1. health and fitness
2. disease
3. cancer

2013 aaCC annual MeetinG PReview
The last decade has seen a worrisome
rise in U.S. cases of prediabetes, a condition associated with a higher risk of
developing type 2 diabetes, according
to a newly published study. In light of
this finding, the authors suggest that
diabetes prevention programs target
demographic subgroups experiencing
the greatest increase in prediabetes
prevalence.
Researchers analyzed data from
19,182 nonpregnant individuals age
12 or older who participated in the
National Health and Nutrition Examination Surveys during three time
periods: 1999–2002, 2003–2006, and
2007–2010. Using hemoglobin A1c
levels of 5.7–6.5% (A1C5.7) or fasting
plasma glucose 100–126 mg/dL, the
team found that age-adjusted prediabetes prevalence increased 21% over
the 10 year period, 1999–2010. The
results are significant because the study
is the first of its kind to use a nationally
snapshoT
Prediabetes Prevalence by BMI Group
1999–2002
Percent Prediabetic
50%
40%
27.9
30%
30.8
2007–2010
35.7 35.5
40.5
19.5
20%
10%
0%
< 25.0/
Normal
25.0–29.9/ ≥ 30.0/
Overweight
Obese
BMI/Weight status
N = 19,182
Source: Diabetes Care 2013; doi: 10.2337/
dc12-2563
representative sample to assess changes
in prediabetes prevalence during the
first decade of the 21st Century.
While prediabetes prevalence rose
for all subgroups studied, it increased
the most for non-Hispanic blacks and
individuals below the federal poverty
level, with both groups undergoing
increases of more than 11 percentage points (ppts). The proportion
of adolescent girls and women with
prediabetes also grew by 7.9 ppts, a rate
nearly twice that of males. Researchers found this statistic particularly
concerning because children exposed
to hyperglycemia in the womb have a
higher risk of becoming diabetic.
Most surprising of all, the study
reveals that individuals with a normal
body mass index (BMI) experienced
an increase in prediabetes cases greater
than any other BMI group, with
A1C5.7 prevalence more than doubling for the normal BMI group.
According to the authors, further
investigation is needed to identify the
factors that might explain this pattern.
They also recommend consistent
population surveillance to identify,
quantify, and characterize the population of high-risk individuals in order
to better target diabetes prevention
efforts.
Clinical
Laboratory
News
The auThoriTaTive
source for The
clinical laboraTorian
june 2013
volume 39, number 6
w w w. a a c c. o rg
Competency Assessment
Does the New CLIA Guidance Mean Big Changes?
By Bill Malone
l
aboratory professionals work in one of the most highly
regulated environments in healthcare. Everything from
specimen integrity to result reporting fits into a continuum that has to meet strict quality standards under
CLIA. As a result, suggesting even a small change to one
part of a lab’s process can be unsettling, especially when labs already have little room to maneuver—be it due to time, budget, or
staff constraints.
Now, new guidance from the Centers for Medicare and Medicaid Services (CMS) aims to clarify the CLIA rules for an area that
seems routine, but one in which many labs have been getting it
wrong—assessing the competency of personnel who perform
testing. During an April 17 AACC webinar with CMS Division
of Laboratories Director Judy Yost, MT(ASCP), questions from
laboratory professionals poured in, highlighting the confusion on
this topic. Surprisingly, many labs get tripped up on the basics, like
which staff members should be assessed by whom and how often.
“Competency assessment is critical to ensure that the personnel
in the laboratory are meeting their duties under CLIA,” Yost said. “Really what that means is that the individuals in the laboratory are providing high quality testing. Performing routine competency assessments is
an important way labs can avoid errors that could lead to patient harm.” But while the CLIA regulations for
competency assessment have not changed, the often vague language in the regulations has led to an increasing
number of inquiries that spiked over the past several years, Yost said. Accreditation organizations also noticed
a high number of citations for this area, which prompted CMS to prepare a new guidance with more detailed
explanation.
See competency, continued on page 3
The Next Generation of
Prostate Cancer Diagnostics
in This issue
Lab 2013
Monitoring Newer
Antiepileptic Drugs
Are Molecular Tests Ready?
8
By Genna Rollins
Annual Meeting Preview
T
he shortcomings of prostate-specific antigen (PSA) as a screening test for prostate cancer have long
been obvious to scientists, to clinicians, and most of all to men who have had elevated levels and
faced difficult decisions about what to do next. A considerable scientific enterprise has been devoted to improving on or replacing the PSA test, which detects prostate disease but not necessarily
prostate cancer. Even as studies continue and controversy roils around how to make the most of
the PSA test, a large contingent of researchers is seeking better biomarkers for prostate cancer that take advantage of genomic technologies. However, even as some genomic tests are making their way into the marketplace,
leading researchers have sounded a note of caution.
“It’s a very daunting task, introducing a biomarker that’s going
to impact clinical care. That’s really the important issue at hand,”
said Mark Rubin, MD, a professor of pathology and laboratory
medicine at Weill Cornell Medical College in New York City. “In
developing biomarkers for prostate cancer, a major clinical question to be addressed is distinguishing between aggressive versus
indolent disease. Conceptually, this is easy and the terms indolent
and aggressive are easily spoken, but are much more difficult to
define.”
Rubin spoke recently at the annual meeting of the American
Association for Cancer Research (AACR) as part of a panel exploring prostate cancer screening now and in the future. He went
See prostate cancer, continued on page 6
Clinical Laboratory News
Prediabetes on the
rise in the U.s.
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Labs Skip Compliance Essentials
Competency, continued from page 1
Defining Roles and Responsibilities
So where are labs having trouble? Based on
CMS surveys and reports from accrediting organizations, labs are failing to follow
some of the ground rules for competency
assessment, not due to negligence, but from
confusion over the nuances of the regulation. Under CLIA, anyone performing
testing must have his or her competency
assessed annually, and during the first year
a person works in the lab, every 6 months.
The new CMS guidance emphasizes that
competency assessment is not the same as
a performance evaluation. Rather, the legal
requirements for competency assessment
mirror the responsibilities of each person’s
role in the lab as defined by regulation: laboratory director, clinical consultant, technical consultant, technical supervisor, general
supervisor, and testing personnel.
Although some of these roles can have
a long list of responsibilities based on how
much the lab director delegates, labs often
miss the minimal requirements for anyone
who performs testing. CLIA defines six elements of competency assessment for anyone who actually performs testing, and all
six must be documented for each person,
each year (See Box, below).
In addition, not just anyone can perform
the assessments. Depending on whether the
lab performs high- or moderate-complexity
testing, only those individuals who meet
the regulatory qualifications of a technical
supervisor, technical consultant, or general
supervisor may perform an assessment.
Accrediting organizations, such as the
Joint Commission, have also spotted trouble.
“Competency assessment is one of our most
frequently cited areas for lack of compliances,” noted John Gibson, MT(ASCP), DLM,
associate director of the Standards Interpretation Group at The Joint Commission, in an
interview with CLN. “In 2012, 39 percent of
labs were cited for non-compliance. In many
cases, we’re seeing that not all six of the competency assessment criteria are being utilized,
and the required frequency of six months
during the first year and annual thereafter
falls short in some laboratories. We’ve also
noted that frequently the individual performing the competency assessment does
not really have the required qualifications.”
Deb Hagen-Moe, a frequent presenter
on competency assessment at lab management meetings, said she always receives
a lot of anxious questions on this topic.
Hagen-Moe is an education coordinator
in the department of laboratory medicine
and pathology at Mayo Clinic in Rochester,
Minn. “I think this is a challenge because
the regulations have to be written broadly,
since laboratories come in a variety of sizes
and complexities,” she said. “I hear a lot of
comments like, ‘I’m not quite sure how to
interpret those regulations. I’m afraid I’ll
do it wrong and I don’t want to risk a citation,’ or even, ‘how do I get started?’”
Often labs get confused about who can
delegate to whom. The important point to
remember is that the task must be delegated in writing, and only to someone who
has the required level of education and
experience. “We’ve had situations where
we found that people were delegating this
to almost anyone, and that was a little bit
too risky for us,” Yost told CLN. “However,
most labs have personnel who have the
education and experience to qualify for a
position as a technical supervisor or consultant but don’t necessarily have that title.
Delegating assessments to these personnel
can give the lab more flexibility, while still
holding the assessments to a high standard.” For example, in a high-complexity
lab, a technical supervisor may delegate to
a general supervisor, or to someone at least
meeting the minimum qualifications for a
general supervisor (See Sidebar, p. 4).
The requirement for an annual competency assessment applies to everyone who
actually performs testing, Yost emphasized,
including pathologists and doctoral-level
personnel. On the other hand, personnel
who only perform waived testing or whose
work in the lab only involves pre- or post-analytical processes are not required to undergo
assessment under CLIA, although some accrediting organizations may require it.
The Question of Test Systems
Under CLIA regulations, all six elements of
competency assessment must be completed
for every test a person performs, not just
testing in general. In order to make competency assessment less burdensome, labs will
naturally want to consolidate the assessment
of multiple steps or analytes. However, they
can easily run afoul of CLIA regulations if
Learn More
Hear directly from CMS Division
of Laboratories Director Judy
Yost, MT(ASCP), answering labs’
questions about competency
assessment. A recording of the
April 17 AACC webinar is available
for download or on CD from the
AACC store, http://direct.aacc.org.
they go too far, Yost warned. “If you have
several analytes that are based on the same
testing platform, labs can certainly combine
them as part of competency assessment,”
Yost said. “But that means one compact device or test system; the regulation does not
give labs the leeway to go further than that.”
See Competency, continued on page 4
Competency Assessment Basics
Six Areas Define Minimum Requirements
Under CLIA regulations, all phases of testing should be reflected in a
lab’s competency assessment program. A new CMS guidance defines
competency as the ability of personnel to apply their skill, knowledge,
and experience to perform their duties correctly. Laboratory directors, consultants, supervisors, and managers must be assessed on their
administrative duties in addition to performing testing. However, the
experience of CMS and accrediting organizations points to the basics of
competency assessment as the area where most labs run into trouble.
CLIA regulations break down competency assessment for performing
testing into six areas, each of which must be completed for each person,
each test, each year.
1. Direct observations of routine patient test performance, including
patient preparation, if applicable, specimen handling, processing, and
testing.
2. Monitoring the recording and reporting of test results.
3. Review of intermediate test results or worksheets, quality control
records, proficiency testing results, and preventive maintenance
records.
4. Direct observations of performance of instrument maintenance and
function checks.
5. Assessment of test performance through testing previously analyzed
specimens, internal blind testing samples or external proficiency testing samples.
6. Assessment of problem solving skills.
CMS’s new brochure on competency assessment, “What Do I Need to Do to
Assess Personnel Competency?” is available online, www.cms.gov/CLIA.
CliniCal laboratory news June 2013
3
Labs Can Document Routine Work
Clinical
Laboratory
News
Competency, continued from page 3
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Senior Editor—Bill Malone
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Juravinski Hospital and Cancer Center,
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Abbott Diagnostics Division, Boston, Mass.
Steven Goss, PhD
Siemens Healthcare Diagnostics, Newark, Del.
Pamela Steele, PhD
Covance, Inc., Indianapolis, Ind.
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CliniCal laboratory news June 2013
CMS’s new guidance on competency assessment recommends labs focus on whether
there are unique procedures for the test. If so,
the test will require a separate assessment of
competency. “As long as there are no unique
aspects, problems, or procedures associated
with any test on the testing platform, all tests
performed simultaneously on the same testing platform may be combined,” the document states. “However, any test with unique
aspects, problems, or procedures within the
same testing platform should be assessed
separately to ensure that staff maintain their
competency to report test results promptly,
accurately, and proficiently.”
According to Yost, the regulation’s definition of a test system draws a clear line
between different analytes on the same
platform versus lumping together broader
categories such as serology or immunology.
CLIA defines a test system as “the instructions and all of the instrumentation, equipment, reagents, and supplies needed to perform an assay or examination and generate
test results.”
Another way to look at consolidating
testing is grouping tests based on platforms,
according to Gibson from The Joint Commission. “We see an instrument as a single
platform of testing—for example, a hematology analyzer or chemistry analyzer,”
Gibson explained. “All of the tests that are
being performed on that analyzer are on a
single platform, and labs can assess competence across the board for all the analytes
on the instrument unless a specific test has
some unique step or process. That simplifies things tremendously.”
This question of assessing competency
for every test—but not necessarily every analyte—comes to the fore with next-generation sequencing, which may explore many
different genes. This is an area where CMS
plans to produce further guidance for labs.
Meanwhile, competency assessment should
tackle reasonable goals, Yost commented.
“We realize that it doesn’t make sense to
require every single possible analyte in this
case,” she said. “Further guidance is coming
for labs, but in the meantime, labs are safe if
they do what they think is best.”
Don’t Reinvent the Wheel
Having a thoughtful system in place for
competency assessment will help labs stay
in compliance. However, a competency assessment plan need not create a lot of new
work. It should be integrated into what
laboratory professionals already do every
day—performing tests, reviewing results,
checking maintenance on instruments—
and simply capture and document these
routine events. “Unfortunately, instead of
using the quality processes that they already have in place, we often see labs trying
to create something completely new from
scratch,” said Stacy Olea, MT(ASCP), a
field director in surveyor management and
development for The Joint Commission.
“But if you actually look at the six elements
under CLIA, laboratorians are doing all of
those on a regular basis.”
For example, one of the requirements is
reviewing intermediate test results or worksheets and quality control records. “Usually
you have a supervisor of the department
who reviews quality control on a regular
basis, so you’re already doing that piece as
part of your existing lab quality program,”
Olea explained. “What labs need to do is
take that documentation and include it in
competency assessment.”
Similarly, many everyday tasks fall under the rubric of problem-solving skills.
For example, an unusual number of delta
flags may prompt a technologist to go back
and investigate a possible instrument error.
“The technologists working the bench are
doing this problem-solving on a day-to-day
basis,” Olea said. “But instead of just fixing
the problem and moving on, the person
could document the problem-solving that
they did, and submit that as part of their
competency assessment program.”
Yost also clarified that the annual requirement does not mean that labs have to
perform all of their assessments at the same
time each year. “Don’t do it all in one day,”
Yost said. “I recently received a question
from a supervisor who said she did a lot of
observation of testing, but didn’t always see
everyone through the entire testing process.
I said, ‘I bet you do over the course of a year,
though, don’t you?’ So she was already doing it, and didn’t realize she was covered.
Often it’s just a matter of documentation—
making sure you have a checklist or spreadsheet to record all of this.”
