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The Peer Reviewed Management Source for Lab Professionals since 1969

CONTINUING EDUCATION

12 Liquid biopsy and droplet digital PCR offer improvements for lung cancer testing By Hestia Mellert, PhD, and Gary Pestano, PhD

15 Variations in crossing thresholds during real-time PCR when using auto-gain settings determined from the fluorescent signal in tube oneBy lka Warshawsky, MD, PhD, Gail Dunphy, MS,

MT(ASCP), Julie Boles, MT(ASCP), and Lisa Ruggles,

MT(ASCP), MB(ASCP)

18 CE TestTests can be taken online or by mail. See page 18 for

testing and payment details.

12 SEPTEMBER 2018 | Vol. 50, No. 9

DEPARTMENTS

4 From the Editor

10 The observatory

PRODUCTS

60 Product Focus: LIS

MARKETPLACE

62 Advertiser’s index

EXECUTIVE SNAPSHOT

64 Deepak Nath drives strategy and operations for Siemens Healthineers Laboratory Diagnostics

Deepak Nath President, Laboratory Diagnostics Siemens Healthineers

FEATURES

CLINICAL ISSUES

20 POC in the lab: a regional experience in urinalysis and pregnancy testingBy Yu Chen, MD, MSc, PhD, Susan McDonald, BSc, MEd, and Jason Weshler, MSc, MBA

SPECIAL FEATURES

24 The case for full-length sequencing for high-resolution HLA typingBy Nezih Cereb, MD

26 New applications for NGSBy David Cook

28 Paradigm shift in infection testing: identifying all pathogens using NGSBy Crystal R. Icenhour, PhD

EDUCATION

30 A novel point-of-care approach for improving acute bleeding managementBy Todd W. Allen and Francesco Viola, PhD

SPECIAL REPORTS

38 What new blood collection methods mean for monitoring HbA1cBy Emerson Dameron

40 Saliva test could improve diabetes control and treatmentBy MLO Staff

WASHINGTON REPORT

42 FDA approves first blood test for concussions By Kevin Hrusovsky

LAB MANAGEMENT

44 Sustainable cost control in the labBy Mark Krhovsky

FUTURE BUZZ

48 Considerations in obtaining quality specimens from DVA patientsBy Jean Tenuta, MS, MBA, MT(ASCP)DLM, SLS, CQA(ASQ)

THE PRIMER

52 The current (and future?) state of nanopore NGSBy John Brunstein, PhD

MANAGEMENT MATTERS

54 How the clinical laboratory can contribute to providing value-based healthcareBy Don Barton, MS, MT(ASCP), and Marie Rath

56 Influenza research updateBy MLO Staff

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MLO - MEDICAL LABORATORY OBSERVER(ISSN: 0580-7247). Published monthly, with an additional issue in August, by Endeavor Business Media, LLC., 2477 Stickney Point Rd, Suite 221B, Sarasota, FL 34231 (941) 388-7050. Subscription rates: $127.60/year in the U.S.; $154.88 Canada/Mexico; Intl. subscriptions are $221.43/year. All issues of MLO are available on microfilm from University Microfilms International, Box 78, 300 N. Zeeb Rd., Ann Arbor, MI 48106. Current single copies (if available) $15.40 each (U.S); and $19.80 each (Intl.). Back issues (if available) $17.60 each (U.S.); $22.00 each (Intl.). Payment must be made in U.S. funds on a U.S. bank/branch within the continental U.S. and accompany request. Subscrip-tion inquiries: [email protected]. MLO is indexed in the Cumulative Index for Nursing and Allied Health Literature and Lexis-Nexis. MLO Cover/CE, Clinical Issues, and Lab Management features are peer reviewed. Title® registered U.S. Patent Office. Copyright© 2018 by Endeavor Business Media, LLC. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage-and-retrieval system, without written permission from the publisher. Office of publication: Periodicals Postage Paid at Sarasota, FL 34276 and at additional mailing offices. Postmaster: Send address changes to MLO MEDICAL LABORATORY OBSERVER, 2477 Stickney Point Rd, Suite 221B, Sarasota, FL 34231.Printed in U.S.A.

2477 Stickney Point Rd., Suite 221B Sarasota, FL 34231Phone: (941) 388-7050 Fax: (941) 388-7490

www.mlo-online.com

MEDICAL LABORATORY OBSERVER Vol.50, No.9

Publisher/Executive EditorKristine [email protected]

EditorAlan [email protected]

Managing EditorLisa [email protected]

Audience Development/List RentalsLaura [email protected]

Ad Traffic ManagerNorma [email protected]

eProduct CoordinatorMary [email protected]

ADVERTISING

East Coast/Midwest Sales (except IL) Classified/Recruitment AdvertisingCarol Vovcsko(941) [email protected]

South/West Coast/Illinois SalesLora Harrell(941) [email protected]

MLO EDITORIAL ADVISORY BOARD

John Brunstein, PhD, Biochemistry (Molecular Virology)President & CSOPathoID, Inc., British Columbia, Canada

John A. Gerlach, PhD, D(ABHI)Laboratory DirectorMichigan State University, East Lansing, MI

Barbara Strain, MA, SM(ASCP)Director, Supply Chain AnalyticsUniversity of Virginia Health System, Charlottesville, VA

Jeffrey D. Klausner, MD, MPHProfessor of Medicine and Public HealthDivision of Infectious Diseases: Global Health, Dept. of Epidemiology, David Geffen School of Medicine,Karen and Jonathon Fielding School of Public Health, University of California Los Angeles, CA

Susan McQuiston, JD, MT(ASCP), SCy(ASCP)Instructor, Biomedical Laboratory Diagnostics ProgramMichigan State University, East Lansing, MI

Donna Beasley, DLM(ASCP)DirectorHuron Healthcare, Chicago, IL

Anthony Kurec, MS, H(ASCP)DLMClinical Associate Professor, EmeritusSUNY Upstate Medical University, Syracuse, NY

Suzanne Butch, MLS(ASCP)CM, SBBCM, DLMCM

Freelance Consultant, Ann Arbor, MI

Paul R. Eden, Jr., MT(ASCP), PhDLt. Col., USAF (ret.)(formerly) Chief, Laboratory Services88th Diagnostics/Therapeutics SquadronWright-Patterson AFB, OH

Chris Ferrell, CEO

Patrick Rains, COO

Scott Bieda, EVP

Kristine Russell, EVP

Tracy Kane, VP, General Counsel

CORPORATE TEAM

FROM THE EDITOR By Alan Lenhof f, Edi tor

Many years ago, when I was a graduate student in English and American literature at the Uni-versity of Chicago, I sometimes gave talks

at a senior activity center in the neighborhood. I have vivid memories of one such presentation: the subject was one of my favorite twentieth-century writers, Christopher Isherwood. (Have you ever seen the play or movie Cabaret? It is based on one of his novels.) Preparing and delivering the lecture was a labor of love, and it was well-received by the 25 or so

seniors who attended it.The reaction from one of them made such an impression on me that I

remember it well to this day, and I choke up a little when I think about it, even now.

A very elderly woman—she probably was 90 or even a bit older—using a walker, came up to me after my talk and said something like this: “Thank you so much, that was just wonderful. So interesting! It reminds me of when I was a student at Northwestern University, 70 years ago, isn’t that amazing! Well, you’re never too old to learn new things…And when my daughter calls me tonight and asks what’s new, I’ll have something to tell her for once…. Thank you for that.”

Isn’t that moving? Think about how pleased the lady must have been when she told her daughter, “Oh, today I attended a wonderful lecture at the senior center, by a student from the university….” And think about how happy the daughter must have been. She must have thought, well, despite her age and physical limitations, my mother still has her mind, she still engages with the world, she still enjoys intellectual stimulation at the senior center, she is still involved, she still has a quality of life….”

What does this good memory have to do with anything, you may be wondering. Well, indirectly it is why, after almost exactly seven years, I have resigned as editor of MLO and am planning to embark on a new chapter of my life. Let me explain.

I like the natural sciences, especially the biological sciences, and I am married to a pharmacist who used to be a laboratorian. (We watch the ads for prescription drugs on TV and talk about their mechanisms of action, and the relevant companion diagnostics.) But I am fundamen-tally a humanities guy. I have spent most of a lifetime reading and loving serious English and American fiction and poetry, and I cannot imagine myself without that grounding in my life. I want to spend more time now living in that world, either avocationally or perhaps vocationally. I want to learn and teach and study in whatever capacity I can. That’s the life I want to lead—not spending many hours each month editing long lists of references into something remotely resembling AMA style. (Said with a smile: The contributors to MLO whom I have worked with have been uniformly wonderful—even if their reference styles have sometimes needed an editor’s help.)

I think that for most people, the humanities can increase their capacity for empathy. And I need more of that, we all need more of that. So I am putting aside molecular diagnostics and immunoassays for Emily Dickin-son and William Shakespeare. I think it will be good for me and for the people in my life. I think it is also a good response to these tough times—a solace and an answer.

I will always cherish the time I spent with MLO, and I leave with enormous respect for you and your vital and noble profession.

Goodbye, and here’s why

4-5_MLO201809_Editorial_FINAL.indd 4 8/14/2018 12:39:47 PM

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Fast FactsSeptember is National Blood Cancer

Awareness Month. Here are some key facts about hematologic malignancies.

3 minutesEvery three minutes someone in the

United States is diagnosed with blood cancer.

174,250people in the United States are expected

to be diagnosed with leukemia, lymphoma, or myeloma in 2018.

10 percentof new cancer cases in 2018 will be

blood cancers.

160Americans die from a

blood cancer every day.

58,100people are expected to die of leukemia,

lymphoma, or myeloma in 2018.

60,300people are expected to be diagnosed

with leukemia in 2018.

4,824children will be diagnosed with

leukemia in 2018.

24,370people are expected to die of

leukemia in 2018.

14 percentwas the overall five-year survival rate for

people with leukemia in 1960.

63.7 percentis the overall five-year survival rate for

people with leukemia in 2013.


people with Hodgkin lymphoma in 2013.


people with non-Hodgkin lymphoma in 2013.

• Source: Leukemia and Lymphoma Society facts and statistics

These findings suggest that targeting vitamin D deficiency could potentially be key to helping patients achieve and maintain RA remission.

PregnancyNot all home ovulation tests are equally reliable. Research reveals that two out of three of the digital home ovulation tests sold by U.S. retailers do not accurately predict when a woman is ovulating. This information is critical for women trying to get pregnant and could improve their chances by helping them to better select at-home tests to guide intercourse timing.

Women in the U.S. are waiting longer and longer to have their first babies. As women continue to post-pone motherhood, at-home ovulation tests are becoming an increasingly popular way for women to detect when they are ovulating so that they can time intercourse precisely and increase the likelihood of concep-tion in the face of waning fertility. It is therefore imperative that these tests perform with high accuracy, as false results can delay or even pre-vent conception, which in turn can result in significant emotional stress as well as unnecessary medical investigations.

A team of researchers led by Sarah Johnson, PhD, however, has found that of the three digital home ovula-tion tests available in the U.S. in 2017, two of them only detected ovulation to within one day in about half of women tested. Only one test gave reliable results, detecting ovulation to within one day in about 95 percent of women tested.

Johnson’s team determined this by testing 33 women with three batches of each digital home ovulation test as well as with transvaginal ultrasonog-raphy. The researchers then compared the at-home test and ultrasonography results.

Notably, all three home tests ac-curately measure lutenizing hormone (LH) levels, which indicate when a woman is ovulating, but the re-searchers found that other elements of test design are equally important. Tests should provide enough LH mea-surement sticks so that women do not run out of test sticks before their day of ovulation—an occurrence that would put an unnecessary bur-den on women to figure out wheth-er they failed to ovulate or simply need to buy more test sticks. Equally

VitaminDVitamin D could alleviate RA symptoms. Scientists have discov-ered that in rheumatoid arthritis (RA) patients, lower levels of vitamin D are associated with increased disease severity. Their findings, announced at the recent 70th AACC Annual Sci-entific Meeting & Clinical Lab Expo, indicate that vitamin D supplementa-tion could significantly improve qual-ity of life for RA patients.

While there is no cure for RA—an autoimmune disease that affects more than 1.3 million Americans—treatment with powerful thera-pies such as biologic or disease- modifying antirheumatic drugs can lead to remission of symptoms. How-ever, research shows that within a year of achieving remission, half of RA patients relapse.

This can be due to patients taper-ing or stopping medication to reduce negative side effects, as well as the fact that some individuals develop antibodies that inhibit biologic drugs in particular. A more effective and sustainable treatment is therefore needed so that more RA patients can benefit from long-lasting remission.

Vitamin D could potentially fill this role, as it is a critical modulator of immune activity and earlier findings have suggested that RA could be tied to vitamin D deficiency. No previous studies, however, have assessed how vitamin D levels impact the clinical course of this condition.

This led a research group helmed by Tomas De Haro Muñoz, MD, of Hospital Universitario Campus de la Salud in Spain, to investigate the relationship between vitamin D levels and the severity of RA symptoms. They measured levels of 25-hydroxyvitamin D (25(OH)D)—a marker of vitamin D status—in blood samples from 78 patients with RA and 41 healthy controls. The research-ers also recorded whether the RA patients had active disease or were in remission.

Statistical analysis of 25(OH)D measurements showed that, overall, the RA patients had low 25(OH)D concentrations compared to healthy individuals, with only 33 percent of RA patients displaying adequate vita-min D levels. Notably, 25(OH)D levels were even lower in patients who had active disease and displayed more severe symptoms, such as a higher number of painful and inflamed joints, compared to patients in remission.

THE OBSERVATORY :: NEWS TRENDS ANALYSIS

10-11_MLO201809_Observatory_FINAL.indd 10 8/14/2018 12:41:54 PM


NEWS TRENDS ANALYSIS :: THE OBSERVATORY

esential is having a reliable digital test reader that not only detects the LH surge that precedes ovulation but also accurately displays that result.

InfectiousDiseasesThe National Institute of Health (NIH) says tickborne diseases are likely to increase. The incidence of tickborne infec-tions in the U.S. has risen signifi-cantly within the past decade. It is imperative, therefore, that public health officials and scientists build a robust understanding of pathogen-esis, design improved diagnostics, and develop preventive vaccines, according to a new commentary in the New England Journal of Medi-cine from leading scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH).

Bacteria cause most tickborne diseases in the U.S., with Lyme dis-ease representing the majority (82 percent) of reported cases. The spi-rochete Borrelia burgdorferi is the primary cause of Lyme disease in North America; it is carried by hard-bodied ticks that then feed on smaller mammals such as white-footed mice and larger animals such as white-tailed deer.

Although there are likely many fac-tors contributing to increased Lyme disease incidence in the U.S., greater tick densities and their expanding geographical range have played a key role, the authors write. For example, the Ixodes scapularis tick, which is the primary source of Lyme disease in the northeastern U.S., had been detected in nearly 50 percent more counties by 2015 than was pre-viously reported in 1996.

The public health burden of tick-borne disease is considerably under-reported, according to the authors. For example, the U.S. Centers for Dis-ease Control and Prevention (CDC) reports approximately 30,000 cases of Lyme disease annually in the U.S. but estimates that the true incidence is 10 times that number. According to the authors, this is due in part to the limitations of current tickborne dis-ease surveillance, as well as current diagnostics, which may be imprecise in some cases and are unable to recognize new tickborne pathogens as they emerge. These limitations have led researchers to explore new, innovative diagnostics with different

platforms that may provide clinical benefit in the future.

PhlebotomyGuide to good capillary blood sampling. EKF Diagnostics has pub-lished an Educational Guide which provides a quick overview of capil-lary blood sampling best practice. It aims to help healthcare profes-sionals understand common causes of pre-analytical errors and reduce their impact on hemoglobin results. Entitled “Capillary sampling and its relevance for correct hemoglobin results,” it is available to download from the company’s website.

Capillary blood (finger-stick) sampling is increasingly being used worldwide due to the growing avail-ability of point-of-care (POC) test-ing. With anemia affecting about 25 percent of the global population and a much higher prevalence in devel-oping countries, hemoglobin is the most frequently performed test in POC hematology. It is also used rou-tinely by blood collection services to ensure safe donations.

Notably, hemoglobin (Hb) values are among the parameters most prone to being affected by pre-analytical errors. Incorrect capillary blood sampling is the most common reason for inaccurate POC hemo-globin results. So, in order to avoid generating variant and misleading Hb results, healthcare personnel drawing blood must adhere to strict and standardized blood sampling techniques which ensure accurate and consistent POCT results that are comparable to laboratory techniques.

In addition to discussing the rea-sons behind the vital importance of good capillary blood sampling, the new guide provides easy step-by-step instructions on best practice capillary sampling. These present a simple visual explanation based on published detailed guidelines from the Clinical and Laboratory Stan-dards Institute and the World Health Organization (WHO), with specific considerations added for hemoglobin testing.

MentalHealthDepression linked to low blood levels of acetyl-L-carnitine. People with depression have low blood levels of acetyl-L-carnitine, according to a Stanford University School of Medi-cine scientist and her collaborators in a multicenter study. The findings,

published online in the Proceedings of the National Academy of Sciences, build on extensive animal research. They mark the first rigorous indica-tion that the link between acetyl- L-carnitine levels and depression may apply to people, too.

Naturally produced in the body, acetyl-L-carnitine is also widely avail-able in drugstores, supermarkets and health food catalogs as a nutritional supplement. People who live with severe or treatment-resistant depres-sion, or whose bouts of depression began earlier in life, have particularly low blood levels of the substance.

In animal studies, rodents responded to acetyl-L-carnitine supplementation within a few days. Current antidepressants, in contrast, typically take two to four weeks to kick in—in animal experiments as well as among patients.

The new study recruited 20- to 70-year-old men and women who had been diagnosed with depression and, amid episodes of acute depres-sion, had been admitted to either Weill Cornell Medicine or Mount Sinai School of Medicine, both in New York City, for treatment. These participants were screened via a detailed ques-tionnaire and assessed clinically, and their blood samples and medical histories were taken. Twenty-eight of them were judged to have moder-ate depression, and 43 had severe depression.

When their blood samples were compared with those of 45 demo-graphically matched healthy people, the depressed patients’ acetyl-L-carnitine blood levels were found to be substantially lower. These findings held true for both men and women, regardless of age.

Further analysis showed that the lowest levels occurred among par-ticipants whose symptoms were most severe, whose medical histo-ries indicated they were resistant to previous treatments, or whose onset of the disorder occurred early in life. Acetyl-L-carnitine levels were also lower among patients who reported a childhood history of abuse, neglect, poverty, or exposure to violence.

