyoming.

■NEW CMS PROPOSAL AIMS TO IMPROVE ACOS

The Centers for Medicare and Medicaid Services (CMS)

released a proposal to strengthen the Shared Savings Program for Accountable Care Organizations (ACOs) through a greater emphasis on primary care services and by using performance-based risk arrange-ments that are meant to attract wary providers.

Many ACOs have not been able to meet benchmarks, and some hospital groups have spurned the program, citing fi nancial risk. In response, CMS now is proposing more fl exibility for ACOs seeking to renew their par-ticipation in the program by making the transition easier to the so-called two-sided model. Under this model, the ACO risks fi nancial losses if it does not meet benchmarks, but also can win a signifi cantly higher share of savings if goals are met.

Another proposal could make those benchmarks more realistic. For example, CMS could make

■NE

2015 AACC ANNUAL MEETING & CLINICAL LAB EXPO

JULY 26-30, 2015 GEORGIA WORLD CONGRESS CENTER ATLANTA, GA • USA

www.aacc.org/2015am

CALL FOR ABSTRACTS FOR POSTER PRESENTATIONS

Share your research and shape the next generation

of laboratory medicine. With more than 18,000

attendees, the AACC Annual Meeting & Clinical

Lab Expo is the ideal venue to present your results.

Submit your abstract for consideration to be:

• Presented as a poster at the 2015 Annual Meeting in Atlanta. Several recognized abstracts will also be selected for podium presentations.

• Published in an October 2015 supplement to Clinical Chemistry.

• Considered for AACC Division and Student Awards.

For more information and to submit your abstract, visit www.aacc.org/2015am. The submission deadline is Thursday, February 26, 2015, 5:00 pm EST.

4 JANUARY 2015

Bench Matters

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Max Chernesky, PhD

W ith an increasing awareness that undiagnosed and untreated infec-

tions such as Chlamydia trachomatis (CT) can cause serious complications in asymptomatic women, healthcare programs are seeking ways to screen patients more effi ciently. Many laboratories are challenged with the task of choosing automated platforms to handle the workload. We conducted two studies to provide some logic for making a decision, and developed protocols to compare four assays and fi ve instruments from prominent diagnos-tic companies.

Choosing an automated laboratory instrument is not an easy task as a lab has to consider both current and future needs. The most transparent considerations are space and costs for equipment, assays, and consumables. Labor costs require an understanding of the amount of hands-on time that is required. Other aspects that need to be considered include testing capacity for the number of tests and the variety of analytes available, work fl ow, time-to-results, mainte-nance, and the accuracy of the assays to be put through the instruments.

Our studies compared four batch processing instru-ments (Abbott m2000, BD Viper XTR, Roche cobas 4800, and Hologic Tigris) and a continuous feed, random access instrument, Hologic Panther. We compared the respective CT assays for sensitivity and specifi city in a head-to-head fashion using urines and self-collected vagi-nal swabs from 575 women. This enabled us to use results from four assays as a patient-infected status of compari-son. We spiked part of each urine and vaginal swab with a laboratory strain of CT to determine whether inhibitors of CT amplifi cation in the samples were playing a role in the comparative outcomes. We recruited four sites per-forming different assays and they served as the sources for instrument comparisons by two investigators conducting two visits of 2 days each to time interactions taking place during runs of 96 and 192 tests.

EIGHT FACTORS OF IMPORTANCEOur studies revealed eight factors of importance in consid-ering automated STI instrumentation.

First is the analytical sensitivity of the assays. In our head-to-head comparisons, we found that the assays varied in their abilities to detect infected patients, and that these

variances likely were due to differ-ences in analytical sensitivity rather than the inhibitors used in the assays.

Another consideration is the amount of laboratory space required for the instruments. The instruments we compared needed as little as 10 square feet and as much as 25 square feet.

Automation time is an important factor as well, because more automa-tion time provides more walk-away time for other technical laboratory tasks. In our studies, we found that automation time ranged from about5 hours to just over 3 hours.

Separate from but related to automation time is time-to-results, as this also impacts workfl ow. Does an instrument start generating results even while it is still in its automa-tion process? We found that one instrument fi nished its automation after 5 hours but started generating its fi rst result at about the same time as another, which completed a batch run at 3.5 hours.

A fi fth factor labs should consider in choosing automated instruments for STI testing is that total testing capacity and testing different sized

Choosing an Automated Instrument for the Diagnosis of Sexually Transmitted Infections

55JANUARY 2015

batches can impact reagent costs. How many specimens does the instru-ment allow during initial loading? Does it allow additional reagent kits and samples to be loaded as needed during processing?

TIME AT THE INSTRUMENTIn today’s cost-conscious environment, hands-on time at the instrument—which is heavily infl uenced by instru-ment design—is another important consideration. We recommend that laboratorians look at whether the instrument has separate units for extraction and amplifi cation, because this requires extra time for return vis-its, regardless of the batch size. Second runs on some instruments require time for loading samples, reagents, and consumables, whereas with others this takes only a few seconds to feed in additional reaction tubes. On a separate but related note, laboratories also would want to consider the time needed for maintenance.

Two features we were unable to compare in our studies include random access to multiple analytes and consumption of reagents and disposables. Random access to mul-tiple analytes is a nice feature, but in our experience only the Panther possessed this feature for multiple STIs. In our published work we didn’t explore consumption of reagents and disposables, but we recently exam-ined this issue and found the differ-ences remarkable. For 192 tests, we used from 240 to 1,504 pipette tips, depending on the instrument.

Overall, we recommend that labs consider assay performance and costs for equipment, reagents, labor, and consumables to provide a true assess-ment of automated instrument value.

References1. Ratnam S, Jang D, Gilchrist J, et al. Work-

fl ow and maintenance characteristics of fi ve automated laboratory instruments for the diagnosis of sexually transmitted infections. J Clin Microbiol 2014;52:2299–304.

2. Chernesky M, Jang D, Gilchrist J, et al. Head to head comparison of second generation nucleic acid amplifi cation tests for Chlamydia trachomatis and Neisseria

gonorrhoeae on female urines and self-collected vaginal swabs. J Clin Microbiol 2014;52:2305–10.

Max Chernesky, PhD, is a professor emeritus at McMaster University and St. Joseph’s Healthcare Hamilton in Hamilton, Ontario, Canada. These

studies were funded by a research grant from Hologic Inc. Dr. Chernesky has no consulting relationships with the four companies involved in these studies. He has received research funding and speaker honoraria from Abbott, Roche, and Hologic. +EMAIL: chernesk@gmail.com

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Optimal Screening Threshold for Gestational Diabetes Mellitus Proposed in Twin PregnanciesThe optimal screening threshold for gestational diabetes mellitus (GDM) in twin pregnancies using a 1-hour, 50-gram glucose challenge test (GCT) is ≥135 mg/dL, according to fi ndings by researchers at the Icahn School of Medicine at Mount Sinai and at New York University School of Medicine, both in New York City (Amer J Obstet Gynec 2014; doi.org/10.1016/j.ajog.2014.08.030). The investigators conducted this study because while GDM screening cutoffs have been recommended for singleton pregnancies, optimal thresholds for twin pregnancies have not been evaluated specifi cally.

Organizations including the American Diabetes Association have endorsed a one-step GDM screening process involving a 2-hour, 75-gram oral glucose tolerance test (OGTT). However, others, such as the American Congress of Obstetricians and Gynecologists, also support GDM screening using a non-

fasting 1-hour GCT followed by a diagnostic fasting 3-hour, 100-gram OGTT for women who exceed a GCT cutoff, usually 130–140 mg/dL.

The GCT cutoffs were based on data from singleton pregnancies, yet “in twin pregnancies, normal physiologic changes are amplifi ed, which may change the characteristics of the GCT and therefore affect the screen-positive rates leading to excessive testing and increased cost with no real improvement in the accuracy of diagnosis,” according to the authors. A dearth of data about an ideal GCT cutoff in twin pregnancy prompted the authors’ study.

The study involved 475 patients with twin pregnancies between 24–28 weeks’ gestation, who underwent a 1-hour,

50-gram GCT. Those with a GCT ≥130 mg/dL subsequently took a 3-hour, 100-g OGTT. Patients who had at least two abnormal OGTT values out of four were diagnosed with GDM.

The authors evaluated the testing characteristics of GCT using three cutoffs, ≥130 mg/dL, ≥135 mg/dL, and ≥140 mg/dL. In evaluating the sensitivity and specifi city associated with these three cutoffs, they determined that ≥135 mg/dL—associated with 100% sensitivity, 76.4% specifi city, 22.8% positive-predictive value, and 100% negative-predictive value—was optimal. Using a ≥130 mg/dL cutoff increased the test-positive rate to 34.7, whereas a ≥140 mg/dL cutoff decreased the test-positive rate to 23.4% but also failed to identify 6.5% of GDM patients.

In comparison to a cutoff of ≥130 mg/dL, ≥135 mg/dL “could potentially decrease cost and anxiety, without decreasing the sensitivity of the test,” wrote the investigators.

The authors called for more research to better understand GDM screening in twin pregnancies, to confi rm their fi ndings in other populations, and to establish the optimal GDM screening and treatment paradigm.

