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The Peer Reviewed Management Source for Lab Professionals since 1969

APRIL 2016 | Vol. 48, No. 4

APRIL 2016 M L O - O N L I N E .C O M 2

DEPARTMENTS

4 From the editor

6 The observatory

44 Tips from the clinical experts

50 Letters to the editor

51 New products

PRODUCT FOCUS

40 Rapid testing

MARKETPLACE

51 Advertiser index

EXECUTIVE SNAPSHOT

52 Developing blood biomarker tests for the detection of cancer

James R. Jett, MDChief Medical Offi cerOncimmune

CONTINUING EDUCATION

12 Diagnosing androgen defi ciency inadult men By Michael Samoszuk, MD

16 CE TestTests can be taken online or by mail. See page 16 for testing and payment details.

30Cover: Laboratory Services representatives from across the Sentara organization. Photo: Steve Budman

FEATURES

THE PRIMER

18 Oncogene panels: a window into the individuality of cancersBy John Brunstein, PhD

CLINICAL ISSUES

22 mRNA-based hrHPV assay in cotesting for cervical cancer screening By Juan Felix, MD

EDUCATION

24 Emerging applications in clinical mass spectrometry

By Lisa Thomas, BS, MBA

LAB MANAGEMENT

30 MLO’s 2016 Lab of the Year: Sentara Laboratory ServicesBy MLO Staff

SPECIAL FEATURE

38 Solving the thrombocytopenia puzzle with immatureplatelet testingBy Maggie Fischer RN, BSN, MS, and Krista Curcio, BS, MBA

MANAGEMENT MATTERS

42 CDC’s more restrictive policy on child lead testingmeans more positives and high QCBy Robert Kapler

FUTURE BUZZ

46 The laboratory’s role in the transformation topatient-centered careBy Donna Beasley, DLM(ASCP)

48 In pursuit of patient-centered careBy Chrystal Adams

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MLO - MEDICAL LABORATORY OBSERVER(ISSN: 0580-7247). Published monthly, with an additional issue in August, by NP Communications, LLC., 2477 Stickney Point Rd, Suite 221B, Sarasota, FL 34231 (941) 388-7050. Subscription rates: $127.60/year in the U.S.; $154.88 Canada/Mexico; Intl. subscriptions are $221.43/year. All issues of MLO are available on microfilm from University Microfi lms International, Box 78, 300 N. Zeeb Rd., Ann Arbor, MI 48106. Current single copies (if available) $15.40 each (U.S); and $19.80 each (Intl.). Back issues (if available) $17.60 each (U.S.); $22.00 each (Intl.). Payment must be made in U.S. funds on a U.S. bank/branch within the continental U.S. and accompany request. Subscrip-tion inquiries: [email protected]. MLO is indexed in the Cumulative Index for Nursing and Allied Health Literature and Lexis-Nexis. MLO Cover/CE, Clinical Issues, and Lab Management features are peer reviewed. Title® registered U.S. Patent Offi ce. Copyright© 2016 by NP Communications, LLC. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage-and-retrieval system, without written permission from the publisher. Offi ce of publication: Periodicals Postage Paid at Sarasota, FL 34276 and at additional mailing offi ces. Postmaster: Send address changes to MLO MEDICAL LABORATORY OBSERVER, 2477 Stickney Point Rd, Suite 221B, Sarasota, FL 34231.Printed in U.S.A.

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Jeffrey D. Klausner, MD, MPHAssociate Clinical Professor of Medicine Divisions of AIDS and Infectious Diseases University of California, San Francisco, CA

Susan McQuiston, JD, MT(ASCP)Instructor, Biomedical Laboratory Diagnostics ProgramMichigan State University, East Lansing, MI

Donna Beasley, DLM(ASCP)ManagerHuron Healthcare, Chicago, IL

Anthony Kurec, MS, H(ASCP)DLMClinical Associate ProfessorSUNY Upstate Medical University, Syracuse, NY

Suzanne Butch, MLS(ASCP)CM, SBBCM, DLMCM

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FROM THE EDITOR By A lan Lenhof f, Edi tor

YEARS AGO, I worked for a company that produced cus-tomized magazines for HMOs and hospital systems; I ed-ited some of them. “Women’s Health” was a popular topic requested by clients, particularly hospitals eager to high-light centers of excellence related to pregnancy/prenatal and HMOs urging breast cancer screenings, for example. Women’s health was such a priority of our clients that one of my fellow editors and I joked that an alien from anoth-er planet, judging what life was like on Earth only from those publications, would conclude that “health” was an attribute possessed only by women, that only women had health issues, (I guess you had to be there….)

It is true that healthcare publications, and individuals and organizations dedicated to educating healthcare con-

sumers, in general have been somewhat tardy in addressing men’s health is-sues. But that is changing. An increased awareness of prostate cancer has been one of the drivers in the progress toward the growing interest in men’s health; another has been issues surrounding the effects of low testosterone in men. In that context, MLO is proud to present this issue’s important Continuing Education article, “Diagnosing androgen defi ciency in adult men,” by Michael Samoszuk, MD (pages 12-14). The article convincingly demonstrates that the clinical understanding of laboratory testing for low-T in men must catch up with the growing demand for testing and treatment.

News of recent studies confi rms that men’s health, seen as a category of healthcare knowledge and research, is coming into its own. For one exam-ple, researchers from the Perelman School of Medicine at the University of Pennsylvania, and twelve other medical centers in the United States, in part-nership with the National Institute on Aging, recently found that testosterone treatment improves sexual activity, walking ability, and mood in men over 65. As men age, testosterone levels decrease, but prior studies of the effects of administering testosterone to older men had been inconclusive.

The Testosterone Trials, or TTrials, are a coordinated group of seven trials, and researchers have analyzed the results of the fi rst three—sexual function, physical function, and vitality. They found that testosterone treatment in-creased the blood testosterone level in the study subjects to the mid-normal range for younger men. Testosterone also improved all aspects of sexual func-tion. Testosterone treatment did not improve energy but did improve mood and depressive symptoms.

“The results of the TTrials show for the fi rst time that testosterone treat-ment of older men who have unequivocally low testosterone levels does have some benefi t,” says the principal investigator of the TTrials, Peter J. Snyder, MD. “However, decisions about testosterone treatment for these men will also depend on the results of the other four trials—cognitive function, bone, car-diovascular, and anemia—and the risks of testosterone treatment.” Stay tuned.

Another example: We often think of osteoporosis as largely a women’s problem, but men experience a loss in bone density as they age as well. Recent research from the University of Missouri-Columbia shows that men can forestall its effects by exercising in their teen and young-adult years. Work by Pamela Hinton, PhD, indicates that high-impact exercise during adolescence and young adulthood is linked to greater bone mass in middle-aged men.

Hinton analyzed data from the physical histories of 203 males aged 30 to 65 years. Participants’ sports and exercise histories varied, both in type and level of activity, and the length of time spent doing various physical activities also differed. But her research found that exercise-associated bone loading dur-ing adolescence and young adulthood benefi ted bone density in adulthood. Moreover, she found that high-impact activity during growth and adulthood is an important determinant for bone health later in life.

It’s an interesting fi nding—and more evidence that men’s health, as a subject for clinical research, is here to stay.

Health—it’s not just for women anymore!

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NE WS T RENDS A N A LYSIS

Infectious Disease

New CDC laboratory test for Zika virus authorized for emergency use by FDA. In response to a request from the Cen-

ters for Disease Control and Prevention

(CDC), the United States Food and Drug

Administration (FDA) has issued an

Emergency Use Authorization (EUA) for

a diagnostic tool for Zika virus that will

be distributed to qualifi ed laboratories

and, in the United States, those that are

certifi ed to perform high-complexity

tests.

The test, called the CDC Zika IgM An-

tibody Capture Enzyme-Linked Immu-

nosorbent Assay (Zika MAC-ELISA), is

intended for use in detecting antibodies

that the body makes to fi ght a Zika virus

infection. These antibodies (in this case,

immunoglobulin M, or IgM) appear in

the blood of a person infected with Zika

virus beginning four to fi ve days after

the start of illness and last for about 12

weeks. The test is intended to be used

on blood samples from people with a

history of symptoms associated with

Zika and/or people who have recently

traveled to an area during a time of

active Zika transmission.

The FDA can use the EUA to permit

use, based on scientifi c data, of certain

medical products in certain circum-

stances, including when there is a deter-

mination by the Secretary of Health and

Human Services that there is signifi cant

potential for a public health emergency

that has signifi cant potential to affect

national security or the health and se-

curity of U.S. citizens. As there are no

commercially available diagnostic tests

cleared or approved by the FDA for

the detection of Zika virus infection, it

was determined that an EUA is crucial

to ensure timely access to a diagnostic

tool. The CDC’s Zika MAC-ELISA is the

fi rst diagnostic test authorized for use

in the U.S. for the detection of Zika vi-

rus during this situation in which there

has been a determination that there is a

signifi cant potential for a public health

emergency that has a signifi cant po-

tential to affect national security or the

health and security of citizens living

abroad and that involves Zika virus.

Results of Zika MAC-ELISA tests re-

quire careful interpretation. A positive

test result indicates that a person was

likely infected recently with the Zika

virus. However, the test can give an

incorrect positive. These false-positive

results can occur when someone has

been infected with another closely

related virus (such as dengue virus).

When positive or inconclusive results

occur, additional testing (plaque reduc-

tion neutralization test) to confi rm the

presence of antibodies to Zika virus

will be performed by the CDC or a CDC-

authorized laboratory.

Moreover, a negative test result does

not necessarily mean that a person has

not been infected with Zika virus. If a

sample is collected just after a person

becomes ill, there may not be enough

antibodies for the test to measure, re-

sulting in a false negative. Similarly, if

the sample is collected more than 12

weeks after illness, it is possible that

the body has successfully fought the

virus and antibody levels have dropped

below the detectable limit.

As with any test, it is important that

healthcare providers consult with their

patients about test results and the best

approach to monitoring their health.

The CDC began distributing the test

last month to qualifi ed laboratories in

the Laboratory Response Network, an

integrated network of domestic and

international laboratories that can re-

spond to public health emergencies.

The test will not be available in U.S.

hospitals or other primary care settings.

Public health offi cials anticipate that

distribution of the tests will improve

laboratory testing capacity for Zika

virus in the U.S.

Zika virus associated with meningoen-cephalitis. An 81-year-old man was ad-

mitted to the intensive care unit 10 days

after he had been on a four-week cruise

in the area of New Caledonia, Vanuatu,

the Solomon Islands, and New Zealand;

he was reported to have been in perfect

health during that time.

