1. health and fitness
2. disease
3. cancer

news brief
U.S. Hospitals
Underperform on
Patient Safety Measures
An update to the Hospital Safety
Score released by The Leapfrog Group
revealed that while some hospitals reliably deliver safe healthcare, many still
lag in their ability to protect patients
from preventable medical errors, injuries, accidents, and infections.
Launched in June 2012, the Hospital Safety Score uses 26 measures of
publicly available hospital safety data
to assign an A, B, C, D, or F score to
U.S. hospitals. This new update to the
report summarizes data from the past
6 months that was collected from 2,618
hospitals and primarily covers their
performance in 2011. On the Hospital
Safety Score website, Leapfrog recommends consumers go to hospitals that
received an A rating; however, of the
Snapshot
Hospital Safety Scores
Percentage of Hospitals
26%
20
10
0
5%
A
B C D
Assigned Score
Will New Clinical Trial Methods Speed Drug,
Biomarker Use?
1%
F
Source: The Leapfrog Group, Hospital Safety
Score, 2012
hospitals studied, only 30% earned
this top score, with 6% getting a D or F
score. These two lowest grades are new
additions to the Hospital Safety Score
rankings and denote hospitals with
the most hazardous environments for
patients.
Though these numbers are far from
optimal, Leapfrog’s findings were not
all negative. For instance, hospitals
of all classes—teaching, public, and
specialty—earned As, with no one type
dominating the highest safety scores.
Another promising discovery was that
not only nationally acclaimed hospitals
earned As, but also hospitals serving
highly vulnerable, impoverished, and
health-challenged populations.
Leapfrog also analyzed statewide
performance. Hospitals in Massachusetts and Maine topped the list of
those garnering As, at 83% and 80%,
respectively.
With 180,000 patients dying annually from errors and infections, the
lack of attention to patient safety in
U.S. hospitals remains a grave problem,
according to the report’s authors.
Through the Hospital Safety Score,
Leapfrog aims to help consumers
make informed decisions about where
to seek care and drive the market
toward making patient safety a
greater priority.
R
apid advances in both molecular diagnostics and the
understanding of cancer biology are transforming the
cancer research and drug development enterprise,
which experts say will lead to new clinical trial paradigms and testing protocols aimed at better matching
patients to studies and therapies. The oncology community largely
is viewing these events with enthusiasm and optimism for their
potential to bring cancer drugs to market sooner, improve patient
outcomes, and to make real the dream of personalized cancer therapy. Such efforts, which depend heavily on validated biomarkers,
also are expected to transform the role of clinical laboratorians in
oncology diagnostics and treatment.
“We’re at a very interesting point. We’ve now spent the last several decades developing cancer therapeutics, but it’s always been
evident that even very successful drugs work in only a fraction of
patients and all too often for a limited time. The reasons for that
have become much clearer with the introduction in the last fiveto-10 years of new technologies that allow us to characterize in detail cancer biology,” said David Parkinson,
MD, a venture partner at New Enterprise Associates, a venture capital firm in Menlo Park, Calif. “We now
understand that selection of therapeutic tools ought to match the biological characterization of the patient’s
See Cancer Diagnostics, continued on page 2
Molecular Diagnostics
Reimbursement in Flux
What Will New Codes Mean for Labs?
By Bill Malone
M
olecular testing has become an economic powerhouse for the lab industry and contributes
a wealth of valuable information to patient care. But even as researchers and labs look for
the latest breakthroughs, the government and other payers are still trying to make up their
minds about what these tests are worth and how to keep track of them. This month, the
Centers for Medicare and Medicaid Services (CMS) implements a completely new system
for coding molecular tests on Medicare claims. For more than a year, the lab community waited in limbo while
physician organizations tried to persuade CMS to move the new Common Procedural Terminology (CPT)
codes to the physician fee schedule—a change that non-pathologist
laboratorians worried would undercut their long-standing professional role overseeing molecular tests.
In November, CMS finally decided it would keep the new codes
on the clinical lab fee schedule as planned. However, the agency now
has replaced last year’s worry for labs with a new one: how will these
tests be paid? Rather than carry over the payment associated with the
old set of codes labs are accustomed to, CMS asked its local administrative contractors to come up with their own payment schemes
from scratch. This so-called gap-filling method has never before been
used for such a large swath of the lab fee schedule, and is creating
See Molecular Test Coding, continued on page 6
Clinical Laboratory News
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A New Paradigm for Companion
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Complexity Stymies Drug Development
Cancer Diagnostics, continued from page 1
tumor at each particular point in the natural history of the patient’s disease. This
means that if we’re going to move toward
more efficient cancer therapy we have to
have parallel development of biologically
targeted therapeutic agents and diagnostics which characterize patients accurately
enough for the efficient use of those tools.”
Parkinson for 5 years led Nodality, a molecular diagnostics start-up, and he co-chairs
the cancer steering committee of the Biomarkers Consortium, a public-private
biomedical research partnership managed by the Foundation for the National
Institutes of Health.
He went on to explain that the old
model of single biomarker test results
being used to select oncology treatments,
monitor the effects of those therapies,
and switch therapies as treatment resistance emerges is no longer viable. “It’s
becoming clear that in order to be able
to predict whether or not a cancer agent
is going to work in a particular tumor
setting is going to require a much more
complex series of measurements, and
the opportunity is that those measurements taken in whole can much more
accurately predict outcomes related to
therapeutics.”
K-ASSAY ®
Cancer: A Chaotic Brew
A substantial body of evidence has dashed
forever the notion that cancer is a monolithic disease with a straightforward path
to cure. “It now is quite clear that diseases
10 years ago we considered one disease are
really a compilation of different tumor
types, each with a different driving biology.
We now realize that in each tumor type if
we just treat with a targeted agent, only a
fraction of patients are going to genuinely
derive benefit,” said Funda Meric-Bernstam,
MD, professor of surgical oncology and
medical director of the Khalifa Bin Zayed
Al Nahyan Institute for Personalized Cancer Therapy at the University of Texas MD
Anderson Cancer Center in Houston.
Oncologists now recognize the disease
as a chaotic brew of genetic rearrangements, mutations, deletions, and amplifications. Toss in epigenetic influences on gene
expression and evolution under therapeutic pressure, and the recipe for devising effective treatments becomes considerably
more complicated, according to John Mendelsohn, MD, co-director of the Khalifa
Institute for Personalized Cancer Therapy
and former president of MD Anderson.
“There are unresolved questions that require aggressive research. The heterogeneity of the cancer. The plasticity of the can-
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Inflammation / Cardiac
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CDx
2006
PMA
2012
Cetuximab,
Panitumumab
Colorectal
Cancer
BRAF V600E Mutation
PMA
2011
Vemurafenib
Melanoma
ALK Fusion
PMA
2011
Crizotinib
NSCLC
EGFR Mutation
LDT
2003
Gefitinib,
Erlotinib
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PMA
1998
PMA
2008
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Imatinib,
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CML
Source: Clin Chem 2013;59:198–201.
cer cells. They can convert from being stem
cell-like mesenchymal cells to epitheliallike cells and back and forth. The stem celllike cells have different responses than the
epithelial-like cells,” he said. “The number
of genes we’re picking up sometimes is in
the hundreds for a single cancer. Most are
important for growth and survival of the
cancer, but only a few are driving the cancer.
We don’t know how to identify those yet.”
A Sketchy Track Record
Cancer’s convoluted pedigree is reflected
in the sketchy track record of the oncology therapeutics industry. Up to 70% of
late-stage cancer trials ultimately fail to
show benefit, and arrive at this unsatisfying conclusion after involving thousands of
patients, costing as much as $1 billion, and
taking 10 years of rigid adherence to strict
clinical trial regulations and protocols.
Yet recent breakthroughs twinning
molecular diagnostics and therapies are
spurring the industry to work smarter in
weeding through candidate drugs and better matching new and existing therapies to
patients more likely to benefit from them.
Within just the past few years, mutation
analysis as a precursor to targeted therapy
has become the standard of care for certain tumor types. For example, the U. S.
Food and Drug Administration (FDA) has
approved trastuzumab for breast cancer
patients with HER2 overexpression, and
cetuximab and panitumumab for patients
with KRAS-wild type metastatic colon cancer (See Table, above).
Adding to the handful of tests used to
guide clinical decision-making around
chemotherapy, two developments in 2011
really captured the industry’s attention. In a
first for the agency, FDA granted landmark
approvals for two drugs and companion
diagnostic testing required for patients to
receive the drugs. First came approval for
BRAF V600E mutation testing in patients
with metastatic melanoma as a precursor to
receiving vemurafenib, and then days later
FDA approved ALK gene rearrangement
testing in patients with late-stage non-small
cell lung cancer (NSCLC) as a condition of
receiving crizotinib.
As significant as these approvals were,
they illustrate just how far the industry has
to go to achieve personalized treatment
based on the patient’s tumor biology, and
For Further Information
® Barrett JC, Frigault MM, Hollingsworth S, Miller GA, et al.
Are companion diagnostics useful? Clin Chem 2013;59:198–201.
Serum Proteins
 Alpha-1 Acid Glycoprotein
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 Transferrin
Kidney Function
 Cystatin C
® Kelloff GJ, Sigman CC. Cancer biomarkers: Selecting the right drug for
the right patient. Nature Reviews 2012;11:201–14.
® Modur V, Hailman E, Barrett JC. Evidence-based laboratory medicine
in oncology drug development: From biomarkers to diagnostics.
Clin Chem 2013;59:102–9.
® Parkinson DR, Johnson BE, Sledge GW. Making personalized cancer
medicine a reality: Challenges and opportunities in the development of biomarkers and companion diagnostics. Clin Cancer Res
2012;18:619–24.
® Poste G, Carbone DP, Parkinson DR, et al. Leveling the playing field:
Bringing development of biomarkers and molecular diagnostics up to the standards for drug development. Clin Cancer Res
2012;18:1515–23.
® Sölétormos G, Duffy MJ, Hayes DF, et al. Design of tumor biomarker-
FAX: 206-575-8094
monitoring trials: A proposal by the European group on tumor
markers. Clin Chem 2013;59:52–9.
www.k-assay.com
Clinical Laboratory News January 2013
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why new drug and biomarker development paradigms are needed, according to
Parkinson.
“We have applications of all these new
technologies and glimpses of just how useful they can be in matching patients with
their therapeutics. Yet we have many challenges, including developing new methodologies and standardizing them if they’re
going to be released into clinical medicine.”
In an opinion piece, Parkinson and his coauthors noted just how rare these parallel diagnostic and therapeutic regulatory
approvals were, and in a nod to cancer’s
complexity, they suggested that the value
of selecting patients with either the BRAF
V600E or ALK mutations is limited because “not all patients respond even within
these marker-selected enriched patient
groups, and the responses achieved vary
significantly in extent and duration” (Clin
Cancer Res 1012;18:619–24).
As many as 60% of melanoma patients
have the BRAF V600E mutation, but at
most only about 7% of lung cancer patients have the ALK gene rearrangement.
The latter suggests that conventional drug
development strategies, based on measuring the effects of the drug in unselected
patients with the type of cancer in question, probably would not have arrived at
this biomarker-drug connection, because
such a large number would have had to
have been enrolled to detect a preferential
response in this subset of patients.
2010, is testing 10 biomarkers and up to 12
different drugs from multiple companies,
and is designed to enable investigators to
incorporate knowledge gained during the
trial into the trial while it is still ongoing.
Patients’ estrogen receptor (ER), progesterone receptor, and HER2 receptor
status, and their MammaPrint scores are
being used to enroll and randomize them
initially, and to stratify them within each
arm of the study. When the patients have
surgery, their tumor response is assessed
and evaluated for biology-specific associations. At this point, the adaptive part of the
trial comes into play. “Let’s say we find that
type 1 breast cancer based on biomarker
signatures responds particularly well to
drug 2, and type 2 cancer biology responds
well to drug 1. As the trial continues, patients with those particular biology types
will be preferentially randomized into the
trial arms where there’s a high likelihood of
response while the control arm still receives
all biological types. This is all based on predefined statistical significance,” explained
Van’t Veer. “Our end point is pathological
complete remission with a threshold of 85
percent predicted likelihood of success in a
300 patient Phase 2 trial. This means 100 to
200 patients are needed for each arm with
a minimum of 60 to find successful drugbiomarker combinations or a failure.”