Even as they reported these interesting results, the research-ers stressed that significantly more research is needed before any recom-mendation can be made that supple-mentation with the substance be used as a treatment for people with depression.

10-11_MLO201809_Observatory_FINAL.indd 11 8/14/2018 12:41:54 PM


Liquid biopsy and droplet digital PCR offer improvements for lung cancer testingBy Hestia Mellert, PhD, and Gary Pestano, PhD

In cases where only a small amount of tissue is obtained for routine pathologic testing, a physician may not want to re-biopsy and may choose to accept incomplete or absent molecular characterization. The use of the traditional tissue biopsy also limits the number of follow-up assays that can be run, since each uses additional valuable tissue specimens. Therefore, clinical labs and physicians must prioritize which diagnostic tests to run and may thus sacrifice potentially useful information due to limited sample availability.

Another challenge of tissue biopsies is the considerable time required for molecular analysis of the tumor. Many molecular testing strategies take weeks and may require additional biopsies to complete testing, possibly delaying the start of therapy. There are liquid biopsy tests with much shorter turnaround times of three to five days, which bypass tissue limitations related to both time and ease of specimen handling. Recently, a retrospective study reported by East Carolina University researchers compared standard molecu-lar analysis strategies to liquid biopsy and showed that liq-uid biopsy can provide actionable results within 72 hours and enable patients to consistently start treatment for their lung cancer within a median of eight days from diagnosis.2

ctDNA/RNA analysisIt should come as no surprise, then, that the promise of non-invasive alternatives to tissue biopsy with a fast turnaround time for patients with lung cancer has been embraced by the clinical community. Liquid biopsy takes advantage of the exquisite sensitivity of advanced molecular techniques to help define a patient’s disease from the evidence it leaves in the bloodstream: circulating tumor DNA (ctDNA) and circulating tumor RNA (ctRNA). These molecules have been shed by the tumor or tumors, and even at low volumes their presence can be detected accurately.3.4

In addition to answering the basic question of whether cancer mutations are present, ctDNA/RNA analysis may reveal more sophisticated details about the cancer—such as disease progression, treatment response, risk of recur-rence, and more. Blood also offers an alternative view of the tumor. While tissue samples can pinpoint the exact genomic state at any location in a tumor, they are unable to provide a complete understanding of the tumor’s heterogeneity due to the bias in the sample location. As blood may carry ctDNA from many points of tumor ori-gin, liquid biopsies have the potential of providing diag-nostic information regardless of tumor origin or tumor heterogeneity.

As a blood draw required to collect a liquid biopsy is less invasive than a tissue biopsy, liquid biopsies offer clinicians the opportunity to collect samples as needed for near real-time monitoring of the cancer. Such frequent check-ins are not feasible with tissue biopsy. Monitoring circulat-ing nucleic acids promises major improvements in cancer treatment by allowing healthcare teams to track treat-ment response and to spot the emergence of biomarkers associated with drug resistance more quickly.

Providing rapid identification of driver mutations can

Blood-based testing, more commonly known in the oncology diagnostics community as liquid biopsy, has transformed the ability to detect targetable muta-

tions and tailor treatments for patients with lung cancer. Performed most commonly using polymerase chain reac-tion (PCR) or next-generation sequencing (NGS), this newer approach to cancer care is swiftly gaining popularity as a noninvasive method of generating diagnostic information that, until now, had been available only through a tissue biopsy. Although PCR and NGS both offer clinically accept-able levels of sensitivity and specificity, they differ dramati-cally in cost, turnaround time, reimbursement factors, and actionability of results.

Research continues to be conducted on designing and optimizing a broad range of technologies for analyzing blood-based tests that can be used in place of, or as a com-plement to, tissue for disease detection, treatment decision making, and disease-state monitoring. Advances in tech-nologies using PCR, such as droplet digital PCR (ddPCR), have made it possible for clinical laboratories to obtain quantitative results with very low limits of detection.

Why liquid biopsy?Tissue biopsy procedures are associated with risk and dis-comfort in most cancer types, but for patients with lung cancer, this procedure is particularly invasive and can result in severe procedural complications. Given that the American Cancer Society projects that 234,030 new cases of lung cancer will be diagnosed in 2018, many patients will undergo this procedure.1 Patients with non-small cell lung cancer (NSCLC), the most common form of lung cancer, are often in advanced stages of the disease at the time of diag-nosis. Those with advanced disease are already physically quite vulnerable, making tissue biopsy more challenging.

CONTINUING EDUCATION :: PCR

Earning CEUs

See test on page 18 or online at www.mlo-online.com

under the CE Tests tab.

LEARNING OBJECTIVES

Upon completion of this article, the reader will be able to:

1. Recall the benefits of liquid biopsy and the reasons for the

trend away from tissue biopsy.

2. Recognize the test theory and methodology behind liquid

biopsy in PCR testing.

3. Identify advantages and disadvantages of using PCR as

opposed to NGS testing.

4. Describe specific mutations being studied that show

promising means for decisions on immunotherapy

response.

continued on page 14

12-17_MLO201809_CEStory_CESidebar_FINAL.indd 12 8/14/2018 12:49:08 PM

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ensure the patient receives the most efficacious therapies. Having initial diagnostic information and starting treat-ment within days may increase the patient’s chance at a successful outcome. In the case where a liquid biopsy is negative, the tissue sample may be analyzed to either con-firm the negative blood-based results or detect mutations from the tumor that were not released into the bloodstream.

PCR in oncologySince the invention of PCR in the early 1980s, scientists have not only adopted but also adapted this powerful molecu-lar diagnostics technique. Quantitative real-time PCR, also known as qPCR, allows relative quantification of results when compared to a control. This advancement increased the clinical usefulness of PCR for a broad range of applica-tions. An even more recent evolution in PCR came in the form of partition-based PCR techniques, including ddPCR, which has enabled absolute quantification of DNA.

ddPCR reactions are partitioned into 20,000 nanoliter-sized droplets of a water-and-oil emulsion. Each droplet houses an individual PCR reaction with a subset of nucleic acids. The thousands of droplets behave as thousands of individual test tubes running independent reactions, but with far smaller sample requirements. Results are generated for each partition—often harboring a single or just a few DNA molecules—and collectively reveal very rare but rel-evant mutations from the solid tumor. ddPCR is then highly sensitive, specific, and quantitative, and additionally is quite rapid, which is why clinical laboratories performing liquid biopsies have been rapidly adopting ddPCR technology.

One study on a ddPCR-based genomic test demonstrated clinical validation results for EGFR mutations (exon 19 dele-tions, L858R and T790M), KRAS mutations (G12C, G12D, G12V), and EML4-ALK fusion tests to have a combined sensitivity and specificity of 90.9 percent and 100 percent, respectively, and was 97.0 percent concordant with tissue. Mutation results were available within 72 hours for 94 percent of tests evaluated.3

ddPCR vs. NGSThe rise of ddPCR has occurred in approximately the same time frame that NGS has gained traction in clinical labs. This has led to much discussion about which method to use for a particular application. For lung cancer testing, there are specific situations where each technique excels.

The argument for NGS, of course, is the comprehensive amount of genomic data this technology can generate from one specimen. While ddPCR is highly multiplexed and can query many genomic regions, it is designed to produce tar-geted information such as clinically actionable information, tailored to the specific patient’s needs, and billed to insurance without excessive cost to the healthcare system.

For patients who have received multiple lines of therapy and are seeking clinical trials that include biomarkers not yet clinically validated, or treatment with novel combinations, whole genome sequencing of the tumor can provide clini-cally useful clues. This is particularly true with regard to areas of the genome that would not be interrogated in a molecular test that is more focused on providing fast results for action-able, guideline-recommended mutations needed for first-line therapy decisions. At this point in the disease progression, physicians are hoping to discover any possible options that remain—and having NGS data for a larger portion of the genome may be the best way to achieve that. Several com-panies and academic institutions offer clinical NGS testing.

Generally, a blood or tissue sample is required and is shipped to a clinical lab for processing. If a sample of sufficient size is submitted for testing, results usually take two to three weeks once the specimen and ordering information are received.

It is important to understand how much information is needed and when to provide the right molecular test to patients. There is often a temptation to apply NGS to obtain information on large gene panels or even whole exome analysis of the tumor at initial diagnosis, but three key con-siderations should be made. First, the use of NGS at such an early stage can trigger reimbursement issues by reducing the molecular testing options available for that patient later in the course of their cancer. Second, broad genomic information is likely to come back with a number of variants of unknown significance in addition to clinically validated variants. These unknown variants can lead to more uncertainty than neces-sary, as well as to delays in finding the right treatment due to the additional time needed for geneticists to understand such variants. Finally, establishing a tumor’s sequence at the outset of a patient’s diagnosis belies the reality that the tumor will continue to evolve, especially once treatment is begun or when metastasis occurs. Too often, medical teams receive a full genome sequence of a tumor from an initial diagnostic workup, and fail to continue testing for possible changes in their genetic profile that could inform therapy for improved outcomes as the patient continues through the course of his or her disease.

The limitations of NGS testing may make ddPCR a better choice for many applications relevant to lung cancer patients at initial diagnosis and in disease monitoring. At the outset, ddPCR returns results much faster than NGS—in hours or days instead of weeks—and therefore can guide treatment selec-tion almost immediately. It is also considerably less expensive and more likely to be reimbursed, as results returned are for guideline-recommended mutations that are tied directly to targeted treatments. Because this technique interrogates only selected mutations, clinical labs can ensure that their ddPCR pipelines return only the most medically actionable informa-tion possible with that specimen. As research evolves, new mutations and variants with clinical utility can easily be added to ddPCR-based testing. The blood-based testing method can also be repeated as needed during the patient’s journey, mak-ing it suitable not just for diagnosis and treatment selection but also for ongoing monitoring of the tumor’s progression, genomic evolution, and response to therapy.

PD-L1 expression by ddPCR An example of how ddPCR can be used for lung cancer patients comes from a PD-L1 expression study reported at the 2018 American Society of Clinical Oncology and the Society for Immunotherapy of Cancer Clinical Immuno-Oncology Symposium.2 PD-L1 expression measured from the tissue has been successfully validated as a biomarker that can match a patient to relevant PD-L1 inhibitor therapies.5 However, labs have struggled to standardize results from several FDA-approved immunohistochemistry (IHC) assays for PD-L1 expression in tumor tissue sections. These IHC assays all use different detection platforms, antibodies, cutoff points, and scoring systems.6

In the reported study, scientists evaluated a blood-based research assay designed to detect the expression of PD-L1. The study compared PD-L1 results from matched plasma ddPCR assays and standard IHC for NSCLC patients, using formalin-fixed paraffin-embedded tissue samples. The ddPCR test detected PD-L1 mRNA in both sample types,

continued from page 12




biopsy and ddPCR that can improve patient outcomes. Incorporation of advancements like these ensures that patients get the best treatment, receive treatment quickly, and may be monitored more frequently, potentially boosting drug response and survival rates.

REFERENCES

1. American Cancer Society. Key Statistics for Lung Cancer. https://www.cancer.org/cancer/non-small-cell-lung-cancer/about/key-statistics.html

2. Mellert H, Jackson, L, Pestano, G. Performance verification of a plasma-based PD-L1 test that reliably measures mRNA expression from patients with NCSLC. J Clin Oncol. 36(5_suppl):156.

3. Mellert H, Foreman T, Jackson L, et al. Development and clinical utility of a blood-based test service for the rapid identification of actionable muta-tions in non-small cell lung carcinoma. J Mol Diagn. 2017;19(3):404-416.

4. Mellert HS, Alexander KE, Jackson LP, Pestano GA. A blood-based test for the detection of ROS1 and RET fusion transcripts from circulating ribo-nucleic acid using digital polymerase chain reaction. J of Vis Experiments. (Jove). 2018 Apr 5;(134). doi: 10.3781/57079/.

5. Lin G, Fan X, Zhu W, et al. Prognostic significance of PD-L1 expression and tumor infiltrating lymphocyte in surgically resectable non-small cell lung cancer. Oncotarget. 2017 Aug 12;8(48):83986-83994.

6. Liu D, Wang S, Bindeman W. Clinical applications of PD-L1 bioassays for cancer immunotherapy. J Hematol Oncol. 2017;10:110. doi: 10.1186/s13045-017-0479-y.

7. Pestano G, Jensen-Long L. Developing liquid biopsy diagnostic testing for cancer immunotherapy selection in NSCLC patients. MLO. 2018;50(4):30-32. https://www.mlo-online.com/developing-liquid-biopsy-diagnostic-testing-for-cancer-immunotherapy-selection-in-nsclc-patients

ranging from 6 to 172.2 copies in tissue and from 32 to 138 copies in plasma. These results confirmed the dynamic range of the ddPCR technique and showed that the test could assess PD-L1 expression in plasma. However, there are mul-tiple hurdles to overcome when comparing the expression level of IHC scores and plasma mRNA copies. Variables may include: different methods and detection systems for IHC; variability in scoring IHC; PDL1 expression on non-tumor cells; potential biological differences related to the measure-ment of protein expression by IHC and RNA transcripts by PCR; and differences between the time of tissue and blood collection. These differences manifest themselves especially when conducting analyses of prospectively collected plasma with a historic diagnostic PD-L1 IHC tissue result.

Scientists have now launched a prospective study using near-simultaneous collection of blood and tissue and a centralized clinical testing laboratory to generate data that reduces complexity in analysis of tissue and blood concor-dance due to methodologic differences.7 Results are expected to show the performance of ddPCR testing for PD-L1 expres-sion and how patients respond to PD-L1 immunotherapy. Additionally, this experimental framework will likely be the first report of a prospective study that uses matched tissue and plasma to readout protein IHC and the emerging ddPCR technology for a dynamically expressed RNA biomarker.

Looking aheadThe shift toward liquid biopsies is a major step in improving the diagnosis and prognosis of cancer, as well as treatment decisions. Simultaneously, the growing use of ddPCR assays for identifying the subset of patients who should be placed on targeted therapy options is providing carefully measured results with rapid turnaround time for optimal clinical utility. This approach enabled by liquid biopsy means that physi-cians do not have to wait weeks for genomic information that may enable the use of a targeted therapeutic against a patient’s cancer, unlike slower molecular analytic meth-ods that often necessitate starting patients on a general chemotherapy regimen until results are received.

Particularly in advanced stages, lung cancer confers a grim prognosis for many patients. It is essential that the medical community take advantage of innovations such as liquid

Hestia Mellert, PhD, serves as a Director

within the Development group for

Biodesix, Inc.

Gary Pestano, PhD, serves as

Vice President of Development

and Laboratory Operations for

Biodesix, Inc.

Variations in crossing thresholds during real-time PCR when using auto-gain settings determined from the fluorescent signal in tube oneThe ability to PCR multiple targets with a single master mix but different primers and probes under identical cycling

conditions with a single real-time PCR instrument allows for an efficient and streamlined workflow. We validated a

variety of sample types for multiple viral targets as single assays that could then be run individually or concurrently.

Assay designUsing RealStar Analyte Specific primers and probes and RealStar QAM positive controls for herpes simplex virus

(HSV)1, HSV2, varicella zoster virus (VZV), adenovirus, and parvovirus B19 (Altona Diagnostics), viral targets were

validated individually by real-time PCR on the Rotor-Gene Q MDx instrument (QIAGEN).

Samples were spiked with Altona internal control (IC) DNA prior to extraction on automated extraction platforms.

Extraction instruments and kits used varied with sample types. Each PCR reaction contained 10µl DNA, 17µl GPR

PCR Master 1.0, 1µl ASR target-specific primer, 1µl ASR target-specific probe, and 1µl water, except for HSV1/2,

which contained 1µl each of HSV1 primer, HSV2 primer, HSV1 probe, and HSV2 probe. Cycling conditions for all

targets were 95oC, 10 minutes followed by 45 cycles of 95oC, 15 seconds and 58oC, 60 seconds. Auto-gain optimiza-

tion was used. All viral targets were detected in the green (FAM) channel except for HSV2, which was detected in the

red (Cy5) channel. IC was detected in the yellow (JOE) channel.

Together, Drs. Pestano and Mellert led development of the company’s GeneStrat

test, a genomic test for patients with non-small cell lung cancer (NSCLC).


September 2018 MLO-ONLINE.COM16

for the green channel.1 “Gain” values are displayed

on Rotor-Gene reports and are low if the fluorescence

signal is strong and high if the fluorescence signal is

weak.

Table 1 shows CT and gain values of the parvovirus

positive control when parvovirus was run alone (12

successive runs) or when adenovirus was run before

parvovirus (18 successive runs). The average CT value

+ 1 standard deviation (SD) of the parvovirus posi-

tive control increased from 34.66+0.48 to 36.71+0.37

when adenovirus was run first. Gains were 8, 9.33, or

10 when parvovirus was run alone and typically 5.33

when adenovirus was run before parvovirus.

Table 2 shows CT and gain values of positive con-

trols from 161 consecutive runs depending on what

target was run in rotor position one: HSV gave gains

of 9.33 or 8 while parvovirus and VZV typically gave

gains of 8. Adenovirus usually had a gain of 5.33.

Running adenovirus first increased the CT values of

all positive controls read in the green channel and

was most pronounced for HSV1 (36.00 versus 38.37).

CT values for HSV2, read in the red channel, did not

change.

ConclusionIf the auto-gain setting is used on the Rotor-Gene and

multiple targets are run concurrently, the target with

the lowest gain identified from individual runs should

be in rotor position 1. Positive control CT ranges should

be established from both individual runs and runs

where the target with the lowest gain is run in position

1. It should be noted that the CT shifts observed did not

affect patient results and that these recommendations

may vary with different real-time PCR instruments.

REFERENCE

1. Rotor-Gene Q MDx User Manual. https://www.qiagen.com/kr/resources/resourcedetail?id=3a8376b5-a48d-4f29-8c0a-d116cd06f10d&lang=en

AUTHORS

Ilka Warshawsky, MD, PhD, serves as Director of the Molecular Diagnostics

laboratory at Akron Children’s Hospital. Gail Dunphy, MS, MT(ASCP), serves as

senior medical technologist at Akron Children’s Hospital. Julie Boles, MT(ASCP), serves as a medical technologist at Akron Children’s Hospital. Lisa Ruggles,

MT(ASCP), MB(ASCP), serves as a Regional Service Representative for Mayo Medical Laboratories.

The authors wish to thank Drs. Karin Rottengatter and Konstance Knox for their

assistance and helpful advice.

Upon implementation

for clinical use, depend-

ing on what orders were

received, HSV1/2, VZV,

adenovirus, and/or parvovirus B19 were run concurrently.

