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January/February 2020
DOUBLED
D-DIMER
THRESHOLD
LOWERS
NEED FOR
IMAGING
30%
BY
Clinical
Laboratory
News
PAGE 6
An AACC Publication | Volume 46, Number 1
SHAPING The Rise of
Metagenomics
YOUR
CAREER CAR-T Cell
QUEST Therapy:
The Lab
Connection
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JA NU A RY/ FE BR U A RY 2020 CONTENTS 1
www.aacc.org
EDITORIAL STAFF
Managing Editor Bill Malone 8 Metagenomic Next-generation Sequencing
Senior Editor Genna Rollins Modern Tool for Diagnosing Infectious Diseases
Senior Manager, Communications and PR
Christine DeLong
BUSINESS STAFF 14 No Wrong Turns
Business Communications Specialist How Clinical Laboratory Scientists Shape Careers to Match Their Passions
Ana Zelada
Board of Editors
Chair
20 CAR-T Cell Therapy From a Clinical Laboratory Perspective
Danyel Tacker, PhD, DABCC, FAACC Careful Monitoring Before and After Infusion Is Critical to
West Virginia University, Morgantown, W.Va. Successful Treatment
Members
Dustin Bunch, PhD, DABCC
Nationwide Children’s Hospital, Columbus, Ohio
8
Sara Love, PhD, DABCC
Hennepin Healthcare, Minneapolis, Mn.
Mark Marzinke, PhD, DABCC, FAACC
Johns Hopkins University School of Medicine,
Baltimore, Md.
Alison Woodworth, PhD, DABCC, FAACC
University of Kentucky Healthcare, Lexington, Ky.
Melanie L. Yarbrough, PhD, DABCC, DABMM
Washington University School of Medicine,
St. Louis, Mo.
AACC Officers
President Carmen L. Wiley, PhD, DABCC, FAACC
President-Elect David G. Grenache, PhD, DABCC,
MT(ASCP), FAACC
Treasurer Steven Kazmierczak, PhD, DABCC,
FAACC
30
Secretary Anthony A. Killeen, MD, BCh, PhD,
DABCC, FAACC
Past President Dennis J. Dietzen, PhD, DABCC,
FAACC
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Editorial Correspondence
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Phone: +1 202.835.8756 or +1 800.892.1400
Email: bmalone@aacc.org
Clinical Laboratory News (ISSN 0161-9640) is published
monthly (10 times per year—Jan/Feb., March, April,
14
May, June, July/August, Sept., Oct., Nov., and Dec.) by
the American Association for Clinical Chemistry. 900
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Phone: +1 202.835.8756 or +1 800.892.1400 Fax:
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Design and Production Management Departments Hereditary thrombophilia
2 Federal Insider
testing is generally
4 Bench Matters
reserved for children
6 The Sample
26 Special Section:
with unprovoked
Lab Stewardship Focus
thrombotic episodes
Cover: LaylaBird / iStock
30 Regulatory Roundup and a family history of
The full text of Clinical 32 Industry Playbook thrombosis. It is usually
Laboratory News can
be found on EBSCO’s 36 Ask the Expert not recommended if
@ CLN_AACC
CINAHL Complete
database and is also
searchable via the EBSCO
a thrombotic episode
Discovery Service™
is provoked by strong
risk factors.
p36
2 J A NU A RY /F E B R U A RY 2020
Hospitals Challenge Price Transparency Rule
Hospital groups took legal action to oppose a new rule from the Centers for Medicare
and Medicaid Services (CMS) that greatly expands price information available to
Federal Insider consumers for everything from laboratory tests to surgeries. Notably, the rule requires
that hospitals not only publish online their standard charges for all services but also
all payer-specific negotiated rates for their services, which the American Hospital
Association (AHA) said will confuse patients.
“Today’s rule mandating the public disclosure of privately negotiated rates between
commercial health insurance companies and hospitals is a setback in efforts to provide
patients with the most relevant information they need to make informed decisions
about their care,” AHA and several other hospital groups wrote in a joint statement.
The legal challenge from AHA and hospitals argues that the rule exceeds the adminis-
tration’s authority.
According to CMS administrator Seema Verma, however, the rule will increase com-
petition and reduce healthcare costs for consumers. “Under the status quo, healthcare
prices are about as clear as mud to patients,” she said. “Today’s rules usher in a new era
that upends the status quo to empower patients and put them first.”
The final rule will require hospitals to make prices public in two ways beginning
in 2021. Hospitals will have to make public all charges—including payer-specific
negotiated charges—via a comprehensive machine-readable file that includes
billing codes. This will allow anyone with the proper software to easily analyze
and publish data for use by consumers.
In addition, hospitals will have to display online so-called shoppable services
in a consumer-friendly manner, including payer-specific negotiated charges, the
amount the hospital is willing to accept in cash from a patient, and the mini-
mum and maximum negotiated charges for 300 common shoppable services.
Shoppable services are those that the consumer could schedule in advance, such
as laboratory testing or a bundle of services like cesarean delivery.
The rule also gives CMS enforcement tools including monitoring, auditing, cor-
rective action plans, and the ability to impose civil monetary penalties of $300 per day.
■ this proposal, if adopted, would further previously been tested with this method,
AACC CALLS FOR IMPROVED limit the ability of patients to obtain which would limit somatic cancer
COVERAGE OF CERTAIN CANCER appropriate, evidence-based assessment testing. “While repeat testing of genes
TESTS of their hereditary risk for breast or for hereditary risk of cancer should not
A ACC is calling on the Centers for
Medicare and Medicaid Services
(CMS) to make significant changes to
ovarian cancer,” the association said.