Gibson echoed this idea. “Too frequently managers feel that competency assessment is a snapshot in time, when you actually have a year to gather the data that’s used
to determine the competence of your staff,”
Gibson said. “It makes a lot more sense to
gather that data as a continuum. The direct
observation of testing, the monitoring of
the recording, review of intermittent results, and so on, does not have to happen at
one point. It happens on an ongoing basis,
and most of it happens in the routine supervisory review process.”
Planning, Teamwork, and Efficiency
If labs follow the rules carefully about who
can perform assessments, they can share
responsibility and avoid overwhelming
one person, according to experts. “One of
the pitfalls we see is the lab manager or the
supervisor trying to run the competency
assessment program all by him or herself—
doing all six elements for every test for every person,” Olea said. “The key is to involve
the testing personnel: they’re the ones who
know when they’re doing maintenance,
testing, or problem solving. At some level,
all of the staff of the laboratory have to
be accountable.” Olea recommends giving each person a binder or folder so that
when they accomplish one of the elements
of their assessment for a test, they can proactively gather documentation.
Creating a schedule for which elements
will be assessed, and by whom, can save
time and keep documentation organized,
said Hagen-Moe. “I often recommend that
labs make sure their staff knows that they’re
responsible for getting this done within a
certain timeframe. It can’t only be the responsibility of the laboratory director to
chase everyone around: set out the expectations and make your staff accountable.”
Overall, a standardized approach across
the organization can help make sure that
regulatory requirements are met while
setting clear expectations for staff. HagenMoe recommends that laboratory directors
and managers sit down with representatives from each area of the lab and design
a process together, along with clear policies
and procedures. “You want to avoid everyone producing variations on the same
thing,” she said.
Laboratory directors and managers
should also explain why competency
assessment is important in the first
place, Hagen-Moe emphasized. “I think it’s
really important to explain to your staff that
competency is not just a compliance issue.
The goal is that we’re doing quality work:
we want to provide the highest quality test
results that we can, and to do that we’re doing quality checks on our staff,” she said.
“Don’t take it as something punitive—we
do quality checks on the instruments, we
do quality checks on the process, so we’re
going to do a quality check on you to make
sure we’re providing our patients with
CLN
accurate test results.”
Who Can Perform
Competency assessments?
Labs Must Delegate Carefully
A common pitfall for labs is the question of who can actually perform a
competency assessment under the regulations. In a moderately complex laboratory, the person performing the competency assessment
must be qualified as a technical consultant. This means at least a bachelor’s degree and 2 years of laboratory training or experience with nonwaived testing. The experience should be in the designated specialty or
subspecialty in which the testing takes place.
In a highly complex laboratory, he or she must qualify as a technical
supervisor, with a bachelor’s degree and 4 years’ training or experience in high-complexity testing. However, a technical supervisor may
delegate the responsibility for competency assessments, in writing, to
a general supervisor. Minimum qualifications for a general supervisor
are an associate degree and 2 years’ of high complexity testing training
or expertise. For technologists who’ve been working in the lab longer,
the regulation makes an exception for those previously qualified as a
general supervisor under federal regulations on or before Feb. 28, 1992.
Personnel who perform point-of-care testing must also have their
competency assessed. In this case, trained nurses may perform the
assessment, but they must still meet the regulatory qualifications—at
least a bachelor’s degree and 2 years’ of training or experience with
non-waived testing. In addition, the laboratory director must delegate
this task to a nurse in writing beforehand.
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New Biomarkers Face High Bars
Prostate Cancer, continued from page 1
on to add that next-generation sequencing has the potential to address the many
demands placed on biomarkers for prostate cancer, from diagnosis all the way to
personalizing drug therapies of the future
(See Table, right). However, he also warned
against being beguiled by the novelty of this
technology if it doesn’t decisively answer
key clinical questions.
PSA’s History
The U.S. Food and Drug Administration
(FDA) first cleared the PSA test in 1986 to
monitor treatment in men already diagnosed with prostate cancer and extended
approval in 1994 for detecting cancer in
symptomatic men. By that time, however,
the PSA horse was out of the proverbial
barn, and the test was being used widely, particularly in the U.S., for screening
asymptomatic men.
Off-label use of PSA as a general screening test has been at the center of the controversy, for many reasons. One is that PSA,
a glycoprotein produced by the epithelial
cells of the prostate, can be elevated for reasons other than prostate cancer, including
from prostatitis, trauma, or benign prostatic hyperplasia. As a consequence, the test is
not very specific for detecting prostate cancer. At modest elevations its specificity is as
low as 20%, but rises to as much as 50% at
levels ≥10 µg/L.
This perhaps would not be such an issue if the prostate cancer field was not
weighed down by over-diagnosis and
over-treatment. American men have a 16%
lifetime risk of developing the disease, but
only about 3% die from it. As many as fourout-of-five prostate biopsies on men with
elevated PSA levels turn out to be negative
for cancer, and up to half the true-positives
are unlikely to pose problems for men during their lifetimes. At the same time, both
prostate biopsies and treatments pose risks:
biopsies have infectious complication rates
ranging from 0.6–4.1%, while radical prostatectomy leads to sexual function issues in
an estimated 20–70% of men and urinary
problems in 15–50%.
Despite these cautionary statistics,
once men hear the word cancer, many still
pursue treatment. The bias toward treatment in the U.S. contrasts sharply with
other countries. For example, an estimated
20–30% of European men choose active
surveillance compared with only about
5–10% of American men. This screenand-treat mentality is beyond frustrating to
Otis Brawley, MD, chief medical officer of
the American Cancer Society (ACS), who
also spoke at the AACR conference. “One
of the problems I’ve had with this frenzy
of prostate cancer screening and treatment
over the last 25 years is that we’ve actually
impeded scientific development of the new
markers we desperately need to figure out
the cancers that kill versus the cancers that
don’t kill,” he contended.
Which Cancers Need to Be Treated?
Knowing which men have indolent disease
that merely deserves active surveillance and
which have aggressive cancer that must be
acted on, has, in fact, been at the heart of
the PSA debate. Quite a number of different strategies for using PSA and its various
6
CliniCal laboratory news June 2013
forms have been proposed to address this
issue, including: PSA density, PSA velocity, PSA doubling time, free PSA (fPSA),
proPSA, and complexed PSA. All of these
have been found to be complementary to
PSA in certain circumstances, and the FDA
has cleared fPSA for use in men with total
PSA in the diagnostic gray zone between
4–10 µg/L.
Different cutoffs also have been proposed to fine-tune PSA’s sensitivity and
specificity. A cutoff of 4 µg/L has been commonly adopted and used in major screening studies, and an ACS literature review
found this threshold to have an estimated
sensitivity of 21% for detecting any prostate cancer and 51% for detecting highgrade cancer. Lowering the cutoff to 3 µg/L
boosts these sensitivities to 32% and 68%,
respectively, but at the cost of specificity,
which drops from 91% to 85%. However,
lower thresholds have not been endorsed
formally by professional organizations. In
fact, the National Academy of Clinical Biochemistry Laboratory Medicine Practice
Guideline on the use of tumor markers
recommends not using age-specific reference intervals and notes that the reported
benefits from lowering the clinical decision limit below 4 µg/L are too uncertain
to make a blanket recommendation (Clin
Chem 2008:54:e11–79).
Demands for Prostate Cancer
Biomarkers
Biomarkers are needed to address prevalent clinical issues in all stages
of prostate cancer.
Prostate Cancer State
Medical Need
Screening/early
detection
Risk stratification, detection, and diagnosis.
15–20% of
asymptomatic men.
Localized prostate
cancer
Treatment stratification,
treatment selection, and
recurrence monitoring.
Active surveillance
monitoring.
Untreated: 33% of
men will suffer with
metastatic cancer and
21% will die from it.
Treated: 22% of men
will suffer with metastatic cancer and 15%
will die from it.
20–40% of men on
active surveillance
will progress to need
intervention over
5–10 years.
Recurrent/
advanced prostate
cancer
Risk stratification, treatment monitoring, and
progression detection.
Rising serum PSA:
30% progress to
metastases over 8
years.
Castration-resistant
prostate cancer
(metastatic and
non-metastatic)
Treatment stratification
and treatment
monitoring.
Treatment selection.
Rising serum PSA:
33% progress to metastases over 2 years.
Significant responses
to abiraterone and
enzalutamide in
40–60%.
A Lack of Clarity
Researchers and clinicians who hoped
clarity about the role of PSA in screening
would come from two major clinical trials—the Prostate, Lung, Colorectal, and
Ovarian Cancer Screening Trial (PLCO),
and the European Randomized Study of
Screening for Prostate Cancer (ERSPC)—
were disappointed. PLCO, a study of 77,000
men at 10 U.S. centers, did not identify a
significant reduction in prostate cancerspecific mortality. However, this study has
been criticized because half of the men assigned to the control group also underwent
screening by virtue of receiving usual care.
“PLCO does not provide an answer to value of screening—it compares screening to
the current U.S. practice of screening,” contended AACR panelist, Fritz Schröder, MD,
PhD, a professor of urology at Erasmus
University in Rotterdam, the Netherlands
and one of the lead ERSPC investigators.
The initial report from ERSPC involving 182,000 subjects from seven countries,
found the death rate of prostate cancer was
20% lower in the screening versus control arm, but 1,410 men would need to be
screened and 48 cases of prostate cancer
detected to prevent one death from the
disease. The second report, published in
March 2012 and reflecting 2 more years of
follow-up, consolidated the authors’ prior
findings that PSA significantly reduced
prostate cancer-related mortality—a 29%
relative risk reduction—but did not affect
all-cause mortality, the crucial criterion for
population-based screening.
More recently, ERSPC researchers examined quality of life issues around prostate cancer screening and concluded that
long-term effects after diagnosis and treatment diminished the benefits of screening
but that more data was needed to make
universal screening recommendations.
“There are significant harms from screen-
Estimated Prevalence
Courtesy of William G. Nelson, MD, PhD
ing, and this is the agreement in general
around the world,” said Schröder. “The
most important message is that the harms
do not exceed the benefits; they adjust the
benefits in a reasonable way.”
Based on the controversial and still confused picture of PSA’s role, Schröder and
Brawley agreed that individual informed
decision-making for now remains the best
prostate cancer screening strategy. “The
present evidence does not justify the introduction of population-based screening
programs,” said Schröder. “However, wellinformed men should not be denied PSAdriven testing.” Brawley drove the point
home more directly. “Mass screening for
prostate cancer is commonly done in the
U.S., and I’ve been on a 22-year mission to
drive it out of the picture and drive screening into the doctor-patient relationship.”
Molecular Biomarkers to the Rescue?
With PSA’s flaws, research to come up with
something better has been intense, particularly in the genomic realm. Molecularbased biomarkers hold the promise of
answering crucial clinical questions, such
as who should be screened, who has prostate cancer, and who needs treatment (See
Table, p. 7). PSA currently plays a more or
less unsatisfying role in addressing these
concerns.
Already, at least 80 single nucleotide
polymorphisms (SNP) have been linked
to prostate cancer, and multigene panel
tests that detect or predict the disease are
available commercially. A recent New York
Times article indicated that more than one
dozen companies have already or intend to
introduce such tests, some intended to be
used as adjuncts to PSA results, others independently. Several are aimed at teasing
out from biopsy samples how aggressive a
cancer is, including Genomic Health’s Oncotype DX Prostate Cancer Test. Others
strive to guide treatment choice or provide
prognostic information after surgery, like
Myriad Genetics’ Prolaris test. Still others
propose to forestall unnecessary second
biopsies in men whose PSA levels stay elevated after an initial negative biopsy. One
such example is the PCA3 test cleared by
the FDA in 2012, which detects a long noncoding RNA elevated in >90% of prostate
cancer tissue but not normal tissue.
In the midst of all this test development,
the Agency for Healthcare Research and
Quality reviewed 15 multigene panels and
concluded that all have “poor discriminative ability” for predicting risk of prostate
cancer. Likewise, leading researchers have
been underwhelmed with some proposed
tests, and AACR panelist William Nelson,
MD, PhD, explained the high bar assay developers face.
“We’re very interested in sensitivity
and specificity, but when we think about
employing these tests for the purposes of
medical decision-making we need to think
a lot more about predictive value,” he said.
“As many as 15 to 20 percent of all men if
biopsied would be found to have cancer in
their prostates. So a test with a negative predictive value of 80 percent is not giving me
any more information than I had just by
walking around anyway. You have to beat
this threshold to have a useful test; otherwise, it’s not adding to the clinical picture.”
Nelson is professor of oncology and director of the Sidney Kimmel Comprehensive
Cancer Center at Johns Hopkins University
in Baltimore.
One of the issues in developing clinically useful multigene panels is that most
genome-wide association studies have
identified relatively more common SNPs.
That means that men both with and without prostate cancer carry at least some of
the risk markers detected in these panels,
making it challenging to set cutoffs for
high- and low-risk groups, and affecting
the positive predictive power of the test.
Promising Genetic Signatures
Some of the genetic signatures that have
been studied the most and show the most
promise in prostate cancer include PTEN,
TMPRSS2, and SPOP. As an example, loss
of PTEN inhibits androgen receptor signaling and causes resistance to androgen
receptor-based therapies. PTEN deletion
also has been associated with poor outcomes, suggesting it may be of both prognostic and predictive importance. Similarly, gene fusions between TMPRSS2 and
ERG—present in about half of all prostate
cancer cases—especially in conjunction
with PTEN deletion, may be a biomarker
of aggressive disease.
Rubin also discussed an intriguing line
of investigation involving chromothripsis, a dramatic rearrangement of DNA
in localized chromosomal regions with
usually one-to-two copy number states
across the rearranged region. Cells not
only survive this catastrophic event, but
through their new genomic make-up
seem to confer selective advantage to the
clone, setting the stage for cancer. First reported in 2010 in the genome of chronic
lymphocytic leukemia, bone cancer, and
small cell lung cancer, it now has been
found in the genome of other cancers, including prostate cancer.
“The lack of stability of the genome
could potentially be a biomarker,” he explained. “From the first study looking at
this, investigators found these rearrangements often incorporated known oncogenes. This suggests that this pattern of rearrangement is a type of biomarker where
there may be a selection for alterations
over-expressing an oncogene or knocking
out a tumor-suppressor gene.”
Rubin was quick to add that the chromothripsis phenomenon represents not
only the excitement and promise but
also the hard work ahead in changing the
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Molecular Biomarkers in Prostate Cancer
Molecular-based biomarkers hold the promise of answering crucial clinical questions from screening
to treatment monitoring in metastatic disease.
Prostate Cancer State
Screening/early
detection
Localized prostate
cancer
Medical Need
Biomarkers Existing
and in Development
Clinical Application
Risk stratification
Who should be screened?
Detection/diagnosis
Who has prostate cancer?
Risk stratification
Who needs treatment?
PSA, prostate cancer genetic
susceptibility loci.
DNA, RNA, protein biomarkers.
