April 2016

ClinicalLaboratory

News

An AACC Publication | Volume 42, Number 4

Giving Physicians

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1CONTENTS

www.aacc.org

Cov

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.com

APRIL 2016

EDITORIAL STAFFManaging Editor Bill MaloneSenior Editor Genna RollinsCommunications Manager Christine DeLongContributors Kristi J. Smock, 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

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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 Patricia M. Jones, PhD, DABCC, FACBPresident-Elect Michael J. Bennett, PhD, DABCC, FACBTreasurer Corinne Fantz, PhDSecretary David G. Grenache, PhD, DABCC, FACBPast President David D. Koch, PhD, DABCC, FACB

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Contents copyright © 2016 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

1CONTENTS

Features 10 The Role of ADAMTS13 Testing in the Work-up of

Suspected Thrombotic Thrombocytopenic Purpura

16 Future of LDT Oversight Still Uncertain Stakeholders Propose Alternatives to FDA Regulation

Departments2 Federal Insider4 Bench Matters

6 The Sample 20 Special Section:

Patient Safety Focus 24 Regulatory Roundup 26 Industry Playbook 28 Ask the Expert

@ CLN_AACC

24

102

16

The full text of Clinical Laboratory News can be found on EBSCO's

CINAHL Complete database and is also searchable via the EBSCO Discovery

Service™

Overall, when modern equations are used creatinine and cystatin C are, on average, fairly comparable tools for estimating GFR. However, in certain patient populations one may be better than the other.p28

2 APRIL 2016

Federal Insider

Quality Measure Overhaul Relies on Lab ResultsThe Centers for Medicare and Medicaid Services (CMS) took another step in its march toward paying for value versus volume, releasing seven sets of new healthcare clinical quality measures. CMS worked on the quality measures with America’s Health Insurance Plans (AHIP), the National Quality Forum, physician groups, and other stakeholders so that public and private payers can agree on how to measure—and eventually how to reward—quality care. According to CMS, this work will inform the agency’s implementation of the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA) during the rulemaking process. The seven sets of measures include accountable care organizations, patient-centered medical homes, and primary care; cardiology; gastroenterology; HIV and hepatitis C; oncology; obstetrics and gynecology; and orthopedics. The goals were to streamline what was becoming a complex system of reporting for

providers and to enable easy comparisons for policymakers, patients, regulators, and insurers.

Many of the quality measures depend on laboratory testing. For example, primary care-related quality measures include: HbA1c testing and the percentage of patients with results >9%; the percentage of women who’ve had recommended cervical cancer screening or non-recommended screening; and the rate of colorectal cancer screening. Under HIV/HCV care, measures include screening for chlamydia, gonorrhea, and syphilis; HIV screening for patients with an acute sexually transmitted infection; and HCV screening for at-risk patients. Measures for oncology include KRAS gene mutation testing for patients with metastatic colorectal cancer who receive anti-epidermal growth factor receptor

monoclonal antibody therapy, as well as appropriate treatment for patients with breast cancer based on HER2 status. Screening for cervical cancer and chlamydia are included under obstetrics and gynecology. The CMS-AHIP collaboration plans to release new measure sets and update current sets over time.

CMS said it already is using some of the quality measures in its various Medicare quality programs, and commercial health plans are expected to implement them when contracts come up for renewal or if existing contracts allow modifi cation of the performance measure set.

■OBAMA’S BUDGET WOULD BOOST BIOMEDICAL RESEARCH

President Obama’s 2017 budget would boost funding to several

biomedical initiatives. Overall, the budget provides $33.1 billion, including an additional $1.8 billion in mandatory funding, to the National Institutes of Health. But the budget also adds additional monies for three of the president’s signature initiatives: precision medicine, cancer research, and the BRAIN initiative.

For the president’s precision medi-cine initiative, the budget includes $300 million for NIH to “[accelerate]

research into the development of treatments tailored to specifi c char-acteristics of individuals.” The budget supports efforts underway to establish a voluntary national research cohort of 1 million or more Americans, expand research to defi ne cancer subtypes and identify new therapeu-tic targets, modernize the regulatory framework for DNA sequence-based diagnostic tests, and improve data sharing and interoperability.

Another $195 million from the budget goes to the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) initiative.

The initiative has grown since its launch in 2013 to include fi ve agencies, and dozens of major foundations, private research institutions, universities, companies, and advocacy organizations, according to the administration.

In a break with tradition, Senator Michael Enzi (R-Wyoming), chairman of the Senate Budget Committee, and Representative Tom Price (R-Georgia) announced they would not invite the president’s budget director to testify before their respective panels. Leaders from neither party have indicated when Congress might consider its own budget resolution for 2017. N

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In contrast, N -terminal

fragments are less infl uenced by renal function, thereby producing fewer false positive results. For this reason, detection of the N -terminal fragment is considered to be a more useful indicator of HHM.

Mayo Medical L aboratories developed an assay using a sandwich approach to capture the N -terminal and mid region of PTHrP. A similar DS L -8 100 PTHrP IRMA (RU O) assay from B eckman is available

commercially and also targets the PTHrP sequence 1-8 6. Esoterix (L abCorp) has improved the sensitivity and precision of this assay by converting to chemiluminescent technology. ARU P L aboratories recently developed a liquid chromatography-mass spectrometry (MS ) assay for the C-terminal (103 -110) peptide of PTHrP, but it had very poor correlation with immunoassay. Competitive immunoassays have lower specifi city, precision, and analytical sensitivity compared to sandwich or MS assays.

At this time, nephrogenous cAMP remains the gold standard as a bio-assay until the PTHrP or other protein assays are able to achieve

maximum clinical sensitivity and specifi city. Existing PTHrP assays lack clinical sensitivity and specifi city for HHM. Without optimal standardized assays, but with potential for PTHrP to be a biomarker for HHM, this is an excellent opportunity for clinical investigators, laboratories, and manufacturers to work together to create a reliable PTHrP test.

Ravinder J. Singh, PhD, is a professor of lab medicine and pathology at Mayo Clinic in Rochester, Minnesota. +EMAIL: Singh.Ravinder@mayo.edu

Parmpreet Kaur is a medical student at the University of Missouri–Kansas City. +EMAIL: pkq4d@mail.umkc.edu

In contrast,N -terminal

fragments are less infl uenced by renalfunction, thereby producing fewer false positive results. For this reason,detection of the N -terminal fragmenis considered to be a more useful indicator of HHM.

Mayo Medical L aboratories developed an assay using a sandwichapproach to capture the N -terminal

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A25-year-old woman with a 2-week history of an upper respiratory infection presents to the emergency department of your hospital with fever, severe headache, and confusion.

A CT scan does not reveal any acute intracranial process. However, she has a number of concerning laboratory abnormalities, including marked anemia (hematocrit 19%, reference interval 34–47%) and thrombocytopenia (15 k/µL, reference interval 180–405 k/µL), markedly elevated lactate dehydrogenase (1050 U/L, reference interval 100–253 U/L), absent haptoglobin (<10 mg/dL, reference interval 30–200 mg/dL), and increased total plasma bilirubin (3.1 mg/dL, reference interval 0.2–1.4 mg/dL), with the indirect fraction representing 2.1 mg/dL.