In addition AACC is concerned with
the agency’s decision to consider breast
be covered, NGS testing to assemble
a somatic profile of a patient’s cancer
is appropriate and should be covered,”
its proposed national coverage determi- and ovarian cancers together as if they AACC wrote. “Determining the molecu-
nation for next-generation sequencing were synonymous. AACC commented lar profile of an advanced cancer can
(NGS) for Medicare beneficiaries with that “many clinical trials assess only specifically dictate treatment and several
advanced cancer. The CMS proposal one cancer type without the other. It is FDA-approved treatments necessitate
would limit Medicare payment for important to note that although breast biomarker measurement.”
breast and ovarian cancer tests to those and ovarian cancer have similarities Finally, AACC recommended that
ryasick / E+ / Getty Images
cleared by the Food and Drug with respect to gene mutations and CMS focus on the clinical indications
Administration (FDA). hereditary risk, there are important with sufficient evidence based on pub-
In a comment letter to CMS, AACC differences in how the two cancers orig- lished practice guidelines rather than
noted that currently FDA has not inate and develop within individuals.” a specific laboratory technology. CMS
cleared nor approved any NGS tests The association also took issue with should use existing guidelines to establish
for hereditary risk assessment of either the CMS decision in the proposal not the coverage policy for cancer type,
condition. “We are also concerned that to cover NGS testing if a patient has genetic alteration, and treatment option.
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4 J A NU A RY /F E B R U A RY 2020
How to Keep Multisite Multi-
Analyzer Validations on Track
Bench I n multisite healthcare organizations, a patient might
present for testing at different laboratory sites during
considerations for assay mapping
include testing volume and required
Matters a single healthcare episode or between healthcare visits,
healthcare providers might practice at multiple locations, and
turnaround time for the test,
specimen stability, and potential for
individual laboratory sites might require operational backup. sample and reagent carryover.
For each of these scenarios, laboratory results are expected to
be sufficiently comparable to ensure optimal care. Multi- THE TEAM
analyzer, multisite validation to ensure comparable patient Our core validation team members
results is not only a good laboratory practice, but also a included staff who perform the stud-
regulatory requirement. ies, and those who manage the data,
Thorough planning, well-documented validation protocols, review, and approve results. We gained
a multidisciplinary team effort, and detailed communications from the knowledge and experience
to all stakeholders will keep a complex multisite multi- of some team members who work at
analyzer validation on track. Here, we describe the approach a single site and others who perform
we took in planning the validation of three automated duties at several sites, such as clinical
platforms across five Ontario sites at LifeLabs, the largest biochemists and IT specialists. The
community laboratory in Canada. Our validation at two large complexity of implementing many
central sites each with 15,000 to 20,000 daily test volume analyzers at multiple sites also requires
and three regional sites each with 1,000 to 6,000 daily test significant involvement from other
volume included 23 analyzers covering 45 assays from a teams, like facilities, procurement,
single chemistry platform, and 28 analyzers covering 27 assays automation specialists, and vendors.
across two immunoassay platforms. We also validated two We found it particularly helpful to
automation lines at two central laboratories. designate a project manager who had
Danijela insights into the operations at all loca-
Konforte, PhD, THE PROTOCOL tions and who knew our validation
FCACB A documented validation protocol outlines the planned and implementation requirements.
validation studies, and we advise having a single validation This individual planned the project
protocol for each platform that is to be validated. The
protocol should be comprehensive and specific, including
detailed step-by-step procedures for each study.
This eliminates variability in how the studies are
performed and allows for adequate comparisons
across the sites. The protocol should include
defined acceptance criteria for each study,
as decided by the lab director. We also
Kika Veljkovic, recommend that each protocol be
PhD, FCACB discussed and formally approved by
MR.Cole_Photographer / Moment / Getty Images
internal stakeholders at each site, since
large scope validation studies come with
a significant resource commitment and
substantial cost. In our experience it
also helps to share validation protocols
with vendors to make them aware if the
validation acceptance criteria are different
from vendor-stated ones and to ensure
easier, faster troubleshooting.
As part of our validation protocol, we
also decided which assays to validate at which
sites and on which analyzers—this is sometimes
referred to as “assay mapping.” Some important
JA NU A RY/ FE BR U A RY 2020 5
Paul Bradbury / Caiaimage / Getty Images
timelines, ensured team communica- sample volumes for the number of multiple sites are involved. In addi-
tions and the pace of validation and, in analyzers to be validated and studies to tion to daily or weekly touch-point
a way, kept the whole team accountable be completed. Sample concentrations meetings, we used validation progress
throughout the validation. should cover the analytical measure- spreadsheets to show visually where
Using a staggered validation ment range. Aliquots might need to sites were in process, assigning colors
approach, in which one site performs be prepared, stored, and transported to validation steps—for example, study
valid ation prior to another site, reduces between sites while preserving sample in progress (yellow); study completed
the number of staff required for valida- stability. Since there could be several (green); follow-up needed (red); etc. In
tion at any one time and puts less stress dozen assays and several analyzers vali- addition, we sent automatic emails to
on laboratory operations overall. This dated simultaneously, we recommend inform all team members each time a
strategy also enabled us to promptly using inventory spreadsheets to log validation stage changed. This enabled
discover and mitigate issues before available samples and concentrations prompt engagement of the accountable
we moved on to validations at other for each assay. team members at each validation stage.
sites. To ensure the entire project has Data management can be a big These activities, although requir-
adequate resources, we suggest identify- validation bottleneck. In multi-analyzer ing considerable time and effort, allow
ing key operators for each platform validations, there could be thousands for a well-coordinated and successful
and group of analyzers. The in-depth of data points from a single validation multisite multi-analyzer validation. This
training they receive from vendors can study, so labs should plan to automate enables adequate assessment of test
be leveraged for internal training of the data management as much as possible. result comparability, ensuring standard-
remaining operators at all sites. For example, data can be exported from ized, high-quality patient care across all
analyzers into validation spreadsheets in sites of the organization.
