clinical genetic cancer testing laboratory news · genetic cancer testing genetic testing plays an...

Public Still Wary of Genetic cancer teStinGGenetic testing plays an integral role in the diagnosis and treatment of cancers caused by inherited mutations. However, 34% of the respondents to a new national poll said they would not seek genetic testing to predict their likelihood of developing a hereditary cancer—even if cost were not an issue.

Conducted by the University of Utah’s Huntsman Cancer Institute, the poll sought to measure public perception about cancer prevention, treatment, and research by surveying 1,202 adults nationwide between the ages of 25–70. One of its key findings was that mistaken beliefs about genetic screening are the main reason why people would choose to forego testing.

Of the respondents who said they would not seek testing, nearly 40% reported concerns that the results would reduce opportunities for employment, while 69% feared the results would interfere with their ability to get insurance, even though current laws prohibit such discrimination.

The survey also shows that only 35% of respondents would be extremely or very likely to seek aggressive prophylactic or preventive treatment, such as a mastectomy, if they had a family history of cancer and genetic testing indicated a genetic predisposition to cancer.

Public perception of genetic cancer screening is not entirely negative, though. On the upside, 63% of respondents reported being extremely or very likely to follow all recommended screenings if there was a history of cancer in their family. Additionally, 85% stated that, if diagnosed with cancer, they would undergo genetic testing if it could help determine the most effective course of treatment.

Only 8% of respondents had actually had a genetic test, though. In light of the low number of individuals who have undergone genetic testing as well as the widespread concerns about it, the survey authors concluded that significant work is still needed to educate the public about the importance of genetic testing, the information it provides, and who should seek it. CLN

ClinicalLaboratoryNews

news brIefThe auThoriTaTive

source for The clinical laboraTorian

march 2014volume 40, number 3

www.aacc.org

the challenge of Diagnosing encephalitis Can Labs, Aided by New Guidelines, Help Clinicians Choose Tests More Wisely?by Deborah levenson

Though encephalitis still is rare, its incidence both in the United States and internationally is increasing along with a rise in viral diseases like herpes, West Nile disease, Japanese encephalitis virus, and tick-borne encephalitis virus, among

other causes. Even in the face of this growing menace, however, lack of consensus on case definitions, standardized diagnostic approaches, and priorities for research have blocked progress in combatting the disease. As a consequence, the process of diagnosing encephalitis is highly variable among clinicians and institutions, and fraught with inappropriate testing.

In response, the International Encephalitis Consortium (IEC), a multidisciplinary committee begun in 2010, recently issued a comprehensive guideline, which proposes standard definitions and a diagnostic algorithm for evaluating both children and adults with suspected encephalitis worldwide (Clin Infect Dis 2013;57:1114–28). “We anticipate that this algorithm can lead to rational, as opposed to shotgun, testing in cases of suspected encephalitis,” said the guideline’s first author, Arun Venkatesan, MD, PhD, assistant professor of neurology and director of the Encephalitis Center

See big Data, continued on page 6

See encephalitis, continued on page 3

nOnPrOfIT OrG.U.s. POsTAGe

paiDLIberTY, MO

Permit no. 190

Clinical Laboratory NewsThe American Associationfor Clinical Chemistry, Inc.1850 K Street, NW, Suite 625Washington, DC 20006

8 cln’s improving healThcare Through laboraTory meDicine series:

Bath Salts Understanding a Pervasive Designer Drug

12 Regulatory Profiles

13 Industry Profiles

14 Diagnostic Profiles

15 News From the FDA

the rise of big DataTrends and Opportunities for the Labby nancy b. Williams

Even as many doctors struggle to give up their pen and paper charts, some innovators are already shifting healthcare information technology into

warp speed. Researchers, health systems, and other stakeholders are analyzing huge amounts of aggregated information—big data—to elucidate patterns that remained hidden under old data models. Blending biostatistics,

bioinformatics, computer programming, and operational research, big data is expected to transform the process of clinical decision-making. And of course, much of this data will come from laboratory medicine. The promise of big data is taking these growing data repositories—from lab results to claims codes—and analyzing them with improved computer power to strengthen the evidence base across the healthcare spectrum.

Several factors are driving this new data binge. The Health Information Technology for Economic and Clinical Health (HITECH) Act, Affordable Care Act, and other payment reform initiatives provided stimulus for change in recent years. The government is pushing providers to adopt electronic health records (EHRs), while at the same time tying more reimbursement dollars to data on quality of care. Similarly, the cost of care and competition in the healthcare marketplace have made investors more data-driven.

In THIs IssUe

@cln_aacc

facebook.com/ clinlabnews

sTAY COnneCTed

snapshoTPoll Respondents Who Would Not Seek Genetic Testing

Source: The Annual Huntsman Cancer Institute Survey

overall

if family has history

of cancer

if already diagnosed

with cancer15%

37%

34%

MCCORMICK PLACE

CHICAGO, IL • USA

2 0 0 + EDUCATION SESSIONS:

Learn from industry leaders and choose

from an exceptional lineup of topics.

70 0 + EXHIBITORS:

Discover new and innovative products

from every clinical lab discipline.

2 0 , 0 0 0 ATTENDEES:

Make global connections and expand

your professional network.

AACC's Annual Meeting & Clinical Lab Expo is the perfect

blend of industry-leading content and the latest technology

trends. Experience the future of laboratory medicine.

Registration opens in April.

Visit www.aacc.org/2014am for more details.

MARCH 2014 Clinical Laboratory News 3

at Johns Hopkins University in Baltimore.Noting that clinicians’ desperation to help

critically ill patients drives inappropriate use of many tests, the guideline’s senior author, Carol Glaser, MD, said the document can augment the role of laboratorians, who are often “the voice of reason” tasked with advising physicians about suitable assays for encephalitis patients. Glaser is chief of the Encephalitis and Special Investigations Section of the California Department of Public Health (CDPH) and former principal investigator of the California Encephalitis Project, a partnership between CDPH and the U.S. Centers for Disease Control and Prevention (CDC).

Encephalitis, the guideline notes, remains steeped in mystery, its causes ill-defined and progress unpredictable. A plethora of viruses, bacteria, and autoimmune diseases can lead to brain inflammation, but more than half the time, the precise culprit remains unknown. Symptoms of encephalitis range from fever, headache, and confusion to seizures, severe weakness, and even language disability. The condition takes a disproportionate toll on the very young and elderly, who often are among the sickest patients, languishing for months in intensive care units. Clinicians become desperate to keep these very ill patients from joining the ranks of severely disabled encephalitis survivors, or worse, the disturbingly large proportion who die from the condition.

A Comprehensive ReferenceThe guideline is notable not only for its wide scope and intended ease of use but also for the new recommendations it makes, said Glaser. Other encephalitis guidelines have made similar recommendations, but targeted specific types of infections or age groups, she added. Glaser, who worked on previous encephalitis guidelines issued by the Infectious Diseases Society of America, noted that they were also quite comprehensive, but “were too unwieldy to use at the bedside.” In contrast, the IEC guidelines include an algorithm the authors hope will make them more useful to clinicians.

The algorithm in question lists routine studies and tests that should be performed on all suspected encephalitis patients, as well as conditional studies based on host and geographic factors, season and exposure, specific signs and symptoms, and both laboratory and neuroimaging features (See chart, p. 4). The guideline also specifies which tests are appropriate for children, and which should be used in adults only.

This stratified approach of performing a clutch of routine tests plus conditional studies—based on patient-specific circumstances—is a pragmatic approach to the diagnostic work-up of encephalitis, given that many of the recommended tests use precious cerebral spinal fluid (CSF), said James Sejvar, MD, a neuroepidemiologist in the Division of High Consequence Pathogens and Pathology at CDC’s National Center for Emerging and Zoonotic Infectious Diseases in Atlanta. “You can’t get much CSF, so you have to be selective about how you use it,” he explained.

Another strength of the IEC document is its inclusiveness. In contrast to previous recommendations for diagnosing encephalitis which came from individuals or institutions, this guideline was written as a consensus by 23 authors representing multiple medical specialties, countries, and institutions, Sejvar pointed out.

The guideline also sets out specific criteria for distinguishing encephalitis from encephalopathy, terms often used interchangeably in the medical literature because of their overlapping sets of symptoms. But the IEC document clearly

defines the two conditions, noting that encephalopathy refers to any dysfunction of the brain, which can be caused by many different conditions, including encephalitis. In contrast, encephalitis refers specifically to brain inflammation as confirmed via histopathology or on the basis of selected clinical, laboratory, electroencephalographic, and neuroimaging features. The distinction is important, noted Sejvar. “In various scenarios, people define encephalitis differently, and this makes it difficult to compare studies and draw conclusions about the disease,” he explained.

The IEC guideline newly suggests three studies as routine, said Glaser. These include enterovirus polymerase chain reaction (PCR), oligoclonal bands, and immunoglobulin G (IgG) index in CSF. Enteroviruses are RNA viruses that typically replicate in the gastrointestinal tract. The viruses can spread to other organs, including the brain, causing severe encephalitis. A positive result on PCR indicates the presence of viral nucleic acid. The presence of oligoclonal bands in CSF, combined with

See Encephalitis, continued on page 4

Routine Test Results Drive Recommended Conditional StudiesEncephalitis, continued from page 1

GMP/GLP

Cerilliant Quality

ISO GUIDE 34

ISO/IEC 17025

ISO 13485

Cerilliant Quality

ISO GUIDE 34

ISO/IEC 17025

ISO 13485

ISO 9001

Cerilliant Quality

ISO GUIDE 34

ISO/IEC 17025

ISO 13485

ISO 9001

GMP/GLP

ISO 9001

GMP/GLP

© 2014 Cerilliant Corporation CLN 03/14

800/848-7837 USA or CANADA 512/238-9974 INTERNATIONAL Cerilliant.com

Cerilliant – when results matter.

Cerilliant Certifi ed Spiking Solutions® - critical raw materials forpreparation of controls and calibrators.