DNA, RNA, protein, circulating
cells, grade/stage, PSA.
Currently based on risk.
PSA
Treatment stratification What treatment is needed?
Treatment monitoring Is treatment effective?
Recurrent/advanced Risk stratification
prostate cancer
Treatment monitoring
Castration-resistant
prostate cancer
(metastatic and
non-metastatic)
When should treatment begin? PSA, previous grade/stage.
Is treatment effective?
PSA
Treatment stratification Which treatment is most
likely to be of benefit?
Treatment monitoring Is treatment effective?
?
PSA
Courtesy of William G. Nelson, MD, PhD
prostate cancer diagnostic landscape. “This
is very complex biology that’s going to take
a while to understand, but my point is it
represents biomarkers that a few years ago
would never have been thought about.”
Mutations and Methylation
Both Rubin and Nelson noted the importance of two studies published in 2012
involving whole genome sequencing in sizable prostate cancer cohorts. One involved
112 cancer tumors at diagnosis prior to
treatment, and the other, 50 treatmentresistant, ultimately fatal cases. Mutation
rates in the two types of disease were fairly
similar, but the treatment-resistant tumors
had markedly increased copy-number alterations. Overlap in mutations in both
types of tumors also suggest that dysregulation of the androgen receptor pathway
could be an early event in prostate cancer
development.
Nelson’s own work and that of other
research teams involves exploring DNA
methylation alterations. He reported that
at least 5,000 of these epigenetic changes
have been found in prostate cancer, and
that the changes tend to be stable in individuals but vary between individuals.
“What’s becoming surprising is just how
many of these look like they’re drivers of
the neoplastic phenotype. We’re working
hard to figure out how that works, which
are drivers, which are passengers,” he said.
If this work seems very far removed
from helping a man and his physician
make an informed decision about prostate
cancer screening and treatment, both Rubin and Nelson suggested otherwise. “By
looking at advanced disease, hopefully it
will provide insight in early detection as to
which tumors will go on to develop into
those aggressive cancers. There are a number of activities going on with dream teams
dedicated to this issue,” said Rubin.
Nelson reflected on how quickly the
field moved in 2004/2005 to begin using the alpha-methylacyl-CoA racemase
(AMACR) monoclonal antibody, P504S,
in immunohistochemistry analysis for
prostate biopsy specimens that are difficult to diagnose by morphology alone.
From the time several research teams discovered that AMACR was very commonly
over-expressed in prostate cancer but not
in normal prostate tissue, he recalled that
the field rallied rapidly to make use of this
finding. “It moved incredibly quickly, using
an enabling technology that had appeared
on the scene at that time—tissue microarrays—and a collaborative spirit among
prostate pathologists. They got together
very quickly, looked at a very large number
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CliniCal laboratory news June 2013
7
Antiepileptic Drugs
Therapeutic Drug Monitoring of the Newer Generation Drugs
MATTHEW D. KRASOWSKI, MD, PHD
ntiepileptic drugs (AEDs) used to treat seizure disorders are today among the most common
medications for which clinical laboratories perform therapeutic drug monitoring (TDM) (7,2).The
first-generation of AEDs-carbamazepine, ethosuximide, phenobarbital, phenytoin, primidone,
and valproic acid-were introduced by u.s. and European drug manufacturers several decades
ago, and TDM quickly became part of using them in clinical practice. Generally speaking, these
AEDs have complicated pharmacokinetics, including absorption, distribution, metabolism, and excretion, as well
as narrow therapeutic ranges that cause significant differences in individuals' therapeutic dosages.
In the last 20 years, 14 more so-called newer generation AEDs entered the market: eslicarbazepine acetate,
felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, rufinamide, stiripen­
tol, tiagabine, topiramate, vigabatrin, and zonisamide (3). Only eslicarbazepine acetate and stiripentol are not
approved in the U.s., while all of the drugs are available in Europe. Compared to first-generation AEDs, the
newer agents generally have wider therapeutic ranges and fewer serious adverse effects.
Despite the fact that evidence for the
of clinical assessment. Furthermore, sei­
metabolites,TDM may also include mea­
clinical benefit of monitoring blood levels
zures by nature occur irregularly and un­
suring the concentration of metabolite
of AEDs in patients is mostly anecdotal and
predictably, making diagnosis difficult.
alone or together with the parent drug.
retrospective, TDM today continues to be
The basic assumption of TDM is that
For example, TDM of oxcarbazepine
widely used in clinical practice. Only two
the measured drug concentration corre­
often focuses on its active metabolite,
10-hydroxycarbazepine.
randomized, controlled studies have been
lates with the concentration at the target
published, and neither showed clear clinical
site of its action, usually an ion channel or
(4, 5). Moreover, these two studies
neurotransmitter transporter in the brain,
Clinical Need for TOM
Clinicians rely upon TDM for managing
benefits
and others indicate that pre- and post­
and therefore with the therapeutic effect.
analytical errors occur frequently, particu­
However, the correlation of drug concen­
patients' AED therapy for multiple reasons.
larly in timing blood draws and interpret­
tration with clinical effect is reduced by
Perhaps the most common is that the pa­
factors such as irreversibility of drug action
tients exhibit significant inter-individual
ing drug levels
(1,2).
variability in their pharmacokinetic re­
sponses to most AEDs
(1, 2). However, a
few AEDs have predictable and consistent
pharmacokinetics and generally require
little or noTDM.
The major pharmacokinetic factor af­
fecting a patient's therapeutic drug levels is
how quickly the liver metabolizes the AED.
It is well known that the cytochrome P450
(CYP) enzyme system plays a major role.
Some drugs actually increase or induce
liver metabolism by CYP enzymes, leading
to quicker metabolism. Classic inducers in­
clude carbamazepine, phenobarbital, phe­
nytoin, rifampin (a tuberculosis drug), and
St. John's wort (an herbal antidepressant).
These drugs may lower patients' blood lev­
els below what is optimal unless the AED
dose is increased.
Other drugs inhibit CYP enzyme me­
tabolism of some AEDs.This inhibition can
lead to excessively high drug concentrations
unless the clinician reduces the patient's
dose. Inter-individual differences may also
result from: impaired organ function, typi­
cally kidney or liver; drug-drug or drug-food
interactions; or genetic or pharmacogenet­
ics factors. In renal failure patients, AEDs
This article will present an overview
or an individual's tolerance of the drug. For
may be removed during dialysis procedures,
of the newer AEDs and why improved
example, TDM has limited utility for vi­
especially those that only bind plasma pro­
education on the proper use ofTDM is an
gabatrin because it irreversibly binds to its
teins weakly. A number of factors also may
important goal for maximizing the safety
molecular target.
and benefits of these drugs for patients.
Current Status ofTOM for AEOs
8
alter serum protein concentrations includ­
Laboratories usually perform TDM
ing liver disease, advanced age, pregnancy,
on serum or plasma samples, and less
uremia, and other drugs (e.g., valproic acid)
commonly on cerebrospinal fl u id or sa­
that also bind serum proteins.
TDM of AEDs is challenging because no
liva. However, the popularity of saliva as a
Clinicians also rely uponTDM to assess
simple diagnostic tests can assess the clinical
specimen for TDM of AEDs is growing. It
patient compliance. Typically, they pre­
efficacy of any of the drugs. Careful clinical
is easy to collect and transport saliva
(6),
scribe the drug for the patient for months
observation and labor-intensive electroen­
although it is not a viable specimen type
or even years, despite the absence of sei­
cephalograms (EEG) remain the mainstays
for some AEDs
(7). For drugs with active
zures. Patients may skip doses or stop taking
CLINICAL LABORATORY NEWS JUNE 2013
the medication altogether because they
haven’t had a seizure, or they may quit taking it due to adverse effects or the cost of the
medication. Lastly, AED levels may also be
useful in managing suspected toxicity due
to inadvertent or intentional overdose.
The Reference Range Dilemma
Although the newer AEDS offer many benefits for patients, laboratories have struggled to establish reference ranges for TDM,
primarily because many of the drugs are effective over a wide range of serum/plasma
concentrations (1, 2, 8). Furthermore, some
individuals show good clinical response at
levels above or below the standard reference range. Reference ranges also vary with
different types of seizures, as well as with
whether the AED is taken as monotherapy
or in combination with other AEDs.
A noted clinical pharmacologist, Emilio
Perucca, MD, PhD, has promoted the concept of “individual therapeutic concentrations” for AEDs, wherein a patient is treated
until good seizure control is achieved (8).
In this model, the clinician assesses the
AED’s serum/plasma concentration at a
clinical endpoint and uses it as the patient’s
individual therapeutic concentration. The
frequency of TDM can be adjusted as
needed when any changes occur that might
alter the AED’s pharmacokinetics. Table 1
presents a summary of the factors that influence clinical use and interpretation of
these drugs.
Analytical Methods
Another reason that TDM of the newer
AEDs has been challenging is that homogeneous immunoassays have only recently
become available on standard chemistry
analyzers. Early on, some clinical laboratories developed analytical methods using
chromatography techniques, with or without mass spectrometry (MS) (9). Many
laboratories, however, send out samples to
reference laboratories.
Today, most reference laboratories employ high-performance liquid chromatography (HPLC) and liquid chromatographytandem mass spectrometry (LC-MS/MS)
for measuring levels of newer-generation
AEDs. Immunoassays are also commercially available for gabapentin, lamotrigine,
levetiracetam, topiramate, and zonisamide,
with assays for other AEDs in development.
Table 2 summarizes the analytical methodologies used for measuring AED serum/
plasma concentrations (9), as well as the
viability of saliva as a specimen type (7).
A Closer Look
The newer AEDs are a welcome addition
to therapeutic options for treating epilepsy;
however, the large number of drugs along
with the variability in patients’ responses
presents a wide array of challenges for assessing their levels in patients. Laboratorians need to be aware of the key clinical and
pharmacokinetic properties of these AEDs
in order to optimize their TDM. Below is a
brief review of each drug that summarizes
key parameters.
Eslicarbazepine Acetate. Approved in
Europe, but not in the U.S., eslicarbazepine
acetate is a pro-drug that is rapidly metabolized by liver esterases to form eslicarbaze-
Table 1
Justifications and Limitations of Therapeutic Drug
Monitoring of Newer Antiepileptic Drugs
Generic Drug Name Clinical Need for TDM
Justification for TDM*
Limitations of TDM
Eslicarbazepine
Intermediate
Clearance decreases with chronic dosing
and liver failure.
Felbamate
Intermediate
Unclear relationship between
Clearance varies significantly by patient age. plasma concentration and
toxicity.
Gabapentin
Infrequent
Clearance decreases with renal failure.
Wide therapeutic reference
range.
Low incidence of toxicity.
Lacosamide
Infrequent
Limited.
Predictable dosing.
Lamotrigine
Frequent
Metabolism is variable.
Possibility of drug-drug interactions.
Wide variability in toxic range,
with some patients tolerating
up to 70 mg/L.
Levetiracetam
Intermediate
Clearance decreases with renal failure.
Wide therapeutic reference
range.
Wide variability in toxic range.
Oxcarbazepine
Intermediate to
frequent
Metabolism is variable.
Relatively well-defined toxic range exits.
Wide therapeutic reference
range.
Pregabalin
Infrequent
Clearance decreases with renal failure.
Wide reference range.
Low incidence of toxicity.
Rufinamide
Intermediate to
frequent
Absorption is variable.
Possibility of drug-drug interactions.
Clearance decreases with renal failure.
Uncertain therapeutic
reference range.
Stiripentol
Frequent
Pharmacokinetics are complex, including
extensive first-pass metabolism, high serum
protein binding, and zero-order kinetics.
Therapeutic and toxic reference
ranges not well defined.
Tiagabine
Intermediate
Shows significant binding to proteins (96%).
Uncertain therapeutic
reference range.
Topiramate
Intermediate
Clearance decreases with renal failure.
Possibility of drug-drug interactions.
Toxic ranges not well defined.
Vigabatrin
Infrequent
Limited.
Irreversible action.
Poor correlation of plasma
concentrations to clinical effect.
Frequent
Metabolism is variable.
Clearance decreases with renal failure.
Good correlation of plasma concentration
with patient response.
Toxic ranges not well defined.
Zonisamide
Generally predictable
pharmacokinetics.
*In addition to assessing compliance.
Source: The data presented are summarized from a number of primary sources that have been recently reviewed (9).
pine, the active metabolite that is the target
of TDM. Overall, the drug has relatively
predictable pharmacokinetics; therefore,
TDM has a minimal role in eslicarbazepine
therapy, except when it is taken by renal
insufficiency patients who may have impaired drug clearance.
Felbamate. The Food and Drug Administration (FDA) approved felbamate
for treating adults with partial seizures and
children with Lennox-Gastaut Syndrome,
a type of childhood epilepsy that is often
refractory to standard AED therapy. By
1994, however, clinicians identified cases of
aplastic anemia, some of which progressed
to severe liver failure, that were associated
with felbamate therapy. While the drug has
remained on the market, FDA sought revised labeling and restricted its use.
Patients taking a typical dose of felbamate have serum/plasma concentrations
of 30–60 mg/L, but children clear the drug
20–65% faster than adults. Overall, felbamate TDM has relatively modest utility,
and unfortunately, toxicity cannot be easily
predicted from laboratory studies. Given
felbamate’s potential adverse effects, laboratorians should advise clinicians to closely
monitor blood counts and liver function of
patients receiving this therapy.
Gabapentin. FDA originally approved
gabapentin for treating epilepsy, but the
drug has achieved far greater popularity
as an adjunctive therapy for chronic pain.
Gabapentin is not metabolized, shows little
binding to serum proteins, and is cleared
almost entirely by the kidneys. A wide
range of serum/plasma concentrations,
2–20 mg/L, are associated with effective seizure control.
Other than optimizing dosing in renal
insufficiency patients, TDM has overall low
utility in gabapentin therapy. Saliva concentrations can be monitored, but they are
only 5–10% of those in serum/plasma.
Lacosamide. This drug has predictable
pharmacokinetics across all ages and is
cleared almost equally by the liver and kidney. Clinically significant drug-drug interactions involving lacosamide are also uncommon. Lacosamide TDM has relatively
low utility except in patients with severe
liver and/or kidney failure.
Lamotrigine. Approved in the U.S.,
lamotrigine is widely used to treat partial
seizures, as well as bipolar disorder. Several
first-generation AEDs have been associated
with severe birth defects, but lamotrigine
has a solid safety record in pregnancy, making it the AED of choice to treat pregnant
women experiencing seizures. Dermatologic reactions occur frequently, however,
and patients should seek medical attention
promptly if any skin reactions occur.