■TROPONIN, CK-MB TESTING COMMON IN EMERGENCY PATIENTS EVEN WITHOUT ACUTE CORONARY SYNDROME SYMPTOMS

An analysis by UT Southwestern Medical Center researchers in Dallas found that

cardiac biomarker testing in emergency patients is common even among those without symp-toms suggestive of acute coronary syndrome

7JANUARY 2015

■

SICKLE CELL TRAIT CONTRIBUTES TO CKD RISK IN AFRICAN AMERICANS

S ickle cell trait (SCT) is associated with increased risk of chronic kidney disease (CKD), decline in estimated glomerular fi ltration rate

(eGFR), and albuminuria, compared with non-carriers (JAMA 2014; doi:10.1001/jama.2014.15063). These fi ndings suggest that SCT also could be associated with the higher risk of kidney disease in African Americans, according to the authors.

The authors conducted the study to further understanding of the relationship between SCT and CKD. Although renal problems like impaired urinary concentration, asymptomatic hematuria, and papillary necrosis are common among patients with SCT, how this relates to long-term functional impairment of the kidney has not been determined clearly, wrote the authors.

To investigate the SCT-CKD relationship, the investigators drew subjects from fi ve large, prospective studies for a total of 15,975 African Americans, 1,248 of whom had SCT. Each study had slightly different kidney function assessment parameters and follow-up periods, but in general they measured serum creatinine at baseline or early in the study and at defi ned intervals. Some also measured cystatin C and urinary albumin:creatinine ratio. The researchers calculated effect sizes for each cohort and then meta-analyzed the data using a random-effects model.

In addition to genotyping for the sickle cell mutation, some participants also underwent genotyping for APOL1, as variants of this gene have been associated with CKD in African Americans.

More SCT carriers than non-carriers had CKD (19.2% versus 13.5%), experienced incident CKD (20.7% versus 13.7%), experienced declining eGFR (22.6% versus 19%), or had albuminuria (31.8% versus 19.6%) during the study period. SCT carriers had increased risk for all these conditions compared with noncarriers. All these associations were independent of APOL1 risk variant.

(ACS) (JAMA Intern Med 2014; doi:10.1001/jamainternmed.2014.5830). The fi ndings suggest more attention is needed to develop strategies for appropriate use of cardiac biomarkers, according to the authors.

The investigators conducted the study because chest pain is one of the most common complaints among emergency patients, yet troponin (cTn) and creatine kinase-MB (CK-MB) testing are not recom-mended for all such patients. When used inappropriately in patients with a low pre-test possibility of ACS, cTn testing could lead to patient anxi-ety, additional inappropriate testing, and unnecessary treatment, they contended.

The researchers accessed data from the National Hospital Ambulatory Medical Care Survey; the primary outcome among 44,448 emergency department (ED) visits was whether cTn or CK-MB tests were ordered. Overall, these tests were ordered in 16.9% of visits, including 8.2% of visits in which patients did not have ACS-related symptoms. Among patients subsequently hospitalized, CK-MB or cTn tests were performed in 47% of related ED visits, including 35.4% in which the patient did not have ACS-related symptoms. Cardiac biomarker tests also were performed frequently during ED visits with a high volume of other tests or services, independent of the patient’s clinical presentation.

■NT-PROBNP IMPROVES CVD RISK PREDICTION IN WOMEN

N -terminal pro-B-type natri-uretic peptide (NT-proBNP)

modestly improves cardiovascular disease (CVD) risk prediction in women, according to a Women’s Health Initiative (WHI) observational study (J Am Coll Cardio 2014;64: 1789–97). The authors conducted the study to better understand the relationship between natriuretic peptides (NPs) and CVD risk in women.

NP tests have gained “widespread acceptance” as diagnostic and CVD risk-stratifi cation tools, according to the authors. In that context, women

typically have higher NT-proBNP levels than men, yet lower absolute risk for CVD than men with similar risk factors. While studies have shown a consistent relationship between NP levels and CVD risk, many included only men, reported the number of CVD events in women but not the association between NP levels and CVD risk, or had too few events in women to analyze.

The study included 1,821 inci-dent cases of CVD and a randomly selected reference cohort of 1,992 women without CVD at baseline.

The researchers divided cases into quartiles based on NT-proBNP levels, and estimated their relative risk of CVD per quartile. Women in the highest quartile with levels ≥140.8 ng/L had the highest risk of CVD, with a hazard ratio of 1.53 versus those in the reference quartile with levels <50.9 ng/L.

The investigators also added NT-proBNP levels as co-variables in traditional risk factor and Reynolds Risk Score (RRS) algorithms. In the case of traditional risk factors, NT-proBNP improved the c-statistic to 0.774 from 0.765, the categorical net reclassifi cation, and the inte-grated discrimination. The authors found similar results when they added NT-proBNP concentrations to RRS algorithms.

Though statistically signifi cant, the improvements in risk prediction were “relatively modest,” according to the authors. They suggested that while NPs might be useful CVD risk prediction markers in women “for whom a decision to start statin therapy otherwise is unclear,” they cautioned that “the therapeutic response to an elevated NP level in an otherwise healthy individual is not clear.”

8 JANUARY 2015

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BY BILL MALONE

Calling on Congress and the Food and Drug Administration (FDA) to limit new regulatory burdens on clinical laboratories, AACC in November released a position statement that urges FDA to limit its proposed laboratory-developed test (LDT) oversight only to high-risk tests, with moderate- and low-risk tests remaining under

the existing authority of the Centers for Medicare and Medicaid Services (CMS). Separately, the association is also pushing FDA to withdraw draft guidance documents the agency released on October 3, 2014 and re-issue

them through the rulemaking process required under the Administrative Procedures Act. The AACC board of

directors visited lawmakers on Capitol Hill on November 21 to explain AACC’s position on LDTs.

“This FDA-proposed action on LDTs is one of the most urgent issues that clinical labora-

tory professionals currently face,” said AACC President David Koch, PhD, DABCC, FACB. “AACC welcomes dialogue with FDA about how to ensure the quality and safety of laboratory-developed tests. However, regulation that is too burdensome will negatively impact patient care, stifl e the progress of innovation, and increase the cost of healthcare.”

Support for Limited FDA RoleAACC’s position statement notes that in

2006 and 2007, FDA issued draft guidance to regulate a narrow subset of LDTs, In Vitro

Diagnostic Multivariate Index Assays (IVDMIAs), which AACC supported. But in 2010, FDA reversed

this decision and proposed that all LDTs should be subject to FDA oversight. AACC opposes this “one-size-fi ts-all approach” to regulating LDTs.

While AACC generally supports FDA’s plan to categorize LDTs as high, moderate, and low-risk, the association recom-mends limiting FDA regulation to joint oversight—with CMS—of the high-risk category. CMS under CLIA subjects

LDTs to stringent personnel, qual-ity control, and profi ciency testing standards, and requires a laboratory director with an MD or PhD and board-certifi cation to oversee the analytical and clinical validation of all tests developed within a lab.

AACC also recommends that professional laboratory associations collaborate with FDA and other stakeholders to fl esh out the criteria for sorting tests within risk categories.

In the position statement, AACC suggests that laboratories should be able to demonstrate clinical valida-tion—a subject on which the FDA has fi xated in its draft guidance—through a variety of means, including the use of existing literature review, providing an assessment of patient benefi t, or documenting that the test has become standard of care.

Crucially, ensuring patient access to a robust pipeline of LDTs also depends on test innovation. LDTs enable labs to assist physicians in diagnosing rare or new conditions for which no commercial tests exist, such as HIV and SARS when they initially emerged, the position statement notes.

Labs are already under tight regulatory and reimbursement pres-sure that leaves little room for new policy hurdles, according to Catherine Hammett-Stabler, PhD, DABCC, FACB, a member of the AACC government relations committee and

AACC Urges FDA to Correct Course on Laboratory-Developed Test Proposal

AACC Past President Steven Wong, PhD, Treasurer Michael Bennett, PhD, and

President David Koch, PhD, met with Texas Senator Ted Cruz’s legislative correspondent Courtney Asbill during the board of directors

November meetings with lawmakers.

9JANUARY 2015

A More Deliberate Policymaking ProcessIn a parallel move to the posi-tion statement, AACC joined the American Medical Association, American Hospital Association, and 48 other healthcare organizations in requesting that FDA promulgate any new regulations through notice and comment rulemaking rather than fi nalizing its current guidance documents. Without the rulemaking process, FDA will not have to publicly respond to comments nor conduct an economic impact analysis of the proposal.

“The FDA’s statutory authority to regulate laboratory-developed testing services and the scope of the proposed guidance remains a mat-ter of signifi cant legal controversy,” noted the joint letter to FDA. “While a number of the undersigned orga-nizations do not waive their legal claim that the FDA lacks the statu-tory authority to regulate laboratory-developed testing services, to the extent that it is established that the FDA does have such authority, all of the undersigned are unanimous that the overwhelming weight of legal authority dictates that the proposed new requirements outlined in the draft guidance must be issued through notice and comment rulemaking.”