In addition, this patient has negative direct and indirect antiglobulin (Coomb’s) testing, normal plasma creatinine, and normal coagulation parameters, including prothrombin time (PT), activated partial thromboplastin time (aPTT), fi brinogen, and only minimally elevated d-dimer. Her peripheral blood smears show severe thrombocytopenia and frequent schistocytes, accounting for 1–2% of red blood cells (also identifi ed as 4+ schistocytes by

THE ROLE OF ADAMTS13 TESTING

BY KRISTI J. SMOCK, MD

the automated hematology analyzer), confi rming microangiopathic hemolytic anemia (MAHA).

Due to the constellation of clinical and laboratory fi ndings, the working diagnosis for this patient is thrombotic thrombocytopenic purpura (TTP)—a medical emergency. Her physician orders ADAMTS13 (A Disintegrin and Metalloprotease with ThromboSpondin type 1 motifs 13) testing and hospitalizes her to start emergency therapeutic plasma exchange (TPE). What assays would you use, and how would you interpret results for this woman presumed to have TTP?

This review examines the use of ADAMTS13 testing in evaluating patients with suspected TTP, a rare thrombotic microangiopathy (TMA) most commonly due to acquired ADAMTS13 autoantibodies causing severe ADAMTS13 defi ciency.

ADAMTS13, a protease also known as von Willebrand factor (VWF) cleaving protease, regulates the size of VWF multimers, and is an important mediator of platelet adhesion. ADAMTS13 regulates VWF size by cleaving a specifi c peptide bond in the A2 domain. Without this regulation, increased ultra-high-molecular-weight VWF

in the Workup of Suspected Thrombotic Thrombocytopenic Purpura

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11APRIL 2016

multimers lead to microvascular platelet thrombi, destroying red blood cells and platelets and compromising blood fl ow to vital organs such as the brain and kidneys.

Although TTP often involves microangiopathic hemolytic anemia, thrombocytopenia, fever, neurological symptoms, and renal impairment, many patients do not exhibit the full pentad of fi ndings. Furthermore, this same combination of abnormalities can be present in other disorders such as classic hemolytic uremic syndrome (HU S ), atypical HU S (aHU S ), or disseminated intravascular coagulation (DIC). With high clinical suspicion of TTP life-saving therapy must be started immediately. In fact, the disorder had a 9 0% fatality rate prior to the advent of modern treatments.

TTP is clinically defi ned as MAHA and thrombocytopenia in a patient without an alternative cause. Clinical prediction scores using readily available laboratory information (creatinine, platelet count, d-dimer, reticulocyte percentage, indirect bilirubin, etc.) have proven useful for acute decision-making. The initial therapeutic regimen for acquired TTP involves immunosuppression and TPE to suppress antibody formation, decrease antibody titer, and provide supplemental ADAMTS 13 . Although confi rming severely decreased ADAMTS 13 activity helps establish the TTP diagnosis, therapy must start even before test results are available.

Pre-Analytical Variables The quality of ADAMTS 13 testing results depends on several important pre-analytical issues. First, and crucially, diagnostic specimens have to be collected before therapy starts, since treatment alters ADAMTS 13 levels. As with other coagulation testing, citrated platelet-poor plasma is the specimen of choice for ADAMTS 13 testing. EDTA plasma is unacceptable since ADAMTS 13 is a metalloproteinase and this anticoagulant strongly chelates metal ions that are necessary for its function. Even plasma from normal control individuals drawn into EDTA will demonstrate absent

ADAMTS 13 activity. S ince thrombin degrades ADAMTS 13 , it also is best not to test serum specimens, which are prepared by allowing blood to clot. L ikewise, hemolyzed plasma (particularly if the hemoglobin concentration is > 2 g/L ) is a concern since free hemoglobin inhibits ADAMTS 13 activity. Consequently, labs should take care not to induce hemolysis in vitro during specimen collection and preparation. S ince patients undergoing initial diagnostic testing can have brisk intravascular hemolysis, some degree of plasma free hemoglobin may be unavoidable. Plasma that cannot be tested within 4 hours of collection, should be frozen until the time of testing. Multiple freeze-thaw cycles should be avoided.

ADAMTS13 Activity Testing Measurement of ADAMTS 13 activity is the most commonly used laboratory test in the workup of suspected TTP. In acquired TTP, the autoantibodies can inhibit function by binding to functional regions of ADAMTS 13 (neutralizing), by causing accelerated ADAMTS 13 clearance (non-neutralizing ), or through both neutralizing and non-neutralizing actions. Activity methods are a fi rst-line choice since they are sensitive to all of these defects. L aboratories rarely use antigen assays due to their insensitivity to purely neutralizing inhibitors.

Although technically complex and time-consuming, labs initially used laboratory-developed tests (L DT) to gauge ADAMTS 13 activity. N ow, however, a number of commercial kits are available, but none have been Food and Drug Administration–approved. The commercial assays utilize synthetic V WF peptides that include the ADAMTS 13 cleavage site. Although these assays are straightforward to perform on widely available laboratory equipment, and generate results within 1–3 hours, many centers refer testing to regional or national reference laboratories since TTP treatment starts prior to result availability and testing generally must be batched to be cost-effective. L aboratories that perform ADAMTS 13 testing must

do so keeping the critical nature of TTP front-and-center, with optimized turnaround times a top priority.

The most widely used activity assays are fl uorescent resonance energy transfer (FRET) methods utilizing a V WF peptide (V WF73 ) containing a fl uorescent moiety and a fl uorescent quencher that fl ank the ADAMTS 13 cleavage site. S ubstrate cleavage by ADAMTS 13 results in fl uorescent emission in direct proportion to the protease activity. However, FRET methods that measure ADAMTS 13 activity in solution, without capture and wash steps, can underestimate activity in icteric specimens with plasma bilirubin concentrations > 100 µ mol/L since bilirubin may quench the fl uorescent emission. This interference is dependent upon which fl uorescent substrate is used and can be minimized by testing diluted specimen.

A newer activity assay with chromogenic endpoint detection

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F1 ADAMTS13 testing algorithm for evaluation of patients with suspected TTP. Diagnostic testing should be performed on pre-treatment specimens. The algorithm depicts the typical case, but note that rare TTP cases with only mild or moderately decreased ADAMTS13 have been reported, as have non-TTP cases with severe ADAMTS13 defi ciency.

12 APRIL 2016

also uses the V WF73 peptide. However, rather than detecting substrate cleavage directly by fl uorescent emission, peptide cleavage in this activity enzyme-linked immunosorbent assay (EL IS A) exposes a specifi c amino acid sequence that an antibody conjugated to horseradish peroxidase (HRP) detects. A subsequent HRP reaction results in color development.

In addition to these common methods, some laboratories use L DTs to perform ADAMTS 13 activity testing using available synthetic substrates. These include L DT FRET methods or more unusual methods such as detecting cleavage products by mass spectrometry.

ADAMTS 13 activity results have been expressed as percentage of normal activity, units/mL , or ng/mL , depending on the kit and calibrators used.

Of note, the World Health Organization (WHO) recently established the WHO 1st International S tandard ADAMTS 13 plasma that may improve harmonization among laboratories. U ntil recently, no commercial profi ciency testing survey offered ADAMTS 13 testing evaluation. However, several organizations, including the College of American Pathologists and N orth American S pecialized Coagulation L aboratory Association, have added ADAMTS 13 to their coagulation surveys.