Crossing threshold (CT) reference ranges for positive

controls were established for each viral target at a fixed

threshold during validation of individual targets.

ObservationsCT shifts of 1-2 cycles for positive controls were

observed when more than one viral target was run

because initial reference ranges for positive controls

were established by running viral targets individually.

CT shifts were due to differences in auto-gain settings

which are determined from the fluorescent signal in

tube one in the Rotor-Gene instrument and are set

parvovirus run alone

#CT

Parvovirus Control

Gain

1 35.36 8.00

2 34.92 8.00

3 34.70 9.33

4 35.20 8.00

5 34.35 9.33

6 34.32 10.00

7 35.41 8.00

8 33.88 10.00

9 34.59 10.00

10 34.63 9.33

11 34.24 9.33

12 34.32 9.33

aver-age

CT + 1

SD

34.66+0.48

adenovirus run before parvovirus

#CT

Parvovirus Control

Gain

1 37.28 5.33

2 36.37 5.33

3 37.00 5.33

4 36.54 5.33

5 36.30 5.33

6 36.62 5.33

7 36.53 5.33

8 36.72 5.33

9 36.18 6.67

10 36.42 5.33

11 36.79 5.33

12 36.62 5.33

13 36.66 5.33

14 37.71 5.33

15 36.47 5.33

17 36.91 5.33

17 36.64 5.33

18 37.02 5.33

average

CT + 1

SD

36.71+0.37

Table 1.

CT of Positive Control + 1 SD

Target in rotor

position 1n Gain HSV1 HSV2 parvovirus VZV adenovirus

HSV 469.33 (n=21)

36.00 +0.75 36.38 + 0.83 34.70 + 0.52 33.64 + 0.32 35.08 + 0.398 (n=25)

parvovirus 11 8(n=11) 37.05 + 0.42 36.24 + 0.66 35.21 + 0.34 33.51 + 0.26

VZV 318 (n=28)

37.06 + 0.67 36.34 + 0.48 34.30 + 1.02 35.37 + 0.286.67 (n=3)

adenovirus 735.33 (n=70)

38.37 + 0.64 36.26 + 0.62 36.35 + 0.61 34.91 + 0.45 36.70 + 0.556.67 (n=3)

Table 2.



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CONTINUING EDUCATION TEST

LIQUID BIOPSY AND DROPLET DIGITAL PCR OFFER IMPROVEMENTS FOR LUNG CANCER TESTING

September 2018 [This form may be photocopied. It is no longer valid for CEUs after March 31, 2020.)

MLO and Northern Illinois University (NIU), DeKalb, IL, are co-sponsors in offering continuing education units (CEUs) for this issue’s CE article. CEUs or contact hours are granted by the College of Health and Human Sciences at Northern Illinois University, which has been approved as a provider of continuing education programs in the clinical laboratory sciences by the ASCLS P.A.C.E.® program. Approval as a provider of continuing education programs has been granted by the state of Florida (Provider No. JP0000496). Continuing education credits awarded for successful completion of this test are acceptable for the ASCP Board of Registry Continuing Competence Recognition Program. Readers who pass the test successfully (scoring 70% or higher) will receive a certificate for 1 contact hour of P.A.C.E.® credit. Participants should allow three to five weeks for receipt of certificate. The fee for this continuing education test is $20. This test was prepared by Amanda Voelker, MPH, MT(ASCP), MLS, Clinical Education Coordinator, School of HealthStudies, Northern Illinois University, DeKalb, IL.

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NAME MAILING ADDRESS

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PHONE E-MAIL ADDRESS

HOME WORK

PLEASE PRINT CLEARLY

13. NGS testing provides data for

{{ a. genomic mutations.

{{ b. genomic substitutions.

{{ c. the whole genome.

{{ d. none of the above

14. What is the approximate turnaround time for

NGS testing?

{{ a. 3 to 5 days

{{ b. 1 to 2 weeks

{{ c. 2 to 3 weeks

{{ d. 4 to 6 weeks

15. ddPCR testing at the initial diagnosis can

trigger reimbursement problems.

{{ a. True

{{ b. False

16. Establishing NGS results at the onset of a

diagnosis is contradictory to the fact that

{{ a. the tumor will continue to evolve.

{{ b. treatment decisions will not change.

{{ c. both a and b

{{ d. neither a nor b

17. What type of expression studies are being

conducted that will conclude how patients

respond to its specific immunotherapy?

{{ a. BD-M1

{{ b. PD-M1

{{ c. PD-L1

{{ d. PD-L2

1. Blood-based testing is also known as

_______________ within the oncology

specialty.

{{ a. serum testing

{{ b. solid biopsy

{{ c. liquid biopsy

{{ d. clot testing

2. Which test methodology is utilized in blood-

based testing to detect mutations in lung

cancer patients?

{{ a. immunoassay

{{ b. PCR/NGS

{{ c. culture

{{ d. none of the above

3. Research continues on blood-based testing

for use in place of or as a complement

to traditional tissue exams for disease

detection, treatment decision making, and

disease-state monitoring.

{{ a. True

{{ b. False

4. What is/are the concern(s) related to

performing tissue biopsies on patients with

non-small cell lung cancer?

{{ a. It is invasive.

{{ b. It can produce severe procedural complications.

{{ c. both a and b

{{ d. neither a or b

5. What is a limitation on the use of tissue

biopsy in terms of sample availability?

{{ a. storage viability

{{ b. time constraints

{{ c. the use of follow-up assays than can be run

{{ d. all of the above

6. Many molecular testing strategies can

take _________ and delay the start of

therapy, while liquid biopsy tests only take

____________.

{{ a. months; 1 day

{{ b. weeks; 1 week

{{ c. months; 1 week

{{ d. weeks; 3 to 5 days

7. What does liquid biopsy detect in the

bloodstream of patients with lung cancer?

{{ a. ctDNA and ctRNA

{{ b. cells of the tumor

{{ c. tumor antibodies


8. Which cancer-specific detail(s) is/are

identified in liquid biopsy testing?

{{ a. disease progression

{{ b. treatment response

{{ c. risk of recurrence


9. If a liquid biopsy is negative, a tissue biopsy

can be collected to confirm the result.

{{ a. True

{{ b. False

10. The evolution of ddPCR in oncology has

allowed for quantification to move from

{{ a. absolute to relative.

{{ b. relative to absolute.

{{ c. relative to mixed.

{{ d. mixed to absolute.

11. A study performed on the validation of

ddPCR mutations showed results consistent

with tissue of _________.

{{ a. 85 percent.

{{ b. 91 percent.

{{ c. 95 percent.

{{ d. 97 percent.

12. What type of molecular testing is ideal for

lung cancer patients who are going through

multiple lines of therapy or treatment with

novel combinations?

{{ a. NGS

{{ b. FISH

{{ c. microarray

{{ d. ddPCR

TEST QUESTIONS Circles must be filled in, or test will not be graded. Shade circles like this: O Not like this: O

Tests can be taken online or by mail. Easy registration and payment options are available through NIU by following the links found at www.mlo-online.com/ce.

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P = Poor; E = Excellent

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P E

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P E

3. How will you use the CE units?

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POC in the lab: a regional experience in urinalysis and pregnancy testingBy Yu Chen, MD, MSc, PhD, Susan McDonald, BSc, MEd, and Jason Weshler, MSc, MBA

on-line training was available through the vendor for users.

A post-implementation survey was conducted in July 2016 via Survey Monkey, sent to 466 end users. Additional analytical data was downloaded from the server. Both the survey results and data identified gaps in preliminary implementation; workflow mapping was utilized to identify root causes of identified gaps. Corrective actions were taken including some retrain-ing, adjustments to some instrument settings, and workflow modifications. Data was downloaded to look at all of 2016.

Overall success of the project was measured using internal audits post-installation and an external audit (IQMH laboratory accreditation) in February-April 2017 to successfully demonstrate adherence to ISO 15189 Plus standards (ISO 22870 requirements not previously met).

ResultsIQMH audit findings between 2013 and 2015 emphasized nine minor non-conformances to ISO 22870:2006, which could not be resolved by current processes and technologies for POC. Pre- implementation survey responses were received from all four regional sites with the opportunity to identify current state challenges that needed to be addressed. Eight key findings are outlined in Table 1, emphasiz-ing the lack of a standard operating procedure (SOP), including no consistent quality control (QC) or traceability.

The implementation phase included a “train the trainer” program that covered change management as well as technical and product training. Questions on the training and implementation process were captured in the post-implementation survey.

Following the implementation, three independent methods were used to demonstrate the effectiveness of the results:

Post-implementation survey. Survey results were received from 74 respondents (16 percent), with the distribution of respondents reflective of the instru-ment distribution across the regions. Training pro-vided by the regional POC trainers was identified as a strength of the implementation process. User feedback highlighted general satisfaction around the program. Positive comments were made about instru-ment ease-of-use, increased confidence in quality of patient results, and reporting process overall. Some key lessons around the need for education on quality (laboratory) standards as well as increased communi-cation and change management will be included in the discussion section.

Instrument utilization data. Instrument utilization was collected by instrument and by site utilizing the data management software to evaluate test utilization

Horizon Health Network operates 12 hospitals and more than 100 medical facilities, clinics and offices in the province of New Brunswick in

Canada. Providing services ranging from acute care to community-based health services, Horizon Health Network has more than 12,400 employees, including 1,000 physicians, and has 5,700 volunteers, auxiliary workers, and alumni. The network consists of four areas with core lab services provided only in the four regional hubs. As part of the provincial laboratory standards, all sites performing point-of-care testing (POCT) must be accredited by the Institute for Qual-ity Management in Healthcare IQMH (former Ontario Laboratory Accreditation 20131). Findings from a 2013 audit identified minor non-conformances specific to ISO 22870 in urinalysis POCT, which remained unre-solved during a subsequent audit in 2015 and were escalated to major non-conformances.

Point-of-care (POC) urinalysis testing has been widely evaluated in the literature; studies have demon-strated both the safety and efficacy of both urine test strips and urine hCG testing using semi-automated platforms.2-4 The utilization of POC middleware further facilitates the management of POC testing by providing enhanced traceability of both operators and results—including elements of training, testing patterns, certification, and quality control.5

It was believed that through the adoption of a semi-automated urinalysis/pregnancy testing analyzer, ISO 22870 deficiencies would be promptly addressed. This project demonstrated that in order to deliver opti-mized patient care and outcomes, laboratory practices and quality processes need to be incorporated into the technology implementation methodology.

Materials and methodsA technology review utilizing a Request for Informa-tion (RFI) in accordance with provincial procurement guidelines was conducted to identify vendors able to address the defined clinical criteria for a regional uri-nalysis POCT solution. Requirements identified were on-board quality control lockout, operator manage-ment, barcode scanning capabilities, and, ideally, a diverse test menu. A vendor was selected to provide the middleware and workflow consulting services.

A pre-implementation needs assessment was con-ducted with each of four regional POC coordinators to identify current state and key needs/gaps. Find-ings were shared with the team as part of a change management seminar.

The implementation plan for both instruments and software was designed with users to adhere to qual-ity standards, and each analyzer was validated at the regional center prior to being distributed to the POC site/location. Training was provided via on-site work-shops utilizing a ‘train the trainer’ format. Additional

CLINICAL ISSUES :: URINALYSIS

SEPTEMBER 2018 MLO-ONLINE.COM20continued on page 22

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and QC compliance. Data was collected in September 2016, and again in December 2016. First data analy-sis identified higher than expected QC frequencies in some locations compared to the implemented SOP, and the workflow analysis uncovered instrument set-tings that were not set in accordance with the once-daily QC requirement. The December 2016 review of data demonstrated that the QC issue was corrected and highlighted an increased utilization of tests across the majority of sites. The ability to easily access data has enabled the regional POC coordinators to bench-mark results on an ongoing basis to identify any differ-ences in practice and address potential variance in an efficient and coordinated way.

Spot and formal audit findings post implementation. Spot audits were conducted at each of the Moncton Area, New Brunswick, sites with additional audits scheduled to be completed on an ongoing basis in each of the regions. Of note, the audits to date identi-fied 100 percent compliance with patient identifica-tion and only one minor issue (results unsigned), which was immediately traced back to the end user and addressed.

Conformance results included in Table 1 highlight the process improvements made from the preliminary audits through today.

DiscussionPOC testing continues to expand, with many sites undergoing similar challenges adhering to increasing rigorous local requirements, including ISO standards. While every clinical situation is unique, there are some key lessons that can be readily applied by our colleagues across Canada and around the world.

Extensive global experience with new technology implementations in core labs provides evidence that new technology alone is not sufficient to achieve objectives. Workflow assessment and process redesign are required to optimize outcomes that are possible with new technology. Holding onto old processes when implementing new technology in any diagnostic path-way, including POC, limits the success of the program. Process redesign, regardless of where it occurs, requires thought and active management. In the laboratory environment, the core stages are common; however, survey results and onsite workflow assessment post-implementation highlight the importance of a differ-ent style of communication when implementing new processes in a POC program.

Working with other healthcare professionals is quite different than working with lab professionals. A laboratorian inherently understands the need for rigor and structure around quality management. As POCT

Table 1. Conformance results.

Pre-Implementation ChallengesISO/IQMH Standard

Non-Conformance Assessed

Post-Implementation

Standards Met

POC Program Outcomes

No user competency review

Has a training program for POCT been established?

Training program certification / operator competency review

Does the training manager oversee the training program?

Is the content of training and re-training sessions defined?

Are training records maintained?

Non certified users performing testing –no method for tracking operator ID

Are there determined criteria in place ensuring that only those personnel designated as appropriately trained are permitted to perform POCT?

Traceability operator & QC lock-out

No Standard Operating Procedure (SOP)

Has the scope of POCT been defined?

Regional Standardization (SOP)Are appropriate POCT documents subject to document control rules and available to users?

Are POCT policies and procedures reviewed regularly?

QC not being performed daily when patient testing is being performed

Are procedures for the performance of POCT established, reviewed regularly and made available to users?

Quality results accreditation standards met

Samples are not consistently being properly labeled with patient ID

No patient ID on printout if POC instrument is used

Patient testing is being performed when QC is out

QC results not recorded on proper log sheet



20-23_MLO201909_ClinicalIssues_DUM_AL.indd 22 8/13/2018 1:50:42 PM


expands to non-laboratorians, qual-ity management can be perceived as a nuisance or barrier to providing immediate care. Feedback received from end users readily acknowl-edged that quality improved, but the process change was challenged due to the perceived delays/incre-mental steps that are required as part of a quality testing process.

In developing training programs for new technology implementa-tion and processes, it is equally critical to explain the “why,” or need for certain standards to be in place, as the “how”—the way things need to be done. Utiliz-ing Kotter’s change management model7 as a foundation, the devel-opment of a change management plan and related practices is critical to quick adoption of new technol-ogy and compliance to SOPs. Feed-back from end users and onsite workflow assessments highlighted the need for a structured change management plan in POC imple-mentations. Change management practices will answer questions such as “Why do I need to run Quality Control?” and provide education for non-laboratorians on how new POC testing process steps are important to patient safety and ISO standard requirements.

The adoption of ISO standards to expanded laboratory services in the POC setting is an opportu-nity to bring lab standards to all aspects of patient care. In order to maximize the program’s success and consequently have a positive impact on patient outcomes, it is critical to combine the right tech-nologies (instruments, assays, mid-dleware) with optimized processes and robust training that includes change management practices.

REFERENCES

1. Ontario Medical Association. Ontario Laboratory Accreditation (OLA) Requirements Version 6, Dec 2013.

2. Tighe P. Urine dry reagent strip ‘error’ rates using different reading methods. Accred Qual Assur 2000;5:488-490.

3. Milhorn DM, Korpi-Steiner NL. Evaluation of Clinitest hCG device susceptibility to high-dose hook effect by intact human chorionic gonadotropin and hCG beta-core fragment at concentrations observed in early natural pregnancy. Clin Chem. 2014;60:s217 B-297.

4. Crocker JB, Lee-Lewandrowski E, Lewandrowski N, Baron J, Gregory K, Lewan-drowski K. Implementation of point-of-care testing in an ambulatory practice of an

academic medical center. Am J Clin Pathol. 2014;142:640-46.

5. Gramz J, Koerte P, Stein D. Managing the challenges in point of care testing. Point of care. 2013;12:76-79.

6. Siemens Healthineers. Siemens health-care consulting solutions change manage-ment guide. 2015.

7. Kotter J, Cohen, D. The Heart of Change: Real life stories of how people change their organizations. Harvard Business School Press. Boston, MA. 2002.

Yu Chen, MD, MSc, PhD, serves as Chief and Medical

Director of the Department of Laboratory Medicine,

Dr. Everett Chalmers Regional Hospital, Horizon Health

Network, Fredericton, NB, Canada, and an associate

Professor of the Department of Pathology, Dalhousie

University, Halifax, NS, Canada.

Susan McDonald, BSc, MEd, serves as Senior

Manager for Healthcare Consulting Solutions,

Siemens Healthineers, Oakville, ON, Canada.

Jason Weshler, MSC, MBA, serves as Director of

Marketing & Business Development, End to End

Solutions, for Point of Care, Diagnostics, Siemens

Healthineers, Norwood, MA.

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The case for full-length sequencing for high-resolution HLA typingBy Nezih Cereb, MD

short reads produced by most NGS or Sanger platforms when variants are more than a few hundred bases apart.

Long-read sequencingLong-read sequencing technology, the latest entry to the DNA sequencing realm, has a number of features that make it a compelling fit for HLA typing. These systems generate indi-vidual reads that are tens of kilobases long, making it possible to capture full-length class I and class II genes in single, con-tinuous reads for a complete sequence. Because the systems work with single molecules, the long reads can phase even distant variants.

Labs that specialize in HLA typing have begun to adopt long-read sequencing and results indicate that this method produces higher-resolution, highly accurate data that could dramatically improve the process of matching transplant donors and recipients. At one lab for instance, scientists typed more than 500,000 samples for the National Marrow Donor Program’s “Be the Match” registry. Thousands of novel vari-ants were detected, including hundreds that could cause null expression or alternative expression of HLA genes.5

Looking aheadThe clear advantages of long-read sequencing to generate full-length HLA gene sequences suggest to many in the industry that this approach should be the new standard for HLA typ-ing. Going forward, the use of exon-based genotyping meth-ods or short-read sequencing methods to analyze only pieces of genes or known variants might be considered inadequate for high-resolution HLA typing and be reserved for specific cases in which DNA quantity and quality are not amenable for long-read sequencing. In the interest of giving patients the best outcomes, clinical labs that outsource their HLA typing to reference labs could ensure that results are being generated with long-read sequencing. Now that it is possible to completely sequence and phase HLA genes for the most comprehensive view of this important genomic region, lab leaders should consider offering this technology to enhance patient care in a critical medical situation.