Helping laboratories improve clinical testing accuracy.Sa

Sarah AijazANALYTICAL OPERATIONS

Compliant to ISO 17511 & 15194

4 Clinical Laboratory News march 2014

Clinical LaboratoryNews

Editorial Staff

managing Editor—Bill Malone Senior Editor—Genna Rollins communications coordinator —Christine DeLongcontributors—Jeffery Moran, PhD, and Kathryn Seely, PhDBu

BuSinESS Staff

manager of Business & Publications marketing—Camille Walker

Board of EditorS

chair—Lorin M. Bachmann, PhD, DABCC VCU Health System, Richmond, Va. members—Joshua Bornhorst, PhD University of Arkansas, Little Rock, Ark.Andrew Don-Wauchope, MD Juravinski Hospital and Cancer Center, Hamilton, OntarioElizabeth Palavecino, MD Wake Forest Baptist Medical Center, Winston-Salem, N.C.Steven Goss, PhD Siemens Healthcare Diagnostics, Newark, Del.Pamela Steele, PhD Covance, Inc., Indianapolis, Ind.

aacc officErS

President—Steven H. Wong, PhD, DABCC, FACBPresident-Elect—David Koch, PhD, DABCC, FACBtreasurer—Michael J. Bennett, PhD, DABCC, FACBSecretary—David Grenache, PhD, DABCC, FACBPast President—Robert H. Christenson, PhD, DABCC, FACB

advErtiSing SalES

Cunningham Associates 180 Old Tappan Rd., Old Tappan, NJ 07675 Phone: (201) 767-4170 Fax: (201) 767-8065 E-mail: [email protected] www.cunninghamassociates.com President—Jim Cunningham Senior vice President—James G. Pattisnational accounts manager— Charlie Meitner traffic manager—Kathy Tamalonis

SuBScriPtionS

American Association for Clinical Chemistry, Inc. 1850 K Street, NW, Suite 625 Washington, DC 20006 Phone: (202) 857-0717 or (800) 892-1400 Fax: (202) 887-5093 E-mail: [email protected] to Clinical Laboratory News are free to qualified laboratory professionals in the United States. AACC members outside the U.S. pay $90 for postage. The subscription price for those who do not qualify for a free subscription is $90/year in the U.S. and $130/year outside the U.S. For more information, contact the AACC Customer Service Depart-ment at (800) 892-1400 or (202) 857-0717 or [email protected].

Editorial corrESPondEncE

Bill Malone, Managing Editor Clinical Laboratory News 1850 K Street, NW, Suite 625 Washington, DC 20006 Phone: (202) 835-8756 or (800) 892-1400 Fax: (202) 833-4568 E-mail: [email protected]

Contents copyright © 2014 by the American Association for Clinical Chemistry, Inc., except as noted. Printed in the U.S.A.

Clinical Laboratory News (ISSN 0161-9640) is the authoritative source for timely analysis of issues and trends affecting clinical laboratories, clinical laboratorians, and the practice of clinical laboratory science.

@cln_aacc

their absence in blood serum, can also mean that immunoglobulins are produced in the central nervous system. Neurologists on the IEC panel suggested these tests, Glaser noted.

A Role for LaboratoriansLaboratorians can help clinicians implement the guidelines by advising them on how to better use and interpret results of recommended assays. This is particularly true with PCR assays, which often produce false-positive or false-negative results, guideline authors told CLN. False-negatives can occur in the presence of inhibitory substances that interfere with the PCR reaction, low viral load, or insufficient amounts of the target in patient samples, Glaser explained. False-positives can enter the picture from contamination

in the laboratory, coincidental detection of the agent in question when it isn’t the cause of the current infection, or from pushing a PCR protocol beyond its limits of detection. The latter can result in amplification of spurious products such as fragments of human DNA instead of the intended target, Glaser noted.

Clinicians, Glaser and others said, often rely too heavily on PCR to diagnose causes of encephalitis, without realizing its limitations. “Molecular tools are wonderful, but you have to know how to use them,” Glaser said.

Despite the challenges presented by PCR, the guideline recommends PCR tests for herpes simplex virus (HSV) and varicella-zoster virus (VZV), all the while cautioning about its pitfalls and the need

for additional testing. For example, PCR for HSV can be negative early in the course of the disease. Because of this, the IEC panel recommended repeating this test with a new CSF sample from a second puncture within 3–7 days if the initial results are negative and the clinician still suspects herpes encephalitis. Many clinicians rely too much on a single CSF sample, according to Glaser. “If the diagnosis still is unknown a few days after the first CSF was obtained, a second sample might be quite helpful, particularly for re-checking herpes PCR.”

Laboratorians can also remind clinicians that PCR testing should be augmented with other assays. This is the case when testing for VZV, a leading cause of encephalitis. The guideline calls for both PCR and antibody testing for VZV because detection of

PCR-Based Tests Crucial but Pose ChallengesEncephalitis, continued from page 3

Encephalitis-related testing routine lab Studies

ADULTS

cSf ✔ Opening pressure, WBC count with differential,

RBC count, protein, glucose

✔ Gram stain and bacterial culture

✔ HSV-1/2 PCR (if test available, consider HSV CSF IgG and IgM)

✔ VZV PCR (sensitivity may be low; if test available, consider VZV CSF IgG and IgM)

✔ Enterovirus PCR

✔ Cryptococcal antigen and/or India Ink staining

✔ Oligoclonal bands and IgG index

✔ VDRL

Serum ✔ Routine blood cultures

✔ HIV serology (consider RNA)

✔ Treponemal testing (RPR, specific treponemal test)

✔ Hold acute serum and collect convalescent serum 10–14 days later for paired antibody testing

other tissues/fluids

With involvement outside of the central nervous system, including clinical features involving skin and lungs, or upper respiratory illness or diarrhea, additional testing is recommended.*

lab features Suggesting need for further testing ✔ Elevated transaminases—Rickettsia serology, tick

borne diseases testing

✔ CSF protein >100 mg/dL, or CSF glucose <2/3 peripheral glucose, or lymphocytic pleocytosis with subacute symptom onset—MTB testing, fungal testing

✔ CSF protein >100 mg/dL or CSF glucose <2/3 peripheral glucose and neutrophilic predominance with acute symptom onset and recent antibiotic use—CSF PCR for S. pneumoniae and N. meningiditis

✔ CSF eosinophilia—MTB testing; fungal testing; Baylisascaris procyonis antibody (serum); Angiostrongylus cantonensis and Gnathostoma sp. testing

✔ RBCs in CSF—Naegleria fowleri testing

✔ Hyponatremia—anti-VGKC antibody (serum); MTB testing

*Refer to guidelines for specific instructions

CHILDREN

cSf ✔ Opening pressure, WBC count with differential, RBC

count, protein, glucose

✔ Gram stain and bacterial culture

✔ HSV-1/2 PCR (if test available, consider HSV CSF IgG and IgM)

✔ Enterovirus PCR

Serum ✔ Routine blood cultures

✔ EBV serology (VCA IgG and IgM and EBNA IgG)

✔ Mycoplasma pneumoniae IgM and IgG

✔ Hold acute serum and collect convalescent serum 10–14 days later for paired antibody testing

other tissues/fluids ✔ Mycoplasma pneumoniae PCR from throat sample

✔ Enterovirus PCR and/or culture of throat and stool

With involvement outside of the central nervous system, including clinical features involving skin and lungs, or upper respiratory illness or diarrhea, additional testing is recommended.*

lab features Suggesting need for further testing* ✔ If EBV serology is suggestive of acute infection,

perform EBV PCR (CSF)

✔ Elevated transaminases—Rickettsia serology, tick borne diseases testing

✔ CSF protein >100 mg/dL, or CSF glucose <2/3 peripheral glucose, or lymphocytic pleocytosis with subacute symptom onset—MTB testing, fungal testing, Balamuthia mandrillaris testing

✔ CSF protein >100 mg/dL or CSF glucose <2/3 peripheral glucose and neutrophilic predominance with acute symptom onset and recent antibiotic use—CSF PCR for S. pneumoniae and N. meningiditis

✔ CSF eosinophilia—MTB testing; fungal testing; Baylisascaris procyonis antibody (serum and CSF); Angiostrongylus cantonensis, Gnathostoma sp. testing

✔ Hyponatremia—MTB testing

✔ Mycoplasma pneumoniae serology or throat PCR positive—Mycoplasma pneumoniae PCR (CSF)

*Refer to guidelines for specific instructions

Legend: CSF, cerebral spinal fluid; EBV, Epstein-Barr virus; EBNA, Epstein-Barr virus nuclear antigen; HSV-1/2, herpes simplex virus; IgG, immunoglobulin G; IgM, immunoglobulin M; MTB, Mycobacterium tuberculosis; PCR, polymerase chain reaction; RBC, red blood cell; RPR, rapid plasma regain; VCA, viral capsid antigen; VDRL, Venereal Disease Research Laboratory; VGKC, voltage-gated potassium channel; VZV, varicella-zoster virus; WBC, white blood cell;

Source: Venkatesan et al. Clin Infect Dis 2013;57:1114–28.

march 2014 Clinical Laboratory News 5

antibodies to VZV in CSF appears to have greater sensitivity than detection of viral DNA, Venkatesan explained. “The same can be said of arboviruses such as West Nile virus, where the virus is often not detectable by PCR in the serum or spinal fluid once symptoms of encephalitis have developed,” he added. “Thus, antibody testing is crucial in such situations.”

Serology: No Silver BulletAs important as serology-based testing for antibodies is in the work-up of suspected encephalitis, it also presents challenges to labs and requires caution, noted both Venkatesan and Sejvar. “The message to labs is that for certain agents, initial serological results may require more specific follow-up tests,” said Sejvar. This is particularly true for arboviruses such as West Nile virus, which can cross-react with antigens from other arboviruses. Additional analysis such as plaque reduction neutralization testing can improve specificity, according to Venkatesan. In the case of mycoplasma, because it is a ubiquitous agent associated with a substantial baseline infection rate, a positive immunoglobulin M (IgM) test may simply indicate concurrent respiratory infection rather than implicating mycoplasma as a cause of encephalitis. “West Nile virus IgM can persist for many months after infection, and therefore a positive result does not necessarily indicate active West Nile infection,” explained Venkatesan.

The pitfalls of serology are aptly illustrated in tests for Lyme disease, according to Sejvar. He noted that although the guideline does not specifically address the disorder, encephalitis caused by the culprit bacterium, Borrelia burgdorferi, is a particular concern in some areas of the U.S. CDC recommends that if an enzyme-linked immunosorbent assay (ELISA) yields a positive result, it should be confirmed with serology by Western blot analysis to avoid inappropriate, long-term treatment, Sejvar emphasized.

Another issue with Lyme disease testing “is interpreting a positive test as meaning active disease,” said Stephen Gluckman, MD, medical director of Penn Global Medicine and professor of medicine at the Perlman School of Medicine at the University of Pennsylvania in Philadelphia. “These antibodies could have been present for years.”

The guideline also recommends corresponding CSF and serum testing for human herpes virus 6 in patients with prominent memory, learning, and emotional symptoms. Research by IEC panelist Katherine Ward has shown that roughly 1% of people worldwide carry the virus in their genomes, but that its levels in CSF due to primary infection differ from those present because of integration of the virus into chromosomes (J Clin Microbiol 2007;45:1298–304). However, latent disease may also confound results, according to the IEC document.