Lamotrigine’s pharmacokinetics are
well understood, but fairly complex. The
drug exhibits: increased metabolism over
time (auto-induction); drug-drug interactions with CYP enzyme inducers and inhibitors; and impaired clearance in renal
failure. But lamotrigine’s clearance is higher
in children and markedly higher (~300%)
in pregnancy.
Researchers have proposed a reference range of 3–14 mg/L for refractory
epilepsy therapy; however, the incidence
of toxic effects is significantly increased
when serum/plasma concentrations are
above 15 mg/L. Given the complicated
pharmacokinetics and well-defined toxicity level, TDM plays a major role in lamotrigine therapy. In addition to serum/
plasma, saliva is a viable specimen type
for lamotrigine TDM.
CliniCal laboratory news June 2013
9
Levetiracetam. A widely used newer
AED, levetiracetam is available in both oral
and intravenous formulations, with the
intravenous form used for acute management in the hospital setting. The drug does
not bind serum proteins, has predictable
pharmacokinetics, and limited drug-drug
interactions because it is not metabolized
by the liver.
Laboratories that perform TDM of levetiracetam should separate serum or plasma
from whole blood rapidly, as hydrolysis of
levetiracetam can occur in the blood tube.
Saliva is also a viable specimen type for levetiracetam. Researchers have proposed a therapeutic reference range of 12–46 mg/L, but
laboratorians should be aware that samples
drawn shortly after a dose of intravenous
levetiracetam can appear to have very high
drug levels. The main value of TDM for levetiracetam is adjusting dosage for pregnant
patients and those with renal insufficiency.
Oxcarbazepine. Oxcarbazepine is structurally related to carbamazepine, but it has
a lower incidence of adverse effects, such
as agranulocytosis and drug-drug interactions. The drug is metabolized primarily
to 10-hydroxycarbazepine, which accounts
for much of the anti-seizure activity. For
TDM, oxcarbazepine is treated like a prodrug, with monitoring focused on 10hydroxycarbazepine. Clearance is reduced
in the elderly and in individuals with renal insufficiency, but increased in pregnant
women and patients taking liver enzymeinducing drugs.
Laboratories have observed that a wide
range of serum concentrations, 3–35 mg/L,
are clinically effective in seizure treatment,
with toxic side effects more common at
>35 mg/L. Overall, TDM is useful especially
in renal insufficiency, pregnancy, and cases
with suspected drug-drug interactions. Saliva is also a possible specimen type, although
10-hydroxycarbazepine has a shorter halflife in saliva compared to serum.
Pregabalin. Pharmaceutical researchers designed pregabalin to be a more
potent analog of gabapentin. Similar to
its predecessor, pregabalin is effective in
treating chronic pain, and since its introduction, FDA approved a separate indication for treating fibromyalgia. Pregabalin
has predictable pharmacokinetics with
no reported drug-drug interactions and
minimal binding to serum proteins; however, renal failure patients generally take
lower dosages.
Within the reference range of 2.8–8.3
mg/L, patients experience beneficial antiseizure effects. However, other than adjusting dosage for renal failure patients or
assessing adherence to therapy, TDM has
minimal benefit in pregabalin therapy.
Rufinamide. Approved in the U.S. for
Lennox-Gastaut syndrome, rufinamide has
very complicated metabolism pathways and
a high potential for drug-drug interactions.
Serum/plasma levels within a broad reference range of 3–30 mg/L correlate well with
seizure control. Monitoring serum levels
can be especially helpful in patients taking
concomitant liver enzyme inducers or who
are receiving hemodialysis. Overall, TDM is
quite useful for this drug.
Stiripentol. Approved in Europe in 2001,
stiripentol has yet to be approved in the
U.S. It has very complex pharmacokinetics,
including non-linear elimination kinetics,
high serum protein binding, and extensive
metabolism by the liver, which resembles
the classic AED phenytoin more than newer AEDs. The stiripentol reference range is
not well-defined, but serum concentrations
of 4–22 mg/L correlate with good management of seizures in children.
Monitoring the free-drug fraction of
stiripentol would appear to be beneficial,
but no methods have been reported to date.
Overall, clinical use of the drug is limited,
and therefore so is experience with TDM.
Tiagabine. The AED drug tiagabine is
not widely prescribed in the U.S. or Europe.
Its limited use has been attributed to a propensity to cause non-convulsive status epilepticus, a serious adverse effect (10). It shows
significant binding to proteins (>96%), as
well as variability in inter-individual metabolism by the liver. Although therapeutic
levels of the drug are substantially lower than
those for other newer generation AEDs, tiagabine has a broad reference range of 0.02–
0.2 mg/L for its anti-seizure effect. Overall,
TDM is very useful for tiagabine due to its
complex and variable pharmacokinetics.
Topiramate. Approved for treating epilepsy in children and migraine headaches
in adults, topiramate is metabolized in the
liver and has the potential for drug-drug
interactions. Researchers have proposed a
reference range of 5–20 mg/L for epilepsy
therapy. TDM of topiramate is valuable because individuals’ metabolism is quite variable. Saliva is also a viable specimen type.
Vigabatrin. An irreversible inhibitor
of GABA transaminase, vigabatrin breaks
one of the principle assumptions of TDM,
namely that the concentration in serum/
plasma correlates with the concentration at
the target site. This may be one reason why
laboratories have observed a wide range,
0.8–36 mg/L, of trough serum/plasma
concentrations found in patients successfully treated with the drug. Consequently,
other than to assess patient compliance or
to evaluate possible drug overdose, there is
little benefit in monitoring vigabatrin.
Zonisamide. Metabolism of zonisamide
is affected by drugs that induce or inhibit
CYP enzyme activity. There is significant
inter-individual variability in metabolism of
the drug, especially in patients who are on
concomitant therapy with other drugs that
also affect expression of liver enzymes. Toxic
side effects are uncommon at serum concentrations <30 mg/L, and researchers have
Online Extras
More on Newer AEDs—
Chemical Structures
Pharmacokinetic Parameters
Commercial Assays
Go to the June issue of CLN at
www.aacc.org
10
CliniCal laboratory news June 2013
Table 2
Analytical Methods for
Therapeutic Drug Monitoring
of Newer Antiepileptic Drugs
Generic
Drug name
Primary Analytical Methodology(ies)*
Viability of saliva
as a specimen Type
Eslicarbazepine
HPLC
Unknown
Felbamate
GC, HPLC, LC-MS/MS
Unknown
Gabapentin
HPLC, LC-MS/MS, immunoassay
Lacosamide
HPLC, LC-MS/MS
Yes
Lamotrigine
HPLC, LC-MS/MS, immunoassay
Yes
Levetiracetam
GC, HPLC, LC-MS/MS, immunoassay
Yes
Oxcarbazepine
HPLC, LC-MS/MS
Yes
Pregabalin
HPLC, LC-MS/MS
Unknown
Rufinamide
HPLC, LC-MS/MS
Unknown
Stiripentol
HPLC
Unknown
Tiagabine
LC-MS/MS
Unknown
Topiramate
GC, HPLC, LC-MS/MS, immunoassay
Yes
Vigabatrin
HPLC
No
Zonisamide
HPLC, LC-MS/MS, immunoassay
Yes
Limited, low
concentrations
in saliva
* Abbreviations: GC, gas chromatography; HPLC, high-performance liquid
chromatography; LC-MS/MS, liquid chromatography-tandem mass
spectrometry.
proposed a reference range of 10–40 mg/L in
serum/plasma for managing seizures. Saliva
is also a viable specimen type for zonisamide
TDM. Overall, TDM is useful for zonisamide.
The Take-Home Message
The past 20 years have seen the introduction of 14 newer AEDs for treatment of
seizure disorders. Clinicians also prescribe
the newer agents for “off-label” conditions,
including bipolar disorder, chronic pain
syndromes such as fibromyalgia and trigeminal neuralgia, or migraine headaches.
As use of these drugs increases, clinical
laboratories will likely see more requests
from clinicians to monitor patients’ drug
levels. Although physicians often order the
tests to assess adherence to therapy, laboratorians should approach TDM for conditions other than seizure disorders cautiously, as it is not well-defined at present.
The availability of more automated immunoassays for measuring these drugs,
as well as the expected development and
introduction of more assays by manufacturers, will allow larger numbers of laboratories to perform in-house TDM of the
newer AEDs. Laboratorians would do well
to recognize this trend and evaluate new
assays carefully so that they can best help
clinicians understand the clinical utility
CLN
of the results.
antiepileptic drugs: Clinical applications.
JAMA 2004;291:615–20.
4. Fröscher W, Eichelbaum M, Gugler R,
et al. A prospective randomized trial on the
effect of monitoring plasma anticonvulsant
levels in epilepsy. J Neurol 1981;224:193–
201.
5. Januzzi G, Cian P, Fattore C, et al. A
multicenter randomized controlled trial
on the clinical impact of therapeutic drug
monitoring in patients with newly diagnosed epilepsy. Epilepsia 2000;41:222–30.
6. Jones MD, Ryan M, Miles MV, et al.
Stability of salivary concentrations of the
newer antiepileptic drugs in the postal system. Ther Drug Monit 2005;27:576–9.
7. Patsalos PN and Berry DJ. Therapeutic
drug monitoring of antiepileptic drugs by
use of saliva. Ther Drug Monit 2013;35:4–
29.
8. Perucca E. Clinical pharmacology
and therapeutic use of the new antiepileptic drugs. Fundam Clin Pharmacol
2001;15:405–17.
9. Krasowski MD. Therapeutic drug
monitoring of the newer anti-epilepsy
medications. Pharmaceuticals (Basel)
2010;3:1909–35.
10. Schapel G and Chadwick D. Tiagabine
and non-convulsive status epilepticus. Seizure 1996; 5:153–6.
RefeRences
1. Neels HM, Sierens AC, Naelerts K, et
al. Therapeutic drug monitoring of old and
newer anti-epileptic drugs. Clin Chem Lab
Med 2004;42:1228–55.
2. Patsalos PN, Berry DJ, Bourgeois BFD,
et al. Antiepileptic drugs—best practice
guidelines for therapeutic drug monitoring: A position paper by the subcommission on therapeutic drug monitoring, ILAE
Commission on Therapeutic Strategies.
Epilepsia 2008;49:1239–76.
3. LaRoche SM and Helmers SL. The new
Matthew D. Krasowski, MD,
PhD, is a clinical associate
professor and medical director of the Clinical Chemistry
and Point of Service Laboratories, and director of clinical laboratories
in the Department of Pathology at the
University of Iowa Hospitals and Clinics,
Iowa City, Iowa.
Email: [email protected].
Disclosure: The author has nothing to
disclose.
all tHe eleMents
of laBoratory
ManaGeMent, researCH
and CuttinG-edGe
teCHnoloGy will
Be tHere. WIll you?
tHe world’s larGest GatHerinG
for laBoratory MediCine
+
annual MeetinG
& CliniCal laB expo 2013
200+ New Product Introductions. this is tHe place to learn
about cutting edge technology in laboratory medicine.
+
17,000+ Attendees. Join the global leaders in clinical chemistry,
molecular diagnostics, mass spectrometry, translational medicine,
+
July 28-August 1, 2013
GeorGe r. Brown
lab management, lab medicine and more.
Convention Center
5 Packed Days. Build your agenda with educational sessions,
Houston, texas usa
networking, new science and technology previews, and more.
The New York Times recently ranked
RegistRation now open
www.aacc.org/2013am
Houston as one of the top places
to see in 2013—save the date and
watch for registration details soon.
The Must-Attend Event
for Lab Medicine
Get ready for the world’s largest gathering focusing on management,
research, and cutting-edge technology in laboratory science.
Medical Marvel
The Texas Medical Center is the
largest medical complex in the world,
with 50 member institutions.
A Culinary Destination
Choose from more than 8,000
restaurants in Houston featuring
cuisines of 35 countries and
American regions.
World-Class Museums
Houston boasts one of the
largest museum districts in the country
with 18 museums within walking
distance of each other.
Five Plenary Speakers Describe
the Future of Laboratory Medicine
Deconvoluting the Metabolic
Syndrome at a Molecular Level
C. Ronald Kahn, MD
Joslin Diabetes Center and Harvard Medical School
Boston, Mass.
2013 Wallace H. Coulter Lectureship Award
The recipient of numerous prestigious scientific awards, Dr. Kahn will open the AACC Annual Meeting as the
winner of the AACC 2013 Wallace H. Coulter Lectureship Award. Dr. Kahn’s research over the last 30 years
has defined the field of insulin signal transduction and mechanisms of altered signaling in disease. He will
present the latest findings from his laboratory using a mouse genetics model and describe how those findings impact our understanding of metabolic syndrome.
Challenging the Dogma: A New View of the
Genomic Programming of Human Development
John Mattick, PhD
Garvan Institute of Medical Research
Darlinghurst, NSW, Australia
The Vitamin D Debate:
Is Enthusiasm Outpacing Evidence?
Bruce Hollis, PhD
Medical University of South Carolina
Charleston, S.C.
Jo Ann Manson, MD, DrPH
Brigham and Women’s Hospital and
Harvard Medical School
Boston, Mass.P
Patient-Based Therapeutics Discovery
Stuart Schreiber, PhD
Broad Institute of Harvard and MIT
Cambridge, Mass.
Dining in With Trillions of Fascinating Friends
Jeffrey Gordon, MD
Washington University School of Medicine
St. Louis, Mo.
12
CliniCal laboratory news June 2013
Why is the Annual Meeting & Clinical Lab Expo
a must-attend event for you?
“I’ve been attending every year since I was a student. It allows young
members to meet some of the biggest names in the field and attend
excellent sessions on the most up-to-date clinical lab practices. I especially
enjoy the poster and oral sessions, and Society for Young Clinical
Laboratorians events, which provide great networking opportunities.”
Maria D. Pasic, PhD
Clinical Biochemist
St. Joseph’s Health Centre
Assistant Professor
Department of Laboratory Medicine and Pathobiology
University of Toronto
“The Annual Meeting and Clinical Lab Expo always has been more to me
than just a meeting. It has been a home where I gain knowledge, establish
collaborations, network with colleagues, and enjoy time with friends.”
Gregory J. Tsongalis, PhD
Director, Molecular Pathology
Professor of Pathology
Dartmouth-Hitchcock Medical Center
Lebanon, N.H.
“The Annual Meeting and Clinical Lab Expo gives me the opportunity to
connect clinical lab testing with those who bring it to fruition in the marketplace, with others from around the world who perform testing, and with
experts who present the latest science. Connecting faces and names is
another highlight of the event!”
Peggy Mann, M.S., MT(ASCP)
Quality, Safety, and Environment Program Manager
Ambulatory Practices POC Coordinator
University of Texas Medical Branch
Galveston, Texas
“It’s a great place to stay connected! Drawing scientists, laboratorians, and
exhibitors from all over the world, the Annual Meeting and Clinical Lab Expo
is a rare opportunity to take in all the latest innovations within our industry.