The next step in FDA’s own pro-cess will be a public meeting January 8 and 9 in Bethesda, Maryland. Hammett-Stabler will give a state-ment for AACC at this meeting, and she will also serve as AACC’s repre-sentative during a panel discussion. a past president of the association.

“The days of labs having four or fi ve platforms or different vendors for routine testing are gone. Most of us have leaned our labs and become more effi cient,” she said. “As a result, if your instrument has an open chan-nel and you take advantage of that by putting a product on that open chan-nel, your vendor may not support it, making it an LDT, even though it’s on the automated platform.” Hammett-Stabler is a professor of pathology and laboratory medicine at the University of North Carolina School of Medicine and director of core laboratories at McLendon Clinical Laboratories in Chapel Hill, North Carolina.

Moreover, laboratories depend on many LDTs which cannot be taken for granted as safe under the proposed FDA oversight scheme, Hammett-Stabler emphasized. “I’m concerned that not everyone has rec-ognized that FDA’s proposal could also apply to many tests that we have used for quite some time,” she said. “For example, newborn screen-ing and the follow-up confi rmation testing for metabolic disorders using gas chromatography and mass spec-trometry, or lamellar body counts using a hematology analyzer—all of those are essentially lab-developed tests with no FDA-cleared products available.”

AACC POSITION ON OVERSIGHT OF LABORATORY-DEVELOPED TESTS

Laboratory-developed tests (LDTs) provide timely, accurate quality testing for many conditions for which no commercial test exists or when an existing test does not meet current clinical needs. The regulation of LDTs should remain under CLIA’88 and its deemed accreditation bodies, except for high risk tests that should be subject to both FDA and CMS oversight.

“This FDA-proposed action on

LDTs is one of the most

urgent issues that clinical laboratory

professionals currently

face.”

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BY GENNA ROLLINS

Efforts to curb colorectal cancer clearly have been successful, as colorectal cancer death

rates have fallen 46% from their peak, according to the American Cancer Society. This good news has to be tempered, though, by the fact that about one-third of the recom-mended population has not been screened, despite colorectal cancer having very high treatment success when detected early.

There are many reasons behind this screening gap, but one no doubt has to do with what Victoria Pratt, PhD, called the “ick factor” associated with colonoscopy—the gold standard method—as well as fl exible sigmoid-oscopy, fecal occult blood testing (FOBT), and iFOBT, also known as fecal immunochemical test (FIT) (Clin Chem 2014;60:1141–42).

A concentrated research effort has blossomed around fi nding bio-markers that could be incorporated in new screening tests that would be better accepted by individuals currently reluctant to be screened, ultimately leading to higher screening rates. Among the many candidates, 2014 was a milestone year for two promising tests, Cologuard (Exact Sciences; Madison, Wisconsin), and Epi proColon (Epigenomics; Berlin, Germany and Germantown, Maryland). Important studies were published about both, and both also were the subject of signifi cant regula-tory actions.

NONINVASIVE TESTS MAKE THEIR MARKS

THE NEW LANDSCAPE FOR

COLORECTAL CA

11JANUARY 2015

A Multi-target Fecal DNA TestIn a study of nearly 10,000 patients, researchers found that in comparison to colonoscopy, Cologuard, a multi-target fecal DNA test, had a sensitiv-ity of 92.3% for detecting colorectal cancer, and a specifi city of 86.6% (N Engl J Med 2014;370:1287–97). This compared with FIT’s 73.8% sensitiv-ity and 94.9% specifi city. Cologuard, which includes quantitative molecular assays for KRAS mutations, NDRG4and BMP3 methylation, β-actin, as well as a hemoglobin assay, performed particularly well in comparison to FIT in detecting advanced precancer-ous lesions (42.4% sensitivity versus 23.8%) and polyps with high-grade dysplasia (69.2% sensitivity versus 46.2%).

“Our study assessed the test performance in an asymptomatic average risk population, which would be the exact population for which the application would be recommended,” explained the study’s lead author, Thomas Imperiale, MD, a professor of medicine at the Indiana University School of Medicine in Indianapolis. “Everything was measured against colonoscopy to determine the multi-target assay’s sensitivity and specifi city. The other purpose was to compare it against another popular, non-invasive test, FIT. The multi-target assay was found to be more sensitive but less specifi c than FIT.”

Based on the results of this study, the Food and Drug Administration (FDA) in August 2014 approved Cologuard, and in an unprecedented move, the Centers for Medicare and Medicaid Services on the same day issued a proposed national coverage determination for the test. The latter would support reimbursement for Cologuard every 3 years in Medicare

benefi ciaries age 50 to 84 with aver-age colorectal cancer risk and no signs or symptoms of the disease.

A Blood Test for DNA MethylationEpi proColon is an entirely different type of test. This blood test detects methylated SEPT9 in circulating cell-free DNA isolated from plasma. In a study assessing the analytical and clinical performance of Epi proColon , four laboratories tested 1,544 samples from subjects enrolled in the PRESEPT trial, a prospective study aimed at assessing the clinical utility of SEPT9 based on the outcome of colonoscopy, polypectomy, biopsy, and surgical tissue histopathology (Clin Chem 2014;60:1183–91). They found the test’s limit of detection for methylated SEPT9 DNA was 7.8 pg/mL, which corresponds to less than two genome copies of methyl-ated SEPT9 per milliliter of plasma.

Epi proColon’s sensitivity for detecting colorectal cancer was 68%, and its specifi city was 79%. Sensitivity was lower for advanced adenomas (22%) and small polyps (20%). Although this particular study did not involve a head-to-head comparison between Epi proColon and FIT, a sep-arate analysis found it “noninferior” to FIT, with 72% sensitivity versus 68%, respectively.

“The primary goals of our study were to determine the analytical as well as clinical performance data for Epi proColon, which is a real-time PCR test targeting a differentially methyl-ated sequence in the promoter of the septin 9 gene,” explained lead author Nicholas Potter, PhD, FACMG, execu-tive vice president of clinical affairs at Molecular Pathology Laboratory Network in Maryville, Tennessee. “We also sought to provide data in the

context of Epi proColon’s potential utilization for screening average risk individuals for colorectal cancer.”

Epi proColon has a CE mark in Europe and applied to FDA in 2013 for premarket approval in the United States. In March 2014, the Molecular and Clinical Genetics Panel of FDA’s Medical Devices Advisory Committee narrowly endorsed premarket approval for the test. However, FDA has asked Epigenomics for additional data on how Epi proColon might improve screening rates in patients not already compliant with screening recommendations who are offered a blood-based test versus FIT. In addition, Epigenomics intends to assess compliance with colonoscopy among patients who have positive Epi proColon or FIT tests, according to a press release issued after the company met with FDA.

The Twists and Turns of DevelopmentIf Epi proColon’s commercialization process hit a speed bump, it in some ways parallels challenges Cologuard faced in its development process. During an initial study, Cologuard detected just half of the invasive can-cers and less than 20% of advanced adenomas.

Imperiale, who also was involved in that effort, recalled the earlier study and subsequent changes in Cologuard. “It was the fi rst time that anybody had put a multi-target assay together and tested it in a screening setting. It didn’t do as well as it had done in preliminary studies though the preliminary studies were done in the same way,” he explained. “We realized the error that was made, with specimen collection. It didn’t do as well because of the failure to apply

NCER SCREENING

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13JANUARY 2015

a buffer that preserved the human DNA and kept it from being broken down by bacterial enzymes.”

Cologuard’s subsequent overhaul included changing the markers—only KRAS made it in both versions—and adding an immunoassay for heme, according to Imperiale. Exact Sciences now expects to conduct post-approval testing to look at the validity of the proposed 3-year testing interval for Cologuard, he added.

On the HorizonEven as Cologuard and Epi proColon continue to make their way into the marketplace, research also is ongoing for yet other candidate biomarkers for detecting colorectal cancer. CLN’s brief survey of the literature identifi ed recent studies looking at methylated SFRP2, GATA4/5, NDRG4, and VIM, ALU in circulating cell-free DNA, and at serum microRNAs miR-21, let-7g, miR-31, miR-92a, miR-181b, miR-203, and miR-135b, among oth-ers. Potter’s analysis of the colorec-tal cancer diagnostic pipeline as of October 2014 revealed quite a range of candidate biomarkers in proposed blood, serum, plasma, and stool-based tests. In addition, emerging research is exploring the potential of emitted fecal volatile organic compounds and exhaled breath compounds.

Does the pathophysiology of colorectal cancer favor any particu-lar molecular pathways, and hence markers? Imperiale has an open mind about the possibility. “The likelihood is that over time, better markers will be identifi ed and will likely be incorporated into future multi-target assays that might help better opti-mize discrimination or improve cost-effectiveness,” he predicted. “It’s going to be a moving target, in a good way. Because the markers could change and as could the ways in which the markers are detected.”

Potter emphasized the need to put any candidate markers—regardless of type—through their paces. “There are a number of panel-based approaches in the preliminary stage of evalua-tion for use as screening targets for colorectal cancer. It’s a question of how the markers behave in prelimi-nary trial investigations, and how those performance characteristics com-pare to potential markers that other

research teams have been exploiting,” he explained. “It then becomes an exercise in exploratory due diligence with regard to setting a threshold of what you need the performance to be.” In the United States, large prospective clinical trials also would be required to provide data in support of any pro-posed screening test, he added.