On medical examination, he was fe-

brile and comatose with hemiplegia of

the left side, paresis of the right upper

limb, a normal response to tendon re-

fl exes, and a Babinski sign on the left

side. The patient’s trachea was intubat-

ed and mechanical ventilation begun; a

transient rash was observed within the

next 48 hours. Magnetic resonance im-

aging (MRI) of the brain was suggestive

of meningoencephalitis.

Computed tomographic angiography

revealed an irregular narrowing of the

right callosomarginal artery.

A lumbar puncture was performed on

day 1, and fi ndings on analysis of cere-

brospinal fl uid (CSF) were suggestive

of meningitis: the leukocyte count was

41 per cubic millimeter (with 98% poly-

morphonuclear leukocytes), the protein

level was 76 mg per deciliter, and the

ratio of CSF to blood glucose was 0.75.

The patient was initially treated with

amoxicillin, cefotaxime, gentamicin,

and acyclovir, but these antimicrobial

agents were stopped on day 5. Investi-

gations in both CSF and blood for other

infections were unrevealing except for a

positive result for ZIKV on reverse-tran-

scriptase–polymerase-chain-reaction

assay of the CSF. ZIKV was grown in

culture from the CSF on a Vero cell line.

These fi ndings all support the diag-

nosis of ZIKV-associated meningoen-

cephalitis.

New Studies

Common blood test could predict risk of second stroke. A new discovery

about ischemic stroke may allow doc-

tors to predict a patient’s risk of hav-

ing a second stroke using a commonly

performed blood test and their genetic

profi le.

The researchers have linked high

levels of C-reactive protein, an enzyme

found in the blood, with higher risk for

recurrent ischemic stroke. C-reactive

protein (CRP) is produced in the liver in

response to infl ammation, and it is al-

ready checked to measure risk of devel-

oping coronary artery disease. The new

research suggests it could be a useful

tool for ischemic stroke patients as well.

Researchers set out to determine

how genes affect the levels of biomark-

ers such as CRP in the blood. Not only

did they fi nd that elevated CRP levels

suggest increased stroke risk, but they

identifi ed gene variations that drive that

risk.

Researchers envision a day when

doctors might focus on CRP levels and

a patient’s genetic makeup to determine

the overall risk for a second stroke. But

CRP levels alone could be a useful tool

in assessing risk after the initial stroke.

Cancer

Low vitamin D predicts aggressive pros-tate cancer. A new study provides a ma-

jor link between low levels of vitamin D

and aggressive prostate cancer. North-

western Medicine research showed that

defi cient vitamin D blood levels in men

can predict aggressive prostate cancer

identifi ed at the time of surgery. The

fi nding is important because it can offer

guidance to men and their doctors who

may be considering active surveillance,

in which they monitor the cancer rather

than remove the prostate.

continued on page 10

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Untitled-1 1Untitled-1 1 3/15/2016 12:08:29 PM3/15/2016 12:08:29 PM


NE WS T RENDS A N A LYSIS

continued from page 6

Previous studies showing an associa-

tion between vitamin D levels and ag-

gressive prostate cancer were based

on blood drawn well before treatment.

The new study provides a more direct

correlation because it measured D lev-

els within a couple of months before

the tumor was visually identifi ed as ag-

gressive during surgery to remove the

prostate.

Pregnancy/Prenatal

Alcohol exposure during pregnancy affects multiple generations. When a

mother drinks alcohol during preg-

nancy, even a small dose, she can in-

crease the chances that the next three

generations may develop alcoholism,

according to a new study.

A research team led by Nicole Camer-

on, PhD, was the fi rst to investigate the

effects of alcohol consumption during

pregnancy on alcohol-related behav-

ior (consumption and sensitivity to the

effect of alcohol) on generations that

were not directly exposed to alcohol in

the uterus during the pregnancy.

Pregnant rats received the equiva-

lent of one glass of wine, four days in a

row, at gestational days 17-20, which is

the equivalent of the second trimester

in humans. Juvenile male and female

offspring were then tested for water or

alcohol consumption. Adolescent males

were tested for sensitivity to alcohol

by injecting them with a high-alcohol

dose, which made them unresponsive,

and measuring the time it took them to

recover their senses. The results sug-

gest that if a mother drinks during preg-

nancy, even just a little, she increases

the risk that her progeny will become

alcoholic.

Drugs of Abuse

Overdose deaths from common seda-tives have surged, new study fi nds. Headlines about America’s worsening

drug epidemic have focused on deaths

from opioids—heroin and prescrip-

tion painkillers such as OxyContin.

But overdose deaths have also soared

among the millions of Americans using

benzodiazepine drugs, a class of seda-

tives that includes Xanax, Valium, and

Klonopin, according to a study led by

researchers at Albert Einstein College

of Medicine, Montefi ore Health System

and the Perelman School of Medicine at

University of Pennsylvania.

“We found that the death rate from

overdoses involving benzodiazepines,

also known as ‘benzos,’ has increased

more than four-fold since 1996—a pub-

lic health problem that has gone under

the radar,” says lead author Marcus

Bachhuber, MD, MS. Overdoses from

benzodiazepines have increased at a

much faster rate than prescriptions for

the drugs, indicating that people have

been taking them in a riskier way over

time.”

In 2013, benzodiazepine overdoses

accounted for 31 percent of the nearly

23,000 deaths from prescription drug

overdoses in the U.S. But little was

known about the national trends in ben-

zodiazepine prescribing or in fatalities

from the drug.

The researchers’ analysis revealed

that the number of adults purchasing a

benzodiazepine prescription increased

by 67 percent over the 18-year period,

from 8.1 million prescriptions in 1996 to

13.5 million in 2013. For those obtain-

ing benzodiazepine prescriptions, the

average quantity fi lled during the year

more than doubled between 1996 and

2013. Most crucially, the overdose death

rate over the 18-year period increased

from 0.58 deaths per 100,000 adults in

1996 to 3.14 deaths per 100,000 adults

in 2013, a more than four-fold increase.

Overall, the rate of overdose deaths

from benzodiazepines has leveled off

since 2010. But for a few groups—adults

aged 65 and over, and blacks and His-

panics—the rate of overdose deaths

after 2010 continued to rise.

Alzheimer’s Disease

Researchers identify virus and two types of bacteria as major causes of Alzheim-er’s. A worldwide team of senior scien-

tists and clinicians have come together to

produce an editorial which indicates that

certain microbes—a specifi c virus and

two specifi c types of bacteria—are major

causes of Alzheimer’s Disease (AD).

This major call for action is based

on substantial published evidence into

AD. The team’s landmark editorial sum-

marizes the abundant data implicating

these microbes, but until now this work

has been largely ignored or dismissed

as controversial. Therefore, proposals for

the funding of clinical trials have been re-

fused, despite the fact that over 400 un-

successful clinical trials for AD based on

other concepts were carried out over a

recent 10-year period.

“We are saying there is incontrovert-

ible evidence that Alzheimer’s Disease

has a dormant microbial component,

and that this can be woken up by iron

dysregulation. Removing this iron will

slow down or prevent cognitive degen-

eration. We can’t keep ignoring all of the

evidence,” Professor Douglas Kell says.

Professor Resia Pretorius, who also

worked on the editorial, says “The mi-

crobial presence in blood may also play

a fundamental role as causative agent of

systemic infl ammation, which is a charac-

teristic of Alzheimer’s disease—particu-

larly, the bacterial cell wall component

and endotoxin, lipopolysaccharide. Fur-

thermore, there is ample evidence that

this can cause neuroinfl ammation and

amyloid-ß plaque formation.”

Swedish study fi nds potential proteomic biomarkers for Alzheimer’s in cerebro-spinal fl uid. A mass spectrometry-based

analysis of cerebrospinal fl uid in Alzheim-

er’s disease (AD) patients has yielded a

handful of potential biomarkers for the

disease.

The researchers used label-free shot-

gun mass spectrometry to look at pro-

teins in the cerebrospinal fl uid of 10 AD

patients and 10 healthy controls. They

also performed protein depletion of high-

abundance proteins to improve detec-

tion and quantifi cation of low-abundance

proteins.

The authors found eight proteins that

were differentially expressed between the

two study groups. “ApoM, LRG, FBLN3,

and PTPRZ have functions related to cell

adhesion, migration, and morphology,”

and may also be associated with other

aging-associated diseases like cancer

and diabetes, they wrote. C1QB, C1QC,

complement C1S, and SEZ6 may be

implicated in synapse development.

“Cerebrospinal fl uid is a proximal fl uid

in direct contact with the brain interstitial

fl uid that potentially refl ects biochemical

changes related to [the] central nervous

system, making it a promising source

of biomarkers in neurological disorders

such as AD,” they added. While Alzheim-

er’s disease is associated with several

proteomic markers, especially the pro-

tein tau and beta-amyloid peptides, those

have limited value for monitoring disease

progression.

In their paper, the authors also pointed

out other factors that might have infl u-

enced results. In addition to the small

study size, they noted that there was a

slight age difference between the two

groups, where the controls were, on av-

erage, nine years older than participants

in the Alzheimer’s group; protein levels in

cerebrospinal fl uid are thought to change

with age. The lower protein levels could

also be the effect of protein depletion.

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MEN’S HE A LT H

In recent years, there has been an explosive increase in prescrip-tions for testosterone replacement therapy (TRT) in adult men who are thought to have adult-onset hypogonadism (i.e., andro-

gen defi ciency [AD], also known as low testosterone or “low T”).1

This increase has been fueled by changing demographics and by increased public awareness of low T syndrome due to extensive advertising and numerous articles in the lay press. Despite recent controversies about risks for cardiovascular complications in men receiving TRT, the trend of increased testing and treatment for low T is likely to continue. Hence, it is imperative for clinical labora-tory professionals to have a good understanding of this important topic.

The diagnosis and treatment of adult-onset hypogonadism in men older than 45 years of age remains controversial. For exam-ple, there is lack of consensus on the thresholds of testosterone that are needed to diagnose AD. Furthermore, evidence shows that testosterone levels in men decrease with age, at approximately one percent per year, beginning at about 40 years old. Because tes-tosterone levels are known to decline as men grow older, there is debate about whether or not to interpret lower testosterone values in older men as being physiologic (i.e., a “normal” part of aging) or abnormal and worthy of treatment. For this reason, a standard approach in older men has been to interpret blood tests for testos-terone in the context of the other clinical features of the patient in order to establish a diagnosis of androgen defi ciency that should be treated.