The authors also call for testing anti-N-methyl-D-aspartate receptor (NMDAR) in CSF if a serum test is negative and there is still clinical suspicion for this entity, Venkatesan noted. While anti-NMDAR

receptor encephalitis is typically diagnosed by clinical symptoms and a positive antibody in the serum, “recent literature suggests that in up to 15 percent of individuals, the antibody may only be present in the CSF and not in the serum,” he explained.

Rabies testing, which the guidelines suggest for patients who have had animal bites, is often riddled with confusion, Glaser observed. “This test should be done only at a public health lab because it entails a lot of nuance,” she said, explaining that rabies tests done at commercial labs don’t diagnose human rabies. Rather, they determine whether a patient who had a rabies vaccine is immune to the virus, a point lost too often in clinical practice, according to Glaser. “I see samples inappropriately sent to commercial labs for rabies testing all the time.”

Gluckman, who did not serve on the IEC panel, cautioned about placing too much stock in any one test result for encephalitis. “There’s no perfect test,” he said. “There are false-positives and false-negatives for every test. You still need to look at patients and decide if the data make sense. Diagnosis requires thinking.”

Too Much? Not Enough?While the IEC guideline is intended to reduce unnecessary testing, Gluckman disagreed with the breadth and scope of the more than 25 tests and studies recommended as routine by the algorithm. Noting that he usually first tests suspected encephalitis patients for herpes, varicella, and HIV, and depending on the season, arboviruses such as West Nile and enteroviruses, Gluckman said that rather than automatically ordering all the studies the IEC guideline lists as routine, he would look to the document when first-line tests fail to pinpoint a cause. “Clinical skills and judgment should temper testing,” he suggested. Still Gluckman said he found the guideline to be a very useful, comprehensive compendium of information about identifying known causes of encephalitis. “This is a great resource listing all the tests you might consider,” he added.

It might be acceptable to skip some tests if clinical evidence points strongly to a specific cause, Glaser agreed. “If a clinician is pretty sure it’s herpes, for example, he could go for that and hold other tests in reserve. But if there’s no big clue, really he should go for all of the routine tests,” she explained, noting that sometimes, one test may indicate the need for another. For example, she said, imaging results sometimes drive herpes testing.

The number of recommended routine tests isn’t particularly large compared to what Glaser, an infectious disease specialist who previously served as the medical officer for CDPH labs, has seen many physicians order. “It’s puny compared to what some patients get,” added Glaser, recalling that she commonly saw clinicians order as many as 50 tests for an individual patient. “So this list isn’t over the top at all.”

Glaser was careful not to fault clinicians for inappropriate testing decisions. If they order a battery of tests that turn out to be unnecessary, it’s only because they’re

in a race to diagnose and treat sometimes desperately ill patients, she suggested.

Looking to the FutureAs the epidemiology of encephalitis changes, research yields new causes, and testing modalities change, so will the algorithm, Venkatesan said. “We view the published algorithm as a starting point,” he explained, adding that the IEC is now developing a living version of this algorithm that it plans to update and make available online as new information regarding encephalitis emerges.

In light of the changing clinical and scientific picture of encephalitis, the authors also proposed research priorities, including a better understanding of genetic risk factors for the disease which one day might explain pathogenic mechanisms, define relevant biomarkers, and suggest potential therapeutic approaches. Researchers also need a more complete view of several leading causes of encephalitis such as arboviruses, Japanese encephalitis virus, tick-borne encephalitis virus, and tick-transmitted Powassan virus, among others.

While this research might identify new

roles for laboratorians in the future, for now, they can make an important contribution to the field by familiarizing themselves with the IEC document, said Glaser. “If you see a problem in how tests are ordered, reach out to physicians. Help them by suggesting more appropriate tests,” she suggested.

In those institutions that regularly include laboratorians in patient rounds, that advice can be offered at the bedside, along with information about quality of tests, the best samples to use, and how to store them, said Gluckman, who sees hospitalized patients along with both a laboratorian and pharmacist. “It’s amazing how helpful laboratorians are,” he said. “They can talk about the quality of tests, and give useful information about how to best obtain and store samples.” CLN

Deborah Levenson is a freelance writer who lives in College Park, Md. Her email address is [email protected]

Suitable for most chemistry analyzers such as Cobas ®,Roche/Hitachi, Beckman Synchron ®, Olympus, etc.

** For Research Use Only. Not for use in diagnostic procedures in the U.S.

Lipid Assessment Apolipoprotein AI Apolipoprotein AII ** Apolipoprotein B Apolipoprotein CII ** Apolipoprotein CIII ** Apolipoprotein E ** Lipoprotein(a)

Coagulation Anti-Thrombin III D-Dimer Factor XIII ** FDP ** FDP-E ** Fibrinogen Plasminogen

Nutritional Status Ferritin Prealbumin Transferrin

Anemia Ferritin

Allergy Total IgE

Inflammation / Cardiac Anti-Streptolysin O Complement C3 & C4 C-Reactive Protein High-Sensitive CRP Wide-Range CRP Ferritin Fibrinogen Microalbumin Rheumatoid Factor

Diabetes / Stroke Alpha-1 Microglobulin Fructosamine Hemoglobin A1c Insulin Microalbumin

Serum Proteins Alpha-1 Acid Glycoprotein Alpha-1 Anti-Trypsin Alpha-1 Microglobulin Haptoglobin IgA, IgG, IgM Transferrin

Kidney Function Cystatin C

Immunoassay Reagentsfor Chemistry Analyzers™

The Assay You Can Trust...K-ASSAY ®

KAMIYA BIOMEDICAL COMPANY12779 Gateway Drive, Seattle, WA 98168800-526-4925 206-575-8068 FAX: 206-575-8094

www.k-assay.com

2011.09 CLN Immunoassay.indd 1 8/5/2011 5:05:28 PM

6 Clinical Laboratory News MARCH 2014

Finally, as genome sequencing drops in cost and rises in speed, everyone’s universe of information is expanding. “The idea of having 1,000 nodes was pretty sexy five to 10 years ago, but it’s kind of a commodity in 2014,” said Christopher Chute, MD, DrPH, section head of medical informatics at Mayo Clinic in Rochester, Minn. “There’s really no limit to the scale of the computational approach when you invoke these big data principles.”

Challenges for the LabAs digitization of healthcare information takes hold through EHRs, providers who seek to leverage their growing data warehouses will also have to deal with issues of access—such as patient privacy and intellectual property—as well as standardization and interoperability. This will require attention and new thinking, according to experts, even as some organizations move ahead quickly with big data projects (See Sidebar, right).

“If data is the new gold, then access to data is going to be key to insights,” explained Viktor Mayer-Schönberger, professor of internet governance and regulation at the University of Oxford in England and co-author, with Kenneth Cukier, of Big Data: A Revolution That Will Transform How We Live, Work, and Think. “On the one hand this may lead to a more protective approach, sharing as little data as possible so that others don’t get to reap the value of one’s data,” Mayer-Schönberger said. “On the other hand, many data holders in the future may not be able to see all the potential reuses of the data they have for novel purposes, and thus let others have access to it, perhaps against a license fee.”

Mayer-Schönberger on July 28 will deliver a plenary address at the 2014 AACC Annual Meeting and Clinical Lab Expo in Chicago, “Understanding Big Data and Its Impact on Your Laboratory.”

Labs will have an essential role in making sure that data is standardized and interoperable if big data is to fulfill its promises. “The naming of things is quite central to the secondary use of data—quality

improvement research, inclusion of patients in clinical trials, and so on,” said Chute, who is principal investigator for the Office of National Coordinator-funded SHARP

grant on secondary data use. The problem of using secondary data for reasons other than immediate patient care has been a long-standing priority of Mayo Clinic, he noted, and now the organization uses a system of data governance.

Inconsistent naming can thwart healthcare analyses, Chute emphasized. “To the degree possible, your analytic efficiency is going to be vastly improved and clarified, and made more focused and resolute, by invoking two things: compatibility and consistency.” For labs, a big part of this name game is using Logical Observation Identifiers Names and Codes (LOINC), a database and universal standard for identifying lab results.

Labs must use LOINC in electronic messages to pass the government’s EHR meaningful use standards, but most don’t yet use these codes internally, Chute noted. Instead of creating idiosyncratic identifiers, labs should use the standard even in the internal coding environment for operations, he stressed.

“Interoperability, in my mind, comes down to these naming issues,” Chute explained. “If you’re going to bring in a new laboratory information system, are you going to populate it with your old laboratory codes? That would make it interoperable with your own historical data, but not with anybody else’s. Do you treat that as an opportunity to migrate the enterprise…

Insights Depend on Lab StandardizationBig Data, continued from page 1

NEXT MONTH IN CLN

Testing for the Spectrum of Gluten Sensitivity

Frontline Forays Provider Organizations Spending Big Money on Big Data

Although the front runners in big data tend to be large health systems and corporations, the big data paradigm will soon be felt even in smaller organizations. The research firm Frost & Sullivan predicts that use of advanced health data analytics solutions in hospitals will increase to 50% adoption by 2016. Networks and other computing infrastructure are becoming commodity products that can reap profits as cloud-based hosted services. In fact, 45% percent of hospitals now have clinical data warehouse applications, as executives seek to get the most out of the money hospitals are pouring into their EHRs, according to a 2013 report from HIMSS Analytics.

With all this activity, big data has a somewhat fluid and flexible meaning in healthcare, explained Michael Hogarth, MD, professor of pathology and internal medicine at UC Davis and medical director of Clinical Registries for UC Davis Health System. “It can mean large volumes of data, complex data, or real-time data supporting actionable information. In healthcare today, it is primarily about integration of complex data coming from multiple source systems in order to support improved healthcare delivery—care that is safer, less costly, and patient centered.”

Organizations interested in using big data analytics require both access to computing power and knowledgeable staff to work the data. The first inroads are being made by top-tier and larger healthcare institutions that have invested hundreds of millions of dollars in analytics capabilities.

The largest managed care organization in the United States, Kaiser Permanente, was reported to have the largest clinical data repository in the world, an enterprise-wide electronic health record (EHR) system for nearly nine million patients. Today, Kaiser’s computer system and use of EHRs allows data exchange among all its medical facilities. An April 2013 report by consulting firm McKinsey & Company estimated that Kaiser Permanente’s big data strategy has saved the organization $1 billion in reduced office visits and lab testing.

At the University of Pittsburgh Medical Center, an enterprise data warehouse launched in 2012 is housing more than 200 sources of information, including clinical, genomic, proteomic, imaging, and finance data from across its health system and outside entities, including labs and pharmacies. Its first test of the new $100 million analytics system in 2013 examined integrated clinical and genomic information from

140 breast cancer patients, with follow-up research ongoing. Flagging patients at risk for kidney failure based on subtle changes in lab results is another target.