If the markers and methods differ, researchers and clinicians agree the

hunt should continue. As Pratt put it, “One thing is certain: early detection improves cancer survival rates. Because only approximately 65% of eligible people are getting the recommended screening for [colorectal cancer], any test that improves screening compli-ance will save lives.”

Disclosures: Dr. Potter serves on the medi-cal advisory board of Epigenomics AG.

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BY GERALYN LAMBERT-MESSERLIAN, PHD, FACB

How old are your ovaries? While a woman’s chronological age is associated with her ovarian age, it is actually not the most accurate indicator of ovarian reserve. The term ovarian reserve refers to the number of primordial follicles—oocytes—in the ovary. Ovarian

reserve status can be used as an aid in predicting the onset of menopause, for family planning, or in treating infertility. The serum marker follicle stimulating hormone (FSH) has conventionally been used to assess ovarian reserve, but like age, it has signifi cant limitations. Anti-müllerian hormone (AMH) is emerging as the serum marker that provides the most accurate assessment of ovarian reserve and with promising emerging clinical applications.

The Biology of AMHAMH is part of the TGF-beta family of growth factors, and like other members of this protein family, it is synthesized as a larger inert precursor protein (140 kDa), called pro-mature AMH. Post-translational processing of the molecule includes cleavage at amino acid 451, resulting in an N-terminal pro region and a C-terminal mature region. These peptide fragments stay in a tight non-covalent complex, and circulate as a molecule called AMHN,C (Figure 1). The AMHN,Ccomplex enhances receptor binding and bioactivity at target tissues.

AMH was discovered and named on the basis of its role in prenatal gender differentiation. The Y chromosome directs differentiation of the gonad into testes. Sertoli cells secrete AMH, causing regression of the müllerian ducts, which would otherwise develop into the female secondary sex organs: fallo-pian tubes, uterus, and vagina.

The ovaries do not secrete AMH in early prenatal development. However, by mid-gestation, ovaries’ small developing follicles begin to produce and secrete AMH. High levels of AMH mRNA and protein are observed in the granulosa cells of primary, secondary, and preantral follicles. AMH inhibits recruitment of follicles from the primordial pool, and also inhibits the response of larger follicles to pitu-itary gonadotropin stimulation.

The New TIEGG

15JANUARY 2015

AMH has the advantage over other serum hormone markers for assessment of ovarian reserve in that it is directly produced by the small follicles of the ovary, which are most proximal to the primordial pool. This contrasts with other serum markers that are either not directly secreted by the ovary or are made by more developed follicles. For example, FSH is an indirect measure of ovarian reserve being produced by the pitu-itary gland, not the ovary. Other can-didate markers, such as inhibin B and estradiol, are produced from larger follicles after FSH stimulation, and are more distal to the primordial pool (Figure 2). Studies have shown that serum AMH has the highest correla-tion with ovarian primordial follicle number, among all serum hormones tested (Figure 3, online).

AMH has another important advantage over other biomarkers of ovarian reserve in that measuring it is more convenient for patients. AMH secretion is independent of gonado-tropin regulation, with relatively stable serum levels throughout the menstrual cycle. As a result, samples can be collected without regard to cycle day. Again, this contrasts with other candidate markers like FSH, inhibin B, and estradiol, which all have variable patterns of secretion across the menstrual cycle. AMH has also proven to have the highest reproducibility between consecutive menstrual cycles.

Clinical UtilityThe majority of data exploring the clinical utility of AMH in women comes from research in the infertile population. Most studies use a model that compares AMH levels before and after infertility treatment. Numerous publications have documented a strong relationship between pre-treatment AMH levels and ovarian response to gonadotropin stimula-tion. For example, investigators in our institution demonstrated that oocyte retrieval for in vitro fertiliza-tion was more successful in women with a higher AMH level than with a lower AMH level, with 18 versus four oocytes retrieved, respectively.

A summary analysis of the studies published to date suggests that AMH

ANTI-MÜLLERIAN HORMONE LEVELS FOR ASSESSING OVARIAN RESERVE

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can predict poor ovarian response to gonadotropin stimulation with about 80% sensitivity and 80% specifi c-ity. AMH is less useful in predicting pregnancy success—not surprising given that AMH is a marker only of ovarian health.

How might AMH be used in assisted reproductive programs? Serum AMH levels can be used as an aid in counseling couples about their prospects for successful outcomes and in considering treatment options. Women with very low AMH levels are likely to have poor oocyte retrieval—critical information when considering the fi nancial and emotional costs of treatment. If a couple opts for assisted reproduction, the AMH level can guide the specifi c treatment protocol. Women with relatively low serum AMH levels may be treated most aggressively, with the highest doses of gonadotropin stimulation, in order to maximize the chances of a good oocyte yield. On the other hand, those with relatively high serum AMH levels are at risk for ovarian hyperstimula-tion syndrome and should be treated more conservatively. Studies have shown that AMH-guided cycles result in fewer cases of ovarian hyperstimula-tion than do FSH-guided treatment cycles. Not only is this a safer protocol, but it is also more economical because of lower stimulation doses and fewer hospitalizations.

AMH also has a clinical role in fertile women with normal

menstrual cycles. Ovarian reserve undergoes a natural attrition with age in all women, although the rate of decline varies between indi-viduals. Menopause is essentially the complete loss of ovarian reserve. Predicting menopause onset has value for family planning and the medical care of related health issues.

As menopause approaches, serum FSH levels increase substantially, but new data show that this occurs only after a signifi cant decline in serum AMH levels. Serum AMH levels decline in women with advancing chronological age as the primordial follicle pool is depleted (Figure 4, online). In fact, AMH levels become undetectable in serum as early as 5 years before the onset of menopause. In this way, AMH may be used as an “egg timer.” Assessing AMH levels can determine a woman’s ovar-ian reserve status and estimate the time remaining before reproductive senescence. Normative data for the decline in AMH levels with age, and tools for predicting menopause, are being developed.

AMH AssaysSeveral AMH immunoassays have been available over the past 20 years. Initial studies in the 1990s were conducted using Beckman Coulter’s Immunotech or Diagnostic Systems Laboratories methods, the latter of which has been discontin-ued. Beckman Coulter modifi ed its

original assay and introduced the widely used Generation II product. The antibodies used in the Gen II assay have now been adopted in the fi rst commercial automated AMH assays from both Roche Diagnostics and Beckman Coulter. Most recently, Ansh Laboratories introduced a new family of AMH assays using novel surface epitope antibodies. In the United States, all available AMH assays are currently labeled for research use only.

Levels of AMH in serum can be very low in some instances, such as in the years leading to the onset of menopause. The existing assay methods have been unable to reliably measure serum AMH levels in such samples. Manufacturers have recog-nized this limitation. In response, the Ansh Labs picoAMH assay offers high sensitivity measurement, which is important for select applications.

Another limitation of current AMH assays is the lack of specifi city for the mature C-terminal protein. All the available methods employ at least one antibody that recognizes an epitope on the precursor region of the AMH molecule. This means that pre-cursor and bioactive forms of AMH in serum are not being distinguished and reported levels actually refl ect a com-bination of forms, or “total AMH.” Whether the secreted forms of AMH might vary among healthy women or in different disease states remains to be seen. Assays with specifi city

PRO-AM

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F1 Model of the AMH protein. The full length AMH precursor

(pro-mature AMH) is a dimeric protein having a total molecular weight of 140 kDa, with each peptide chain consisting of 560 amnio acids. Cleavage at amino acid 451 results in the mature C-terminal protein (approximately 25 kDa); however, a tight non-covalent bond is maintained with the N-terminal precursor segment (AMHN,C), and appears to aid in receptor binding and bioactivity. An additional cleavage site of unknown biological signifi cance is present at amino acid 229.

17JANUARY 2015

for mature AMH, in addition to precursor-specifi c options, would be helpful for this investigation.

The variety of AMH assay options has led to some confusion among clinical laboratorians and scientifi c researchers. The fi rst issue is the lack of a universal standard for calibra-tion between methods. In addition, there have been reports of apparent AMH molecule instability under certain handling and storage condi-tions. Levels of AMH appeared to increase signifi cantly with storage at room temperature or -20°C. After investigation, complement proteins were found to interfere with antigen binding to the capture antibody in the Gen II assay, leading to artifi cially reduced serum AMH levels. Since complement varies between samples and under different storage condi-tions, this factor led to high variabil-ity in AMH levels both within and between laboratories using the assay.

To deal with this problem, a new protocol was introduced in 2013 for the Gen II assay, in which all samples are mixed with buffer before add-ing to the AMH antibody-coated microtiter plate, thus avoiding the

interference of complement proteins. Laboratorians should use caution when interpreting absolute levels of AMH, especially for data published using the Gen II assay method before introduction of the pre-mix protocol.

Collectively, raised awareness of assay limitations, attention to sample handling, improved protocols, newer methods, and the new universal standard will lead to more reproduc-ible AMH levels and the ability to better defi ne normative data in the near future.