To earn CEUs, see test on page 16 or online at www.mlo-online.com under the CE Tests tab.

LEARNING OBJECTIVESUpon completion of these articles, the reader will be able to:

1. Identify the limitations that are currently problematic when diagnosing androgen defi ciency.

2. Describe the signs and symptoms of androgen defi ciency.3. List ways in which the criteria for diagnosing androgen

defi ciency can be improved upon.4. Identify the metabolites of testosterone and their possible

use for future laboratory diagnostic value.

Continuing Education

Diagnosing androgen defi ciency in adult menBy Michael Samoszuk, MD

Biology of testosteroneTestosterone is a steroid hormone that develops and maintains the primary and secondary sex characteristics in men (Figure 1). Its metabolites include estradiol (produced by aromatase enzyme found in fat and other tissues such as testes) and dihydrotestoster-one (DHT)—an androgenic hormone that is approximately three to ten times more potent than testosterone.2,3 DHT is produced from testosterone by 5-alpha reductase, an enzyme that is found primarily in hair follicles, prostate, testes, and adrenal glands, but not in skeletal muscle.4

Measuring total testosteroneTotal testosterone can be accurately measured by immunoassay and by mass spectroscopy.5 Even in men with severe defi ciency of testosterone, enzyme immunoassays will provide accurate and reliable results. There is no clinical advantage to using mass spec-troscopy for measuring total testosterone, although the results may be more precise and accurate at very low levels that are not normally seen even in hypogonadal men.5

In younger men, there is marked diurnal variation in testos-terone levels, with the highest levels occurring in early morning upon awakening.6 The diurnal variation in total testosterone be-comes less pronounced in older men.7 Nevertheless, current rec-ommendations are that blood samples for total testosterone levels should be drawn before 10 a.m. in all men. There is currently no consensus regarding whether or not fasting is required, and most laboratories do not require it.

Total testosterone levels can vary considerably from day to day in the same man.8 Factors that can affect total testosterone on a day-to-day basis include sleep, diet, stress, illness, and exercise. Consequently, it is not advisable to make a diagnosis of low T on the basis of a single blood test result. Instead, two or even three tests taken on different days are recommended in order to ensure an accurate diagnosis.9

Lack of consensus on diagnostic criteria There are considerable variations in the reference intervals for total testosterone assays that are produced by various manufacturers of in vitro diagnostics and reference labs (Table 1). It is notable that the reference intervals are based on the range of values between the fi fth and 95th percentiles of men of various ages. The popu-lations of men that were used to derive these reference intervals are poorly defi ned with respect to age distribution and possible

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13APRIL 2016 M L O - O N L I N E .C O M

MEN’S HE A LT H CE

symptoms of low T, and it is unclear if these reference intervals provide a reliable basis for interpreting test results from men being tested for low T. Of particu-lar concern are the lower limits of the reference inter-vals, which may be too low to identify the signifi cant proportion of men who are truly hypogonadal but whose total testosterone levels still fall above the fi fth percentile of the reference range.

Reference intervals for total testosterone levels re-ported by various reference laboratories also have considerable variation (Table 1). Once again, the variation is of particular concern at the low end of the reference interval, because many clinicians use this value to determine whether or not a man should be diagnosed as having low T.

An emerging approach to interpreting total testos-terone levels in men is to use a clinical threshold cutoff value for the level. Based on recommendations from various sources,10-12 it appears that the clinical thresh-old for diagnosing low T probably lies somewhere between 300-500 ng/dL. Notably, this broad range lies considerably above the fi fth percentiles for the testosterone values in Table 1. It should also be noted that all sources of the clinical thresholds recommend the primacy of clinical signs and symptoms when in-terpreting total testosterone values. For example, the Endocrine Society recommends “making a diagnosis of androgen defi ciency only in men with consistent symptoms and signs and unequivocally low serum testosterone levels.”10 The American Urological Association goes even further and states that “there is no universally accepted threshold of T concentration that distinguishes eugonadal from hypogonadal men.”13

To resolve this conundrum, many experts now recommend that numerical values for total testosterone should be interpreted only in the context of the other clinical features of the patient. For this purpose, various clinical criteria for diagnosing or sus-pecting low T in men have been proposed (Table 2, page 14). Although all of these signs and symptoms are somewhat non-specifi c, the sexual symptoms appear to be the most useful in-dicators of potential low-T. Consequently, in men older than 45 years of age who present with complaints of erectile dysfunc-tion or other sexual problems, there should be a high index of suspicion for low T.

Testosterone binding and circulation Testosterone circulates in the blood in a free (un-bound) form and a bound form.14 Sex hormone-binding globulin (SHBG) and albumin are the primary sources of binding of testosterone. Ap-proximately two percent of total testosterone cir-culates in the free form. Current thinking is that free testosterone is mostly responsible for the bi-ological activity of the hormone, and the bound form is thought to be mostly inactive.

The free and bound forms can be directly mea-sured by a variety of methods, or a mathematical formula can be used to calculate the percentage of free testosterone, based on the values for total testosterone, SHBG, and albumin.15,16 Regardless of the method used to determine free testoster-one, there is still substantial confusion and un-certainty regarding how to interpret the results. Some experts use both total testosterone and free testosterone to evaluate men presenting with symptoms of low T.

Figure 1. Effects of testosterone in men.

Effects of age and other factors The levels of total testosterone in men decline gradually with age.17 By contrast, there is a much more pronounced decrease in free tes-tosterone levels with age, which is probably due to a correspond-ing, age-related increase in SHBG levels. The reduced levels of free testosterone then stimulate secretion of higher levels of luteinizing hormone, which is the primary driver of testosterone synthesis in testes.

Other conditions besides aging also contribute to signifi cant de-clines in testosterone in men older than 45 years of age. Chronic opioid use and obesity are two of the most signifi cant drivers of reduced total testosterone.18,19 AIDS, hypertension, overtraining, certain medications, and diabetes are also associated with low T.20 Finally, there is emerging evidence that poor sleep quality and

SOURCE DESCRIPTION REFERENCE INTERVAL

Abbott ArchitectApparently Healthy Males

21-49 years old>50 years old

240-870220-716

Beckman CoulterMales 18-66 years old,not otherwise specifi ed 175-781

Roche DiagnosticsHealthy Adult Males

20-49 years old>50 years old

249-836193-740

Lab CorpAdult Males, Lean,

Healthy, 19-40 years old 348-1197

Mayo Medical Men > 19 years old 240-950

Quest Diagnostics Adult male 250-827

Sources:Package labeling for testosterone assays from Abbott, Beckman, Coulter and Roche Diagnosticswww.Labcorp.comwww.mayomedicallaboratories.com/test-catalog/8533www.questdiagnostics.com/testcenter/TestDetail.action?ntc=873&fromFlyOut=true

Table 1. Reference intervals for testosterone by IVD manufacturer and reference laboratory.

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MEN’S HE A LT H

5. Wang C, Catlin DH, Demers LM, Starcevic B, Swerdloff RS. Measurement of total serum testoster-one in adult men: comparison of current laboratory methods versus liquid chromatography-tandem mass spectrometry. J Clin Endocrinol Metab. 2004;89:534-543.

6. Crawford ED, Poage W, Nyhuis A, et al. Measure-ment of testosterone: how important is a morning blood draw? Curr Med Res Opin. 2015;31:1911-1914.

7. González-Sales M, Barrière O, Tremblay PO, Nekka F, Desrochers J, Tanguay M. Modeling testosterone circadian rhythm in hypogonadal males: effect of age and circannual variations. AAPS J. 2016;18:217-227.

insuffi cient sleep are also associated with low T.21 Interestingly, poor sleep seems to be both a cause and an effect of low T.

Testing for dihydrotestosterone and estradiol Testing for DHT levels is not a routine part of the workup for men being evaluated or treated for hypogonadism. At this time, it is not clear how to interpret the test results. It is likely that as our un-derstanding of testosterone replacement therapy improves, there will be an increased interest in clinical testing for this metabolite of testosterone.

There is now considerable evidence that estradiol levels in men play an important role in modulating the effects of testosterone on sexual function, body fat, lean muscle mass, and bone density.11 Nevertheless, estradiol levels are still not commonly measured in men who are being evaluated or treated for low T. This is because the interpretive criteria for such testing are still not well under-stood. In some men, estradiol levels are measured in order to de-termine if testosterone therapy is causing an increase in estradiol due to aromatization of the testosterone. This can lead to symp-toms of high estradiol such as bloating, fl uid retention, and breast tenderness or gynecomastia.22 Some experts now recommend cal-culating a ratio of testosterone to estradiol, but this approach is not yet widely accepted. Nevertheless, it is likely that clinical labora-tories will experience an increased demand for estradiol testing in men as our understanding and the prevalence of testosterone therapy increases.

ConclusionFrom the preceding discussion, it should be apparent that our un-derstanding of laboratory testing for low-T in men lags consider-ably behind the growing demand for testing and treatment of low T. Clinical laboratories, manufacturers of in vitro diagnostic tests, and clinicians should be aware of the many unanswered questions in this fi eld. They should also begin to educate themselves about the important changes in this fi eld that are likely to occur in the next few years.

REFERENCES

1. Annual testosterone drug revenue in the U.S. in 2013 and 2018 (in billion U.S. dol-lars). http://www.statista.com/statistics/320301/predicted-annual-testosterone-drug-revenues-in-the-us/.

2. Yeap BB, Alfonso H, Chubb SA, et al. In older men an optimal plasma testosterone is associated with reduced all-cause mortality and higher dihydrotestosterone with re-duced ischemic heart disease mortality, while estradiol levels do not predict mortality. J Clin Endocrinol Metab. 2014;99:E9-18.

3. Dias JP, Melvin D, Simonsick EM, et al. Effects of aromatase inhibition vs. testoster-one in older men with low testosterone: randomized-controlled trial. Andrology. 2016;4: 33-40.

4. Sato K, Iemitsu M. Exercise and sex steroid hormones in skeletal muscle. J Steroid Biochem Mol Biol. 2015;145 :200-205.

SEXUAL SYMPTOMSOF LOW T

NON-SEXUAL SYMPTOMSOF LOW T

SIGNSOF LOW T

Diminished libido Fatigue Decreased bone density

ED Decreased energy/motivation Body composition

Change in orgasm experience Depressed mood/irritabilty Anemia

Delayed or absent orgasm Decreased muscle mass/strength

Reduced ejaculate volume Increased fat (abdominal)

Decreased sense of well-being

Table 2. Symptoms and signs of androgen defi ciency in men.

