ADA ENDORSES HBA1C

FOR DIABETES DIAGNOSIS

In its newly released set of recom-
mendations, Standards of Medical
Care in Diabetes2010, the Ameri-
can Diabetes Association (ADA)
now officially recommends HbA1c
testing for the diagnosis and moni-
toring of diabetes. This annually
released document recommends
new standards for the treatment of
diabetes based on the latest scien-
tific evidence.
The report proposes a diagno-
sis of diabetes for HbA1c levels
6.5%, when testing is performed
by a laboratory method certified
by the National Glycohemoglo-
bin Standardization Program
and standardized to the Diabetes
Control and Complications Trial
assay. Other criteria for diagnosis
include a fasting plasma glucose
level of 126 mg/dL, a 2-hour
plasma glucose level 200 mg/dL
during an oral glucose tolerance
test, and a random plasma glucose
level of 200 mg/dL in patients
with symptoms of hyperglycemia
or a hyperglycemic crisis. The new
standards also advise monitoring
individuals with pre-diabetes on a
yearly basis to prevent progression
to full-blown diabetes.
The ADA changed the name of a
previous section of the report from
Diagnosis of pre-diabetes to
Categories of increased risk for di-
abetes, with the recommendation
that HbA1c levels of 5.7%6.4% be
considered a sign for increased risk
for future diabetes. In addition, the
report suggests that HbA1c testing
be performed at least twice per
year in patients meeting treatment
goals and quarterly for those who
either have not meet their glycemic
control goals or have recently
changed therapy.
A full copy of the ADAs recom-
mendations for this year are avail-
able at http://care.diabetesjournals.
org/content/33/Supplement_1.
Clinical
Laboratory
News
N E WS B R I E F
THE AUTHORITATIVE
SOURCE FOR THE
CLINICAL LABORATORIAN
FEBRUARY 2010
VOLUME 36, NUMBER 2
www. a a c c . o r g
An Optimistic Outlook for
the Diagnostic Market
What Will it Take to Succeed
in a New Business Environment?
BY BILL MALONE
I
n vitro diagnostics (IVD) manufacturers have good reason
to feel like they are between a rock and a hard place. With the
Great Recession affecting every aspect of the U.S. economy
and the tortuous path towards healthcare reform spreading
uncertainty, IVD manufacturers have had to rethink their
strategies as the second decade of the 21st century gets underway.
But despite the murky beginnings of an economic recovery and
the specter of an unwelcome mix of higher taxes on the industry
and lower reimbursement for lab tests coming from Congress, the
IVD market continues to grow. In a recent survey of medical device
and IVD companies from Emergo Group, a consulting firm, 71%
of executives said they expect overall sales to increase in 2010, and
70% said they felt very positive or somewhat positive about the
overall business environment.
With their fingers crossed that the early signs of economic re-
covery will continue, IVD manufacturers are preparing for steady,
albeit slower growth while working harder than ever to hold onto decent prices for their products, according to
industry observers. All too often for manufacturers, declining prices due to reimbursement hassles and compe-
tition mean that growth in testing eventually stops translating into growth in revenue. For this and other rea-
sons, IVD companies are betting on strong returns from molecular diagnostics and advanced lab automation
components to be profitable in a competitive and evolving business landscape.
Emerging Biomarkers
for Acute Kidney Injury
Is There a Winner in the Offing?
BY GENNA ROLLINS
A
cute kidney injury (AKI) is a complex, increasingly common syndrome, the diagnostics and treat-
ments for which have remained essentially unchanged for decades, to the great frustration of
clinicians and researchers. However, thanks to concerted efforts by key professional organizations,
governmental agencies, and numerous research teams, considerable progress has been made since
2004. Now, many experts predict that the field is poised for transformation over the next decade.
Novel urine and serum biomarkers will be central to this revolution in care.
The field of acute kidney injury rests upon development of new
biomarkers, explained Mark Okusa, MD, FASN, John C. Buchanan
distinguished professor of medicine and chief of nephrology at the
University of Virginia School of Medicine in Charlottesville. Were
trying to find what cardiologists found with troponin I for acute coro-
nary syndrome. Our goal is to find a kidney troponin I. Okusa also is
chair of the AKI advisory group for the American Society of Nephrol-
ogy (ASN).
Changing Definitions, Terms
Although definitions and even the nomenclature for AKI have
changed over the years, the condition generally is recognized as the
See IVD Market, continued on page 3
See Acute Kidney Injury, continued on page 6
IN THIS ISSUE
Lab 2010
8
Preeclampsia Diagnosis
& Management
11
Expert Access:
Infectious Diseases
12
Regulatory Proles

13
Industry Proles

14
Diagnostic Proles

15
News from the FDA
N O N P R O F I T O R G .
U . S . P O S T A G E
P A I D
G R E E N F I E L D , O H
P e r m i t N o . 4 3 6
C l i n i c a l L a b o r a t o r y N e w s
T h e A m e r i c a n A s s o c i a t i o n
f o r C l i n i c a l C h e m i s t r y , I n c .
1 8 5 0 K S t r e e t , N W , S u i t e 6 2 5
W a s h i n g t o n , D C 2 0 0 0 6
SNAPSHOT
Estimated Number of Newly Diagnosed
Cases of Diabetes
Source: 20042006 National Health Interview
Survey estimates projected to year 2007.
Number of Cases
(in thousands)
2039
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Were better together.
Copyright 2009 Beckman Coulter, Inc. Beckman Coulter and the stylized logo are registered trademarks of Beckman Coulter, Inc.
Olympus is a registered trademark of Olympus Corporation.
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Che mi s t r y Di s e a s e Ma na ge me nt I nf o r ma t i o n Sy s t e ms L a b Aut o ma t i o n F l o w Cy t o me t r y Pr i ma r y Ca r e
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depend on us to help you achieve faster, more reliable results in every testing discipline. Now we are even better
together with you our laboratory partners.
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CLINICAL LABORATORY NEWS FEBRUARY 2010
3
For 2009, we estimated a growth rate
for the worldwide IVD market of approxi-
mately 5.3 percent, and for 2010, were
projecting 6.1 percent growth, said Gerard
Conti, vice president at the healthcare mar-
ket research firm Enterprise Analysis Cor-
poration (EAC). It makes sense that 2010
will be better for manufacturers because we
see hospital budgets starting to thaw out,
the credit crunch has eased up, and many
hospitals put off big purchases that they
cant put off any longer.
Ready to Spend Again?
A huge drop in available credit for hospitals
and other organizations, along with lower
patient demand and increasing numbers
of patients unable to pay for care, made the
last 2 years some of the most difficult for
IVD manufacturers. In 2009, it was very
difficult to win market sharecustomers
tended to be fairly cautious, often defer-
ring purchase decisions, and the capital
expenditure environment was very lim-
ited, explained Alan Harris, vice president
for global marketing, chemistry systems,
at Beckman Coulter. Sectors like automa-
tion, where there is strong demand, stalled
in that people didnt have large capital
budgets to deploy. However, labs can only
forestall purchases of needed equipment
or upgrades to a certain point. One year
you can do without it, two becomes a
strain, and three becomes a stretch, Harris
quipped. Eventually, labs that have deferred
capital expenditures will have to buy; oth-
erwise they could end up spending more
on service than it would cost to replace an
instrument.
Even with recovery from the recession
looking tenuous at best, there are signs that
hospitals and other customers are begin-
ning to have more funds to make the big
purchases IVD manufacturers depend
on, according to Rich Ramko, a medtech
partner with Ernst & Youngs global life
sciences division. Lately weve seen more
confidence from hospitals when it comes
to issues like bad debt and capital expendi-
tures, he said.
Even better, recent declines in the qual-
ity of the hospital payer mix seems to have
finally flattened out, Ramko said, an im-
portant indicator of if and how much hos-
pitals can expect to get paid. Commercial
insurance usually pays the best, followed by
Medicare and Medicaid. The most worri-
some elementpatients who pay out of
pocketcan only be counted on about
20% of the time. Weve seen that percent-
age of Medicaid and uninsured go up over
the last year or so, and lately thats abated,
said Ramko. But that payer mix will dete-
riorate again if unemployment goes up or
stays where it is for a long time. People can
only put off healthcare for so long, and af-
ter they wait, their ability to pay is even less
than it was to begin withtheir COBRA
has run out, the medical situation is worse,
and then uncompensated care at hospitals
will rise.
Unemployment isnt the only linger-
ing concern thats part of what Harris de-
scribed as macroeconomic overhang.
Outside the U.S., emerging markets may
still suffer from devalued currencies that
makes buying U.S. products more ex-
pensive, he explained. Facing a signifi-
cant economic downturn, every central
bank began to dump liquidity, whether it
was money supply, lower interest rates, or
however they could better offset the global
economic downturn. With central banks
pushing out this much cash, some curren-
cies became greatly devalued and emerging
marketsincluding Korea, South Africa,
Turkey, and othersgot hit hard.
In other cases, the reverse was true when
the dollar was comparatively low, bringing
revenue for U.S.-based companies down
with it. While the actual quantity of prod-
ucts and services U.S. manufacturers deliv-
ered may have not changed dramatically,
or may have even gone up, the amount
of revenue that the global manufacturers
received for that may have fluctuated sig-
nificantly in certain countries because of
changes in currency exchange rates, said
Harris.
Fighting the Price Plunge
No matter how innovative their technology
or how in sync their instruments are with
the needs of laboratories, IVD manufac-
turers inevitably have to ask themselves the
question: how do I hold onto a fair price?
The recurring theme we hear is, how do
you keep pricing from devolving, said
Mark Hughes, also a vice president and
senior consultant at EAC. Manufacturers
want to know how to charge a decent price
and get reimbursement for their novel test
that represents its true value so it doesnt
become a five dollar test.
Hughes and his colleagues find that
more and more, companies are looking for
solid evidence of the value of their tests by
performing health economic studies. More
companies are now performing studies to
try and prove that what they are bringing
to market truly has value and that the test is
displacing certain care protocols, said Su-
san Farber, vice president of operations at
EAC. We are seeing more price pressure in
diagnostics, so theyre trying to show that
as part of the whole value stream, their test
should be valued a little more highly than
other products may have been in the past.
To get better reimbursement, manu-
facturers will have to demonstrate that
a new test is truly an improvement over
whats on the market already, emphasized
Ernst & Youngs Ramko. If the demand is
there, then the reimbursement will work
itself out, he said. Those that show they
can reduce the cost of care and are better
than whats currently available will get re-
imbursement and will be successful in the
market. But if its a me too productyou
wont see those products coming through
to commercialization.
Molecular Diagnostics Lead the Way
While 4 to 5 years ago testing in the diabe-
tes area helped to propel pre-recession an-
nual market growth in the 8% range, now
the diabetes share of the market has flat-
tened out and left molecular testing as the
leader in rapid growth. Part of this change
has to do with the especially intense pric-
ing pressure on diabetes testing, creating a
counter-intuitive scenario with an explod-
ing disease population but frozen revenues
for testing.
We see the incidence and prevalence
of diabetes going through the roof, and its
only going to get larger. Payers have done
their best to mitigate the cost, and for a
time, those techniques have been very ef-
fective, said Harris. But eventually quan-
tity will trump price and the market will
grow again. In this market you have to dis-
tinguish growth in testing versus revenue
generated by it.