REFERENCES 1. Mayor N, Robinson J, Alasdair JM, et al. HLA typing for the next genera-tion. PLoS One. 2015. DOI:10.1371/journal.pone.0127153. 2. Hosomichi K, Shiina T, Tajima A, Inoue I. The impact of next-generation sequencing technologies on HLA research. J Hum Genet. 2015;60:665–673; http://www.nature.com/jhg/journal/v60/n11/full/jhg2015102a.html . 3. HLA Alleles Numbers (online database). Nomenclature. http://hla.alleles.org/nomenclature/stats.html. 4. Mayor N. Better HLA matching as revealed only by ultra-high resolution HLA typing results in superior overall survival. 32nd European Immunoge-netics and Histocompatibility Conference, Venice, Italy. 5. Cereb N. New Horizons in HLA typing and haplotyping: revolution in HLA genomics. 32nd European Immunogenetics and Histocompatibility Conference, Venice, Italy.

Advances in DNA sequencing have revolutionized many tests commonly used in or ordered by clinical laboratories, but the implications for HLA typing have

been particularly impressive. This task, a complete analy-sis of a person’s human leukocyte antigen (HLA) genes, is critical for matching donors and patients prior to organ or hematopoietic stem cell transplantation.

The results of HLA typing are used to inform clinicians about histocompatibility between a patient and donor blood or organs. When there is a high degree of matching, patient outcomes are much better—from transplant success to overall survival times. A bad match, on the other hand, can put the recipient’s life in danger.

While HLA typing is essential, it is by no means simple. The HLA genes are some of the most polymorphic and complex in the entire human genome. Thousands of alleles are currently known, and novel variations are continually being discovered. They span a 3.6 Mb region of the genome on chromosome 6. Over time, scientists and clinicians involved in HLA typing efforts have added more markers to the process in an attempt to improve the accuracy of a match between donor and recipi-ent. More recently, they have shown that fully sequencing the HLA genes instead of just scanning key regions to genotype them facilitates a more robust matching process.1

Technology, however, has been a limitation on the ability to resolve the HLA region.2 A new approach to HLA typing that uses long-read DNA sequencing has demonstrated improved resolution, higher accuracy, and more complete information. This method is rapidly enhancing the community’s under-standing of the HLA region and providing data that should translate directly to more successful transplants.

Full-length HLAIt may seem obvious that fully sequencing the HLA genes rather than just looking for known variable regions would provide more information that could be used to match trans-plant donors and recipients.

The more we learn about HLA variation, the more impor-tant it becomes to represent it accurately. Today there are more than 16,000 known HLA alleles for the class I and class II genes in this complex.3 Just a few decades ago, there were only 100 known HLA antigens, a number that seemed remark-ably high at the time. As technical resolution has improved, the number of potential classifications has soared. A single category once generated by serology tests, for instance, has been so fine-tuned that it is split out into 700 different sub-types today.

The increasing resolution from sequence-based typing has led to more successful transplant outcomes. In a report from scientists at Anthony Nolan, a UK charity that launched the world’s first bone marrow registry in 1974, transplant patients matched with ultra-high resolution had 20 percent better probability of survival after five years compared to patients matched with lower resolution.4

Ideally, high-resolution views of the HLA genes would also factor in phasing information to help experts under-stand whether detected variants occur on the same or differ-ent chromosomes. Phasing variants would add a new level of precision to HLA typing, but it cannot be done with the

SPECIAL FEATURE :: NGS

Nezih Cereb, MD, is CEO and co-founder of

Histogenetics, which performs high-volume,

sequence-based HLA typing for clinical

laboratories, hospitals, and research facilities.

24-25 _MLO201809_SpecialFeature.PacBio_MECH_AL.indd 24 8/13/2018 1:52:54 PM


As next-generation sequencing (NGS) is expanding into a wider range of applications, laborato-

ries face constant challenges that they need to tackle to fully benefit from the power of NGS. In this article we discuss some of these challenges—as well as innovative ways of addressing them to enable reliable analysis of a wider range of variants and samples.

Archived tissue biopsiesWhen studying the development and progression of cancers, archived tis-sue biopsies are a valuable resource. However, these samples are typically stored as formalin-fixed, paraffin-embedded (FFPE) blocks—a process that can severely damage DNA. When older samples are used for analysis, it is likely that the integrity of the DNA has deteriorated even further. Low-quality DNA limits a sample’s suitabil-ity for analysis by NGS, and can make distinguishing true, low-frequency mutations more difficult.

To improve the likelihood of success when analyzing FFPE-derived DNA, one can utilize a hybridization-based target enrichment approach. This enrichment method relies on random shearing of DNA followed by selec-tive capture of relevant fragments. It provides superior tolerance to the effects of fragmented DNA compared to amplicon-based approaches.

Further improvements in sequenc-ing quality, and subsequent results,

New applications for NGSBy David Cook


with FFPE samples can be made by including a DNA pre-treatment in the library preparation workflow. DNA pre-treatment repairs certain types of DNA damage, such as cytosine deami-nation, nicks and gaps, oxidized bases, and blocked 3’ ends.

To investigate the effect of DNA repair with formalin-compromised samples, the performance with

increasing levels of DNA damage was compared—both with and without repair. DNA repair resulted in signifi-cant improvements in DNA integrity, resulting in a considerable increase in pre-capture library yields and a sub-sequent improvement in mean target coverage (Figure 1). The results show that hybridization-based enrich-ment can enable high sequencing coverage—even with low input amounts of severely damaged DNA.

Overcoming technical limitationsIn the detection of rare genomic variants, molecular techniques such as digital droplet PCR (ddPCR) and Sanger sequencing, though well established, have limi-tations. ddPCR is hampered by covering only one known mutation per assay and offering limited possibili-ties for multiplexing, while Sanger sequencing offers

limited sensitivity, restricted to 20 percent allele frequency (AF). These issues can be overcome by the use of targeted sequencing panels offering multi-gene analysis at high sensitiv-ity. The following case study from a large UK hospital demonstrates the benefits that targeted NGS can bring to the laboratory.

When analyzing myeloproliferative

neoplasm (MPN) samples, ddPCR was routinely used to identify and quan-tify the common V617F mutation in JAK2. If the test was negative, follow-up analysis with Sanger sequenc-ing and capillary electrophoresis was needed to look for alternative causative mutations.

This particular case was compli-cated by the presence of a rare second mutation only three bases upstream (c.1852C>T). As a result, the V617F mutation was not detected because of

Figure 1. Samples with different levels of DNA damage were repaired using an FFPE DNA repair mix, followed by shearing and library preparation. Samples were enriched with a custom, hybridization-based NGS panel and sequenced. With DNA repair and target enrichment, 50 ng of input DNA was sufficient to achieve a mean target coverage of over 500x at all levels of DNA damage. (Samples provided by Horizon Diagnostics.)

Figure 2. Targeted sequencing of an MPN sample clearly reveals the two JAK2 mutations that were missed by ddPCR.


26-29_MLO201809_SpecialFeature_MERGED_FINAL.indd 26 8/14/2018 1:03:34 PM



Figure 3a. Sophisticated bait design creates uniform coverage across genes and exons, which is essential for clearly identifying variants in hard-to-sequence areas. In FLT3, wild-type DNA (E) is easily distinguished from samples containing ITDs of 38 bp (A), 57 bp (B), 108 bp (C) and 201 bp (D).

Figure 3b. Reliable detection of a point mutation in a GC-rich region of the CEBPA gene.

Figure 4b. Targeted sequencing of two samples with confirmed CNVs in LDLR. Heterozygous deletions (red boxes) and mid-exon breakpoint (red ar-row) are clearly visible. (Samples provided courtesy of Mafalda Bourbon, PhD, Instituto Nacional de Saúde Doutor Ricardo Jorge.) All images courtesy of Oxford Gene Technology.

Figure 4a.



Paradigm shift in infection testing: identifying all pathogens using NGSBy Crystal R. Icenhour, PhD

of the 16S gene, it is subject to the inherent biases of PCR. For example, bacteria that are rich in adenine and thymine (AT-rich) will amplify more easily than bacteria with more guanine and cytosine (GC-rich). This bias can result in very different bacteria iden-tifications if the sample contains GC-rich bacteria, providing patient results that may not accurately reflect the bacterial populations and resulting in an ineffective antibiotic choice. Meanwhile, sequence diversities can cause different efficiencies on primer affinity during amplification, which will also intro-duce bias in the result. Additionally, 16S sequencing cannot identify viruses, parasites, or fungi. In clinical cases, it is important to have an unbiased view of all microbes present in a patient sample to give the best possible information for clinicians to develop the best possible treatment plans.

Opening Pandora’s boxWith shot-gun metagenomic sequencing gaining traction in clinical testing, much is being learned about human microbiomes, as well as infectious disease. There is much to learn about the intimate relationship between the human body and microbes, which comprise ~six pounds of the body weight. Humans rely upon microbes to syn-thesize vitamins, digest food, and protect us from infec-tion. It is becoming increasingly clear that infections are far more complex and dynamic than ever before appreci-

ated. It is not uncommon to identify high levels of numerous pathogenic bacterial species in a single clini-cal sample. In many respects, we are entering uncharted territory and we are on the verge of huge discoveries that will have a profound impact on human health.

Many of the clinical cases being explored by firms utilizing deep shot-

gun metagenomic sequencing are patients who have suf-fered from chronic infection for many years. It is com-mon to identify microbes at high levels that have never been reported as pathogens in humans. And microbes responsible for relatively rare conditions such as Myco-bacterium leprae and Rickettsia felis can also be identified. The beauty of metagenomic approaches to pathogen identification is that one is not required to know what is being sought, but to simply identify what is present.

Data analytics for metagenomic sequencing require high complexity tools and deep expertise in bioinformatics. Once the raw data are analyzed, the next challenge is in interpreting the clinical relevance of the microorganisms identified in the sample. The mere presence of a microorganism in a clinical sample does not mean that there is infection; context is needed to determine the clinical significance of all findings. For example, E. coli

Up to 75 percent of infections are not diagnosed in a timely manner, and they sometimes go undiagnosed for decades.1-2 The issue

of undiagnosed infection has led to growing antibiotic resistance and the spread of infection. Additionally, new research is increasingly showing that undiagnosed infection is linked to numerous autoimmune conditions. Examples of autoimmune conditions that have been linked to infection include fibromyalgia, rheumatoid arthritis, and interstitial cystitis.3-5 Traditional diagnostic technologies identify only one or a few microbes at a time. This limited scope has created bias in what we know about infection and the microbes capable of causing human disease. Such limitations can now be overcome, however, through the use of next-generation sequencing (NGS), which is capable of identifying every known bacteria, virus, parasite, and fungus from clinical samples in a single test.

Not all NGS is equalThe NGS technology that is most commonly used by clinical labs is called 16S sequencing. 16S sequenc-ing is an amplicon-based method that is similar to polymerase chain reaction (PCR) testing. It creates many copies of a small portion of DNA, in this case a ~400bp region of the 16S gene. This gene is present in all bacteria and can be used to identify bacteria based upon sequencing differences in the amplified region. Comparing the sequenced fragments to a database of 16S genes can identify the types of bacteria present. This method can identify thousands of bacteria to the genus level and some to the species level, and a similar strategy can also be applied to 18S genes to identify fungi.6-9

Another type of NGS being used for infection test-ing is deep shot-gun metagenomic sequencing. This more comprehensive method creates genetic finger-prints of every living creature in a sample. Because of the complexity of the sequencing data, a robust data analytic method and a comprehensive microbial whole genome database is required for data analy-sis. The benefit of metagenomic sequencing is that every known bacteria, virus, parasite, and fungus can be identified in this manner. Additionally, DNA is sequenced across many regions of the genome instead of a single portion of one gene, giving better specificity than 16S sequencing.

Some labs use 16S sequencing because it is less expen-sive than shot-gun metagenomic sequencing, but it is crucial that the limitations of its use be understood. Because 16S sequencing relies on PCR amplification


“...NGS...is capable of

identifying every known bacteria,

virus, parasite, and fungus

from clinical samples

in a single test.”


29MLO-ONLINE.COM September 2018


Crystal R. Icenhour, PhD, is CEO

of Aperiomics, which provides

metagenomic sequencing

services to doctors and labs.

She is an expert in infectious

diseases and is committed to

improving world health through

better infection testing.

is a normal bacterium found in fecal samples. But if the fecal sample is composed of 80 percent E. coli, and if the patient is experiencing clinical symptoms consistent with bacterial infection, this finding is likely to be clinically significant. If E. coli is identified circulating in blood, the mere presence of this bacteria at any level could be clinically significant.

Possibilities for healingAs more is learned about microbes and how they interact with the human body, the possibilities for healing patients with chronic illnesses grow.


this second variant under the primer binding site, resulting in a false nega-tive result. Using a custom hybridiza-tion-based myeloid NGS panel, both mutations were detected at an AF of 32 percent (Figure 2). Although rare, this case highlights the accuracy and precision of a targeted sequenc-ing approach in identifying muta-tions that could not be picked up otherwise.

Hard-to-sequence regionsAs comprehensive analysis of genes or exons is a key strength of NGS, it is important that NGS methods pro-vide good uniformity of coverage to ensure that variants are detected with as high a degree of certainty as pos-sible. A common challenge that can negatively affect coverage uniformity is the presence of hard-to-sequence genomic regions, such as internal tandem duplications (ITDs) and regions with high GC or AT content. These phenomena occur in many genes, for example CEBPA and FLT3 in acute myeloid leukemia (AML).

FLT3 contains several ITDs that can be long and are often masked, making it hard to obtain consistent, high coverage across the gene. How-ever, when using hybridization-based target enrichment, intuitive modi-fications to the bait design makes it possible to bait right up to the repeat region. This enables high-coverage sequencing of the repeat region and therefore clear detection of the ITD itself (Figure 3a).

Several key mutations that can lead to AML are linked to the CEBPA gene. NGS analysis of this gene is chal-lenging due to areas with high GC content across the gene as well as the

presence of several repeat regions. When coverage of these areas is too low, they may require supplementary fill-in with Sanger sequencing. Again, an optimized bait design in terms of sequence and bait length—in con-junction with a hybridization-based targeted sequencing approach—ensures high-quality, uniform cov-erage in these regions, minimizing the requirement for supplementary analysis (Figure 3b).

Copy number variationCombining the detection of point mutations with copy number varia-tion (CNV) can result in significant time savings in laboratories. How-ever, detecting CNVs reliably from NGS data is only possible with deep coverage that is highly uniform across all target sites. Achieving this can often be expensive and time-con-suming. Furthermore, due to the size and complexity of the dataset, there are also software challenges that need to be considered to ensure effective CNV calling.

A good example of the benefits that can be achieved by combining the detection of point mutations and CNV is the analysis of the LDLR gene, which is involved in familial hypercholesterolemia (FH). FH samples are often characterized by multiple point mutations in LDLR as well as intragenic CNVs in 10 percent of cases.

The analyses in Figure 4 show sequencing results of two LDLR genes with confirmed CNVs. They clearly show a single heterozygous dele-tion in one sample (Figure 4a) and a heterozygous deletion across two regions with a mid-exon breakpoint

in the other (Figure 4b). This dem-onstrates how targeted sequencing can reliably detect CNVs, enabling combined point mutation and CNV detection in a single assay.

Overcoming challengesNGS has transformed the sequenc-ing landscape with ever-increasing speed, precision, and affordability. Overcoming challenges is the key to expanding NGS into new applica-tions. When using targeted sequenc-ing to study specific regions of the genome, the deep, uniform coverage of hybridization-based enrichment enables reliable analysis in a range of demanding sequencing applica-tions, such as FFPE-derived DNA, discovering rare mutations, detect-ing CNVs, and studying challenging areas of the genome.

What if many autoimmune con-ditions are actually undiagnosed infection? What if ailments such as Alzheimer’s and multiple sclerosis are caused by infection? What if the human condition and aging are heav-ily driven by colonization/infection by microorganisms? What if we can dramatically improve the quality of life by modulating the microbiomes of the human body?

While the challenges of metage-nomic sequencing may seem intimi-dating, engaging strong strategic partners with expertise in NGS and high-complexity data analysis can

David Cook serves as senior product manager for

Oxford Gene Technology (OGT), provider of world-

class genetics research solutions. OGT’s SureSeq

portfolio of next-generation sequencing products

includes SureSeq myPanel hybridization-based NGS

custom cancer panels and SureSeq FFPE Repair Mix.

ease these challenges. Pathogen test-ing is entering a revolutionary phase through the adoption of metage-nomic sequencing. As clinical labora-tories embrace NGS, patient care will dramatically improve.

Please visit mlo-online.com for references.


continued on page 34SEPTEMBER 2018 MLO-ONLINE.COM30

A novel point-of-care approach for improving acute bleeding managementBy Todd W. Allen and Francesco Viola, PhD

clot (representing initial fibrin formation) to be detected. The rate of fibrin polymerization or clot amplification is deter-mined by the length of time (in seconds) the clot takes to increase from 2 mm to 20 mm of clot stiffness.

Next, overall clot stiffness, which reflects the contributions of fibrinogen and platelets, is measured at various times until a maximum level (measured in mm) is achieved. Interest-ingly, the use of millimeters as a measure of the viscoelastic properties of a clot has no physical meaning in this context. It was simply the original method used for recording the range of pin movement on a film that was 100 mm wide. Hartert arbitrarily assigned values of 0 to 100 mm for the measure-ment range.19 Finally, various fibrinolysis parameters are sub-sequently measured as clot stiffness (in percent lost or percent remaining) diminishes due to normal or pathological process. Several comprehensive reviews of both currently available technologies, including system descriptions, features and limitations, have previously been published.20-23

Using the classic methods, VET is a relatively laborious process that is fraught with potential causes of preanalyti-cal errors. These methods require multiple pipetting steps and the open transfer of blood from the collection tube to the measuring cups, factors that limit their acceptance at the POC. Additionally, the measurement of the sample may be disrupted due to susceptibility to environmental disturbances such as vibration or movement and drying artifact because of exposure to air. Finally, the ability to interpret the graphi-cal output and the numerous parameters that are reported requires individual dedication to education and interpreta-tion training. The steep learning curve, combined with the operational complexities of more classical VET, provides an impediment to broader use by physicians, and this may limit the clinical benefits to narrower patient populations.