In New York City, Mount Sinai Hospital is also investing in big data. In April 2013, this venerable institution finished building its own $3 million supercomputer, named Minerva after the Roman goddess of wisdom and medicine, and hired over 100 data scientists. Mount Sinai’s big data team includes laboratory experts in genomics to help doctors make personalized predictions about patients. The aim is to learn to predict risk more precisely, for example, by reclassifying diabetics or identifying patients likely to be readmitted.

“With Minerva, Mount Sinai has the ability to quickly analyze genomic patterns to provide a greater understanding of the causes of disease and how to personalize treatments according to an individual’s genetic composition,” said Dennis Charney, MD, dean of the Icahn School of Medicine at Mount Sinai in a statement. “The supercomputer is able to accomplish real-time visualization of advanced molecular models, promoting drug development and allowing us to test the effects of molecular variations on different receptors in the body.”

In a research project involving primary care practices with an EHR system, Sutter Health in California and Geisinger Health System in Pennsylvania are working with IBM on new data analytics tools, under a $2 million grant from the National Institutes of Health. The initial focus is using data in the EHR to improve early detection of heart failure. The project aims to identify best practices that help health systems integrate big data analytics into primary care for more tailored disease management.

Big data has plenty of opportunities to keep growing. Experts say that healthcare organizations are motivated to improve patient safety by reducing hospital-acquired infections, for example, and to monitor patients beyond the healthcare setting, such as looking for signs of depression after a cancer diagnosis. As more hospitals and physician offices embrace EHRs, burgeoning health information exchanges want to compare how member providers, such as diabetes care clinics, manage large groups of patients. Similarly, public health officials see an opportunity to improve their monitoring of population health.

48089 Fremont Boulevard, Fremont, CA 94538 877.869.2320

[email protected]

ARK introduces its homogeneous enzyme immunoassay for methotrexate.

Liquid, stable, ready-to-use formulations deliver convenience for routine use.

ARK produces assays of choice – high-quality, rapid and reliable – for precise results on automated clinical chemistry analyzers.

Call or email today.

Also available, AED assays:

Levetiracetam Topiramate Zonisamide Lamotrigine Gabapentin

Assays for the Next Generation

Methotrexate AssayTM

Now Available FDA Cleared

MARCH 2014 Clinical Laboratory News 7

to using a national or international standard for laboratory data, which would solve a lot of headaches?”

Navigating a Paradigm ShiftIn their book, Mayer-Schönberger and Cukier note that big data analytics can extract transformative insights that have the power to overturn established practices. The findings of big data research and analytics can run up against conventional ways physicians make decisions and interpret information.

Laboratorians may find themselves on the forefront of these shifts, helping clinicians cope with change. “Labs will churn out more data,” said Mayer-Schönberger. “They won’t necessarily grow larger, but they will produce vastly more data—and this requires more resources to store and analyze the data, plus new expertise in what tools to use to do this. In some sense the natural sciences, more generally, and labs, in particular, will become a bit more like cutting-edge social sciences—with a strong emphasis on the ability to make sense of the data.”

Clinical laboratorians can participate and contribute leadership as healthcare harnesses big data. In the view of one expert, laboratorians should seek a data collaboration role as much as expecting to deal with large data sets. “This has been part of the laboratory tradition—to exchange data with EHRs—but what we have done in the past revolves almost exclusively around provisioning data for a specific transactional clinical workflow, such as lab ordering or results delivery,” said Michael Hogarth, MD. “What I mean by data collaboration—as a philosophy to support integrated multidimensional data—is not something anyone has really done in healthcare, regardless of being in the lab or elsewhere. To support the population-based analytics needed to characterize how we deliver care, and thus work to improve that, will require that those who have source systems can provide data to an aggregated data set in a timely fashion, with high data fidelity, and perhaps to transform some of the data in the process.” Hogarth is professor of pathology and internal medicine at UC Davis and Medical Director of Clinical Registries for UC Davis Health System.

Pushing the Envelope in Genomic MedicineIn genomics, the limits of how genomic data can be used are really the limits of bioinformatics. Perhaps no other discipline, in fact, will depend on rapid advances in computing power to harness the full power of raw, biomedical data. For example, the importance of genomic variants needs to be learned before medical care can advance, said Eric Green, MD, PhD, director of the National Human Genome Research Institute.

With sharp declines in the cost of next-generation DNA sequencing technologies, demand for genomic-guided care is rising. Laboratorians will help make the massive amounts of genome sequencing data on each single patient easy for physicians to employ in clinical decision-making. “You only want to know about the relevant genomic variants. You want it to be a

quick lookup, maybe with alert values. Already, that’s happening in some places for pharmacogenomics,” said Green.

At l ead ing-edge ins t i tut ions such as the Mayo Clinic Center for Individualized Medicine, laboratorians and bioinformaticians collaborate as part of teams to integrate DNA information into patient care. “Pathologists are absolutely at the table, as they often are, when it comes to the ability to take lots of data and interpret it,” Green noted. “They will be at the table, with others, helping to determine what is relevant and what is not. In particular, anatomic pathologists will be deep in this on cancer, since routine cancer diagnostics will soon have a major genomics component. It already does for some kinds of cancer.”

In the case of clinical laboratories, these innovations mean laboratorians need to become more comfortable with big data terms and technologies. “Everybody’s threshold of big data is different, but they’re going to have to get used to looking at a lot of data about genomes of patients,” Green said. “The next generation will have genomic information as a routine part of medical care. Every patient will present with hundreds and hundreds of genomic variants, and healthcare providers will need to know which of those are relevant. Hopefully, we’ll have in place systems that streamline that information and give them recommendations: how that changes what medications they should get, how they should be treated for different disorders, and so forth,” said Green.

Clinicians must learn to work with big data, too—with help from the lab and others. “We need total experts, but then, we need everyone to have their game up a little bit,” said Green. “We need everybody to be facile—not experts, just very comfortable. That’s the next-generation physician, next-generation biomedical researcher. Even if they are not a data science expert, they need to have minimum competencies.” Midcareer professionals who are in practice right now also need training, said Green: “Since the time they were in school, the world has changed with respect to big data. They haven’t gotten these credentials. How do we train individuals who still have 20 to 30 years of their careers left?” The National Institutes of Health (NIH) is already thinking about how to tackle the training necessary for these jobs, Green added. And other healthcare organizations can do likewise.

Labs should get ready, too, for big data experts—quants—to join lab researchers and work with them, counseled Mayer-Schönberger. Quants will play “integral if not key roles in research. They will come from far afield, with little substantive knowledge initially, but still be able to be valuable contributors because of their data skills.”

A Federal and Global PushDespite the huge leaps made during just the past few decades in computing power and biomedical knowledge, big data is just getting started. NIH and other organizations and experts worldwide are serious about moving forward.

For starters, NIH made the world’s largest set of data on human genetic variation,

produced under the 1000 Genomes Project, freely available on the Amazon Web Services cloud. Cloud-based collaborations such as this let researchers use data at a fraction of the cost an institution would spend to acquire the needed internet bandwidth, data storage, and computing capacity. Development of a unified clinical genomics database (ClinGen) is another data-sharing collaboration ultimately meant to advance medicine. The Centers for Medicare and Medicaid Services, Centers for Disease Control and Prevention, and Food and Drug Administration also are making more data available.

In June 2013, a global alliance to enable responsible sharing of genomic and clinical data was announced. Influential sequence-data holders—including NIH, the Wellcome Trust Sanger Institute of Hinxton, England, and BGI-Shenzhen of China—pledged to be members, as did nearly 70 healthcare, research, and patient advocacy organizations in 13 countries. They’re not necessarily agreeing to share their data. The alliance is interested in setting interoperable standards and policies on ethics, privacy, and technical issues related to aggregating and sharing data.

According to Mayer-Schönberger, laboratory professionals can be champions of the coming improvements to healthcare stemming from big data. “To realize what is in the offing, it’s helpful to realize that most of the methods, the processes, the institutions that we currently use to collect data and eventually produce knowledge are artifacts of small data thinking, of the need to squeeze the most value out of the least data, but only for one purpose and then throw it away,” Mayer-Schönberger commented. “As the constraints in collecting, storing, and analyzing vastly more data are greatly diminished, we need to rethink everything, including the very foundations of how we organize and conduct research. Because labs have long worked with data, lab experts intuitively understand the power of data—and when they realize the power of big data, they can become natural early champions for this change.” CLN

Nancy B. Williams is a freelance writer in Arlington Heights, Ill. Her email address is [email protected].

Lipoprotein Assays

Immunoassay Re agentsfor Chemistry Analyzers™



www.k-assay.com

For use on most chemistry analyzers including:Abbott Aeroset / Architect , Beckman Synchron & Olympus AU, Horiba ABX Pentra, Mindray, Roche / Hitachi, Roche Cobas, Siemens / Bayer Advia & Dimension, and others.

• Apolipoprotein AI

• Apolipoprotein B

• Lipoprotein(a)

For in vitro diagnostic use.

• Apolipoprotein AII

• Apolipoprotein CII

• Apolipoprotein CIII

• Apolipoprotein E

For research use only. Not for use in diagnostic procedures in the U.S.

> Apo AII> Apo CII

> Apo CIII> Apo E

Laboratory Testing Service Available For:

2013.07 CLN Lipoprotein.indd 1 7/10/2013 1:25:22 PM


Bath SaltsUnderstanding a Pervasive Designer DrugBy Jeffery moran, PhD, anD Kathryn Seely, PhD

Designer drugs continue to make headlines in the U.S. and abroad. In one recent large-scale incident, New York City officials shut down the 2013 Electric Zoo music festival on Labor Day weekend after two concertgoers died and several others were hospitalized from an apparent ecstasy overdose. Investigators later discovered that the usual psychoactive substance found in ecstasy—3,4-methylenedioxy-N-methylamphetamine (MDMA)—had been replaced or combined

with a more potent synthetic designer stimulant known as methylone, one of many substances found in a new breed of stimulant/hallucinogenic designer drugs called bath salts (1). Bath salts are rising in popularity along with a wave of other new designer drugs like synthetic cannabinoids and opioids. Today, 10% of U.S. high school seniors admit to recent use of synthetic cannabinoids (2).

Given the prevalence of and public alarm about designer drugs, clinical laboratories face a formidable challenge in validating testing platforms for bath salts and other emerging drugs. Unfortunately, information gaps and a lack of appropriate analytical reference standards make it difficult for a laboratory to meet stringent accreditation requirements. In this article, we review the complex nomenclature and drug composition encountered with bath salt formulations, along with available pharmacology, pharmacokinetics, and testing information. Together, this information highlights challenges that clinical laboratories face and provides strategies for overcoming these barriers.