Michael Samoszuk, MD, serves as

Chief Medical Offi cer for Beckman Coulter, Inc.

8. Brambilla DJ, Matsumoto AM, Araujo AB, McKinlay JB. The effect of diurnal varia-tion on clinical measurement of serum testosterone and other sex hormone levels in men. J Clin Endocrinol Metab. 2009;94:907-913.

9. Bebb RA. Testosterone defi ciency: practical guidelines for diagnosis and treatment. BCMJ. 2011;53:474-479.

10. Bhasin S, Cunningham GR, Hayes FJ, et al. Task Force, Endocrine Society. Testos-terone therapy in men with androgen defi ciency syndromes: an Endocrine Society clini-cal practice guideline. J Clin Endocrinol Metab. 2010;95:2536-2559.

11. Finkelstein JS, Yu EW, Burnett-Bowie SA. Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med. 2013;369:1011-1022.

12. Morgentaler A, Khera M, Maggi M, Zitzmann M. Commentary: who is a candidate for testosterone therapy? A synthesis of international expert opinions. J Sex Med. 2014;11:2636-2645.

13. Paduch DA, Brannigan RE, Fuchs EF, Kim ED, Marmar JL, Sandlow JI. The labora-tory diagnosis of testosterone defi ciency. Urology. 2014;83:980-8.

14. Bhasin S, Jameson J. Disorders of the Testes and Male Reproductive System. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. eds. Harrison’s Principles of Internal Medicine, 19e. New York, NY: McGraw-Hill; 2015. http://accessmedicine.mh-medical.com/content.aspx?bookid=1130&Sectionid=79752467.

15. Woodworth A, Lakhani V, Aleryani SL, Laposata M. The Endocrine System. In: Laposata M. eds. Laboratory Medicine: The Diagnosis of Disease in the Clinical Labora-tory. New York, NY: McGraw-Hill; 2014. http://accessmedicine.mhmedical.com/content.aspx?bookid=1069&Sectionid=60777928.

16. Ho CK, Stoddart M, Walton M, Anderson RA, Beckett GJ. Calculated free testos-terone in men: comparison of four equations and with free androgen index. Ann Clin Biochem. 2006;43:389-397.

17. Wu FC, Tajar A, Pye SR, et al. European Male Aging Study Group. Hypothalamic-pituitary-testicular axis in older men are differentially linked to age and modifi able risk factors: the European Male Aging Study. J Clin Endocrinol Metab. 2008;93:2737-2745.

18. Smith HS, Elliott JA. Opioid-induced androgen defi ciency (OPIAD). Pain Physician. 2012;15(3 Suppl):ES145-156.

19. Camacho EM, Huhtaniemi IT, O’Neill TW, et al. Age-associated changes in hypotha-lamic-pituitary-testicular function in middle-aged and older men are modifi ed by weight change and lifestyle factors: longitudinal results from the European Male Ageing Study. Eur J Endocrinol. 2013;168:445-455.

20. Kaltenboeck A, Foster S, Ivanova J, et al. The direct and indirect costs among U.S. privately insured employees with hypogonadism. J Sex Med. 2012;9:2438-2447.

21. Wittert G. The relationship between sleep disorders and testosterone. Curr Opin Endocrinol Diabetes Obes. 2014;21:239-243.

22. Tan RS, Cook KR, Reilly WG. High estrogen in men after injectable testosterone therapy: the low T experience. Am J Mens Health. 2015;9:229-234.

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MLO and Northern Illinois University (NIU), DeKalb, IL, are co-sponsors

in offering continuing education units (CEUs) for this issue’s article

DIAGNOSING ANDROGEN DEFICIENCY IN ADULT MEN. CEUs or contact

hours are granted by the College of Health and Human Sciences at

Northern Illinois University, which has been approved as a provider of

continuing education programs in the clinical laboratory sciences by the

ASCLS P.A.C.E.® program. Approval as a provider of continuing education

programs has been granted by the state of Florida (Provider No. JP0000496).

Continuing education credits awarded for successful completion of this

test are acceptable for the ASCP Board of Registry Continuing Competence

Recognition Program. Readers who pass the test successfully (scoring 70%

or higher) will receive a certifi cate for 1 contact hour of P.A.C.E.® credit.

Participants should allow three to fi ve weeks for receipt of certifi cate. The

fee for this continuing education test is $20. This test was prepared by Amanda Voelker, MPH, MT(ASCP), MLS Clinical Education Coordinator, School of Allied Health and Communicative Disorders, Northern Illinois University, DeKalb, IL.

TEST QUESTIONS

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P = Poor; E = Excellent

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P E 2. To what extent was the article

well-organized and readable?

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Tests can be taken online or by mail.Easy registration and payment options

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TEST ANSWER FORM DIAGNOSING ANDROGEN DEFICIENCY IN ADULT MEN

April 2016 [This form may be photocopied. It is no longer valid for CEUs after October 31, 2017.)

PRINT CLEARLY

CON TINUING EDUCATION T ES T - DIAGNOSING ANDROGEN DEF ICIENCY IN

ADULT MEN

1. What factors have led to an explosive increase in the prescription of testosterone replacement therapy (TRT) in men?

a. increased public awareness b. changing demographicsc. an increase in interest in

weight-lifting by mend. both a and b

2. What risk factor has most recently added to the controversy associated with men receiving TRT?

a. kidney diseaseb. muscular/joint complicationsc. cardiovascular complications d. none of the above

3. Testosterone levels in men begin to decrease at what age and at approximately what rate?

a. 40 years old, 2% per year b. 50 years old, 1% per yearc. 50 years old, 2% per yeard. 40 years old, 1% per year

4. Currently, there is controversy regarding the diagnosis and treatment of adult-onset hypogonadism, with a primary debate over whether or not it is a normal physiologic process or abnormal and requiring treatment.

a. True b. False

5. What are the two metabolites of testosterone?

a. estradiol and DHT b. estradiol and estronec. DHT and estroned. none of the above

6. Which metabolite of testosterone has been found to be three to 10 times more potent than testosterone itself?

a. estradiolb. DHTc. estroned. progesterone

7. What laboratory methods are used to measure total testosterone?

a. immunoassayb. mass spectroscopyc. both a and b d. neither a nor b

8. The current recommendation is for blood specimens for total testosterone testing to be drawn upon awakening in the morning.

a. Trueb. False

9. What additional specimen collection measure(s) is/are recommended to ensure accurate diagnosis of androgen defi ciency?

a. fasting blood specimenb. two or three collections taken

on different days c. two collections per day; one in

morning and one in eveningd. all of the above

10. According to the article, current laboratory diagnostic criteria of androgen defi ciency are of concern because of the following factors:

a. There is considerable variation in the reference ranges among different reference laboratories.

b. There is controversy about the lower end of the limits used to establish the reference range.

c. The population used to defi ne the reference range has been poorly defi ned.

d. all of the above

11. A new recommended approach in diagnosing androgen defi ciency is to

a. establish a whole new reference range.

b. use clinical features of the patient.

c. use clinical threshold cutoff numerical values.

d. all of the above

12. According to Table 2, what clinical symptoms appear to be the most useful indicators of potential androgen defi ciency?

a. sexual symptoms b. non-sexual symptomsc. other signs/symptomsd. all of the above

13. Besides aging, what are two of the most signifi cant factors in reduced testosterone in men?

a. overtraining and diabetes b. chronic opioid use and obesity c. obesity and diabetesd. AIDS and hypertension

14. What factor seems to be both a cause and an effect of low testosterone?

a. overtrainingb. poor sleep c. hypertensiond. diabetes

15. What laboratory test shows promise for future use in the management of testosterone therapy?

a. DHTb. estradiol c. free testosteroned. total/free testosterone ratio

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A GUIDE TO MOL ECUL A R DIAGNOS TICS

Cancer has been a scourge of human-ity for as long as we know, with written descriptions extending back

at least as far as the Ebers and Smith papyri, estimated to have been written around 1600 B.C. and postulated to be derived from earlier sources from circa 2500 B.C. As such, it has been subjected to intensive study, perhaps more so than any other single class of ailment. The pace of progress in battling cancers has steadily accelerated, and a relatively new tool—the oncogene panel—is beginning to prove its value. In this month’s Primer we’ll examine briefl y what these MDx tools do, and how they are both changing our understanding of cancer and, in some instances, allowing for effective applica-tion of what might otherwise have been unlikely treatment options.

On the surface, cancers are mislead-ingly simple pathologies. Cells making up the various organs and systems of the body can replicate, and normally only do so when required for development or repair; replication ceases when the cells making up an organ system reach their required size and functions. Simplistical-ly, cancer occurs when replication of a cell becomes uncontrolled and a single cell divides repeatedly to become a tumor, ignoring and overrunning surrounding tissues. This physical disruption of well-behaved cells by tumor tissue leads to disruptions in proper organ function and all of the downstream consequences.

Traditionally a major tool in classify-ing and directing treatment of cancers has been through identifi cation of the underlying cell type which has become dysregulated. Cancers sharing an origin type such as lymphoma, lung cancer, or colon cancer might reasonably be expect-ed to share commonalities in pathology, disease progression, and best treatment strategies. In reality, however, it is ob-served that cancers sharing overt similari-ties in terms of cell type, appearance, and progression stage may respond quite dif-ferently to the same drug treatment. We are beginning to appreciate that for some cancer types that have been known under a single name, individual cases can be just that—individual, with regard to the root defects and thus best treatment strategies.

To understand this a bit better and the role of oncogene panels, we should go back to the basic concepts of cell divi-sion and its regulation. There are large numbers of highly complex multistep biochemical pathways which either act to turn on cell division or to shut it off. Individual cells are controlled by several such pathways simultaneously, and for progression to cancer generally several of these pathways have to be disrupted in a coordinated fashion. This adds com-plexity to the underlying cause, but also suggests that effective treatment might be possible through blocking any one of the dysregulated paths. The questions, then, are: “Which path?” and “Where can we block it?” These are the questions that oncogene panels seek to directly answer.

Pathways to malignancyLet’s consider a hypothetical pathway re-lating to cell division, as sketched out in Figure 1. This consists of an extracellular signal “ligand”(1); a trans-membrane re-ceptor spanning across the membrane of the cancer cell, with extracellular receptor domain (2); an intracellular effector do-main (3); an intracellular secondary mes-senger (4); and a transcription factor (6) with its inhibitory partner (5).