Novel ultrasound technologyIn recent years, different technologies utilizing novel clot-detection methods have emerged. These technologies employ a variety of different principles to generate vibration

Whole blood viscoelastic testing (VET) for periopera-tive bleeding management is systematically increas-ing in clinical use and is approaching the level of

standard of care for many clinical settings such as cardio-vascular surgery, liver transplantation, trauma, and obstetric hemorrhage. Conventional coagulation testing has proven to be inadequate for directing therapeutic intervention in these critical settings.1-5

Physicians managing acute bleeding events require faster turnaround times for test results and prefer assays that more accurately reflect the whole blood or cell-based hemostatic process described by Hoffman and Monroe.6 The benefits of VET have been well-documented. There exists an abundance of publications and systematic reviews in a variety of clini-cal settings,7-10 including review articles in this area published in previous issues of MLO.11-13 Several medical societies have given strong recommendations for the use of VET in conjunc-tion with goal-directed treatment algorithms guided by VET for managing acute bleeding in the perioperative setting.14-17 To date, two technologies have emerged at the forefront of whole blood VET: thromboelastography and rotational thromboelastometry. Both employ an adaptation of the clas-sic methodology, first reported by Hartert in 1948,18 involving a pin suspended in a cup containing a whole blood sample.

Despite some advancements in the testing process and vari-ous modifications of the assays, the clot detection method-ology using a cup and pin shared by these two systems has remained relatively unchanged for over seventy years.

The objective of this article is to review the classic VET clot-detection principles and to describe a novel approach with a new point-of-care (POC) hemostasis platform that may offer a higher resolution of clot detection, a simplified testing process and an intuitive results output that rapidly provides action-able information, thus potentially making clinical application and interpretation easier.

Classic VET methodClassic VET methods detect the onset of clot initiation and the increasing development of clot stiffness by measuring the resistance to the movement between two surfaces. These sur-faces are provided by a small cup containing whole blood and reagents and a pin that is inserted into the blood-filled cup. The pin displaces the blood and reagent sample to create a one mm gap between all surfaces. Depending on the technol-ogy, either the cup or pin rotates with a slight degree (4.45o to 4.75o) at a rate of five to six times per minute. As the acti-vated blood begins to clot, it forms connections between the surfaces of the cup and pin. These connections are fractured by the mechanical movement of the surfaces until the clot develops enough strength to resist fracture and increasingly impede the movement of the cup and pin surfaces. The mea-sured increase in clot stiffness is then graphically displayed as a curve (Figure 1) from which numerous parameters are derived that represent various aspects of the coagulation pro-cess. These parameters assess clot initiation, which reflects the length of time (in seconds or minutes) it takes for a nascent

EDUCATION :: HEMOSTASIS

Figure 1. Common measured parameters of TEG and ROTEM.

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the POC. Relative to the primary objective of clinical performance,

one analyzer has been evaluated and compared to classic VET methods in a variety of clinical settings including car-diac surgery,27,28 spine surgery,29 and other critical care set-tings30 and has demonstrated good correlation with similar clotting parameters reported by standard laboratory testing

and good concordance with the clinical presentation (i.e., bleeding or non-bleeding). Second, cartridge-based systems have automated the testing process by eliminating the need to openly transfer blood from the collection tube or to manu-ally mix reagents. This reduces the chance for untimely pre-analytical processing errors that can delay the time to obtain results needed to treat patients. Furthermore, this offers the opportunity to use the system by nonlaboratory healthcare personnel at the point of care. Improvements in automating steps in VET have been proven to reduce inter-operator and intra-operator variability of results in multiuser settings.31 In addition, automation of VET can presumably help to reduce testing costs by reducing product waste from errant testing.

Finally, with a unique and intuitive display (Figure 3), the interpretation of test results can be made easier for less expe-rienced clinicians to arrive at the correct conclusions about enzymatic factor deficiencies (CT = clotting time), platelet

and are detected and related to changes in viscoelastic properties as a function of the coagulation and fibrinolysis properties of the sample. One of the novel devices uses a pat-ented, “ultrasound” technology called SEER (Sonic Estima-tion of Elasticity via Resonance) sonorheometry.24 The use of ultrasound is common in medical practice, with ultrasound-based imaging devices being utilized across a broad spectrum of patient populations. Ultrasound signal processing techniques are also employed to characterize changes in mechanical properties of soft tissues that might be indicative of diseased tissues. This growing area of clinical research is called elastography.25

SEER sonorheometry uses high-frequency ultrasound pulses like those used in diagnostic imaging to measure changes over time in shear modulus, a direct physical measure of clot stiffness (Figure 2). The utilization of ultrasound allows the sample to be interrogated with-out having physical contact with moving parts, thereby reducing the potential interference with the coagulation process as occurs in classic VET methods. This results in increased sensitivity to early clot formation and increased sensitivity to soft clots, which are often those associated with clinical bleeding. Furthermore, in contrast to other VETs, the direct measurement of the sample shear modulus allows accurate estimation of the relative contributions of platelets and fibrinogen to overall clot stiffness.26

Expanded testing at the POCAs new technology for bleeding management is introduced to the clinical market, the primary goal is to not compromise clinical performance in exchange for testing automation, speed, and space-saving design. However, while analytical performance is paramount, important considerations must be given to reducing the complexity of the testing process and simplifying the interpretation of the results. Improving these aspects of VET is key to expanding this type of testing to a broader range of clinical settings and move it closer to


Figure 2. Sonorheometry analysis.

Figure 3. SEER Sonorheometry dial-screen, Quantra. CTH, Clot Time w/Heparinase; CT, Clot Time; CTR, Clot Time Ratio; CS, Clot Stiffness; PCS, Platelet contribution to CS; FCS, Fibrinogen contribution to CS.




Todd W. Allen serves as Director of Clinical

Training for HemoSonics, LLC (Charlottesville,

VA). He worked for many years in various

perioperative clinical positions before entering

the medical industry and has been working

with POC coagulation testing systems for more

than 14 years.

Francesco Viola, PhD, serves as Chief

Scientific Officer for HemoSonics, LLC. He

co-founded HemoSonics following his doctoral

work at the University of Virginia. He has more

than 15 years of experience in the areas of

medical ultrasound imaging, advanced signal

processing, POC testing, and coagulation

testing.

contribution of CS, FCS = fibrinogen contribution to CS), or the influence of heparin (CTH = CT with heparinase, CTR = CT:CTH ratio) that may cause coagulopathic bleeding. This new display incorporates dials that are ubiquitous in every-day life. Clinicians can easily detect coagulation characteris-tics that may clarify the reason for bleeding or thrombosis or portend an increased risk for either condition.

SummaryVET devices have been proven to be effective tools to help manage perioperative bleeding and improve patient out-comes by enhancing the physician’s ability to stop bleed-ing quickly and thereby reduce unnecessary transfusions and complications associated with transfusions. Numerous physicians and researchers using the classic VET technolo-gies of thromboelastography and thromboelastometry have done much of the heavy lifting to challenge convention and to transform acute bleeding management in many clini-cal settings. The challenges now for companies with novel approaches are to improve on the clot-detection methods, to create more user-friendly technologies, and to provide uncompromised clinical results that can be easily performed by clinicians in clinical settings moving ever closer to the patient. The benefits of the emergence of these new technol-ogies is better hemostasis management with faster diagnos-tics and easier clinical application. This can now be realized for more patients who experience bleeding complications than ever before.

REFERENCES

1. Haas T, Spielmann N, Mauch J, et al. Reproducibility of thrombelastometry: Point-of-care versus hospital laboratory performance. Scand J Clin Lab Invest. 2012;72:313-317.

2. Akay OM. The double hazard of bleeding and thrombosis in hemostasis from a clinical point of view: a global assessment by rotational thromboelas-tometry (ROTEM). Clin. Appl. Thromb. Hemost., 2018 Jan 1.

3. Smart L, Mumtaz K, Scharpf D, et al. Rotational thromboelastometry or conventional coagulation tests in liver transplantation: comparing blood loss, transfusions, and cost. Ann Hepatol. 2017;16:916-923.

4. Saner FH, Abeysundara L, Hartmann M, Mallett SV. Rational approach to transfusion in liver transplantation. Minerva Anestesiol. 2018; 84:378-388.

5. Snegovskikh D, Souza D, Walton Z, et al. POC viscoelastic testing improves the outcome of pregnancies complicated by severe postpartum hemorrhage. J Clin Anesth. 2018;44:50-56.

6. Hoffman M, Monroe DM. A cell-based model of hemostasis. Thromb. Haemost. 2001;85:958-965.

7. Franchini M, Mengoli C, Cruciani M, et al. The use of viscoelastic haemo-static assays in non-cardiac surgical settings: a systematic review and meta-analysis. Blood Transfus.2018;16:235-243.

8. Deppe AC, Weber C, Zimmermann J, et al. POC thromboelastography/thromboelastometry-based coagulation management in cardiac surgery: a meta-analysis of 8332 patients. J. Surg. Res. 2016;203:424-433.

9. Veigas PV, Callum J, Rizoli S, et al. A systematic review on the rotational thrombelastometry (ROTEM) values for the diagnosis of coagulopathy, predic-tion and guidance of blood transfusion and prediction of mortality in trauma patients. Scand J Trauma Resusc Emerg Med.2016;24:114.

10. Wikkelsø A, Wetterslev J, Møller AM, Afshari A. Thromboelastography or thromboelastometry to monitor haemostatic treatment versus usual care in adults or children with bleeding. Cochrane Database Syst Rev. 2016;8:CD007871.

11. Allen TW. Thromboelastometry: Its method, application and benefits. MLO.

2014;46:26-29.

12. Allen TW. Clinical application of thromboelastometry in cardiovascular and thoracic surgery. MLO. 2015;47:20-22.

13. Allen TW, Sheldahl K. Meeting thromboelastometry clinical needs and new quality standards. MLO. 2016;48:20-22.

14. Pagano D, Milojevic M, Meesters MI, et al. 2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery. Eur J Cardiothorac Surg. 2018;53:79-111.

15. Shaylor R, Weiniger CF, Austin N, et al. National and international guidelines for patient blood management in obstetrics: a qualitative review. Anesth. Analg. 2017;124:216-232.

16. Practice guidelines for perioperative blood management: an updated report by the American Society of Anesthesiologists Task Force on Periop-erative Blood Management. Anesthesiology. 2015;122: 241-275.

17. Kozek-Langenecker SA, Ahmed AB, et al. Management of severe periop-erative bleeding: guidelines from the European Society of Anaesthesiology: First update 2016.Eur J Anaesthesiol. 2017;34:332-395.

18. Hartert H. Blutgerinnungsstudien mit der Thrombelastographie, einem neuen Untersuchungsverfahren. Klin Wochenschr. 1948;26:577-583.

19. Hochleitner G, Sutor K, Levett C, et al. Revisiting Hartert’s 1962 Calcula-tion of the Physical Constants of Thromboelastography. Clinical and Applied Thrombosis/Hemostasis 2017;23(3):201-210.

20. Bolliger D, Tanaka KA. POC coagulation testing in cardiac surgery. Semin Thromb Hemost. 2017;43:386-396.

21. Williams B, McNeil J, Crabbe A, Tanaka KA. Practical use of thrombo-elastometry in the management of perioperative coagulopathy and bleeding. Transfus Med Rev. 2017;31:11-25.

22. Bolliger D, Seeberger MD, Tanaka KA. Principles and practice of throm-Principles and practice of throm-boelastography in clinical coagulation management and transfusion prac-tice. Transfus Med Rev. 2012;26:1-13.

23. Othman M, Kaur H. Thromboelastography (TEG). Methods Mol Biol. 2017;1646:533-543.

24. Corey FS, Walker WF. Sonic estimation of elasticity via resonance: a new method of assessing hemostasis. Ann Biomed Eng. 2015;44:1405-1424.

25. Gennisson JL, Deffieux T, Fink M, Tanter M. Ultrasound elastography: principles and techniques. Diagn Interv Imaging. 2013;94:487-495.

26. Solomon C, Ranucci M, Hochleitner G, et al. Assessing the methodol-Assessing the methodol-ogy for calculating platelet contribution to clot strength (platelet com-ponent) in thromboelastometry and thrombelastography. Anesth Analg. 2015;121:868-878.

27. Huffmyer JL, Fernandez LG, Haghigian C, et al. Comparison of SEER sonorheometry with rotational thromboelastometry and laboratory param-eters in cardiac surgery. Anesth Analg. 2016; 123:1390-1399.

28. Reynolds PS, Middleton P, McCarthy H, Speiss B. A comparison of a new ultrasound-based whole blood viscoelastic test (SEER sonorheom-etry) versus thromboelastography (TEG) in cardiac surgery. Anesth Analg. 2016;138:96-102.

29. Naik BI, Durieux ME, Knisely A, et al. SEER sonorheometry versus rota-tional thromboelastometry in large volume blood loss spine surgery. Anesth Analg. 2016;123:1400-1407.

30. Ferrante EA, Blasier KR, Givens TB, et al. A novel device for the evaluation of hemostatic function in critical care settings. Anesth Analg. 2016;123:1372-1379.

31. Anderson L, Quasim I, Steven M, et al. Interoperator and intraoperator variability of whole blood coagulation assays: a comparison of thromboelas-tography and rotational thromboelastometry. J Cardiothorac Vasc Anesth.

2014;28:1550-1557.

Special thanks to colleagues Debbie Winegar, PhD, Wim

Houdijk, PhD, and Jeffrey Light for valuable review and edits.

30-35_MLO201809_Education_FINAL.indd 35 8/14/2018 1:11:49 PM

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38 SEPTEMBER 2018 MLO-ONLINE.COM

Technology is evolving quickly. Its currents cut across all aspects of our lives, including healthcare. Fast-moving technological advances help explain why the

mHealth (mobile health) industry is growing so rapidly. Mobile technology is proving useful for a broad range

of new applications, and it has inspired a rethinking of many aspects of healthcare. According to several stud-ies, the modern technology behind the new discipline of remote patient monitoring has helped patients maintain independence, minimize personal costs, prevent complica-tions, and participate more effectively in their own care, sometimes in their own homes.1

Remote patient monitoring has progressed in tandem with precision medicine, a field based around leveraging new cascades of data to provide more personalized care. Industry leaders are currently engaged in pioneering stud-ies that measure the effectiveness of precision medicine for a growing array of purposes.

Precision medicine and remote patient monitoring tech-nologies represent significant breakthroughs for healthcare providers and also for patients, who have access to an increasing range of options that provide greater comfort, convenience, and agency.

Diabetes managementIn the management of diabetes and screening for HbA1c, the challenges of point-of-care (POC) blood collection are well-documented.2 Quickly and comfortably drawing small volumes of blood, in the range of 10 μl, has often entailed a tradeoff in quality and reliability of results.

To be fair, modern point-of-care testing has come a very long way in terms of quality. But concerns remain about reliability over time; the test has a +/- 6 percent tolerance. When POC tests aren’t properly QCed, results can slip out of a lab’s control. And there are other practical limitations. Ten uL is about all that standard analyzers can absorb at one time. HbA1c analyzers can detect much more than just HbA1c. A better sample can generate more detailed information—for example, it can show whether a person is heterozygous for sickle cell anemia—so there is a demand and a purpose for more robust sampling solutions.

From a patient-centric perspective, other practical con-cerns have persisted. Effective diabetes management and screening requires lab visits; many patients must show up to clinics for this purpose as often as four times per year. This has the potential to negatively impact patient adher-ence and compliance with treatment, and it has definite impacts on convenience and economics. It makes it more difficult for patients to engage actively in their own care, which impedes the pursuit of a more patient-centered lab.

A more value-based approach to HbA1c monitoring can lead to the rethinking of entire systems of care. Medicine will shift away from decision-making based on tactical averages and toward more personalized planning. The future of care will be predictive, preventative, personal-ized, and participatory (sometimes called the P4 model). To achieve widespread adoption, emerging healthcare technologies will integrate this approach into their design.

Diabetes management cuts across populations and affects millions, which makes it an ideal area in which to see new ideas in action.

The implementation of remote patient monitoring tech-nologies and a philosophical gravitation toward a more patient-centric approach offer the potential to improve the treatment and lives of those who suffer from diabetes, and those who want to prevent it. But how do these big ideas translate into practice? A crucial and often neglected element in this equation is the sampling event itself.

The sampling eventLarger and larger amounts of data can now be generated from smaller and smaller amounts of blood. However, problems still exist at the moment when human skin is pricked and blood is drawn or absorbed. Venipuncture remains painful, and results generated from dried blood spot (DBS) cards still suffer from certain drawbacks. It’s problematic for many patients and participants, and it’s costly and cumbersome for many labs.

Newer microsampling technologies are designed to collect quantitative, volumetrically accurate specimens. Results from these methods correlate to those associated with wet blood, eliminating much uncertainty and con-cern, and creating a smarter sampling event. These tech-nologies have the potential to catalyze innovation in precision medicine and remote monitoring, and to allow clinical labs to adopt more patient-centric approaches.

A recent study was conducted to examine the use of microsampling collection devices that allow patients to self-collect their capillary samples.3 The procedure requires minimal training, and can be conducted in a patient’s home or at a remote clinical site. The study’s findings indicate that most patients were at ease with self-collecting a capillary sample at home rather than going to a clinic, laboratory, or other phlebotomy collection site.

Remote monitoring for HbA1c Compared to older methods, remote sampling and moni-toring for HbA1c is convenient and saves time and costs. Most important, it has demonstrated effectiveness through improved outcomes for patients.

Scientists from Belgium’s Ghent University Hospital recently conducted a study in which they looked into the user-friendliness of various sampling techniques as well as the techniques patients preferred to use in the future.4 Remote and at-home sampling techniques, in which patients manage their blood samples by themselves, stood out as most popular. The future of remote monitor-ing for patients with diabetes opens new options and facili-tates greater choice for people with diabetes and those who care for them.

Through such interventions as remote sampling, remote patient monitoring, and precision medicine, management of chronic illnesses could become a less taxing challenge for healthcare systems. The use of technology to implement cost-effective healthcare management is an increasingly realistic possible alternative for diabetes management.

What new blood collection methods mean for monitoring HbA1cBy Emerson Dameron

SPECIAL REPORT :: DIABETES


38-41_MLO201809_SpecialReport_FINAL.indd 38 8/14/2018 1:18:52 PM

The Only Glucose Meter FDA Clearedfor Capillary Testing

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Use of any other glucose meter is considered off label by the FDA and high complexity testing under CLIA if used with critically ill patientsamples. A hospital cannot override these regulations with their own glucose meter validation testing.