VALIDATION SAMPLES AND DATA .csv files. We also recommend that labs
MANAGEMENT take advantage of statistical software Danijela Konforte, PhD, FCACB, and
We advise labs to start collecting valida- packages like Excel with Analyse-it, EP Kika Veljkovic, PhD, FCACB, are
tion samples early—including patient Evaluator, and R. clinical biochemists at LifeLabs Medical
samples, proficiency testing materials, Laboratory Services in Toronto,
reference materials, and spiking materi- COMMUNICATION Ontario, Canada.
als—that will be needed based on each Communication matters with any +EMAIL: Danijela.Konforte@lifelabs.com;
validation protocol. Plan sufficient validation, but even more so when Kika.Veljkovic@lifelabs.com
S
6 J A NU A RY /F E B R U A RY 2020
Raising D-dimer Threshold Cuts Need for Chest Imaging
by 30% in Suspected Pulmonary Embolism
Raising the D-dimer threshold for patients with low or moderate clinical
pretest probabilities of pulmonary embolism (PE) effectively rules out PE
and reduces the need for chest imaging by one-third (N Engl J Med 2019;
381:2125–34).
The Sample The primary goal of diagnostic testing for suspected PE is to determine
which patients should be treated with anticoagulants and which should not,
according to investigators in the Pulmonary Embolism Graduated D-Dimer
study. Current practices generally rule out PE in patients with low clinical
pretest probabilities when they have D-dimer results
JA NU A RY/ FE BR U A RY 2020 7
■ system, which is based on Cerner’s 95. When at
SEPSIS DIGITAL ALERT SYSTEM St. John Sepsis Algorithm. Initially least three of the criteria were met,
IMPROVES 3 KEY OUTCOMES this integrated part of Imperial’s an alert would fire.
I mplementation of a digital sepsis
alert system in a multisite U.K.
hospital network was associated with
electronic health record (EHR) ran in
silent mode, during which alerts were
not visible to clinical staff, then was
Similarly the system would fire
an alert for suspicion of severe
sepsis when two or more of these
improved outcomes—including low- switched to live mode. The implemen- criteria were met along with at
ered odds of 30-day mortality across all tation started in inpatient units, before least one criteria indicative of organ
patients (0.76 odds ratio)—and shorter spreading to emergency departments, dysfunction, including: serum creati-
hospital length of stay and more timely hematology units, and finally all other nine increase over baseline ≥0.5 mg/
start of antibiotics for patients who inpatient units. dL (72 hr lookback); total bilirubin
alerted in emergency departments Coupled with the alert system, ≥2.0 mg/dL or 2.0
tively) (J Am Med Inform Assoc 2019; multidisciplinary care pathway that mmol/L (12 hr lookback); and sys-
doi:10.1093/jamia/ocz186). would launch when a clinician con- tolic blood pressure
Victor Habbick Visions / Science Photo Library / Getty Images
8
J A NU A RY /F E B R U A RY 2020
META GJA NU A RY/ FE BR U A RY 2020 9
W
hen culture, serology,
and polymerase chain
reaction (PCR) can’t
identify the cause of a
patient’s infection, inappropriate
therapy, excess healthcare costs, or
even the individual’s death all are
possibilities. In contrast to these
tests that generally look for one
pathogen at a time, metagenomic
next-generation sequencing
(mNGS) analyzes a broad spectrum
of microorganisms at once, poten-
tially providing quicker diagnoses
and avoiding untoward outcomes.
A clinical mNGS test is expen-
sive—sometimes more than $2,000.
But it might be worthwhile when
routine tests don’t provide infor-
mation, for immunocompromised
patients infected with pathogens that
do not affect healthy people, or for
A GENOMIC
patients who can’t tolerate invasive
diagnostic procedures, said clinical
laboratorians who use the test.
“It’s exciting to think about how
mNGS can help us improve care.
There’s a lot of promise in these
methods,” said David Peaper, MD,
PhD, an assistant professor of labora-
tory medicine at Yale University and
director of clinical microbiology at
Yale New Haven Hospital in New
Haven, Connecticut. However, these
tests are limited by risk of con-
tamination, designs geared to specific
types of pathogens, bioinformatics
challenges, and databank deficiencies,
said Peaper and others.
Diverse Pathogen Detectors
Clinical mNGS typically involves
extracting cell-free (cf) DNA,
cfRNA, or both from a body fluid,
amplifying the nucleic acids via PCR,
generating libraries, and shotgun
sequencing nucleic acids at a very
high depth. Genomic laboratories
use software to analyze the millions
of reads generated in each sample
NEXT-GENERATION SEQUENCING
and identify those that align to
nucleotide sequences of pathogens
in various databases, such as the
National Center for Biotechnology
Information (NCBI) GenBank.
A $2,200 University of California,
Modern Tool for Diagnosing Infectious Diseases San Francisco (UCSF) test analyzes
both DNA and RNA to diagnose
causes of meningitis and encephali-
tis from bacteria, viruses, fungi, and
BY DEBORAH LEVENSON parasites found in cerebrospinal fluid.10 J A NU A RY /F E B R U A RY 2020
UCSF software analyzes reads, iden- published data on the first 100 tests scientific officer at BioID Genomics,
tifies those that align to pathogens used at a children’s hospital showed a biotechnology company that spe-
in GenBank, and issues a qualitative that sensitivity and specificity of the cializes in sequencing and software
report noting the pathogens present test for a clinically relevant infec- solutions to identify and character-
in the sample, along with interpretive tion were 92% and 64%, respec- ize microbes.
clinical notes. A sequencing board, tively (Open Forum Infect Dis
modeled on a tumor board, discusses 2019;6:pii:ofz327). Challenges Ahead
results in real time with treating Published evidence is emerging mNGS involves many challenges,
physicians and may make recom- on using the Karius test for diagnos- according to recent reviews of
mendations about additional testing. ing endocarditis, including a case the technology (Clin Infect Dis
Turnaround time from shipping in which the test helped identify 2018;66:778–88; Nat Rev Genet
samples to delivery of a qualitative a Coxiella burnetii infection (Open 2019;20:341–55). These include
report is generally within a week, Forum Infect Dis 2019;6:ofz242). sample contamination with nucleic
said Charles Chiu, MD, PhD, a key The company’s website lists several acid during collections and from
developer of the UCSF test and a unpublished abstracts it says support sequencing reagents, and design of
professor of laboratory medicine and use of the test in diagnostic and man- tests for particular pathogens. For
director of the clinical microbiology agement algorithms. example, a test must process RNA
laboratory at UCSF. Karius is planning to use the to detect RNA viruses. So mNGS
The test performs well in head- test to discern sepsis causes, often pneumonia assays that do not test for
to-head comparisons with routine missed by culture. A paper describ- RNA might miss respiratory syncytial
clinical testing and can make diagno- ing validation of the test for this virus, an RNA virus that commonly
ses usual microbiology tests cannot, purpose compared Karius test results causes pneumonia, Chiu said.