Building Evidence for Biomarkers
At the same time that I-SPY 2 is helping
identify which investigational drugs lead
to pathological complete response, the
research team also expects the trial will
advance evidence around biomarkers,
potentially moving some from strictly experimental status to being on the pathway
for FDA clearance (See Table, p. 4). For
instance, Van’t Veer’s lab developed a gene
expression signature that in experimental
systems predicted response to a PARP inhibitor, and I-SPY 2 will test whether that
experimental finding holds in patients.
Efforts like this will be crucial going
forward as more mutations are found with
putative associations to various malignancies and therefore certain treatments, according to Vijay Modur MD, PhD, chief
medical officer at HTG Molecular Diagnostics in Tucson. “It’s exceedingly important to generate clinical evidence so that we
don’t pocket every mutation in the same
space and say the same drug works with all.
For example, we know that in melanoma,
treatment of BRAF mutations with BRAFtargeted therapy results in a dramatic response. But for colorectal cancer, at least in
preliminary studies, the response doesn’t
See Cancer Diagnostics, continued on page 4
New Models for Clinical Trials
Given the caveats of not only the BRAF
V600E-vemurafenib and ALK-crizotinib
stories but also other molecular diagnostic
tests used in oncology clinical decisionmaking, researchers are pursuing new clinical trial designs. The goals of these efforts
are many, including learning earlier in the
drug development pipeline which agents
will fail or succeed, speeding approvals for
the drugs that succeed, predicting which
patients will benefit from therapy, and personalizing the use of biomarkers and therapeutics.
Without new and different paradigms,
the oncology field will never speed up its
knowledge turn, the time it takes for experiments to proceed from hypothesis to results and on to new hypotheses, according
to Laura Van’t Veer, PhD, Angela and Shu
Kai Chan endowed chair in cancer research
at the University of California San Francisco. “There are more than 800 targeted investigational agents in development and if
we keep doing the traditional way of testing
drugs in Phase 1–4 trials where the Phase 3
trial would be a large randomized adjuvant
trial, we will continue to need several thousands of patients to prove that a new drug
is better than the standard. We’ll also continue to wait five-to-10 years for each drug
to come to its endpoint. We need to screen
drugs more quickly,” she explained.
Van’t Veer is an investigator with
I-SPY 2, one of the most notable in a new
breed of clinical trials utilizing an adaptive design based on Bayesian statistics.
This groundbreaking $26.5 million, 5-year
study involving 20 major cancer centers
and sponsored by the Biomarker Consortium, is testing whether adding novel
agents to standard chemotherapy in the
neoadjuvant setting improves outcomes in
women with high-risk, fast-growing breast
cancer. The trial, which was launched in
Clinical Laboratory News January 2013 3
Adaptive Trials Not a Total Solution
Clinical
Laboratory
News
Cancer Diagnostics, continued from page 3
Editorial Staff
Editor—Nancy Sasavage, PhD
Senior Editor—Genna Rollins
Senior Editor—Bill Malone
Editorial Assistant—Christine DeLong
Contributor—Chamindie Punyadeera, PhD
Board of Editors
Chair—Lorin M. Bachmann, PhD, DABCC
VCU Health System, Richmond, Va.
Members—Joshua Bornhorst, PhD
University of Arkansas, Little Rock, Ark.
Andrew Don-Wauchope, MD
Juravinski Hospital and Cancer Center,
Hamilton, Ontario
Jacqueline Fisher, MS, C(ASCP)
Abbott Diagnostics Division, Boston, Mass.
Steven Goss, PhD
Siemens Healthcare Diagnostics, Newark, Del.
Pamela Steele, PhD
Covance, Inc., Indianapolis, Ind.
AACC Officers
President—Robert H. Christenson, PhD,
DABCC, FACB
President-Elect—Steven H. Wong, PhD,
DABCC, FACB
Treasurer—Michael J. Bennett, PhD, DABCC,
FACB
Secretary—Elizabeth L. Frank, PhD, DABCC,
FACB
Past President—Greg Miller, PhD, DABCC,
FACB
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Contents copyright © 2013 by the American
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except as noted. Printed in the U.S.A.
seem to be the same, even if the mutation
is the same.
In an opinion article in Clinical Chemistry’s January 2013 special issue on cancer,
Modur argued that in addition to a need
to demonstrate clinical utility, both FDAcleared and lab-developed companion diagnostics have room for analytical improvement. Even FDA-cleared tests, like ER, HER2,
and BRAF, have large inter-lab and patient
variabilities. Modur and his co-authors called
for improved and more flexible approaches
to developing oncology companion diagnostics to respond to how quickly evidence
is being generated around matching the right
patients with the right therapy.
The Downsides of Adaptive Trials
Given the urgent need to press on with
companion diagnostic development, the
oncology field can’t—and isn’t—relying
only on the adaptive trial model to make
leapfrog advances toward personalized
cancer therapy. That’s because I-SPY 2 and
trials like it, including BATTLE in NSCLC,
are logistically challenging and perhaps not
as well-suited to less prevalent cancers, according to Meric-Bernstam.
“This is a really outstanding model;
however, it’s not doable on a small scale
and it’s logistically difficult. If you want to
give more than one drug you need to have
multiple drugs available potentially from
multiple different companies that may or
may not be enthusiastic about comparison of their compounds to each other. One
also needs a large enough pool of patients
to draw from, as well as the commitment
to prioritize this trial over all else to ensure
that it is successfully recruiting so that all
arms remain relevant while the trial is ongoing,” she explained. “Those are not easy
things to accomplish, and that’s why only a
handful of trials will be done like this.”
I-SPY 2 also required special involvement from the FDA to consider this new
paradigm, including using pathological
complete response rather than long-term
outcomes as the primary endpoint. The
agency has acknowledged that diagnostic
tests used to measure biomarkers can have
a role in the selection of patients who are
The Vanguard of Trial Enrollment
To continue advancing molecular diagnostics and drug development for patient
populations and cancer types not suited
to adaptive clinical trial models, leading
cancer centers, such as MD Anderson and
Memorial Sloan-Kettering Cancer Center
in New York City, have implemented protocols for performing molecular subtyping
on at least certain populations, and using
this information to enroll patients in other
clinical trials. MD Anderson has two such
initiatives, its clearinghouse and unusual
responder protocols.
Under the former, patients with advanced disease undergo molecular testing
with a 46-gene panel looking for common cancer mutations. This information
is used to assign patients to any relevant
clinical trials the institution is involved in.
If this process fails to uncover anything
significant, the next step is targeted exome
sequencing. “This is done in the research
setting. The protocol is set up so that if an
abnormality is identified and there’s a clinical trial that would be relevant, then the
treating oncologist can order CLIA validation testing for clinical trial selection,” said
Meric-Bernstam.
Biomarker Categories in the I-SPY 2 Trial
The landmark I-SPY 2 trial is testing 10 biomarkers and up to 12 different drugs. The trial’s novel adaptive
design aims to enable investigators to incorporate knowledge gained during the trial into the trial while it is
still ongoing. In addition to determining which therapies work best with particular cancer biology types,
I-SPY 2 investigators also expect the trial to advance evidence around biomarkers, potentially moving some
from strictly experimental status to being on the pathway for FDA clearance and widespread clinical use.
Biomarker Category
Qualifying biomarkers
Exploratory biomarkers Hypothesis testing
Hypothesis generating
*FDA cleared or approved
**Biomarker investigational device exemption (IDE) by the FDA as part of investigational new drug
application facilitates companion diagnostic pre-market approval
Source: adapted from and used with permission of Laura Van’t Veer, PhD
@CLN_AACC
4 Purpose in I-SPY 2
Established biomarkers*Trial stratification, randomization
IDE biomarkers**
Clinical Laboratory News (ISSN 0161-9640)
is the authoritative source for timely analysis of issues and trends affecting clinical
laboratories, clinical laboratorians, and the
practice of clinical laboratory science.
likely to respond to specific therapies. It
also has recommended using analytically
validated biomarkers that have strong evidence of being fit for purpose to evaluate
patient response to therapy, toxicity, and
drug resistance.
The agency’s commitment to revisit
existing regulatory requirements given recent scientific advances is encouraging, but
Parkinson contended that still more regulatory clarity and even new business models
for the molecular diagnostics industry are
needed. “The FDA, not inappropriately, has
said these tests are going to drive the use
of regulated therapeutics, therefore we intend to use our enforcement discretion and
regulate them. We’re starting to see some
guidance, but there still is confusion with
regard to regulatory interfaces and the need
for them or not. This is leading to a lot of
uncertainty around business models and
hesitancy about putting new financing into
molecular diagnostic test companies.”
MD Anderson’s unusual responder
protocol is for patients such as those experiencing an unexpected rapid progression.
Here, the focus is on deep characterization
of patients’ tumors to identify mechanisms
of resistance and predictors of response.
Clearly these approaches are on the
vanguard and not ready for widespread
adoption. Indeed, sequencing performed
in MD Anderson’s research labs for both its
clearinghouse and unusual responder protocols are supported through philanthropy.
However, clinical laboratorians across the
country will do well to keep abreast of
these efforts as this is the direction in which
oncology is moving, according to Marc
Ladanyi, MD, William J. Ruane endowed
chair in molecular oncology and attending
pathologist on the Molecular Diagnostics
Service at Memorial Sloan-Kettering Cancer Center.
“It’s a rapidly evolving field. Everybody assumes we’ll end up with these allpurpose assays that will sequence all the
major cancer genes. Things are moving very
quickly and it’s quite possible that within
one-to-three years labs that haven’t gotten
into tumor sequencing yet might be able to
leapfrog some of these growing pains and
go from multiple single-gene tests to more
comprehensive testing platforms that are
being developed,” he said.
Modur sees reasons for all clinical labs,
even those not currently performing tumor
sequencing, to keep their dials tuned to this
ever-changing scene. “Laboratorians should
be able to have discussions with oncologists
to determine what the laboratory test menu
is going to look like, both for established
and qualifying markers. Many oncologists
already are requesting that their patients
be tested for qualifying biomarkers because
the level of evidence for some of them is
pretty high,” he explained. “Then there are
exploratory biomarkers that are driving
clinical trials and may be performed without clinical laboratory oversight right now.
The field is moving away from that because
many trial protocols pre-specify that even
exploratory biomarkers have to be done in
a CLIA regulatory environment. So laboratorians need to understand the spectrum of
biomarkers, categorize them, and have an
educated discussion with oncologists on
where each one falls and how the clinician’s
CLN
demands for testing can be met.”
Clinical Laboratory News January 2013
Payment Uncertainty Could Last a Year
Molecular Test Coding, from page 1
even more uncertainty over the fate of
molecular testing.
According to lab coding expert Charles
Root, PhD, Medicare contractors have their
work cut out for them as they come up with
payment for the new codes, as most have
little expertise in molecular diagnostics.
“Ultimately, the only way labs will really
know what they will be paid in January will
be to submit a claim to Medicare and see
what comes back,” he said. The founder and
president of CodeMap, LLC, Root spoke as
part of AACC’s Reimbursement and Regulatory Update webinar on November 27.
Flying in the Dark
Overall, the shift to the new coding system
looks like an improvement to labs and diagnostic companies, but the devil is in the
details, emphasized industry consultant
Rina Wolf. “This should be good news. But
the whole pricing issue is absolutely key, because we’re totally flying in the dark right
now,” she said. “We don’t know what this
is going to mean from any of the payers,
whether from CMS or the commercial payers, who usually follow the lead of CMS.”
Wolf is vice president of commercialization
strategies, consulting, and industry affairs
at XIFIN, a revenue cycle management solutions company.
At CLN press time in mid December,
CMS had yet to offer any instructions to its
contractors on how they should go about
paying claims with such a short window to
gap-fill their pricing. Wolf urged CMS to
take a balanced approach that would allow
contractors to make informed decisions. “I
think it’s very important for CMS to balance
our need to get the answers on pricing with
the ability to get the job done in a considered
and appropriate way,” she said. “This is one
of the biggest issues facing the business of
clinical laboratories right now, and the business of the lab directly affects patient care.
Some diagnostic companies run on such
incredibly slim margins that this will have a
huge impact on their ability to survive.”
Some contractors have almost nothing
to go on for pricing the new codes, due to
the way the previous system of stacking
multiple codes for each test obscured what
was being paid for. “With the old way of using code stacks, some of these contractors
probably weren’t even aware that they were
seeing claims for certain tests,” Wolf said
(See Box, right).
Even the contractor with unquestionably the most experience in molecular diagnostics, Palmetto GBA, would have a lot
of work to do before rolling out a new pricing scheme, explained Elaine Jeter, MD, the
medical director of Palmetto’s Molecular
Diagnostics Services Program (MolDX).