Molecular testing is also surpassing oth-
er areas of the IVD market by encroaching
on territory that traditionally belonged to
the microbiology lab, offering speed and
turnaround times that traditional culture
methods cant match. Rapid molecular
tests to detect respiratory pathogens in
hospitalized patients are new weapons to
help control outbreaks of serious bacterial
and viral infections, such as methicillin-
resistant Staphylococcus aureus (MRSA),
said Keith Chaitoff, divisional vice presi-
dent, U.S. marketing of Abbott Diagnos-
tics. Healthcare-acquired infections are a
major source of patient complications that
increase lengths of stay and prolong re-
covery time. Under pressure from payers,
patients, and even Congress, hospitals need
better solutions for managing healthcare-
acquired infections, with more and more
facilities testing patients for bacterial and
viral infections before admission.
With fast and sensitive molecular tests,
physicians get answers back in hours or a
day, not in the week to 10 days it can take
for traditional microbe identification. This
change in patient care will continue to
drive the adoption of molecular methods,
emphasized Jack Zakowski, director of sci-
entific affairs and professional relations for
Beckman Coulter. He offered the example
of a respiratory panel. The physician would
like to know whether an infection is viral or
bacterial, and whether they can rule out the
most serious illnesses. With traditional mi-
crobiology, the physician sends the sample
to the microbiology labeither hospital
or reference lab-basedand waits for 13
days for bacterial identification or 510
days for myobacterial identification.
The clinical condition of the patient
tends to answer the question much soon-
er than the laboratory in this situation,
Zakowski said. Were dealing with meth-
odologies that are more than 100 years
oldagar plates and Petri dishesand the
new molecular-based methods that are ei-
ther in use today or that will be available in
the next few years are going to transform
that. Zakowski thinks the biggest hurdle at
this point may be the human onegetting
people adapted to and comfortable with
using the new technologies. Still, it will be
challenges like MRSA that will create more
demand. This is all going to be driven
by both an economic and clinical need,
See IVD Market, page 4
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IVD Market, from page 1
4
CLINICAL LABORATORY NEWS FEBRUARY 2010
Clinical
Laboratory
News
EDITORIAL STAFF
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McMaster University Medical Center
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Siemens Healthcare Diagnostics, Newark, Del.
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CDC, Atlanta, Ga.
Amy Saenger, PhD
Mayo Clinic, Rochester, Minn.
AACC OFFICERS
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he said. These tests can make a huge dif-
ference in patient care and that will drive
adoption of the technology.
The molecular diagnostic sector also
tends to be more profitable than tradi-
tional microbiology, which is more of a
commodity business and has lower mar-
gins, explained EACs Hughes. Molecular
tests also command a much higher price
per test, though in some instances the
manufacturer has to pay patent royalties
that eat into profits. There has just been
a continuing trend toward molecular test-
ing, and some of that is taking away from
traditional microbiology. Having said that,
I dont see traditional microbiology going
away any time soonwere still going to be
doing traditional culture plates for many
years to come. But there are specific tests
and areas where molecular is encroaching
on traditional culture methods because of
the speed and turnaround time advantages
that it offers. So I think well continue to
see that eating away at some of the tradi-
tional microbiology. EAC is projecting the
microbiology market to grow at a steady
5% per year, while the molecular segment
will see double-digit growth, between 12%
and 14% per year. Hughes also predicted
that manufacturers will continue to push
for more simple instrumentation for their
molecular tests, the sample-in, answer-out
model.
Labs Still Hungry for Automation
IVD manufacturers will also continue to
push hard to get laboratorians the automa-
tion solutions they need to cope with more
complex, consolidated operations as well
as lingering staffing shortages. Just taking
a look at exhibit halls and conference pro-
grams demonstrates both the enthusiasm
and challenges laboratorians have with
automation. In coping with cost pressures
and personnel shortages, laboratories in-
creasingly are being forced to do more with
less, said Abbotts Chaitoff. This is fueling
development and market share growth of
highly automated analyzers with automat-
ed sampling handling features and sophis-
ticated informatics to improve throughput,
results reporting, and coordination with
the LIS.
Beckman Coulters Zakowski echoed
this assessment. The technology is advanc-
ing rapidly, and I think youll see automa-
tion become better, cheaper, and faster
and thats true whether were talking about
the analyzers themselves, the kinds of assays
they can perform, the kind of track lines
theyre connected to, or the information
technology, he said. Were doing things
now we didnt dream of 10 years ago, and
I think that will be the case 10 years from
now.
Prices are already coming down, with a
handful of companies that are very com-
petitive and willing to cut an amazing deal
to place an automation solution, noted
EACs Farber. Manufacturers know that if
they can get their automation solution in,
they tend to have a hold on that labs busi-
ness. Ive heard of some ridiculously low-
priced deals where pieces of automation
were practically given away, said Farber. As
a result, she thinks its possible that, in terms
of dollar investment, the market for auto-
mation could start to flatten out eventually;
however, with regard to the number of labs
that are looking to move toward automa-
tion, thats still a very strong number, she
indicated. From what Ive seen in the last
few months, laboratorians are quite serious
about automation and about standardiza-
tion on automation, so I think there is still a
very good outlook for this market.
Advanced analyzers, more molecular
testing, and more automation will all lead
to dramatic changes in what the clinical lab
looks like, emphasized Beckman Coulters
Harris. The chem-immuno line will be-
come the chem-immuno-coag-hematology
line over time, and likewise, those individ-
ual disciplines that have remained relatively
separate in specialty labs, like microbiology,
flow cytometry, and molecular tests, will all
benefit from more automation and more
specific and sensitive techniques, so I think
thats a good view of our future.
Point-of-Care Market Faces Hurdles
Another area of growth in the IVD market is
coming from point-of-care testing (POCT),
which EAC projects will grow in the range
of 7%8% per year for the next few years.
While the firms consultants noted a strong
desire on the part of providers to move test-
ing out to decentralized locations, POCT
still hasnt met the growth expectations that
investors and analysts initially expected.
Lab Automation Now More Affordable
IVD Market, from page 3
AdvaMed Launches AdvaMed Dx
for Diagnostics Companies
After years of debate among in vitro diagnostic (IVD) companies about
how best to work together to advocate for the industry, a new associa-
tion under the auspices of the Advanced Medical Technology Associa-
tion (AdvaMed) is creating enthusiasm among IVD companies as they
look toward coping with changes in healthcare reform in the years
ahead.
This is a particularly sensitive period, where weve had healthcare
reform running the profile of many aspects of our industry from a gov-
ernment affairs standpoint, said Scott Garrett, Beckman Coulters chair-
man, president, and CEO, who will serve as chair of the AdvaMed Dx
board of directors. We also have new regulatory issues coming out of
China, and a continual emphasis on Japan and Europe. Its an important
time where it will be very helpful to get senior executives throughout
diagnostics very involved in the association.
AdvaMed Dx will work as an association-within-an-association,
where the new organization can take advantage of the staff and capa-
bilities of AdvaMed while still focusing exclusively on issues that matter
to the IVD industry. With AdvaMed covering such a large spectrum of
companiesmanufacturers of everything from stents to orthopedics
and wound care productsGarrett sees AdvaMed Dx as a way for IVD
companies to have a strong voice on issues and perspectives that are
unique to their industry. Its our expectation that the positions and is-
sues of AdvaMed Dx will rarely be in conflict with the rest of AdvaMed,
but they might often be different than the priorities or agenda of Ad-
vaMed, said Garrett. Though it would be great to have an independent
global diagnostics organization, our industry is relatively small, and the
level of infrastructure and staff that we could afford as a completely
separate organization is probably not significant enough for us to have
a strong voice. So I think this approach is the best of both worlds.
Issues of particular importance to the new association will include
following FDA regulation of diagnostic tests and working to curb any
further cuts to the lab fee schedule. With a lot of new people in the FDA
office, Garrett expects AdvaMed Dx to help companies establish a closer
relationship with the agency. FDA is under pressure to be tougher
pressure from the public and from Congress, he said. So we have an
opportunity to improve their understanding of all that goes on in the
industry in a way that is more balanced than what they might have
picked up so far. But I have a lot of confidence that the new FDA leader-
ship is quite capable and has the right objectives in mind.
In working with the Center for Medicare and Medicaid Services
(CMS), AdvaMed Dx will have a chance to do a lot better for the IVD
industry than what has been done before, Garrett said. We want to
make sure that our customers, the labs and the hospitals in the U.S.,
are reimbursed fairly for the services they provide in the lab, he said. I
think there will probably be an opportunity over the coming years to
take a good hard look at the lab fee schedule and try and get it in line
with reality.
Garrett expects the new organization to get off to a fast start this
year, and said hes been encouraged by the level of enthusiasm from the
major diagnostics companies. We expect AdvaMed Dx to be an impor-
tant part of our industry in the future, he said.
CLINICAL LABORATORY NEWS FEBRUARY 2010
5
While certain segments of the POCT
market have expanded rapidly, such as
rapid testing for the 2009 H1N1 virus,
POCT certainly cannot substitute for all
core lab tests. Point-of-care has to balance
a lot of things: turnaround, precision and
accuracy, and cost-per-test, and I dont see
the technology there yet for point of care to
take over as much as people are predicting,
said Beckman Coulters Zakowski. The in-
creased cost of POCT has to be trumped by
some workflow advantage within the site
of care, or it cant be successful. Essentially,
the test must help the hospital move the pa-
tient forward in a meaningful way, such as
blood gas in intensive care units or coagu-
lation tests in emergency departments and
operating rooms. These kinds of tests allow
clinicians to test and treat more efficiently,
and have moved forward at an ambitious
rate, Zakowski said.
However, a manufacturer must study
the cycle of care attentively if it wants to
make the extra dollar or so for a POC test
to be worth it. For instance, with blood
gas testing, clinicians might actually need
blood gas, basic metabolic panel and lactate
results before theyre comfortable moving
the patient forward, explained Zakowski.
So just offering the quick blood gas will,
in some situations, do nothing for clini-
cians because they still have to wait for the
other tests from the main lab. It can actu-
ally make the workflow more complicated
because clinicians have to look for answers
from two separate places. I think POCT
is a promising piece of the market, but it
has some very particular demands, he
said. And its not really taking from main
lab volumes, but mostly complementary,
in fact. So its an opportunity more than a
threat for the main lab.
POCT is also a hot area for startup
companies with many of them develop-
ing POCT multiplexing platforms that use
disposable cartridgessome in hematol-
ogy, and even in the molecular area, noted
the consultants from EAC. Hughes and
Farber indicated that technology has by
no means peaked for POCT, considering
all the promising innovations at these new
companies.
According to Abbotts Chaitoff, the abil-
ity of manufacturers to pull out all the stops
in POCT technology is what will make the
difference in the marketplace of the future.
Whether we are talking about POCT, mo-
lecular, or traditional core lab diagnostics,
the key is that advanced technology
microfluidics, nanotechnology, advanced
chemistries, biologic breakthroughs, and
information sciencesall are going to have
to converge more and more to achieve goals
around productivity, outcomes, and physi-
cian and patient satisfaction, he said. And
yes, reduced overall healthcare costs.