CLN’simproviNgheaLthCare through LaboratorymediCiNeseries

What Are Bath Salts?In illicit designer drug markets, bath salts are far removed from the ordinary salt crystals purchased for a relaxing spa. These synthetic drugs are formulated for their potent stimulant and hallucinogenic properties. As might be expected, there is no quality control in the manufacturing of bath salts. Dosages, formulations, and drug mixtures vary from product to product and from batch to batch, and adulterants ranging from caffeine to methamphetamine are common. Adding to the complexity of the problem, bath salts are found under a variety of labels, packaging, and physical formulations, such as a white powder, tablets, or liquid. As a result, users never know exactly what they are about to consume, and an unusual assortment of disingenuous labels like plant food, insect repellant, or even “Vanilla Sky” and “Meow Meow” add further confusion—especially for new drug users, adolescents, and parents.

Bath salts contain several psychoactive substances thought to have stimulant and/or hallucinogenic properties. Bath salts possessing primarily stimulant-like properties are commonly considered phenethylamine or piperazine analogs, which have a similar chemical structure as the well characterized stimulants cathinone, amphetamine, or benzylpiperazine (BZP) (Figure 1). Winstock et al. recently surveyed patrons of night clubs in the U.K. and found that nearly 50% used the cathinone analogs mephedrone and/or methylone (Figure 1) (3). Similar to other studies, the authors tracked for nearly 4 years the prevalence of designer


drugs seized by law enforcement in Arkansas (3, 4). Analysis of 489 items identified the six most common psychoactive drugs as MDPV (methylenedioxypyrovalerone), 4-MEC (4-methyl-N-ethylcathinone), pentedrone (2-(methylamino)-1-phenylpentan-1-one), α-PVP (α-pyrrolidinopentiophenone), BZP, and TFMPP (3-trifluoromethyl-phenylpiperazine). These substances were formulated as powders, tablets, and capsules (Figure 2).

While rare, designer stimulants are also found in plant material and smoked like K2 synthetic cannabinoids. Also, bath salt compounds are commonly found as mixes containing other synthetic drugs or illicit substances, like methamphetamine, ketamine, and MDMA (5). Of the total 489 items analyzed in Figure 2, only 189 (39%) contained a single compound and more than 100 unique drug mixtures were identified. These dangerous drug combinations pose significant clinical and analytical challenges.

Bath salts can also contain potent hallucinogenic drugs biochemically characterized as analogs of mescaline or LSD (Figure 1). Mescaline is a natural hallucinogenic phenethylamine compound found in the peyote cactus (Lophophora williamsii), whereas tryptamine hallucinogens are similar to LSD. Alexander Shulgin is well known for his books PiHKAL and TiHKAL, which provide detailed synthesis procedures and a firsthand account of the pharmacological effects (6, 7). These hallucinogens are also formulated as powders, capsules, and tablets and may be used to lace blotter paper (5). Marketing names vary greatly from “smiles,” “7th-heaven,” and “Foxy” to an abbreviated biochemical name like 2C-B or 2C-E. The LSD analog 25I-NBOMe was the most common hallucinogen detected as part of our 4-year surveillance program in Arkansas, in which 10% of the pills, tablets, capsules, and blotter paper contained 25I-NBOMe (Figure 2).

PharmacologyWhen insufflated, ingested, or injected, bath salts have dire toxicological consequences. In general, these drugs modulate neurotransmitter release and/or neurotransmitter reuptake mechanisms, but the molecular mechanisms underlying human toxicity remain to be determined. The toxicology of the synthetic cathinones and piperazines is similar to MDMA, with most substances inhibiting re-uptake of dopamine and norepinephrine through inhibition of the monoamine uptake transporters. Serotonin levels also may be modulated due to inhibition of reuptake (8–10). On the other hand, the molecular mechanism of tryptamine and phenylethylamine hallucinogenic analogs found in bath salts, such as 5-MeO-DALT and the 2C compounds, are probably mediated through agonistic action at several serotonin receptors and ion channels (11–13).

The physical and neurological effects of bath salts can be extreme, debilitating, and even fatal (15, 18, 19). The toxicodynamics and toxicokinetics of the bath salts are unknown in humans, but animal studies are starting to emerge (14). Clinical reports

demonstrate that the adverse effects of bath salts are similar to other stimulants, like MDMA. For example, multiple case reports indicate tachycardia, agitation, hyperthermia, hypertension (early on presentation), and confusion (15). Symptoms can be extreme, such as myocardial infarction in teens, brain swelling, and renal failure (15). Likewise, the adverse effects of the hallucinogen 25I-NBOMe commonly include tachycardia, agitation, visual and audio hallucinations, hypertension, and seizures (16, 17). In an extreme example, an individual who ingested the hallucinogen 2C-B experienced

progressive encephalopathy and paralysis that did not improve over a 6 month period (18).

The LawIn the United States, most drugs sold as bath salts are listed in Schedule I of the Controlled Substances Act or regulated through analog law provisions (20, 21). Most state and federal analog provisions in the U.S. require structural and pharmacological comparison. Many other countries, particularly throughout Europe, regulate the sale and distribution of bath salts. Unfortunately, the availability of these drugs online and their low cost limit

the effectiveness of regulation. For example, bulk amounts of methylone and 2C-B (500 g) can be purchased online for around $2.50 per 1 gram of pure compound, whereas a normal dose of methylone is 100–250 mg and 2C-B is 15–25 mg (22, 23, 24).

Testing for Bath SaltsSe ver a l cont r ac t and re search testing laboratories have used liquid chromatography/tandem mass spectrometry (LC-MS/MS), gas chromatography/mass spectrometry (GC-MS), and liquid chromatography/time-of-flight mass

Figure 1

chemical structures of common bath salt stimulant and hallucinogenic compounds


spectrometry (LC/TOF-MS) testing platforms to develop qualitative and quantitative testing procedures for assaying bath salts in blood, urine, serum, and plasma (25–27). However, analytical capacity is still limited for several of the phenethylamine and tryptamine analogs listed in Figure 1. Further complicating matters is the expanding list of emerging drugs. Methodology also can become complex; for example, polarity switching is often required in mass spectrometry methods (14). While laboratories struggle to keep pace with the proliferating new bath salt compounds, users continue to evade detection in standardized drug tests.

Responding to the ChallengeWhether the compound is a phenethylamine, piperazine, or tryptamine, bath salts are gaining popularity and represent a major challenge for healthcare professionals, public health officials, clinical laboratories, and law enforcement. The easy availability of these drugs online has enabled users to evade attempts at regulation. Although the biomedical community is responding, educational efforts aimed at local communities and healthcare professionals are still necessary to demonstrate the toxic nature of these stimulant and/or hallucinogenic substances. The effects in humans are difficult to predict and more studies are required. Since chemical compositions continually change to purposely avoid detection and regulation, it is difficult to determine what drugs need to be studied. Seemingly, researchers are always one step behind.

Since most, if not all, synthetic stimulants and hallucinogens are not detected using routine clinical toxicology tests, healthcare providers and clinical laboratories should be aware of potential toxicity of these compounds even with negative test results. Screening methods for bath salts are not widely available, and several designer stimulants cross-react in amphetamine immunoassays (28). Thus, designer stimulant use should be considered in clinical cases where amphetamine exposure is suggested by positive immunoassay but mass spectral confirmation fails.

The growing abuse of bath salts highlights the need for clinical laboratories to develop robust methodologies that keep pace with new drugs as they keep emerging. This is a lofty goal, but with open communication among laboratories and commercial vendors, success may not be as far off as it seems. The problems associated with designer drug testing are here to stay and the demands on clinical laboratories will only increase, especially as reports of morbidity and mortality drive public concern. CLN

REFERENCES1. The New York Times. Overdoses of

“Molly” led to Electric Zoo deaths. http://artsbeat.blogs.nytimes.com/2013/09/12/overdoses-of-molly-led-to-electric-zoo-deaths/?_r=0 (Accessed October 2013).

2. Vandrey R, Dunn KE, Fry JA, et al. A survey study to characterize use of Spice products (synthetic cannabinoids). Drug Alcohol Depend 2012;120:238–41.

3. Winstock AR, Mitcheson LR, Deluca P, et al. Mephedrone, new kid for the chop? Addiction 2011;106:154–61.

4. Leffler AM, Smith PB, de Armas A, et al. The analytical investigation of synthetic street drugs containing cathinone analogs. [Epub ahead of print] Forensic

Sci Int October 22, 2013 as http://dx.doi.org/10.1016/j.forsciint.2013.08.021.

5. Seely KA, Patton AL, Moran CL, et al. Forensic investigation of K2, Spice, and “bath salt” commercial preparations: A three-year study of new designer drug products containing

synthetic cannabinoid, stimulant, and hallucinogenic compounds. [Epub ahead of print] Forensic Sci Int October 22, 2013 as http://dx.doi.org/10.1016/j.forsciint.2013.10.002.

6. Shulgin AT, Shulgin A. Pihkal: A Chemical Love Story. California: Transform Press 1991.

Figure 2

analysis of 489 bath salt cases demonstrates the prevalence of stimulant and hallucinogenic compounds in tables, capsules, powder, and blotter paper seized by arkansas law enforcement during a 4-year period.

Data are tracked by the Center for Drug Detection and Response at the University of Arkansas for Medical Sciences.


7. Shulgin AT, Shulgin A. Tihkal: A Continuation. California: Transform Press 1997.

8. Baumann MH, Ayestas MA, Jr., Partilla JS, et al. The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue. Neuropsychopharmacology 2012;37:1192–203.

9. Baumann MH, Partilla JS, Lehner KR. Psychoactive bath salts: Not so soothing. Eur J Pharmacol 2013;698:1–5.

10. Lehner KR, Baumann MH. P s y c h o a c t i v e “ b a t h s a l t s ” : Compounds, mechanisms, and toxicities. Neuropsychopharmacology 2013;38:243–4.

11. Brandt SD, Tearavarich R, Dempster N, et al. Synthesis and characterization of 5-methoxy-2-methyl-N,N-dialkylated tryptamines. Drug Test Anal 2012;4:24–32.

12. Hill SL, Thomas SH. Clinical toxicology of newer recreational drugs. Clin Toxicol (Phila) 2011;49:705–19.

13. Rose SR, Poklis JL, Poklis A. A case of 25I-NBOMe (25-I) intoxication: A new potent 5-HT2A agonist designer drug. Clin Toxicol (Phila) 2013;51:174–7.

14. Lopez-Arnau R, Mart inez-Clemente J, Carbo ML, et al. An integrated pharmacokinetic and pharmacodynamic study of a new drug of abuse, methylone, a synthetic cathinone sold as bath salts. [Epub ahead of print] Prog Neuropsychopharmacol Biol Psychiatry April 18, 2013 as doi:10.1016/j.pnpbp.2013.04.007.