“The time is short and a lot of information is
required,” she said. “We don’t have any information on the resources required for an assay, only what the labs have been billing.” Palmetto’s MolDX program covers Medicare
claims in California, Nevada, and Hawaii.
One reason that experts worry about
CMS’s choice of gap-filling is that CMS has
employed this method infrequently and imperfectly. In most cases, CMS prices new codes
by borrowing prices from existing, similar
codes in a centralized fashion. This simpler,
kinder method is called crosswalking.
“There are usually 10 to 20 new lab
codes every year, and CMS has in the past
only used gap-fill for a test about once every
4 years, so it’s been very exceptional for any
test to go through the gap-fill process,” said
Bruce Quinn, MD, PhD, senior health policy specialist at Foley Hoag, LLP. “The only
one in my nine years of experience with
Medicare was for HbA1c measured directly
in the office, and that was very messy. A lot
of contractors were uncertain about how to
price it, and local prices varied almost by a
factor of three. Finally, Congress stepped in
and decided what the payment would be,
effectively canceling the gap-fill process.”
Private payers are in a jam, too. They
depend on Medicare’s published price list,
which no one expects for some time. And
even when CMS does give contractors parameters to begin gap-filling, commercial
payers will still have to sort out which contractor they will follow if prices vary across
the country, Wolf noted. “This is of tremendous concern to diagnostic companies. Of
course, the industry wants to provide the
best patient care, but these are also busi-
2013 Molecular
Reimbursement Timeline
This year, hundreds of new CPT codes created for molecular diagnostics
must replace the old code stacks labs used for more than a decade. The
government surprised labs and diagnostic companies when it announced
late last year that it would not use the same prices as the old codes, but
rather ask its local contractors to build their own pricing schemes through
a little-used process called gap-filling. Under final Medicare regulations announced in November, final prices for molecular diagnostics will remain in
flux until January 2014. Between now and then, CMS will let each contractor
set its own prices and take an average of these as the maximum allowed
price, or National Limitation Amount, going forward.
®By April 30, CMS posts interim contractor-specific amounts online
®A 60-day comment period on interim amounts
® CMS posts final contractor-specific amounts and National Limitation
Amounts (NLA) online
® CMS sets the NLA for each CPT code at the median of the contractorspecific amounts
®Reconsideration requests accepted for 30 days
®Final NLAs become effective January 1, 2014 for the entire country
Source: Charles Root, PhD, CodeMap, LLC
6 Clinical Laboratory News January 2013
New Molecular Codes
Take Effect for 2013
Despite uncertainties about how they will be reimbursed, the new molecular codes that come into full effect this year solve some long-standing problems. Without unique, analyte-specific codes for molecular tests, labs have
for decades cobbled together their own lists of other codes that describe
the various steps of performing the test. For labs, this led to headaches with
denied claims or underpayment. For payers, it meant they never really knew
which tests they were paying for or what the tests really cost, since all they
could track were the fragments of each lab’s unique bundle of codes, rather
than the whole.
Perhaps just as significant, claims data have been almost worthless for
tracking physicians’ utilization of these advanced tests. A white paper from
UnitedHealthcare’s Center for Health Reform and Modernization noted as
an example that under the old coding system, the genetic test for Canavan
disease required six steps and thus six procedure codes. However, labs also
used these same procedure codes for genetic tests for five other diseases,
including cystic fibrosis and Tay-Sachs, leaving the payer unable to distinguish one test from the other.
In 2011, the American Medical Association (AMA) released its overhauled coding system for molecular tests with a new tiered approach that
featured analyte-specific codes. The Centers for Medicare and Medicaid Services (CMS) essentially outsources this work to AMA, but in this case could
not decide how to implement AMA’s work. AMA, as well as the College of
American Pathologists (CAP), pushed CMS to make molecular coding and
reimbursement a pathologist-centered rather than a lab-centered system,
arguing that molecular tests require a pathologist’s interpretation and
should reside on the physician fee schedule.
Diagnostic companies and many others in the lab community welcomed the news late in 2012 that CMS would keep the new codes on the
lab fee schedule for 2013, according to Rina Wolf, vice president of commercialization strategies, consulting, and industry affairs at XIFIN, a revenue
cycle management solutions company. “We believe that this is good news
because our contention has been that these are not new tests, these are
new codes for existing tests for which the components all previously were
on the clinical lab fee schedule,” she said. “We also believe that the majority of these tests do not require additional pathology interpretation. CMS
did acknowledge that, and provided a temporary code, G0452, for those
circumstances where an ordering physician believes that it is appropriate
to have an additional pathology interpretation.”
Under the new coding system, tests that make up the majority of the
volume of molecular diagnostics fall into the first tier of a two-tier system.
Tier 1 is home to some 100 codes that together represent more than 90%
of the volume of molecular tests currently performed. Tier 2 is reserved for
low-volume, esoteric tests, within which are nine buckets based on test
complexity. A different CPT code is reserved for each of the nine levels.
Within each level, many different tests can reside. Notably, it is up to AMA to
list which particular tests can be coded under each level—labs cannot selfassign. Labs have to be sure that AMA has listed the particular test they use
under one of these codes in order to bill Medicare.
nesses that have to survive so that they can
do that. With no clarity on pricing, they can
do no revenue modeling for 2013—they
don’t even know if they’ll be able to afford
to do these tests anymore.”
According to Root, gap-filling allows
contractors to use four methods to calculate pricing: what is charged for each test;
the resources and actual costs of performing the test; payment amounts determined
by other payers; and the payment amounts
or resources required for comparable tests.
CMS may give contractors some direction
on which of these methods they should use.
However, because the previous coding system concealed what contractors were paying for, it seems likely the first two options
would be very difficult. “My own opinion
is that most contractors will be looking to
see what Palmetto does,” Root said. “They
will be the leader here and should have the
most data on what they’re actually paying
for right now.” In either case, CMS will not
even publicly post interim contract-specific
amounts until April (See Box, left).
Palmetto Takes Center Stage
As Medicare’s contractors try to make sense
of how to price the new molecular codes,
all eyes will be on Palmetto GBA, the first
and only contractor to develop its own program specifically to address the burgeoning
field of molecular diagnostics. Palmetto’s
MolDX program requires each test to carry
a unique identifier. This way, Palmetto can
keep track of which tests it pays for and
how they are used. With the new ability
to recognize these tests for what they are,
MolDX also requires a technology assessment before deciding on whether it should
be covered under Medicare as “reasonable
and necessary.” The technology assessment
looks at analytical and clinical validity as
well as clinical utility.
Since Palmetto is the only entity in
Medicare that appears to have a grasp of
molecular testing, some experts believe
that the best route for CMS would be to
adopt MolDX as a national program. According to Mike Barlow, vice president of
Palmetto’s Jurisdiction 1 operations under
which MolDX operates, such a move would
be easier said than done. “We’ve had discussions with CMS about this since we have a
very successful program with demonstrated results,” Barlow said. “At the same time,
CMS has limited options on this within the
regulations.”
Not to be confused with the new CPT
codes, MolDX unique identifiers go a step
further in that they differentiate between
different companies’ FDA-approved tests
or different labs’ laboratory-developed tests
(LDTs). The new CPT codes, developed by
the American Medical Association (AMA),
are analyte-specific, so they’re blind to
methodology—and to a lab or company’s
particular assay.
Although the old code stacking system
created problems for both payers and labs,
molecular tests under the new codes will still
require unique identifiers and technology assessments under MolDX, Jeter noted. “Code
stacking was worse, but there are still gaps,”
she said. “Without the unique identifiers, we
still don’t know what we’re paying for.” For
example, Jeter noted that for BRAF gene
testing, three FDA-cleared tests exist, and at
least 25 LDTs. Under the old system, each
FDA-cleared test and most of the LDTs billed
Medicare with unique code stacks. Although
the new molecular CPT codes will fix that
problem, they still don’t differentiate among
the 30 or more assays for BRAF, as they’d all
share the same analyte-specific code.
On the other hand, just because AMA
has assigned a new CPT code to a test does
not mean MolDX will automatically cover
it, Jeter emphasized. Certain esoteric, lowvolume tests will reside on a second tier of
CPT codes under the AMA system that are
not analyte-specific and coded by level of
complexity, offering even less transparency.
“ApoE is an assay in Tier 2, Level 2. Since this
assay has no proven clinical utility, how will
other payers separate this non-covered assay
from others in Tier 2, Level 2 that warrant
coverage?” Jeter said. “With unique identifiers, Palmetto GBA is able to create edits to
deny coverage for ApoE, yet appropriately
pay for other assays in Tier 2, Level 2.”
Even if CMS chooses not to adopt
Palmetto’s MolDX program nationally
for Medicare, private payers are eager to
capitalize on MolDX’s work. According to
Wolf, several payers have approached Palmetto requesting access to their database of
unique test identifier codes. “It’s the opinion
of many of us in the diagnostics industry
that this could be a good thing,” Wolf said.
Multi-analyte Algorithmic Tests in Limbo
In rolling out the new molecular codes, AMA
also created codes for a new breed of tests
that use multiple analytes and an algorithm
to produce a result, such as a risk score. In
some cases, the algorithms are proprietary.
Laboratorians might be familiar with the
Food and Drug Administration (FDA) term
for these tests, In Vitro Diagnostic Multivariate Index Assays (IVDMIA). AMA’s term,
adopted by CMS, is Multi-analyte Assays
with Algorithmic Analysis (MAAA).
For now, CMS will not pay for these
tests and their codes will not appear on
Medicare fee schedules. According to CMS,
“Medicare does not recognize a calculated
or algorithmically derived rate or result as a
clinical laboratory test since the calculated
or algorithmically derived rate or result
alone does not indicate the presence or
absence of a substance or organism in the
body.” CMS prefers to pay only for the individual component tests that feed into the
algorithm, but not the MAAA as a whole.
According to Root, when CMS doesn’t
recognize codes, commercial payers usually
will not either, making reimbursement that
captures the full value of MAAAs highly
uncertain. “CMS is sustaining its policy
that algorithms are simply arithmetic, no
matter how sophisticated, and have no
value in reimbursement,” he said. “Obviously, this is contrary to fact in some cases,
because some algorithms have cost millions of dollars to develop and may be extremely expensive. And they will probably
be licensed as well—that’s the only way the
developers will get any money back—so a
laboratory that licenses the use of a multianalyte panel will not get Medicare payment for that use of the algorithm.”
More Pain for Pathology Labs
If pathologists saw CMS’s decision to put
the new molecular codes on the clinical
lab fee schedule as a loss, they should prepare for even greater worries ahead when
it comes to reimbursement for traditional
anatomic pathology services. Depending
on how often a pathology lab performs cer-
tain procedures, a cut this year to a single
code—88305—could have a big impact.
Pathology labs frequently use this code to
bill for preparing slides, representing about
$1.5 billion a year for Medicare.
The 2013 physician fee schedule slashes
payment for the lab work involved in this
code by 51%. As with many pathology
codes, the code is used for both the pathologist’s interpretation as well as the labor of
other lab professionals and supplies needed
to prepare the slide. For 2013, the lab portion of this payment is $33.70, down from
$69.78 in 2012, according to Root.
Even though CMS increased the payment slightly for the professional interpretation element of this code, it could have
a big impact on certain labs, depending
on what constitutes the core of their business, explained Quinn. “The affect of this
cut will be somewhat selective. If you were
running a shop that performed thousands
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A Waiting Game
According to experts, labs are limited in
how they can plan for reimbursement
changes coming with the new codes. Labs
must use the new CPT codes and make
sure the old codes are deactivated in their
billing systems, Root noted. As CMS and
local Medicare contractors negotiate a way
through the gap-fill process, labs should
keep in close contact with their own contractor and make sure they receive e-mail
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CLN 1/13
Clinical Laboratory News January 2013 7
CLN’s
improving
healthcare
through
laboratory
medicine
series
Saliva
An Often Forgotten, but Convenient Diagnostic Fluid
By Chamindie Punyadeera, PhD
F
or decades, dental healthcare professionals have measured the buffering capacity and bacterial
content of saliva to assess a person’s risk of developing tooth decay (1). Today, scientific and technological advances in biochemistry, microbiology, and immunology are leading to the discovery
of new biomarkers in saliva that can be used to detect systemic illnesses such as ischemic heart
disease and heart failure (2–4) and cancer (5).This growing recognition of the association between an
individual’s oral and overall health has led to renewed interest in using saliva as a diagnostic fluid.