NEWS FLASH: NEW FDA CLEARANCE



SPECIAL REPORT :: DIABETES

REFERENCES

1. Tep S. 8 studies that prove the value of remote monitoring for diabetes. https://www.glooko.com/2015/05/8-studies-that-prove-the-value-of-remote-monitoring-for-diabetes

2. Broderick JA. Point‐of‐care haemoglobin measurement – state of the art or a bleeding nuisance? Anaesthesia. 2015;70(11):1225-1229.

3. Jannetto P, Mbughuni M, Stevens M, et al. Capillary versus venous therapeutic drug monitoring of tacrolimus and cyclosporine A. Mayo Clinic poster presentation. https://hubs.ly/H0cnldM0

4. Verougstraete N, Lapauw B, Van Aken S, Delanghe J, Stove C, Stove. V. Volumetric absorptive microsampling at home as an alternative tool for the monitoring of HbA1c in diabetes patients. Clin Chem Lab Med. 017;55(3):462-469.

Emerson Dameron serves as the Content

Marketing Manager for Torrance,

California-based Neoteryx. He acknowledges

the assistance of James Rudge, PhD, Technical

Director at Neoteryx, and Stuart Kushon, PhD,

Chief Scientific Officer at Neoteryx, in writing

this article.

Saliva test could improve diabetes control and treatmentBy MLO Staff

Proteins in saliva can identify uncontrolled type 1 diabe-

tes in children and adolescents, helping to both predict

and prevent complications associated with the disease.

Diabetes assessment currently relies on measurement

of blood sugar levels—but a simple saliva sample could

replace this, says new research. The study, published in

Frontiers in Physiology, and the most comprehensive of

its kind to date, finds that proteins in saliva reflect high

blood sugar and associated disease processes in young

patients with type 1 diabetes, long before the appearance

of clinical symptoms. This could lead to better prediction

and prevention of long-term complications of the disease.

People with type 1 diabetes produce too little insulin. This

hormone is required for the body to use sugar for energy,

so lack of insulin causes unused sugar to accumulate in

the blood. This excess sugar in turn leads to complications

like cardiovascular, kidney, eye and nerve damage.

With no known cure for type 1 diabetes, the key to pre-

venting these complications is careful control of blood

sugar levels. This is achieved with insulin injections—

balanced with lifestyle factors like diet and exercise—and

requires regular blood testing to monitor sugar control.

But this invasive monitoring can be problematic,

particularly in children and adolescents.

“Blood collection through repeated sampling causes

discomfort and hinders patients’ compliance,” explains

study co-author Professor Heleni Vastardis of Northern

Kentucky University (NKU) Athens School of Dentistry.

“Easy, simple, painless, non-invasive saliva collection is

the most attractive diagnostic medium when examining

children.”

Our saliva contains thousands of proteins produced

by our salivary glands and gums, with important roles

like healing, digestion, and fighting disease. Previ-

ous research shows that the amounts of each of these

proteins—collectively called the “salivary proteome”—

differ between healthy people and those with diabetes.

Vastardis and colleagues see great potential in this

finding. “Saliva is considered a mirror of the body’s health

and disease and a possible game changer in healthcare

and clinical practice,” she says.

Their new study is the most comprehensive charac-

terization of the salivary proteome to date. It analyzed

saliva samples from young type 1 diabetics with satis-

factory or poor blood sugar control and from matched

healthy subjects, using a highly sensitive technique to

identify and quantify more than 2,000 different proteins.

The researchers found that young type 1 diabetics

with good blood sugar control had similar saliva protein

profiles to non-diabetics.

In contrast, young people with poorly controlled type

1 diabetes showed a very different saliva protein profile.

The differences were in proteins known to have key roles

in inflammation, clotting and blood vessel function—pro-

cesses that are disrupted by high blood sugar and thereby

underlie the major long-term complications of diabetes.

Crucially, none of these young patients yet had any

clinical signs of eye, kidney, or nerve damage.

“In other words, the signs of diabetic pathology are

already in place way before manifestation of clinical

complications,” Vastardis points out.

This suggests that the diabetic salivary proteome

could be used to predict complications—and help pre-

vent them. “Salivary diagnostics enable the assessment

of asymptomatic diabetic patients and the identification

of high-risk patients likely to face diabetic complications.

This knowledge may offer access to novel points of

intervention.”

To demonstrate this principle, the group used their

results to identify a potential new preventive treatment

for young patients with poor diabetic control. By search-

ing a gene database, they found a drug candidate capable

of reversing the salivary proteome changes associated

with high blood sugar.

This proof-of-concept study demonstrates the power

of salivary protein analysis in diabetes research—and

soon in the diabetes clinic, Vastardis believes.

“We envision that in the near future we will be able to

diagnose and monitor therapeutic strategies in diabetes

with only a drop of saliva, through ultra-sensitive and

highly specific techniques such as the Multiple Reac-

tion Monitoring used in our study as well as real-time,

non-invasive, salivary glucose monitoring devices.”

“However, larger cohorts are required to completely

utilize the information and to account for the potential

variance.”



FACT CHECK.

Contact your Roche account executive to make sure you know the facts: go.roche.com/informfacts

When it comes to professional blood glucose monitoring systems, you need a partner you can trust to deliver not only reliable results but also reliable information.

System integrity checks and 24/7/365 live support give you confidence you can count on.

More POC glucose tests have been performed worldwide by the Accu-Chek® system than by any other company.*

Roche is the only professional total glucose monitoring solution provider with meter/strips, lancets and a data management system.

© 2018 Roche. ACCU-CHEK is a trademark of Roche.

*Roche data on file 2018.


August 2018 MLO-ONLINE.COM42

WASHINGTON REPORT

In February 2018, the U.S. Food and Drug Administration (FDA) authorized the marketing of the first blood test to evaluate mild traumatic brain injury (mTBI), com-

monly referred to as a concussion, in adults. The FDA’s decision was made in less than six months as part of its Breakthrough Devices Program, and it enabled a California-based company to introduce an assay for that purpose. This marks the first-ever approval of a blood test for concussions by the FDA.

The assay works by measuring levels of proteins, known as UCH-L1 and GFAP, that are released from the brain into the blood after a hit to the head. These proteins have been shown to be indicative of brain injuries and other neu-rodegenerative diseases. For the approval, the FDA evalu-ated data from a clinical study of 1,947 individual blood samples from adults with a suspected mTBI and reviewed the blood test’s performance in comparison to the results of a computed tomography (CT) scan. Results showed that the assay was able to predict the presence of intracranial lesions on a CT scan 97.5 percent of the time. Further, it was able to predict lack of intracranial lesions on a CT scan 99.6 percent of the time. These findings prove that the test can reliably and accurately indicate whether or not a patient has suffered an mTBI. That rules out the need for a CT scan in at least one-third of patients who are suspected of having mTBI. The FDA thus has validated a less-invasive approach to a concussion diagnosis.

What this meansPatients, patient advocates, researchers, clinicians, and other stakeholders have long advocated for an objective, noninvasive way to detect concussions and improve head health. Currently, most patients with a suspected head injury are examined using a neurological scale, called the 15-point Glasgow Coma Scale. This is typically followed by a CT scan to detect brain tissue damage or intracranial lesions that may require treatment; however, CT scans only show more severe brain bleeding and are not always a good indicator of an mTBI. In fact, the majority of patients eval-uated for mTBI do not have detectable intracranial lesions on their CT scans.

Now, hospitals will be able to administer a blood test to detect elevated levels of the proteins indicative of brain injury and, only if there are elevated levels, move forward with a CT scan—thus minimizing the need for unneces-sary and expensive scans. This will prevent unnecessary neuroimaging and associated radiation exposure for patients, and it will allow medical professionals to defini-tively diagnose mTBIs that may have otherwise gone undetected by subjective tests.

Why this mattersThe test still lacks the sensitivity needed to diagnose the most minute concussions. Obtaining advanced sensitivity and specificity for a test like this is the only way clinicians will be able to detect brain injuries at their onset, before symptoms present. This is critical for improving safety for

FDA approves first blood test for concussions By Kevin Hrusovsky

athletes in contact sports, for instance, and preventing second-impact syndrome. Research shows that repeated hits to the head can potentially lead to other serious neurodegenerative diseases such as chronic traumatic encephalopathy (CTE) and Alzheimer’s disease later in life.

And it may have implications for society, as well. For one dramatic example: former NFL star Aaron Hernandez, who was convicted of murder and later took his own life while in prison, was diagnosed with CTE post-mortem. We can-not know—we cannot judge whether brain injury was a factor in his crime—but it might never have been commit-ted if an objective test for mTBI had been administered to him after every hit to the head. In the future, professional athletes (and their teams and leagues), armed with infor-mation, may be able to make better decisions about how many concussions to sustain before calling it a career.

Where this may lead The recently approved test alone will have an impact; however, of perhaps greater importance in the long run, the FDA’s approval of a blood test for concussions helps to validate the approach as a viable method. The next step is to advance the technology, making it more sensitive and economical, and work toward a point-of-care device. Bring-ing a blood test for concussion detection to the sidelines of football and other games could dramatically improve player outcomes.

Now that the assay has been approved, its maker and other vendors are concentrating on increasing the element of sensitivity. Not only will heightened sensitivity enable doctors to diagnose concussions and other brain injuries earlier, but it will also help in the development of improved diagnostics and more effective drugs for TBIs and other neurological diseases. Ongoing research is also focused on improving the speed of the test. With the current test, results take about three to four hours to see. For profes-sional athletes—and for anyone who might have suffered a concussion—that’s too long. Researchers are working on speeding up output time.

Ultimately, a test that can detect proteins in the blood that are indicative of brain injuries or neurodegenerative diseases will be necessary to disrupt today’s insufficient methods. There is reason for optimism that the industry will continue down this path of innovation and discov-ery. Further advances will also help clinicians gain a bet-ter understanding of the long-term effects of concussions and the pathology of diseases associated with repeated head trauma.

Kevin Hrusovsky serves as CEO and Chairman

of Lexington, Massachusetts-based Quanterix

Corporation.

42-43_MLO201809_WashRep_MECH_AL.indd 42 8/13/2018 2:09:36 PM

1. Percentage of samples with numerical results that do not require additional intervention or handling, such as manual smear review, spun hematocrit, dilution, or other repeat/reflex testing. DxH series side-by-side results documentation.

© 2018 Beckman Coulter, Inc. All rights reserved. Beckman Coulter, the stylized logo and the Beckman Coulter product and service marks mentioned herein are trademarks or registered trademarks of Beckman Coulter, Inc. in the United States and other countries.

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Sustainable cost control in the labBy Mark Krhovsky

Demand high service levels and price transparency from your distribution partner. Don’t settle for poor customer service from your lab distributor. Find a distributor with a sales specialist interested in working alongside you and your team. Make sure your distributor offers you visibility into your lab spend-ing across manufacturers and facilities so you can make data-driven decisions and actively monitor contract compliance, price parity, and distribution fees.

Consider product choice. Which brand-name commodity items can you switch to in order to minimize costs? If your lab has had full product choice available to it, you may be over-paying on the commodity products just for the brand name. You also may be missing out on standardization opportuni-ties that drive savings by enabling you to purchase in higher volumes. Your distributor can help you re-evaluate how to validate items and systematize ordering options within each product category, and whether to switch to lower-cost, clini-cally equivalent products where applicable and acceptable.

Ask your distribution partner how you can save costs from a logistical standpoint. If tight storage areas prevent your team from working efficiently, your distributor may be able to help. Ask your distributor to bring its logistics directors on-site to perform an assessment and identify opportunities for opti-mized inventory levels, delivery type, and frequency, and sup-ply room layouts. Perhaps increasing your delivery frequency will allow you to keep less on-hand while avoiding stock-outs. Or switching to low unit-of-measure delivery may mean less time for your team breaking down corrugate and more time on the bench.

Is your distributor a strategic partner?Comparison-shop as your distributor’s contract expiration nears. Who your distribution partner should be is one deci-sion you can make that will have a huge impact on your lab’s profitability for years to come. The best laboratory distributors are able to customize services to support you as your needs evolve with a broad lab product portfolio, a strong focus on customer service, logistical expertise, and transparent pricing, giving you access to real-time data to manage your business. With all the challenges lab leaders face, it is imperative that they have a distribution partner that will go above-and-beyond to meet their needs.

Ultimately, making one or two changes in your lab can have a huge impact on cost savings. Whether that means building partnerships with your supply chain colleagues, or asking your distribution partner how to save costs logistically, taking these steps can have a significant and lasting effect on your bottom line. Whatever decisions you make, your distri-bution partner plays a key role in ensuring these cost-control measures come to fruition.

Preparing the enterprise for sustainable cost control is now the number-one concern for hospital executives, accord-ing to a recent Advisory Board nationwide Health Care

CEO Survey.1 This fact is not surprising when you consider that providers are dealing with uncertainty over regulatory changes from Washington, declining patient admissions, waning reimbursements, and higher operating expenses.2 That is why health systems are placing greater emphasis on reducing the price of care, now more than ever. Laboratory and medical supply distributors and manufacturers know that their provider customers are becoming even more proactive at finding ways to deliver high-quality care with better out-comes at reduced costs by taking a closer look at their internal operations. A key tenet to achieving these efficiencies is the ability for healthcare institutions to broaden how they evalu-ate and choose the strategic vendor partners who help them develop and deliver those very solutions.

How is this relevant to the lab? The focus on sustainable cost control is spreading into clinical labs, which play a critical role to providers, as they guide 70 percent of medical decisions within the acute care setting.3 Labs are striving to generate more revenue and reduce overall costs. However, labs are experiencing market-wide challenges that make this difficult to accomplish. They are experiencing an increased demand for testing, both in volume and speed, and yet are simultaneously facing a myriad of challenges in meeting those demands, including (but not limited to) staff shortages, tightening budgets, and declining reimbursement rates.

In the midst of this pressure, lab directors must decide on a best path forward with limited options and the proverbial one hand tied behind their back. Do we combat labor shortages with automation and technology? Are there creative options within our logistics or supply chain to cut out waste, cost, or both? Do we have the right partners to bring us flexibility and nimbleness in an ever-changing healthcare landscape? These are the types of questions clinical lab directors are asking themselves every day—and it is the answers to these questions that will allow providers to not only maintain but persevere and progress.

Four impactful changes labs can make To achieve sustainable cost control, many lab directors are viewing their labs as stand-alone businesses that need solid financial foundations. Rather than attempting to identify one-off cost savings through individual items, they instead identify supply chain strategies that can drive a larger savings impact across the entire department. Here are some options to consider for your lab.

Build partnerships with your supply chain colleagues. By break-ing down silos and partnering with supply chain colleagues, lab directors may benefit from understanding cost-control initiatives that supply chain has already implemented across the rest of the healthcare system. Healthcare supply chain executives are partnering with clinicians to learn brand preferences before streamlining clinicians’ ordering options within each product category. Since supply chain experts may have more experience with these cost-control initiatives, they may be able to share best practices with you before you make similar changes in the lab.

LAB MANAGEMENT :: SUPPLIES AND EQUIPMENT

Mark Krhovsky serves as Vice President of

Laboratory Sales at Northfield, Illinois-based

Medline Industries. He manages Medline’s

growing Laboratory Specialist Sales force with

verticals covering both the Acute Care and

Non-Acute Care laboratory environments.

Please visit mlo-online.com for references.

44-45_MLO201809_LabMgmt_FINAL.indd 44 8/14/2018 1:27:42 PM

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Considerations in obtaining quality specimens from DVA patientsBy Jean Tenuta, MS, MBA, MT(ASCP)DLM, SLS, CQA(ASQ)

suffered bruising and 84 percent felt more pain.8 Overall, eight of 10 patients surveyed indicated that the experience of their blood collection affected their satisfaction with the care institution, as well as their confidence in the staff and its abil-ity to provide good customer service. Hospital administrators are more concerned than ever, with reimbursements increas-ingly being tied to patient satisfaction.8

Patient circumstances that affect device selection Patient population. Pediatric and neonatal patients have con-siderably smaller veins than adults. Veins in elderly patients can be elusive, and the further complications of dehydration, low blood pressure, and limited range of motion from injury or structural diseases may restrict the number of available col-lection sites. Veins become more fragile with aging, and loss of strength and elasticity in connective tissue decreases over time.3

Critical conditions. Critically ill and/or oncology patients may demonstrate similar issues to those presented by the elderly. Oncology patients receiving chemotherapy may have veins that are harder to locate and exhibit sclerosis from multiple draws and injections. Critically ill, non-ambulatory patients may exhibit edema because of the treatments received and lack of activity.3 Other conditions that also may prohibit routine venipuncture include obesity, chronic illness, hypovolemia, intravenous drug abuse, and vasculopathy.9

Vein location. Veins in the antecubital fossa, located just below the elbow crease, are preferred; however, these veins may not be accessible because of intravenous fluid adminis-tration, frequent injections in the past, or surgery involving the lymphatic system. Existing lymphedema prohibits the use of tourniquets to palpate veins. The only accessible veins may be in the hand, and they are significantly smaller.3

Patient preference. The AOR participants were shown a col-lage of devices used to draw blood. No explanation was given about any of the devices. Approximately 40 percent preferred wingsets to others; other devices were not viewed as favor-ably. Afterward, the participants were given brief descriptions of each. The information provided increased the percent-age of those who preferred wingsets to 60 percent. Patients perceived that the wingsets created less bruising, were less painful, appeared less intimidating, were easier to insert and withdraw; and contributed to more success in collection from the first attempt.8

Collector circumstances that affect device selectionSurveys of phlebotomists, nurses, and other medical profes-sionals reveal that about 50 percent prefer to use wingsets for blood collection. The patient-centric reason is that the patients have a better experience, particularly those who exhibit delicate or fragile veins, where use of a smaller bore needle, such as the 25-gauge, is indicated.10

Some phlebotomists like using wingsets because of the “flash,” the observance of blood in the hub or tubing, a visual indication that entry into the vein has been achieved. Per-sonal safety also is of concern. Wingsets with in-vein activa-tion of a retractable needle minimize the possibility of the

Imagine having the kind of job in which customers are reluctant, if not unwilling, to use the service you provide; they want as little contact with you as possible; and are

unforgiving if the service is not provided flawlessly on first try. This is the type of pressure phlebotomists (for this article‘s purposes, “phlebotomist” refers to anyone who performs the act of collecting blood, not just those with the job title) feel daily with every patient. In addition to being confident and knowledgeable about the types of equipment to use and proper draw order, tube labeling, mixing, and handling, phle-botomists must be compassionate, offering words of comfort and reassurance to gain cooperation from even the most needle-averse patients.