15. Miotto K, Striebel J, Cho AK, et al. Clinical and pharmacological aspects of bath salt use: A review of the literature and case reports. Drug Alcohol Depend 2013;132:1–12.

16. Hill SL, Doris T, Gurung S, et al. Severe clinical toxicity associated with analytically confirmed recreational use of 25I-NBOMe: Case series. Clin Toxicol (Phila) 2013;51:487–92.

17. Smolinske SC, Rastogi R, Schenkel S. Foxy methoxy: A new drug of abuse. J Med Toxicol 2005;1:22–5.

18. Ambrose JB, Bennett HD, Lee HS, et al. Cerebral vasculopathy after 4-bromo-2,5-dimethoxyphenethylamine ingestion. Neurologist 2010;16:199–202.

19. Tanaka E, Kamata T, Katagi M, et al. A fatal poisoning with 5-methoxy-N,N-diisopropyltryptamine, Foxy. Forensic Sci Int 2006;163:152–4.

20. Synthetic Drug Abuse Prevention Act. 2012. In: Justice Do (ed) XI, vol 112-114.

21. Schedules of Controlled Substances. CP 1308. 2011;76:11075–8.

22. Legal Powder Ltd. http://legalpowder.cn.com/home.html (Accessed October 2013).

23. Erowid. Methylone Dosage. http://w w w . e r o w i d . o r g / c h e m i c a l s /methylone/methylone_dose.shtml (Accessed October 2013).

24. Erowid. 2C-B Dose. http://www.erowid.org/chemicals/2cb/2cb_dose.shtml (Accessed October 2013).

25. Redwood Toxicology Laboratory. Designer Stimulant Test. https://www.redwoodtoxicology.com/services/designer_stimulant_testing (Accessed October 2013).

26. NMS Labs. Comprehensive Stimulants and Hallucinogens Panel, Liquid Test. http://www.nmslabs.com/tests/Comprehensive-Stimulants-and-Hallucinogens-Panel--Liquid/7210LI (Accessed October 2013).

27. Laboratory Corporation of America. Mephedrone, MDPV, and Methylone, Urine. https://www.labcorp.com/ (Accessed October 2013).

28. Petrie M, Lynch KL, Ekins S, et al. Cross-reactivity studies and predictive modeling of “bath salts” and other amphetamine-type stimulants with amphetamine screening immunoassays. Clin Toxicol (Phila) 2013;51:83–91.

Kathryn A. Seely, PhD, is laboratory manager of Chemical Terrorism at the Arkansas Public Health Laboratory, Arkansas Department

of Health. Email: [email protected]

Jeffery H. Moran, PhD, is branch chief of Environmental Chemistry at the Arkansas Public Health Laboratory, Arkansas Department

of Health and assistant professor in the College of Medicine, University of Arkansas for Medical Sciences. Email: [email protected]

REGISTER BY APRIL 4TH AND SAVE! WWW.AACC.ORG/ECLD14

Keynote PresentationThe Evolution of a Point-of-Care Company: From R&D to Commercial LaunchKaren Hedine, President, Micronics, Inc.

Scientific Sessions ■ The Promise of Noninvasive Connected Devices ■ Mobile Medical Apps: The New Frontier ■ Miniaturized Devices of the Future ■ Point-of-Care Diagnostics for Resource-Limited Settings

The Emerging Clinical & Laboratory Diagnostics Conference is THE event industry leaders attend to stay informed on today’s hottest topics and future trends. This is one conference you can’t afford to miss.

Emerging Clinical & Laboratory Diagnostics Conference: The Portable Lab

A P R I L 2 4 - 2 5 , 2 0 1 4 | S A N J O S E , C A , U S A

Now in its 46th year, this conference, formally known as the Oak Ridge Conference, will showcase the latest developments and trends in diagnostics and focus exclusively on pre-commercial technologies. Let by academic and industry experts, sessions will focus on analytical techniques and enabling technologies that are shaping the future of clinical laboratory testing. Sessions include:

New Technology Reception & Poster Session ■ Thursday, April 24, 4:30 pm - 6:00 pmMeet with the technology incubators, researchers, clinical laboratory professionals, and IVD industry representatives who are developing the diagnostic devices of the future.

12 Clinical Laboratory News MARCH 2014

HHS Finalizes Rule on Patient Access to Lab ReportsThe Department of Health and Human Services (HHS) published a final rule that will give patients or a person designated by the patient direct access to completed laboratory test reports, preempting a patchwork of state laws that sometimes prohibit direct patient access to lab reports.

The final rule amends the Clinical Laboratory Improvement Amendments of 1988 (CLIA’88) regulations and eliminates the exception under the Health Insurance Portability and Accountability Act of 1996 (HIPAA) Privacy Rule to an individual’s right to access his or her protected health information when it is held by a CLIA-certified or CLIA-exempt laboratory.

While patients can continue to access their laboratory test reports through their doctors, these changes give patients a new option to obtain their test reports directly from laboratories while maintaining strong protections for patients’ privacy, according to HHS.

Under the HIPAA Privacy Rule, patients, patients’ designees, and patients’ personal representatives can see or be given a copy of patients’ protected health information, including an electronic copy, with limited exceptions. In most cases, copies must be given to the patient within 30 days of request to the lab.

The Final Rule is effective April 5, and covered entities must comply by October 2.

The final rule is available for review at www.federalregister.gov.

Payment Reform Showing Progress, SavingsAccording to the Centers for Medicare and Medicaid Services (CMS), key healthcare delivery reforms under the Affordable Care Act are demonstrating significant savings based on new CMS financial reports. The programs include the Medicare Accountable Care Organization (ACO) initiatives, Pioneer ACOs, the Physician Group Practice demonstration, and expanded participation in the Bundled Payments for Care Improvement Initiative. Savings from both the Medicare ACOs and Pioneer ACOs have now exceeded $380 million.

ACOs are supposed to achieve savings by improving coordination of care and by incentivizing providers to aim for value over volume. The interim financial results released for the Medicare Shared Savings Program ACOs show that, in their first 12 months, nearly half—54 out of 114—of the ACOs that started in 2012 already had lower expenditures than projected.

The Pioneer ACO Model also demonstrated significant savings. This ACO model is designed for more advanced organizations willing to take on even more financial risk. Pioneer ACOs generated gross savings of $147 million in their first year. Results showed that of the 23 Pioneer ACOs, nine had significantly lower spending growth compared to Medicare fee for service while exceeding quality reporting requirements.

CMS also found that the Physician Group Practice Demonstration initiatives have produced savings for 7 out of every 10 physician group practices that participate, totaling $108 million.

Finally, CMS announced that 232 acute care hospitals, skilled nursing homes, physician group practices, long-term care hospitals, and home health agencies have entered into agreements to participate in the Bundled Payments for Care Improvement initiative that bundles payments for episodes of care.

More information about these programs is available from http://innovation.cms.gov.

Joint Commission Proposes Revised Laboratory Accreditation StandardsA revised version of the Joint Commission’s cl inical laborator y accreditat ion requirements is open for public comment through March 20. The Joint Commission reviewed the current standards to identify disparities against the Clinical Laboratory Improvement Amendments of 1988 (CLIA ‘88) and contemporary clinical best practice guidelines. Among the numerous requirements that the Joint Commission has clarified and revised in the proposed standards, the organization also created new requirements to deal with existing and emerging issues. Some redundant requirements were also deleted. The majority of these changes occurred in cytology, human resources, quality control, and transfusion medicine.

Comments can be submitted online at www.jointcommission.org. CLN

PROFILES

R E G U L A T O R Y

Critical and Point-of-Care Testing:Real World and Emerging Applications for Improved Clinical Outcomes

CPOCT 25th International SymposiumSEPTEMBER 17-20, 2014SAN DIEGO, CA

Call for Papers

The CPOCT Call for Papers is now open. Be a part of the CPOCT 25th International Symposium and join industry experts as they explore the practical and promising applications of point-of-care testing for clinical decision making.

The AACC is seeking new and innovative research in the following areas:

• POCT for emergency preparedness and resource limited settings

• POCT for infectious disease

• POCT and molecular diagnostics

• POCT for assessment of coagulation

• Practical applications for POCT: Data driven solutions for improved outcomes

S U B M I T Y O U R PA P E R T O D AY A T W W W. A A C C . O R G / C P O C T 1 4 .

S U B M I S S I O N D E A D L I N E I S M AY 1 , 2 0 1 4 .


profiles

myriad acquires autoimmune Diagnostics company crescendo BioscienceFor $270 million in cash, Myriad Genetics has bought Crescendo Bioscience, a molecular diagnostic laboratory that specializes in inflammatory and autoimmune diseases. Crescendo’s core product, Vectra DA, is a quantitative, protein-based test for the routine assessment of rheumatoid arthritis (RA) disease activity. The company is also building a comprehensive understanding of the biology of other autoimmune diseases and is developing a pipeline of products for a wide range of diseases and conditions managed by rheumatologists. Additionally, Crescendo has created software products for physicians such as VectraView, which provides a comprehensive overview of RA patients’ level of disease activity, and MyRA, which is a patient tracking and communications tool. By acquiring Crescendo, Myriad hopes to facilitate its entry into the autoimmune market while also enhancing the company’s strength in protein-based diagnostics.

The transaction is expected to close before the end of Myriad’s fiscal year 2014. Under the terms of the acquisition, Crescendo will retain its name and operate as a wholly owned subsidiary of Myriad.

GenomOncology, roswell Park cancer Institute collaborate on NGS Informatics SolutionGenomOncology and Roswell Park Cancer Institute have entered a partnership to develop a software platform that will enable the identification of clinically useful mutations in next-generation sequencing results. This platform will integrate laboratory information management systems, electronic health records, information technology, and bioinformatics, and will provide a workflow that allows genomic analysts and pathologists to create actionable reports. “The challenges of translating the vast amounts of data from next-generation sequencing into a resource that can be easily and effectively incorporated into clinical and research programs are significant,” said Carl Morrison, MD, executive director of the Center for Personalized Medicine at Roswell Park. “We need next-generation

tools that will help us to deliver the best and most appropriate therapies to our patients through a streamlined process.”

Boston children’s, mcW Launch Pediatric Pharmacogenomics StudyBoston Children’s Hospital has entered a collaboration with the Medical College of Wisconsin (MCW) and the Children’s Hospital of Wisconsin Research Institute to use genetic information to predict children’s reactions to medications. The primary goal of the study, known as InforMED Kids, is to determine whether individual genetic differences in enzymes involved in the metabolism or action of a drug predict how patients respond to the drug. Currently, the study is enrolling patients from Boston Children’s epilepsy, end-stage renal, inflammatory bowel disease, and cardiology programs, and may expand to the psychiatry department. The researchers initially plan to enroll 1,000 patients along with their healthcare providers, with an eventual goal of offering this testing to all patients at the hospital.