CovariatesAs AMH is studied in women’s repro-ductive health, other variables emerge that can affect serum levels. For exam-ple, several studies have now demon-strated that there is a difference in age-related AMH levels among Caucasian, African-American, Hispanic, and Chinese women. Perhaps even more intriguing, the rate of AMH decline with advancing chronological age also differs among these groups. African American women, despite having the lowest AMH levels at younger ages, demonstrate the most gradual rate of decline with age. Researchers have not

yet identifi ed the genetic and environ-mental infl uences responsible for this difference.

Most studies fi nd that serum AMH levels are lower in women with a higher body mass index (BMI). There is an inverse correla-tion of BMI and serum AMH levels in women with normal menstrual cycles, as well as in women with infertility (polycystic ovary syn-drome). Whether this is a simple effect of AMH dilution in the higher blood volume of larger women, or whether there is actual decreased synthesis and production, is unknown. Nevertheless, AMH data should be interpreted in the context of a woman’s BMI, as well as her age.

Smoking is known to have a negative effect on ovarian health, and serum AMH levels refl ect this with lower levels observed in current smokers. The impact is transient given that prior smokers have serum AMH levels within the range of age matched non-smokers. Oral con-traceptive use, of various types, has also been shown to cause a dramatic reduction in serum AMH levels in some, but not all, studies. These and

F2 Model of ovarian follicle development showing the

production of AMH from small primary, secondary, and antral follicles. AMH is effective as a marker of ovarian reserve because the small follicles are proximal to the primordial follicle pool. In contrast, larger follicles produce the endocrine hormones, estradiol and inhibin B. AMH is a local regulator of follicle development and inhibits both initial follicle recruitment and the later responsiveness of larger follicles to FSH stimulation. AMH = Anti-Müllerian hormone. FSH = follicle stimulating hormone. Reprinted with permission from Broer SL, Mol B, Dólleman M, et al. The role of anti-Müllerian hormone assessment in assisted reproductive technology outcome. Current Opinion in Obstetrics and Gynecology 2010; 22:193–210.

INITIAL RECRUITMENT

AMH FSH

CYCLE RECRUITMENT

SELECTION AND DOMINANCE

Ovulation

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Atretic

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—

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18 JANUARY 2015

ovarian reserve markers: From theory to practice. Hum Reprod Update 2014;20:124–40.

Nelson S. Biomarkers of ovarianresponse. Fertil Steril 2013;99:963–9.

Robertson DM, Kumar A, Kalra B, et al. Detection of serum anti-müllerian hormone in women approaching the menopause using a sensitive antimüllerian hormone enzyme-linked immunosorbent assays. Menopause 2014;21:1277–86.

Rustamov O, Smith A, Roberts SA, et al. The measurement of anti-Müllerian hormone: A critical appraisal. Clin Endocrinol Metab 2014;99:723–32.

Visser JA, Schipper I, Laven JSE, et al. Anti-Müllerian hormone: An ovarian reserve marker in primary ovarian insuffi ciency. Nat Rev Endocrinol 2012;8:331–41.

Geralyn Lambert-Messerlian, PhD, FACB, is professor of pathology and laboratory medicine at the Alpert Medical School of Brown University and director of medical screening and special testing at Women and Infants Hospital in Providence, Rhode Island.+EMAIL: gmesserlian@wihri.org

Disclosure: The author has a fi nancial interest in Beckman Coulter and Ansh Labs.

BEYOND OVARIAN RESERVEOther Applications of Anti-müllerian Hormone

Polycystic ovary syndromeWomen with polycystic ovary syndrome (PCOS) have infertility, often have insulin resistance, and struggle with lifelong metabolic health. While defi ning PCOS is important for appropriate care, ovarian ultrasound is costly, subject to inter-operator variability, consid-ered invasive for young girls, and unavailable in some rural or resource-poor settings.

Serum AMH levels can act as a surrogate for ultrasound determina-tion of polycystic ovary. Multiple ovarian follicles—arrested at an early developmental stage—are present in some women with PCOS, and this is refl ected by high AMH levels in serum.

GonadotoxicityChemotherapeutic agents and radiation exposure used to treat cancer are known to compromise ovarian health. AMH may be used as a tool to assess ovarian damage after exposure to select agents. Further-more, measuring AMH before cancer treatment may be used to establish ovarian reserve and help predict future fertility in these women.

Ovarian tumor markerSerum AMH levels are dramatically elevated in cases of ovarian granulosa cell tumors of the ovary. Serial serum AMH measurements can be used to monitor disease after treatment, with increased levels reported to occur many months prior to clinical recurrence.

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other potential variables affecting serum AMH levels warrant further investigation.

ConclusionsProper utilization of AMH provides essential reproductive health informa-tion for women. All women poten-tially could benefi t from AMH data—from young women with irregular menstrual cycles, to fertile adults seeking to conceive, as well as infertile women, or those with cancers. AMH provides a window to the ovary, giv-ing a view not previously available from other endocrine markers.

The immediate challenges ahead lie in standardizing assays and in developing robust and reproduc-ible normative data against which individual patient results can be interpreted. Tools to aid in predicting fertility, preferably taking advantage of multiple marker algorithms, would also advance care.

Suggested readingBroer SL, Broekmans FJM, Laven

JSE, et al. Anti-Müllerian hor-mone: Ovarian reserve testing and its potential clinical implica-tions. Hum Reprod Update 2014; 20:688–701.

Dewailly D, Andersen CY, Balen A, et al. The physiology and clinical utility of anti-Müllerian hormone in women. Hum Reprod Update 2014;20:370–85.

Han X, McShane M, Sahertian R, et al. Pre-mixing serum samples with assay buffer is a prerequisite for reproducible anti-Müllerian hormone measurement using the Beckman Coulter Gen II assay. Hum Reprod 2014;29:1042–8.

Iliodromiti S, Kelsey TW, Wu O, et al. The predictive accuracy of anti-Müllerian hormone for live birth after assisted conception: A sys-tematic review and meta-analysis of the literature. Hum Reprod Update 2014;20:560–70.

Knowlton NS, Craig LB, Zavy MT, et al. Validation of the power model of ovarian nongrowing follicle depletion associated with aging in women. Fertil Steril 2014;101: 851–6.

LaMarca A, Sunkara SK. Individualization of controlled ovarian stimulation in IVF using

20 JANUARY 2015

RegulatoryRoundup

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FDA Clears SQI Diagnostics Celiac PanelSQI Diagnostics has received clearance from the Food and Drug Administration (FDA) for its Ig_plex Celiac DGP panel as an aid in the diagnosis of celiac disease in conjunction with other laboratory and clinical fi ndings. Celiac disease is an autoimmune disorder in which an inappropriate immune response to gluten damages the absorptive surface of the small intestine, resulting in an inability of the body to absorb necessary nutrients. According to a study published in the New England Journal of Medicine, it affects an estimated 1 in 100 people in the U.S. Research published in the American Journal of Gastroenterology has also reported that as many as 97% of celiac patients could be undiagnosed, highlighting a need for improved tests.

The SQI celiac panel is designed for the semi-quantitative detection in blood of the IgA and IgG immunoglobulin classes of antibodies

to deamidated gliadin peptide (DGP) and tissue transglutaminase (tTG)—autoantibodies produced as part of the body’s immune response to gluten. The test also requires the use of SQI’s sqid-X system. Both the American College of Gastroenterology and the American Gastroenterology Association recommend that healthcare providers use assays for anti-tTG and anti-DPG as a part of routine testing for celiac disease. Testing for the IgA class of anti-tTG is the most

sensitive and specifi c non-invasive method for celiac disease screening, while tests for the IgA or IgG class of anti-DGP may

be positive in some people with celiac disease who are negative for anti-tTG, especially children younger than 2 years old.

■SIXTH EBOLA TEST AUTHORIZED FOR EMERGENCY USE BY FDA

FDA has issued an emergency use authorization (EUA) to green-

light the use of Altona Diagnostics’ RealStar Ebolavirus RT-PCR Kit 1.0 for the diagnosis of Ebola. This is the sixth Ebola test that FDA has authorized for emergency use since Secretary of Health and Human Services Sylvia Burwell declared that the West African Ebola outbreak justifi es the emergency use of in vitro diagnostics for detection of the virus. The RealStar Ebolavirus kit differs from the previous fi ve tests to receive emergency use authorization in that it can detect RNA from several different species of Ebola in addition to Zaire ebolavirus, which is the cause of the current outbreak. The other Ebola species that this kit detects include Sudan ebolavirus, Tai Forest ebolavirus, Bundibugyo ebolavirus, and Reston ebolavirus. The kit does not

distinguish between the different species or strains, however. Under the terms of the EUA, this test can only be used on specifi ed instruments by CLIA high complexity laboratories.