according to recent research (NEJM to standard of care on 350 patients Meanwhile, tests do not detect
2019;380:2327–40). Among 204 with suspected sepsis. The Karius all pathogens equally. For example,
pediatric and adult patients in eight test identified responsible pathogens mycobacteria might be more dif-
hospitals, the UCSF test detected at a rate about three times higher ficult to detect because lysing them
58 infections in 57 of the patients. than blood culture, and 28% higher for nucleic acid release requires
Hospitals’ routine tests missed 13 than all microbiology testing com- more significant cell wall disrup-
or 22% of these infections. Among bined. Results from Karius agreed tion. Also, a negative result might
seven of those 13 diagnoses made with blood culture 93.7% of the time only reflect high leukocyte count
solely by mNGS, results guided tar- (Nat Microbiol 2019;4:663–74). of a sample (corresponding to high
geted treatment with clinical effect. The UCSF and Karius tests may human DNA and/or RNA host
Redwood City, California-based be the most prominent in the mNGS background) or low sequencing
Karius matches sequences from space, but they aren’t the only ones. depth of a specimen, rather than the
cfDNA in blood plasma to a curated San Francisco-based IDbyDNA, in absence of a pathogen.
company database of 21,000 refer- partnership with ARUP Laboratories, Databases also may contain
ence microbe genomes and delivers offers a $500 test of DNA and RNA mislabeled information and include
reports that show species occurring detecting 200 pathogens in samples pathogen strains that do not infect
in greater than expected concentra- from respiratory disease patients. humans. Other challenges include
tion. Turnaround is fast—typically The company delivers results within differentiating colonization from
about 48 hours from blood draw, 29 hours after receiving samples. infection, lack of method standard-
including shipping. A team of on-call Robert Schlaberg, MD, PhD, MPH, ization, bioinformatic data storage,
infectious diseases specialists review IDbyDNA’s chief medical officer and patient privacy.
results with clinicians, particularly and co-founder, attributed the quick
for challenging cases, said Timothy turnaround to data analysis via the mNGS in Practice
A. Blauwkamp, PhD, Karius’s co- company’s Exemplify platform, Alexander McAdam, MD, PhD,
founder and chief scientific officer. which it markets to other labs. director of the infectious diseases
The $2,000 Karius test helps Tests from Scottsdale, Arizona- diagnostic laboratory at Boston
diagnose acute infections in immu- based Fry Laboratories use blood Children’s Hospital (BCH) and an
nocompromised patients, invasive and sequence a region of the 16S or associate professor of pathology at
fungal infections, and cardiovascular- 18S rRNA gene found in bacteria, Harvard Medical School, said that
related infections, according to the archaea, fungi, protozoa, amoeba, it’s difficult to fit mNGS into cur-
company. A recent study showed and algae. Tests, which do not use rent microbiology testing paradigms
that the test identified responsible shotgun sequencing, cost $1,495 built on tests costing less than $100.
pathogens in 86% of 15 children and generally take a week with However, his lab has integrated
with pneumonia and resulted in shipping, said Jeremy Ellis, PhD, Fry mNGS into its normal battery of
changes in antibiotics for almost Laboratories’ chief scientific officer. tests. McAdam regularly sends
half of them. Meanwhile, stan- Fry Laboratories compares findings mNGS tests to Karius and UCSF,
dard methods diagnosed only 46% to “a curated NCBI ‘nt’ and ‘16s’ but only after preliminary negative
of the children (Diagn Microbiol database” about these organisms, results on routine tests and approval
Infect Dis 2019;94:188–91). Other added Ellis, who also serves as chief from a BCH laboratory director.JA NU A RY/ FE BR U A RY 2020 11
“People are showing what’s
possible with mNGS. We still
have to fit it into existing
systems in a way that’s realistic
about resources available and
the value provided.”
– ALEX GRENINGER, MD, PHD
Victor Habbick Visions / Science Photo Library / Getty Images12 J A NU A RY /F E B R U A RY 2020
“It’s exciting to think about how mNGS The BCH lab works with ordering
clinicians to ensure they understand
the tests’ utility and the workflow
and deep-seated liver abscesses that
can’t be biopsied, and suspected
endocarditis when valve replace-
can help us improve care. There’s a involved.
At Yale, Peaper occasionally uses
ment is not an option. Before
ordering, Peaper and clinicians
lot of promise in these methods.” mNGS tests for scenarios including
diagnostic conundrums, critically ill
immunosuppressed patients with
discuss how positive, inconclusive,
and negative results would affect
care. More data from select patient
– DAVID PEAPER, MD, PHD tissue-based infections, brain lesions populations would make decisions
easier, he added.
Sometimes results show zero
or few reads of the true culprit,
so diagnosis requires another
method. Peaper recalled recent
encephalitis cases detected by
antibody, not the UCSF test. Chiu
recollected seeing too few reads of
Mycobacterium tuberculosis to call a
test positive for it. A different test
confirmed M. tuberculosis.
Current mNGS tests can iden-
tify diagnostic gaps in hospital lab
testing and remind physicians about
the breadth of organisms covered
in differential diagnoses, said Alex
Greninger, MD, PhD. The sensitiv-
ity of mNGS is much less affected
by antibiotics than that of culture,
added Greninger, who participated in
early development of the UCSF test
and is now developing an mNGS test
at University of Washington, where
he is an assistant professor of labora-
tory medicine and associate director
of virology.