In fact, human saliva offers several benefits compared to traditional blood-based biochemical analyses. Saliva
collection is non-invasive and therefore stress-free for patients. For the person collecting the sample, saliva also
poses minimal risk for contracting infectious diseases such as HPV, HCV, and HIV. Finally, saliva is an ideal biofluid
for developing countries due to the low cost of collecting and processing samples (Figure 1).
This article describes the current state
of knowledge for saliva diagnostics and the
obstacles that researchers, manufacturers,
and laboratorians will need to overcome
before saliva is widely accepted as a reliable
diagnostic fluid.
Three major glands—the parotid, submandibular, and sublingual—and about
400 minor glands located within the oral
cavity produce saliva. A healthy adult produces an average of 500–1,500 mL saliva/
day at a rate of approximately 0.5 mL/
min. Human saliva has a multitude of
functions within the oral cavity, including: maintaining homeostasis; promoting
Human saliva harbors a repertoire of
proteins, lipids, RNA, DNA, and some 700
microbial species. To move toward less
invasive clinical management of patients,
researchers have been pursuing saliva as
a biofluid for early disease detection and
prognosis, risk stratification, and monitoring treatment response. In fact, saliva has
already been used as a biological fluid for
diagnosis and prognosis of oral, head, and
neck cancers, periodontal diseases, diabetes, and autoimmune disorders.
Researchers also have found other diagnostic uses for saliva. One research team
identified biomarkers in saliva for detecting
early-stage pancreatic cancer (9), and another measured soluble c-erbB-2Her2/neu
wound healing; lubricating the oral cavity;
facilitating mineralization of dental surfaces; digesting carbohydrates by salivary
α-amylase; digesting lipids via salivary
lipase; and facilitating chewing, speaking,
swallowing, and taste perception (6, 7).
While the human mouth provides good
growth conditions for many microorganisms, the anti-microbial properties of
saliva also help maintain oral hygiene by
clearing and inhibiting growth of microorganisms (8).
levels in saliva collected from breast cancer
patients and concluded that c-erbB may be
useful in detecting and monitoring recurrence of this disease (10).
Current research also is producing
valuable datasets for further analysis. Salivaomics is an open-access database (www.
hspp.ucla.edu) that contains salivaomicsbased studies and includes information on
the biology, diagnostic potential, pharmacogenomics, and pharmacoproteomics of
saliva.
A Saliva Primer
8 Clinical Laboratory News January 2013
Saliva Proteome
Human saliva is a plasma ultra filtrate and
contains proteins either synthesized in
situ in the salivary glands or derived from
blood. It contains biomarkers derived from
serum, gingival crevicular fluid, and mucosal transudate. To date, researchers have
identified 2,340 proteins in the salivary
proteome, of which 20–30% are also found
in blood (11), an encouraging indicator for
the clinical utility of saliva as a diagnostic
fluid.
In contrast to the plasma proteome, in
which 99% of the total protein content is
contributed by 22 highly abundant proteins (8), the 20 most abundant proteins in
human whole saliva (WS) constitute only
40% of the protein content (12). This composition suggests that detecting biomolecules of clinical sensitivity and specificity in
saliva should be feasible and easier than in
blood. Unlike the plasma proteome, however, the WS proteome is highly susceptible to a variety of physiological and biochemical processes, such as salivary protein
modifications occurring in the mouth that
are catalyzed by host and bacterial derived
enzymes. Such modifications also could
present unique challenges for clinical saliva
proteomics.
The dynamic range of proteins in
saliva is another challenge. For instance,
a-amylase, an abundant protein in saliva, is
present at mg/mL concentrations, while the
IL-6 and IL-8 cytokines of potential clinical relevance are present at concentrations
of only pg/mL. This disparity highlights the
importance of developing tools and strategies for discerning low abundance proteins
with clinical relevance in saliva.
How molecules are transported from
blood into saliva may also be important
for successful use of saliva as a diagnostic
fluid. Lipophilic molecules such as steroid
hormones passively diffuse into saliva,
while water and electrolytes pass through
the pores of acinar cells. Various peptides
in blood move through protein channels,
and large proteins are transported via
pinocytosis (4).
Commercially Available Saliva Tests
Two U.S. companies were early pioneers of
oral diagnostics: Epitope, Inc. and Saliva
Diagnostic Systems, Inc. They both commercialized saliva collection devices in the
early 1990s, and in 1996 the Food and Drug
Administration (FDA) approved Epitope’s
Table 1
Figure 1
The Advantages and Disadvantages
of Saliva as a Diagnostic Fluid
Efficacy of Saliva Collection Methods
Collection Device
Drool cup
Median/IQR
Salimetrics
oral swab
Median/IQR
Salivette
cotton swab
Median/IQR
Salivette
synthetic swab
Median/IQR
CRP (pg/mL)
28/9–51
9/5–30*
19/7–46
14/5–44
IgE (pg/mL)
72/38–202
72/35–123
43/30–153
37/30–164*
Myoglobin
(pg/mL)
98/31–140
23/2–54*
23/12–52**
59/34–136
Analyte
The table summarizes data for the median and interquartile range
(IQR) levels for three analytes collected by four different methods. We
observed significant differences (*p<0.05) for both CRP and myoglobin
levels using the drool cup versus the Salimetrics collection device, as
well as significant differences (**p<0.01) for myoglobin using the drool
cup versus the Salivette cotton swab. For IgE, the levels collected in the
drool cup versus the Salivette synthetic devices were correlated more
closely (*p<0.05) (14).
Orasure HIV test, the first test that used
oral fluid to test for an infectious disease.
More recently, FDA approved the first
over-the-counter salivary HIV test that
allows people to test themselves in the
privacy of their homes for the HIV virus.
The OraQuick HIV test, which takes only
15 minutes from start to finish, detects the
presence of HIV antibodies in saliva via
mouth swab.
Several companies outside the U.S. have
commercial tests to detect drugs-of-abuse
in a spit sample, including Cozart Biosciences, Securetec, and Mavand. Some of
these companies send their kits via regular
mail to customers, allowing individuals to
collect their own saliva either in a cup or
with a swab and then send the sample to a
laboratory for analysis.
Other tests target DNA in saliva. Canadabased DNA Genotek was the first company
to commercialize a broad range of saliva
collection tools for genotyping based on
the polymerase chain reaction (PCR),
microarrays, and sequencing. Oral DNA
Labs, a subsidiary of Quest Diagnostics,
also offers two salivary tests in the U.S.
in its CLIA-approved testing facility. My
PerioPath is a DNA test that determines the
risk of periodontal infections by detecting
bacterial pathogens in saliva. OraRisk HPV
is a salivary test that determines an individual’s risk of developing HPV-related oral
Figure 2
Saliva Collection Devices
cancers. It identifies various HPV genotypes, including HPV 8, 11, 16, and 18.
Emerging Clinical Applications
Other applications of salivary diagnostics
are emerging, including for the detection of
cardiovascular disease (2–4) and head and
neck cancer (5).
Our group and others have demonstrated that salivary C-reactive protein
(CRP) levels can be used as a biomarker to
differentiate patients with ischemic heart
disease from healthy controls (2, 3) (Figure
3). Work by Denver et al. also has demonstrated that salivary endothelin concentrations (13) and salivary natriuretic peptide
levels (4) are useful as biomarkers to assess
heart failure.
In addition, we tested commercially
available saliva collection devices (Figure 2)
to determine their efficacy for detecting
salivary proteins with varying molecular
weights, such as CRP, myoglobin, and IgE,
in healthy controls (14) (Table 1). Our data
demonstrated significant differences in analyte levels based on the collection device.
Early detection of head and neck squamous cell carcinoma (HNSCC), cancers that
occur in the nasal passages, sinuses, mouth,
larynx, and pharynx, is another focus of salivary diagnostics. Tobacco use is a major risk
factor for this type of cancer, and 30–50% of
HNSCCs are a direct result of HPV 16, and
to a lesser extent HPV 18, infections. DNA
methylation in cells is an early event that occurs during tumor initiation, and we have
found methylation of three tumor suppressor genes (DAPK1, RASSF1A and p16) in
saliva collected from HNSCC patients that is
not present in healthy controls (5).
Roadblocks to Advancement
Shown here is the wide variety of commercially available saliva collection devices in use today: drool collected
in a sterile specimen container (A); Salimetrics oral swab (B); Salivette cotton and synthetic device (C); Greiner
Bio-One saliva collection system (D); OriGene DNA collection device (E); and DNASal collection device (F).
Expansion of salivary diagnostics is hampered by several factors. First, analytes in
saliva are usually present at only 0.1–0.001
of the levels found in blood; therefore, very
sensitive detection technology is required
to develop effective tests. Another impediment is the lack of information about
baseline levels or reference ranges of molecules in saliva within a healthy control
population. This information is crucial to
discriminating disease-specific changes.
To be clinically useful, there also must
be reliable correlations between levels of the
target substance in saliva and in blood or
plasma. For example, we know that salivary
Clinical Laboratory News January 2013 9
diagnostics are not well suited to measuring
glucose levels because blood and salivary levels of this analyte are poorly correlated. This
could be the case for other analytes as well.
Another complication is that contamination of saliva samples with even a small
amount of blood will lead to a false-positive
result. In fact, bleeding after brushing or
flossing occurs quite frequently and could
contribute to high false-positive rates for
salivary tests. Research also is needed on
how levels of molecules vary diurnally. For
example, we know that salivary growth
hormone levels are higher in the morning
than during the day, which could also be
the case for other biomarkers.
The lack of standardized saliva collection
methods also makes the widespread adoption of salivary diagnostics more challenging. In one study, researchers reported that
the OraSure saliva collection device detects
hepatitis C virus with greater sensitivity than
the Salivette device (15). Such differences
may be related to the collection device itself.
What Does the Future Hold?
As our knowledge of the biomolecules present in saliva grows, the potential applications
for oral and systemic disease diagnosis will
expand. While the scientific link between
salivary biomarkers and oral diseases is clear,
more studies are needed to delineate the
mechanisms by which saliva reflects other
systemic diseases. Furthermore, before saliva
Figure 3
Salivary CRP Levels
A
B
A. Salivary CRP levels in healthy volunteers (n = 55) and in patients with ischemic heart disease (n = 28).
B. Correlation of salivary to plasma CRP levels.
can become widely recognized as a reliable
diagnostic fluid, we need to more fully understand a number of important variables.
First, we need to define the normal
biological variability of biomolecules in
saliva, such as diurnal rhythms, inter- and
intra-subject variation, and age and gender effects. The influence of diet, medication, smoking, alcohol, and physical activity
status may also influence levels of biomolecules in saliva. From an analytical stand-
Simple and direct saliva collection
with Evergreen’s new Oro-Col
point, methodological variations caused by
saliva sampling, handling, and storage conditions will need to be defined, as well as
methodological variations due to the analytical techniques used. Since the salivary
proteome is sensitive to both extrinsic and
intrinsic factors, analyte reference ranges in
saliva will need to be carefully documented.
Salivary diagnostics has enormous potential for the future, but we need to lay a
solid scientific foundation in the present in
order to realize that potential. Non-invasive
tests for detecting breast cancer, viral, and
bacterial diseases, cardiovascular and metabolic diseases, and general nutritional deficiencies could make a tremendous impact
on global health.
The key parties responsible for translating salivary research from a laboratory setting to clinical practice, including
scientists, regulatory agencies, and third
parties such as insurance companies, will
need to work together to determine how
new saliva diagnostics are adopted by the
health care community. But undoubtedly,
a saliva swab test in the privacy of one’s
home or at the general practitioner’s office will become a reality for diagnosing
CLN
systemic diseases.
References
• Simple,non-invasivesamplecollection.
• Directcollectionprocessprovidinganoptimalamountof
oralfluidsampleintoacalibratedvial.
• Biomarkerconcentrationsinoralfluidsreflectthe
concentrationsinblood.
• Oralfluidhasbeenusedasthealternatesampleforthe
detectionandmeasurementofdrugsofabuseandbiomarkersforvariouscancers,cardiacdiseases,stressand
otherclinicalconditions.
https://www.evergreensci.com
info@evergreensci.com
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10 Clinical Laboratory News January 2013
1. Lawrence HP. Salivary markers of systemic disease: noninvasive diagnosis of
disease and monitoring of general health. J
Can Dent Assoc 2002;68:170–4.
2. Christodoulides N, Floriano PN, Miller
CS, et al. Lab-on-a-chip methods for pointof-care measurements of salivary biomarkers of periodontitis. Ann N Y Acad Sci
2007;1098:411–28.
3. Punyadeera C, Dimeski G, Kostner K, et
al. One-step homogeneous C-reactive protein assay for saliva. J Immunol Methods
2011;373:19–25.