■FDA RELEASES GUIDANCE ON MOLECULAR DIAGNOSTIC INSTRUMENTS WITH COMBINED FUNCTIONS

FDA has announced the availabil-ity of the guidance, “Molecular

Diagnostic Instruments With Combined Functions,” which details the agency’s current thinking on regulation of molecular diagnostic instruments that combine in a single instrument both approved/cleared device functions and device functions for which approval/clearance is not required. Molecular diagnostic instruments such as real-time thermocyclers are often used to perform multiple unrelated assays,

such as those that detect methicillin resistant Staphylococcus aureus, hepatitis C virus, and genetic markers of cystic fi brosis. These types of instruments cannot generally be approved or cleared without an accompanying assay, because their safety and effectiveness cannot be evaluated without reference to the defi ned performance parameters of the tests they run. However, the same instruments may also be used for additional purposes that do not require FDA approval or clearance, such as basic scientifi c research.

In the past, FDA has provided informal advice in response to individual inquiries regarding the permissibility of having functions for which approval/clearance is not required on an instrument intended for use with approved/cleared diag-nostic assays. This guidance is meant to offi cially lay out FDA’s policy regarding these types of instruments.

21JANUARY 2015

It also outlines what information FDA recommends applicants include in a submission for a molecular diagnostic instrument that measures or characterizes nucleic acid analytes and has combined functions.

■CMS SEEKS TO CLARIFY THATAUTOMATED FECAL OCCULT BLOOD TESTS ARE NOT WAIVED

The Centers for Medicare and Medicaid Services (CMS) has

proposed amending the CLIA regulations to clarify that the waived test categorization for fecal occult blood tests applies only to the non-automated version of these tests.

Fecal occult blood is one of the original eight waived tests published in the Federal Register in 1992. At the time the regulation was adopted, fecal occult blood was a manual test method. Since then, however, automated fecal occult blood analyz-ers have been developed that use complex and sophisticated technology and do not meet the CLIA criteria for waiver. It is important to clarify that these tests are not included in the list of tests waived in the CLIA regula-tions, and CMS proposes revising the current regulation to specify that only non-automated fecal occult blood tests are automatically waived.

Furthermore, since the develop-ment and proliferation of the waived test for hemoglobin by single analyte instruments with self-contained or component features, CMS has come to the understanding that the non-automated hemoglobin by copper sulfate method may no longer be in use. If comments support this conclu-sion, CMS proposes removing this test from the list of waived tests.

CMS is seeking public comment on this proposal through January 6. Electronic comments may be submit-ted at www.regulations.gov.

■FDA GIVES NOD TO ROCHE’S MOLECULAR POINT-OF-CARE STREP A TEST

Roche has earned 510(k) clearance for the cobas Strep A

test for the detection of group A streptococcus bacterial (strep A)

DNA in throat swab specimens. The cobas Strep A offers a time to result of 15 minutes, versus conventional methods such as culture testing, which can take up to 2 days to produce results, or rapid antigen testing, which still requires confi rma-tion with culture due to lower sensitivity. Additionally, the test uses polymerase chain reaction

technology and runs on the cobas Liat System, a molecular point-of-care diagnostic instrument that will be launched later this year. The cobas Liat analyzer is designed for on-demand testing in physician clinics, pharmacy, and hospital lab settings, and will include the cobas Infl uenza A/B test in addition to the cobas Strep A.

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US Unnecessary and Unintended 1,25 Dihydroxyvitamin D

Order Patterns: A Metaphor for Life

Sendout tests are associated with error and patient harm due to their complexity. Ordering the

right test is challenging for a variety of reasons, including limited physi-cian training in specialty areas, dif-fi cult computerized physician order entry (CPOE) systems, numerous reference laboratory options, unique insurance authorization require-ments, confusing test nomenclature, and rapidly evolving testing strate-gies (1,2). When the wrong test is ordered or the result is unacknowl-edged, patient harm is possible from delayed diagnosis and treatment, need for sample recollection, and false reassurances from a normal test result. In fact, fi nding the best solution for improving test order practices can be a lot like developing a new lab test: it takes the willing-ness to try and fail before fi nding the best match.

The Facts About Vitamin D TestsVitamin D is an example of a test that is challenging to get right. In our institution, we found that 66% of the 1,25 dihydroxyvitamin D tests were ordered in error, and that in these cases, 25-OH vitamin D was the intended test. As laboratorians know, 25-OH vitamin D is most useful in nutritional assessment, primarily due to its longer half-life of approxi-mately 3 weeks. 25-OH vitamin D is elevated with vitamin D intoxica-tion, and decreased with malabsorp-tion, nutritional defi ciency, and in liver disease. Conversely, the circu-lating half-life of 1,25 dihydroxy-vitamin D is relatively short (4–6 hours), limiting utility for overall vitamin D assessment.

A 1,25 dihydroxyvitamin D test also can be useful in the diagnosis of renal dysfunction in conjunction with parathyroid hormone. It is elevated in sarcoidosis and primary hyperparathy-roidism, and decreased in renal failure and hypoparathyroidism.

Many Paths to the Top of the Mountain: Route 1A variety of tools from the utiliza-tion management toolbox can be used to improve utilization of a test (Table 1)—ranging from gentle to strong, and from manual to technology-based interventions. We began with a manual email interven-tion describing the utility of both vitamin D tests, and asked the provider to decide whether to modify his or her request to 25-OH vitamin D, or to continue with the order as entered (3). After 1 year of the interven-tion, we found that 53% of 1,25

dihydroxy vitamin D test orders were canceled and modifi ed to 25-OH vita-min D, reducing our monthly orders for the former from 25 to less than 10. We removed the intervention for 2 months to see if the year of active intervention education was sustainable. 1,25 dihydroxyvitamin D test orders jumped back up to 17 per month, suggesting that not much learning had occurred and that we needed a perma-nent intervention (Figure 1).

Another Path to the Top: Route 2Several other institutions with similar misorders of 1,25 dihydroxyvitamin D demonstrated success using CPOE tools. Simple name changes and pop-ups on test ordering screens seemed reasonably effective and straight-forward to implement. While an IT solution isn’t easy or feasible in some institutions, we decided it was time to try.

SPONSORED BY

T1 Utilization management tools, adapted from Solomon DH, et al. (4 )

Gentle Medium Strong

• Posting guidelines on requisition

• Utilization report cards • Utilization report cards with peer or leadership review

• Computerized reminders on utilization guidelines

• Changes to manual requisitions or CPOE

• Privileging

• Sendouts formulary

• Requirement for high-level approval (e.g. pathologist, doctoral level consultant, genetic counselor)

• Rules requirement

BY JANE DICKERSON, PHD, DABCC, AND MICHAEL ASTION, MD, PHD

23JANUARY 2015

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In the fi rst phase—and in col-laboration with our endocrinolo-gists—we changed the name from 1,25 dihydroxyvitamin D, which appears fi rst in searches for “vitamin D,” to “Vitamin D, Bone Disease” and “Vitamin D, Renal Disease.” The 25-OH vitamin D was changed to “Vitamin D, Nutritional Assessment.” This had an interesting, unintended effect of increasing orders for 1,25 dihydroxyvitamin D from less than 10 per month to greater than 20. After investigating, we discovered that this increase was due to bone specialists (orthopedists) and renal specialists (nephrologists) adding the orders to their routine ordersets because it had their specialties in the title.

If at First You Don’t Succeed: Route 3In phase two of our CPOE interven-tion, we implemented a pop-up using adapted language from other similar institutions that had seen a reduc-tion in orders (Figure 1). The pop-up

began, “Do not order 1,25 dihy-droxyvitamin D….” After 4 months, we confi rmed the theory that pop-up messages easily can be ignored, and are not enough to change behavior (5). Orders for 1,25 dihydroxyvita-min D remained at an average of 19 per month.

Let’s Try That Again: Route 4Our fi nal effort involved hiding the 1,25 dihydroxyvitamin D orderable entirely within our CPOE. We made sure it was available in the order sets for endocrinology and nephrology, but it was not searchable otherwise. Providers intentionally looking for 1,25 dihydroxyvitamin D who were not endocrinologists or nephrologists would have to order a miscellaneous test.

Since implementing this solution 1 month ago, we sent out seven tests, three of which were ordered as miscel-laneous. We have not received any calls or complaints from providers looking for the test. Is it too soon to declare

victory? Maybe, but I choose cautious optimism and believe that this could be the end of our 2-year struggle.

ConclusionWhile IT solutions often seem like an attractive fi x for utilization man-agement problems, the interventions require fi tting within the confi nes and culture of your particular insti-tution, and there should be a process in place to measure and check success. Many times, interventions require a bit of tweaking to achieve that perfect fi t.

References 1. Dickerson JA, Cole B, Conta JH, et al.

Improving the value of costly genetic refer-ence laboratory testing with active utiliza-tion management. Arch Pathol Lab Med 2014;138:110–3.

2. Dickerson J, Cole B, Astion M. Ten ways to improve the quality of send-out testing. Clin Lab News April 2012;38:12–3.

3. Dickerson JA, Cole B, Jack RM, et al. Another laboratory test utilization program: Our approach to reducing unnecessary 1,25 vitamin D orders with a simple intervention. Am J Clin Pathol 2013;140:446–7.

4. Solomon DH, Hashimoto H, Daltroy L, et al. Techniques to improve physicians’ use of diagnostic tests: A new conceptual frame-work. JAMA 1998;280:2020–7.

5. Procop GW, Yerian LM, Wyllie R, et al. Duplicate laboratory test reduction using a clinical decision support tool. AJCP 2014; 141:718–23.