Plus, catching up with old friends, making new friends, and maybe even
agreeing to new research collaborations. I come away with a great sense
of renewed energy and fresh approaches, and I’d never miss it!”
Sihe Wang, PhD, DABCC, FACB
Section Head, Clinical Biochemistry
Cleveland Clinic
Cleveland, Ohio
AACC DIVISION EVENTS
Connect
Boost your AACC Annual Meeting experience by
connecting with other laboratory professionals who
share your interests! Select from these special events
and others when you register.
JuLy
27
SyCL Workshop and Mixer
Practical Approaches to Sustainable
Planning in Achieving LEAN Success
1–5:30 p.m. (Mixer 5:30–7:30 p.m.)
Hilton Americas
Sponsored by Abbott, AB Sciex, Beckman Coulter, Inc., Bio-Rad
Laboratories, Nova Biomedical, Ortho Clinical Diagnostics, Roche
Diagnostics, Sysmex America, Inc., The Binding Site, Inc., Thermo
Fisher Scientific, UTAK Laboratories, and Waters Corporation.
Geared toward current trainees, as well as new and junior
laboratory directors, this workshop will cover topics including LEAN
implementation in the clinical laboratory, how to financially justify
and implement laboratory automation, and how to create an early
and successful career path.
REGISTRATION fEE: $30
27
Saturday
Biomarkers of Acute Cardiovascular Diseases forum
Applications of High-Sensitivity
Troponin in Clinical Practice
4–6:30 p.m. Hilton Americas
Sponsored by the AACC Biomarkers of Acute Cardiovascular
Diseases Division, Singulex, and Abbott.
The next generation of high-sensitivity troponin assays will be on
the market soon. Attend this symposium if you are confused about
the current generation of troponin assays and their cutoffs, and in
particular, to learn about how the next generation of troponin assays
will be used.
REGISTRATION fEE: $20 AACC members, $30 non-members
(includes reception).
JuLy
27
Saturday
29
Monday
Annual Lipoproteins and Vascular
Diseases Division Dinner Meeting
Current Topics in Cardiovascular Disease
5:30–9:30 p.m. Hilton Americas
Saturday
JuLy
JuLy
18th Annual Management Sciences
and Patient Safety Leadership Seminar
Errors in Selection of Appropriate Laboratory
Tests and Interpretation of Test Results:
A Major Cause of Poor Patient Outcomes
5:30–8 p.m. Hilton Americas
Sponsored by the AACC Management Sciences
and Patient Safety Division.
Sponsored by the AACC Lipoproteins and
Vascular Diseases Division.
Division members are invited to this annual awards celebration and
scientific session on current topics in cardiovascular disease. The
dinner will include presentations from experts on microRNAs in lipid
metabolism, novel biomarkers, and drug targets.
REGISTRATION fEE: $50 (includes reception and dinner).
Division members only.
JuLy
30
Tuesday
International Lipoprotein Standardization forum
6–9:30 p.m. Hilton Americas
Sponsored by the AACC Lipoproteins and Vascular Diseases
Division. Cosponsored by the Japan Healthcare Technology
Foundation and Pacific Biometrics Research Foundation.
Division members are invited to join international leaders in a
discussion of recent findings related to lipoproteins, with a focus on
new technologies and standardization efforts.
REGISTRATION fEE: $40 (includes reception and dinner).
Division members only.
JuLy
30
Tuesday
Annual Nutrition Division Networking Seminar
6–9:30 p.m. Hilton Americas
Sponsored by the AACC Nutrition Division.
This meeting is an excellent opportunity for networking with
laboratory professionals interested in advancing science in the field
of nutrition. The scientific presentations will include an overview
of the clinical significance of trace elements in health and disease,
how laboratories should measure and interpret trace metal
concentrations, and the factors that influence trace metal levels in
blood.
REGISTRATION fEE: $20 (includes reception).
AuGuST
1
Thursday
11th Annual Point-of-Care Coordinators forum
The Role of Point-of-Care Testing in a Disaster Plan
7:30–10 a.m. George R. Brown Convention Center
Sponsored by the AACC Critical and Point-of-Care Testing Division.
Laboratory leaders are in a position to have a big impact on
patient safety. failure to select appropriate laboratory tests and
misinterpretation of laboratory test results can have potentially
disastrous outcomes for patients, including misdiagnosing common
disorders such as pulmonary embolism, bleeding disorders, and
hypercoagulable states. This presentation will focus on the cause
of diagnostic errors and potential solutions, particularly those that
leaders of clinical laboratories can influence.
Point-of-care testing (POCT) has become an integral part of
hospital disaster planning. Attend this event to learn how to develop
emergency and disaster response plans that fit your institution. The
program features presentations from four perspectives: real-world
scenarios from a health services officer in the Centers for Medicare
and Medicaid Services, hospital and regional disaster plans from two
point-of-care coordinators, and a discussion of a POCT emergency
and disaster guidance document now under development.
REGISTRATION fEE: $20 (includes reception).
REGISTRATION fEE: $20 (includes breakfast).
CliniCal laboratory news June 2013
13
clinical lab
JULY 30-AUGUST 1,2013
expo
HOUSTON, TEXAS
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Bangs Laboratories/Polysciences ... 3967
Chembio Diagnostic Systems,Inc. .. 2045
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A2LA American Association for
Laboratory Accreditation ......... 1337
BBlnternational .................... 3363
Chemelex,SA ...................... 2654
Eppendorf ......................... 3527
Innovize ........................... 4262
BD
Equitech - Bio Inc. ................. 3262
INOVA Diagnostics,Inc.
AACC .............................. 3728
Beckman Coulter ................... 4751
Chongqing Tianhai Medical
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Institut fur Microtechnie
Mainz GmbH .................... 5322
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Eurospital S.P.A. .................... 3948
Instrumentation Laboratory (lL) ..... 2429
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Standards Institute .........3624,3626
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Berthold Detection Systems GmbH . 3266
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Bethyl Laboratories, Inc. ............ 2766
Cognex Corporation ............... 1914
Accudynamics LLC ................. 2609
Big C: Dino-lite Scopes .............. 1950
COLA .............................. 2317
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Copan Diagnostics, Inc. ............ 3058
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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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CTK Biotech,Inc. ................... 2507
. . . . . . . . • . . . . . . . . . . . . . . . .
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bioMerieux,Inc. .................... 3205
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Daan Diagnostics Ltdl
DAAN GENE CO.Ltd. ............. 2712
Ahram Biosystems,Inc. ............. 1920
. . . . . . • . . . . . . . . .
3663
FAMECO ........................... 3006
Fapon B'lotech Inc................... 1635
Far East B'10 - Tec C 0., Lt d. ........... 2010
Festo Corporation .................. 1750
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FlexLink Systems, Inc.
. . . . • • . . . . .
1934
. . . . . . . . • . . . . .
4427
Fluid Metering,Inc. ................ 3062
Focus Diagnostics .................. 4817
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Freezerworks ...................... 2049
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Gale Force Software Corporation ... 2563
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Japanese Association of
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GenPrime,Inc. ..................... 5945
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GenWay B'lotech,Inc. ............... 1850
Jiangsu Kangjian
Medical Apparatus Co. ........... 5250
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Allen Thermal,Inc. ................. 1440
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Tech.Co. ........................ 1654
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Denka Seiken Co.,Ltd. .............. 4053
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Biosearch Technologies ............ 3163
DenLine Uniforms,Inc. ............. 5334
American Board of
Clinical Chemistry ................ 3728
Biosensia .......................... 4064
Desert Biologicalsl
Omega Biologicals ............... 2358
Grace Bio-Labs ..................... 3366
Greiner Bio-One North America ..... 4511
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H & H System,Inc. .................. 1335
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Hamilton Company ................ 4855
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American Proficiency Institute ...... 5741
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& Science Inc. ................... 5426
DFI Co.,Ltd. ........................ 5312
Harlan Bioproducts for Science,Inc. . 2968
AMHYSPIN - CECOTEPE ............. 2949
BiosPacific ......................... 3604
Dia Carta .......................... 1815
HB Optical ......................... 2868
Analis .............................. 2848
Biotix .............................. 2705
Diagam ............................ 2852
Healgen Scientific LLC .............. 1935
AnaSpec,Inc. ...................... 5249
Ani Labsystems Ltd.Oy
BIOTRON DIAGNOSTICS USA ....... 2452
DiagCor Bioscience Inc.Ltd. ........ 4252
Health Care Logisitics .............. 1913
. . . . . • . . . . . . .
4563
BIOWEST ........................... 3008
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. . . . . . . . . . . . . • . . . . . . .
1341
BIT Group
Diagnostic Automationl
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Diagnostic Consulting Network ..... 2963
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Anthro Corporation ................ 1819
Boval Company,L.P. ................ 1544
Diagnostic Net ..................... 2645
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Apacor Ltd . ........................ 2015
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Hemo bioscience .................. 2047
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. . . . . . . . . . • . . . . .
3505
. . . . . . • . . . . . . .
5128
BUHLMANN Laboratories AG ....... 2142
DIALAB GmbH ..................... 5029
Hemosure ......................... 2404
. . . . . . . . . . . • . . . . . . .
2463
Burkert Fluid Control Systems ...... 3249
Diametra ........................... 4906
Hettich ............................ 4363
Arista Biologicals Inc. .............. 2562
C & A Scientific Co.,Inc. ............. 5243
Diamond Diagnostics Inc. .......... 2615
Hipro Biotechnology Co.,Ltd. ....... 5226
ARK Diagnostics,Inc. ............... 3835
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DIARECT AG ....................... 1438
Hitachi Chemical Diagnostics ....... 1910
ARKRAY ............................ 3653
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Hologic ............................ 4213
Arlington Scientific Inc. ............ 2112
Calzyme Laboratories,Inc. .......... 2925
DiaSys Diagnostic Systems ......... 3957
Hoover Precision Products, LLC ..... 3853
Artel ............................... 3324
Cambridge Consultants ............ 4307
Diatron ............................ 3204
HORIBA Medical ................... 1323
Artron BioResearch Inc.
3066
CapitalBio Corporation ............. 4562
Diazyme Laboratories .............. 4613
Hycor Biomedical Inc.
ARUP Laboratories ................. 2815
Capralogics Inc. .................... 4209
DIBA Industries,Inc. ................ 2605
HyTest Ltd
Asahi Kasei Fibers Corporation ...... 4566
Capricorn Products LLC ............ 2744
DiCon Fiberoptics DBA Scope LED .. 1342
12A
ASCLS ............................. 3128
Cardicare Company,Ltd. ........... 5315
Dierks & Bohle,RAE ................ 2647
IBL- International Corp.............. 2508
ASCO Numatics .................... 4505
Cardinal Biologicals,Inc. ............ 5246
DIESSE Diagnostica Senese S.p.A. ... 4663
IDEX Health & Science .............. 3463
Associates of Cape Cod,Inc. ........ 2858
CARE diagnostica .................. 3469
Dirui Industrial Co.,Ltd. ............ 1617
IFCC -Inti Federation of .............. 3407
Association for Molecular Pathology 3525
Carolina Liquid Chemistries ........ 4534
DOCRO,Inc. ........................ 1611
lIine Microsystems S.L. ............. 1704
Atlas Link,Inc. ..................... 5551
CDI/Biochem ...................... 1441
Douglas Scientific,LLC .............. 5449
IMMCO Diagnostics
Audit MicroControls,Inc. ........... 5835
Cedarlane ......................... 3111
DRG International,Inc. ............. 3305
Immucor,Inc. ...................... 4829
Auer Precision Co. ................. 1320
CeliaVision ......................... 2545
Drummond Scientific .............. 4163
Immundiagnostik AG .............. 2726
Aurora Biomed ..................... 1354
CeliTrend GmbH ................... 2645
D-Tek .............................. 3048
Immuno Concepts ................. 2048
AUS BIO R&D Europe ............... 5841
Centers for Disease Control
& Prevention .................... 1348
DTx Inc. ............................ 3267
immunochemical intelligence GmbH 2645
Dynex Technologies Inc. ........... 2753
Immunodiagnostic Systems Inc. .... 3910
EastCoast Bio,Inc. .................. 2263
APTEC Diagnostics NV
. . . . • . . . . . . .
Autobio Diagnostics Co.Ltd......... 4063
Centers for Medicare
& Medicaid Services ............. 3024
. . . . . . . • • . . . . .
3949
. . . . . . . . . . . . . . . . . . • • . . . . .
3227
. . . . . . . . . . . . . . . . . . . . . . . . . . • . . . . .
2911
.
. . . . . . . . . . • . . . . .
3904
eBI'osc'lence ....................... 1343
Immunology Consultants
Laboratory,Inc. .................. 3368
Cepheid ........................... 4529
EDAN INSTRUMENTS, INC. .......... 1318
ImmunoReagents,Inc.
Awareness Technology,Inc. ......... 2904
Ceragem Medisys,Inc. .............. 2034
Elga Labwater ...................... 5450
Improve Medical ................... 1517
AWEX .............................. 2947
Cerilliant
Elitech Group Company ............ 4707
IMRA America Inc. ................. 3867
Axxin .............................. 2651
Cerner ............................. 5846
EMD Millipore ...................... 2855
InBios International,Inc. ............ 1823
AZOG,Inc. ......................... 1535
CERTEST BIOTEC S.L. ............... 2557
Emergo Group ..................... 1437
Informa Life Sciences ............... 5406
B&E Scientific Inc.
CETAC Technologies ................ 2625
Entrocomponent Solutions (ECS) ... 2742
Innogenetics Inc. .................. 1817
AutoGenomics,Inc.................. 2415
AVE Science & Technology
Industrial Co. .................... 1634
. . . • . . . . . • • . . . . . . .
5326
. . . . . . . . . . . . . . . . . . • . . . . . . . .
4824
Chata Biosystems .................. 1546
14
CLINICAL LABORATORY NEWS JUNE 2013
.
ITSP Solutions Inc. ................. 3966
IVD Industry Connectivity
Consortium ..................... 5847
Jadak,LLC .......................... 1536
Bio-Rad Laboratories ............... 3929
Aries Filterworks
ITC Nexus DX ...................... 5421
GenMark Diagnostics,Inc. .......... 4407
ALCOR Scientific Inc. ............... 1538
Anteo Diagnostics ................. 3664
2724
Jackson ImmunoResearch Lab,Inc... 2128
Golden West Biologicals,Inc. ....... 3845
3349
. . . . . . . . • • . . . . . . • . . . . . . .
IT41P ............................... 2749
General Biologicals Corp. ........... 2708
BioPorto Diagnostics A/S ........... 1834
. . . . . . . . . . . . . . . • • . . . . . . . . .