S evere defi ciency, defi ned in the literature as < 10% of normal activity, appears to have good sensitivity (about 9 0% ) and specifi city (approximately 9 0% or higher) for TTP, although there is some variability depending on the datasets and defi nitions used. S tudies also have shown that severe defi ciency predicts good response to TPE, with approximately 8 0-9 0% of severely defi cient patients responding to fi rst-line therapies. Clinicians determine the duration of TPE based on platelet count recovery and resolution of hemolysis and neurologic symptoms, rather than recovery of ADAMTS 13 activity. Although severe ADAMTS 13 defi ciency predicts good response to TPE, it also portends a signifi cant risk

false-positive results or falsely elevated antibody titers.

B ecause approximately one-third of TTP cases result from antibodies that do not neutralize function, B ethesda-style assays won’t detect a subset of the pathogenic antibodies. However, EL IS A assays in which the EL IS A plate is coated with full-length recombinant ADAMTS 13 will identify the latter. Commercial EL IS A kits are available for this purpose. Interestingly, EL IS As have detected ADAMTS 13 antibodies in a small percentage of healthy individuals. B ecause EL IS As are more sensitive, while B ethesda assays are more specifi c, a refl exive testing algorithm is likely the optimal approach for antibody detection.

A commonly used refl exive algorithm fi rst measures ADAMTS 13 activity, and if defi cient, refl exes to the B ethesda assay. This algorithm calls for performing an EL IS A antibody test only if a B ethesda assay detects no antibodies. Due both to technical limitations of the assays and certain aspects of TTP pathophysiology, there may be a subset of acquired TTP cases in which an ADAMTS 13 antibody cannot be identifi ed. For instance, the B ethesda methodology generally cannot detect antibody titers below 0.5 B U , and both B ethesda and EL IS A assays are incapable of detecting antibody bound to ADAMTS 13 in circulating immune complexes.

Genetic Testing A few clinical laboratories offer ADAMTS 13 gene sequencing, which can help identify the mutations responsible for hereditary TTP. In addition, absence of a mutation may help to exclude a hereditary form in complex cases, such as when antibody tests do not identify an autoantibody. Figure 1 depicts an ADAMTS -13 testing algorithm incorporating activity, antigen, and genetic tests.

Case Conclusion Returning to our opening case, clinicians confi rmed the patient’s working diagnosis of acquired TTP based on laboratory fi ndings of severe ADAMTS 13 defi ciency (< 5% of normal activity) and an ADAMTS 13 inhibitor of 1.8 B U identifi ed in

of disease relapse, which occurs in at least one-third of cases. S ome patients demonstrate severe ADAMTS 13 defi ciency even while in clinical remission, which is likely highly predictive of relapse risk.

Of note, mild to moderately decreased ADAMTS 13 activity can be seen in a variety of illnesses due to decreased synthesis or

increased consumption, so this fi nding alone is not diagnostic of TTP. V ery rare cases of TTP have been reported with minimal, or even no defi ciency. Conversely, severe defi ciency has been rarely reported in other conditions. L abs and ordering providers should approach such unusual fi ndings with great caution.

Tests for ADAMTS13 Antibodies To supplement ADAMTS 13 activity testing, labs increasingly are performing tests for ADAMTS 13 autoantibodies. Identifying the causative antibodies may help solidify the TTP diagnosis and provide prognostic information related to response to TPE and risk of relapse. ADAMTS 13 autoantibody testing also differentiates acquired TTP from rare cases of hereditary TTP caused by ADAMTS 13 mutations (U pshaw-S chulman syndrome).

ADAMTS 13 B ethesda assays detect antibodies that neutralize function, which are present in approximately two-thirds of TTP cases. These are similar to the traditional B ethesda assays used to detect and titer coagulation factor V III or IX inhibitors. They

involve incubating patient plasma with normal pooled plasma to determine if recovery of ADAMTS 13 activity in the

mixture is lower-than-expected due to a patient antibody. The amount of inhibitor that decreases residual activity to 50% of expected is defi ned as 1 B ethesda unit (B U ). B ethesda assays are L DTs that utilize commercial activity assays to measure the residual ADAMTS 13 activity in the mixtures. S ubstances mentioned previously that can affect the activity assays, such as hemoglobin and bilirubin, also affect antibody identifi cation and quantifi cation in B ethesda assays and can cause

OF NOTE, THE WORLD HEALTH ORGANIZATION (WHO) RECENTLY ESTABLISHED THE WHO 1ST INTERNATIONAL STANDARD ADAMTS13 PLASMA THAT MAY IMPROVE HARMONIZATION AMONG LABORATORIES. UNTIL RECENTLY, NO COMMERCIAL PROFICIENCY TESTING SURVEY OFFERED ADAMTS13 TESTING EVALUATION.

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Screening with HPV-Alone invites more risk into women’s lives than you may think.

One out of 5 cases of cervical cancer were missed with HPV-Alone screening in a recent landmark, retrospective study—the largest ever conducted to evaluate the effectiveness of cervical cancer screening strategies in women ages 30-65.1* And screening with Pap+HPV Together™ (co-testing) identified more than 70% of those missed cancers.1 So is HPV-Alone screening really worth the risk?

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14 APRIL 2016

ADAMTS 13 activity, although not available immediately as part of the initial workup, is a useful differentiator when considering these possibilities since these other disease conditions are not associated with severe ADAMTS 13 defi ciency. Mild to moderate decreases in the activity could be seen in these disease conditions due to the negative effects of infl ammation and severe illness on the production and/or survival of ADAMTS 13 . Table 1 summarizes testing useful in the evaluation of suspected TTP.

The patient responded well to TPE and immunosuppression with prednisone. Indeed, her headache and confusion completely resolved after a single exchange, and her platelet count totally recovered and her hemolysis resolved after several more exchanges. Repeat ADAMTS 13 testing while in clinical remission revealed a persistently low but improved ADAMTS 13 activity of 15% of normal and persistence of a low-level inhibitor of 0.6 B U . Due to the high risk of relapse in acquired TTP, she is being monitored closely for disease recurrence, particularly during times of infl ammation or stress such as illness, surgery, or pregnancy.

Conclusion ADAMTS 13 laboratory testing provides valuable information contributing to the diagnosis, management, and prognosis of TTP. While ADAMTS 13 activity is the mainstay of this testing, a growing body of medical literature supports the utility of antibody testing. L aboratory professionals armed with knowledge of test performance characteristics and appropriate clinical use can greatly contribute to the care of patients with this life-threatening disease.

Suggested Reading 1. Barrows BD, Teruya J. Use of the

ADAMTS13 activity assay improved the accuracy and effi ciency of the diagnosis and treatment of suspected acquired TTP. Arch Pathol Lab Med 2014;138:546–9.

2. Bentley MJ, Wilson AR, Rodgers GM. Performance of a clinical prediction score for TTP in an independent cohort. Vox Sang 2013;105:313–18.

3. George JN. How I treat patients with TTP: 2010. Blood 2010;116:4060–9.

4. Hubbard AR, Heath AB, Kremer Hovinga JA, Subcommittee on von Willebrand Factor. J Thromb Haemost 2015;13:1151–3.

5. Mannucci PM, Canciani MT, Forza I, et al. Changes in health and disease of the metalloprotease that cleaves von Willebrand factor. Blood 2001;98:2730–5.

6. Meyer SC, Sulzer I, Lammle B, et al. Hyperbilirubinemia interferes with ADAMTS-13 activity measurement by FRETS-VWF73 assay: Diagnostic relevance in patients suffering from acute thrombotic microangiopathies. J Thromb Haemost 2010;5:866–7.