Difficult venous access (DVA) Obtaining a high-quality blood sample that accurately reflects the patient’s clinical status for laboratory testing can be chal-lenging. Even healthy, active, and well-hydrated individuals can present problems for a phlebotomist on a given day. Patients exhibiting a clinical condition called difficult venous access (DVA) lack readily visible or palpable veins and require multiple attempts, multiple operators, or specialized interven-tions to achieve and maintain peripheral venous access, and they challenge even the most skilled of phlebotomists.¹ DVA occurs in an estimated 12 percent of patients.² Patient popula-tions exhibiting DVA and fragile veins include children, the elderly, those who are chronically or critically ill (chemo-therapy, dialysis, sickle cell disease) and, sometimes, those who are fearful of having their blood drawn.3 Of the patients who report difficult collections, 95 percent report that two or more attempts were required before blood was obtained.4 Blood collection success may require using technology other than a 21- or 22-gauge straight needle.

Selecting the appropriate deviceSelecting the appropriate device and gauge size may involve a tradeoff between the ability to obtain a high-quality sample and collecting one that might have its quality compromised by hemolysis. The 2010 World Health Organization Guide-lines on Drawing Blood recommended that either a 22-gauge straight needle or a 23-gauge winged set (butterfly) be used for pediatric, neonatal, and elderly patients and other patients with small veins.5 Use of needles with a smaller bore, such as a 25-gauge needle, was discouraged because of the risk of hemolysis and slower fill times. Such circumstances can lead to rejected specimens.6,7 Potential for repeat draws increases as the risk of compromised sample quality also increases.

Impact on patient satisfactionMultiple attempts to collect a specimen, as well as issues with pain or bruising, may negatively impact the patient’s phlebot-omy experience. An American Opinion Research (AOR) study (2012) indicated that one bad experience in blood collec-tion decreases patient satisfaction and may cause significant anxiety in future blood draws.4 The survey found that three-fourths of 200-plus patients reported that the phlebotomist had difficulty collecting their blood, and, of those, 90 percent

FUTURE BUZZ :: PHLEBOTOMY


48-51_MLO201809_FutureBuzz_BD&Randle.FINAL.indd 48 8/14/2018 4:59:24 PM

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Jean Tenuta, MS, MBA, MT(ASCP)DLM, SLS,

CQA(ASQ), serves as Medical Affairs

Specialist, Pre-analytical Systems,

for BD Life Sciences.

user experiencing a needle stick after collection is complete. Phlebotomist skill with using any device can influence device preference.8

Phlebotomists, faced with time constraints and the need to keep up with workload demands, look for ways to increase success rates on the first attempt. Patients with DVA can require up to 13 minutes of time dedicated to intrave-nous access, significantly higher than an average of 2.5 minutes to collect a sample routinely. If multiple attempts or multiple phlebotomists are required, that time commit-ment can increase to 30 minutes or more.9

Previous editions of the Clinical and Laboratory Standards Institute (CLSI) document GP41, Collection of Diagnostic Venous Blood Specimens, specifically discouraged phleboto-mists from using needles as small as the 25-gauge variety because of the risk of hemolysis and potentially slower blood flow. The seventh edition was modified to recognize that the interior diameters of needles vary. It states that use of 25-gauge needles should only be avoided if frequent hemolysis is observed.6

DVA can challenge even the most skilled phlebotomist. Awareness of the patient’s condition, as well as leverag-ing skill and available technology, can produce specimens of high quality and accurately reflect the patient’s clinical status. Higher patient satisfaction may also be achieved by minimizing the number of attempts, and incurring less pain or bruising.

REFERENCES

1. Witting MD, Moayedi S, Beverly SK, et al. Incidence of advanced intra-venous access in two urban EDs. Amer J Emerg Med. 2015; 33(5):705-707.

2. Fields JM, Piela NE, Au AK, Ku BS. Risk factors associated with difficult venous access in adult ED Patients. Amer J Emerg Med. 2014;32(10):1179-1182.

3. Paxton A. Sticking points: how to handle difficult blood draws. http://captodayonline.com/Archives/0311/0311e_sticking points.html.

4. American Opinion Research. Patient preference for blood collection devices. July 2012.

5. WHO. WHO guidelines on drawing blood: best practices in phlebotomy. WHO Press: Geneva, Switzerland. 2010 ISBN 978 92 4 159922 http://apps.who.int/iris/bitstream/handle/10665/44294/9789241599221_eng.pdf;sequence=1

6. Clinical and Laboratory Standards Institute (CLSI). Collections of Venous Blood Specimens, Standard GP41, 7th Edition. CLSI: Wayne, PA. April 2017. ISBN 1-56238-813-814.

7. BD White Paper VS9249. Evaluation of Tube Fill Time of the BD Vacutainer UltraTouch Push Button Collection Set with Thin Wall 3-Bevel Cannula. Becton, Dickinson and Company, Franklin Lakes, NJ.

8. Stankovic A. Putting patients first during blood collection. MLO. 2013;45(8):44-45: https://www.mlo-online.com/putting-patients-first-during-blood-collection.php

9. 2011 ENA Emergency Nursing Resources Development Committee, Crowley M, Brim C, Proehl J, et al. Emergency nursing resource: difficult intravenous access. J Emerg Nurs. 2012; 38(4):335-343.

10. The Lewin Group. The value of diagnostics: innovation, adoption, and diffusion into health care. Advanced Medical Technology Association, 2005. https://dx.advamed.org/sites/dx.adamed.org/files/resource/Lewin%20Value%of%20Diagnostics%20Report.pdf

11. Hotaling M. Efficacy of a retractable safety winged steel needle (butterfly needle performance improvement project). The Joint Commission Journal on Quality and Patient Safety; 2009;35(2):100-105.

DVA continued from page 48



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1 Mouser A, Uettwiller-Geiger D, Plokhoy E, Berube J, Ahuja AJ, Stankovic AK. Evaluation of pain and specimen quality by use of a novel 25-gauge blood collection set with ultra-thin wall cannula and 5-bevel tip design. J Appl Lab Med. 2017;2(2):201-210.



NGS instruments are, by and large, well…. large! They’re suited for use in a core lab environment, with samples (and subsequent libraries) coming to them. That is, of course, the successful common model for many lab instruments, but if you could imagine some application where you wish you could have NGS technology with you in your back-pack and deploy it in some remote or resource-limited set-ting—that’s not going to happen with any of the common NGS platforms.

NGS workflows require heavy bioinformatics servers just to handle the tiling steps. Tiling, as long-time readers of this series may recall, is where you take all of your short random fragment DNA (or RNA derived cDNA) reads, and look for ones that overlap. By placing these overlaps in sequence, longer and longer “contigs” (contiguous reads) can be assembled to place each short bit in its critical larger genomic (or transcriptional) context. It’s a com-putationally intensive task though, and one which can have challenges in reading through the longer stretches of repetitive DNA which are dotted about the average eukaryotic genome.

Nanopore sequencing to the rescue?The family of methods we examine today is known as nano-pore sequencing, and it has the promise of avoiding each of the downsides we just listed above. As the name suggests, nanopore sequencing is based on having a barrier of some sort with very tiny holes—the nanopores. Essentially the concept is that one dissolves DNA from a test sample into an electrically conductive buffer, with the individual molecules being very long. “Long” here is something of a relative term; we’re talking on the order of a million base pairs, which is pretty long compared to the 150-300 base pairs per readable fragment of most by-synthesis NGS systems, but pretty short compared to an intact human chromosome; for example Chromosome 11, near the middle of the cytogenetic pack, is ~135 million base pairs long. Just routine handling such as pipetting of an average DNA extract induces random chro-mosome fragmentation though, which conveniently means that a sample-like human cellular DNA is pretty much in the right size range by the time it’s collected and purified. This conductive solution with DNA is applied to one side of our barrier with pores, with conductive solution (without DNA) on the other. An electric current is applied with positive polar-ity to the no DNA side, and the DNA (being intrinsically nega-tively charged, due to the phosphate ions in the backbone) will try to migrate through the only available channels—the nanopores.

What’s critical here is that the pore sizes be very uniform, and small enough so that only one strand of the DNA can fit in and start spooling through at a time. Second, the pore

The promises of the Human Genome Project and person-alized medicine based on individual genomes are predi-cated on technologies to read out the said individual

genomes. Barriers to application have always been ones of cost and throughput, with the history of DNA sequenc-ing technologies routinely punctuated by relatively abrupt methodological and technological advances. In turn, each of these—from Maxam and Gilbert chemical sequencing, to isotopically labeled Sanger sequencing in slab gels, to fluores-cently labeled Sanger sequencing in capillary electrophoresis instruments, to massively parallel short read sequencing by synthesis approaches read out via pyrosequencing, ionic pulses, or fluorescent methods—has appeared, gone through rounds of optimization, and yielded more information more easily, faster, and cheaper per base pair than prior methods. (Note that these metrics are per base pair, not necessarily per reaction, which is why in today’s market of sub-$1,000 full human exome NGS services there’s still an active role for older methods such as capillary sequencing when you just want to know the sequence of a particular small region.)

None of these new methods has appeared complete and perfect overnight; each had to make the arduous trek from research lab bench through engineering, chemistry, and bioinformatics processing development and improvements to become reliable, mature methods suitable for clini-cal application. Similarly, what will probably be the next significant method change in sequencing technology has been working its way through this path for a few years now. So, it’s an opportune time to take a closer look at what that new method is, and what benefits it might bring to clinical sequencing. Nanopores are the core of this approach, but before we get into a look at the state of a few competing applications of this technology to sequencing, let’s pause to consider what some of the drawbacks are to the most widely used NGS methods today.

Drawbacks to NGSNGS instruments are expensive, requiring significant capi-tal investment. Regardless of platform, they’re pretty com-plex machines with high manufacturing costs that have to be recouped through a mix of base instrument purchase price and cost of any associated consumables.

NGS short-read-by-synthesis platforms require signifi-cant upstream handling of each sample for library prepa-ration: the genomic DNA must be sheared to billions of short pieces of a narrow-size window suited for analysis, and tagged with various linkers, adapters, and barcodes to allow each to be tracked and read through the process. Library preparation is relatively slow and painstaking, despite ongoing improvements in kits, reagents, and auto-mation of various workflow steps.

THE PRIMER :: MOLECULAR DIAGNOSTICS

The current (and future?)

state of nanopore NGSBy John Brunstein, PhD

52-53_MLO201809_Primer_FINAL.indd 52 8/13/2018 2:15:21 PM


THE PRIMER :: MOLECULAR DIAGNOSTICS

John Brunstein, PhD, is a member of the MLO

Editorial Advisory Board. He serves as President

and Chief Science Officer for British Columbia-

based PathoID, Inc., which provides consulting for

development and validation of molecular assays.

must have some observable and dif-ferentiable changes (usually electri-cal in nature) which occur as a given nucleotide slides through. Such pores do exist, both in the form of naturally occurring or slightly modified protein porins (such as human α hemolysin or Mycobacterium smegmatis porin A), or various controlled synthesis solid state materials including metals, metal alloys, and carbon nanotubes. Each of these pore types has its own strengths and weaknesses, such as uniformity of size, ease of manufacture, accuracy of base discrimination, and working lifespan; a significant part of nanopore sequencing becoming mainstream will likely be a convergence on one or at most a handful of pore types and pore cell production methods that effectively balance these issues.

In any event, we should now be picturing two wells of conductive buf-fer, a nanopore-perforated membrane in between, our bulk DNA sample on one side, and single DNA strands starting to poke through the pores. Under the influence of the electric field, these single strands extrude out into the positive buffer well at quite amazing speeds; it has been estimated that each individual base spends only a few microseconds within the sensing region of a pore, meaning our 1 mega-base fragment is totally through (and hopefully, read out) in a matter of a few seconds.

Once a pore is open, another waiting DNA molecule engages and starts translocating and being read. Assuming for the sake of argument that we’re able to accurately read and record the whole fragment at one pass like that, a single pore would be able to sequence our Chromosome 11 example in its entirety in something like nine minutes. If your barrier had 135 pores and each different Chromo-some 11 fragment magically went to a different pore, you’d get the entire sequence of someone’s Chromosome 11 in something like five seconds.

In current reality, challenges to this occur due to most pore systems not being able to accurately read every base as it spools through. Strategies to address this include modifying the pores to slow and restrict strand trans-location, and/or requiring multiple reads with consensus building to yield final accepted “output sequence.” While these approaches slow the process down, we’re also able to put many more pores (hundreds to even

low thousands per barrier) as a com-pensation, so speeds achievable with current nanopore systems are still very fast; more on that below.

Where we’re at todaySo where are we now with this technol-ogy, and how does it address the NGS issues raised above? Several companies are active in this space and have either prototypes or available-for-purchase devices, so let’s look at how these stack up at present.

Size, portability, and cost. The smallest and least expensive commer-cially available nanopore sequencer at present is just a bit larger than your average USB thumb drive; in fact, it even looks like a thumb drive, as it’s got a USB plug sticking out to port its data back to your data collection computer. Costing around $1,000, it’s essentially a disposable single-use device capable of providing several gigabases of read on a sample over 24 to 48 hours. While that’s not enough to sequence a human genome, it’s more than adequate for things like in-depth environmental microbial sam-pling or even capturing smaller whole genomes of some organisms. While that is the extreme in portability and can be used in field settings, larger core facility benchtop versions of the same platform have much higher through-put capacities into the terabase range.

Sample prep. No complex library preparation is required. Basically, puri-fied DNA or RNA sample of interest is mixed with conductive buffer at an appropriate concentration and applied to the device. Note “RNA” there: that’s right, no intermediate conversion to cDNA is required (although usual caveats about RNA instability apply). Sequence data collects “in real time” on the attached computer.

Read length. We’ve used a 1 million base length in our examples above; in reality, usual read lengths range from a few hundred kilobase to the current published record of 2.2 megabases. With 1 Mb being a reasonable mid-point to these values, it’s easy to see where this approach can both read through many repetitive regions at a single pass, and where much less bioin-formatics work is needed in tiling than on short-read systems.

Nanopores in the futureSo with all of these great features, why are sequence-by-synthesis NGS instru-ments still the standard of most core

labs? There are a number of factors here, with probably no single answer. A major point, however, is that nanopore systems at present don’t equal NGS instruments’ level of accuracy per read. In a clinical setting, accuracy remains a paramount concern. Sheer read depth (number of repeat reads) can be used to increase confidence levels in nano-pore-based data, but this comes at the expense of longer run times and higher costs. The high capital costs of main-stream NGS instruments can be amor-tized out over truly massive data collec-tions, making them cost-effective on a per-base metric. Since most molecular methods are already restricted to being done in clean, well-equipped core facilities, we’re used to adapting exper-imental workflows to remote sample collection and in-facility analysis. This means that for many purposes, lack of portability in an NGS sequencer is not a significant detriment.

Nanopore-based methods continue to show signs of accuracy improve-ment, however, and within the last few months they’ve been demon-strated to be capable of generating entire human genome sequences1 at acceptable accuracy levels, albeit with some contribution from traditional short-read methods. In fact, in the near future, the best approach for NGS may well be a hybrid combination of short-read high-accuracy methods, with nanopore long reads constructing scaffolding on which to place these shorter reads and by which to work through long repetitive stretches. And if nanopore-based methods can be fur-ther refined to improve accuracy and increase pore system lifespans, they will probably start to play an increas-ingly primary role in human sequenc-ing applications with clinical signifi-cance. If we’re to reach a point where part of every routine medical visit is a “full genome workup,” done in a few hours, we’ll have to make a quantum jump in technology from sequence by synthesis methods. For now, nano-pore approaches look like the most promising way to make the leap.

REFERENCE

1. Jain M, Koren S, Miga KH, et. al. Nanopore sequencing and assembly of a human genome with ultra-long reads. Nature Biotechnology 2018;36(4):338-345.

52-53_MLO201809_Primer_FINAL.indd 53 8/13/2018 2:15:22 PM


Table 1. Cost by season


Time Period Pos/Pos+ Neg Positivity Rate Cost/PositiveRelative Cost

Index

Dec-April 470/237+7 20% $425 1x

May-November 8/353 2% $3,698 8.7x

June-August 0/20 0% N/A N/A

How the clinical laboratory can contribute to providing value-based healthcareBy Don Barton, MS, MT(ASCP), and Marie Rath

our study by analyzing how many tests were ordered over the years, months, age distribution, gender, and flu type. Gathering and processing this information was straight-forward and did not involve the need for any specialized support from any outside group, but was a shared project between laboratory and IT departments. The key finding that helped answer our question was derived when we looked at the number of positive tests compared to the total number of tests ordered (positivity rate) by month, or how many tests must be run before a positive result is found. So, if one test out of five ordered was positive, and each test cost $40 to run, then the cost to the community for the diagnosis of a positive result was $200. We deter-mined the cost figure by including the hands-on time to run the test at $25/hour (that includes an average of MT and MLT wage) plus the cost of the kit. These numbers are readily determinable by any laboratory.

The question and the answer When charted, our results told us immediately of an oppor-tunity. For each of the five years, we found three consistent times or zones of positivity. The highest zone of positivity was obviously during “flu season” and for our geographic area (rural western Colorado) was between December and April. The second zone of positivity was May to November, which was significantly lower. The third zone was a sub-set of the second zone and was the summer months from June through August. This zone showed no positive results and had the fewest tests run by month, which was to be expected. Table 1 shows the positivity rates by time period.

Each positive result during the flu season cost the community $425 (one in five tests). During the non-flu season (April to November) as defined by our study, that cost jumped 8.7-fold to $3,698 to diagnose a positive result (one in 37 tests). During the summer months, there were no positives at all, even though some tests were still ordered.

These findings suggest that a more judicious use of influ-enza testing during the non-flu season months could save

healthcare dollars for the community. In addition, based on the five-year trends, the recommendation should be to not test for influenza during the summer months.

The lab’s important roleIt is important to understand that the laboratory does not dic-tate what test should be performed or not (for the most part)

The future of healthcare will put patient health out-comes at the center of reimbursement—a concept that is commonly known as value for service. Even as

far back as 2009, Michael Porter wrote in the New England Journal of Medicine, “The central focus must be on increas-ing value for patients—the health outcomes achieved per dollar spent.”1

How, for decades, a volume-based reimbursement model survived and even flourished—while increasingly leaving more and more people financially unable to get adequate medical coverage (if any at all)—is a huge topic in itself. This leads to the issue raised by the title of this article.