Greninger pointed out that no
mNGS tests have been cleared by
the Food and Drug Administration
(FDA). Draft FDA guidance issued
in 2016 gives labs developing tests an
idea of “what validation should look
like for a test that’s very different
from traditional tests,” he added.
Noting that now-commonplace
PCR was new and labor-intensive in
Victor Habbick Visions / Science Photo Library / Getty Images
the 1980s, Greninger envisions a day
when mNGS could become a usual
test. “People are showing what’s pos-
sible with mNGS,” he said. “We still
have to fit it into existing systems in
a way that’s realistic about resources
available and the value provided.”
Dr. Chiu has a patent on algorithms
used in automated software developed
by UCSF to analyze and interpret
metagenomic sequencing data.
Deborah Levenson is a freelance writer
in College Park, Maryland.
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WRONG
J A NU A RY /F E B R U A RY 2020
NO How Clinical Laboratory Scientists Shape Careers to Match Their Passions
14JA NU A RY/ FE BR U A RY 2020 15
LaylaBird / iStock
BY KIMBERLY SCOTT16 J A NU A RY /F E B R U A RY 2020
W
ith the job outlook for For 14 years she worked for United auto-verification. This ultimately led
clinical laboratory Hospital in St. Paul, first as a general- her off the bench where she crafted
scientists (CLS) ist on the evening shift, then as chem- rules for auto-verification.
expected to grow much istry lead on the day shift. In 2016 “I like that my job changes every
faster than for other professions, the she took a job as chemistry technical day,” she explained. “I like the fast
career possibilities for people just specialist at Children’s Minnesota. In pace, and I like the challenges I
entering the field appear limitless. her current position, Bartos performs face. Analyzers are going down,
From working at the bench to competency assessments (including the phone is ringing, there’s always
focusing on research to performing proficiency testing review for the something going on. I also enjoy
data analysis, CLS professionals have College of American Pathologists) and interacting with healthcare provid-
a wide range of potential career ensures that the chemistry laboratory ers and collaborating. This allows me
paths from which to choose. meets all federal and state regulations. to use my critical thinking skills and
According to the Bureau of Labor “What I like best about my job is to play detective. It’s what makes
Statistics, the job market for clinical that I do a lot of troubleshooting and this job so exciting.”
laboratory technologists and techni- problem-solving,” said Bartos, who Rockefeller advises new CLS
cians is expected to grow by 11% recently completed her MBA with a professionals to volunteer when
between 2018 and 2028, compared concentration in business analytics. growth opportunities are offered
to 5% for the average growth rate for “I like using data to drive informed within a laboratory to gain exposure
all occupations. This growth is being decisions, and I’m very interested in
driven, in part, by an increase in the quality control.”
aging population and an increase in Bartos advises junior CLS to
the number of laboratory tests being be open to new experiences and
ordered by clinical providers. to get involved with professional
CLS staff members, also known organizations. Conferences are a
as medical technologists, earn a great way to stay current, as are
bachelor of science degree and then certificate programs such as those
typically complete a 1-year training offered through AACC, she added.
internship program before sitting For example, Bartos is certified as a
for a comprehensive written exam. specialist in chemistry and also holds
Once certified, CLS professionals can a graduate certificate from University
pursue a variety of career trajectories. of Minnesota in performance
But where they launch their careers improvement.
is often not where they land. Below
we highlight the stories of several Facing Everyday Challenges
CLS professionals who have found Amy Rockefeller, MLS(ASCP),
career success, all anchored in their switched her major from account-
passion for science and patient care ing to microbiology at the begin-
and in an insatiable curiosity that ning of her college career and never
keeps them on creative journeys. looked back. She received a bach-
elor’s degree in microbiology with
The Joy of Problem-solving a CLS option from California State
Erin Bartos, MT(ASCP)SC, a chem- University, Chico, and performed a
istry technical specialist at Children’s 1-year internship at University of
Minnesota in St. Paul, knew from an California, Irvine.
early age that she wanted to work Rockefeller’s first job was with
in healthcare. As a child she was Sharp Healthcare System in San
diagnosed with aplastic anemia and Diego, where she worked as a gen-
received a bone marrow transplant eralist for 6 years. Eventually, she
at the University of Minnesota. “I moved to University of California,
became fascinated with what hap- San Diego, where she started as a
pened to my blood after it was taken,” senior specialist and was promoted
she explained. to supervisor and then to clinical lab
After high school, Bartos was manager.
offered a scholarship to Mount Mercy As a generalist, Rockefeller
College in Cedar Rapids, Iowa, and was exposed to various specialties,
decided immediately to pursue including hematology, coagulation,
medical technology. After completing chemistry, and urinalysis. Working
her internship at St. Luke’s Hospital on the bench allowed her to be a
in Cedar Rapids, Bartos worked at key operator on different analyz-
Trident Hospital in Charleston and ers and to work on middleware
eventually moved back to Minnesota. information technology projects forJA NU A RY/ FE BR U A RY 2020 17
– JEFFREY YOUNG, MLS(ASCP)CM
which meant that I traveled continuously.”
different clinical systems. I had a large territory,
“I became a subject matter expert on five or six
to different specialties. She also rec- From CLS to Application labs with validation studies. I would
ommends taking advantage of online Specialist make sure they understood how to
resources, such as online communi- When his plans to attend medical use the analyzers and the software. I
ties like AACC Artery (artery.aacc. school changed after getting his micro- became a subject matter expert on
org) and continuing education, as biology degree from the University of five or six different clinical systems.
well as networking through atten- Idaho, Jeffrey Young, MLS(ASCP)CM, I had a large territory, which meant
dance at conferences. decided to pursue a career in clini- that I traveled continuously.”