Jane Dickerson, PhD, DABCC, and Michael Astion, MD, PhDSeattle Children’s Hospital, Department of Laboratories and University of Washington, Department of Laboratory Medicine

F1 Monitoring the impact of various interventions aimed at improving 1,25 dihydroxyvitamin D

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BY TABITHA BARKER, MLT, AND JAIME NOGUEZ, PHD

Workplace morale plays an important role in produc-tivity and job satisfaction,

making it a key determinant in an organization’s success. As such, it has become increasingly important for clinical laboratory managers, since low morale can have signifi -cant implications for patient safety. Low morale can lead to a dangerous disconnect between employees and their jobs that may cause them to cut corners, not pay attention to details, or simply not care whether or not they do the right thing. Previ-ous issues of CLN’s Patient Safety Focus have discussed research that shows happy and engaged employees are less likely to make mistakes and are more likely to make signifi cant contributions to overall productivity (1,2). In comparison to those with disengaged employees, healthcare institutions with engaged employees also experience 41% fewer patient safety incidents such as falls, medi-cal errors, and infection rates (1).

Monitoring and proactively dealing with low morale in the clinical labo-ratory not only avoids considerable downstream costs associated with absenteeism, re-hiring, and training, but also contributes to a better and safer workplace.

Strategies for Boosting MoraleSocial events that encourage staff to interact and build stronger profes-sional bonds are an excellent way to transform a frigid workplace climate and motivate employees during tough times. At University Hospitals Case Medical Center in Cleveland, we throw monthly potluck-style par-ties and let the technologists choose

a different theme each month. We have found that these regular events help to create a sense of unity in our laboratory.

We also socialize with other hos-pital departments. One of our most successful efforts is the Christmas in July event in which we pick two

wards within the hospital and work closely with them to donate gifts to patients in recovery. This event not only provides our staff with an opportunity to interact with other departments, but also serves as a reminder of how the labora-tory impacts patient care. Helping technologists connect with patients is one of the best ways to restore or enhance their sense of purpose.

Managers can also help staff con-nect with patients without stepping foot outside of the laboratory. We rec-ommend sharing a brief case presen-tation each week that highlights how the laboratory made a difference in the care of a patient. Another option is to partner with a patient safety advocacy group and invite patients to discuss their personal accounts of how the laboratory helped them.

Our managers have implemented huddles at shift change to share these interesting cases and to disseminate important information about what has been going on in the laboratory that day. We also use these huddles

to relay progress reports on concerns raised by staff members in previ-ous huddles, to seek input regarding upcoming changes that will affect the staff, and to explain the reason-ing behind management decisions. We have found that including our employees in the decision-making

process when possible and sharing news with them as we hear it has had a positive impact on morale.

In our laboratory we also have implemented what we call “Lab Cash” to reward employees who go above and beyond their required duties. Staff members can give this form of currency to thank co-workers for stepping in to help. Managers also use it to acknowledge a job well done. Recipients use LabCash to purchase hospital merchandise such as water bottles, scrubs, jackets, and hats.

Although everyone working in the laboratory contributes, it is up to managers to set the tone and to deal with problems swiftly. Short-term solutions might raise morale immedi-ately, but they do not get to the root cause. For lasting results, managers must fi nd the sources of low morale and address them proactively as opposed to reactively. Taking proac-tive measures not only keeps your staff happy, but also promotes an atmosphere crucial for high-quality patient care.

SPONSORED BY

The High Cost of Low Morale in the Clinical Laboratory:How Workplace Environment Impacts Patient Safety

HEALTHCARE INSTITUTIONS WITHengaged employees experience 41% fewer patient safety incidents.

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OCCUPATIONAL STRESS Stress is a hallmark of most demanding careers. The increasing demands on laboratory staff, the workforce shortage, and high turnover can quickly lead to both physical and emotional exhaustion. Technologists who experience chronic occupational stress are more likely to experience burnout. To counter this problem:

• Establish an open door policy with management to share concerns

• Ensure breaks and lunches no matter how heavy the workload

• Match work demands to technologist knowledge and abilities

LACK OF POSITIVE FEEDBACK The importance of praising and thanking employ-ees is often neglected. Managers who are quick to criticize and slow to give praise can have a devastating effect on morale: employees perceive a lack of respect for their time, work, and com-mitment. To address this issue:

• Celebrate successes due to combined efforts of staff

• Thank people for doing a job well

• Publicly recognize hard work

• Praise staff commitment during diffi cult times

LACK OF A SENSE OF PURPOSEThe rapid evolution of laboratory medicine along with a perceived lack of recognition by other spe-cialties can leave technologists with confl icted feelings about their roles. When laboratory staff lose the sense of purpose they had early in their careers, it diminishes their satisfaction with their achievements. Laboratory professionals at all levels need to understand how their efforts make a difference in other people’s lives. To accomplish this:

• Organize events with patients

• Present specifi c patient cases in which the lab played a crucial role

LACK OF SOCIAL SUPPORTNot infrequently, technologists experience feelings of social isolation from other health-care professionals and even from laboratory

References1. Harter JK, Schmidt FL, Killham EA, et

al. Q12® meta-analysis: The relationship between engagement at work and organiza-tional outcomes. http://www.aamga.org/fi les/hr/MetaAnalysis_Q12_WhitePaper_2009.pdf (Accessed November 17, 2014)

2. Nahrgang JD, Morgeson FP, Hofman DA. Safety at work: A meta-analytic investiga-tion of the link between job demands, job resources, burnout, engagement, and safety outcomes. J Appl Psychol 2011;96:71–94.

Further ReadingAstion M. A new model for patient safety:

Laboratory huddles—what a great idea. CLN 2013;39(4):13–4.

Maier CL. Improving patient safety by con-necting technologists to patients. CLN 2013;39(7):20–1.

Astion M. Burnout: A new frontier in patient safety? CLN 2013;39(10):20–1.

Jaime H. Noguez, PhDAssistant Director of Chemistry LaboratoriesUniversity Hospitals Case Medical CenterCleveland, OhioEditor, Patient Safety Focus

Tabitha Barker, MLT (ASCP)Technical Coordinator of Automated ChemistryUniversity Hospitals Case Medical CenterCleveland, Ohio

coworkers. The laboratory often is physically set apart from the rest of the hospital, limiting interaction with other specialties. Even within the laboratory, fast-paced and compartmen-talized work means technologists may not get to know their co-workers. The quality of workplace relationships is a key component of job satisfaction and employee retention. Employees need to feel as though they fi t into the organization’s culture and blend with their colleagues. Solutions:

• Plan social events for lab staff

• Participate in interdepartmental events

• Use staff bulletin boards to share pictures of personal interests (family, pets, etc.)

LACK OF CONTROLLack of autonomy can cause stress and dis-satisfaction. Feeling as though their voice is not heard or that they are not included in decision-making contributes to employees’ perceived lack of control. Remedy this by:

• Employing routine huddles to share important information

• Providing progress reports on issues raised by technologists

• Confi ding in employees about forthcoming changes when possible

• Soliciting staff input about decisions affecting their work

LACK OF INTELLECTUAL STIMULATIONPerforming the same routine or mundane tasks can lead to feelings of intellectual stagnation. When employees feel their jobs offer no chal-lenges, they become less engaged and less satis-fi ed. Left unaddressed, this creates a feeling of career stagnation. Solutions:

• Plan in-service training about particular diseases

• Share interesting cases

• Recruit technologists to participate in new method validations or other projects

• Delegate some managerial tasks to staff and guide them through the process

Dealing With Root Causes of Low Morale in the Lab

TRY PATIENT SAFETY HUDDLES

A daily or weekly 15-minute huddle can improve accountability and teamwork. To read more, search “huddle” on www.aacc.org.

26 JANUARY 2015

Industry Playbook

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Vista Therapeutics to Develop Nanowire-Based Real-Time Biomarker Monitoring SystemVista Therapeutics has inked license agreements with both Harvard University and Nanosys securing the rights to several patents and patent applications related to the use of nanowires as biosensors. Under the terms of these contracts, Vista has gained access to a portfolio of intellectual property derived from the work of Charles Lieber, PhD, one of the company’s co-founders and a professor of chemistry at Harvard. This portfolio includes a wide range of applications in nanotechnology, nanomaterials, and the use of nanowire-based fi eld effect transistors (FETs) as biosensors.

Specifi cally, Vista plans to focus on the use of nanowire-based FETs to provide real-time measurement of multiple blood and urinary biomarkers

associated with organ and tissue injury, as well as with treatment- or therapeutics-associated adverse response. The company ultimately aims to commercialize these nanowire-based biosensors as part of its NanoBioSensor platform. Vista CEO and co-founder Spencer Farr, PhD, stated that he believes this technology will enable physicians, clinicians, and pharmaceutical researchers to continuously monitor a variety of biomarkers in the same way that EKG instruments allow physicians to continuously monitor a patient’s heart function.

“The potential to commercialize this portfolio of nanowire technologies is quite signifi cant and could fundamentally reshape approaches to the monitoring of medical emergency situations,” said Isaac T.