It seems that in the current climate many are waiting for the government to guide the healthcare delivery system along this path, but private industry is also taking the lead. Recently industry giants Amazon, Berkshire Hathaway, and Chase formed a healthcare alliance with the goal of “creating an independent company that is free from profit-making incentives and restrictions”2 in an attempt to bring affordable healthcare to their employees. In addition, the state of Colorado recently attempted to move ahead of any Federal mandate by trying to implement its own solutions to lower healthcare costs.3 Clinical laboratories, regardless of where they are located, can contribute now to this new value-based healthcare for their communities.

Finding value in dataIf laboratories have a lot of anything, it is data. For years, we have been pushing data out to paper, providers, public health departments, and EMRs. Throw in Health Infor-mation Exchanges, Accountable Care Organizations, and whatever comes next, and it seems that everyone wants what we have to offer. Unfortunately, we often do not real-ize the value of the data we create each day and how we can use it. The key to finding value in the data starts in the questions we are asking of it.

For our laboratory, affiliated with Delta County Memorial Hospital in Delta, Colorado, we identified two very straightforward criteria: (1) the data must be quantifi-able; and (2) it must save the community money. We then sought an answer in the data to a specific question: “How much does a positive influenza A and B test result cost the community?” Harvesting the data was not quite as straightforward as we had anticipated, as the influenza test changed departments from microbi-ology to the main laboratory during the study. However, that was only a small set-back and did not influence the outcome.

Gathering the dataWe started with a 2016-2017 seasonal review of influenza A and B test results and presented our findings to hospital administration. They were impressed by our presentation and asked us to expand our study to include the last five years (2012-2017). We looked at the numbers and structured

MANAGEMENT MATTERS: FLU TESTING

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continued on page 58SEPTEMBER 2018 MLO-ONLINE.COM56


Don Barton, MS, MT(ASCP), is a

laboratory informaticist at

Delta County Memorial Hospital in Delta, CO.

Marie Rath is a Systems Engineer at Delta County Memorial Hospital in Delta, CO.

but may play an important role in proposing ways for better test ordering practices through analytic studies. This simple study looking at seasonal ordering patterns and positivity rates for influenza testing is just one example of the way labo-ratories may contribute by sharing cost-saving information and better outcomes to providers in their local communities. The decision to determine which laboratory tests to perform and when is still the providers’ responsibility.

Earlier in the now-fading era of payment by volume, this information would not have been of interest to providers or administration, as it would have meant a reduction in an almost guaranteed reimbursement. However, as we move to a value-based reimbursement model, it is not just a matter of how we get paid. Human labor resources, time, and supplies all come into play as we try to reduce healthcare costs and save money for our communities while we provide exceptional levels of healthcare. While the exact definition of “value” is still a work in progress and will no doubt continue to evolve, laboratories can play a significant role in contributing to this goal now without waiting for top-down mandates from fed-eral or state officials. By analyzing the data we have, and sug-gesting more effective test utilization for our providers, we can contribute to reducing unnecessary costs to our communities and at the same time improve the efficiencies and value of the delivery of healthcare.

Editor’s note: ‘Tis the season—the flu season, that is, and labs will soon be

busy with all the diagnostic testing that requires. In the meantime, here’s a

roundup of some recent research news.

Obesity extends duration of flu A virus sheddingObesity, which increases influenza disease severity, also

extends by about 1.5 days how long influenza A virus is

shed from infected adults compared to non-obese adults,

according to a multi-year study of two cohorts of Nicara-

guan households. The findings implicate chronic inflamma-

tion caused by obesity as well as increasing age as reasons

for extended viral shedding, which puts others at risk of

infection.

The National Institute of Allergy and Infectious Diseases

(NIAID), part of the National Institutes of Health (NIH), pro-

vided primary study funding through its Centers of Excel-

lence for Influenza Research and Surveillance (CEIRS) pro-

gram. University of Michigan researchers coordinated the

study in collaboration with colleagues at the Nicaraguan

Ministry of Health, the Sustainable Sciences Institute in

Nicaragua, and the University of California-Berkeley.

The researchers monitored 1,783 people from 320 house-

holds in Managua, Nicaragua, during the three flu seasons

between 2015 and 2017. Overall, 87 people became ill with

influenza A and 58 with influenza B. As defined by body

mass, obesity was found in two percent of the people up to

age four, nine percent of those ages five to 17, and 42 per-

cent of those ages 18 to 92. Obese adults with two or more

symptoms of influenza A (n=62) shed the virus 42 percent

longer than non-obese adults—5.2 days, compared to 3.7

days. Obese adults with one or no symptoms of influenza

A (n=25) shed the virus 104 percent longer than non-obese

adults—3.2 days compared to 1.6 days. Obesity was not a

REFERENCES

1. Porter M. A strategy for healthcare reform—toward a value-based system. N Engl J Med. 2009;361:109-112.

2. Industry Watch: Amazon, Berkshire Hathaway, Chase form health-care alliance. HMT. 2018;39(2):4. https://www.healthmgttech.com/industry-watch-%e2%80%93-marapr-2018

3. Ingold J. ColoradoCare measure amendment 69 defeated soundly. The Denver Post.. November 9, 2016.

risk factor for increased viral shedding duration in children

ages five to 17 or for adults with influenza B.

According to the researchers, the amount and duration of

viral shedding likely affects how efficiently influenza viruses

are transmitted to others. Obesity alters the immune system

and leads to chronic inflammation, which also is known to

increase with age. The authors propose that chronic inflam-

mation caused by obesity may be responsible for increased

influenza A viral shedding. The researchers are continuing

to study the correlations among obesity, inflammation,

and viruses. However, they note that reducing obesity rates

could be an important target to limit the spread of viral infec-

tious diseases. The study also notes that obesity rates range

widely throughout the world: in 2014, adult obesity in the

United States was 35.5 percent, compared to 17.4 percent

in Nicaragua and 4.4 percent in other low-income countries.

Clues for improved influenza vaccine designInfluenza vaccines that better target the influenza surface

protein called neuraminidase (NA) could offer broad protec-

tion against various influenza virus strains and lessen the

severity of illness, according to new research published in

the journal Cell. Current seasonal influenza vaccines mainly

target a different, more abundant influenza surface protein

called hemagglutinin (HA). However, because influenza

vaccines offer varying and sometimes limited protection,

scientists are exploring ways to improve vaccine effec-

tiveness. The new research builds on previous studies

of NA and was conducted by a team of scientists including

investigators from the CEIRS program.

Investigators analyzed blood samples from people who

were vaccinated against influenza and people diagnosed

with either the 2009 H1N1 influenza virus or H3N2 influenza

Influenza research updateBy MLO staff



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risk of influenza complications. The influenza vaccine is

annually updated to adapt to the rapid virus evolution. It is

the only vaccine that is recommended on an annual basis.

For people in the risk groups, influenza could lead to

pneumonia and exacerbation of chronic underlying dis-

eases. Influenza can result in hospitalization, and in the

elderly this may lead to institutionalization and, in the most

severe cases, death. “That is why it is so important that we

can continue to recommend annual vaccination, especially

now that we know that it does not prevent natural immu-

nity,” says Cox.

How flu shot manufacturing forces virus to mutateAccording to a new study from scientists at The Scripps

Research Institute (TSRI), the common practice of growing

influenza vaccine components in chicken eggs disrupts the

major antibody target site on the virus surface, rendering

the flu vaccine less effective in humans.

“Now we can explain—at an atomic level—why egg-

based vaccine production is causing problems,” said TSRI

Research Associate Nicholas Wu, PhD, first author of the

study, published recently in the journal PLOS Pathogens.

For more than 70 years, manufacturers have made the

flu vaccine by injecting influenza into chicken eggs, allow-

ing the virus to replicate inside the eggs, and then purifying

the fluid from the eggs to get enough of the virus to use in

vaccines.

The subtype of influenza in this study, H3N2, is one of

several subtypes shown to mutate when grown in chicken

eggs, and the researchers say the new findings add sup-

port to the case for alternative approaches to growing the

virus.

“Any influenza viruses produced in eggs have to adapt

to growing in that environment and hence generate muta-

tions to grow better,” explains study senior author Ian Wil-

son, D.Phil.

The new study shows exactly why egg-based manufac-

turing is a problem for the H3N2 subtype. As H3N2 influ-

enza has become more prevalent, scientists formulating

the seasonal flu vaccine have sought to include this virus

and teach the human immune system to fight it. Despite

this effort, recent flu vaccines have proven only 33 percent

effective against H3N2 viruses.

Wu used a high-resolution imaging technique called

X-ray crystallography to show that—when grown in eggs—

the H3N2 subtype mutates a key protein to better attach to

receptors in bird cells. Specifically, there was a mutation

called L194P on the virus’s hemagglutinin glycoprotein

(HA). This mutation disrupts the region on the protein that is

commonly recognized by our immune system.

This means a vaccine containing the mutated version of

the protein will not be able to trigger an effective immune

response. That leaves the body without protection against

circulating strains of H3N2.

In fact, Wu’s analysis shows that the current strain of

H3N2 used in vaccines already contains this specific muta-

tion L194P on HA. “Vaccine producers need to look at this

mutation,” cautions Wu.

The researchers say that further studies are needed to

investigate replacing the egg-based system. “Other meth-

ods are now being used and explored for production of

vaccines in mammalian cells using cell-based methods and

recombinant HA protein vaccines,” says Wilson.“There’s a

huge need for flu vaccine research,” adds Wu.

viruses. The volunteers were recruited for this study or had

taken part in prior influenza research studies. The analyses

indicate that influenza vaccines rarely induce NA-reactive

antibodies, whereas natural influenza infection induces

these types of antibodies at least as often as it induces HA-

reactive antibodies. Additional studies in mice reinforced

the human data, indicating that current influenza vaccines

do not induce NA-reactive antibodies efficiently.

Additional laboratory experiments show that the NA-

reactive antibodies induced during natural influenza infec-

tion are broadly reactive, meaning they could potentially

protect against diverse strains of influenza. To test this theory,

scientists isolated NA-reactive monoclonal antibodies from

the H3N2 and H1N1 influenza patients (N2-reactive antibod-

ies and N1-reactive antibodies, respectively). They adminis-

tered 13 N2-reactive antibodies to mice and subsequently

infected the mice with a different H3N2 virus strain. Eleven

of the 13 N2-reactive antibodies partly or fully protected the

mice. They also administered eight N1-reactive antibodies

to mice and subsequently infected the mice with a similar

H1N1 virus strain or an H5N1-like virus strain. Four of the

eight antibodies completely protected the mice against both

virus strains.

The authors note that the findings suggest that influenza

vaccines should be optimized to better target NA for broad

protection against diverse influenza strains. In this regard,

NIAID is supporting research to characterize NA responses

in infected and vaccinated individuals and to determine the

mechanism of action of NA protection. NIAID also supports

“NAction!” a CEIRS working group that identifies knowl-

edge gaps in our understanding of NA and sets NA research

priorities for improved influenza vaccines. These efforts con-

tribute to NIAID’s larger plan to develop a universal influenza

vaccine—a vaccine that can durably protect all age groups

against multiple influenza virus strains.

Annual vaccination doesn’t prevent natural immunityEarlier studies have suggested that having repeated annual

influenza vaccination can prevent natural immunity to the

virus, and potentially increase the susceptibility to influ-

enza illness in the event of a pandemic, or when the vaccine

does not “match” the virus circulating in the community.

But now, researchers at the Influenza Centre in Bergen

(Norway) have published an important study which con-

cludes that annual influenza vaccination does not increase

susceptibility to influenza infection in years of vaccine

mismatch.

These findings are important because they show that

having annual influenza vaccination is only a positive

thing, and they support continuing the policy of repeated

annual vaccination, says Professor Rebecca Cox, Head of

the Influenza Centre.

Over a period of five years, researchers at the Centre

followed 250 healthcare workers. They were vaccinated

in 2009, and either had annual vaccination in all subse-

quent seasons or no further vaccination between 2010

and 2013. Three thousand blood samples were collected.

The results showed that both healthcare workers who

had annual vaccination and those who were not annu-

ally vaccinated had the same second-line defense, but

those who had gotten annual vaccines had a better

first-line defense. The group that had annual vaccination

were not prevented from developing natural immunity

Almost 1.5 million people in Norway have an increased



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QC and result management software The soon-to-be-released Atellica Data Manager from Siemens Healthineers operationalizes lab data to standardize testing, opti-mize quality control (QC) performance and maximize the potential of autoverifica-tion while reducing operator interventions, unwarranted variations, and errors. Open and scalable, Atellica Data Manager is built on the pow-erful CentraLink solution which has been used by more than 1,000 laboratories to optimize clinical operations, increase testing volumes, and improve turnaround times. This QC and result management software delivers the clinical details needed for informed decisions using a distinctive and intuitive new user interface.Siemens Healthineers, www.rsleads.com/809-154

LIS for AP labs conducting NGS Sunquest PowerPath and Sunquest CoPathPlus can now be integrated with the Sunquest Mitogen Genetic Analysis tool. With the availability of this integra-tion, AP labs conducting nest-generation sequencing (NGS) can benefit from inte-grated, actionable report-ing, combining the power of pathology-focused LIS and genetic variant anno-tation and interpretation offering. Labs inte-grating AP and genetic reporting will benefit from single, integrated reports delivered by the Sunquest AP solution that a) combines pathology and genetic testing results; b) eliminates manual and duplicate data entry in multiple systems; and c) grants contextual access to results. Sunquest, www.rsleads.com/809-155

LIS for smaller and start-up labsThe xLab Starter LIS is a very cost-effective com-plete laboratory informa-tion system (LIS) that includes all of the features and benefits of the xLab LIS. The xLab Starter is designed specifically for smaller and start-up labs and includes: one instru-

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Optimize revenue, workflowCGM LABDAQ from CompuGroup Medical (CGM) is an evolved LIS (laboratory information system) that leverages a modern platform and decades of experience. CGM LABDAQ empowers labs of all sizes to optimize revenue and improve customer retention by increasing efficiency, streamlining workflow, reducing turnaround times, and promoting patient safety. Rules-based technology supports compliance with best practices. Order routing rules can automatically order reference lab vs. in-house tests based on patient insurance to ensure reimbursement and minimize denials. Instrument

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Deepak NathPresident

Laboratory DiagnosticsSiemens Healthineers

Professional

I began leading the global Laboratory

Diagnostics business for Siemens

Healthineers in February 2018. Prior to that,

I was president of Abbott’s Vascular division

and an executive officer of the company.

Education

My degrees are all from the University of

California at Berkeley. I hold BS and MS

degrees in Mechanical Engineering and a

PhD in Theoretical Mechanics.

Personal

I am an avid reader and enjoy spending time

with family and friends.

shortage and aging population have been challenges for quite some time. These challenges equate to an increasing workload—without sacrificing turnaround time—with less financial and staffing support. Recognizing the impending chal-lenges, we began rolling out automated solutions with varying capabilities to support laboratories with their growing operations, with workflow efficiencies and automations at several levels: automation within the analyzer environment; in multi-disciplinary solutions; and managing data, inventory, processes, and connectivity.

Total laboratory automation can be a significant investment to undertake at one time, however, so we’ve also deployed a number of resources and scalable solu-tions to transition laboratories into auto-mation. Innovative instrument features on our Atellica Solution, such as automated quality control and calibration, sophisti-cated vision systems, intelligent sample management and test scheduling, and bidirectional magnetic sample transport technology, help labs optimize the work-loads of highly skilled operators. Less hands-on time for routine tasks maximizes existing resources to help refocus skilled attention in higher-value activities in the lab, and may reduce the need for additional operators as laboratory operations grow.

Please describe the career path that has led you to your current position at Siemens Healthineers. Prior to my current role as President of the Laboratory Diagnostics business for Siemens Healthineers, I was president of Abbott’s Vascular division and executive officer of the company. My 10-year career with Abbott comprised a variety of global leadership roles, includ-ing president (and corporate officer) of the molecular diagnostics division, divisional vice president, and general manager of Ibis Biosciences, and several commercial leadership positions across mature and emerging markets.

Earlier in my career I held positions at Amgen, where I led process improve-ment initiatives, and at McKinsey, where I worked with a range of clients in the medical device and pharmaceutical industries. Before that, I was a scientist in the computational physics group at the Lawrence Livermore National Laboratory.

Today the clinical laboratory industry is facing both regulatory and reimburse-ment challenges. How do these impact Siemens Healthineers and its custom-ers? Regardless of the instrument or offering, Siemens Healthineers is focused on outcomes that matter most to our customers and being a valuable partner to them on that journey. We aim to serve as a trusted partner for labora-tories worldwide by closely observing laboratory trends and understanding our customers’ pain points. With this infor-mation we are able to respond through continuous investment in technology and innovation. The result is a wide range of options that fulfill and often anticipate the needs of laboratories worlwide.

Another challenge the industry faces is the aging lab workforce and the result-ing shortage of skilled laboratorians. How can current and future technolo-gies address this problem? The staffing

Deepak Nath drives strategy and operations for Siemens Healthineers Laboratory Diagnostics

EXECUTIVE SNAPSHOT :: BY ALAN LENHOFF, EDITOR

My experience in the medical technology field, and in the areas of strategy, sales, operations and R&D, have equipped me well for the role of overseeing and driving strategy, operations, R&D, and sales and marketing globally for the Laboratory Diagnostics business area of Siemens Healthineers.

What skills, professional, interpersonal, or otherwise, are vital for a position like yours? My position requires extensive cross-functional operational experience, and a deep understanding of the clini-cal laboratory space, the instrument and assay technologies, and the dynamics of the healthcare market worldwide.

From a personal perspective, it requires the ability to align a large and globally dis-tributed organization toward a common goal and genuinely inspire others to do their best. I am fortunate that the business principles at Siemens Healthineers are aligned with my own personal principles, and that I can count on professional, dedi-cated people who love what they do and are proud of the company they work for.

What role do you play in managing prod-uct launches? Product launches are a key area of focus and responsibility for me. I oversee all aspects of product launches—whether instrument, assay, automation, or IT—from the points of conception and R&D, to marketing and sales, to pricing, to implementation and service.

In the case of Atellica Solution, we think that we have brought to the market a true game-changer, which requires a new way of selling, implementing and integrating into our customers’ labs. As such, operationalizing new approaches has been instrumental to drive prefer-ence and adoption, and to drive success-ful installations and delight laboratory customers. Our customers emcompass reference labs, hospitals, healthcare net-works, and teaching hospitals, all with dif-ferent priorities and business objectives. From this perspective, the enablement of the sales force and the readiness of the implementation and service organization are continuous areas of investment and focus for our organization. This interview continues online at mlo-online.com, Executive Snapshot, Sept.

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