Still Betting on Pharmacogenomics
Part of the surprisingly positive outlook
for the overall IVD market draws from the
consensus among laboratorians and IVD
companies that in the final analysis, diag-
nostics can improve both healthcare qual-
ity and cost-effectiveness. Of course, this is
in spite of the way payment policy handed
down from Congress and the Center for
Medicare and Medicaid Services (CMS)
rarely seems to recognize this fact. For
many, pharmacogenomics symbolizes the
way in which advances in diagnostics can
have a big impact on the future of medi-
cine. And manufacturers want to be sure
they get a piece of the action when the field
matures.
While the 20th Century witnessed
an unprecedented growth in the develop-
ment of medications and therapies, this
century will witness a similar explosion in
the development of diagnostic tests, said
Abbotts Chaitoff. Human blood is over-
flowing with molecules and proteins that
each have a story to tell. Until recently, we
had very limited knowledge of what these
molecules and proteins did. Advanced di-
agnostics will lead to a wider recognition of
the value of the lab and diagnostics to solve
many of our pressing healthcare needs
from optimizing patient care to reduce the
financial burden on the healthcare system.
Ironically, the federal governments
drive to eliminate waste and reduce the
amount of reimbursement will turn into
an advantage for pharmacogenomic tests
if manufacturers play their cards right, said
Ernst & Youngs Ramko. The challenge will
be to prove to payers that advanced tests
really do make a difference in care, reduce
costs, and therefore deserve reimburse-
ment themselves. With big pharma devel-
oping fewer small-molecule type drugs and
moving to more expensive biologics, there
will be an emphasis on making sure that a
treatment will really work, he said. Clear-
ly the push is going to be to reduce costs, to
not pay for things that are unnecessary. As
the move to reduce cost is more and more
acute, suppliers of treatments are going to
need pharmacogenomics to prove how a
therapy can work for certain targeted indi-
viduals instead of offering it to everybody
to see what works.
Pharmaceutical companies will be us-
ing pharmacogenomics in the research
and development phase of drugs and as
a tool to show the government and other
payers why they should get reimburse-
ment, Ramko emphasized. And just like
more mature sectors of the IVD market,
manufacturers will have to put a focused
effort into proving the value of a new test
for this purpose.
Although widespread use of pharma-
cogenomic tests has not yet arrived, manu-
facturers want to make sure that theyre not
left out when the time comes, said EACs
Farber. People are really starting to come
to grips with the reality of companion di-
agnostics, and were now getting very seri-
ous inquiries about where the market is go-
ing and how a company can position itself
to do something about it.
CLN
6
CLINICAL LABORATORY NEWS FEBRUARY 2010
abrupt loss of kidney function that leads to
fluid retention, accumulation of metabolic
waste products, and dysregulation of extra-
cellular volume and electrolytes. Common
causes of AKI range from decreased renal
perfusion and contrast-induced neph-
ropathy to sepsis and nephrotoxicity from
medications such as aminoglycoside anti-
biotics and non-steroidal anti-inflamma-
tory drugs. AKI now is the preferred term
over acute renal failure, to emphasize the
range of AKI disease from early injury to
progressive loss of function requiring renal
replacement therapy.
Two classification systems for the con-
dition proposed in recent years are gaining
acceptance. Both rely on changes in serum
creatinine levels and urine output. The
Acute Kidney Injury Network (AKIN) de-
fined AKI as an reduction in kidney func-
tion within 48 hours, involving an absolute
increase in serum creatinine of 0.3 mg/dL,
a percentage increase of 50% or 1.5 times
above baseline, or documented oliguria of
less than 0.5 ml/Kg per hour for more than 6
hours. Meanwhile, the Acute Dialysis Quality
Initiative issued the Risk, Injury, Failure, Loss
and End-stage (RIFLE) criteria, which use
graded increases in glomerular filtration rate
based on serum creatinine levels and weight-
dependent urine output parameters.
Nationally, AKI accounts for at least
3%4% of all hospitalizations and may be
a contributing factor in more than one-
third of all admissions, at a cost of about
$10 billion annually. At the same time,
the incidence of AKI in the community is
rising, with an estimated rate of 500 per
100,000 population in 2002, up from ap-
proximately 61 per 100,000 population in
1988. Adding to the magnitude of these
figures, 20%30% of critically ill patients
develop AKI, and depending on the patient
population, mortality following an episode
of AKI is estimated to be between 40% and
60%. Validation of both the AKIN and
RIFLE systems has underscored the impor-
tant effects of small declines in glomerular
filtration rate on the overall outcome of
critically ill patients, according to Okusa.
Even the least severe categories, R in
RIFLE or AKIN stage I, have been associ-
ated with a mortality rate of approximately
30 percent, he indicated.
In addition, recent research has changed
the thinking about the natural course of
AKI. Previously kidney function was gen-
erally thought to completely return to nor-
mal, but information now suggests that the
long-term course for a significant number
of patients with AKI is high-stage chronic
kidney disease, noted Paul Kimmel, MD,
senior advisor in the Division of Kidney,
Urologic and Hematologic Diseases at the
National Institute of Diabetes and Digestive
and Kidney Diseases (NIDDK). AKI seems
to go on to progressive injury, and the idea
now is that there is a spectrum of functional
kidney responses after AKI. Kimmel also is
project scientist for the NIDDK-funded As-
sessment, Serial Evaluation, and Subsequent
Sequelae in Acute Kidney Injury (ASSESS-
AKI) research initiative.
A Lackluster Gold Standard
Even as research is elucidating the pathol-
ogy of and outcomes associated with AKI,
treatment advances have been hampered
by lack of sensitive and specific biomarkers
for the condition. Although it is still con-
sidered the gold standard, serum creatinine
is far from an ideal parameter, according
to Norbert Lameire, MD, emeritus profes-
sor of medicine at the University of Gent,
Belgium, and co-chair of the Kidney Dis-
ease: Improving Global Outcomes clini-
cal practice guidelines on AKI. In AKI it
takes at least 24 hours, and in many cases,
48 hours, before you see a significant in-
crease in serum creatinine. So you lose this
crucial, lets say 36 hours, in which a lot of
injury has gone on before you see it in your
serum creatinine. As much as 50% of kid-
ney function can be lost by the time serum
creatinine levels reach abnormal levels.
Serum creatinine also is affected by non-
renal factors, such as protein intake, muscle
mass, age, and sex, and it is not sensitive to
kidney insults that do not affect filtration.
Until recently, these biological variances
were compounded by analytical challenges,
but over the past several years considerable
industry-wide effort has gone into stan-
dardization and commutability of serum
creatinine measurements.
All-in-all, these shortcomings have had
the compound effect of not only holding
back treatment advances but also delay-
ing anti-AKI drug development. A series
of summits in 2004, sponsored by the ASN
and with participation from NIDDK, FDA,
and other professional associations, high-
lighted that reliance on serum creatinine
was stifling therapeutic progress, accord-
ing to Chirag Parikh, MD, PhD, associate
professor of medicine at Yale University
School of Medicine. People realized wed
not made any progress in terms of patient
care and morbidity and mortality of AKI.
Serum creatinine was not only hindering
diagnosis and treatment, but it was weaken-
ing the drug development process. Earlier,
more sensitive biomarkers would enable
physicians to fine-tune the basics of AKI
treatmentblood pressure management
along with reperfusion and vasopression
therapyand enable them to start dialysis
earlier when needed. Above all, better bio-
markers ultimately would lead to develop-
ment of drugs that would halt quickly the
progression of AKI.
Unprecedented Enthusiasm
Since the 2004 summits, research has accel-
erated rapidly, to the point that some pro-
posed biomarkers are tantalizingly close
to being implemented in clinical practice.
Theres now unprecedented enthusiasm
in nephrology for early AKI biomarker de-
tection research, observed Parikh. There
is a pipeline of development full of numer-
ous possibilities and it is very likely a test
or tests will come from that pipeline that
are good enough to replace the current
paradigm of care. A review he conducted
in 2008 identified 21 serum and urine
biomarkers of AKI that had utility in the
differential diagnosis, early detection and/
or prognosis of the condition (Kidney Int
2008;73:100816). These markers also have
been associated with injury to specific seg-
ments of the kidney nephron, such as the
proximal and distal tubules, Loop of Henle,
and collecting ducts, placing them in the
realm of structural indicators of injury
in contrast to serum creatinines role as a
functional parameter.
Of the many potential markers, neutro-
phil gelatinase-associated lipocalin (NGAL)
is at the top of many researchers lists. Also
known as lipocalin-2 or siderocalin, NGAL
is a protein in neutrophils that rises within
24 hours after kidney injury. Arguably
the most studied emerging marker of AKI,
NGAL has been investigated across a broad
range of clinical settings, including post-car-
diac surgery, critical and emergency care, as
well as in adult and pediatric populations. A
recent meta-analysis of 19 studies involving
more than 2,500 patients found that the area
under the curve/receiver operating char-
acteristic of NGAL to predict AKI overall
was 0.815, 0.775 in cardiac surgery patients,
0.728 in critically ill patients, and 0.894 fol-
lowing contrast infusion, respectively (Am
J Kidney Dis 2009;54:101224). NGAL
showed better predictive ability in children
than adults, and it appeared to be useful in
predicting renal replacement therapy and,
to some extent, in-hospital mortality. Our
analysis found that NGAL appears to have
diagnostic value for early AKI and prognos-
tic value for renal replacement therapy and
mortality, both overall and across a range of
subgroups, said lead author Michael Haase,
MD, assistant professor of nephrology and
intensive care medicine at Charit-Universi-
ty Medicine Berlin in Germany.
The Need for More Data
As promising as this analysis appeared to be,
it highlighted the challenge facing imple-
mentation of all the AKI biomarkers under
Serum Creatinine Inadequate Measure
Acute Kidney Injury, from page 1
For Further Information
Acute Kidney Injury Network:
report of an initiative to improve
outcomes in acute kidney injury,
http://ccforum.com/content/11/2/
R31
Acute renal failuredefinition,
outcome measures, animal
models, fluid therapy and infor-
mation technology needs: the
Second International Consensus
Conference of the Acute Dialysis
Quality Initiative (ADQI) Group,
http://ccforum.com/content/8/4/
R204
Kidney Disease: Improving
Global Outcomes, www.kdigo.org
Tracking the Course
of Acute Kidney Injury
Landmark Study Will Evaluate New Markers
Although numerous potential biomarkers for acute kidney injury (AKI)
have been identified and investigatedmany with favorable perfor-
mance profilesthe candidate markers need further evaluation in
larger, more diverse populations for longer periods of time in order to
achieve breakthroughs in AKI care. A major National Institute of Diabe-
tes and Digestive and Kidney Diseases (NIDDK) initiative seeks to do just
that.
Assessment, Serial Evaluation, and Subsequent Sequelae in Acute
Kidney Injury (ASSESS-AKI) is a landmark study that will follow for a
mean of 3 years a diverse population of 1,200 patients in a range of
clinical settings at three participating centers. ASSESS-AKI has two
primary goals: determining whether hospitalized patients with an
episode of AKI are at greater risk of developing chronic kidney disease
than patients without AKI, after adjusting for pre-existing levels of
kidney function and potential confounders; and determining whether
these AKI patients are at higher risk for death, cardiovascular and other
adverse events after hospitalization than control subjects.