4. Yang Foo JY, Wan Y, Kostner K, et al.
NT-ProBNP levels in saliva and its clinical
relevance to heart failure. [Epub] PLoS One
October 31, 2012 as doi:10.1371/journal.
pone.0048452.
5. Ovchinnikov DA, Cooper MA, Pandit P, et al. Tumour-suppressor gene promoter hypermethylation in saliva of head
and neck cancer patients. Transl Oncol
2012;5:321–6.
6. Pfaffe T, Cooper-White J, Beyerlein P, et
al. Diagnostic potential of saliva: Current
state and future applications. Clin Chem
2011;57:675–87.
7. Mohamed R, Campbell JL, CooperWhite J, et al. The impact of saliva collection and processing methods on CRP,
IgE, and Myoglobin immunoassays. CTM
2012;1:19.
8. Schulz BL, Cooper-White J, Punyadeera
CK. Saliva proteome research: Current
status and future outlook. [Epub ahead of
print] Crit Rev Biotechnol May 21, 2012.
9. UCLA Newsroom. Researchers find biomarkers in saliva for detection of early-stage
pancreatic cancer. http://newsroom.ucla.edu
/portal/ucla/early-detection-biomarkersof-153212.aspx (Accessed August 2012).
10.Streckfus CF, Mayorga-Wark O, Arreola
D, et al. Breast cancer related proteins are
present in saliva and are modulated secondary to ductal carcinoma in situ of the
breast. Cancer Invest 2008;26:159–67.
11.Bandhakavi S, Stone MD, Onsongo G,
et al. A dynamic range compression and
three-dimensional peptide fractionation
analysis platform expands proteome coverage and the diagnostic potential of whole
saliva. J Proteome Res 2009;8:5590–600.
12.Loo JA, Yan W, Ramachandran P, et al.
Comparative human salivary and plasma
proteomes. J Dent Res 2010;89:1016–23.
13.Denver R, Tzanidis A, Martin P, et al.
Salivary endothelin concentrations in the
assessment of chronic heart failure. Lancet
2000;355:468–9.
14.Topkas E, Keith P, Dimeski G, et al.
Evaluation of saliva collection devices for
the analysis of proteins. Clin Chim Acta
2012;413:1066–70.
15.Judd A, Parry J, Hickman M, et al. Evaluation of a modified commercial assay in
detecting antibody to hepatitis C virus in
oral fluids and dried blood spots. J Med Virol 2003;71:49–55.
Chamindie Punyadeera,
PhD, is the lead research scientist in the Saliva Translational Research Group, Tissue
Engineering and Microfluidics Laboratory, Australian Institute for
Bioengineering and Nanotechnology at the
University of Queensland in Queensland,
Australia.
Email: c.punyadeera@uq.edu.au
Disclosure: The author has nothing to
disclose.
A Look Into the Crystal Ball—Budget Cuts, Healthcare Reform
What Laboratory Professionals Can Expect in 2013
By Vince Stine, PhD
T
he 2012 presidential election is
history, and the White House
and Congress are back at work
in Washington, D.C. By winning, President Barack Obama
became the third incumbent President in a
row to be re-elected and the fifth Chief Executive to do so since 1972. Similarly, voters
returned a Democratic Senate and Republican House of Representatives, allowing
Senator Harry Reid (D-Nev.) and Representative John Boehner (R-Ohio) to keep their
respective leadership positions. Now as the
new year begins, the two sides need to put
aside the bitterness of the past year and work
together to resolve a number of pressing issues facing the nation, particularly budgetary matters, that are likely to impact healthcare spending and clinical laboratories.
Falling into the Abyss?
At CLN press time in December, all of
Washington was talking about the pending ‘fiscal cliff.’ This term, first coined by
Federal Reserve Chairman Ben Bernanke,
reflects his concerns about the impact of
$700 billion in spending cuts and tax increases scheduled to take effect on January
1, 2013. The immensity of these budgetary
changes could, according to the Congressional Budget Office (CBO), result in the
“economy toppling back into recession.”
This concern about the state of the economy has lawmakers scrambling to work out
deals to develop a long-term deficit reduction package and enact legislation to retain
most of the Bush-era tax cuts.
The current crisis is a byproduct of the
Budget Control Act of 2011 that Congress
passed to forestall an earlier budgetary shortfall. This legislation required $1.2 trillion in
across-the-board spending cuts over 10 years
starting in 2013 and split evenly between
domestic and defense spending. Although
certain programs such as Medicaid, Social
Security, and Veterans benefits were exempted from these reductions, Medicare was not.
The law did allow Congress to replace the indiscriminate cuts with more targeted reductions prior to the effective date. Until now,
Congress has been unable to do so.
Another element of the fiscal cliff is the
Bush-era tax cuts that are set to expire at
the end of 2012. President Obama has
proposed extending these tax benefits to
families making $250,000 annually or less.
According to the Citizens for Tax Justice,
this limited extension would reduce federal
revenues by $243 billion in 2013 and more
in the following years. Congress is likely to
pass some variation of the President’s offer,
and this means the legislative branch will
need to find additional revenues to pay for
extending the tax cuts.
Payment Reductions for Labs Looming
Also looming as part of this fiscal nightmare is a projected 26.5% cut in Medicare
physician payments. Past congressional efforts to restrict the growth in physician reimbursement created what many consider
a formula that specifies annual deep reductions in physician payments. Now, every
year Congress has to intervene to prevent
these cuts. Legislators passed a $17 billion
fix in 2012 that included a number of cuts
to healthcare providers, including a 2% cut
in the clinical laboratory fee schedule beginning in 2012. Another temporary fix in
2013 is expected to cost $25 billion, so legislators will have to find money to pay for
this budgetary issue as well.
Physicians aren’t the only ones facing pay
cuts. Payment reductions in 2013 are coming for labs too as a result of the 2010 healthcare reform law. The reform package included two annual cuts for clinical laboratories:
a permanent reduction in the clinical laboratory consumer price index (CPI) update
by a “productivity adjustment” and a 5-year
annual cut in the CPI update of 1.75% that
expires in 2015. These cuts, combined with
physician fix reductions, will cut laboratory
payments by 2.95% in 2013. But this figure
could increase to 4.95% if Congress fails to
address the fiscal cliff and the across-theboard Medicare cuts take effect on January
1st as a down payment for deficit reduction.
More on the Table
Given the scope of the U.S. budgetary issues,
Congress has even been discussing such sacred cows as reducing the mortgage interest and charitable tax deductions. In other
words, everything is on the table, and it’s likely that clinical laboratories will be a target to
contribute more. Lawmakers have a laundry
list of potential items to choose from that will
hurt laboratory budgets (See Box).
In the short-term, Congress may agree
to a 6-month delay to work out a longterm deal with the White House given the
sensitivity and politics surrounding the issues. However, the window of opportunity
is small because legislators will soon start
thinking about the 2014 mid-term elections.
Healthcare Reform Resurfaces
Another issue that will receive a lot of attention in 2013 will be healthcare reform.
Potential Congressional Targets
for Cost Savings in Labs
®Laboratory co-payments for Medicare recipients.
®Competitive bidding for laboratory services.
®Extending the 1.75% annual cut in the lab consumer price index due
to expire in 2015.
®Further reductions in the laboratory fee schedule.
®Bundling payments.
Legislators are looking for ways to save money to pay for potential tax cuts
and healthcare reform in 2013. Laboratory professionals should pay close
attention to the issues and be proactive with their legislators. AACC’s Government Affairs Advocacy Network allows you to contact your elected officials
and regulators to express your opinion on a variety of legislative and regulatory issues important to clinical laboratorians. Go to our website at www.aacc.
org and visit the Government Affairs pages for more information.
With the election over and Republicans
conceding they are unable to repeal the
law, policymakers will focus their attention on implementation of the act. Some
of the more popular and easier to implement provisions of the law are already in
effect, such as allowing children up to age
26 to remain on their parents’ insurance,
barring the denial of insurance coverage
to individuals under 19 due to pre-existing
conditions, and expanding prevention and
wellness benefits. Over the next 2 years,
however, some of the more complicated,
costly, and controversial provisions will go
into effect.
One difficult provision involves implementing state insurance exchanges. These
local entities will be responsible for reviewing and approving qualified health plans,
educating consumers and small businesses,
and enrolling participants in the plans. To
date, 17 states and the District of Columbia have agreed to create and manage such
exchanges; however, nearly 20 states have
declined to participate and the rest are
undecided or partnering with the federal
government. If a state chooses not to create an exchange, the Department of Health
and Human Services (HHS) is required to
develop and oversee it. At this point, it’s unclear whether HHS can get these exchanges
up and running by the fall of 2013 so potential enrollees can select a plan.
Of importance to clinical laboratories
is that each participating insurance plan
must cover certain “essential health benefits” as prescribed by the act. Included
among the 10 required services is laboratory testing. The good news for laboratories
is that implementing this provision should
result in an increase in the volume of laboratory services ordered. CBO estimates
that nearly 12 million people will obtain
coverage through the exchanges in 2014, a
number that is expected to increase to 27
million by 2018.
Another feature of the healthcare reform law makes parents, children, and
childless couples with family incomes be-
low 133% of the federal poverty level eligible for Medicaid. More than half of the 30
million newly insured will receive coverage
through the federal-state poverty program.
This expanded coverage, in addition to increasing volume, may reduce the level of
uncompensated care borne by healthcare
providers, as well as increase the volume of
testing for clinical laboratories. However, as
with the exchanges, there are complications.
Last summer, the Supreme Court ruled
that states do not have to expand their
Medicaid programs as specified in the
healthcare law to continue participation in
the program. Many states argue that Medicaid is already costly and that they cannot
afford the expansion prescribed in the law.
Currently, more than a dozen states, including Texas and Florida, which have large
uninsured populations, have stated they
will not participate in the Medicaid expansion. If these states maintain their opposition to this policy change, the benefits derived from healthcare reform, at least in the
short-term, will be less than expected.
Stay Informed and Prepare to Take Action
Over the next 12 months, laboratory professionals will need to remain actively engaged in policy debates involving the federal budget and healthcare reform. Each
of these issues could significantly affect
laboratory operations in the short and long
term as lawmakers seek to pull the U.S.
back from the fiscal cliff and implement
the most far-reaching federal health legislation since the passage of Medicare and
Medicaid in 1965.
AACC and CLN will continue to keep
you abreast of these issues as decisions are
made and announce opportunities for you
CLN
to influence policy.
Vince Stine, PhD, is director
of government affairs at
AACC.
Email: vstine@aacc.org
Clinical Laboratory News January 2013 11
PATIENT SAFETY FOCUS
T a k ing A im at R educing L ab E rr o rs
Preventing Infections Related to Using
Point-of-Care Testing Devices
An Interview with Sharon M. Geaghan, MD
The convenience and immediacy of point-of-care
testing (POCT) has led to its use in many settings.
But untrained or busy healthcare workers may
overlook some basic sanitary practices when using POCT devices. This lack of attention is leading
to nosocomial infections that can be attributed to
contaminated devices. Here, Sharon M. Geaghan,
MD, discusses how these infections occur and
how to prevent them. Dr. Geaghan is professor of
pathology and pediatrics at Stanford University
School of Medicine in Palo Alto, Calif.
Michael Astion, MD, PhD, chair of the Patient Safety Focus Editorial Advisory Board, conducted this interview.
How would you sum up the problem
related to POCT and nosocomial
infections?
Overall, I would say that there is a significant and pervasive lack of awareness about
nosocomial infections associated with
POCT, especially hepatitis B infections.
In what settings do these infections
occur?
Typically, these infections occur during
assisted monitoring of a POCT analyte.
By assisted monitoring, I mean a POCT
procedure performed by a nurse or other
healthcare provider for the patient, rather
than by the patient. Frequently, this involves a diabetic patient who is being
helped with monitoring his or her blood
glucose; however, any POCT device can
transmit infection. These infections have
been found in a variety of health care settings, including hospitals, ambulatory
surgery centers, outpatient clinics, and assisted living facilities.
What infectious agents are most likely to
be transmitted by POCT devices?
Hepatitis B and C are the most likely, although any blood-borne pathogen can be
transmitted. For example, in one assisted
living facility in North Carolina, officials
discovered unsafe POCT practices that
had significant consequences. Eight of 15
patients who had assisted POCT glucose
monitoring contracted hepatitis B, and six
died from the infection. While the severity
of any infection transmitted in this manner can vary, this example illustrates that
patients can suffer dire outcomes from
POCT-transmitted nosocomial infections.
How are these infections transmitted?