“There really are a lot of differ- cal laboratory science at Idaho State When his family grew and he
ent paths you can take,” she said. University. The CLS program with a needed a position that required less
“You can stay on the bench, you 90-day clinical rotation allowed him to travel, Young took a job as a develop-
can go into administration. If you graduate with a CLS degree at about ment technologist for Providence
stay on the bench, there are many 15 months. Young worked as a bench Health in Portland, Oregon. The role
different departments you can work technologist for a short period before was similar to the one he performed
in depending on the size of your taking a position as a field application for Beckman Coulter, but from the
healthcare system. You can get into specialist for Beckman Coulter. perspective of the customer, not the
biotech. There are many options. If “It was kind of a hybrid role, part vendor.
you have a CLS license, you won’t technical support and part customer “I perform validation studies,
have a problem finding a job.” service,” he explained. “I would help I write procedures, I help set up
LaylaBird / iStock18 J A NU A RY /F E B R U A RY 2020
instrument interfaces and verify that mentors, she decided to continue
the vendor’s equipment is communi- pursuing laboratory medicine. It
cating with our laboratory informa- took Ayala-Lopez 7 years to gradu-
tion system,” he explained. ate from the program at University
While he is in a somewhat uncon- of Nevada, Las Vegas, because she
ventional role for a CLS professional, was working full-time and going to
Young noted that there are many dif- Clinical Laboratory school part-time. After graduating,
ferent career pathways for laboratory Scientist Career she got a job at St. Rose Dominican
scientists, and that there are a lot Hospital in Las Vegas, where she
of options outside of the traditional Resources was a generalist, rotating throughout
AACC’s clinical laboratory Erin Bartos
bench tech to lead tech to supervi- the lab.
sor/manager career pathway. scientists (CLS) community Ultimately, Ayala-Lopez decided
“It’s a stable career choice and has offers scientific, career, and to pursue research and moved to
been dependable through times of networking opportunities the University of Washington so
economic turmoil,” he said. Like the for all members who work in that she could get academic medi-
others interviewed for this article, laboratory management and cal laboratory experience. Following
Young advised that all CLS profes- operations. For career advice that, she attended Michigan State
sionals get involved with professional videos, mentoring, certification University, where she earned her
organizations early in their career. resources, and more, visit the graduate degree in pharmacology
“Go to conferences, network, and AACC CLS community online, and toxicology.
participate,” he said. www.aacc.org/community/ “My research was on how adipose
clinical-laboratory-scientists- tissue affects blood vessels,” she Amy Rockefeller
Broadening Horizons community explained. “I graduated in 2016 and
After taking part in an allied health did a research post-doc fellowship
services camp while in high school, at Yale University, where I was in
Pamela Banning, MLS(ASCP)CM, she advances promotion of vocabu- lab medicine studying leukemia. My
PMP(PMI), knew she wanted to lary terminology, provides technical plan was to do a clinical chemistry
study science in college. She obtained support in database management fellowship after my research fellow-
her bachelor’s degree in biology at for various clients, and represents ship, and that’s what I am doing now
Boise State University in Idaho and 3M HIS clients with standards at Vanderbilt. I’m four months into
then completed a 1-year medi- development organizations, such a two-year fellowship to prepare fel-
cal technology program. Banning’s as Regenstrief Institute’s Logical lows to be lab directors.”
internship was at St. Alphonsus Observation Identifier Names and “I love being a CLS. Being a CLS Jeffrey Young
Regional Medical Center in Boise. Codes (LOINC) Committee. requires that you have analytic skills,
Banning’s first job was at Holy “It’s like the ultimate puzzle for that you can interpret data and
Rosary Hospital in Ontario, Oregon. me because I didn’t build any of the trends, that you can communicate
After marrying a Marine, she moved information systems, but we apply those, both written and orally,” she
around often, but always found there LOINC for the assays and SNOMED said. “As a CLS, you must be able
was a need for CLS professionals. “I CT for the non-numerical values to to adjust to new procedures since
never had a problem finding work,” all of them,” she explained. “All my science is always changing. There is a
she said. “I worked at a doctor’s earlier jobs prepared me for this. I lot of room for growth, especially in
lab, a trauma center, different sized use my medical terminology every molecular and informatics.”
hospitals. I had about eight differ- day. It would be so much harder to Ayala-Lopez recommends that
ent positions over 16 years, but that do this job without medical technol- CLS students find mentors in their
really helped me be a generalist. I got ogy certification.” programs who can guide them along Pamela Banning
to do blood banking, microbiology, Banning advises new CLS profes- their career paths. She also suggests
lots of different things.” sionals to broaden their horizons, reaching out to people on LinkedIn
By the late 1980s, as labora- keep up with technology changes, or through professional organizations
tory information systems first came and be involved online. “Seek to find out more about jobs they find
into play, Banning found that she out opportunities to be in cross- interesting. “Just ask them if they
enjoyed working with information department teams, to see how other would be willing to talk to you for
technology. She was hired by ARUP departments work,” she said. “Learn 20 minutes. I’ve never had anybody
Laboratories to convert microbiology to see things from a different point turn me away,” she said. “There are so
department workcards to computer- of view.” many options for a CLS professional.
based templates. Eventually, she You can work in a government lab,
migrated to the IT department doing From Bench to Research forensics, public health. Find what Nadia
database administration. Nadia Ayala-Lopez, PhD, interests you and then pursue it!” Ayala-Lopez
After 7 years at ARUP, Banning MLS(ASCP), initially saw a clini-
joined 3M Health Information cal laboratory science degree as a Kimberly Scott is a freelance writer
Systems (HIS) almost 19 years ago as stepping-stone to medical school, who lives in Lewes, Delaware.
a healthcare data analyst. In this job, but after discussions with several +EMAIL: kmscott2@verizon.netNew FDA Regulations, Hospital Glucose Meters
FDA Product Code PZI, 2019:
Blood Glucose Meter for Near-Patient Testing
FDA Product Code NBW, 2019:
Blood Glucose Test System, Over the Counter. These device types are not
intended for use in healthcare or assisted-use settings such as hospitals,
physician offices, or long-term care facilities because they have not been
evaluated for use in these professional healthcare settings.
Use of a meter cleared by the FDA as Product Code NBW is
considered “OFF-LABEL” when used anywhere in a hospital.