Our purpose is two-fold. One is to provide more information about
the natural history of AKI, particularly acute tubular necrosis in hospital-
ized patients, explained ASSESS-AKI project scientist Paul Kimmel, MD,
who also is senior advisor in the Division of Kidney, Urologic and Hema-
tologic Diseases at NIDDK. The other is to develop our understanding
of how biomarkers can help in predicting outcomes, specifically long-
term kidney response in patients who develop AKI.
ASSESS-AKI began enrolling patients in December 2009; outcomes
from the trial are expected by the end of 2013. Evaluating currently
used and novel biomarkers will be a key aspect of the study. At least five
unique blood and urine samples will be collected over the course of 3
years from 600 patients with AKI and 600 matched controls. A minimum
of 16 novel urine and 10 novel serum biomarkers will be measured, in
addition to standard tests such as urine and serum creatinine, blood
urea nitrogen, urine and blood albumin, calcium, and glucose, among
others. Its quite likely, because well have enough patients, statistical
power, and tests, that well be able to find any relationships between
new biochemical assays and long-term outcomes that may exist, said
Kimmel.
ASSESS-AKIs precise sample collection, handling and storage
protocols also are expected to advance the AKI evidence base, ac-
cording to Kimmel. One of the things were trying to do is to put our
measurements into a clinical context. So if we learn that urine has to be
handled in a certain way or we lose certain markers, but find that theres
a six hour delay until its processed in a standardized manner in all the
studys different clinical sites, that will be very important. The utility of
something that has to be collected under extremely specified condi-
tions will be less generalizable.
CLINICAL LABORATORY NEWS FEBRUARY 2010
7
investigation. Most importantly, there has
yet to be a prospective validation study in
a large number of patients with different
causes of AKI. The majority of studies have
been in small populations or single centers
examining AKI in one setting or clinical
circumstance, such as post-cardiac surgery
or in critically ill children. In addition, with
NGAL and various other proposed bio-
markers, a variety of test platforms have
been used with different protocols and ref-
erence ranges. For instance, the majority of
studies identified in Haases meta-analysis
used CLIA-waived ELISAs, with NGAL
reference ranges for the non-AKI control
populations varying from <10 ng/mL to
<550 ng/mL. ASSESS-AKI is expected to
fill crucial gaps in the AKI evidence base
(See Tracking the Course, p. 6).
Analytics will be a key in implement-
ing any AKI biomarkers, according to Won
Han, MD, assistant professor of nephrolo-
gy at Thomas Jefferson University in Phila-
delphia. If you look at the assays out there,
they all have different protocols, so its kind
of hard to compare them head-to-head, he
explained. We need to be thinking about
how to standardize the assays and what
substances can interfere with a given assay.
Another thing is the stability of the various
proteins. Without that youre not going to
have something thats accurate. Han was
lead author of a recent study that explored
the stability of NGAL and two other uri-
nary proteins in an investigation of AKI af-
ter cardiac surgery (Clin J Am Soc Nephrol
2009;4:873882). The researchers found
that the three biomarkers were stable un-
der a variety of storage times, tempera-
tures, and freeze and thaw cycles, except
that urinary NGAL degraded significantly
after prolonged storage at 20C.
Other biomarkers considered by some
researchers to be the most promising for
AKI diagnosis, treatment and/or progno-
sis include urine kidney injury molecule-
1(KIM-1), urine interleukin 18 (IL-18),
N-acetyl--D-glucosaminidase (NAG) and
urinary liver-type fatty acid binding pro-
tein (L-FABP) (See Table). KIM-1 is a renal
tubular protein that has been shown to dif-
ferentiate acute tubular necrosis from other
types of kidney injury. IL-18 is a pro-inflam-
matory cytokine indicative of renal tubular
inflammation that has been found in sig-
nificantly higher concentrations in patients
with acute tubular necrosis in comparison
to a variety of other conditions. NAG is a
high molecular-weight lysosomal enzyme
with considerable activity in renal proximal
tubular cells that has been shown to rise in
urine when there is proximal tubular cell
necrosis. L-FABP binds unsaturated fatty
acids and lipid peroxidation products dur-
ing tissue injury from hypoxia and has been
shown to be significantly higher in patients
with poor AKI outcomes. Pre-clinical stud-
ies also have shown renal papillary antigen
1 and 2 (RPA-1 and RPA-2) to be promis-
ing site-specific markers for drug-induced
nephrotoxicity (Toxicologic Pathology
2009;37:629643).
One Super-Marker or a Panel?
Several of these potential biomarkers, par-
ticularly NGAL, KIM-1 and NAG, have
been evaluated together and have shown
higher predictive value as a panel. As much
as nephrologists dream of a single troponin-
like marker of AKI, given the conditions
complexity and specificity of the markers to
certain types of insults to selected parts of
the kidney, a panel of tests ultimately may
prove to have the most clinical benefit. Im
finding that the consensus is that a suite of
markers will be much more useful in pre-
dicting preclinical effects than a single bio-
marker. Certain nephrotoxic drugs only im-
pact certain parts of the nephron and if we
just relied on one biomarker we might miss
that effect, explained Peter Goering, PhD,
leader of the toxicology laboratory in FDAs
Center for Devices and Radiological Health.
Goerings lab is part of a public-private
team investigating biomarkers that could
identify drug-induced nephrotoxicity. In
2008, the FDA and European Medicines
Agency jointly agreed to allow drug compa-
nies to submit, in addition to serum creati-
nine and blood urea nitrogen, results of sev-
en biomarkers that measure kidney damage
during animal studies of new drugs. The
newly allowed tests include KIM-1, albu-
min, total protein, 2-microglobulin, cysta-
tin C, clusterin, and trefoil factor-3. Pharma
companies are not required to collect data
on these parameters, but if they do, it must
be submitted to FDA. At the time the joint
agreement was announced, Janet Wood-
cock, MD, director of FDAs Center for
Drug Evaluation and Research commented
that the agency hoped these biomarkers
will lead to human tests that detect drug-
induced kidney injury in people earlier than
is now possible and help healthcare profes-
sionals better manage potential kidney
damage from drugs.
POCT: Coming Soon?
As the potential AKI biomarkers edge to-
wards clinical implementation, technologi-
cal advances will need to go hand-in-hand
with the evidence base, according to Han.
We need to have some sort of rapid assay.
We dont want to wait six to eight hours
before the result comes back. We need to
be able to detect these biomarkers at the
bedside with 10 to 20 minutes. From that
well know the patients at high risk for
kidney injury and can start treatment, he
explained. Already, rapid ELISA kits for
NGAL are commercially available, and a
rapid assay for KIM-1 has been described
(Kidney Int 2009 76(1):10814).
As the field awaits further development
of proposed AKI biomarkers, Okusa urged
laboratorians in the meantime to focus on
analytics associated with and the overall use
of todays gold standard. Its becoming in-
creasingly evident that even a small increase
in serum creatinine can diagnose AKI and
predict mortality, and thats the only com-
monly used test that we have now, he said.
If there are any improvements in repro-
ducibility and turnaround time that can be
made that will be helpful. And physicians
need to order serum creatinine more than
once per day if they suspect AKI to deter-
mine a small rise in serum creatinine so
treatment can be instituted.
CLN
Proposed Biomarkers of
Acute Kidney Injury
Numerous biomarkers have been proposed for the differential diagno-
sis, early detection and prognosis of patients with AKI.
Differential Diagnosis in Established AKI
Serum Markers
Carbamylated hemoglobin (carb Hb)
Cystatin C
Neutrophil gelatinase-associated lipocalin (NGAL)
Urine Markers
-1 microglobulin
Glutathione-S-transferase (GST)
Interleukin-18 (IL-18)
Kidney injury molecule-1 (KIM-1)
N-acetyl--D-glucosaminidase (NAG)
NGAL
Sodium hydrogen exchanger 1 (NHE3)
Matrix metalloproteinase-9 (MMP-9)
Early Detection of AKI
Serum Markers
Cystatin C
Prohormone of atrial natriuretic peptide (ProANP)
Neutrophil-CD11b
NGAL
Urine Markers
-GST
-glutamyl transpeptidase
-GST
Alkaline phosphatase
GST
KIM-1
IL-18
Lactate dehydrogenase (LDH)
NAG
NGAL
MMP-9
Prognosis of AKI
Serum Markers
Cystatin C
IL-6
IL-8
IL-10
NGAL
Urine Markers
-1 microglobulin
-GST
-2 microglobulin
Cystatin C
-glutamyltransferase
IL-18
KIM-1
LDH
NAG
NGAL
Retinol-binding Protein
Adapted from Coca, SG, Yalavarthy, R, Concata, J, and Parikh, CR, Kidney Intl
2008;73:1008-16.
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CLINICAL LABORATORY NEWS FEBRUARY 2010
Despite being well recognized as a
complication of pregnancy, many un-
knowns still surround prediction, di-
agnosis, and pathophysiology of preec-
lampsia, earning it the common name,
disease of theories. Efforts to lessen the
risks associated with preeclampsia have
been focused on accurate and earlier di-
agnosis of the disorder. New biomarkers
for predicting and possibly preventing
preeclampsia promise to give the labo-
ratory a major role in the care of at-risk
pregnant women. Here we describe the
current understanding of the etiology
of preeclampsia, the labs current role
in monitoring at-risk women, as well as
how new biomarkers on the horizon may
lead to greater involvement of the lab in
earlier prediction of the condition.
Risk Factors for Preeclampsia
Epidemiological and clinical risk factors for
preeclampsia are classified as maternal, pa-
ternal, and/or pregnancy-specific (Table 1,
p. 9). One hypothesis concerning the etiol-
ogy of preeclampsia is that it is an autoim-
mune disorder and may reflect the imma-
turity of the maternal immune system to
properly respond to the pregnancy. This
hypothesis originates from the fact that
the frequency of preeclampsia is higher in
nulliparous women, women who conceive
with assisted reproductive techniques, and
women with autoimmune conditions.
In addition, pre-existing metabolic,
renal, or vascular conditions increase the
risk of preeclampsia due to the physi-
ological stress of pregnancy combined
with widespread endothelial dysfunction.
Obese (BMI 30 Kg/m
2
) females are at very
high risk for preeclampsia compared to
lean women (odds ratio = 3.3), as well as
women who have hypercholesterolemia or
hypertriglyceridemia. On the other hand,
smoking actually decreases a womans risk
of preeclampsia.
Use of low-dose aspirin in women with
these risk factors has been shown to slightly
reduce the risk of preeclampsia (OR 0.86,
95% CI: 0.760.96) and perinatal mortal-
ity, but it failed to reduce placental abrup-
tion or delivery of low-birth-weight babies
(1). Researchers have also studied vita-
mins C and E and calcium supplements in
both low- and high-risk populations but
found no evidence that these nutritional
supplements reduced the prevalence of
preeclampsia, hypertension, or eclamp-
sia. Furthermore, preventive preeclampsia
trials so far have produced disappointing
results, perhaps due to an overall lack of
understanding of the causal mechanisms
of preeclampsia.