There are several mechanisms, such as using
a multi-lancet, finger-stick device on more
than one patient; inadequately disinfecting
and cleaning the POCT device between patients; placing meters in contaminated storage areas; and failing to change gloves and
thoroughly wash hands between patients.
It’s important to note that the highest risk
for inadequate hand hygiene and glucose
meter disinfection occurs when healthcare
workers must assist large numbers of patients and only a few devices are available.
As laboratorians know, POCT devices
frequently become contaminated with
blood. What many healthcare workers fail to
recognize, however, is that transmission of
infectious agents can occur even if no blood
is visible on the finger-stick or POCT device.
Recommendations for Reducing
the Risk of POCT-related Infections
®Use finger-stick devices on only one patient.
®Use auto-disabling, single-use safety lancets for blood collection.
®Assign POC devices to a single patient whenever possible.
®Clean and disinfect POCT devices after every use if single-patient
assignment is not possible.
®Change gloves between patients no matter what other precautions
are being taken.
Source: Reference 5
12 Clinical Laboratory News January 2013
Healthcare professionals need to take extra precautions in assisted living
facilities to prevent transmitting infections from contaminated POCT devices.
Do glucose meters have to be cleaned
and disinfected after every use?
Yes, especially if the meter is being used sequentially on different patients. In assisted
living facilities, patients usually have dedicated meters. Even so, proper storage of the
device is still important. It’s best to store
the meter in the patient’s room, so that the
risk of accidentally using the device on another patient and cross-contamination by
contact with a blood-contaminated storage
area or other equipment is eliminated. If
the meter is reassigned to another patient,
then it must be cleaned and disinfected.
Healthcare workers may not be aware that
meters can become contaminated in unsanitary storage areas. Even if the meter does not
come in direct contact with patients, indirect
transmission can occur via healthcare workers who handled the contaminated device.
It’s also important to note that many institutions use alcohol wipes to disinfect devices.
These wipes are not effective against hepatitis
B virus present in dried blood. Instead, devices should be cleaned and disinfected with
bleach-based disinfectants that are effective
against hepatitis B and C.
Can you summarize the recommendations to reduce the risk of POCT-related
infections?
The Food and Drug Administration and
the Centers for Disease Control and Prevention have made some recommendations
(See Table). The recommendations focus
on cleaning and disinfecting instruments,
proper hand hygiene, and implementing
single-use finger-stick devices whenever
possible. Assigning POCT instruments to
a single patient is recommended as a best
practice.
References
1.Louie RF, Lau MJ, Lee JH, et al. Multicenter study of the prevalence of blood contamination on point of care glucose meters
and recommendations for controlling contamination. Point Care 2005;4:158–63.
2.CDC. Notes from the field: deaths from
acute hepatitis B virus infection associated
with assisted blood glucose monitoring in
an assisted living facility—North Carolina, August–October 2010. MMWR Morb
Mortal Wkly Rep 2011;60:182.
3.CDC. Multiple outbreaks of hepatitis
B virus infection related to assisted monitoring of blood glucose among residents
of assisted living facilities—Virginia, 2009–
2011. MMWR Morb Mortal Wkly Rep
2012;61:339–43.
4.Thompson ND, Schaefer MK. “Never
Events”: hepatitis B outbreaks and patient
notifications resulting from unsafe practices during assisted monitoring of blood
glucose, 2009–2010. J Diabetes Sci Technol
2011;5:1396–402.
5.FDA Patient Safety News. Preventing infections while monitoring glucose.
www.accessdata.fda.gov/psn/printer-full.
cfm?id=164 (Accessed November 2012).
Failure to Follow Up on Test Results
Failing to follow up on test results is a major problem in healthcare that contributes to unsafe patient care, particularly in ambulatory settings. In fact, almost a quarter of all medical errors
occurring in outpatient settings can be attributed to poor followup of abnormal test results and are believed to represent 25% of
malpractice lawsuits involving failures or delays in diagnosis.
In the October 2012 issue of CLN’s Patient Safety Focus, I asked
readers to respond to the following question: How does your lab
ensure that pending lab results get to providers after a patient
is discharged? Jaime Noguez, PhD, a clinical chemistry fellow at
Emory University, Atlanta, provides her healthcare
system’s information technology (IT) approach to
this communication problem, as well as that used by
Brigham and Women’s Hospital in Boston.
Corinne Fantz, PhD
Patient Safety Editorial Board Member
No News Is Not Always Good News
How IT Solutions Can Help Avert the Failures
By Jaime Noguez, PhD
Clinical laboratorians have primarily focused their efforts on reducing errors in
the analytical phase of testing. Today, this
phase of the total testing process is one of
the most reliable systems in healthcare.
However, the measure of success in laboratory medicine is based on all phases
of the total testing process, from test ordering to appropriately interpreting and
reacting to results. Because the clinical
laboratory has historically been at the
forefront of quality improvement activities in healthcare, we are well positioned
to take on the next challenge for laboratory medicine: helping clinicians and other
healthcare providers tackle the errors in
the “extra-analytic” phases of the total
testing cycle (Figure 1) (1).
Test Result Management Systems
In 2008, Emory University Hospitals implemented a unique system to improve the
emergency department’s (ED) management of test results. Known as aftER Care,
the system consists of an automated information service that enables clinicians
and other qualified healthcare providers to
manage results by automatically generating
aftER Care events for every discharged patient with pending test results. These pending test results are usually for tests with long
turnaround times, such as blood cultures
or sexually transmitted diseases. The system
populates these events into a list that must be
reviewed by the end of each shift (Figure 2).
Once the provider has acknowledged
receipt of the test results, the event is signed
electronically and cleared from the list. If
the discharged patient cannot be reached
by phone after several attempts, the system generates a letter using the address on
file and it is sent to the patient via certified
mail. Because patients in the ED sometimes
provide incorrect contact information, the
discharge documentation given to patients
includes a phone number they can call
to follow up on test results or with other
questions regarding their treatment plans.
Table 1
Overcoming IT Problems in Electronic
Results Management Systems
IT Problem
Patient Safety Net
Test result delivery.
Track acknowledgement of test
result delivery and report failures
to responsible party.
Data organized in departmental
silos.
Integrate reports, including
pharmacy changes linked to
pertinent lab results.
Too many general alerts leading
to alert fatigue.
Design alerts to fit in clinician
workflow and use them sparingly.
The Consequences of Failure to
Follow Up on Lab Results
An Illustrative Case
A 22-year-old woman presented to the clinic with complaints of
headache and a low-grade fever for the past 3 days. The physical examination was unremarkable and the patient’s only other
complaint when further questioned was intermittent abdominal
pain that she attributed to pending menstruation. The physician ordered routine blood work and urinalysis with microscopic
exam. Her blood tests were normal, and urinalysis results did
not indicate a urinary tract infection. She was discharged and
informed that she would be notified of additional pending test
results.
About 10 days later, the woman’s abdominal pain had become
constant and she began experiencing dysuria, so she decided to
go to the emergency department (ED). The ED physician ordered
the same tests, but when he reviewed the results in her chart, he
noticed that the patient had a positive urine PCR test for
Chlamydia trachomatis. He was surprised to see that the result
had been entered almost a week ago, but that it was never
acknowledged in the patient’s medical record or acted upon by
the attending physician.
Before starting the woman on antibiotics, the physician performed a pelvic exam that revealed evidence of inflammation
of the reproductive organs, possibly due to pelvic inflammatory disease. A pelvic ultrasound revealed thickened, fluid-filled
fallopian tubes supporting the diagnosis of upper genital tract
inflammation.
ED chief nurse practitioner, Antionette
Ward, NP, DNP, believes the aftER Care
program has made pending test result
management much easier compared to
the previous paper-based system by condensing and organizing these events into
a single-file format that can be tracked
easily. The system also has been benefi-
Figure 1
Conceptual Framework of the Testing Process
Test
ordered
Test
implemented
Pre-analytic
Test
performed
Analytic
Test results
returned to
clinician
Clinician
responds to
test results and
documents
Patient
notified of
test results
Post-analytic
Patient
monitored
through
follow-up
cial as a tool to document follow-up and
provide feedback to clinicians about their
diagnostic successes and failures. Recent
data indicate that aftER Care has allowed Emory to close the loop on 99.8%
of test results.
A similar system to address efficiency and
reliability of test result follow-up has been
developed and implemented at Brigham
and Women’s Hospital in Boston. The Longitudinal Medical Record Results Manager
allows clinicians to review all chemistry, microbiology, hematology, radiology, and pathology results and document electronically
that the appropriate caregiver has received
the results. A major benefit of this system is
that it enables clinicians to review the results
in the context of the patient’s previous findings, in addition to the individual’s clinical
history and medication list.
Clinical Laboratory News January 2013 13
A few fail-safe mechanisms have been
built into this system, such as nightly e-mail
reminders that are sent to providers if critical lab results have been filed, but not acknowledged, and the ability for users to allow colleagues to review test results on their
behalf (2). Although more comprehensive
studies evaluating the success of Results
Manager are underway, a small, randomized trial found that the percentage of
documented follow-ups to post-discharge
microbiology culture results more than
doubled (3).
Figure 2
Summary Screen of aftER Care
The Pros and Cons of IT Solutions
Managing follow-up of test results is a
complex process. Using IT clearly has the
potential to reduce the number of missed
results by ensuring a safer and more systematic process; however, implementing
technological solutions alone will not solve
the problem of inadequate test follow-up.
Busy physicians are tasked with assimilating massive amounts of information
dumped into the electronic medical record
(EMR) by different departments, including the lab, the pharmacy, radiology, and
others. This requires physicians to spend
a considerable amount of time filtering
the information provided by each department in order to create a clinical picture of
the patient and to develop a diagnosis and
treatment plan. Because this data assimilation process is so intensive and prone to
error, patient care is safer when these data
can be easily visualized in an organized
manner.
IT solutions fail, however, when the data
are present but critical information is overlooked. A root cause of this type of failure
is organizing data into separate silos in the
EMR. For example, lab data on microbial
resistance and pharmacy data related to
medication and dosage filed in two separate places in the EMR may cause a physician to continue an inappropriate antibiotic treatment because he didn’t check both.
Connecting these two sets of data is likely
to result in a decrease in medical errors.
Furthermore, overall utilization and quality of laboratory testing, pharmacotherapy,
This screen allows healthcare providers to view all pending laboratory results and clear the event from the list
after results have been acknowledged.
and patient safety improves, as one study
documented (4).
IT also fails when tools intended to aid
medical providers, such as alerts, actually
hamper their efforts. For example, pop-up
alerts can be beneficial to notify physicians
that the test being ordered is potentially
redundant. But poorly executed systems
sometimes produce excessive alerts that
can overburden busy physicians and result
in what is commonly called alert fatigue.
When this happens, physicians often ignore
important messages (5).
On the other hand, IT solutions can improve result management if they are properly integrated into healthcare providers’
workflow. For instance, high-priority alerts
with clinically significant information like
low glucose levels in a patient on high-dose
Does laboratory
result management
tie your physicians down?
insulin must be delivered on a timely basis
so that providers have sufficient time to
take action. Similarly, structured handoffs
based on computerized checklists can help
transmit clinically significant test results
during shift changes (6, 7).
tion to help clinicians develop a systematic
method for test result follow-up using the
same or similar strategies already used to
effectively manage patient results within
the laboratory.
Sharing Knowledge of Systems
1.Hickner J, Graham DG, Elder NC, et al.
Testing process errors and their harms and
consequences reported from family medicine practices: A study of the American
Academy of Family Physicians National
Research Network. Qual Saf Health Care
2008;17:194–200.
2. Poon EG, Wang SJ, Gandhi TK, et al. Design and implementation of a comprehensive outpatient Results Manager. J Biomed
Inform 2003;36:80–91.
3. Poon EG, El-Kareh R, Roy C, et al. Impact of automated alerts on follow-up of
post-discharge microbiology results: A
cluster randomized controlled trial. J Gen
Intern Med 2012;27:1243–50.
4. Schiff GD, Klass D, Peterson J, et al. Linking laboratory and pharmacy: Opportunities for reducing errors and improving care.
Arch Intern Med 2003;163:893–900.
5. Appold K. Alert fatigue: When too many
alerts lose physicians’ attention. Clin Lab
News 2010;36:19.
6.Grimm, E. Shift-to-shift communication: What can labs learn from NASA and
other highly reliable organizations. Clin
Lab News 2011;37:14.
7. Fantz, C. The checklist movement: Why
laboratories should embrace memory aids.
Clin Lab News 2011;37:18–19.