If this represents a pro-replication sig-nal pathway, then it would function effec-tively as follows: a positive signal (such as a growth hormone (1), binds (2), causing an activating conformational change in (3); this enzymatically transiently modi-fi es (4), which in its modifi ed state causes inhibitory subunit (5) to release (6), which now translocates to the nucleus, binds specifi c signal sequences in the DNA upstream of a pro-replication gene, and upregulates or induces transcription of the product RNA, which then is trans-lated to an active protein which function-ally proceeds to drive a cell division cycle (providing other required pro-replication factors are present, and anti-replication factors are absent—thus the above state-ment on need for multiple coordinated errors before cancer occurs). This whole pro-division pathway acts for a fi nite time, as the ligand at (2) is released or internalized and degraded, the modi-fi cation of (4) decays off, and the RNA

transcript and fi nal protein product both undergo normal turnover processes. Note that we could just as easily postulate this model for an anti-replication pathway, if we called ligand (1) a negative signal such as contact inhibition, and the RNA codes for a replication inhibitory protein; for sake of argument, though, we’ll stick to a pro-replicative model for now.

With this pathway model in mind, let’s ask ourselves what different changes could occur to be cancer-causing (pro-oncogenic). Some immediate possibilities could include:

• Excess or inappropriate expression of ligand (1);

• Alteration of the transmembrane recep-tor, either in domain (2) or (3), such that it behaves as if ligand is bound even when it’s not;

• Alteration of secondary messenger (4) so it’s constitutively active, thus con-stantly relaying a signal from (3) that’s not really there; or

• Alteration of (5) such that it loses ability to sequester and inactivate (6).

These are hardly exhaustive or exclu-sive, and the reader is invited to try to postulate some other possible pro-on-cogenic changes to our model path. For instance, consider alteration of the DNA creating a binding site for (6) upstream of a pro-replication gene where it shouldn’t be, such that a signal intended for some-thing unrelated to replication is now “un-derstood” by the cell as a signal for repli-cation. If that sounds far-fetched, it isn’t; essentially that’s the basis of Burkitt’s lymphoma, where the promoter DNA for IgG heavy chain production gets fused in front of a pro-replication gene c-Myc; signals for the cell, which are intended to cause it to make antibodies, now make it go into a cell-division cycle.

Clinical implicationsThe point of this hypothetical pathway and exercise in imagining all the ways in which it can become dysregulated is to begin to appreciate that two cells of the same type, both of which have become cancerous through inappropriate acti-vation of the same pathway, may have done so through very different under-lying changes. Both will present, on the

Oncogene panels: a window into the individuality of cancersBy John Brunstein, PhD


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THE PRIMER A GUIDE TO MOL ECUL A R DIAGNOS TICS

surface (or perhaps we should say, in thin sections below the surface, as seen through the pathologist’s microscope) as very similar, or even identical. Likely both will respond similarly to crude chemotherapies, such as those which generically block DNA replication; how-ever, those chemotherapies are also, for obvious reasons, the ones with the worst side effects. As our knowledge of the mechanisms of cancer have increased, so too have the clinician’s options for highly targeted drug therapies which can block or interfere very specifi cally with steps on the pathway. For oncogenic pathways similar to our model, drugs exist which can bind and inactivate (2) from binding excess or ectopic ligand (1); others block the activation of secondary messenger (4), or interfere with the binding of (6) to its target DNA sequence.

In the right setting, these drugs can be highly effective. For instance, some types of lung cancer originate through dysregulation of a pathway very similar to our model, through overexpression of ligand—and highly specifi c drugs have been developed which bind and mask the receptor extracellular domain (2) to stop it from responding to the ligand. These drugs, while expensive, are highly

effective, in this case in halting further progression. However, in some cases which present with identical appearance, the defect occurs in (4), (5), or (6)—in the parlance of signal transduction biology, “downstream” from the receptor and point of drug action. In these cases ad-ministration of the drug is ineffective and possibly harmful, as valuable time is lost before observing that it’s ineffective.

The key to using these pathway and step-selective drugs in an effective man-ner is therefore to know, on a highly indi-vidual basis, what the exact set of genetic changes in the cancer cell is, so that a drug with appropriate point of action can be selected—something downstream of at least one of the critical mutations. (Re-member, usually multiple coordinated mutations must be active to result in full-on cancer; so interfering with even one of these may be enough to stop progression.) Thanks to years of research and the Hu-man Genome Project, cancer researchers now know of literally hundreds of genes whose products play known roles in the multiple pathways promoting or supress-ing cell division. They also have detailed libraries of mutations in these genes, known to lead to unwanted activation or inactivation of the gene product.

John Brunstein, PhD, is

a member of the MLO

Editorial Advisory

Board. He serves as

President and Chief

Science Offi cer for

British Columbia-based

PathoID, Inc., which

provides consulting for development and

validation of molecular assays.

Oncogene panelsAn oncogene panel is a targeted next-generation sequencing (NGS) approach, which can take a patient sample (from tumor tissue, not unaffected tissue) and simultaneously sequence all of these hundreds of understood genes on cell division control pathways. The exact platform and sequencing method is unimportant; from a technical stand-point, however, it is worth noting that the amount of sequence data needed per patient is relatively small on an NGS scale, allowing for multiplexing of many patient samples in a single instru-ment run and bringing per-patient costs down. The key comes in bioinformatics, where the resulting per-patient data is examined against known sequences and pathogenic sequence variants for each of the genes examined. By doing this, oncologists can obtain a highly detailed picture of each of the points of dysregu-lation in a specifi c tumor; with luck, one or more of these may be the target (or im-mediately upstream of the target) for an available specifi c drug. Rather than treat-ing all cancers as the same, oncologists now begin to have the ability to select a treatment which is customized to the unique root cause.

Already, the literature is beginning to include reports where use of an on-cogene panel has identifi ed that a can-cer presenting as one type (based on cell type and appearance) is discovered at a genetic level to share commonali-ties with another very different cancer type—for which a specifi c drug is avail-able. Informed by the oncogene panel results, use of a chemotherapeutic agent which would not otherwise have been considered has yielded highly effective treatments in these cases. While this opens complexities related to appropri-ate drug labeling—whether it should be more related to specifi c genetic defect, than to cancer class—the increasing use of oncogene panels and the concomitant development of yet more therapeutic agents targeted to specifi c pathways promise to provide signifi cant advances in the treatment of cancers as highly individual presentations.

Figure 1. Hypothetical pathway relating to cell division.


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ADS-01466-001 Rev. 001 © 2016 Hologic, Inc. All rights reserved. Hologic, The Science of Sure, Aptima, Panther, ThinPrep and associated logos are trademarks and/or registered

trademarks of Hologic, Inc. and/or its subsidiaries in the United States and/or other countries. This information is intended for medical professionals in the U.S. and is not intended as

a product solicitation or promotion where such activities are prohibited. Because Hologic materials are distributed through websites, eBroadcasts and tradeshows, it is not always

possible to control where such materials appear. For specific information on what products are available for sale in a particular country, please contact your local Hologic representative

or write to [email protected].

For more information visit AptimaHPV.com

Run the AHPV assays from a single ThinPrep® patient sample - on the Panther® system.

The Aptima HPV assays detect both HPV presence and activity to target the infections most likely to lead to cervical disease.

Don’t just sense a presence.

Sense a threat.

MLO201604_AD Hologic.indd 21MLO201604_AD Hologic.indd 21 3/10/2016 4:44:47 PM3/10/2016 4:44:47 PM


mRNA-based hrHPV assay in cotesting mRNA-based hrHPV assay in cotesting for cervical cancer screeningfor cervical cancer screeningBy Juan Felix, MD

distinguishing the minority of HPV infections or lesions prone to progression from the vast majority likely to regress. Improv-ing the ability to make this distinction would limit unnecessary follow-up costs.

There are currently fi ve nucleic acid-based hrHPV assays available in the U.S. for cervical cancer screening.7,8 Four of the assays analyze HPV DNA; one analyzes HPV messen-ger RNA (mRNA). By detecting HPV mRNA, as opposed to DNA, this latter test identifi es expression of HPV E6 and E7 oncoproteins.

Comparing specifi cityNumerous studies have demonstrated that the mRNA-based hrHPV assay has higher clinical specifi city for detection of cer-vical cancer lesions than DNA-based hrHPV assays 8-10 (Figure 1). The underlying explanation for improved specifi city is detec-tion of mRNA encoding E6 and E7 oncogenic proteins indicating lesion progression to invasive cancer. When E6 and E7 proteins are detected, as opposed to HPV DNA detection indicating vi-ral presence only, fewer false positive test results have been re-ported. A recent study by Reid et al. demonstrated a 24 percent reduction in false positive test results with mRNA-based com-pared with DNA-based hrHPV assays.11 Whether mRNA-based hrHPV testing performs comparably to DNA-based hrHPV test-ing in a cervical cancer screening protocol was also explored in this study.

Comparing sensitivity The Reid study compared the clinical performance of DNA-based hrHPV assays and an mRNA-based hrHPV assay using a cotest strategy for cervical cancer screening in a cohort of 10,860 women aged 30 years or older.11 The cumulative three-year ab-solute risk for CIN3 (cervical intraepithelial neoplasia) or higher was comparably low for either test for women with a negative result, indicating both tests provide a high negative predictive

value (Figure 2). In contrast, and consistent with current U.S. cervical cancer screening,12 a similar signifi cantly greater risk of CIN3 or higher with either test was observed for women with positive results. Together these data, and other studies,8-10

indicate that cotesting with mRNA-based compared with DNA-based hrHPV assays de-livers equivalent clinical sensi-tivity, but mRNA-based testing was more specifi c for detection of CIN2 or worse.

Comparing cost-effectiveness The impact of the improved specifi city on cost-effectiveness of cervical cancer screening was investigated in a study by Ting et al.13 that compared costs and

The dramatic decline in cervical cancer in women is attribut-able fi rst to screening with the Papanicolaou (Pap) test, fol-lowed later by the addition of the human papilloma virus

(HPV) test, which enhanced screening sensitivity.1,2 In keeping with this excellent performance record, the current standard of care for cervical cancer screening for most women (those over 30), as currently recommended by U.S. guidelines, is cotesting with Pap and HPV tests.3,4 In 2014, the Food and Drug Admin-istration (FDA) approved an HPV assay to be used alone as a primary screening test,5 initiating a debate about what is the best way to detect cancer.