Isensix,Inc.
Genisphere,LLC .................... 3869
Gold Standard Diagnostics ......... 4411
Ansh Labs,LLC
lonics Mass Spectrometry Group .... 4907
IQuum,Inc. ........................ 4725
IVD Technologies .................. 1443
Daitron,Inc. ........................ 2464
American Medical Technologists .... 2750
Invetech ........................... 2735
Iwaki America Inc. .................. 2627
Dako .............................. 4469
BioSero ............................ 1314
in.vent Diagnostica GmbH .......... 2645
Inverness Medical Innovations
Hong Kong ...................... 1442
Gems Medical Sciences ............ 3806
Bionostics .......................... 2466
Dawning Technologies,Inc. ........ 4443
2521
GE Healthcare ...................... 3014
1705
Aim Lab Automation Technologies
. . . . . . • . . . . . .
. . . . . . . • . . . . .
3068
Jiangsu Zhengji Instruments Co.Ltd. 4069
Jiangyin Hongmen
Rubber Plastic Product ........... 5320
JSR Life Sciences ................... 3468
Kamiya Biomedical Company ....... 3825
Kem-En-Tec Diagnostics ............ 4606
Kestrel ............................. 2365
Kewaunee Scientific Corporation ... 1448
Key Tech ........................... 3950
Kikkoman Biochemifa Company .... 1435
Kinematic Automation Inc. ......... 2863
KMC Systems,Inc. .................. 2304
KNF Neuberger Inc. ................ 4405
Kova International,Inc. ............. 3952
KRONUS,Inc. ....................... 3934
Lab Medica International ........... 1542
Lab Products,Inc. .................. 1906
LabCorp ........................... 5415
LABiTec GmbH ..................... 4353
Labnovation Technologies,Inc. ..... 2315
Laboratory Desk Reference ......... 3946
Labotix Automation,Inc............. 3847
Labroots,Inc.
. . . . . . . . . . . . . . . • . . . . . . .
1306
Labtest ............................ 1317
Lampire Biological Laboratories,Inc. 4607
LasX Industries,Inc. ................ 5747
Lathrop Engineering Inc.
. . . • . . . . . . .
3856
Lee Company,The .................. 1839
LGP Consulting,Inc. ................ 1543
Life Technologies .................. 3504
LifeSign LLC ........................ 5409
Linear Chemicals, S.L. .............. 2555
LipoScience ........................ 5535
Liuyang Medical Instrument Factory 5329
Lohmann Precision Die Cutting ..... 1404
LRE Medical, Esterline Corp. ........ 2253
LSI International Inc. ............... 5346
Luminex Corporation .............. 4539
LW Scientific ....................... 2353
MagArray,Inc. ...................... 3865
Magellan Diagnostics,Inc. .......... 5340
MagnaBioSciences ................. 2207
MagnaMedics ...................... 3965
MagneMotion ..................... 4863
Magnisense
. . . . . . . . . • . . . . . . • . . . . . . .
2809
Magsphere Inc. .................... 4264
Maine Biotechnology Services ...... 3607
Maine Manufacturing,LLC .......... 3964
Maine Standards Co.LLC ........... 3515
MAKER Biotechnology .............. 5443
March Manufacturing Inc. .......... 4167
Market Diagnostics International ... 2008
GEORGE R. BROWN CONvENTiON CENTER
TO REGisTER, GO TO WWW.AACC.ORG/2013AM
MATEST Systemtechnik GmbH . . . . . . 4756
MBL International . . . . . . . . . . . . . . . . . . 5154
McKesson . . . . . . . . . . . . . . . . . . . . . . . . . . 3938
MD Anderson Cancer Center . . . . . . . . 5941
MediaLab, Inc . . . . . . . . . . . . . . . . . . . . . . 4558
Medica 2013/Messe Duesseldorf . . . . 3610
Medica Corporation . . . . . . . . . . . . . . . . 1324
Medical Device Safety Service GmbH 4458
Medical Electronic Systems . . . . . . . . . 2704
Medical Laboratory Evaluation . . . . . . 2807
MedicalLab Management Magazine 1316
MEDIPAN GmbH . . . . . . . . . . . . . . . . . . . 2641
MediSensor, Inc . . . . . . . . . . . . . . . . . . . . . 1717
Medix Biochemica . . . . . . . . . . . . . . . . . 3606
Megatone Electronics Corp . . . . . . . . . 5339
Meizhou Cornely Hi-Tech Co . Ltd . . . . 5248
Mercodia Inc . . . . . . . . . . . . . . . . . . . . . . . 3908
Mercy Ships . . . . . . . . . . . . . . . . . . . . . . . . 5935
Meridian Bioscience, Inc . . . . . . . . . . . . 4514
Meridian Life Science, Inc . . . . . . . . . . . 4508
Michigan Diagnostics, LLC . . . . . . . . . . 2465
Micro Digital Co ., Ltd . . . . . . . . . . . . . . . . 1312
Micro Lab Instruments . . . . . . . . . . . . . 1912
Microbix Biosystems . . . . . . . . . . . . . . . 2558
MicroDiscovery GmbH . . . . . . . . . . . . . 2645
microfluidic ChipShop GmbH . . . . . . . 2663
Microliter Analytical Supplies . . . . . . . 5047
Micronics, Inc . . . . . . . . . . . . . . . . . . . . . . . 1505
Micropoint Bioscience, Inc . . . . . . . . . . 2029
Midland BioProducts Corporation . . 3916
Mikrogen . . . . . . . . . . . . . . . . . . . . . . . . . . 5341
MiniFab . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2410
MiniGrip . . . . . . . . . . . . . . . . . . . . . . . . . . . 1855
Minitubes . . . . . . . . . . . . . . . . . . . . . . . . . 3304
Miracle Electronic Devices Pvt . Ltd . . . 2041
Mitsubishi Chemical USA, Inc . . . . . . . 3924
MK Fluidic Systems . . . . . . . . . . . . . . . . . 1351
ML LifeSciences . . . . . . . . . . . . . . . . . . . . 1956
MLO-Medical Laboratory Observer . . 5253
Moduline Systems, Inc . . . . . . . . . . . . . . 1349
Moeller Medical GmbH . . . . . . . . . . . . . 3268
Monobind Inc . . . . . . . . . . . . . . . . . . . . . . 2915
Moss, Inc . . . . . . . . . . . . . . . . . . . . . . . . . . . 4109
Motoman Yaskawa . . . . . . . . . . . . . . . . . 2453
MT Promedt Consulting GmbH . . . . . 4266
Multisorb Technologies . . . . . . . . . . . . 2445
m-u-t AG . . . . . . . . . . . . . . . . . . . . . . . . . . 3355
Nanjing Liming Bio-Products Co ., Ltd 5343
Nanjing Perlove Medical
Equipment Co .Ltd . . . . . . . . . . . . . . . . 5318
Nano-Ditech Corporation . . . . . . . . . . . 1350
Nanoq . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2850
Nantong Egens Biotechnology
Co ., Ltd . . . . . . . . . . . . . . . . . . . . . . . . . . . 5344
Neogen Corporation . . . . . . . . . . . . . . . 2506
New England Biolabs, Inc . . . . . . . . . . . 4463
New England Small Tube . . . . . . . . . . . 2013
NewScen Coast Bio-Pharmaceutical
Co .,Ltd . . . . . . . . . . . . . . . . . . . . . . . . . . . 5221
NICHIREI BIOSCIENCES, INC . . . . . . . . .
Nihon Dempa Kogyo Co ., Ltd . . . . . . .
Nikon Instruments Inc . . . . . . . . . . . . . .
Ningbo Ruiyuan
Biotechnology Co ., Ltd . . . . . . . . . . .
NIST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
NOF America Corporation . . . . . . . . . .
Norgen Biotek Corporation . . . . . . . . .
Nor-Lake Scientific . . . . . . . . . . . . . . . . .
Nova Biologics, Inc . . . . . . . . . . . . . . . . . .
Nova Biomedical . . . . . . . . . . . . . . . . . . .
Novatec Immundiagnostica GmbH . .
NuAire Inc . . . . . . . . . . . . . . . . . . . . . . . . . .
OAKRIDGE PRODUCTS . . . . . . . . . . . . .
OAPI Medical Devices . . . . . . . . . . . . . .
ODPM . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Olympus America, Inc . . . . . . . . . . . . . .
Omega Bio-tek . . . . . . . . . . . . . . . . . . . . .
Omega Diagnostics Group PLC . . . . .
OPERON . . . . . . . . . . . . . . . . . . . . . . . . . . .
OPTI Medical Systems, Inc . . . . . . . . . .
OptiGene Limited . . . . . . . . . . . . . . . . . .
OPTRICON GMBH . . . . . . . . . . . . . . . . . .
OraSure Technologies, Inc . . . . . . . . . . .
Orchard Software Corp . . . . . . . . . . . . .
Ortho Clinical Diagnostics . . . . . . . . . .
OYC Americas, Inc . . . . . . . . . . . . . . . . . .
Oyster Bay Pump Works, Inc . . . . . . . . .
Pacific Die Cut Industries . . . . . . . . . . .
PAML . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Parallel - Synthesis Technologies, Inc .
Parker Precision Fluidics Division . . . .
Path - Tec . . . . . . . . . . . . . . . . . . . . . . . . . .
Pel-Freez Biologicals . . . . . . . . . . . . . . .
Perfect Ease Biotech Co ., Ltd . . . . . . . .
Pevco . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Pharmasan Labs . . . . . . . . . . . . . . . . . . .
Phytronix Technologies Inc . . . . . . . . . .
Plasma Services Group . . . . . . . . . . . . .
PlexBio Co . Ltd . . . . . . . . . . . . . . . . . . . . . .
Pointe Scientific, Inc . . . . . . . . . . . . . . . .
Poly-AN GMBH . . . . . . . . . . . . . . . . . . . . .
Polymed Therapeutics, Inc . . . . . . . . . .
Polymedco Cancer Diagnostic
Products LLC . . . . . . . . . . . . . . . . . . . .
Polymedco, Inc . . . . . . . . . . . . . . . . . . . . .
Polymer Technology Systems, Inc . . . .
POLYMICROSPHERES . . . . . . . . . . . . . . .
Pozzetta Scientific . . . . . . . . . . . . . . . . . .
Precision Converting Solutions, LLC
Precision Dynamics - St . John . . . . . . .
Precision Systems Inc . . . . . . . . . . . . . . .
Preco, Inc . . . . . . . . . . . . . . . . . . . . . . . . . . .
PrimeraDx . . . . . . . . . . . . . . . . . . . . . . . . .
PrimerDesign Ltd . . . . . . . . . . . . . . . . . . .
Princeton BioMeditech Corp . . . . . . . .
Prior Scientific, Inc . . . . . . . . . . . . . . . . . .
Pro-Lab Diagnostics . . . . . . . . . . . . . . . .
5424
3968
1534
2969
2026
3064
4369
2325
3369
3935
2662
3026
1550
3108
2913
1638
5146
1927
2551
5115
1811
2649
2752
2134
4229
3167
1734
1804
1445
1911
1511
1322
4368
1745
1606
1548
2667
2669
1907
3837
2643
2307
4204
4207
2012
2869
1744
2311
5336
4504
1746
5946
5152
5411
4269
1915
Proliant Health and Biologicals . . . . .
Puritan Medical Products . . . . . . . . . . .
PZ CORMAY S .A . . . . . . . . . . . . . . . . . . . .
Qarad . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
QBC Diagnostics . . . . . . . . . . . . . . . . . . .
Qiagen Lake Constance GmbH . . . . . .
Qingdao Hightop Biotech Co ., Ltd . . .
Quansys Biosciences . . . . . . . . . . . . . . .
Quanterix . . . . . . . . . . . . . . . . . . . . . . . . . .
QUANTI SCIENTIFICS . . . . . . . . . . . . . . .
Quantimetrix Corporation . . . . . . . . . .
Quest Diagnostics . . . . . . . . . . . . . . . . . .
Quimica Clinica Aplicada, S .A . . . . . . .
R D Plastics Company . . . . . . . . . . . . . . .
Radiometer America . . . . . . . . . . . . . . .
Rainin Instrument, LLC . . . . . . . . . . . . .
Randox Laboratories US Ltd . . . . . . . . .
Randox Life Sciences . . . . . . . . . . . . . . .
Rayto Life & Analytical Sciences
Co, Ltd . . . . . . . . . . . . . . . . . . . . . . . . . . .
R-Biopharm AG . . . . . . . . . . . . . . . . . . . .
Response Point of Care . . . . . . . . . . . . .
Retractable Technologies, Inc . . . . . . .
Rheonix, Inc . . . . . . . . . . . . . . . . . . . . . . . .
RND Group, Inc ., The . . . . . . . . . . . . . . . .
Roche Diagnostics Corporation . . . . .
Rockland Immunochemicals, Inc . . . .
Rocky Mountain Diagnostics . . . . . . .
ROHM CO ., Ltd . . . . . . . . . . . . . . . . . . . . . .
Rotek Industries . . . . . . . . . . . . . . . . . . . .
Runlab Labware Manufacturing
Co ., Ltd . . . . . . . . . . . . . . . . . . . . . . . . . . .
RURO Inc . . . . . . . . . . . . . . . . . . . . . . . . . . .
SA Scientific LTD . . . . . . . . . . . . . . . . . . .
Samsung Electronics . . . . . . . . . . . . . . .
Sansure Biotech, Inc . . . . . . . . . . . . . . . .
Sarstedt, Inc . . . . . . . . . . . . . . . . . . . . . . . .
Sartorius Stedim Biotech . . . . . . . . . . .
Scantibodies Laboratory Inc . . . . . . . .
SCC Soft Computer . . . . . . . . . . . . . . . . .
SCETI K .K . . . . . . . . . . . . . . . . . . . . . . . . . .
Scienion AG . . . . . . . . . . . . . . . . . . . . . . . .
Scienion US, Inc . . . . . . . . . . . . . . . . . . . .
Scientific Systems, Inc . . . . . . . . . . . . . . .
Scimedx Corporation . . . . . . . . . . . . . . .
Sclavo Diagnostics International Srl
Scripps Laboratories . . . . . . . . . . . . . . .
ScyTek Laboratories, Inc . . . . . . . . . . . . .
SDIX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Sebia Electrophoresis . . . . . . . . . . . . . .
Seegene, Inc . . . . . . . . . . . . . . . . . . . . . . . .
Sekisui Diagnostics . . . . . . . . . . . . . . . . .
SelectScience . . . . . . . . . . . . . . . . . . . . . .
Sequenom, Inc . . . . . . . . . . . . . . . . . . . . . .
SeraCare Life Sciences . . . . . . . . . . . . . .
Shanghai Kehua Bioengineering . . . .
Shanghai Chemtron Biotech . . . . . . . .