Under the terms of Boston Children’s partnership with MCW, blood samples from study participants will be sent to MCW for genetic analysis. The results will then be returned to the patients’ healthcare providers at Boston Children’s. Ultimately, the study’s investigators hope to reduce the occurrence of adverse drug reactions by building a database of the effects of different genetic variants on drug responses. This database could then be used to develop prescribing guidelines that tailor treatments to patients’ genetic makeup. The study data will also be used to encourage health insurance companies to reimburse the cost of pharmacogenomics screening.

companionDx to Use GenomOncology Platform for cancer TestsCompanionDx has chosen GenomOncology’s GO Clinical Workbench to be the platform for a series of next-generation sequencing–based oncology assays. The GO Clinical Workbench is a step-by-step workflow that takes raw data from the sequencer and translates the molecular profile of each patient’s tumor genome into a report that

includes clinical interpretations of somatic mutations. “As we develop new tests that leverage next-generation sequencing, we require a solution that meets our current needs but is scalable over time,” said David Lasecki, president of CompanionDx. “GenomOncology’s platform and services will allow us to efficiently add new cancer panels and expand our testing options to best serve our clients.”

PGDx, Johns hopkins Sign Licensing agreement for Genome-mapping TechnologyPersonal Genome Diagnostics (PGDx) has licensed from Johns Hopkins University exclusive rights to the genome-mapping technology known as digital karyotyping (DK). Developed by the company’s founders at Johns Hopkins, this technology quantitatively analyzes DNA copy number at high resolution and can identify large chromosomal changes in human cancer cells along with amplifications and deletions, including those in regions not previously known to have been altered. As PGDx expands its cancer genomics services, the company expects that DK will complement

other technologies it has licensed from Johns Hopkins, including the CHASM computational method for identifying cancer-related mutations. Currently, PGDx uses cancer exome analysis to identify cancer-related mutations in approximately 20,000 relevant genes. The company also employs in-depth computational analyses to differentiate between unimportant and cancer-associated mutations.

companies to Offer Free Genomic Testing to rare Disease Patients Global Genes and Syndromes Without a Name USA launched a pilot program on March 1 that will provide free whole exome sequencing to undiagnosed rare disease patients who cannot afford genomic testing, which can cost from $3,500 to more than $5,000 per test. Boston-based Parabase Genomics and the UCLA Clinical Genomics Center have been selected as the first clinical genomic sequencing providers for this program. To start, funding from Global Genes will cover testing for approximately 30 patients, and with additional funding underway, the program is expected to expand in the future. CLN

I N D U S T r y

Immunoassay Reagentsfor Chemistry Analyzers™


www.k-assay.com


For in vitro diagnostic use.

• InsulinNow it is possible to run quantitative insulin assays onyour existing chemistry analyzer without the hazardousradioactivity of RIAs or the high cost of ELISAs.

The insulin assay is highly specific and features liquid-stable reagents requiring no dilution or mixing.

Assay Range: 1 - 100 µIU/mLSample Type: serum or plasma

• α-1 Microglobulin Assay Range: 1.0 - 137 mg/L (serum / plasma) 0.2 - 34 mg/L (urine)

• Fructosamine Colorimetric assay. Includes calibrator. Assay Range: 1 - 10 mmol/L

• Direct Hemoglobin A1c Non-enzymic assay. No patient fasting required. On-board lysis step on many analyzers. Assay Range: 2 - 16%

Adaptable to most chemistry analyzers (including Abbott Aeroset ®, Bayer Advia®, Beckman Synchron CX ® and LX ®, Dade Dimension ®, Roche / Hitachi, Olympus ® AU ™)

2011.09 CLN Insulin.indd 1 8/5/2011 5:19:18 PM

Next MoNth iN CLN

Pharmacogenetics in Anticoagulant Testing: Boon or Bust?


meta-analysis: FITs moderately Sensitive, highly Specific in Detecting colorectal cancerA systematic review and meta-analysis found fecal immunochemical tests (FITs) to be moderately sensitive and highly specific with high overall diagnostic accuracy for detecting colorectal cancer (Ann Intern Med 2014;160:171–81). The authors emphasized, however, that the diagnostic performance of FITs depends on the cutoff value for a positive test result.

The researchers conducted the analysis because several professional associations have endorsed FITs in place of fecal occult blood tests (FOBTs) for their purported improved performance characteristics. However, the scientific literature has shown quite varied FIT results, with reported sensitivities for detecting colorectal cancer ranging from 25–100%, and specificities often higher than 90%. This has left questions in the clinical community about how best to apply FITs in colorectal cancer screening, the optimal number of stool samples for testing, the optimal cutoff value for positive results, and whether any particular FIT is better than others.

The authors considered 19 studies involving a total of 113,360 patients. They found that FITs had a pooled sensitivity of 79% in detecting colorectal cancer, and a specificity of 94%. The overall diagnostic accuracy of FIT was 95%.

The researchers were not able to identify an optimal cutoff value for colorectal screening, but they did find that a cutoff value <20 µg/g had the best sensitivity and specificity and the lowest negative likelihood ratio.

Overall, no single commercial FIT test performed markedly better or worse than others. However, studies that used quantitative FITs reported lower sensitivity compared with qualitative FITs. Overall sensitivity of the former improved, however, after the researchers recalculated sensitivity without the now discontinued OC-Hemodia test.

Sepsis risk model Promising for risk-Stratifying Pediatric PatientsAn updated version of a previously developed sepsis risk model prospectively estimated the probability of death reliably in a heterogeneous test cohort. These findings lay the groundwork for this model to be used as a benchmark to objectively evaluate septic shock outcomes, and to conduct risk-stratified analyses of clinical data, according to the authors (PLoS ONE 2014;9:e86242).

A consortium of researchers previously reported development and validation of the pediatric sepsis biomarker risk model (PERSEVERE), which incorporates five biomarkers along with clinical variables to assess risk of 28-day mortality in children hospitalized with septic shock. The five biomarkers include C-C chemokine ligand 3, interleukin 8, heat shock protein 70kDa 1B, granzyme B, and matrix metallopeptidase 8.

After initially developing and validating PERSEVERE, the researchers combined the derivation and validation cohorts, updated PERSEVERE, and then sought to test the prognostic value of the updated version in an independent test cohort. The latter involved 182 subjects at 17 participating institutions. All were 10 years old or younger, and had been admitted to the pediatric intensive care unit (PICU) and met pediatric-specific criteria for septic shock. All serum samples were obtained within 24 hours of patients’ presentation to PICU.

The overall actual mortality in the test cohort was 13.3%, compared with 9.3% predicted by PERSEVERE. Using a risk cutoff of 2.5%, the researchers found that PERSEVERE had a sensitivity of 83% for predicting mortality, specificity of 75%, positive-predictive value of 34%, and negative-predictive value of 97%.

Fructosamine, Glycated albumin Viable alternatives to hba1c in certain SettingsNew research shows that fructosamine and glycated albumin not only are strongly associated with incident diabetes and diabetes-related microvascular disease, but also have prognostic value comparable to HbA1c (Lancet 2014; http://dx.doi.org/10.1016/S2213-8587(13)70199-2). The findings suggest that these two analytes might be useful complements to HbA1c in clinical practice, especially when HbA1c testing is not available, or when HbA1c results might be considered unreliable.

Fructosamine and glycated albumin are markers of short-term, 2–4 week glycemic control, but neither are used routinely in clinical practice. On the other hand, HbA1c, a measure of long-term glucose exposure in the blood, has been the primary test used to manage diabetes, and in 2010, also was recommended as a diagnostic test for the disease. However, HbA1c has some limitations, including assay interferences such as hemoglobin variants, and other conditions like hemolytic anemia and pregnancy that can affect validity of HbA1c results.

The authors measured fructosamine and glycated albumin from 11,348 non-diabetics and 958 diabetics, as part of the Atherosclerosis Risk in Communities (ARIC) studies. All ARIC participants included in the analysis had undergone ARIC’s second clinical examination between 1990 and 1992 as well as visit three, when retinal photographs were taken. The outcomes of interest were relationships between fructosamine and glycated albumin with

risk of incident diabetes, retinopathy, and risk of incident chronic kidney disease (CKD) during 2 decades of follow up.

The researchers found that hazard ratios for incident diabetes were 4.96 and 6.17, respectively, for fructosamine and glycated albumin above the 95th percentile. Fructosamine and glycated albumin also were strongly associated with retinopathy. Fructosamine and glycated albumin predicted incident CKD almost as well as HbA1c, although the reverse was true when it came to predicting incident diabetes.

The authors used a standard commercial assay to measure fructosamine, but employed a novel enzymatic method for glycated albumin. Both showed “excellent” performance, with coefficients of variation ≤3%. However, they also have limitations, including being affected by alterations in serum protein turnover, and by certain conditions, including liver disease, hyperuricemia, and thyroid dysfunction.

Based on their findings, the authors suggested that fructosamine and glycated albumin testing might be particularly useful when short-term measurement of glycemic control is important, such as for monitoring changed treatment regimens.

IGras Six to Nine Times more Likely Than Tuberculin Skin Testing to Yield False-Positive results A longitudinal study involving 2,563 healthcare workers tested for latent tuberculosis (TB) infection at four institutions found that in comparison to tuberculin skin testing (TST), interferon-γ release assays (IGRAs) were six to nine times more likely to have false-positive results (Am J Respir Crit Care Med 2014;189:77–87). The findings suggest that individuals newly converting from negative to positive results should be repeat tested to identify false-positive results.

TST for decades has been the mainstay of TB testing, but it has low sensitivity, a subjective end point, and its results can be influenced by prior bacillus Calmette-Guerin (BCG) vaccination or infection with nontubercular mycobacteria. However, TSTs have annual conversion rates <1% in most U.S. hospitals. IGRAs offer the advantages of requiring just one patient-provider interaction to obtain results and of not being affected by prior BCG vaccination. However, studies have shown them to have high rates of positivity, negative-to-positive conversion, and positive-to-negative reversion.

The study involved healthcare workers undergoing annual occupational screening for TB. In addition to TST, the researchers evaluated two IGRAs, QuantiFERON-TB Gold In-Tube (QFT-GIT), and T-SPOT.TB, both of which are U.S. Food and Drug Administration-cleared for diagnosing TB infection. Overall, 5.2% of participants had positive TST results, 4.9% positive QFT-GIT

results, and 6% positive T-SPOT.TB results. A baseline positive TST but negative IGRA was strongly associated with BCG vaccination, with a 25.1 odds ratio. Conversions ranged from 0.9% for TST to 8.3% for T-SPOT.TB. Of T-SPOT.TB and QFT-GIT converters, 77.1% and 76.4%, respectively, had negative results when retested 6 months later.