Pathophysiology of Preeclampsia
Current concepts and theories of the
pathophysiology of preeclampsia revolve
around the common theme of endothe-
lial cell dysfunction, primarily placental in
origin, but extending to other organs such
as the brain, liver, and kidneys. This long-
standing hypothesis focuses on placental
implantation and trophoblast invasion and
originated after observations that delivery
of the placenta quickly reversed the clini-
cal manifestations of preeclampsia and ec-
lampsia in a majority of patients. Immune
maladaptation between the mother and fe-
tus is also likely a factor in the development
of preeclampsia, but the exact mechanisms
are still unknown.
In normal pregnancy, the maternal-fetal
interface and blood flow are established very
early after conception. Proper placental im-
plantation allows for adequate circulation
between the mother and fetus and occurs
Preeclampsia
Prediction, Diagnosis, and Management
Beyond Proteinuria and Hypertension
BY DARCI R. BLOCK, PHD, AND AMY K. SAENGER, PHD
P
reeclampsia is a multisystem disorder of pregnancy characterized by the presence of hypertension
and proteinuria after 20 weeks gestation. While estimated to affect only 3%5% of all pregnancies
in the U.S., the disorder is responsible for 15% of premature deliveries and up to 18% of maternal
deaths. In fact, complications from hypertension in pregnancy are the third leading cause of mater-
nal death, surpassed only by embolism and hemorrhage. Other risks associated with preeclampsia
include placental abruption, liver or renal failure, disseminated intravascular coagulopathy, cardiovascular com-
plications, and seizures or other neurological manifestations (eclampsia).
The incidence of preterm birth is also higher in preeclamptic women, primarily because obstetricians attempt
to minimize the risks to both the mother and fetus by delivering the fetus early. However, preterm infants are
at risk of complications as well. They have a greater probability of developing respiratory distress syndrome, in-
traventricular hemorrhage, cerebral palsy, and other neurological and developmental delays. In women whose
preeclampsia is caused by placental anomalies, severe intrauterine fetal growth restriction may occur, leading to
higher prevalence of intrauterine asphyxia and placental abruption.
CLNS
IMPROVING
HEALTHCARE
THROUGH
LABORATORY
MEDICINE
SERIES
CLINICAL LABORATORY NEWS FEBRUARY 2010
9
when the placenta cytotrophoblast cells
invade the maternal spiral arteries, causing
them to lose their smooth muscle and en-
abling expansion of vascular capacity and
angiogenesis. In preeclamptic patients the
implantation of the placenta may be dys-
functional, such that the spiral arteries are
poorly remodeled, resulting in inadequate
circulation between the placenta and the
uterus and ultimately a shallow placental
implantation. This lack of perfusion or
ischemia is thought to induce a majority of
the endothelial dysfunction and lead to de-
velopment of widespread organ alterations
and detectable alterations in the cardio-re-
nal system. Therefore, even though the lo-
calized endothelial changes originate from
the placenta, the consequences of decreased
perfusion extend to all other organs. Blood
flow is further compromised by activation
of the coagulation cascade and formation
of microthrombi.
The severity of symptoms has also pro-
vided clues as to the pathophysiology of the
disorder. Preeclampsia diagnosed early in
pregnancy, before 34 weeks, has a higher
probability of placental abnormalities and
represents the most severe cases of preec-
lampsia and intrauterine growth restric-
tions in the baby. However, a majority of
preeclampsia cases are late onset, diagnosed
after 34 weeks, and notably lack placental
anomalies and major adverse complica-
tions.
Diagnosis and Laboratory Testing
Obstetricians typically diagnose preec-
lampsia after 20 weeks gestation. Maternal
presentation of new onset hypertension,
proteinuria, and often edema trigger the di-
agnosis. Severe preeclampsia is recognized
by a greater magnitude of increased blood
pressure and a greater degree of proteinu-
ria. Other clinical manifestations of severe
preeclampsia include oliguria, cerebral or
visual disturbances, and pulmonary edema.
While the presence of hypertension is often
the first sign of preeclampsia, hypertension
alone does not define the disorder. The
pathogenic evolution and progression of
preeclampsia likely originates shortly after
conception, and hypertension becomes ap-
parent later in the pregnancy.
The American College of Obstetricians
and Gynecologists recognizes four major
classifications of hypertension-related dis-
orders in pregnancy (2). These disorders
include chronic hypertension, preeclamp-
sia/eclampsia, preeclampsia superimposed
on chronic hypertension, and gestational
hypertension (Figure 1).
Chronic hypertension is unrelated to the
pregnancy itself and is diagnosed if there is
a documented pre-existing condition prior
to 20 weeks gestation or if the hyperten-
sion persists at 12 weeks postpartum. Pre-
eclampsia is defined as hypertension and
proteinuria after 20 weeks gestation, while
eclampsia is a severe progression and com-
plication of preeclampsia and is indicated
by new onset of seizures in previous pre-
eclamptic women. Full eclampsia is rela-
tively rare and estimated to occur in only
1% of preeclamptic patients.
Preeclampsia superimposed on chronic
hypertension is characterized by new-onset
proteinuria or by a marked increase in pro-
tein concentration if already present, an
acute increase in hypertension, or develop-
ment of HELLP (hemolysis, elevated liver
enzymes, low platelet count) syndrome.
Women may also have gestational hyper-
tension. This condition is diagnosed when
there is documented maternal hyperten-
sion without the presence of proteinuria,
and the hypertension ceases by 12 weeks
postpartum. However, approximately 25%
of women with gestational hypertension
develop proteinuria and progress to preec-
lampsia.
Currently, diagnosis and therapeutic
monitoring of the progression of preec-
lampsia does not involve specific or sen-
sitive blood biomarkers (Table 2, p. 10).
Therefore, involvement of the laboratory in
the diagnosis has been minimal. However,
the search for novel diagnostic markers for
preeclampsia is an active focus of research,
and there are several promising new bio-
markers on the horizon that have the po-
tential to give the lab a greater role.
Emerging Biomarkers for Preeclampsia
Research has shown that endothelial
dysfunction produces an imbalance of pro-
and anti-angiogenic factors, making fac-
tors involved with the angiogenesis process
of placental formation and implantation
good candidate biomarkers for preeclamp-
sia. Several circulating factors have been
identified that are involved in this process.
Pro-angiogenic factors include vascular
Table 1
Preeclampsia Risk Factors
Maternal Considerations
Inherent
l Age < 20 or 3540 years
l Nulliparity
l Black race
l Prior or family history of PE or cardiovascular disease
l Woman born small for gestational age
Medical conditions
l Obesity
l Chronic hypertension
l Chronic renal disease
l Diabetes mellitus (insulin resistance, type 1, and gestational)
l Antiphospholipid antibody syndrome
l Connective tissue diseases
l Thrombophilia
l Stress
Pregnancy specic
l Multiple gestation
l Oocyte donation
l Urinary tract infection
l Congenital conditions affecting the fetus
Hydatidiform mole
Hydrops fetalis
Structural anomalies
Paternal Considerations
Limited sperm exposure
l Barrier contraception
l First-time father
l Donor insemination
Partner who fathered a preeclamptic pregnancy in another woman
Adapted from reference 2 and Dekker G, Sibai B. Primary, secondary, and tertiary
prevention of preeclampsia. Lancet 2001;357:20915.
Figure 1
Classification of Preeclampsia
and Pregnancy Related Hypertension
Adapted from reference 2 and Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in
Pregnancy. Am J Obstet Gynecol 2000;183:S122.
10
CLINICAL LABORATORY NEWS FEBRUARY 2010
endothelial growth factor (VEGF) and
placental growth factor (PlGF), while anti-
angiogenic factors include soluble fms-like
tyrosine kinase 1 receptor (sFlt-1) and sol-
uble endoglin (sEng).
Expressed by the placenta, VEGF and
PlGF promote angiogensis by interacting
with the VEGF receptor. PlGF serum con-
centrations in pregnancy increase signifi-
cantly and to a much greater extent than
VEGF levels. Several studies have shown
that PlGF and VEGF concentrations both
decrease prior to the onset of clinical preec-
lampsia symptoms, although the magni-
tude of difference from normal pregnancy
values is greater for PlGF than VEGF. In
particular, researchers have found that
women who later developed preeclampsia
had reductions in serum PlGF in the sec-
ond trimester.
In addition to placental growth factors
recruited for the purposes of angiogen-
esis and placental implantation, researchers
have identified proteins that counteract the
effect of PlGF and VEGF. sFlt-1, also known
as soluble VEGF receptor 1, circulates in the
blood and is capable of binding VEGF and
PlGF to further inhibit receptor binding
and angiogenic effects. Studies have shown
that sFlt-1 is elevated in women with preec-
lampsia compared to controls, correlates to
disease severity, and subsequently decreases
following delivery (3, 4). Moreover, the ra-
tio of sFlt-1 to PlGF is useful as an index
of anti-angiogenic activity, reflecting both
increased sFlt-1 and decreased PlGF in
women who develop preeclampsia.
Studies have also indicated that the
sFlt-1:PlGF ratio predicts preeclampsia up
to 5 weeks earlier than clinical diagnosis
made with current markers or either pro-
tein alone. Interestingly, sFlt-1 given exog-
enously in pregnant rats triggered devel-
opment of hypertension, proteinuria, and
glomeruloendotheliosis (5).
Another factor involved in angiogen-
esis of the placenta is soluble endoglin
(sEng). This protein is a circulating form
of endoglin that is expressed on the vascu-
lar endothelium and trophoblast cells and
functions as a modulator of transform-
ing growth factor (TGF-) signaling. sEng
competes directly with TGF- and acts as a
negative regulator of angiogenesis. Similar
to sFlt-1, soluble endoglin concentrations
correlate to the occurrence and severity
of preeclampsia and resolve following de-
livery. Furthermore, sEng levels have been
shown to be significantly higher 3 months
prior to the development of proteinuria or
hypertension, whereas the sFlt1:PlGF ratio
increases closer to disease onset (3, 4).
Pregnancies in which there is intrauter-
ine growth restriction unrelated to preec-
lampsia also demonstrate elevated levels
of sEng, suggesting this marker may not
be specific for preeclampsia but rather for
a dysfunctional placenta. Animal model
studies demonstrate that induction of the
hepatic and renal complications that occur
with HELLP syndrome transpire after ad-
ministration of sEng and sFlt-1, suggesting
that the two proteins may have a synergistic
effect responsible for the more severe cases
of PE (6).
Although PlGF, VEGF, sFlt-1, and sEng
all appear to be important in the pathogen-
esis of preeclampsia, they do not have suffi-
ciently high positive-predictive value when
used alone. Based on the overall findings,
it seems likely that a combination of these
markers will improve their utility as predic-
tors or preeclampsia.
There are several other biomarkers that
also show promise in the prediction to
management of preeclampsia. These in-
clude: placental protein 13 (PP-13); asym-
metric dimethylarginine (ADMA); cell-free
DNA; pregnancy-associated plasma protein
A (PAPP-A); autoantibodies against the an-
giotensin II type 1 (AT1) receptor; inhibin
A; and activin A. Larger longitudinal, case-
controlled trials are needed to validate the
clinical and analytical characteristics of
these markers.
Treatment of Preeclampsia
Delivery of the baby is the only cure for
preeclampsia. Prenatal treatment options
are limited due to the potential risks to
the fetus; therefore, patients with preec-
lampsia are simply monitored for signs
and symptoms of distress. Obstetricians
monitor blood pressure and lab tests results
in women with mild preeclampsia twice
weekly to indicate progression to HELLP
or eclampsia with liver and kidney involve-
ment. Women with severe preeclampsia are
put on mandatory bed rest and monitored
in a similar manner to prevent seizures and
lower their blood pressure.