Clinical laboratorians are well positioned to
play a greater role in reducing test result follow-up errors. We are well versed in using
information systems to flag and document
abnormal test results and critical values.
In addition, we have stringent protocols,
strategic processes, and efficient workflow
designs along with clear definitions of the
responsibilities of each individual in the
laboratory. Given this combination of skills
and systems, we stand in a unique posi-
References
Jaime Noguez, PhD, is a
clinical chemistry fellow
at Emory University,
Atlanta, Ga.
Email: jaime.noguez@
emory.edu.
14 Clinical Laboratory News January 2013
A Family Physician’s Perspective
Laboratory Testing and Diagnostic Errors
An Interview with Peter Weir, MD, MPH
ARUP Laboratories’ workplace clinic serves
roughly 4,500 employees, spouses, and dependents, and takes full responsibility for an
individual’s healthcare, from mental and physical health to disease prevention and chronic
disease management. Patients of the clinic
include newborns, as well as patients over the
age of 70. Seven health care practitioners—
two family medicine physicians, four mid-level
providers, three physician assistants, one nurse
practitioner, and a half-time clinical pharmacist—attend to the needs of the entire patient
population. Peter Weir, MD, MPH, is the medical director of the clinic and assistant clinical professor in the University of
Utah Department of Family and Preventive Medicine in Salt Lake City. Here Dr. Weir gives his perspective on diagnostic errors.
Brian Jackson, MD, MS, of the Patient Safety Focus Editorial
Advisory Board, conducted this interview.
Please describe your clinical responsibilities and practice setting.
My role in the clinic is to see my own patient panel, as well as to supervise the medical care of all patients seen in our clinic. I’m
fortunate to work with partners who are
very competent and knowledgeable within their own area of expertise: pediatrics,
women’s health, and sports medicine.
So would you describe your clinic as a
medical home, in other words a teambased healthcare delivery model that
provides comprehensive and continuous
medical care to patients with the goal of
obtaining maximized health outcomes?
Yes, that’s what we’re trying to accomplish.
What are some of the challenges that
you encounter in diagnostic testing?
Every time I order a test of any kind, I’m
very aware of the potential for ordering the
wrong test for the patient’s condition, as
well as the fact that even correctly ordered
tests have weaknesses, for example false
negatives and false positives. Ordering the
incorrect test happens far more often than
healthcare professionals probably realize.
For example, in our clinic, many providers
including me were ordering the serum H.
pylori antibody test that gives very limited
information. We later learned how much
more appropriate the H. pylori breath test
and stool antigen test are for determining if
a patient has an active infection. Disruptive Behavior
in the Laboratory
At ARUP, we have an unusual patient
population in that they tend to like being
tested and often ask us to test for things that
may not be clinically indicated. An example
would be a patient who wants a test for a
biomarker to screen for cancer even though
the individual has no clinical indications. Ordering a cancer biomarker in this
situation can lead to panic and a wild goose
chase if the result comes back elevated.
Another common problem is dealing with unexpected results. I’ve learned
to repeat a lab or study if it doesn’t fit the
clinical picture. Not infrequently, the repeat comes back with a normal result and
avoids wasting a lot of time and resources.
For example, I remember monitoring serial
hemoglobins on a hospitalized patient with
suspected upper gastrointestinal bleeding
to determine if the patient would need an
immediate transfusion and/or an urgent
EGD to look for the source of bleeding.
One hemoglobin result came back 50%
lower than the previous one. I rushed to
the patient’s bed expecting to find him very
unstable and pale, yet he looked no different
from when I last saw him. I ordered a CBC
to confirm the result and then watched the
phlebotomist as he drew the blood from a
vein that the patient’s IV fluids were connected to. I realized in an instant that the
last blood sample was diluted 1:1 with IV
fluids, which led to the erroneous result.
Do you encounter diagnostic testing
issues that are specific to mid-level
providers?
I have found that inexperienced clinicians,
not necessarily mid-level providers, tend to
over-order tests when they are uncomfortable with a clinical situation. The problem
they run into, however, is the more tests that
are ordered, the more interpretation of results that is needed. For example, consider a
patient with unusual joint pain. A less experienced provider might begin the workup with
a panel of rheumatologic lab tests rather than
carefully taking a history, doing a complete
physical exam, and then targeting the appropriate laboratory work-up. Ordering panels
of lab tests that are not well thought-out can
generate misleading, and sometimes conflicting, results, and leads to confusion, unnecessary referrals, and patient anxiety.
Can you think of other examples of
patient harm resulting from diagnostic
testing? The one that first comes to mind is the
PSA test. I have followed the prostate cancer screening controversy for the past 12
years. In the late 1990s, many of us were
concerned that there was no data to prove
that mortality rates were decreasing despite
the huge increase in prostate cancer detection. The worry was that we were catching a
whole bunch of very slow, indolent tumors
that probably would never have caused
any clinical manifestation. In the last few
years, large randomized controlled trials
have confirmed that fear: PSA screening in
asymptomatic men has not significantly reduced mortality. I am now reluctant to order PSA screening in men for fear that I will
be doing the patient more harm than good. If you had a magic wand to wave over
the clinical laboratory, what would you
change?
I would somehow bring the expertise from
the clinical laboratory into our clinic. I am
surrounded by physicians and scientists
who have an exceptional knowledge base
that I wish I could tap into at the point-ofcare. No doubt, every provider has limits to
his/her own knowledge, and collaboration
with colleagues often leads to better care for
patients. An Invitation to Readers
How has your lab improved patient safety?
Send your success stories to me for inclusion in
a future issue of Patient Safety Focus.
Michael Astion, MD, PhD
micheal.astion@seattlechildrens.org
“Here is what I think of all your vitamin D tests!!!”
Key Point: Disruptive behavior adversely affects laboratory quality and
teamwork and can decrease the safety of our patients.
References
Astion ML. Disruptive behavior: How labs can recognize and overcome
its negative effects. Clin Lab News 2011;37(7):16.
Hernandez J. Confronting conflict in the lab: How lab managers can
curb the effects of disruptive behavior. Clin Lab News 2011;37(7):15.
Patient Safety Focus Editorial Board
Chair
Michael Astion, MD, PhD
Seattle Children’s Hospital
Seattle, Wash.
Members
Peggy A. Ahlin, BS, MT(ASCP)
Consultant
Salt Lake City, Utah
Corinne Fantz, PhD
Emory University
Atlanta, Ga.
James S. Hernandez, MD, MS Mayo Clinic Arizona Scottsdale and Phoenix, Ariz.
Brian R. Jackson, MD, MS
ARUP Laboratories Salt Lake City, Utah Clinical Laboratory News January 2013 15
profiles
PT Referral Legislation
Signed Into Law
I
r e g u l at o r y
Supreme Court to Take Up
Gene Patent Case
A
fter bouncing back and forth between
appeals courts and the U.S. Supreme
Court for almost 4 years, the Supreme
Court has finally agreed to rule on the
patentability of genes associated with
breast and ovarian cancer, a decision
that could have far-reaching effects on
the business of molecular diagnostics.
The American Civil Liberties Union and
the Association for Molecular Pathology
(AMP) originally filed the lawsuit in 2009
against the U.S. Patent and Trademark
Office, as well as Myriad Genetics and the
University of Utah Research Foundation,
which hold the patents on the BRCA1
and BRCA2 genes. The lawsuit charges
that patents on human genes violate the
First Amendment and patent law because
genes are “products of nature” and therefore cannot be patented.
K-ASSAY ®
The first time a decision was handed
down on the case was in March 2010, when
a New York federal court ruled the patents
invalid. Myriad appealed, and a year later,
the Court of Appeals for the Federal Circuit
ruled that companies can obtain patents
on the genes but cannot patent methods to
compare those gene sequences.
The case made its way to the Supreme
Court for the first time in March 2012, when
the court vacated the decision of the appeals
court and instructed the court to reconsider
the case in light of Mayo v. Prometheus, a
Supreme Court decision unanimously invalidating patents on methods for evaluating a patient’s response to a drug. However,
the appeals court essentially repeated its
original ruling. Finally, in September 2012,
the plaintiffs again asked the Supreme
Court to rule on the patentability of genes,
and the court agreed to hear the case.
More information is available from
AMP, www.amp.org.
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16 Clinical Laboratory News January 2013
2011.09 CLN Insulin.indd 1
n a welcome victory for the lab community, President Obama on December 4
signed the Taking Essential Steps for Testing (TEST) Act, easing automatic penalties
for labs that refer a proficiency testing (PT)
specimen unintentionally.
Under the existing law, a lab that referred
a PT specimen to an outside laboratory
could lose its CLIA certificate for 2 years,
even if the specimen was not referred to
deliberately cheat on a PT challenge. Since
many labs have policies that automatically
refer certain specimens to another lab, the
statute has worried labs for years, although
harsh punishments have been rare. If CMS
discovered a PT referral, the sanctions under previous versions of the law would also
have extended to the lab director and even
the hospital in which a lab operated, potentially forcing a hospital to find another organization to perform all lab testing.
With the changes to the law prescribed
in the TEST act, CMS will now have legal
leeway on how to punish a guilty lab, such
as levying fines instead of revoking the lab’s
CLIA certificate. The TEST act also makes
clear that CMS can differentiate between a
PT referral that happened through a clerical error in good faith, or through the lab
knowingly trying to subvert the regulation.
House Representatives Michael Grimm
(R-N.Y.) and Michael Burgess (R-Texas)
championed the act along with 13 cosponsors. In the Senate, Senator Amy Klobuchar
(D-Minn.) introduced the bill with six cosponsors.
The new legislation is posted on the
Library of Congress’s THOMAS website,
http://thomas.loc.gov.
Medicare Pays First,
Asks Questions Later
R
ather than make sure bills are correct
before paying them, Medicare relies too
much on after-the-fact audits, and as a result,
wastes money, according to a recent Government Accountability Office (GAO) report.
While a limited number of so-called prepayment edits saved Medicare $1.76 billion in
2010, the Centers for Medicare and Medicaid
Services (CMS) could save more if the agency
employed this approach more widely.
In its investigation, GAO illustrated this
point using analysis of certain Medicare
coverage policies that govern in what cases
or how frequently a test or procedure can be
reimbursed. GAO identified $114.7 million
in payments made in 2010 that appeared to
be inconsistent with national and local policies and which could have been prevented
through automated prepayment edits.
Even when Medicare does use prepayment edits to screen bills from hospitals
and other providers, Medicare’s system
often fails, the report found. For example,
GAO found that Medicare paid $8.6 million for claims that exceeded limits on
the quantity of certain services that can
be provided to a beneficiary by the same
provider on a single date of service. In the
GAO investigation, although CMS had ostensibly implemented prepayment edits to
8/5/2011 5:19:18 PM
limit service quantities, a weakness in the
agency’s systems allowed providers to bypass the quantity limits.
The report noted that CMS most recently reported an improper payment rate
of 8.6%—or nearly $30 billion—for 2011.
More information is available from
www.gao.gov.
Warnings of EHR Incentive
Abuses as Adoption Rises
A
ccording to a new report from the
Medicare watchdog agency, the Office
of the Inspector General (OIG), the Centers
for Medicare and Medicaid Services (CMS)
faces some serious holes in its system meant
to reward physicians and hospitals that
adopt electronic health records (EHRs).
As physicians and labs have rushed to
adapt to burgeoning networks of EHRs,
CMS often does not go far enough to make
sure that it only offers incentives to organizations that truly have the required technology, OIG found. CMS expects to give
close to $7 billion in incentive payments
between 2011 and 2016.
OIG emphasized that because professionals and hospitals self-report data to
demonstrate that they meet EHR incentive
program requirements, CMS needs to verify that this data will help ensure the integrity of Medicare EHR incentive payments.
OIG is recommending that CMS in at least
some cases ask for proof from physicians
and hospitals that their EHR systems measure up before paying, as well as issue better
guidance to organizations on how to demonstrate compliance.
CMS reviewed OIG’s report before publication, and disagreed with the first recommendation for stepped-up prepayment
review. CMS believes requiring more documentation from providers up front could
prove burdensome for physician offices
and hospitals and delay payments. The full
report is available online, http://oig.hhs.gov.
Physician Adoption of EHRs
Continues Rapid Growth
I
n related news, a December 2012 report
from the National Center for Health Statistics (NCHS) found that 72% of officebased physicians used some kind of EHR
system in 2012, a 26% increase over 2011.
However, fewer physicians report using
EHRs that meet certain minimal requirements suggested by the government, such
as the ability to view lab results electronically. In 2012, 40% of physician offices had
such systems, up from 34% in 2011.