7. Peyvandi F, Palla R, Lotta LA, et al. ADAMTS-13 assays in TTP. J Thromb Haemost 2010;8:631–40.

8. Rieger M, Mannucci PM, Kremer Hovinga JA, et al. ADAMTS13 autoantibodies in patients with thrombotic microangiopathies and other immunomediated diseases. Blood 2005;106:1262–7.

9. Sadler JE. Von Willebrand factor, ADAMTS13, and TTP. Blood 2008;112:11–8.

10. Starke R, Machin S, Scully M, et al. The clinical utility of ADAMTS13 activity, antigen and autoantibody assays in TTP. Br J Haematol 2007;136:649–55.

Kristi J. Smock, MD, is an associate professor of pathology at the University of Utah and medical director of the Hemostasis/Thrombosis Laboratory at ARUP Laboratories in Salt Lake City, Utah. +EMAIL: kristi.smock@aruplab.com

Get continuing education credit for reading CLN

mini-reviews. AACC designates 0.5 ACCENT ® credit hours.

Visit www.aacc.org/pub lications/cln/accent for more information.

0.5

T1 Summary of testing used to evaluate suspected TTP

TEST Indication/Utility/Limitations

Routine hematology and plasma chemistry testing

• Widely available essential testing for initial evaluation of MAHA and thrombocytopenia

• In TTP, results indicate intravascular hemolytic anemia with frequent schistocytes, marked thrombocytopenia, strikingly high LDH, and minimal renal dysfunction

• Clinical prediction scores using routine tests facilitate initiation of appropriate therapy

• Used to monitor treatment effi cacy and help determine length of TPE (continued to recovery of hemolysis and thrombocytopenia and resolution of neurologic symptoms)

Routine coagulation testing

• Widely available • Used to exclude DIC as a cause of MAHA and

thrombocytopenia• Normal or only mild derangements in most

TTP cases

ADAMTS13 activity

• Evaluate suspected TTP, defi ned as MAHA and thrombocytopenia without alternative cause

• Limited availability, treatment decisions made before results available but are frequently modifi ed when results are available

• Diagnostic testing must be performed on pre-treatment specimens

• Severe defi ciency (<10% of normal activity) compatible with TTP (high sensitivity and specifi city)

• Severe defi ciency correlates with response to therapy and risk of relapse

ADAMTS13 antibody testing

• Can be used to confi rm acquired TTP in cases with severe ADAMTS13 defi ciency

• Differentiates acquired from hereditary TTP • Limited availability, Bethesda assays are

technically complex LDTs• Diagnostic testing must be performed on pre-

treatment specimens• Presence of antibodies correlates with response

to therapy and risk of relapse• Bethesda assays are more specifi c but less

sensitive than ELISA assays, algorithmic testing panels are useful

• Currently available methods do not detect the causative antibodies in every case of acquired TTP

ADAMTS13 gene sequencing

• Expensive and with limited availability• Identifi es the mutations responsible for

hereditary TTP (Upshaw-Schulman syndrome), which confi rms the diagnosis and simplifi es testing for family members

• May assist in differentiation of acquired and inherited TTP in complex cases

testing from acute (pre-therapy) specimens. Her initial clinical history and laboratory results largely excluded other processes associated with microangiopathic hemolytic anemia and thrombocytopenia, like HU S , aHU S , and DIC.

Legend: MAHA = Microangiopathic hemolytic anemia; TTP = thrombotic thrombocytopenic purpura; DIC = disseminated intravascular coagulation; LDT = laboratory-developed tests

16 APRIL 2016

After years of back-and-forth on the issue, the debate over which federal agency will

regulate laboratory-developed tests (L DT) going forward is far from settled. The Food and Drug Administration (FDA) says it has the statutory authority to regulate L DTs and will release a fi nal guidance on L DT oversight this year. Meanwhile, some lawmakers and industry groups are circulating alternative proposals that would either give FDA more authority over L DTs or give the authority to the Centers for Medicare and Medicaid S ervices (CMS ) under an expanded CL IA program. Other groups are threatening litigation once the fi nal guidance is released unless there are signifi cant changes that make the new framework more palatable.

“ I think at this point, everything is pretty much up in the air,” said James N ichols, PhD, professor of pathology, microbiology, and immu-nology, and medical director for clini-cal chemistry and point-of-care test-ing at V anderbilt U niversity S chool of Medicine in N ashville. N ichols also is chair of the AACC Government Affairs Committee. AACC recently released a position statement on CL IA calling for CMS , not FDA, to be responsible for L DT oversight. V anderbilt has developed hundreds of L DTs and would be signifi cantly impacted by a requirement that it fi le a premarket submission for each one, N ichols noted.

FDA Plowing AheadEven as legislative drafts dealing with L DTs circulate in Congress, FDA is moving ahead with plans to issue a fi nal guidance in 2016, said

STAKEHOLDERS PROPOSE ALTERNATIVES TO FDA REGULATIONBY KIMBERLY SCOTT

FUTURE OF LDT OVERSIGHT

STILL UNCERTAIN

Eric Pahon, an FDA spokesperson. The agency in 2014 issued a draft guidance under which it would implement a risk-based, phased-in approach for oversight of high- and moderate-risk L DTs. It would continue to use enforcement discretion for low-risk L DTs, as well as certain categories of moderate- and high-risk L DTs. “ We are in the fi nal drafting phase of the fi nal guidance,” Pahon told CLN. “ We have carefully considered the comments and concerns that have been brought up. We take the comments very seriously. The FDA doesn’t want to stifl e innovation or stifl e access, but we do want to make sure that the public is safe.” Once the agency fi nishes drafting the guidance, it will have to go through an additional review with the Department of Health and Human S ervices and the Offi ce of Management and B udget before being announced.

At the heart of the debate over L DTs is the question of whether these tests actually pose a risk to patients. FDA argues that many do, and in a report issued in N ovember 2015 it presented 20 case studies of L DTs that it believes may have caused or could cause harm to patients. “ I question the premise that there is a problem with L DTs,” N ichols said. “ I don’t think the issue is with the tests themselves, but perhaps with communication and interpretations of the test results. That’s not something the FDA guidance would solve.”

Expanding CLIAAACC and several other laboratory industry groups, including the Association for Molecular Pathology (AMP) and the College of American G

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18 APRIL 2016

“IF A REPUBLICAN IS ELECTED PRESIDENT, THERE’S A

POSSIBILITY THAT THE

GUIDANCE WILL BE

RESCINDED.”

— JEFF GIBBS, ATTORNEY;

HYMAN, PHELPS AND MCNAMARA

Pathologists (CAP), are advocating an alternate approach to oversight of LDTs that would build on the existing CLIA framework. In its recent position statement, AACC recommends that CLIA remain the primary mechanism for overseeing clinical laboratories and supports modernizing the regulations to ensure that they continue to meet the changing needs of the healthcare community.

“Revisions to the regulations should particularly address the laboratory inspection process, quality control recommendations, profi ciency testing requirements, and the defi nition of what constitutes an LDT,” the position paper says.

In response to concerns that CLIA does not require clinical validation of tests, AACC notes that more than 8,000 labs are accredited by CAP or the Joint Commission, both of which require clinical validation of any claims relating to the use of LDTs for patient care. The New York State Department of Health also requires such validation.