Magnesium sulfate has been used to
decrease the incidence of seizures and may
also have the added benefit of decreasing
placental abruption. Patients receiving this
therapy must be monitored closely for mag-
nesium toxicity, especially for decreased
liver and kidney function. Antihypertensive
drugs may also be used for the treatment
of acute maternal symptoms, and the fetus
may be given corticosteroids to assist with
lung maturity as a precaution for impend-
ing delivery.
Other treatment options are also being
explored. Administrating a VEGF variant
to an sFlt-1 overexpressing rat model was
found to reverse the preeclamptic pheno-
type without apparent harm to the fetus
(7). This and other ongoing studies are
aimed at elucidating the etiology of disease,
as well as restoring angiogenic balance.
Beyond Postpartum
Although preeclampsia is a disorder of
pregnancy, the higher relative concentra-
tions of anti-angiogenic factors are thought
to trigger widespread vascular endothe-
lial cell injuries, as well as induce an altered
cardiovascular state during the affected
pregnancy and beyond. The risk factors for
cardiovascular disease and preeclampsia
are remarkably similar and include: obesity,
hypertension, hyperglycemia, insulin resis-
tance, diabetes, and dyslipidemia (Table 1,
p. 9).
Several epidemiological studies have
provided convincing evidence that cardio-
vascular risk is increased in women with a
history of preeclampsia compared with nor-
mal control subjects, particularly if they de-
liver a preterm, low-birth weight baby. One
contributing factor may be the occurrence
of microalbuminuria 35 years postpar-
tum, which occurs in up to 50% of women
with a history of preeclampsia compared to
women with no history of the disorder. It is
uncertain how long this condition persists,
but there is a significant link to increased
cardiovascular risk and microalbuminuria
in menopausal women (8).
Authors of a recent meta-analysis also
reported several associations between pre-
eclampsia and cardiovascular morbidity
and mortality. In women diagnosed with
preeclampsia, there is approximately a
four-fold risk of future hypertension and
an approximate two-fold risk of ischemic
heart disease, venous thromboembolism,
and stroke (9). In addition, if preeclampsia
is diagnosed in a subsequent pregnancy, the
risk of future hypertension and cardiovas-
cular events increases even further.
On the Horizon: Preeclampsia Biomarkers
Preeclampsia is clearly a complex disorder
that involves a delicate balance between
the maternal immune system, fetus, and
placenta. Readily accessible screening tests
for preeclampsia would ideally reduce the
incidence of maternal and neonatal com-
plications.
Several preeclampsia biomarkers are in
development and being evaluated on auto-
mated immunoassay platforms. If these
markers prove to have adequate sensitivity
and positive-predictive value in screening
for preeclampsia, labs will have the op-
portunity to help improve the quality of
care for outcomes of obstetrical patients.
With new biomarkers, earlier prediction of
preeclampsia in high-risk pregnancies will
allow obstetricians to treat women earlier
and hopefully improve outcomes for both
the mother and the fetus.
CLN
REFERENCES
1. Coomarasamy A, Honest H, Papaioan-
nou S, Gee H, et al. Aspirin for prevention
of preeclampsia in women with historical
risk factors: a systematic review. Obstet Gy-
necol 2003;101:131932.
2. Gilstrap L, Ramin S. ACOG Committee
on Practice Bulletins: Diagnosis and man-
agement of preeclampsia and eclampsia.
ACOG Practice Bulletin Clinical Manage-
ment Guidelines for Obstetrician-Gynecol-
ogists 2002;33:19.
3. Carty DM, Delles C, Dominiczak AF. Nov-
el biomarkers for predicting preeclampsia.
Trends Cardiovasc Med 2008;18:18694.
4. Levine RJ, Lam C, Qian C, Yu KF, et al.
Soluble endoglin and other circulating
antiangiogenic factors in preeclampsia. N
Engl J Med 2006;355:9921005.
5. Maynard SE, Min JY, Merchan J, Lim
KH, et al. Excess placental soluble fms-like
tyrosine kinase 1 (sFlt1) may contribute to
endothelial dysfunction, hypertension, and
proteinuria in preeclampsia. J Clin Invest
2003;111:64958.
6. Venkatesha S, Toporsian M, Lam C, Ha-
nai J, et al. Soluble endoglin contributes to
the pathogenesis of preeclampsia. Nat Med
2006;12:6429.
7. Steinberg G, Khankin EV, Karumanchi
SA. Angiogenic factors and preeclampsia.
Thromb Res 2009;123:S939.
8. Davison JM, Homuth V, Jeyabalen
A, Conrad KP, et al. New aspects in the
pathophysiology of preeclampsia. J Am Soc
Nephrol 2004;15:24408.
9. Bellamy L, Casas J, Hingorani AD, Wil-
liams DJ. Pre-eclampsia and risk of car-
diovascular disease and cancer in later life:
systematic review and meta-analysis. BMJ
2007;335:97485.
Darci S. Block, PhD, is a
clinical chemistry fellow in
the Department of Labora-
tory Medicine and Pathology
at the Mayo Clinic, Rochester,
Minn. Email: block.darci@mayo.edu.
Amy K. Saenger, PhD, is
the director of the Central
Clinical Laboratory and
an assistant professor in the
Department of Laboratory
Medicine and Pathology at the Mayo Clinic,
Rochester, Minn. Email: saenger.amy@
mayo.edu.

Disclosure: Dr. Saenger has received grant/
research support from Roche.
Table 2
Laboratory Tests for
Preeclampsia and Eclampsia
Assessment for High Risk of Developing Preeclampsia
Goal: Establish baseline levels early in pregnancy and monitor for
progression to HELLP or severe preeclampsia.
CBC
l Hemoglobin
l Hematocrit
l Platelet count
Urine protein (12 or 24 hour)
Serum creatinine
Serum uric acid
Diagnosis of HELLP Syndrome
Hemolysis
l Bilirubin . . . . . . . . . . . . . . . . . . . . . . >1.2 mg/dL
l Peripheral blood smear . . . . . . . abnormal
l Lactate dehydrogenase . . . . . . . >600 U/L
Liver function tests
l ALT & AST . . . . . . . . . . . . . . . . . . . . elevated
Platelet count . . . . . . . . . . . . . . . . . . <100 x10
9
/L
Diagnosed Preeclampsia (Therapeutic Monitoring)
All of the above
Albumin
Coagulation testing
Adapted from Report of the National High Blood Pressure Education Program Working
Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol. 2000;183:S122.
CLINICAL LABORATORY NEWS FEBRUARY 2010
11
Expanding Role of the Clinical Lab in Infectious Disease Testing
Q
What are the best laboratory tests
for the diagnosis of sepsis and septic
shock in emergency departments? What is
likelihood ratio of procalcitonin (PCT) in
septic syndrome triage in emergency de-
partments?
A
Sepsis is a complex disorder with
confusing clinical manifestations and
conflicting signs and symptoms that can
lead to increased morbidity and mortality.
This is especially true for the ED clinician
who must make rapid medical decisions
about triage, diagnosis, and disposition to
the appropriate level of care for ED pa-
tients with clinical signs and symptoms of
sepsis. Blood cultures have played a vital
role in the differential diagnosis of sepsis,
but PCT is an early biomarker of inflam-
mation and bacterial sepsis and may be
useful as a rapid risk stratification tool in
the ED using negative and positive pred-
icative values. However, laboratorians need
to read and review the package insert for
their particular PCT assay to determine the
tests intended use. Considerations include
how the assay was cleared by the FDA and
whether it was cleared for use only in the
ICU setting or can be used in other set-
tings, such as the ED. The likelihood ratio
may contribute additional information,
providing clinicians are familiar with how
this information can be used appropriately
in their decision making process.
Q
Our ED physicians order influenza
(A&B) and group A strep testing si-
multaneously. Are the symptoms similar,
and is this a common ordering pattern?
A
Symptoms of the flu and strep can be
very similar. Upper respiratory symp-
toms, as well as rash, sore throat, and fever
may be common to both diseases, but the
appearance of white pus in the adenoid
area is more typical of a strep infection.
Since these symptoms can overlap quite
extensively it is appropriate, depending on
the presentation, that both screening tests
be performed.
Q
There are a few high-risk HPV test-
ing techniques. What are the advan-
tages of each?
A
An HPV test is done to find a high-
risk HPV infection in women, and
there are many types of HPV. High-risk
types of HPV (such as types 16, 18, 31, and
45) cause changes in the cells of the cervix
that can be seen as abnormal findings on a
Pap test and have a higher risk of progress-
ing to cancer. The first screening test fre-
quently used is a hybrid capture DNA assay
that detects the HPV high-risk genotypes
16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59
and 68. Some disadvantages of this assay
include: false negatives due to inadequate
cellularity; suboptimal vaginal specimens
due to limited clinical correlative data; and
cross-reactions with other genotypes. The
screening test, if positive, may be a reflec-
tion of the DNA genotyping test. As to
which particular techniques are better than
another, I think one needs to do side by side
evaluations and compare the data.
Q
How much demand is there cur-
rently for infectious diseases testing
with very rapid turnaround? How do you
see this changing over the next 5 years or
so, and what are the drivers of change that
may result in molecular testing in point-
of-care settings?
A
There is an increasing demand for
rapid testing in all areas of the labo-
ratory so clinicians can make important
rapid medical decisions regarding the tri-
age, assessment, treatment, and disposition
of their patients to the appropriate level of
care. This is particularly true in the hospital
setting. In my opinion, we will see molecu-
lar testing at the point-of-care setting. An
example might be molecular testing for
methicillin-resistant Staphylococcus aureus.
Q
Should laboratorians help physicians
interpret results? Currently, infec-
tious disease experts are rarely knowl-
edgeable about rapid tests, their high
false-negative rates, or in HIV testing, false
positives if the timing of the reading is not
absolutely exact.
A
There is an expanding role for labo-
ratorians, especially in assisting physi-
cians with the interpretation of laboratory
tests. Laboratorians understand better than
physicians the strengths and limitations of
the tests performed in their laboratories,
and physicians know better than laboratori-
ans the physiological functions of the body
and what a result means in the context of a
particular patient. I believe patients clearly
benefit when professionals from both are-
nas collaborate on their behalf. On lab re-
ports from our lab we provide additional
information such as sensitivity, specificity,
NPV, PPV, and clinical conditions.
DisclaimerThe opinions and infor-
mation are the sole responsibility of the
presenter. AACC reviews the presentations
for overall appropriateness, but this should
not be construed as an endorsement by the
association or its employees of the opinions
and information offered here.
Supported in part by an education grant
from Siemens Healthcare Diagnostics.
AACC S EXPERT ACCESS
Each month, AACCs Expert Access Live Online Program
features a different hot topic. Visit AACCs website for more
information and an archive of past presentations.
The following is an excerpt from the May 2009 presen-
tation by Denise L. Uetwiller-Geiger, PhD, MT(ASCP),
DLM(ASCP), director of laboratories and clinical research at
John T. Mather Hospital in Port Jefferson, N.Y.
The easiest decision
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publication, Clinical Laboratory News.