Since this FDA decision, a retrospective, cross-sectional analy-sis performed in 256,648 women demonstrated that HPV-alone testing missed 18.6 percent of 526 cervical cancer cases detect-ed by cotesting.6 The challenge is to improve screening cost-effectiveness without compromising effi cacy, and the notion that screening with one test may be more cost-effective than two tests seems reasonable upon fi rst consideration—but closer ex-amination reveals this assumption to be wrong. Understanding the cost-benefi t ratio of screening methods requires a thorough analysis of HPV assay technologies, what they detect, and how these factors infl uence the cost-effectiveness of cervical cancer screening.

Assays for HPV detectionNot all HPV assays are the same, and the fi rst step in understand-ing their differences is to review the relationship between HPV and cervical cancer. Cervical cancer is predominantly caused by a small group of 14 genetically related high-risk (hr) HPV spe-cies, and more than 70 percent of cervical cancers are caused by the hrHPV 16 and 18 genotypes.2 The majority of hrHPV infec-tions spontaneously regress; however, persistent hrHPV infec-tion and expression of the E6 and E7 oncoproteins are associated with neoplastic transformation. The hurdle that must be over-come to improve cervical cancer screening cost-effectiveness is

Figure 1. Studies demonstrating higher clinical specifi city with mRNA-based assay.

HP VCLINICAL ISSUES

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5. Laine S. FDA approves fi rst human papillomavirus test for primary cervical can-cer screening http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm394773.htm Published April 24, 2014.6. Blatt AJ, Kennedy R, Luff RD, Austin RM, Rabin DS. Comparison of cervical cancer screening results among 256,648 women in multiple clinical practices. Cancer Cytopa-thol. 2015;123(5):282-288.7. The fi ve FDA-approved HPV assays. MLO. 2012;44(7):14-18.8. Luhn P, Wentzensen N. HPV-based tests for cervical cancer screening and man-agement of cervical disease. Curr Obstet Gynecol Rep. 2013;1(2):76-85.9. Haedicke J, Iftner T. A review of the clinical performance of the Aptima HPV assay. J Clin Virol. 2015, Nov 6. 10. Iftner T, Becker S, Neis KJ, et al. Head-to-head comparison of the RNA-based Ap-tima human papillomavirus (HPV) assay and the DNA-based hybrid capture 2 HPVtest in a routine screening population of women aged 30 to 60 years in Germany. J Clin Mi-crobiol. 2015;53(8):2509-2516. 11. Reid JL, Wright TC Jr, Stoler MH, et al. Human papillomavirus oncogenic mRNA testing for cervical cancer screening: baseline and longitudinal results from the CLEAR study. Am J Clin Pathol. 2015;144(3):473-483.12. Gage JC, Schiffman M, Katki HA. Reassurance against future risk of precancer and cancer conferred by a negative human papillomavirus test. J Natl Cancer Inst. 2014;106(8). 13. Ting J, Smith JS, Myers ER. Cost-effectiveness of high-risk human papillomavirus testing with messenger RNA versus DNA under United States guidelines for cervical cancer screening. J Low Genit Tract Dis. 2015;19(4):333-339. 14. Castle PE, Eaton B, Reid J, Getman D, Dockter J. Comparison of human papilloma-virus detection by Aptima HPV and cobas HPV tests in a population of women referred for colposcopy following detection of atypical squamous cells of undetermined signifi -cance by Pap cytology. J Clin Microbiol. 2015;53(4):1277-1281. 15. Monsonego J, Hudgens MG, Zerat L, Zerat JC, Syrjänen K, et al. Evaluation of onco-genic human papillomavirus RNA and DNA tests with liquid-based cytology in primary cervical cancer screening: the FASE study. Int J Cancer. 2011;129(3):691-701. 16. Felix JC, Lacey MJ, Miller JD, Lenhart GM, Kulkarni R. Cost-effectiveness of DNA and mRNA based cervical cancer screening strategies: Preliminary results from an economic modeling analysis. Presented at 30th International Papillomavirus Confer-ence and Clinical Workshop Lisbon, Portugal September 17-21, 2015.17. Felix JC, Lacey MJ, Miller JD, Lenhart GM, Kulkarni R. Clinical-economic modeling analysis of human papillomavirus (HPV) cotesting with genotyping versus primary HPV testing for cervical cancer screening. Value Health. 2015;18(7):A353.

Juan Felix, MD, serves as Professor of

Clinical Pathology and Obstetrics &

Gynecology at the University of

Southern California Medical Center.

Among his areas of expertise is

gynecologic pathology and cytology.

health outcomes between mRNA-based and DNA-based hrHPV assays in the context of current U.S. cer-vical cancer screening guidelines. Screening effi ciency was examined using two different screening strategies: cotesting with HPV and liquid-based cytology in wom-en 30 to 65 years; and triage of women with mild cervical cytological abnormalities (ASC-US) in the United States. A Markov model for stochastic cost-effectiveness analy-sis was constructed using data from the Reid study and another by Monsenego et al.,13-15 both conducted in pop-ulation-based settings. The model followed a theoreti-cal cohort of women from age 12 to 100 years, not vac-cinated for HPV, and assumed that at the beginning of the simulation that no woman was infected with HPV, or had CIN or cancer.

For both cotesting and ASC-US triage screening pro-tocols, mRNA-based hrHPV testing cost less than DNA-based hrHPV testing; however, differences between the protocols were not statistically signifi cant.13 To better estimate cost-effectiveness differences, an analysis of willingness-to-pay thresholds was performed. Results indicated a 100 percent probability that DNA-based testing was not cost-effective, relative to mRNA-based testing, at the $100,000 per life-year saved threshold for ASC-US triage, and a 50 percent probability that DNA-based testing was not cost-effective at the $100,000 per life-year saved threshold for cotesting.

Preliminary results from another study16,17 comparing cost-effectiveness between cotesting with an mRNA-based hrHPV assay and a DNA-based hrHPV assay alone found that mRNA-based cotesting (combined with follow-up genotyping) provided improved clinical and economic outcomes.

These studies show cervical cancer screening effi ciency can be affected by the type of HPV assay used as well as the overall strategy. Results from these studies provide evidence that co-testing with an mRNA-based hrHPV assay is more likely to be cost-effective than DNA-based hrHPV testing, whether DNA-based hrHPV testing was used in cotesting or alone as a primary screening strategy.

It is worth noting that DNA-based primary screening has not been recommended by screening guidelines at this time. The cost-benefi t associated with the mRNA-based hrHPV assay ob-served in these analyses arises from the improved specifi city of the mRNA-based assay that detects expression of HPV oncogen-ic proteins, as opposed to DNA-based testing that reports only presence of the virus. The ability to detect expression of HPV on-cogenic proteins favors the distinction between HPV infections that will progress to cervical cancer from those that will regress, leading to fewer cases where HPV nucleic acids are detected but disease is not present. The information provided by an mRNA-based hrHPV assay result gives healthcare providers and pa-tients greater assurance about whether or not there is a need for follow-up procedures. The improved specifi city of mRNA-based hrHPV assays, together with improved sensitivity of mRNA-based hrHPV assay cotesting compared with DNA-based hrH-PV testing, suggest transitioning to DNA-based hrHPV testing alone as a primary screening would be not only less effi cacious, but also more costly.

REFERENCES

1. GLOBOCAN Cancer Fact Sheet. Cervical cancer estimated incidence, mortality, and prevalence worldwide in 2012. http://globocan.iarc.fr/old/FactSheets/cancers/cervix-new.asp.2. Schiffman M, Solomon D. Clinical practice. Cervical-cancer screening with human papillomavirus and cytologic cotesting. N Engl J Med. 2013;369:2324-2331. 3. Saslow D, Solomon D, Lawson HW, et al. American Cancer Society, American Soci-ety for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. J Low Genit Tract Dis. 2012;16(3):175-204. 4. Massad LS, Einstein MH, Huh WK, et al. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. 2012 ASCCP Consensus Guidelines Conference. Obstet Gynecol. 2013;121(4):829-846.

Editor’s note: Please note that some of the studies cited in this article were sponsored by the manufacturer of the mRNA-based hrHPV assay to which the article alludes.

Figure 2. Cumulative absolute risk for CIN3 or worse according to test result.

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EDUCATION M ASS SPEC T ROME T RY

Emerging applications in Emerging applications in clinical mass spectrometryclinical mass spectrometryBy Lisa Thomas, BS, MBA

diseases, monitor drug therapy, analyze peptides and proteins for diagnostic testing, and identify causes of infections for targeted therapies.2,3

Technology drivers of mass spectrometry The American Association for Clinical Chemistry (AACC) and Mass Spectrom-etry and Separation Sciences (MS3) car-ried out a survey of 63 clinical laboratory representatives to determine the outlook for clinical mass spectrometry testing. Results indicate the current demands that are likely to drive the future technol-ogy trends in clinical mass spectrometry.

The organizations asked: Of the en-vironments where mass spectrometry tools ARE NOT currently in use, in which ones would you like to see the technology take hold by 2020? The most frequent answers are shown in Figure 1, below. Other uses that were specifi ed by the survey respon-dents include continued immunoglobu-lin work, protein analysis, and peptide determinations, and large molecule bio-analysis. To support new clinical mass spectrometry applications, laboratories expect to see improved technical func-tionality to automate sample acquisition and preparation as well as data analysis and reporting.

Mass spectrometry (MS) is being used by an increasing number of clinical laboratories to mea-

sure small sample volumes with im-proved confi dence across an expanding range of healthcare applications—from toxicology to personalized medicine. Enhanced assay performance and new laboratory-developed test (LDT) meth-ods offer rapid results at a reduced cost and potentially more clinically relevant information, enticing more clinical core testing laboratories to implement mass spectrometry technology.

Current clinical mass spectrometry applicationsWith origins in basic research, mass spectrometry emerged as a clinical re-search tool when it was fi rst applied to fi ngerprint molecules for drug screen-ing in the fi ght against drugs of abuse. Since then, the technique has evolved, and with the advent of tandem mass spectrometry (MS/MS) technology to support targeted experimental test-ing—combined with separation tech-nologies such as gas chromatography (GC), liquid chromatography (LC), and ion mobility spectrometry (IMS)—ever smaller concentrations and metabolites can be targeted. Macromolecule ioniza-tion methods, such as electrospray ionization (ESI) and matrix-as-sisted laser desorption/ionization (MALDI), enable the study of pro-tein structure.