“Expanding clinical validity to all LDTs under CLIA appears to be a viable regulatory option that would achieve the goal of ensuring clinical validity without the prohibitive administrative burden of dual oversight by FDA and CMS,” notes AACC in its position statement. To implement this requirement, CMS could either hire additional staff to review the laboratory validation data, use the existing processes already in place at CAP, Joint Commission, and New York State, and/or contract with third parties to conduct the reviews.

The issue of resources needed to ensure clinical validity is a critical one that would need to be addressed by whichever agency ends up with LDT oversight authority. During a November 17 hearing before the House Energy and Commerce Committee, Patrick Conway, the CMS deputy administrator for innovation and quality and chief medical director in the offi ce of the administrator, said repeatedly that CMS does not have the resources or expertise to conduct premarket review of LDTs and that giving CMS that responsibility could cause a backlog that would stifl e innovation.

FDA would also need additional staff to conduct premarket reviews if it moves forward with oversight of LDTs. FDA estimates there are about 11,000 LDTs nationwide, but industry stakeholders believe the number is substantially larger. “It’s hard to know how many LDTs there are without defi ning them,” said Jeff Gibbs, an attorney with Hyman, Phelps and McNamara, PC in Washington, D.C. and a contributor to the FDA Law Blog. If a premarket submission was required every time an existing test was modifi ed by a laboratory as FDA seemed to propose, the numbers could be staggering, he noted. It its position statement, AACC recommends defi ning LDTs based on clinical claims—excluding routine modifi cations to FDA cleared or approved tests, as well as off-label use of tests by physicians.

Alternate ProposalsCurrently there are several alternate proposals being fl oated around Capitol Hill. Two, put forth by AMP and CAP, are similar in many ways, with both exempting low-risk tests from premarket reviews and giving CMS or third-party reviewers the sole authority to review moderate-risk tests. FDA would only be involved in review of high-risk tests.

A third proposal, put forth by the House Energy and Commerce Committee, is based on an alternate framework drafted by the Diagnostic Test Working Group, a coalition of IVD companies and laboratories. This draft legislation would create a new FDA center for in vitro clinical tests, which would use a new standard—reasonable assurance of analytical validity and clinical validity—in reviewing all high-risk in vitro clinical tests, regardless of whether the test is offered by a laboratory or as a distributed product. FDA would handle premarket review of LDTs while CMS would continue oversight of laboratory operations.

FDA was asked to provide input on the Energy and Commerce draft legislation and said it will continue to engage with lawmakers and other stakeholders on the issue. “We continue to communicate our

concerns that patients are making critical health decisions based on laboratory-developed tests without the assurances that these tests are entirely accurate or effective,” Pahon said. “Without premarket review by the FDA—neither patients, their healthcare providers, nor FDA itself can be assured these tests are accurate and effective.”

Legal Challenge LikelyWith so many competing proposals and fi nal guidance reportedly on the way, what is the most likely outcome? According to Gibbs, there are several possible scenarios. In one, the fi nal guidance would be modifi ed enough to be palatable to the laboratory industry. Another possibility is that the guidance would be held up at the Offi ce of Management and Budget and not released this year. Under the third scenario, the fi nal guidance would be issued and a legal challenge brought before the guidance goes into effect. Finally, Congress could enact legislation. Gibbs believes the third scenario is the most probable.

“The single most likely outcome in my view is that FDA will issue a fi nal guidance this year, and there will be litigation,” Gibbs said, noting that the American Clinical Laboratory Association has retained two high-powered attorneys and has indicated a willingness to take FDA to court over this issue. “I think the FDA would lose if there is a challenge under the Administrative Procedure Act,” Gibbs added. “The argument is that the FDA cannot make these kinds of changes through a guidance document, but instead needs to go through a rulemaking process.”

If that were to occur, it could be some time before any kind of rulemaking is fi nalized, Gibbs predicted, noting that the outcome of this year’s presidential election could also infl uence the outcome. “If a Republican is elected President, there’s a possibility that the guidance will be rescinded,” he said. “Because it is a guidance, it could be more easily undone than if it were a rule. Anything could happen.”

Kimberly Scott is a freelance writer who lives in Lewes, Delaware. +EMAIL: kmscott2@verizon.net b

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Accepted abstracts will be displayed as posters throughout the meeting, and several outstanding abstracts will be selected for oral presentations.

Abstracts are invited in the following categories:• Point-of-Care Testing in the Emergency Department

• Point-of-Care Testing in the Intensive Care Setting

• Point-of-Care Testing in the Primary Care Setting

• Point-of-Care Testing in the Pediatric Setting

• Direct to Consumer Testing—the New Face of Point-of-Care?

The CPOCT Division will award two travel grants of $500 each for the best abstracts.

SUBMIT YOUR ABSTRACT TODAY: www.aacc.org/CPOCT2016SUBMISSION DEADLINE: May 1, 2016

Sponsored by the AACC Critical and Point-of-Care Testing Division

Developed in cooperation with the Danish Society for Clinical Biochemistry

Point-of-Care Testing Across the Clinical Spectrum

Call for Abstracts

The Benefits & Challenges of

Submission deadline

May 1 2016

Accepted abstracts will be displayed as posters throughout the meeting, and several outstanding abstracts will be selected for oral presentations

26th International CPOCT Symposium

September 21-24, 2016

The Scandic Copenhagen Hotel, Copenhagen, Denmark

20 APRIL 2016

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Hospital-acquired anemia (HAA) is a fairly common condition associated with poor patient

outcomes and increased hospital resource utilization (1). Preventing HAA demands a team approach and the clinical lab is a key player, since chronic phlebotomy-associated blood loss may lead to anemia. Labs can help limit diagnostic blood loss by implementing strategies that reduce the amount of blood required for testing and encourage appropriate test ordering. Improve ments in these areas increase patient safety by reducing the risk of iatrogenic anemia as well as the need for blood transfusion.

What is HAA?Anemia is a condition of decreased red blood cells (RBC) or hemoglobin due to blood loss, decreased RBC production, or increased RBC breakdown. HAA develops as a result of hospitalization in patients who have a normal hemo globin level on admission and can be categorized as mild (Hgb < 11.0 g/dL), moderate (Hgb 9.1 – 11.0 g/dL), or severe (Hgb < 9.0 g/dL) (2).

What are the risk factors for HAA?Every hospitalized patient is at risk for developing HAA, but the longer the stay the greater the risk (1). Neonatal, geriatric, and malnourished patients are predisposed to higher risk. HAA also frequently occurs in critically ill patients, those with a lower body mass index, and those

suffering from long-term or serious illnesses such as kidney disease, cancer, or diabetes.

How does diagnostic blood loss contribute to HAA?The development of HAA is multifactorial. Frequent and/or large blood draws for diagnostic testing have been identified as major contributing factors (3, 4). Normal bone marrow can compensate for blood loss associated with daily draws in most hospitalized patients, but patients with bone marrow suppression or other conditions affecting blood production may become anemic. Estimates for average daily diagnostic blood loss in hospitalized patients ranges from approximately 12 mL per day in general medicine wards to 40–50 mL per day in intensive care units (ICU), the latter being higher because

critically ill patients typically require more testing (5). ICU patients with an indwelling catheter can lose up to 900 mL of blood during their hospital stay because a discard tube is required to flush the line before sample collection (5). This degree of phlebotomy-associated blood loss occurs most often in patients with long-term ventilation, coagulation disorders, or those who have undergone surgery. Patients admitted for acute myocardial infarction also experience substantial phlebotomy-associated blood loss. One study suggests that for every 50 mL of blood collected during hospitalization, the risk of developing HAA increases by 20% (6).