Is your hospital glucose meter cleared as FDA Product Code PZI
for hospital use or NBW cleared and off label for hospital use?
GLUCOSE
Cleared as FDA Product Classification PZI. novabiomedical.com
Intended for use in near-patient testing.
U.S. Food and Drug Administration. Product Classification PZI. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpcd/classification.cfm?id=680
U.S. Food and Drug Administration. Product Classification NBW. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpcd/classification.cfm?id=633
U.S. Food and Drug Administration. Self-monitoring blood glucose test systems for over-the-counter use. Guidance for industry and Food and Drug Administration staff.
Silver Spring, MD: 2018. https://www.fda.gov/media/87720/download
Centers for Medicare & Medicaid Services. Reissuance of S&C 15-11. https://www.cms.gov/Medicare/Provider-Enrollment-and-Certification/SurveyCertificationGenInfo/
Downloads/Survey-and-Cert-Letter-15-11.PDFSteve Gschmeissner / Science Source
20
J A NU A RY /F E B R U A RY 2020JA NU A RY/ FE BR U A RY 2020 21
BY SUZANNE THIBODEAUX, MD, PHD
CAR-T
Cell Therapy
From a Clinical Laboratory Perspective22 J A NU A RY /F E B R U A RY 2020
Careful monitoring before and after infusion is critical
to successful treatment
C
areful monitoring of for manufacturing, either in-house
patients throughout the where the cells were collected and the
duration of chimeric patient will be infused, or at an exter-
antigen receptor nal central manufacturing facility, the
(CAR)-T cell therapy, including their typical model for most sites (8).
laboratory profiles, helps guide and Many important considerations
refine clinical management—from for product preparation and trans-
preparing and considering potential port center on the safety of both
candidates to monitoring the long-term patient and product. Labs must use
recovery of those who receive this special handling for any product that
powerful new therapy. Two CAR-T cell requires cryopreservation before the
products, tisagenlecleucel and axicabta- product gets packaged and shipped.
gene ciloleucel, have been approved by This includes performing cell counts
the Food and Drug Administration on a hematology analyzer, character-
(FDA) and are quickly becoming izing the cellular composition by flow
mainstays in hematologic and oncologic cytometry, adding cryoprotectant and
treatment strategies (See page 24). This proper labeling, and checking both
minireview considers CAR-T cell patient and product identification
therapy from the perspective of clinical multiple times (8).
laboratories, with the goal of empower- During manufacturing, which can
ing clinical laboratorians with informa- take 2 weeks, patients need clinical
tion so that patients receive optimal monitoring to ensure that they remain
care regardless of clinical setting. stable until the CAR-T cells can be
infused. The manufacturing process
The Role of Laboratories Before is typically monitored by release
CAR-T Cell Infusion testing, which helps ensure product
Collecting source material is criti- safety, purity, and potency. Laboratory
cal to the CAR-T cell manufactur- assessment typically includes product
ing process. Since CAR-T cells are composition by flow cytometric char-
autologous, i.e. the donor is also the acterization of CAR-T cells; product
recipient, patients must be evaluated sterility by microbial culture and
carefully before they become can- testing for endotoxin and mycoplasma
didates for CAR-T cell therapy and contamination; and functional assays
cellular collection by apheresis. In the to assess in vitro cytotoxic function
case of tisagenlecleucel, patients must and activation (9).
stop certain treatments, including Once manufacturing is complete
allogeneic therapies and immunosup- and testing has confirmed that the
pressants, for up to 12 weeks before product can be released for use, the
apheresis collection. Monitoring product is then frozen, shipped back
hematologic parameters or immuno- to the infusion site, and stored in a
suppressant levels in the blood may cellular therapy laboratory until the
be necessary to ensure patients are patient is ready for product infusion. Detecting CAR-T cells themselves
adequately prepared leading up to is not as straightforward. CAR-T cells
cellular collection and continued dur- After CAR-T Cell Infusion can exhibit atypical morphologic fea-
ing treatment to adjust their therapy After a patient has been infused with tures, and methods to detect the CAR
as needed to maintain their health CAR-T cell product, the T cells ideally protein itself are not commercially
status (7). recognize their target antigen, activate, available. In addition, the potential
Steve Gschmeissner / Science Source
Although most cellular collec- and begin to proliferate and exert anti- customization of CAR proteins pro-
tions are successful, certain laboratory tumor effects. Response to therapy can hibits at this time development of any
parameters are crucial to determine be monitored by detecting malignant single assay to detect CAR-T cells (2).
whether a patient can proceed with cells. The clinical lab examines periph- Patients can exhibit expected and
collection. There must be enough eral blood or other potentially affected unexpected effects from CAR-T cell
T cells in the peripheral blood to be tissues by standard means such as therapy infusion. A well-characterized
collected, as measured by absolute examining peripheral blood smears for and potentially serious adverse effect
lymphocyte count and/or peripheral morphology and/or using flow cytom- is cytokine release syndrome (CRS).
blood CD3 counts. After collection, etry to detect malignant cells by protein Characterized by high fever, organ dys-
cells must be prepared and transported expression (7). function, hypotension, and increasingJA NU A RY/ FE BR U A RY 2020 23
encephalopathy, agitation, delirium,
and seizures (10). Laboratory evalu-
ations currently do not aid in charac-
terizing neurotoxicity. The ASTCT
encouraged continued exploration of
potentially useful laboratory charac-
terization of patients who demonstrate
clinical signs and symptoms of adverse
events from CAR-T cell therapy (10).
Additional laboratory characterization
of patients who experience adverse
effects from CAR-T cells could help
inform the larger community about
laboratory testing that has diagnostic,
therapeutic, or prognostic potential for
CRS and neurotoxicity.