The adoption of liquid chroma-tography-tandem mass spectrom-etry (LC-MS/MS) for small mol-ecule targeting and translational clinical applications was driven by a need for higher immunoas-say accuracy, a lack of availability in approved immunoassays, and the desire for cost reduction. While sample preparation can be more labor-intensive than immunoas-says and an ever-increasing de-mand for automation integration, in-house mass spectrometry-based assays can be cost-effective, even for smaller labs.1

MS technology is now routinely applied in clinical laboratories to improve the sensitivity and speci-fi city of clinical tests, screen for

AACC and MS3 also asked: In 2020, which of the following laboratory processes would you anticipate will be automated on your mass spec testing line? The responses are shown in Figure 2 on page 28.

Advancing technologies and potential applicationsRecent advances in clinical research and MS technology promise even more so-phisticated extensions to current clinical applications and potential new LDTs.

Matrix assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) now supports direct tis-sue analysis with diagnostic potential and reduced analysis time.5 Pathologists are now able to examine biological tis-sue directly, detecting cancerous tissue in real time during an operation using MS with smart electroknives.6 Mass spec-trometry imaging (MSI) enables histolo-gists to defi ne tissue types by chemical composition rather than structure.7

Able to distinguish and measure the separate contributions of molecules such as the 25-hydroxy vitamins D2 and D3 and thyroid hormones, MS/MS meth-ods have enabled clinical laboratories to overcome the limitations of immuno-assays caused by nonspecifi c antibody binding and cross-reactivity with me-

tabolites.8 Endocrinologists are also now investigating a “lab on a plate” method to more accurately predict risk of heart attack and stroke in di-abetes patients.6 Application of MS technology in clinical and transla-tional research is opening up new lines of discovery in blood-based biomarkers, tumor markers, and even endogenous metabolites as new disease biomarkers.9,10

More sensitive urine screening methods capable of detecting de-signer drugs are available in the market, and vendor investments assure continued development. Some clinical research and foren-sic toxicology laboratories already use high-resolution, accurate-mass (HRAM) or time-of-fl ight (TOF) MS, for multi-analyte drug screens. Whereas triple quad-based tech-niques can quantitate targeted ana-lytes, newer HRAM systems can simultaneously detect and deliver

Figure 1. Results from a survey of 63 clinical laboratory representatives. SOURCE: AACC / MSSS Outlook for Clinical Mass Spec Testing Q13 p15 4


MLO201604-Education_MECH_AL.indd 24MLO201604-Education_MECH_AL.indd 24 3/14/2016 8:29:04 AM3/14/2016 8:29:04 AM

The Specialist Protein Company

www.thebindingsite.com

MLO201604_AD BindingSite.indd 25MLO201604_AD BindingSite.indd 25 3/10/2016 4:48:30 PM3/10/2016 4:48:30 PM

ADS-01326-001 Rev. 001 © 2015 Hologic, Inc. All rights reserved. Hologic, Science of Sure, Pap+HPV Together, ThinPrep and associated logos are trademarks and/or registered trademarks of Hologic, Inc. and/or its subsidiaries in the United States and/or other countries. All other trademarks, registered trademarks, and product names are the property of their respective owners. This information is intended for medical professionals in the U.S. and is not intended as a product solicitation or promotion where such activities are prohibited. Because Hologic materials are distributed through websites, eBroadcasts and tradeshows, it is not always possible to control where such materials appear. For specific information on what products are available for sale in a particular country, please contact your local Hologic representative or write to [email protected].

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* A positive HPV screening result may lead to further evaluation with cytology and/or colposcopy.

Reference: 1. Blatt AJ, Kennedy R, Luff RD, Austin RM, Rabin DS. Comparison of cervical cancer screening results among 256,648 women in multiple clinical practices. Cancer Cytopathol. 2015 April (Study included ThinPrep®, SurePath, Hybrid Capture 2 assay).

One out of 5 cases of cervical cancer were missed with HPV-Alone screening in a recent landmark, retrospective study—the largest ever conducted to evaluate the effectiveness of cervical cancer screening strategies in women ages 30-65.1* And screening with Pap+HPV Together™ (co-testing) identified more than 70% of those missed cancers.1 So is HPV-Alone screening really worth the risk?

Recommend screening with Pap+HPV Together to your customers. Because every woman deserves the best possible protection from cervical cancer.

See more data at PapPlusHPV.com.

Screening with HPV-Alone invites more risk into women’s lives than you may think.

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EDUCATION M ASS SPEC T ROME T RY

6. Cutting-edge lab technology used to create labs-on-a-plate, intelligent surgical knives - AACC.org. https://www.aacc.org/media/press-release-archive/2016/janu-ary/cutting-edge-lab-technology-used-to-create-labs-on-a-plate-intelligent-surgical-knives.

7. Mass spectrometry imaging used for tissue analy-sis | the digital pathology blog. http://tissuepathology.com/2014/01/16/mass-spectrometry-imaging-used-for-tissue-analysis/#axzz40Q2HOys2.

8. Soldin SJ, Soukhova N, Janicic N, Jonklaas J, Soldin OP. The measurement of free thyroxine by iso-tope dilution tandem mass spectrometry. Clin Chim Acta. 2005;358(1-2):113-118. doi:10.1016/j.cccn.2005.02.010.

9. Taguchi A, Hanash SM. Unleashing the pow-er of proteomics to develop blood-based cancer markers. Clin Chem. 2013;59(1):119-126. doi:10.1373/clinchem.2012.184572.

10. Psychogios N, Hau DD, Peng J, et al. The hu-man serum metabolome. PLoS One. 2011;6(2):e16957. doi:10.1371/journal.pone.0016957.

11. Carter S, Owen LJ, Kerstens MN, Dullaart RPF, Keevil BG. A liquid chromatography tandem mass spectrometry assay for plasma renin activity using online solid-phase extraction. Ann Clin Biochem. 2012;49(Pt 6):570-579. doi:10.1258/acb.2012.011186.

12. Rhea JM, Ritchie JC, Molinaro RJ. Development of a liquid chromatography tandem mass spectrometry method for iothalamate measurement to assess renal function for potential kidney donation. Clin Chim Acta. 2013;420:104-108. doi:10.1016/j.cca.2012.12.003.

13. Liotta E, Gottardo R, Bertaso A, Polettini A. Screen-ing for pharmaco-toxicologically relevant compounds in biosamples using high-resolution mass spectrometry: a “metabolomic” approach to the discrimination be-tween isomers. J Mass Spectrom. 2010;45(3):261-271. doi:10.1002/jms.1710.

14. Rashed MS, Bucknall MP, Little D, et al. Screening blood spots for inborn errors of metabolism by elec-trospray tandem mass spectrometry with a microplate batch process and a computer algorithm for automated fl agging of abnormal profi les. Clin Chem. 1997;43(7):1129-1141. http://www.ncbi.nlm.nih.gov/pubmed/9216448.

15. Sauer S, Kliem M. Mass spectrometry tools for the classifi cation and identifi cation of bacteria. Nat Rev Mi-crobiol. 2010;8(1):74-82. doi:10.1038/nrmicro2243.

16. Meng Q. Mass spectrometry applications in clinical diagnostics. J Clin Exp Pathol S. 2013:4172. doi:10.4172/2161-0681.S6-e001.

Lisa Thomas, BS, MBA,

serves as senior

director, Clinical,

Forensic, Toxicology

Markets,

Chromatography and

Mass Spectrometry,

for Thermo Fisher Scientifi c. As a former bench chemist,

Lisa has moved quickly from research to

industry. She has developed and globally

marketed scientifi c solutions, medical

devices, software, and professional

services which span numerous markets.

the full product ion spectrum, and retain high selectivity with greater resolution and mass accuracy.

Advanced mass spectrometry meth-ods are producing novel functional assays. Liquid chromatography MS/MS using online solid-phase extraction (XLC-MS/MS) was used to develop a plasma renin activity (PRA) assay for monitoring mineralocorticoid therapy and screening hypertensive individuals for primary aldosteronism (PA).11 A fur-ther LC-MS/MS method for quantifying iothalamate in plasma and urine can ac-curately assess glomerular fi ltration rate (GFR) in early stages of renal dysfunc-tion to screen potential kidney donors.12

Analyte multiplexing and automation deliver superior and highly reproducible data to simplify increasingly sophisti-cated LDT methods and support clinical test validation. HRMS using triple quad-rupole MS/MS is now used to screen and quantify toxic drugs, offering novel metabolomic methods to distinguish be-tween and eliminate candidate isomers.13 Electrospray MS/MS and a computer-assisted metabolic profi ling algorithm can automatically fl ag abnormal pro-fi les in newborns from a single spot of blood.14 Automated MALDI-TOF MS enables clinical microbiology laborato-ries to identify and classify bacteria and other microorganisms.15,16

The impact of mass spec in clinical labsExponential growth in MS methods in clinical laboratories is expected in high-throughput and quantitative clini-cal and translational workfl ows, bacte-rial identifi cation, imaging of tissue sec-tions, diagnostic testing, and functional

assays. Improvements in automation will support validation and seamless com-munication with laboratory information management systems (LIMS) to bring mass spectrometry-based detection into larger and more complex clinical labo-ratories. The development of handheld mass spectrometers will enable clinical measurements in remote environments opening up the possibility of point-of-care applications.1

In conclusion, as technology advances and technological challenges such as sample preparation, online extraction, throughput, automation, and system interfacing are overcome, we can expect the impact of MS in clinical laboratories to mature. “Mass spec” will increas-ingly be relied upon for sensitive, highly reproducible, accurate results.

REFERENCES

1. The Future of Clinical Mass Spectrometry - AACC.org. https://www.aacc.org/publications/cln/ar-ticles/2015/february/future-of-mass-spec.

2. January issue of AACC’s Clinical Chemistry journal sheds light on how mass spectrometry is transforming clinical testing and leading to global improvements in patient health - AACC.org. https://www.aacc.org/media/press-release-archive/2016/january/clinical-chemistry-journal-sheds-light-on-how-mass-spectrometry-is-transforming-clinical-testing.

3. Applications of Mass Spectrometry to the Clini-cal Laboratory. http://www.medscape.com/viewarti-cle/753445_2.

4. Choices A, Vendor I. AACC / MSSS outlook for clini-cal mass spec testing q1 my lab is ... aacc / msss outlook for clinical mass spec testing q2 currently, do you view clinical mass spec applications being used as … ( select all that apply ). 2015:1-17.

5. Norris JL, Caprioli RM. Imaging mass spectrom-etry: a new tool for pathology in a molecular age. Pro-teomics Clin Appl. 2013;7(11-12):733-738. doi:10.1002/prca.201300055.