Shanghai Fosun
Long March Medical . . . . . . . . . . . . .
4609
4554
4667
5410
1805
4068
4465
5448
1504
2364
3757
4917
2553
2362
4650
1310
3245
3225
1735
4657
1454
1942
5005
5114
4049
2259
1640
1739
2462
5015
1845
3768
4765
2668
2540
5206
5111
1411
5314
2645
3263
1549
5213
1849
5211
2568
1840
3453
3115
1627
1645
2613
4404
3568
2363
1938
Shanghai Upper Biotech . . . . . . . . . . .
Shanghai ZJ Bio-Tech . . . . . . . . . . . . . .
Shel Lab
(Sheldon Manufacturing Inc .) . . . . .
Shenzhen Emperor Electronic
Technology . . . . . . . . . . . . . . . . . . . . . .
Shenzhen iCubio Biomedical
Technology Co . . . . . . . . . . . . . . . . . . .
Shenzhen Landwind Industry . . . . . . .
Shenzhen Mindray Bio-Medical
Electronics . . . . . . . . . . . . . . . . . . . . . .
Shenzhen Procan Electronics Inc . . . .
Shenzhen Xilaiheng Medical
Electronics . . . . . . . . . . . . . . . . . . . . . . .
SIAS AG . . . . . . . . . . . . . . . . . . . . . . . . . . .
Siemens Healthcare . . . . . . . . . . . . . . . .
SIFIN GMBH BERLIN . . . . . . . . . . . . . . . .
Sigma-Aldrich . . . . . . . . . . . . . . . . . . . . . .
Siloam Biosciences . . . . . . . . . . . . . . . . .
SimPort Scientific . . . . . . . . . . . . . . . . . .
SLR Research Corporation . . . . . . . . . .
SMC Corporation of America . . . . . . .
SNIBE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Softtech Health . . . . . . . . . . . . . . . . . . . .
Sol-Millennium Medical, Inc . . . . . . . . .
Sony DADC . . . . . . . . . . . . . . . . . . . . . . . .
SouthernBiotech . . . . . . . . . . . . . . . . . . .
Span Diagnostics Ltd . . . . . . . . . . . . . . .
Spark Holland B .V . . . . . . . . . . . . . . . . . . .
Sparton Medical . . . . . . . . . . . . . . . . . . .
Spherotech, Inc . . . . . . . . . . . . . . . . . . . .
Spinreact S .A .U . . . . . . . . . . . . . . . . . . . . .
Stanbio Laboratory . . . . . . . . . . . . . . . . .
STRATEC Biomedical AG . . . . . . . . . . . .
Stratos Product Development . . . . . .
Streck, Inc . . . . . . . . . . . . . . . . . . . . . . . . . .
Sunostik Medical Technology . . . . . . .
Sunquest Information Systems . . . . .
SurModics IVD . . . . . . . . . . . . . . . . . . . . .
Swisslog . . . . . . . . . . . . . . . . . . . . . . . . . . .
Syntron Bioresearch, Inc . . . . . . . . . . . .
Sysmex America, Inc . . . . . . . . . . . . . . . .
Taigen Bioscience Corporation . . . . . .
Tarcine BioMed Inc . . . . . . . . . . . . . . . . .
Tecan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Technidata . . . . . . . . . . . . . . . . . . . . . . . .
Techno Medica Co . Ltd . . . . . . . . . . . . . .
Teco Diagnostics . . . . . . . . . . . . . . . . . . .
TELCOR . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Tetracore, Inc . . . . . . . . . . . . . . . . . . . . . . .
THERADIAG . . . . . . . . . . . . . . . . . . . . . . . .
Therapak Corporation . . . . . . . . . . . . . .
Thermo Scientific . . . . . . . . . . . . . . . . . .
thinXXS Microtechnology AG . . . . . . .
Tianjin Bio-Enoche Engineering . . . .
TOKYO BOEKI MACHINERY LTD . . . . . .
Topscien Instrument (Ningbo) . . . . . .
Tosoh Bioscience . . . . . . . . . . . . . . . . . . .
Toyobo U .S .A ., Inc . . . . . . . . . . . . . . . . . . .
1949
1644
1742
5943
1647
3942
3321
1446
1843
3456
3449
2639
1649
4165
5011
2327
3063
4263
1943
1847
2564
3565
1355
4557
2763
3165
2650
3614
3763
4439
2144
1751
2212
1434
4408
2762
2149
1846
1646
4811
1954
1948
5212
4451
3963
3012
4113
5140
4468
5440
1916
1941
4642
5110
Tricontinent . . . . . . . . . . . . . . . . . . . . . . .
TRINA BIOREACTIVES AG . . . . . . . . . . .
Trinity Biotech . . . . . . . . . . . . . . . . . . . . .
UBIFRANCE . . . . . . . . . . . . . . . . . . . . . . . .
UCLA Health System . . . . . . . . . . . . . . .
UCP Biosciences, Inc . . . . . . . . . . . . . . . .
UCSF Medical Center . . . . . . . . . . . . . . .
UNICO/United Products
& Instruments . . . . . . . . . . . . . . . . . . .
URIT Medical Electronic Co ., Ltd . . . . .
UTAK Laboratories, Inc . . . . . . . . . . . . . .
ValuMax International . . . . . . . . . . . . . .
Vector Laboratories, Inc . . . . . . . . . . . . .
VEDA .LAB . . . . . . . . . . . . . . . . . . . . . . . . . .
Vircell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ViroStat, Inc . . . . . . . . . . . . . . . . . . . . . . . . .
Vital Diagnostics . . . . . . . . . . . . . . . . . . .
Viva Products . . . . . . . . . . . . . . . . . . . . . .
Vonco Products . . . . . . . . . . . . . . . . . . . .
Wako Diagnostics . . . . . . . . . . . . . . . . . .
WAMA Diagnostica . . . . . . . . . . . . . . . .
Warde Medical Laboratory . . . . . . . . . .
Waters Corporation . . . . . . . . . . . . . . . .
Watson Bio Lab . . . . . . . . . . . . . . . . . . . .
Werfen Group . . . . . . . . . . . . . . . . . . . . .
West Medica Produktins-GmbH . . . . .
WesTgard QC, Inc . . . . . . . . . . . . . . . . . . .
Wheaton . . . . . . . . . . . . . . . . . . . . . . . . . .
WHPM . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Wi Medical Device Development . . .
Wiener Laboratorios SAIC . . . . . . . . . .
Wiley . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Wisepac Active Packaging
Components Co . . . . . . . . . . . . . . . . .
Wondfo USA . . . . . . . . . . . . . . . . . . . . . . .
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Zeta Corporation . . . . . . . . . . . . . . . . . . .
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Zhejiang Medicines &
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Zhongke Meiling Cryogenics
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Zhongshan Chuangyi Biochemical . .
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5207
3158
2907
1643
1754
1947
1838
4253
4435
2459
3666
3669
2656
1844
3926
1338
1738
4129
1648
1637
4923
5848
2421
5428
4127
5045
2408
1650
5225
1748
1339
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3962
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As of May 8, 2013
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CliniCal laboratory news June 2013
15
Disease Control and Prevention (CDC).
not use these products to meet the require­
In 2006, CDC recommended that opt-out
ments of the Medicare and Medicaid EHR
HN screening be a part of routine clinical
Incentive programs.
EHRMagic-Ambulatory and EHRMag­
care for American adolescents and adults
ages 13-64.
REGULATORY
•
•
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USPSTF now recommends that clini­
ethical questions, such as neurology and ge­
•
ic-Inpatient, both developed by EHRMagic
Inc. of Santa Fe Springs, Cali£, no longer
cians screen all people ages 15 to 65, as well
meet the EHR certification requirements.
as younger adolescents and older adults
The EHRs must be certified by a certifica­
tion body authorized by the Office of the
Presidential Commission Will
netics, in addition to various settings such
who are at increased risk for HN infection.
Study Inci dental Findi ng s
as clinical and research. The implications of
It also recommends that all pregnant wom­
National Coordinator for Health IT (ONC)
how incidental findings are handled affect
en, including those in labor whose HN sta­
before regaining certification.
tus is unknown, be screened.
T
he Presidential Commission for the
Study of Bioethical Issues announced
research participants, patients, consumers,
that in an upcoming report it would focus
and healthcare professionals, they noted.
More about ONe's certification process
The task force's grade A recommenda­
on the ethical implications of incidental
In a forthcoming report, the commission
tion is important because, under the Af­
findings resulting from genome sequenc­
plans to cover the importance of what pa­
fordable Care Act, private health insurance
ing, an area receiving growing attention as
tients and participants are told by health­
policies must offer free preventive services
after
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•
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that have been given an A or B recommen­
PCORI Awards $88.6 Million
dation by USPSTF. In addition, Medicaid
in Funding for Comparative
programs receive financial incentives to fol­
Effectiveness Research Projects
More information is available from
low these recommendations. Many profes­
T
part of the informed consent process.
www.bioethics.gov.
sional societies also base their recommen­
dations on USPSTF decisions.
Medical Genetics and Genomics released
•
•
as
aims or goals of testing discovered during
recommendations for incidental findings,
•
a proce­
care professionals, not only
dure or a test is performed, but
In March, the American College of
healthit.gov.
before
sequencing becomes more routine. Inci­
dental findings are data beyond the original
sequencing a genome or exome.
for EHR technologies is available at www.
•
•
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The task force noted in its report that
•
he Patient-Centered Outcomes Re­
search Institute (PCORl) has approved
51 new awards, totaling $88.6 million over
3 years, to fund comparative clinical ef­
listing 24 conditions and associated genes
USPSTF Releases Final HIV
although there is no cure for HN infection,
fectiveness research (CER) projects under
and variants that should be reported for in­
Screenin g Rec ommendat ions
treating people with HN earlier can not
the first four areas of its National Priorities
cidental findings in all patients regardless of
T
age (See eLN, May 2013).
he u.s. Preventive Services Task Force
only reduce their risk of developing AIDS
for Research agenda. Established under the
(USPSTF) released its final recommen­
and delay its onset, but it also decreases the
Affordable Care Act, PCORl has now
awarded nearly $130 million.
dation statement on screening for HIV,
chance that they will pass on the infection
mission members discussed several fields
bringing the task force closer in line with
to someone else. In addition, treating preg­
The projects approved include studies
in which incidental findings raise serious
recommendations from the Centers for
nant women reduces the chances that the
of how to best care for people with kidney
virus will be transmitted to their babies.
disease, certain cancers, obesity, asthma,
In a recent meeting, presidential com­
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The recommendations are online in
diabetes, and various mental health condi­
Annals of Internal Medicine, as
well as
tions. Other projects will explore ways to
on the USPSTF website, www.uspreventive
support patient decision-making, reduce
the
healthcare delivery systems.
•
•
•
Insulin
Now it is possible to run quantitative insulin assays on
your existing chemistry analyzer without the hazardous
radioactivity of RIAs or the high cost of ELiSAs.
•
•
•
•
•
•
PCORl's funding announcements con­
•
sist of three annual cycles and seek propos­
Two EHR Systems
als for research that will provide patients
he government is sending the message
and those who care for them with the
that its electronic healthcare record
evidence-based information needed to make
(EHR) certification requirements have to
better-informed health decisions. Twenty of
be taken seriously. Two EHRs previously
the latest awards address PCORl's national
certified for healthcare providers to use as
research priority area of assessment of pre­
part of the Medicare and Medicaid Elec­
vention, diagnosis, and treatment options;
tronic Health Record EHR Incentive Pro­
13 align with the priority area "improving
grams have had their certifications revoked.
healthcare systems;" eight address "commu­
The insulin assay is highly specific and features liquid­
Farzad Mostashari, MD, the national coor­
nication and dissemination research;" and 10
stable reagents requiring no dilution or mixing.
dinator for health information technology
align with "addressing disparities:'
Assay Range:
1 -100 IlIUlmL
Sample Type:
serum or plasma
in the Department of Health and Human
More information on the awards is
Services, announced that the products do
available from the PCORl website, www.
not meet standards and that providers can-
pcori.org.
a-1 Microglobulin
Assay Range:
mglL (serum /plasma)
mg/L (urine)
1.0-137
0.2-34
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Government Rejects
T
/
specific health disparities, and improve
servicestaskforce.org.
Fructosamine
Colorimetric assay. Includes calibrator.
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ed for clinical diagnostic use of this HCC
•
•
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decisions for cancer patients. Approximate­
tial for a large-scale global surveillance test­
ly 60% of all cancer patients receive radio­
ing opportunity:' said Yujin Hoshida, MD,
therapy during their treatment, according
PhD, who led the discovery of the signature
to Javier F. Torres-Roca, MD, co-founder
while working as a postdoctoral fellow at
and chief scientific officer of CvergenX.
The Broad Institute.
The goal of the research is to develop an
assay that will reduce the need for radia­
diagnosed with hepatocellular carcinoma
OHSU and Intel to Collaborate
(HCC) and hepatitis C-related early-stage
•
on Computing Solutions
cirrhosis are at the highest risk for poor
CvergenX, NCI Work to
•
•
•
•
•
•
•
•
tion therapy by identifying which patients
will not respond to treatment. Initially, the
prognosis. NanoString plans to assess the
Develop Predictive Test for
company will focus on rectal cancer, where
regon Health & Science University
feasibility of developing a diagnostic as­
Radiation Therapy Success
pre-operative radiotherapy is part of the
for Genomic Analysis
O
that could lead to better radiation therapy
gene signature, especially given the poten­
(OHSU) and Intel have joined forces
say based on the HCC gene signature that
to develop next-generation computing
would run on the nCounter Analysis Sys­
technologies that will increase the speed,
tem. "This platform could provide the mul­
precision, and cost-effectiveness of ana­
tiplexed gene expression capabilities need-
T
he National Cancer Institute has grant­
standard-of-care for patients with stage
ed CvergenX more than $2 million to
two or three disease. In this group, approxi­
develop a reliable radiosensitivity test us­
mately 40% of patients do not respond to
ing a molecular signature index technology
the therapy.
lyzing an individual's genetic profile. This
multi-year collaboration combines Intel's
extreme-scale,
high-performance
com­
puting solutions with OHSU's innovative
four-dimensional approach to imaging
and analyzing the molecular drivers of
cancer and other diseases. By joining their
resources, the two organizations hope to
develop a way to create a highly detailed
circuit diagram of the genome. This infor­
mation would allow clinicians to compare a
patient's circuitry with the map of a healthy
genome in order to isolate the patient's ge­
netic abnormalities and determine which,
if any, are linked to disease. The partner­
ship's first projects will focus on genetic
profiling of patients' tumors to look for
patterns in disease progression and how to
use this information to predict the tumor's
response to treatment.