Notably, CAR-T cells can effec-
tively eliminate normal cells if they
express the target antigen; this phe-
nomenon is known as on-target/off-
tumor toxicity. In the context of the
FDA-approved therapies that target
CD19, B cell aplasia is an anticipated
effect, since normal B cells also express
CD19 and are therefore subject to
elimination by anti-CD19 CAR-T
cells. This requires monitoring patients
who receive CAR-T cells directed
against CD19 to assess whether they
develop B cell aplasia, mainly by
measuring serum gammaglobulins
(7). Hypoglobulinemia can be man-
aged clinically with immunoglobulin
replacement therapy.
ALTHOUGH MOST CELLULAR COLLECTIONS ARE
SUCCESSFUL, CERTAIN LABORATORY PARAM-
ETERS ARE CRUCIAL TO DETERMINE WHETHER
A PATIENT CAN PROCEED WITH COLLECTION.
oxygen requirements, CRS ranges quantitation, are not widely available, Clinical laboratorians should be
from mild to life-threatening and is which translates into a long turnaround aware of the potential laboratory
attributed to extremely high levels of time since they must be sent out. abnormalities that accompany treat-
cytokines, specifically interleukin 6 The nonspecific nature of other lab ment with CAR-T cells. For example,
(IL-6) (10, 11). parameters that might be altered during patients might experience cytopenias
The American Society for the course of CRS—such as ferritin in the period following infusion. In
Transplantation and Cellular Therapy and C-reactive protein—as well as the this instance, they might resemble a
(ASTCT) recently published guidelines potential lag time between symptoms patient who has undergone a hema-
for defining and grading CRS. While and altered lab values, support treat- topoietic progenitor cell transplant,
certain aspects of CRS are almost ing patients empirically based off their although they received entirely differ-
certainly determined by laboratory clinical presentation. ent cells. Prolonged B cell aplasia and
values, such as transaminitis and other Neurotoxicity, also called immune hypogammaglobulinemia associated
signs of organ dysfunction, laboratory effector cell-associated neurotoxicity with CAR-T cells directed to CD19
parameters are not included as factors syndrome, is another adverse effect of could predispose them to develop
to determine the presence or severity CAR-T cell infusion and can present infections. These patients might then
of CRS. Some tests, such as serum IL-6 with neurological symptoms such as be similar to other patients who are24 J A NU A RY /F E B R U A RY 2020
How CAR-T Cell Therapy Works
Chimeric antigen receptor (CAR)-T cells are The two Food and Drug Administration Notably, while CAR-T cell products
autologous T cells that undergo genetic (FDA)-approved CAR-T cell products in clinical have shown very promising results, they
modification to express a receptor that use—tisagenlecleucel (Kymriah) and axicabta- have only gained approval for certain
contains four basic components: 1) gene ciloleucel (Yescarta)—both contain scfvs hematologic malignancies and have
extracellular single chain variable fragment directed against CD19, a cell surface protein less-than-100% response rates. In addi-
(scvf) specific to a target antigen, 2) a expressed on many B cell malignancies. The tion, efforts to use CAR-T cells in solid
transmembrane region, 3) intracellular T CAR constructs for the two commercial malignancies have not yet proven success-
cell receptor (CD3 zeta chain), and 4) T cell products differ mainly in the intracellular ful. So while at this point CAR-T cell
co-receptor domain. The T cell receptor costimulatory component that renders the therapy has not yet been proven to be a
and co-receptor activates the T cell to cytotoxic T cell function: CD28 in axicabta- magic bullet, it does have the high
exert its cytotoxic T cell functions upon the gene ciloleucel and CD137/4-1bb in tisagen- potential to become a mainstay in
target cell (1). lecleucel. They also differ in the vector used to oncologic therapy.
These CAR-T cell components are deliver the genetic material into T lympho- Most clinical and laboratory character-
customizable. For example, different scvfs cytes: Tisagenlecleucel is manufactured using ization in patients has taken place in the
can be used to recognize different targets, a lentiviral vector, and axicabtagene ciloleucel context of the two FDA-approved CAR-T
or different T cell coregulatory molecules uses a gammaretroviral vector (2). cell products, and some laboratory profile
can be added. CAR-T cells, via the scvf, It is interesting to speculate that these components in patients are specific to the
recognize surface targets that are reproduc- noted differences between the commercial particular CAR T cell therapy. For instance,
ibly expressed on malignant cells and not products might be due to the almost B cell aplasia is an expected side effect of
expressed on tissues that are known to simultaneous and parallel progression of each CAR-T cells directed against CD19, since
cause irreparable damage to nonmalignant through the FDA approval process. As data normal B cells also express CD19 and are
tissues that cannot be readily managed accrue over time, the different profiles of the therefore eliminated in the same manner as
clinically. two CAR-T cell products might become the malignant cells expressing CD19.
CAR-T cells are manufactured from clearer. Tisagenlecleucel and axicabtagene However, this side effect would not be
peripheral blood T cells. After collection of ciloleucel have shown impressive results expected in a patient who received CAR-T
starting material by apheresis, the cells are treating malignancies that, up until this point, cells directed against a different target
transported to a processing facility where a have had extremely poor prognoses (3). antigen not expressed on B cells.
vector, typically retroviral in nature, contain- Treatment with axicabtagene ciloleucel Familiarity with the different types of
ing the genetic material for the CAR is demonstrated a 58% complete response rate CAR-T cell products currently in clinical use
introduced into the T cells. The T cells are after 2 years in patients with relapsed as well as those in clinical development will
then cultured and stimulated to proliferate. refractory diffuse large B cell lymphoma (3, 4). be useful for anticipating potential
Once the desired number of cells for Treatment with tisagenlecleucel yielded an scenarios that might arise during evalua-
infusion has been obtained, the cells are overall survival rate of 73% at 1 year (4). Both tion of these patients. Laboratory involve-
transported back to the site of infusion. The products received FDA approval for large B ment is essential throughout the process of
patient then receives the cells, and is cell lymphomas; tisagenlecleucel also has CAR-T cell treatment so that care can be
monitored for response in both acute and approval for relapsed and refractory B acute delivered in a timely manner that optimizes
chronic settings (2). lymphoblastic leukemia (5, 6). patient outcomes.You can also read