Does HAA affect patient outcomes?A growing body of evidence suggests that patients with normal hemoglobin levels on hospital admission who subsequently develop HAA have increased risk of morbidity and mortality compared with those who do not (1, 6). These patients also experience increased length of stay and consume more hospital resources (1). Treatment of severe HAA in critically ill patients may involve RBC transfusion. This carries significant risk and may lead to additional complications.

Are there lab-based interventions to prevent HAA?Clinical labs play an important role in decreasing phlebotomy-associated

JAIME NOGUEZ, PHD, DABCC

Tackling Hospital-Acquired AnemiaLab-Based Interventions to Reduce Diagnostic Blood Loss

Labs can improve test utilization by

providing more guidance for test

selection, notifying physicians of

duplicate orders, and eliminating standing orders.

21APRIL 2016

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blood loss and preventing HAA (Table 1). In general, hospital labs collect up to 12 times more blood than the required analytical volume, with the majority of the sample being discarded (7). Studies suggest that most labs can decrease collection volumes without compromising their ability to report reliable and timely results (7). Using small volume blood collection tubes for at-risk populations, drafting a minimum sample volume chart for each test, and using previously collected samples for “add on” tests where appropriate are simple lab-based interventions to reduce diagnostic blood sampling volume and waste. Other blood conservation strategies include increasing the use of point-of-care testing in certain settings and

monitoring blood volumes drawn from susceptible patient populations.

Tackling inefficient test ordering practices can also help reduce diagnostic blood loss and transfusion requirements. Labs can improve test utilization by providing more guidance for test selection, notifying physicians of duplicate orders, and eliminating standing orders. In addition, educating clinicians about the consequences of phlebotomy overdraws and encouraging batched test orders (so the same blood sample can be used for all tests in the batch) promotes a team approach toward blood conservation.

Recent advances in blood collection techniques and analytical instrumentation have reduced test volume requirements considerably, decreasing the risk of phlebotomy-induced HAA. Clinical labs can reduce this risk further by modifying routine practices as described in this article. Implementing these proactive blood management strategies not only increases patient safety but also reduces the cost of care.

References1. Koch CG, Li L, Hixson ED, et al.

Hospital acquired anemia: Prevalence, outcomes, and healthcare implications. J Hosp Med 2013;8:506–12.

2. Ahmed AH. Prevention and management of hospital-acquired

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

• Develop a minimum sample volume chart for each test

• Use small-volume blood collection tubes to reduce blood volume

• Use previously collected samples for “add on” tests where appropriate

• Educate clinicians about test utilization and blood waste

• Increase POCT to reduce required sample volume when possible

• Provide decision support for appropriate test selection

• Notify physicians of duplicate orders

• Eliminate standing orders

• Document/monitor blood volumes drawn from high-risk patient populations

T1 Lab-based interventions to prevent hospital-acquired anemia

anemia. Hosp Med Clin 3 2014;e71–84.

3. Thavendiranathan P, Bagai A, Ebidia A, et al. Do blood tests cause anemia in hospitalized patients? The effect of diagnostic phlebotomy on hemoglobin and hematocrit levels. J Gen Intern Med 2005;20:520–4.

4. Lin JC, Strauss RG, Kulhavy JC, et al. Phlebotomy overdraw in the neonatal intensive care nursery. Pediatrics 2000;106:E19.

5. Smoller BR, Kruskall MS. Phlebotomy for diagnostic laboratory tests in adults. Pattern of use and effect on transfusion requirements. N Engl J Med 1986;314:1233–5.

6. Salisbury AC, Alexander KP, Reid KJ, et al. Incidence, correlates and outcomes of acute, hospital-acquired anemia in patients with acute myocardial infarction. Circ Cardiovasc Qual Outcomes 2010;3:337–46.

7. Dale JC, Ruby SG. Specimen collection volumes for laboratory tests: A College of American Pathologists study of 140 laboratories. Arch Pathol Lab Med 2003;127:162–8.

Jaime Noguez, PhD, DABCC, is the assistant director of clinical chemistry at University Hospitals Case Medical Center and assistant professor of pathology at Case Western Reserve University in Cleveland, Ohio. +EMAIL: Jaime.Noguez@UHhospitals.org

22 APRIL 2016

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When it comes to persuading physicians to do things differently, there are two

prevailing schools of thought. The fatalistic school holds that physicians are simply unmanageable. This perspective reflects the old—and sadly, too often accurate—stereotype of arrogant and intransigent physi-cians. To follow this approach means there is no choice but to defer to individual physician preferences. The other school of thought, which I’ll call the top-down school, acknowledges this stereotype and then asserts that to change physician behavior, it is necessary to take away their freedom of action. This school scoffs at weak behavioral interventions such as education, and promotes strong tactics such as forced clinical algorithms along with monetary rewards and penalties. MacArthur fellow and Harvard surgeon Atul Gawande’s famous proposal to run hospitals like Cheesecake Factory restaurants falls into this latter category (1). Unfor-tunately, neither the fatalistic nor the top-down approach present a fully satisfying theory of physician manage-ment, and both can bring negative consequences when applied broadly.

The problem with both approaches lies in the incredible complexity at the intersection of human biology and modern medi-cal technology. Neither unassisted individual physicians nor administra-tors acting from a distance are fully capable of navigating this complex-ity alone. In Gawande’s Cheesecake

Factory example, the limited number of inputs (ingredients, appliances, utensils, and the orderable options on the menu) can be controlled rigor-ously all the way through to the final product. In medicine, on the other hand, the primary inputs—patients and their diseases—are strikingly more complex. Each individual is different. Each disease presenta-tion is different. Comorbidities are common. Every patient has different values and preferences for care. And great physicians customize care to individual patients to achieve superior outcomes.

Certainly, most factors in health-care delivery can and should be standardized. But to become a great healthcare system, it’s also necessary to identify the factors that should remain flexible in order to support the work of of our best doctors. What we need, in other words, is a theory of active, engaged management that respects the professional role of

physicians and takes full advantage of their education, skills, and ingenuity.

One useful tactic under this approach is nudging, i.e. steering physicians in the direction that we know is usually right, while still giv-ing them freedom to deviate where appropriate. This requires engineer-ing the information environment in which they act, such that usually correct actions become the default, and deviation requires a conscious choice. In more formal terms, nudging is an application of behavioral eco-nomics, which blends economics and psychology.

The book, Nudge, written in 2009 by two University of Chicago profes-sors, popularized this concept (2). Classic economic theory holds that people will always act in their rational self interest. Psychology, on the other hand, knows that there are all kinds of reasons why people don’t, rang-ing from misperceptions to inertia. Over the past 2 decades, researchers

Nudging Our Way to More Effi cient CareHow to Win Friends Among Doctors While Infl uencing Them

BRIAN R. JACKSON, MD, MS

If we are to solve the considerable challenges of achieving accountable care, it will require creative collaboration among all players in the healthcare system: clinicians, administrators, laboratory professionals, insurance companies, and others.

23APRIL 2016

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have been studying practical ways to exploit these biases in order to steer people into changing their behavior.