Based on these findings, the researchers called into question the existing practice of routinely serial testing healthcare workers at low risk for TB infection.

KDIGO Panel: No Need to routinely check LDL-c Levels in cKD Patients Patients newly diagnosed with chronic kidney disease (CKD) should have lipid profile testing with measurement of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglyceride levels, but follow-up lipid testing is not needed in most patients (Ann Intern Med 2014;160:182–9). These were two of 13 recommendations contained in a guideline on lipid management in CKD made by a workgroup of the Kidney Disease: Developing Global Outcomes (KDIGO) organization.

The authors specified that after patients undergo initial lipid profile testing, it is “unnecessary” to measure LDL-C in situations in which the results would be unlikely to change management. They also found no direct evidence that routine lipid testing improves clinical outcomes or adherence to lipid-lowering drugs. LDL-C, the authors wrote, is not suitable for assessing coronary risk in CKD patients. The guideline’s de-emphasis on using LDL-C levels to manage statin therapy mirrors that of controversial new guidelines on assessing and managing cardiovascular disease risk issued by the American College of Cardiology and American Heart Association.

The panel recommended statin therapy in all adults age 50 or older with CKD who have an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73m2, and in those who are at least 50 years old with eGFR <60 mL/min/1.73m2, but who have not been treated with chronic dialysis or kidney transplantation. CLN

D I a G N O S T I c

profiles

Connect with other readers, follow breaking news, and comment on CLN stories.

www.facebook.com/clinlabnewsread cLN on your iPad.

Download our FrEE app at the apple app Store


FDa announces meeting to Vote on Premarket approval for roche hPV TestThe U.S. Food and Drug Administration (FDA) has announced an upcoming meeting of the Medical Devices Advisory Committee’s Microbiology Devices Panel that will be open to the public. At this meeting, the committee will discuss, make recommendations, and vote on a premarket approval application from Roche Molecular Systems for a new indication for the cobas human papillomavirus (HPV) test. The cobas HPV test qualitatively detects 14 high risk HPV types in a single analysis, with a specific focus on HPV genotypes 16 and 18. The test accomplishes this by amplifying target DNA through polymerase chain reaction and nucleic acid hybridization.

Currently, the cobas HPV test is approved for use in conjunction with cervical cytology. Roche’s new application seeks to have the test approved for use as a first-line primary cervical screening test as well. Per the proposed indication, women who test negative for high risk HPV types by the cobas HPV test would undergo follow up in accordance with a physician’s assessment of screening and medical history, other risk factors, and professional guidelines. Women who test positive for HPV 16 and/or 18 would be referred to colposcopy. Additionally, women who test negative for

16/18 but positive for any of the other 12 high risk HPV types would be evaluated by cervical cytology to determine the need for referral to colposcopy.

This meeting of the Medical Devices Advisory Committee will take place on March 12 in College Park, Md. Interested persons may submit data, information, or views on the cobas HPV test in writing on or before March 3.

To make a submission and/or for more information, please contact Shanika Craig of the Center for Devices and Radiological Health at [email protected].

FDa announces meeting to Vote on Premarket approval of Epigenomics, Exact Sciences colon cancer Tests In late March, the Medical Devices Advisory Committee’s Molecular and Clinical Genetics Panel will hold a 2-day public meeting to discuss, make recommendations, and vote on information related to Epigenomics’ premarket approval application for the Epi proColon and Exact Sciences’ premarket approval application for the Cologuard device.

The Epi proColon test is designed to screen for colorectal cancer (CRC) in patients who are at average risk for developing it. Using plasma derived from whole blood samples, the test detects methylated Septin

9 DNA, which is associated with the occurrence of CRC. The Epi proColon test is not intended to replace colorectal screening by colonoscopy, however, and patients with a positive Epi proColon test result should be referred for diagnostic colonoscopy.

Cologuard is also indicated for CRC screening, as well as premalignant colorectal neoplasia screening. It analyzes patients’ stool for the presence of occult hemoglobin, multiple DNA methylation and mutational markers associated with colorectal neoplasia, and the total amount of human DNA. Like the Epi proColon test, Cologuard should be used in conjunction with colonoscopy and other test methods in accordance with recognized screening guidelines.

This meeting of the Medical Devices Advisory Committee will take place in Gaithersburg, Md. and will address the Epi proColon test on March 26 and the Cologuard device on March 27.

Interested persons may present data, information, or views, orally or in writing, on both of these tests. Requests to make an oral presentation may be submitted on or before March 10, while written submissions will be accepted on or before March 17.

To make an oral presentation request, a submission, and/or for more information, please contact Jamie Waterhouse of the Center for Devices and Radiological Health at [email protected].

John cunningham Virus Serological reagents reclassified as class II (Special controls)FDA has issued a final order changing the classification of John Cunningham Virus (JCV) serological reagents from class III to class II (special controls). By identifying JCV antibodies in patient serum and plasma, these reagents aid in the risk stratification for the development of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis and Crohn’s disease patients undergoing natalizumab therapy. Under this new classification, devices using these reagents will be subject to less stringent regulatory control, though they will not be exempt from premarket notification requirements. Additionally, FDA believes that the measures set forth in “Class II Special Controls Guideline: John Cunningham Virus Serological Reagents” are necessary, in addition to general controls, to reduce problems such as false-positive or false-negative test results that could potentially harm patient health. Following this final classification order, any firm submitting a 510(k) premarket notification for this device type will need to comply with the special controls.

FDa approves First continuous Glucose monitoring System for childrenFDA announced approval for the expanded use of the Dexcom G4 Platinum Continuous Monitoring System for patients with diabetes ages 2 to 17 years. Continuous glucose monitors (CGM) use small sensors inserted just under the skin and provide a steady stream of information about glucose levels in interstitial fluid. When used along with blood glucose meters, CGMs can help people

with diabetes detect when blood glucose values are approaching dangerously high or dangerously low levels. The devices require a prescription and are meant to complement, not replace, information obtained from standard home glucose monitoring devices.

In a statement, FDA noted that the agency has not approved the use of CGM values alone to determine dosing of diabetes medications. CGMs must be calibrated by blood glucose meters, and treatment decisions such as insulin dosing should be based on readings from a blood glucose meter.

“This device can provide valuable glucose trend information to children with diabetes and their families, but it is important that those using this device understand the expected performance of this device compared to blood glucose meters, especially for detecting low glucose, in pediatric patients,” said Alberto Gutierrez, PhD, director of the Office of In Vitro Diagnostics and Radiological Devices in FDA’s Center for Devices and Radiological Health. “This approval for expanded use is part of the FDA’s work to meet the needs of children living with diabetes.”

Before the approval, FDA reviewed data from a pivotal clinical study of in-clinic and home-use patients to assess the accuracy and precision of the system. The study demonstrated that the G4 Platinum (Pediatric) System performance in pediatric subjects was not as accurate as the performance of the same device in adults. In addition, the performance of the hypoglycemic detection alert in the pediatric study was poor relative to that seen in the adult study, particularly at blood glucose concentrations <70 mg/dL. Despite these limitations, the study demonstrated that the device is effective for tracking and trending to determine patterns in glucose levels, and for alerting patients when glucose values are approaching potentially hyperglycemic or hypoglycemic levels.

To communicate the reduced accuracy in pediatric patients to users, two warnings are included in the labeling, and are displayed on the receiver screen when a new sensor session is started or the alert thresholds are changed. CLN

InDEx To aDVErTISErSPlease visit these websites to learn more about the products in this issue.

ark Diagnostics ...................... 6 www.ark-tdm.com

BD .......................................... 16 www.bdbiosciences.com/go/canto

cerilliant ................................. 3 www.cerilliant.com

Kamiya Biomedical company ....................... 5, 7, 13 www.k-assay.com

news from the fDA

FDa to address concerns about new Glucose meter regulationsAACC Webinar March 19

In the live AACC webinar, “new Blood Glucose meter Guidance Unveiled: A Discussion with the fDA,” the director of fDA’s Division of Chemistry and toxicology Devices, Courtney Lias, PhD, will answer questions about the recently released draft guidance documents that establish new premarket submission requirements for blood glucose monitors.

Currently, the agency only uses one set of criteria to evaluate the performance of blood glucose monitors, regardless of whether they are designed for use in professional healthcare settings or at home. this draft guidance now seeks to

improve patient care by defining separate submission requirements for the two kinds of glucose meters. If implemented, these changes could have a significant impact on device manufacturers by increasing the submission requirements for point-of-care blood glucose monitors. Additionally, hospitals, long-term care facilities, and other healthcare providers that use these monitors would need to comply with more stringent personnel and quality control standards.

In light of these potential consequences, this draft guidance has raised important questions in the lab community about how it may affect point-of-care glucose programs. this webinar aims to answer these questions, while also explaining how blood glucose meters are currently regulated and helping laboratorians to understand the new professional use requirements.

to register, visit http://www.aacc.org/events/meetings/Pages/9079.aspx.

new Blood Glucose meter Guidance Unveiled: a Discussion With the FDa

Wednesday, march 19 2:30–3:30 p.m.

courtney Lias, PhD

The BD FACSCanto™ flow cytometry system with 10-color capabililty delivers reliable performance, accuracy, and ease-of-use for today’s busy clinical labs to further expand your lab’s best-in-class clinical diagnostic services.

The BD FACSCanto system’s new, powerful lasers deliver enhanced sensitivity, leading to higher resolution and greater accuracy. The 4-3-3 configuration is designed to help reduce spillover. As with all BD FACSCanto systems, a high degree of automation, quality control, and single-tube instrument setup enables workflow efficiency, reducing hands-on time

for technicians while improving the reliability of results. TheBD FACS™ Loader option features walkaway sample introduction to help operators rapidly adopt routine clinical applications.

Our clinical solutions are designed to deliver dependable outcomes while speeding workflow, easing operation, and reducing training require-ments. They reflect our commitment to live by, reach to, and measure our products and services by ever higher standards. To learn more about 10-color flow cytometry BD FACSCanto systems, visit bdbiosciences.com/go/canto.

A Perfect Ten.

For In Vitro Diagnostic Use (IVD).Class 1 Laser Product.BD, BD Logo and all other trademarks are property of Becton, Dickinson and Company. © 2013 BD23-15329-01

BD Biosciences 2350 Qume Drive San Jose, CA 95131bdbiosciences.com

The BD FACSCanto™ SystemProven reliability, new 10-color power.

clinical genetic cancer testing laboratory news · genetic cancer testing genetic testing plays an...

Documents