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ll out and mail the subscription card in this issue or go to
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12
CLINICAL LABORATORY NEWS FEBRUARY 2010
Electronic Health Record
Incentive Taking Shape
T
he Centers for Medicare & Medicare
Services (CMS) and the Office of the
National Coordinator for Health Informa-
tion Technology (ONC) announced two
regulations that will help implement the
electronic health record (EHR) incentive
programs enacted under the American Re-
covery and Reinvestment Act of 2009 (Re-
covery Act).
Part of the Obama administrations push
for improved health information technolo-
gy, physicians stand to gain from $44,000 to
$64,000 each by demonstrating meaning-
ful use to CMS over a 5-year period, and
hospitals may be able to get millions. Begin-
ning in 2015, CMS will financially penalize
providers who dont show meaningful use
of EHRs. Incentive payments may begin as
soon as October 2010 to eligible hospitals,
while incentive payments to other eligible
providers are slated for January 2011.
The most anticipated and controversial
element of the program has been how CMS
would define meaningful use so that phy-
sicians and hospitals will know that their
investments in EHRs will measure up and
earn the rewards. The new regulations in-
clude a proposed rule that finally defines
the central concept of meaningful use of
EHR technology. The other regulation, is-
sued by ONC, sets initial standards, imple-
mentation specifications, and certification
criteria for EHR technology. Both regula-
tions are open to public comment through
the end of February.
It will not be easy to meet the defini-
tion of meaningful use. The proposed
rule requires that the physician or hospital
demonstrate use of certified EHRs in a way
that improves quality, safety, and efficiency
of healthcare delivery; reduces healthcare
disparities; engages patients and families;
improves care coordination; improves
population and public health; and ensures
adequate privacy and security protections
for personal health information.
The ONC regulation describes standard
electronic formats for clinical summaries
and prescriptions; standard terms to de-
scribe clinical problems, procedures, labo-
ratory tests, medications and allergies; and
standards for the secure transmission of
this information using the Internet. It also
sets forth how an EHR can be certified.
Both agencies noted that regulations
will need to be updated over time as tech-
nology advances. The CMS proposed
rule and fact sheets are available from the
CMS website, www.cms.hhs.gov/recovery/
11_healthit.asp. ONCs interim final rule
may be viewed at http://healthit.hhs.gov/
standardsandcertification.
HHS Outlines First
Health Security Strategy
D
epartment of Health and Human Ser-
vices (HHS) Secretary Kathleen Sebe-
lius announced the national health security
strategy, the nations first comprehensive
strategy focused on protecting peoples
health during a large-scale emergency. The
plan sets priorities for government and non-
government activities over the next 4 years.
Sebelius defined national health secu-
rity as the nation and its people being pre-
pared for, protected from, and resilient in
the face of health threats or incidents with
potentially negative health consequences,
such as bioterrorism and natural disasters.
The plan provides a framework that aims
to build community resilience, strengthen
and sustain health emergency response sys-
tems, and fill current gaps.
The national health security strategy and
the accompanying interim implementation
guide outline 10 broad objectives to achieve
health security: foster informed, empow-
ered individuals and communities; develop
and maintain the workforce needed for
national health security; ensure situational
awareness so first responders are aware of
changes in an emergency situation; foster
integrated healthcare delivery systems that
can respond to a disaster of any size; en-
sure timely and effective communications;
promote an effective countermeasures en-
terprise; ensure prevention or mitigation of
environmental and other emerging threats
to health; incorporate post-incident health
recovery into planning and response; work
with cross-border and global partners to
enhance national, continental, and global
health security; and ensure that all systems
that support national health security are
based upon the best available science, eval-
uation, and quality improvement methods.
The strategy and implementation guide
is available from the HHS website, www.
hhs.gov/disasters.
ISO Developing eHealth Resource for
Developing Countries
T
he International Standards Organiza-
tion (ISO) announced that it will cre-
ate a technical report to help emerging and
developing countries implement an inter-
nationally harmonized health informatics
system. The report will present information
in an accessible way to guide and facilitate
the adoption of international standards by
countries with limited resources and infra-
structure. ISO will work on the document
(ISO/TR 14639) in partnership with the
World Health Organization.
The design, deployment, and main-
tenance of a national eHealth infrastruc-
ture can be a complex task, especially for
those new to the area, ISO noted in the
announcement. Scarce resources and IT
expertise make it difficult to put together
systems that are scalable, robust, and meet a
countrys long-term needs. Most resource-
limited countries have multiple vertical
systemsprograms geared to individual
diseases like HIVand lack a common
framework that could improve data collec-
tion and reporting.
According to ISO, international stan-
dards can help by providing globally har-
monized specifications for the architectural
framework used to design eHealth systems,
plan implementation, make build-or-buy
decisions, and decide on acquisitions. More
information is available from the ISO web-
site, www.iso.org.
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CLINICAL LABORATORY NEWS FEBRUARY 2010
13
QIAGEN Completes Purchase
of SABiosciences
Q
IAGEN announced the completion
of its acquisition of SABiosciences,
a developer and manufacturer of PCR as-
say panels. The closing follows approval
by SABiosciences stockholders and the
expiration of the statutory 30-day waiting
period as required by law. The acquisition
gives QIAGEN access to more than 100
PCR assay panels for the analysis of DNA,
RNA, and microRNA targets associated
with specific diseases or pathways. I would
like to use this opportunity to welcome our
new employees to QIAGEN, said Peer M.
Schatz, chief executive officer of QIAGEN.
Their competence will help us leverage the
combined companys value proposition in
the field of biomarker discovery and valida-
tion for the development of future diagnos-
tics and pharmaceuticals. QIAGEN plans
to further expand the business of the dis-
ease- and pathway-focused assay panels, as
well as develop SABiosciences headquarters
in Frederick, Md. as a center of excellence
in biological content development. The ac-
quisition was valued at approximately $90
million in cash.
Abbott to Pay $123 Million
for STARLIMS
A
bbott announced a definitive agree-
ment to acquire STARLIMS Technolo-
gies, a provider of laboratory information
management systems, for approximately
$123 million in cash. The acquisition is ex-
pected to strengthen Abbotts standing in
the global diagnostics market by providing
web-based applications to help labs more
efficiently store, retrieve, and analyze clini-
cal data. The acquisition of STARLIMS
will provide Abbott with leading products
to build upon existing technologies and
expertise in the emerging field of health-
care informatics, said Edward L. Michael,
executive vice president of diagnostic prod-
ucts at Abbott. STARLIMS advanced web-
based technologies can help our customers
operate efficiently across the core laborato-
ry, molecular, and point-of-care segments
of the global diagnostics market. Abbott
expects the transaction to close in the first
quarter of 2010 following customary clos-
ing procedures.
Clarient Buys Applied
Genomics for $17.6 Million
C
larient announced that it has acquired
Applied Genomics (AGI) in an all-
stock merger valued at approximately
$17.6 million. As a result of this acquisition,
AGI has become a wholly-owned subsid-
iary of Clarient. AGI and Clarient repre-
sent a strong and technical fit providing
for multiple proprietary tests that can be
commercialized via the Clarient national
footprint, said Ron Andrews, chief execu-
tive officer of Clarient. The combination
of these organizations populates the Clari-
ent proprietary pipeline of cancer tests, in-
cluding the planned commercial launch of
an important lung cancer test, Pulmotype,
in the first quarter of 2010, followed by a
series of proprietary tests to be commer-
cialized in the following 24 months across
a range of cancers including lung, breast,
and ovarian. In addition to the Pulmotype
lung cancer test, AGIs pipeline includes
theranostic tests designed to assist in the
selection of therapies, as well as a breast
cancer panel that could be incorporated
for use with Clarients Insight Dx Breast
Cancer Profile.
Lab21 Acquires Selah Technologies
L
ab21, a U.K.-based healthcare diag-
nostics company, announced the ac-
quisition of Selah Technologies, a South
Carolina-based company specializing in
proprietary nanotechnologies for in vitro
diagnostic products. Lab21 intends to de-
velop new diagnostic products that have
potential as rapid, low-cost, and sensitive
tests based on Selahs nanoparticle technol-
ogy. Lab21 also announced the formation
of Lab 21 Inc., a U.S.-based subsidiary to be
headquartered in Greenville, S.C. As a new
diagnostic service laboratory, Lab21 Inc.
will conform to CLIA requirements and
focus primarily on oncology testing. The
acquisition of Selah Technologies is a key
step in the development of Lab21s strat-
egy as we look to expand our technology
platforms as well as our global commercial
operations, said Graham Mullis, chief ex-
ecutive officer of Lab21. The formation of
Lab 21 Inc. is a significant investment and
a major step forward in Lab21s planned
international expansion. The U.S. market
is expected to be an exciting opportunity
for Lab21 as we expand our market-leading
products and services in the worlds largest
diagnostic market.
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AACC Expands Global Patient Education Network
Lab Tests Online Now Available in China and France
AACC recently launched two new versions of its award-
winning website, Lab Tests Online, providing people in
China and France with access to free, non-commercial,
peer-reviewed information on laboratory testing in their
native languages. The Chinese version of the site is the first
in Asia, while the French Lab Tests Online is the ninth to go
live in Europe.
AACC president Barbara Goldsmith, PhD, attended the
formal ceremonies in Beijing on November 6 to mark the
launch of Lab Tests Online-CN. It is truly humbling to cel-
ebrate the fruits of our first collaboration with the Chinese
Society of Laboratory Medicine, an organization that is
half a planet removed from us, and to recognize again that
Lab Tests Online has indeed become a global standard for
patient education,she said.
The French Society of Clinical Biochemistry celebrated
the launch of Lab Tests Online-FR on the same day. D.
Robert Dufour, MD, executive editor of Lab Tests Online
attended the event in Paris. Information, and especially
medical information, is much easier to understand if it is
presented in ones native language,said Dufour. Starting
today, Lab Tests Online will be available to more than one-third of the worlds population in their everyday language.
The ten Lab Tests Online sites that were live prior to the addition of these two new sites average about 2 million
visitors each month. The U.S. version of Lab Tests Online has won numerous awards, and has been called one of the
smartest health sites on the webby a leading consumer health magazine.
Chinese lab society celebrates the launch of AACCs Lab Tests Online.
Pictured from left to right: Dr. Baishen Pan, vice president of the Chinese
Society of Laboratory Medicine; AACC member Dr. Pauline Lau, who facilitated
negotiations between AACC and CSLM; George Linzer, Lab Tests Online executive
producer; Dr. Barbara Goldsmith, AACC president; Dr. Hong Shang, president,
CSLM; and Dr. Zhenhua Yang, past president of CSLM. The Chinese version of the
website is the first to become available in an Asian country.
14
CLINICAL LABORATORY NEWS FEBRUARY 2010
PSA Velocity Found to have
Little Value in Cancer Detection,
Biopsy Decisions
T
he authors of a new study examining
the clinical utility of prostate-specific
antigen velocity (PSAV) for the early detec-
tion of prostate cancer conclude that there
is little evidence that PSAV can enhance
cancer detection in men with elevated PSA
(European Urology 2009;56:753760).
Furthermore, the investigators see little
justification for formal calculation of PSAV
and subsequent incorporation into a statis-
tical model, and no justification for PSAV
cut points, in determining indication for
biopsy. In light of their findings, the au-
thors also suggest that existing guidelines
on the use of PSAV to guide biopsy should
be revised.