For example, herd mentality is one common type of bias. Applying this to doctors, we see that they tend to adopt the practice styles of their more experienced peers. This can be a bad thing when those peers are wasteful or unsafe. But the herd mentality bias can be turned to advantage by identi-fying local physicians whose practice patterns are desirable and holding up their practice patterns as a standard. This creates the perception that these physicians are the primary peers, or “herd.”

In 2010, British Prime Minister David Cameron established a Behavioral Insights Team within his government. This body’s mandate is to use the principles of behavioral economics to influence the behavior of Britons in useful ways. For exam-ple, one of its most prominent experiments tackled the problem of citizens who didn’t pay their taxes on time. The British government already had a database that was used for sending out threatening reminder letters to delinquent citizens. But these letters didn’t seem to have much effect. So David Halpern, a former psychology professor at the University of Cambridge and the director of the Behavioral Insights Team, experimented with several alternative messages. Some letters cited the proportion of British taxpayers who paid on time. Others simply said that the majority of Britons in the recipients’ same income bracket had paid on time. Both messages turned out to have a significant positive impact on the rate of on-time payment (3).

A recent JAMA article described a randomized controlled trial of three behavioral interventions to nudge primary care doctors to reduce their use of antibiotics for acute respira-tory tract infections (4). Most such infections are viral in origin, and the unnecessary use of antibiotics contributes to antibiotic resistance. One intervention, “suggested alterna-tives,” used popup messages within the electronic medical record. These messages recommended a non-antibiotic approach and facilitated ordering of applicable alternatives

such as decongestants. A second, “peer comparison,” issued reports to physi-cians that compared their antibiotic ordering rates to their top-performing peers—notably, not the average of their peers. A third, “accountable jus-tification,” required physicians to type in their reasons for deviating from the recommended therapy. All three interventions lowered the rate of inappropriate prescribing, and two of them achieved statistical significance. There were additive effects among the three, so that providing two or three interventions produced a bigger effect than any one alone. All three interventions respected physicians’ clinical judgment and allowed them to prescribe according to their judg-ment without penalty.

The direct implications of these experiments on lab utilization management are straightforward: we should provide alternative orders to commonly misordered tests; compare physicians’ ordering patterns to those of high-performing peers; and require written justification for orders that deviate from the standard recommen-dations. A less obvious implication is that these activities are better done in concert rather than in isolation. More broadly, the lesson is that in many use cases, hard controls may not be either necessary or even desirable for managing laboratory utilization.

If we are to solve the considerable challenges of achieving account-able care, it will require creative

collaboration among all players in the healthcare system: clinicians, admin-istrators, laboratory professionals, insurance companies, and others. This necessitates that each party bring out the best in the others. We need to be active and assertive in setting goals and holding each other accountable to those goals. But we also need to do this in ways that promote, rather than suppress, teamwork. Nudging can be a valuable tool in that it actively steers subjects in a particular direction, while preserving respect for their professional judgment.

References1. Gawande A. Big med. New Yorker.

August 13, 2012. 2. Thaler RH, Sunstein SR. Nudge:

Improving decisions about health, wealth, and happiness. London: Penguin Books 2009.

3. Bennhold K. Britain’s ministry of nudges. New York Times. December 7, 2013.

4. Meeker D, Linder JA, Fox CR, et al. Effect of behavioral interventions on inappropriate antibiotic prescribing among primary care physicians: A randomized controlled trial. JAMA 2016;315(6):562–70.

Brian Jackson, MD, MS, is vice president and chief medical informatics offi cer at ARUP Laboratories, and an associate professor of clinical pathology at the University of Utah in Salt Lake City. +EMAIL: jackson@aruplab.com

• Eliminate obsolete or almost-never-indicated tests from computerized physician order entry systems, while permitting doctors to order them via free text, provided that they provide a written justifi cation.

• Measure test utilization patterns and provide feedback to doctors on how they compare numerically to their top-performing peers.

• On order sets, display the most commonly needed tests higher than less commonly appropriate ones. Consider visually separating less common appropriate tests into a separate section along with a brief explanation of indications.

Examples of nudging doctors to use lab tests more appropriately

• Only allow tests to be grouped in panels when it is truly reasonable and cost-effective to order all of the tests at the same time.

• Provide refl ex panels that refl ect recommended diagnostic algorithms.

• When a physician enters a new order for a recently-performed test, display the most recent date/time and result of that test.

• For tests with known poor sensitivity or specifi city, display those performance characteristics in a popup box at the time of order.

Attend this online

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your POCT program

through best practices

and real-life examples.

Organizing committee:

Peggy Mann, MS, BS, MT (ASCP) Ambulatory POC Coordinator and Program Manager, University of Texas Medical Branch Healthcare System, Galveston, TX

Ross Molinaro, PhD, DABCC, FACB Medical Officer and Head of Medical Affairs, Siemens Healthcare Diagnostics, Inc., Newark, DE

Lou Ann Wyer, MS, MT ASCP, CQA ASQ Directory of Laboratory Services, Sentara Healthcare, Norfolk, VA

Leading the Way to Positive Outcomes:

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Register today!

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An Online Conference

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26 APRIL 2016

Industry Playbook

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PROOF Centre, AstraZeneca Collaborate on CKD Prognostic TestThe Centre of Excellence for the Prevention of Organ Failure (PROOF Centre) has partnered with AstraZeneca and the Canadian Study of Prediction of Death, Dialysis, and Interim Cardiovascular Events (CanPREDDICT) to develop a blood test to predict the rate of disease progression in patients with chronic kidney disease (CKD). For the discovery phase of the project, PROOF Centre and AstraZeneca researchers will use the large cohort and extensive clinical data available from the CanPREDDICT study. The collective team of clinical, computational, technical, and biological experts will also use the PROOF

Centre’s computationally-driven omics biomarker development pipeline to identify genomic and proteomic biomarkers that can discriminate between patients who have rapid versus slow CKD progression. Overall, the PROOF Centre will support the analysis from front-end experimental design to downstream statistical and biological analysis.

An effective prognostic test would enable clinicians to manage CKD more aggressively in patients expected to decline rapidly, potentially delaying end-stage renal disease. It could also potentially reduce healthcare costs by identifying stable or improving patients who require less frequent monitoring. Additionally, the partnering organizations believe that a prognostic CKD assay could be extremely valuable for research and drug development.

“Knowing which patients with this disease are likely to face rapid decline and which ones are not is a major hurdle

in clinical trials for new therapeutics,” said Peter Greasley, PhD, director of clinical research at AstraZeneca. “Biomarkers identifi ed in this collaboration will enable patient stratifi cation that in turn may reduce the time, number of patients, and costs needed for such trials.”

■QIAGEN ENTERS NEW BIOINFORMATICS AGREEMENTS

Q iagen has formed new partnerships to enhance the profi le and expand the use

of its bioinformatics solutions for microbiome, metagenomics, and other applications. In the fi rst of these collaborations, Qiagen Bioinformatics has signed an agreement with genomics big data company CosmosID. This will allow users of Qiagen’s CLC Genomics Workbench to access CosmosID’s metagenomics analysis platform and employ shotgun metagenomics analysis for routine testing involving next-generation sequencing.

Qiagen has also awarded a contract to its partner, Trigent Solutions, that will grant seven centers of the Food and Drug Administration (FDA) streamlined access to Qiagen’s bioinformatics solutions. The products made available to FDA centers include software for infectious diseases research and outbreak analysis, as well as solutions in human genomics. The contract also includes services that aim to combat infectious outbreaks by enabling the uploading and sharing of public health data with U.S. and international institutions via the National Center for Biotechnology Information’s Sequence Read Archive.