The NCHS report also found that EHR
adoption varied by state. In 2012, the percentage of physicians using any EHR system ranged from 54% in New Jersey to
89% in Massachusetts, and the percentage
having a system that met the criteria for a
basic system had an even wider range: from
22% in the District of Columbia to 71% in
Wisconsin. Notably, 66% of all office-based
physicians surveyed reported that they
planned to apply, or already had applied,
for the EHR incentive program.
The NCHS report is available through
the Centers for Disease Control and Prevention website, www.cdc.gov/nchs.
profiles
industry
D
ioGenix has entered a sponsored research agreement with Fast Forward, a
subsidiary of the National Multiple Sclerosis Society, to develop a novel blood test for
multiple sclerosis (MS). DioGenix’s current MS diagnostic, MSPrecise, uses nextgeneration sequencing technology to detect
changes to the adaptive immune system.
It accomplishes this by measuring mutations found in rearranged immunoglobulin genes in B cells isolated from cerebral
spinal fluid. Under the terms of the agreement, DioGenix will receive up to $500,000
of funding from Fast Forward to determine
if MSPrecise’s approach also works with
blood samples. If it does, it could give clinicians the ability to diagnose MS earlier
and to distinguish MS from other similar
immune-mediated neurological diseases.
Roche Breaks Ground on New
Customer Training Center
will allow Insight to continue developing
lung cancer companion diagnostics. The
first, a Phase II contract, will give Insight
$1.5 million to further validate its Insight
ALK Screen, a real-time qPCR-based test
designed to identify the approximately
5–10% of lung cancer patients with oncogenic anaplastic lymphoma kinase (ALK)
mutations and fusions. Screening for
these mutations is essential for determin-
Quanterix Licenses Immunoassay
Technology to bioMérieux
Q
uanterix and bioMérieux have signed
a strategic agreement granting bioMérieux worldwide exclusive rights to
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CardioDx Participates in Study of
Heart Disease Diagnostics
Considered by many to be the best
at delivering hands-on, lab-focused
information, Clinical Laboratory News
is a must-read for everyone in the lab.
oche has broken ground on a new
Learning and Development Center at
its North American headquarters in Indianapolis. The center will host the training of
more than 1,500 customers each year, and
is the first element of a $300 million site
transformation intended to support the
company’s growing diagnostics and diabetes care businesses.
C
ardioDx has joined the Prospective
Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE), the first
large randomized trial to compare the effectiveness of anatomical versus functional
noninvasive diagnostic tests for assessment
of patients with suspected coronary artery
disease (CAD). As a secondary goal, the trial
will also evaluate the ability of CardioDx’s
blood-based gene expression test, Corus
CAD, to predict major clinical cardiovascular events. “The findings of PROMISE also
will help us determine the potential for developing a new test specifically focused on
prognosis for CAD patients, which could
involve the use of next generation technologies to identify expression of genes predictive of future events,” said David Levison,
CardioDx president and CEO. Researchers
expect 10,000 patients to enroll in the study,
which is sponsored by Duke University in
collaboration with the National Heart Lung
and Blood Institute.
NCI Funds Insight Genetics’
Development of Lung Cancer
Co-Diagnostics
T
he National Cancer Institute granted
Insight Genetics two Small Business
Innovation Research (SBIR) contracts that
Quanterix’s Simoa platform. Simoa is an
immunoassay technology with multiplex
capability that measures single molecules
and is highly sensitive for proteins that
traditional analog-based methods cannot detect. Using this platform, bioMérieux plans to develop a menu of tests focused on infectious diseases. Quanterix
also hopes that this alliance will give the
company the “flexibility to leverage Simoa
technology and apply it in other commercial opportunities of interest, whether
that be in biomedical research, bioterrorism, blood banking, or point-of-care diagnostics,” said Paul Chapman, Quanterix
president and CEO.
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DioGenix and Fast Forward Partner
to Develop Multiple Sclerosis Dx
ing when to prescribe ALK inhibitors. The
second SBIR grant, a Phase I Fast Track
contract of $200,000, will fund creation of
a panel test for detecting RET and ROS1
fusions along with DEPDC1 expression in
non-small cell lung cancer (NSCLC). With
this funding, Insight Genetics hopes to create a high-throughput diagnostic panel that
could identify these biomarkers, which account for up to 9% of NSCLC cases.
To receive your free* subscription to Clinical Laboratory News,
go to www.aacc.org and click on Publications, Clinical Laboratory News.
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Clinical Laboratory News January 2013 17
profiles
mance in detecting current or recently circulating virus strains. CDC also cautioned
that respiratory specimens should be collected when influenza virus is at its peak,
with 24–72 hours of symptom onset.
diagnostic
Rapid Flu Tests Have Variable
Detection at Lower Virus
Concentrations
A
n evaluation of 11 commercially available rapid influenza diagnostic tests
(RIDT) by the U.S. Centers for Disease
Control and Prevention (CDC) found that
while most tests detected viral antigens in
high-concentration samples, detection varied by test and viral subtype at lower concentrations (Morb Mortal Wkly Rep 2012
Nov 2;61:873–76). The results suggest that
clinicians and laboratorians should use
RIDTs cautiously for diagnostic treatment
and infection control decisions in clinical
settings.
CDC conducted the study because there
had not been a recent comprehensive analytical evaluation of RIDTs using a standard
method and involving all 11 U.S. Food and
Drug Administration-cleared RIDTs. In
partnership with CDC, researchers at the
K-ASSAY ®
Medical College of Wisconsin prepared
swab samples or mock nasal wash specimens from several dilutions of 16 stock
influenza A and seven influenza B viruses
provided by CDC. The stock viruses were
all representative of those circulating in the
U.S. since 2006. The researchers measured
concentrations of the viruses’ nucleoproteins (NP) using isotope dilution tandem
mass spectrometry, and the egg infectious
dose per milliliter values were at least as
high as those reported in human clinical
specimens.
The investigators performed three separate tests for each virus/RIDT combination,
with positivity defined as two positive results out of the three. Although all RIDTs
detected virus at the highest virus concentrations, some did not detect at subsequent
dilutions. Since part of this variation could
be due to the use of different antibodies in
the various tests, CDC recommended that
users periodically evaluate RIDT perfor-
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18 Clinical Laboratory News January 2013
2011.09 CLN Lipoprotein.indd 1
L
ower baseline high-density lipoprotein cholesterol (HDL-C) level is a
significant independent predictor of the
development and progression of diabetic
nephropathy, but not retinopathy, in type 2
diabetics (Diabetes Care 2012;35:2201–6).
The results suggest that measuring HDL-C
may be useful in tailoring screening and
therapeutic strategies.
The ADVANCE study involved 11,140
patients with type 2 diabetes who were at
least 55 years old at the time of enrollment
and had at least one other cardiovascular disease risk factor. Baseline lipid levels,
HbA1c, and creatinine levels were determined, and creatinine and HDL-C levels
were repeated at 24 and 48 months. Urine
samples also were collected at baseline,
24, and 48 months for calculation of the
albumin-to-creatinine ratio (ACR).
Participants’ mean baseline HDL-C
level was 1.3 mmol/L. Nearly one-third developed new or worsening microvascular
disease during follow-up, with 28% experiencing a renal event and 6% a retinal event.
Compared with subjects in the highest
third of HDL-C values, those in the lowest
third had a 17% adjusted increased risk of
microvascular event. Patients in the lowest
third of HDL-C levels also were more likely
to maintain or progress to a worse category
of urinary ACR over time, compared with
those in the middle or upper thirds of
HDL-C levels. In contrast, the researchers
observed no association between baseline
HDL-C levels and development of retinopathy or any specific type of retinal event.
The findings suggest that there are differences between the pathophysiologies
of the two types of microvascular disease.
The authors called for further research to
explore possible benefits of HDL-C-raising
therapies in patients with type 2 diabetes.
Fructosamine, Glycated Albumin,
and 1,5-AG all Independent
Predictors of Diabetes Risk
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ructosamine, glycated albumin, and
1,5-anhydroglucitol (1,5-AG) are
strongly associated with subsequent development of diabetes, independent of baseline HbA1c and fasting glucose (Diabetes
Care 2012;35:2265–70). The findings suggest that elevations in these analytes may be
useful indicators of future diabetes risk.
The researchers investigated this association because fructosamine, glycated albumin, and 1,5-AG all have been of recent
interest in assessing glycemic control in patients for whom use of HbA1c is problematic, including those with anemia, hemolysis,
or renal disease. However, little investigation has taken place in terms of their levels
in nondiabetic populations or association
with future development of diabetes.
The study, a subset of the long-standing
Artherosclerosis Risk in Communities
8/5/2011 5:15:25 PM
study, involved 1,200 participants without
an initial diagnosis of diabetes who were
followed for a median of 3.3 years. During
the study period, there were 119 new cases
of diabetes. When compared with the lowest quartile, the highest quartile of baseline
fructosamine and glycated albumin levels
were significantly associated with diabetes
risk, with hazard ratios of 3.99 and 5.22, respectively. These associations remained significant after adjustment for fasting glucose
and HbA1c concentrations.
Higher baseline quartiles of 1,5-AG
were inversely associated with incident diabetes, and remained so after adjustment for
diabetes risk factors and fasting glucose and
HbA1c levels.
The authors called for additional studies to evaluate more extensively the associations between all three markers and longterm complications of diabetes, as well as
their potential clinical utility for monitoring glycemic control.
Meta-analysis Supports
Age-independent Definition
and Staging of CKD
A
meta-analysis of 46 different cohorts
involving more than 2 million participants found that both estimated glomerular filtration rate (eGFR) and high albuminuria were independently associated
with mortality and end stage renal disease
(ESRD) regardless of age across a wide
range of populations (JAMA 2012;308:
doi:10.1001/jama.2012.16817). The findings suggest that although clinicians might
consider some variation in managing
chronic kidney disease (CKD) based on
age, cost, and benefits, with respect to risk
of mortality and ESRD, a common definition and CKD staging based on eGFR and
albuminuria regardless of age would be
more appropriate.
The authors conducted this analysis because there has been interest in using eGFR
and albuminuria to define and stage CKD.
However, controversy exists about whether
age modifies their independent and combined associations with clinical risk
The investigators found that risk of
mortality and ESRD were higher at lower
eGFR and higher albuminuria at every age
category. Relative mortality risk for reduced
eGFR decreased with increasing age. In the
case of higher albuminuria, the reduction
in relative risk with increasing age was less
evident. In patients with CKD, the adjusted relative hazards of mortality did not
decrease with age, and in all cohorts, the
relative risk of ESRD associated with lower
eGFR or higher albuminuria were comparable across age categories.
The findings indicate that kidney measures used for defining and staging CKD
are strong predictors of clinical risk across
the full range of ages, including patients
older than age 75.
2013 AACC Annual Meeting
July 28–August 1
Houston, Texas
news
f ro m t h e
fda
CDRH Releases Proposed Guidance
Development for FY 2013
Nanosphere Screen for CYP2C19
Mutations Receives FDA Nod
DA’s Center for Devices and Radiological Health (CDRH) has released its list
of priorities for developing guidance documents for 2013. These priorities include
medical device guidance documents that
the agency fully intends to publish within
a year (the A-list), and guidance documents FDA will publish within the year
as resources permit (the B-list). Guidance
documents prioritized to the A-list include:
In Vitro Companion Diagnostic Devices;
Mobile Medical Applications; The 510(k)
Program: Evaluating Substantial Equivalence in Premarket Notifications; and De
Novo Classification Process (Evaluation of
Automatic Class III Designation). Among
the B-list items, CDRH included Direct to
Consumer Genetic Testing: IVDs. Neither
the A nor B list mention the long-awaited
guidance document for lab-developed tests
(LDTs). In July 2010, FDA announced it
planned to require all LDTs to undergo regulatory review. The complete lists are available online, www.fda.gov/MedicalDevices/
DeviceRegulationandGuidance/Overview/
MDUFAIII/ucm321367.htm.
DA has cleared Nanosphere’s CYP2C19
Nucleic Acid Test on the Verigene System.
The test identifies variants in the gene for the
cytochrome P450 2C19 (CYP2C19) enzyme
that metabolizes approximately 15% of all
prescribed drugs. Two variants in the CYP2C19 gene, *2 and *3, lead to reduced drug
metabolism, while the *17 variant causes
increased drug metabolism. Using wholeblood samples, the Verigene CYP2C19 Test
detects the presence of these mutations in
less than 2.5 hours, providing clinicians with
essential guidance for treating patients with
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Clinical Laboratory News January 2013 19
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