The researchers initiated their investiga-
tion after conducting a systematic review of
PSAV following prostate cancer diagnosis,
and discovering that there was little direct
evidence that PSAV could help predict bi-
opsy outcome. Their study involved a sub-
group of 2,742 screening arm participants
from the European Randomized Study of
Screening for Prostate Cancer (ERSPC),
a trial involving 182,000 subjects in seven
European countries. All the participants
had an elevated PSA 3 ng/mL and had
a biopsy following subsequent biennial
screens, but not after their baseline PSA
test. Measurements of total, free, intact PSA
and human kallikrein-related peptidase
2 (hK2) also were evaluated in relation to
changes in PSAV.
PSAV was associated with small en-
hancements in predictive accuracy, with
AUC of 0.569 versus 0.531, and 0.626 ver-
sus 0.609 when % fPSA was included. This
relationship was not evident in men with
high-grade disease. The predicted probabil-
ity of prostate cancer with increasing PSAV
peaked at 0.5 ng/mL, and declined below
and above that point. In decision curve
analyses showing the clinical benefit of bas-
ing biopsy decisions on various models of
PSAV with other variables, PSAV provided
clinical benefit only to a small number of
men with high PSAV >0.75 ng/mL per year.
According to the authors, this finding sug-
gests that formally calculating PSAV and
incorporating it in a multivariate model
may be unnecessary. Instead, an informal
assessment of PSAV will likely be of more
value, such as evaluating men with a sud-
den rise in PSA levels for prostatitis before
performing biopsy.
Testing Ranks High in
Source of Diagnostic Errors
A
recent report of the Diagnostic Er-
ror Evaluation and Research (DEER)
project found that lab and radiologic test-
ing had the greatest number of reported er-
rors in the overall diagnostic process (Arch
Intern Med 2009;169:18811887). DEER
is a multi-year patient safety grant funded
by the Agency for Healthcare Research
and Quality, and the study was the largest
reported case series of diagnostic errors to
date, according to the researchers.
The investigators surveyed physician-
respondents via anonymous written sur-
veys during 20 grand ground sessions and
by mail at two collaborating institutions. In
all, there were 583 case reports of diagnostic
error, an average of 2.2 per respondent. The
most frequently missed diagnoses included
pulmonary embolism, drug reaction or
overdose, lung, colorectal and breast can-
cer, and acute coronary syndrome. In the
category of lab or radiology tests, failure
to order or a delay in ordering needed tests
was the most common source of error, fol-
lowed by erroneous lab or radiology read-
ing of the test, failed or delayed reporting of
results to the clinician, and technical errors
or poor processing of the specimen or test.
While the study had limitations such as
recall bias, it pointed out the overlapping
and clustering of certain patterns of errors
while enabling the researchers to identify
generic factors that contribute to diagnos-
tic errors. The analysis also highlighted
the complexities behind diagnostic errors,
including mingling between cognitive and
system errors.
Subclinical Hypothyroidism
Associated with Slight Mobility
Advantage in the Elderly
A
recent analysis of generally well-func-
tioning seniors in their 70s found that
individuals with mild subclinical hypothy-
roidism had a slight mobility advantage
over their euthyroid counterparts (Arch In-
tern Med 2009;169:201117). After 2 years,
even though there was a uniform decline in
mobility across categories of thyroid func-
tion, subjects with subclinical hypothyroid-
ism retained a slight functional advantage.
The researchers evaluated functional
mobility because it is generally regarded
as a global marker of current health status
and risk of future negative health events in
the elderly. The question was of interest be-
cause subclinical hypothyroidism has been
associated with risk of numerous negative
health outcomes, but evidence has been in-
consistent, particularly in the elderly.
The investigators defined subclinical
hypothyroidism as elevated thyrotropin
(TSH) with normal levels of free thyrox-
ine (FT4), in keeping with U.S. Preventive
Service Task Force definitions. Subjects
were assigned to three categories according
to baseline TSH levels, including euthy-
roid (0.4 to <4.5 mIU/L) mild subclini-
cal hypothyroid (4.5 to <7 mIU/L), and
moderate subclinical hypothyroid (7 to
20 mIU/L). In addition to baseline TSH
and FT4 measurements, participants un-
derwent baseline and 2-year assessments
of mobility based on usual and rapid gait
speed and endurance walking ability.
The study did not attempt to address
whether mildly elevated TSH levels con-
tribute directly to higher functional mobil-
ity or whether they reflect some underlying
physiologic adaption that promotes better
health. The researchers called for further
investigation into the meaning and any
benefits of age-related increases in TSH
levels.
Higher Urate Concentration
Linked to Slower Progression
of Parkinson Disease
N
ew research indicates that higher se-
rum and cerebrospinal fluid (CSF)
urate levels are associated with slower rates
of clinical decline in Parkinson disease (PD)
(Arch Neurol, 2009;66:146068). The find-
ings, which correlate closely with another
recent study, establish urate as the first mo-
lecular predictor of clinical progression in
PD and provide a rationale for investigating
the possibility that a therapeutic increase of
urate in patients with PD might act favor-
ably to slow the disease course, according
to the authors.
The study involved 800 subjects with
early PD in the Deprenyl and Tocoph-
erol Antioxidative Therapy of Parkin-
sonism (DATATOP) trial, a 2-year study
that explored the effects of deprenyl and
-tocopherol in delaying clinical decline
in PD. The investigators found an inverse
relationship between both serum and CSF
urate concentrations and progression to
DATATOPs primary endpoint, clinical
disability requiring levodopa therapy. The
hazard ratios for reaching the primary
endpoint were 36% and 35% lower among
participants in the highest quintile versus
lowest quintile of serum and CSF urate
concentrations, respectively. These asso-
ciations were present only among subjects
who were not treated with -tocopherol,
an unexpected and unexplained outcome.
Since urate is an antioxidant and oxi-
dative damage is thought to contribute
to the neurodegenerative process in PD,
the findings suggest a possible therapeutic
role for elevating serum urate concentra-
tion, either through diet or drugs. How-
ever, this potential benefit would need to be
weighed against possible adverse effects of
such therapy. The study does not provide
enough data to warrant a recommendation
for or against urate therapy, according to
the researchers.
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nsulin CLN 10-2009.indd 1 9/2/2009 5:26:52 PM
CLINICAL LABORATORY NEWS FEBRUARY 2010
15
Cepheid Receives H1N1 EUA for
CLIA Moderate Complexity Labs
C
epheid announced that it received FDA
emergency use authorization (EUA)
for its Xpert Flu A Panel test for the diagno-
sis of the 2009 H1N1 influenza virus. The
test runs on Cepheids GeneXpert System
and is able to identify the virus in less than
1 hour. The test is the first H1N1 assay to
receive an EAU that allows moderate com-
plexity labs under CLIA to perform the test,
thereby enabling in-hospital testing close to
patient care sites. FDAs EUA will remain in
place until April 26, unless the agency ter-
minates it sooner or extends it.
AdvanDx Receives Clearance
for Blood Pathogen Assays
A
dvanDx received FDA 510(k) clear-
ance for a 90-minute protocol for
its Staphylococcus aureus PNA FISH and
Staphylococcus aureus/CNS PNA FISH tests.
The faster protocol reduces the turnaround
time from 2.5 hours to 90 minutes by re-
ducing the PNA probe hybridization from
90 to 30 minutes. The tests are distributed
by bioMrieux in the U.S.
EUA Granted for New H1N1 Test
F
DA granted emergency use authoriza-
tion (EUA) to DxNA for the GeneSTAT
2009 A/H1N1 Influenza Test for use in the
detection of the 2009 H1N1 influenza vi-
rus. The test is a reverse-transcriptase PCR
assay designed for use in combination with
the Roche High Pure RNA Isolation Kit
and the GeneSTAT Analytical Platform.
The GeneSTAT Platform allows for point-
of-care testing and can determine infection
status from a cheek or nasal swab in about
50 minutes.
FDA Expands Clearance for
Agendias MammaPrint
A
gendia announced an expanded FDA
clearance for its MammaPrint breast
cancer recurrence test. The new clearance
permits the use of the test on women of all
ages. The first and only FDA-cleared breast
cancer recurrence test available to patients
and physicians, MammaPrint has received
four additional FDA clearances over the
past 3 years that expand the indications for
use of the test. All MammaPrint tests are
conducted in Agendias CLIA-accredited
service laboratory.
BD STD Assays Cleared
B
D Diagnostics, a segment of BD, an-
nounced that it received FDA clearance
for its ProbeTec Chlamydia trachomatis Q
x

and BD ProbeTec Neisseria gonorrhoeae Q
x

Amplified DNA Assays. The tests use sam-
ples collected from routine, liquid-based
Pap testing and run on the BD Viper Sys-
tem with XTR Technology. The ProbeTec
Q
x
Amplified DNA Assays are the first to
receive FDA clearance for gynecological
specimens collected and transported in the
two leading types of liquid-based cytology
preservative media currently in use.
First Vancoymycin-resistance
Assay Cleared
C
epheid announced that it received FDA
clearance to market Xpert vanA, the
first rapid and accurate test released to de-
tect vanA, the antimicrobial resistance gene
commonly associated with vancomycin-
resistant enterococci. One of the most seri-
ous healthcare-associated infections (HAI),
vancomycin-resistant enterococci are very
difficult to treat because fewer antibiotics
are effective against the bacteria. The 45-
minute test runs on Cepheids GeneXpert
System and is the fifth test for HAIs from
Cepheid to receive FDA clearance.
INDEX TO ADVERTISERS
Please visit these websites to learn more
about the products in this issue.
Beckman Coulter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2, 16
www.beckmancoulter.com/tls
The Drucker Company . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
www.qbcdiagnostics.com
Kamiya Biomedical Company . . . . . . . . . . . . . . . . . . . . . . . . . . 3, 12, 14
www.kamiyabiomedical.com
Nova Biomedical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
www.novabiomedical.com
Wako Diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
www.wakodiagnostics.com
NEWS
FROM THE
FDA
For abstract specications and the electronic abstract submission form,
visit: http://www.aacc.org/events/meetings
23rd International Symposium
5eptember 22-25, 2010 * Marrictt 0cpIey PIace hcteI * 8cstcn, MA, u5A
New Directions in Point-of-Care and Critical Care Testing:
Innovation, Controversies, and Partnerships
Call For Abstracts
and the CPOCT present
Abstract Submission Deadline: May 1, 2010
Abstracts are invited in the following
categories:
Integrating POCT into Patient Care Pathways
and Patient Outcomes
Microbiology and Infectious Disease Testing
Innovation and New Technologies
Point-of-Care Partnerships
Controversies in POC and Critical Care Testing
Award for Best Abstracts
The CPOCT Division will award two travel
grants of $500 each for best abstracts. One of
the listed authors must attend the meeting.
Oral Presentations
8-10 abstracts will be selected for oral
presentation during the symposium.
Publication of Proceedings
Accepted abstracts and meeting proceedings
will be published in Point of Care: The Journal
of Near-Patient Testing & Technology.
Poster Session
Posters of accepted abstracts will be
displayed throughout the symposium.
1850 K Street, Suite 625, Washington, DC 20006-2213 Email: custserv@aacc.org Web: http://www.aacc.org
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