27APRIL 2016

■ILLUMINA ACQUIRES HLA TYPING COMPANY

I llumina recently bought Conexio Genomics, a company focused on

human leukocyte antigen (HLA) typing, in order to advance its work developing next-generation sequencing (NGS) solutions for the HLA typing market. According to a press release from Illumina, Conexio’s innovations played a key role in kick-starting the sequencing era for HLA typing. Since then, Conexio has introduced a complete line of sample-to-report products for genotyping HLA genes with both Sanger sequencing and NGS. Conexio’s NGS development programs have been integrated into Illumina. This will enable Illumina to develop NGS-based transplant diagnostics assays, including a new solution for interrogating genomic variants in the gamma genomic block of the major histocompatibility complex.

■ABBOTT BUYS ALERE TO EXPAND POCT OFFERINGS

Abbott has entered a defi nitive agreement to acquire Alere in

order to advance its point-of-care testing portfolio. Upon completion of the transaction, the combined business will offer a broad point-of-care menu in infectious diseases, molecular, cardiometabolic, and toxicology testing, expanding Abbott’s platforms to include benchtop and rapid strip tests. Alere’s complementary portfolio of products will provide Abbott with access to new channels and markets, including entry into fast-growing outlets such as doctors’ offi ces, clinics, pharmacies, and at-home testing. Abbott’s capabilities and infrastructure will also drive accelerated growth of Alere’s portfolio, which has a rising presence in key international markets. Under the terms of the agreement, Abbott will pay $56 per common share at a total expected equity value of $5.8 billion, and Alere will become a

subsidiary of Abbott. Abbott’s and Alere’s respective boards of directors have approved the transaction, which is now subject to the approval of Alere shareholders and the satisfaction of customary closing conditions.

■THERMO FISHER, CHLA TO DEVELOP NGS PANEL FOR CHILDHOOD CANCERS

Thermo Fisher Scientifi c and Children’s Hospital Los Angeles

(CHLA) are collaborating to develop a comprehensive next-generation sequencing (NGS)-based panel designed specifi cally for pediatric cancer research. With this assay, the two organizations aim to improve understanding of the pathogenesis and future therapy of pediatric cancer patients. Using as little as 10 ng of DNA and RNA from fi xed, fresh, or frozen tumor tissue, the panel will detect virtually all somatic genetic alterations identifi ed for childhood cancer to date in the scientifi c literature. This will include DNA mutations, gene amplifi cations, more than a thousand gene fusion variants, and more than a hundred tumor-specifi c gene translocations. The assay will use Thermo Fisher’s Ion Torrent NGS platform and Ion AmpliSeq technology. It builds on the experience and expertise of a team of laboratory research scientists and pathologists from CHLA’s Center for Personalized Medicine, and of clinicians and pediatric cancer investigators at CHLA’s Children’s Center for Cancer and Blood Diseases, which is home to one of the largest pediatric hematology-oncology programs in the country.

■SYSMEX, EISAI PARTNER ON BLOOD TESTS FOR DEMENTIA

Sysmex Corporation and Eisai have joined forces to create

next-generation diagnostics that will enable early diagnosis of dementia, while also improving selection of

treatment options and the ability to monitor the effects of treatment. The partnership will build on Sysmex’s diverse expertise in the fi eld of clinical diagnostics as well as the company’s technologies for detecting genetic, protein, and cellular biomarkers in blood samples. It will also leverage Eisai’s experience from more than 30 years of drug discovery work in the fi eld of dementia. Under the terms of the agreement, Sysmex will lead the development of diagnostics and will exclusively market these tests worldwide after receiving regulatory approval. Eisai will receive payments for meeting development milestones and launching products, as well as royalties on sales, and will use these next-generation diagnostics for drug discovery and development in the fi eld of dementia.

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28 APRIL 2016

QAsk The Expert

Cystatin C and Creatinine: Complementary Markers of GFR

EXPERT

John C. Lieske, MD

individuals with the same level of kidney function.

The most recent equations for estimating GFR get around this issue to some extent by adjusting for age, sex, and race, which account for much of the inter-individual variability in muscle mass. The equations do not account for other factors that might be important, though, such as chronic illness, malnutrition, or even a larger-than-average muscle mass.

What are the advantages of cystatin C versus creatinine?Cystatin C is made by all nucleated cells, not just muscle. As a result, cystatin C production varies less than creatinine production between individuals, and blood concentrations of cystatin C are fairly similar between individuals who have the same GFR. However, cystatin C has other potential confounders. For example, chronic infl ammation seems to increase cystatin C blood concentrations slightly. Perhaps for this reason, relatively higher blood cystatin C concentrations seem to be a poor prognostic marker.

Overall, when modern equations are used creatinine and cystatin C are, on average, fairly comparable tools for estimating GFR. However, in certain patient populations one may be better than the other, as my research group recently found (Clin Chem 2015;61:1265–72).

How do different assays for cystatin C compare with each other?Over the last 15 years clinical laboratories and manufacturers have strived to standardize serum creatinine measurement across virtually all platforms. They are in the early phases of a similar process with cystatin C. An international reference material for cystatin C (ERM-DA471/IFCC) was released in June 2010 and certain assays are traceable to this material. As of 2016, though, biases might still exist between commercially available cystatin C assays.

Should cystatin C be used by itself or with other markers?With modern estimating equations,

Why do labs need a marker in addition to creatinine to estimate glomerular fi ltration rate (GFR)?

A: Creatinine is a byproduct of muscle metabolism that

is freely fi ltered by the kidney, the blood concentration of which refl ects GFR. However, because muscle mass varies depending on age, sex, race, and level of fi tness, the serum concentration of creatinine can still differ between

serum creatinine can be used to obtain an estimated GFR (eGFR) for most individuals that can adequately guide clinical decision making. However, cystatin C is a helpful adjunct in certain subsets of patients. Importantly, cystatin C can be useful when a healthcare provider suspects that a patient’s muscle mass differs from average for his or her age and sex.

Another important setting where cystatin C might have an advantage is among hospitalized patients. In acutely ill individuals GFR often changes rapidly, and cystatin C tends to track this more accurately due to its shorter blood half-life. Muscle mass can also decline rather abruptly in the hospital, further confounding the relationship between GFR and creatinine. Overall, the optimal use of cystatin C among acutely hospitalized patients is an area ripe for further research.

A third approach is applying the combined Chronic Kidney Disease Epidemiology Collaboration equation that uses both cystatin C and creatinine. In effect this averages together the errors of each biomarker alone, since the confounders differ between the two. Personally, I favor using both biomarkers and eGFR equations separately, since differences in the respective eGFRs can provide helpful insights.

How can cystatin C and creatinine be used together to identify and stage patients with chronic kidney disease (CKD)?I fi nd cystatin C a very useful tool for evaluating CKD patients. If the cystatin C eGFR is greater than the creatinine eGFR, this is usually reassuring. On the other hand, if the cystatin C eGFR is lower than the creatinine eGFR, such individuals appear to have a worse prognosis. This group might benefi t the most from intensive efforts to reduce CKD risk factors to the greatest extent possible.

John C. Lieske, MD, is professor of medicine and medical director of the Renal Testing Laboratory at Mayo Clinic, Rochester, Minnesota. +EMAIL: Lieske.John@mayo.edu

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