Kohlberg, senior associate provost and chief technology development offi cer at Harvard. “Working together with Nanosys to license these patents to Vista, we’re able to move the technology forward and give it every opportunity to evolve from initial laboratory fi ndings to commercial applications, which will benefi t society.”

■QIAGEN, PROTAGEN PARTNER ON PROTEIN-BASED CO-DIAGNOSTICS FOR AUTOIMMUNE DISORDERS

P rotagen AG has entered into a long-term collaboration with Qiagen to develop

protein-based companion diagnostics for autoimmune disorders. Under the terms of the agreement, Qiagen will gain access to Protagen’s proprietary SeroTag biomarker identifi cation and development engine, which is an automated multiplex technology for the discovery and clinical validation of novel autoantigens. This platform enables the high-throughput discovery

of biomarker candidates by measuring the levels of autoantibodies to thousands of different antigens in serum samples from thousands of patients.

“Following cancer, autoimmune disorders are currently the second largest therapeutic area for companion diagnostics in drug develop-ment with a signifi cant unmet medical need,” said Rainer Metzger, vice president of Business Development Pharma at Qiagen. “Thanks to the collaboration with Protagen, we’ll now be able to offer our partners in the pharma-ceutical industry a new diagnostic technology

27JANUARY 2015

particularly well suited to advance personalized healthcare in autoim-mune disorders and further expand our activities in this indication area.”

■ARUP AND PIERIANDX TEAM TO ADVANCE GENETIC TESTING

ARUP Laboratories has formed a partnership with PierianDx, a

company whose primary offerings include a bioinformatics platform, workfl ow solutions and software, and a knowledgebase of clinical informa-tion from thousands of previous genomic tests. ARUP will join the PierianDx partner network to share tools, assays, and clinical information to expedite and improve the personal-ized interpretation of next-generation sequencing (NGS) tests. Additionally, ARUP will use PierianDx’s workfl ow management tools and NGS knowl-edgebase to more effectively access its own comprehensive knowledgebase of variants and clinical outcomes, as well as to benefi t from the collective insights of other institutions in the PierianDx partner network. Together, the two organizations hope to provide faster and more effi cient genetic testing for thousands of patients across the U.S.

“Our expectation is that by leverag-ing PierianDx’s visionary software and database, we will be able to more effectively learn from past assays and provide even more personalized rec-ommendations to physicians so they can better match their patients to the right therapies,” said Edward Ashwood, MD, CEO and president of ARUP.

■MEDGENICS, CHOP COLLABORATE ON PEDIATRIC RARE AND ORPHAN GENETIC DISEASES

Medgenics, an ex vivo gene therapy company, has

initiated a major research collabora-tion with The Children’s Hospital of Philadelphia (CHOP) focused on pediatric rare and orphan genetic diseases. The goal of this partnership is to accelerate the development of new therapies for these underserved patients. Under the terms of the

collaboration, Medgenics will gain access to the the biobank at CHOP’s Center for Applied Genomics, which is home to one of the largest bio-repositories of pediatric genetic infor ma tion and peptide and protein targets in the world. This wealth of data will enable CHOP and Med-genics researchers to identify new rare and orphan disease targets and speed the development of novel therapies into clinical stage programs.

“Approximately 10 percent of all rare and orphan disease patients in North America come through CHOP. This will give Medgenics and CHOP opportunities to link diseases and their genetic abnormalities with potential new treatment paradigms,” said Steven M. Altschuler, MD, CEO of CHOP.

■USAID, BROAD INSTITUTE, ILLUMINA JOIN FORCES ON EBOLA SEQUENCING INITIATIVE

The U.S. Agency for International Development, the Broad

Institute of MIT and Harvard, and Illumina have formed a public-private partnership to help combat the Ebola epidemic in West Africa. The partner-ship aims to train local and outbreak-deployed personnel to sequence viral genomes from the epidemic, and will also extend Ebola surveillance opera tions. Genome sequencing of the virus is critical for tracking how the virus is moving and changing in real-time, and the information it provides may infl uence the develop-ment of diagnostics, vaccines, and therapies. To facilitate this effort, the partnership will equip facilities in West Africa with state-of-the-art genome sequencing technology that will aid in Ebola response now and in clinical monitoring and pathogen surveillance in the future. Sequencing and patient monitoring facilities will be created fi rst in Liberia, Nigeria, Senegal, and Sierra Leone, and over the longer term in other West African countries. These centers will also serve as hubs for the deployment of mobile laboratories to remote districts where large-scale capacity is not available.

■PATHWAY GENOMICS, PROMPT PARTNER ON HEREDITARY CANCER RESEARCH

Pathway Genomics Corporation has entered a collaboration with

the Prospective Registry of Multiplex Testing (PROMPT), an online registry for patients who have undergone testing for cancer-causing genetic mutations. PROMPT is a recently formed consortium of physicians and scientists at academic centers across the nation, including Memorial Sloan Kettering Cancer Center, Mayo Clinic, Abramson Cancer Center of the University of Pennsylvania, and the Dana-Farber Cancer Institute. The goal of the registry is to provide data needed to better understand the level of risk associated with and outcomes following testing for “panels” of cancer-associated genes.

Its fi rst phase will involve creating a cohort of individuals and families who have consented to participate in studies examining cancer-causing genetic mutations. Pathway Genomics, which is a San Diego-based clinical laboratory that offers genetic testing services globally, is one of several labs that will provide infor-mation about the PROMPT registry site to patients and healthcare provid-ers receiving panel test results. The second phase of the PROMPT study will then collect more clinical details, assess outcomes, and characterize individual gene variants in families.

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28 JANUARY 2015

QAsk The Expert

Using Glucose Meters in Intensive Care Units

EXPERT

Brad Karon, MD, PhD

Major hospital-use glucose meters marketed in the U.S. are CLIA-waived devices. When used according to manufacturers’ indications and instructions, no in-house validation of analytical performance is required by the Centers for Medicare and Medicaid Services (CMS). However, using the device other than according to the intended use or manufacturer instructions—or with patients or under conditions described in the limitations section of the package insert—may make such uses off-label, and as such high complexity under CLIA. For some devices, off-label use applies to glucose meter measure-ment in patients who are “critically ill.” One hospital-use glucose meter has received FDA approval for glucose measurement in “intensively treated” adult patients, though only with arterial and venous whole blood.

As a result, the extent of analytical performance validation required by CMS depends upon the meter being used (intended use and limitations), sample types (arterial, venous, and/or capillary whole blood), and intended patient population. Note that neither FDA nor CMS have defi ned “critically ill” or “intensively treated” patient populations. Therefore, each institu-tion must defi ne these in order to understand when use of glucose meters may be off-label and therefore high complexity.

For high complexity tests, labo-ratories must validate the accuracy, precision, reportable range, reference range, analytical sensitivity, and ana-lytical specifi city of the method. The approach outlined above would cover many of the requirements. However, personnel requirements for high com-plexity testing also differ markedly from those for waived testing. If use of high complexity testing personnel is not practical, this may preclude use of glucose meters in the ICU or limit the sample types that can be tested.

Brad Karon, MD, PhD, is director of the hospital clinical laboratories and point of care testing and an assistant professor of laboratory medicine, at Mayo Clinic in Rochester, Minnesota. He is a past-chair of AACC’s Critical and Point-of-Care Testing division.

How should I approach evaluating a glucose meter for use in the ICU?

A:The answer to this question has both patient care and

regulatory considerations. For patient care purposes, the choice of sample type may be as important as the choice of device: arterial whole blood offers the most accurate measure-ment in the ICU, while capillary sampling may lead to erroneous results in patients with poor tissue

perfusion. Venous catheter sampling can lead to overestimation of glucose at higher concentrations depending on meter technology.

The ideal approach to evaluating a meter is to collect nearly simultane-ously whole blood glucose meter sam-ples and plasma or serum laboratory samples. Using the actual end users to perform bedside measurement—and the intended sample type from ICU patients—allows observation of the variables most likely to impact glucose meter accuracy, such as hema-tocrit effect, medication interferences, and user errors.

To complement a patient-based assessment of meter accuracy, residual serum or plasma specimens can be spiked with medications used in the ICU to detect interferences. While accuracy (bias) and interfer-ences are the most important factors, meter precision at normal, high, and low glucose concentrations is also important. Fortunately, precision of most hospital-use glucose meters is quite good, with a coeffi cient of variation <5%.

Laboratories should also consider using multiple laboratory methods to determine the reference glucose value, as commercially available laboratory methods may differ signifi cantly. Paired whole blood and reference glucose values can be used to determine the impact of observed differences on insulin dosing deci-sions according to the institution’s glycemic protocol. The data can also be compared to accuracy guidelines produced by groups like the National Academy of Clinical Biochemistry and the Clinical and Laboratory Standards Institute (CLSI). CLSI recommends a minimum of 200 measurements for such a compari-son. While this may be challenging, keep in mind that small studies will not allow the laboratory to measure the frequency and magnitude of outlier results or fl iers. These are equally if not more important to measure than mean or median bias. There is no consensus on the level of accuracy required or the optimal number or extent of outliers, though recent CLSI guidelines are probably a reasonable benchmark.

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