•
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Qiagen Inks Deal to
Buy Ingenuity Systems
Q
iagen finalized a deal on April 29 to
acquire Ingenuity Systems, a provider
of software solutions to analyze and inter­
pret the biological meaning of genomic
data, for $105 million. The centerpiece of
Ingenuity's product portfolio is the Inge­
nuity knowledge base, a 14-year effort to
manually curate, model, and computation­
Elevated levels of Lipoprotein(a) are considered to be both a causal risk factor and independent
genetic marker of atherosclerotic disorders. Lipoprotein(a) levels are genetically determined and
ally structure the vast amount of existing
are unaffected by diet, exercise or other lifestyle modifications used to lower lipid levels. Increased
biomedical literature, including genomic
Lipoprotein(a) levels mean an individual will always be at increased risk of a cardiovascular event,
variations implicated in human disease and
thousands of disease models. The Ingenuity
making Lipoprotein(a) testing an essential addition to the lipid profile.
knowledge base and software applications
allow users to interpret the increasingly
large amounts of biological data produced
by human genome sequencing in hopes of
Randox Lipoprotein(a)
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Ingenuity is also developing a new prod­
uct to enable broader adoption of next­
generation sequencing in molecular diag­
nostics by offering an optimized and scal­
able solution for interpreting and scoring
clinical variants identified by sequencing­
based molecular diagnostic tests. The acqui­
producing more accurate results
•
-
giving a true reflection of the isoforms
present in the population
•
sition of Ingenuity will significantly expand
and strengthen Qiagen's own curated data­
Five point calibrator
•
Extensive measuring range
Applications available for a wide range of analyzers
base, which is commercially embedded in
lab assays sold through Qiagen's GeneGlobe
content portal.
•
•
•
•
•
•
•
•
•
NanoString Acquires Liver Cancer
Gene Signature From Broad Institute
T
he Broad Institute has granted an exclu­
sive worldwide license to NanoString
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CLINICAL LABORATORY NEWS JUNE 2013
17
risk of any diabetic complication, with an
respectively. After multivariate adjustment,
odds ratio of 3.1.
each 1 nglmL increase in galectin-3 was
associated with an estimated 2.9% higher
•
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•
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risk of mortality, 2.1% increased risk of
Displaying Fees Leads
first morbid event, and 2.2% greater risk of
to Fewer Test Orders
•
•
•
•
•
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•
•
•
sity, individuals with type 1 diabetes may
M
heart failure hospitalization. Including the
erely displaying the Medicare allow­
change in other measurements, such as left­
able fee for diagnostic laboratory
ventricular ejection fraction, serum sodi­
eGDR Linked to Complications
share genetic and environmental factors
tests at the time of order entry can influence
um, and uric acid, the change in galectin-3
in Type 1 Diabetes
that result in reduced insulin sensitivity, a
physician ordering behavior, even without
from baseline to 4-months and baseline to
12-months remained significantly associat­
L
ow estimated glucose disposal rate
phenomenon sometimes called double­
any other type of educational interven­
(eGDR) is associated with micro- and
diabetes, according to the authors.
tion (JAMA Intern Med 2013 doi:1O.1001/
ed with all endpoints. However, because of
Researchers at Montefiore Medical Cen­
jamainternmed.2013.232). These findings
the smaller number of events, the associa­
macro-diabetic complications in patients
with type 1 diabetes, suggesting that eGDR
ter in New York City wanted to explore the
suggest that this simple measure might
tion with heart failure hospitalization was
could be useful in identifying patients who
distribution of eGDR in type 1 diabetics
reduce the number of inappropriately or­
no longer significant.
would benefit most from early, aggressive
and the association between eGDR and
dered diagnostic tests.
prevention strategies (Diabetes Care 2013
diabetes complications, because the hospi­
Researchers at Johns Hopkins Hospital
doi:10.2337/dcl2-1693).
Valsartan was not associated with a ben­
eficial effect on any outcome in the subset
tal's surrounding community has the high­
in Baltimore were interested in evaluat­
of Val-HeFT subjects who provided base­
A formula based on HbA1c, presence
est rates of type 2 diabetes and obesity in
ing whether an uncomplicated method
line galectin-3 levels. However, in patients
of hypertension, and waist circumference,
New York City and among the highest in
to reduce lab test ordering would actually
with baseline galectin-3 levels below the
eGDR is an alternate method of estimat­
the country.
result in fewer tests ordered. From a total
median, use of valsartan was associated
ing insulin sensitivity and has been vali­
In a cohort of 207 white, black, or
of 70 tests representing the 35 most fre­
with a significant decrease in hospitaliza­
dated in patients with type 1 diabetes. It
Hispanic adults with type 1 diabetes, the
quently ordered and the 35 most expensive,
tions for heart failure.
also is more practical than the accepted
authors found that ethnicity was strong­
the authors randomly selected 61 tests for
standard for measuring insulin sensitivity,
ly associated with eGDR, with African­
the study: 31 in the control arm, without
•
the euglycernic-hyperinsulinernic clamp. Al­
Americans having significantly lower eGDR
charges displayed, and 30 in the active arm
Scalp Cortisol
though insulin resistance is a hallmark of
than Hispanics or whites. In comparison to
with charges displayed.
type 2 diabetes, in populations with high
patients with the highest eGDR, those with
During a 6-month baseline period,
prevalence of type 2 diabetes and obe-
the lowest eGDR had a significantly greater
the authors collected data about usage of
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With Cardiovascular Disease
E
levated long-term cortisol levels mea­
sured in scalp hair are associated with
for tests in the active arm were displayed
equivalent to the effect of traditional CVD
alongside the test name in Johns Hopkins'
risk factors (J Clin Endocrinol Metab
physician order entry system. Physicians
2013;doi:10.1210/jc.2012-3663). The find­
were not informed about why fees for only
ings suggest that long-term elevated corti­
certain tests were displayed; if any physician
sol might be an important CVD risk factor.
asked the investigators about the charge
The impact of chronic stress on CVD
display, they were told it was for a research
has been studied by measuring the stress
effort, but not the specifics of the study.
hormone cortisol in serum and saliva.
In comparing the baseline and interven­
However, these one-time measurements
tion periods, the authors found a 9.1% re­
poorly reflect long-term cortisol levels
duction in tests ordered in the active arm,
due to factors such as the diurnal pattern
but a 5.1% increase in tests ordered in the
of cortisol secretion and acute stress. El­
control arm. This resulted in a net charge
evated hair cortisol levels previously have
reduction >$400,000.
been associated with chronic stress, so the
•
long-term cortisol levels in scalp hair were
•
•
•
•
•
•
•
•
"
"'\
associated with CVD.
The study involved a subset of 283 par­
aieCtin-3 is elevated in a substantial
ticipants in a larger cohort study of pre­
portion of patients with heart failure,
dictors and consequences of changes in
especially those with more severe disease
physical, cognitive, emotional, and social
and renal dysfunction. In addition, in pa­
function in older adults. The authors used
tients who received the angiotensin recep­
a commercial enzyme-linked immunosor­
tor blocker valsartan, researchers found a
bent assay kit for cortisol to measure levels
Apolipoprotein CII
significant reduction in hospitalizations for
in hair samples cut as close to the scalp as
heart failure only in those with galectin-3
possible. They extracted cortisol from the
Apolipoprotein cm
levels below the median of 16.2 nglmL
hair using an overnight methanol incuba­
(Eur J Heart Fail 2013;15:511-8), suggest­
tion.
•
Apohpoprotem All
•
•
•
a history of cardiovascular disease (CVD),
G
.
•
charges
Outcomes in Heart Failure Patients
Apolipoprotein B
.
period,
Galectin-3 Associated With Negative
Lipoprotein(a)
For in vitro diagnostic use.
/'
•
authors sought to investigate whether high
Cobas, Siemens/Bayer Advia & Dimension, and others.
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intervention
•
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the tests in question. During a subsequent
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The investigators found significantly
higher hair cortisol levels in men than in
The Valsartan Heart Failure Trial (Val­
women, with a median of 26.3 pglmg hair
HeFT) evaluated the efficacy of valsartan in
versus 21.0 pglmg, respectively. In com­
5,Ql0 patients with symptomatic heart fail­
parison to subjects in the lowest quartile of
ure. Researchers measured galectin-3 and
cortisol levels, those in the highest quartile
other biomarkers such as high-sensitivity
had a 2.7-fold increased risk of CVD and a
C-reactive protein, high-sensitivity tropo­
3.2-fold higher risk of type 2 diabetes. The
nin, and B-type natriuretic peptide at three
authors found no association between hair
time points in a subpopulation of the trial
cortisol levels and non-CVD diseases.
patients. The time points were at baseline
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and 4- and 12-months after randomiza­
tion.
The median baseline galectin-3 level in
1,650 patients was 16.2 nglmL, and levels
increased significantly from baseline at both
4- and 12-months post-randomization,
with 1.0 nglmL and 2.2 nglmL increases,
18
CLINICAL LABORATORY NEWS JUNE 2013
Visit
AACC.org
n ew s
f ro m t h e
fda
FDA Announces New Draft Guidance
on Molecular Diagnostic Instruments
Luminex Receives FDA Clearance
for Multiplexing Instrument
he Food and Drug Administration
(FDA) released new draft guidance,
“Molecular Diagnostic Instruments With
Combined Functions,” which outlines the
agency’s thinking on regulation of molecular diagnostic instruments including
approved or cleared functions as well as
functions that do not require approval or
clearance. The new guidance applies to instruments used with assays that measure or
characterize human or microbial nucleic
acid analytes, as well as to software intended for use with these instruments or with
approved molecular diagnostic assays.
The guidance also details the information
FDA recommends applicants include in a
submission for a molecular diagnostic instrument with combined functions. In the past,
FDA has handled the permissibility of such
instruments on a case-by-case basis, providing informal advice in response to individual
inquiries. When finalized, the agency intends
that this draft guidance will standardize its
approach to these instruments.
FDA is accepting comments on the draft
guidance until July 8 at www.regulations.gov.
DA granted clearance to Luminex for
its Magpix instrument along with its
xTAG Gastrointestinal Pathogen Panel
(xTAG GPP). Based on Luminex’s xMAP
Technology, the Magpix instrument is a
compact, multiplexing platform that analyzes proteins and nucleic acids in a variety
of sample matrices. It can perform up to 50
different tests in a single reaction. In January 2013, the xTAG GPP became the first
test cleared in the U.S. that simultaneously
detects 11 common viral, bacterial, and
parasitic causes of infectious gastroenteritis.
T
FDA Issues Emergency
Use Authorization for
H7N9 Influenza Screening
W
ith the threat of a deadly outbreak of
avian influenza spreading to the U.S.,
Secretary of Health and Human Services
Kathleen Sebelius on April 19 authorized the
emergency use of in vitro diagnostics for detection of the avian influenza (H7N9) virus.
FDA quickly took action, issuing an Emergency Use Authorization (EUA) on April 22
for the CDC Human Influenza Virus RealTime RT-PCR Diagnostic Panel-Influenza
A/H7 (Eurasian Lineage) Assay. Laboratories can use this test in conjunction with the
FDA-cleared CDC Human Influenza Virus
Real-Time RT-PCR Diagnostic Panel in
real-time RT-PCR assays for the presumptive detection of the H7N9 virus in patients
with respiratory infection symptoms.
Under the new EUA, the Applied Biosystems 7500 Fast Dx Real-Time PCR instrument from Life Technologies also received
clearance for use under the CDC protocol for
emergency H7N9 screening. Along with the
company’s SuperScript III One-Step qRTPCR reagent kit, laboratories can monitor
the spread of the pathogen with the 7500 Fast
Dx Real-Time PCR instrument and CDC’s
Human Influenza Virus Assay.
F
ARK Diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
www .ark-tdm .com
BD Biosciences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
www .bdbiosciences .com/go/canto
Cerilliant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
www .cerilliant .com
College of American Pathologists . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
www .cap .org
Kamiya Biomedical Company . . . . . . . . . . . . . . . . . . . . . . . . . . 7, 16, 18
www .k-assay .com
Kronus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
www .kronus .com
Randox Laboratories . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
www .randox .com
Roche Diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
http://becauseofus .roche .com/Carmen
medication monitoring?
ask the experts
For a complete list of our
Certified Spiking Solutions®
for Clinical Applications,
visit Cerilliant.com
•
Analgesics
Cerilliant offers a wide range of Certified Spiking Solutions®
•
Antidepressants
suitable for use in medication monitoring applications by
•
Antiepileptics
LC/MS or GC/MS to assist laboratories in establishing patient
•
Antipsychotics
adherence to prescribed medications.
•
Caffeine-related Drugs
•
Cardiac Drugs
•
Catecholamines
•
Hormones
Featured products for Medication Monitoring including
parent compounds, internal standards & metabolites:
—
—
—
—
—
Female
Male
Neonatal
OH Vitamin D
Thyroid
•
Retigabine
•
Amiodarone
•
Lacosamide
•
Oxycodone
•
Immunosuppressants
•
Citalopram
•
NSAIDs
•
Vitamins (including
Vitamins A, B, D, & E)
Visit Cerilliant.com or call:
— Josh Cooper, PhD
ANALYTICAL R&D
FDA Clears BD Diagnostics
C. difficile Test
800/848-7837
USA or CANADA
512/238-9974
INTERNATIONAL
Also available through select
Sigma-Aldrich locations.
Visit www.sigma-aldrich.com
for more information.
B
D Diagnostics received FDA clearance
for the BD Max Cdiff Assay for detecting the toxin B gene (tcdB), an essential
gene in Clostridium difficile infection. Designed for use on the fully-automated BD
Max System, the BD Max Cdiff assay is the
third FDA-cleared assay on this system.
Other assays cleared for the BD Max platform include the BD Max MRSA for the
detection of methicillin-resistant Staphylococcus aureus, and BD Max GBS for the
detection of Group B Streptococcus.
INDEx To ADvERTISERS
Please visit these websites to learn more about the products in this issue.
Cerilliant Quality
ISO GUIDE 34
ISO/IEC 17025
ISO 13485
ISO 9001
GMP/GLP
© 2013 Cerilliant Corporation
CliniCal laboratory
ab
CLN 6/13
©2013 Roche Diagnostics. All rights reserved. 671-52177-0113
Because of us, Carmen’s smile is coming
straight from her heart.
Every day at Roche Diagnostics we work to help
patients like Carmen live longer, healthier lives
and not let things like a cardiac emergency define
them. That’s why we develop diagnostic tests that
help save lives by saving time when every heartbeat
matters. Together, we’re making a difference. And it’s
written all over Carmen’s face.
Doing now what patients need next
Learn more about Carmen’s story at
http://becauseofus.roche.com/Carmen.
Please visit us at booth #4049 at AACC Clinical Lab Expo.