Figure 2. Results from a survey of 63 clinical laboratory representatives.SOURCE: AACC / MSSS Outlook for Clinical Mass Spec Testing Q9 p10 4


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LAB MANAGEMENT L AB OF T HE Y E A R

physician practice and have all their medical infor-mation available to the healthcare team. Physicians also have access to patient results in Epic.

In recognition of the fact that the time patients spend waiting affects the quality of their healthcare ex-perience, SLS has worked to reduce the amount of time patients spend scheduling procedures and blood draws. SLS partnered with the Transplant, Registration, and IT departments to change the scheduling process so patients can go to any Sentara facility to have draws and other tests performed. SLS also teamed up with the Imaging department to assist with specimen collection in order to expand the service line to patients at multiple points of entry. “Today’s patient has a choice; convenience plays a major role in the selection of laboratory services,” says Kathy Prussock, MT(ASCP), Laboratory Manager.

ProductivitySLS has aggressively adopted automation to reduce turnaround times and increase productivity across the benches. The labs have implemented a line of high-volume chemistry and hematology in-strumentation. An automated sample handler provides the chem-istry lines with a continuous stream of samples. The design and workfl ow of the department ensure that testing never ceases and that the majority of testing panels are available at all times, thereby eliminating the need to perform batch testing.

SLS’s reference Hematology department implemented the automated Sysmex HST-N cell counting line, incorporating cell counters, slide maker, and slide stainer into the workfl ow. The new instrumentation and workfl ow improved the effi ciency of the department even as the workload increased. This was followed by the addition of CellaVision’s automated differential reader, which signifi cantly reduced the turnaround time for differential reporting.

Clostridium diffi cile infection (CDI) has been named a top clini-cal initiative at Sentara. The Microbiology Department, Infectious Disease physician group, and pharmacists work together to pro-vide the right antibiotics to streamline therapy for the patient. In order to enhance detection of CDI, a two-step algorithm utilizing simultaneous detection of C. diffi cile glutamate dehydrogenase with toxin A and B followed by PCR testing, if indicated, is per-formed. This initiative allows quicker identifi cation of C. diffi cile and control of processes and costs. “Microbiology underwent a renovation, leaned the department, brought anaerobe testing back in house, and expanded their hours of culture reading to two shifts. Processes are now more effi cient, and there is a decreased turnaround time for antibiotic reporting, which supports our Antibiotic Stewardship Program, DNV-MIR certifi cations, reduc-tion in CDI, and overall improvement of patient care,” explains Kathy Judge, MT(ASCP), Clinical Specialist of Microbiology.

Based in Norfolk, Virginia, the not-for-profi t Sentara system operates more than 100 sites of care with more than 2,800 hospital beds, including 12 acute care hospitals in Virginia

and North Carolina. The system, which has a 3,800-provider med-ical staff, includes the area’s only Level I Trauma Center, advanced imaging centers, assisted-living and nursing centers, physical therapy and rehabilitation services, home health and hospice ser-vices, and medical transport and air ambulances.

Sentara Laboratory Services (SLS) is a key component of this outstanding, and growing, healthcare system. Sentara laboratories are dedicated to addressing and meeting the clinical diagnostic and monitoring needs of patients throughout Virginia and north-eastern North Carolina. System wide, more than 700 Sentara clini-cal laboratory professionals are vital to the high quality of health-care provided at Sentara’s 12 hospitals. In addition, SLS’s reference laboratory and consolidated laboratories, based in southeast Virginia, perform more than eight million tests annually, serving providers and patients throughout the region. The reference lab includes clinical diagnostics in hematology, chemistry, coagula-tion, microbiology, and transfusion as well as anatomic pathology services. Specialty laboratories include Molecular Diagnostics, Flow Cytometry, and Cytogenetics.

MLO asked those submitting nominations for the 2016 Lab of the Year award to discuss their lab in terms of six criteria: Customer Service, Productivity, Teamwork, Education and Training, Strategic Outlook, and Lab Inspections. SLS gave MLO waaaaaay more interesting information than we have space for in this article, but, to organize the article, we will use those categories as sub-sections—and review some highlights.

Customer serviceSLS has embraced the concept of consumer-driven healthcare and partnered with the Sentara IT team to educate patients in signing up for MyChart, the Sentara Healthcare app which allows patients to view their health information on their personal electronic devic-es. The SLS marketing department created a written step-by-step procedure that patients can use to easily check and see if their test results are available.

SLS recently implemented Epic Beaker and Haemonetics SafeTrace as its laboratory information systems (LIS). This pro-vides a common platform across the organization of Epic hospi-tals and provider practices for a single electronic medical record. Laboratory staff have realized numerous effi ciencies as a result. Workfl ows were adapted to maximize the effi ciency provided by the two new LIS systems. The staff, utilizing the expertise from lab super users and IT, worked together to maintain the highest standard of quality healthcare during the transition.

Patients have benefi ted signifi cantly from the standard plat-form. Additionally, they may present to any hospital, draw site, or

MLO’s 2016 Lab of the Year


By MLO Staff


Sentara Laboratory Services:

Laboratory staff at Chemistry bench

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Losing a specimen is a serious event in any lab, and SLS has introduced an initiative to directly reduce the number of opportu-nities for losing a specimen and the number of resources required in locating samples. As part of this initiative, the laboratory set out to fi nd a waste receptacle that would fi t in its current spaces. The receptacle was to have a solid top and a side opening so no speci-mens could accidentally fall into the can from counters above.

After a search of available receptacle models on the market, and after several model trials, it was determined that the best approach for the system would be to design and have manufactured a cus-tomized receptacle. The design included a single-sized removable lid with two separate openings on opposing sides. The standard lid would fi t three different cans of varying heights and a single footprint size so that they could be used in different lab locations. The design was given to a manufacturer and prototypes were cre-ated. Once approved, the product was placed into production and several receptacles were put in place across the system of labs.

TeamworkLaboratory services were critical components in two of the hos-pitals achieving DNV-MIR (Det Norske Veritas—Managing Infec-tion Risk) certifi cation. The DNV-MIR Standard adopts a structure based on 18 elements covering all areas associated with the de-sign, operation, and management of healthcare facilities. The MIR Standard was developed by DNV to provide a framework to help organizations improve their management of infection risk. This standard is compatible with World Health Organization and U.S. Centers for Disease Control and Prevention (CDC) guidelines.

Two Sentara hospitals were the very fi rst to achieve this cer-tifi cation worldwide. All of the hospital’s ancillary departments

were recognized by the accreditation surveyors as providing out-standing support to the clinical nursing units and for their ability to communicate effi ciently and consistently. Communication and collaboration were key components in achieving the certifi cation.

One large project embraced in 2015 was the start-up of an Ebola Assessment Center at Sentara Princess Anne Hospital. In re-sponse to the Ebola outbreak in Africa and the sudden emergence of patients being treated in the U.S., Sentara was selected as an assessment center. A Task Force was developed to include the col-laboration of many disciplines, and the lab was at the center. Much work was done to decide upon test menus, lab equipment, and staffi ng. Ten lab staff members went through intensive training in order to be able to work in the Center—training that included don-ning and doffi ng of personal protective equipment (PPE), speci-men handling, equipment training, packing and shipping, waste handling, and test result distribution. Several point-of-care testing (POCT) staff provided training on POCT devices to members of the interdisciplinary team. An on-site assessment was conducted by the Virginia Department of Health and a CDC representative in October. When the Ebola crisis passed, the unit was renamed the Highly Infectious Communicable Disease Unit. “This has enabled Sentara to maintain a laboratory at the ready for any highly com-municable disease that may be coming in the future,” notes Dan Scungio, MT(ASCP), SLS, CQA(ASQ), Laboratory Safety Offi cer.

Groundbreaking discoveries in healthcare have brought person-alized medicine to the forefront. The SLS Hematology department partnered with a group of Oncology specialists to provide “target-ed medicine” to improve the level of care delivered to hematology oncology patients. Through this collaboration, pathologists have been provided education on utilizing specifi c algorithms to render




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a diagnosis. The development of new phy-sician order sets improved the processing or ordering of tests and reduced the num-ber of unnecessary tests being performed. Currently, the Hematology department is reviewing the coagulation order sets to further eliminate duplicate and other unnecessary testing.

Teamwork has also been a key to improvements in the SLS labs’ blood banks. To meet the needs of the community, SLS Transfu-sion Service has developed sickle cell protocols. One example: as patients develop more antibodies, it becomes increasingly diffi cult for Transfusion Services to fi nd compatible blood. “Our sickle cell protocol has been very advantageous in preventing allo-immuni-zation to the Rh and Kell blood groups, which makes it easier to fi nd compatible units of blood,” says Noel Janolino, MT(ASCP), Clinical Specialist of Transfusion Services.

Education and trainingAll new employees complete a thorough onboarding process at Sentara. They attend a standard orientation and then deploy to their lab departments, where they are required to demonstrate competencies prior to reporting test results. This includes the tech-nical tasks, as well as general laboratory and safety competencies.

The laboratory competency program is standardized. Sentara has developed tools to meet the needs for the documentation of each method of competency performed. The College of American Pathologists (CAP) reports that competency is the most frequent defi ciency cited during its inspections of laboratories. To address this issue, SLS developed a standardized competency process. A PowerPoint presentation was created to provide education on the CLIA regulations relative to competency and the qualifi cations required to be a competency assessor. The focus was to offer com-petency for a specifi c discipline at a specifi ed time during the cal-endar year to ensure each laboratory is working on the same type of competency at the same time.

To compliment the competency initiative, SLS created an Edu-cation Department that fulfi lls the needs of the laboratory staff and students. The initial focus of the new department will be on stan-dardizing and optimizing the orientation process.

Strategic outlookSLS leaders say the strategic imperative for their system’s opera-tions includes a focus on lab technology and effi ciency and the creation of a lab formulary. “Our focus on technology has always been to ensure that we are using the best equipment to perform the job with our large volumes,” says Tabetha Sundin, PhD, MB (ASCP), Laboratory Director. “After making the selection for equipment that is scientifi cally sound and cost-effective, we strive to standardize the equipment across our health system. This al-lows us effi ciencies such as collective bargaining power, and sharing of resources and best practices. With the ever-rising cost of operating a reference laboratory and impending reimburse-ment cuts, it has become critical to ensure the right tests are being

ordered at the right time. We can control this better with the implementation of a laboratory formulary. This will help us keep cost low, while also providing the necessary results for patient treatment.”

Among the advances that are in SLS’s fi ve-year plan is an increased level of automation in Microbiology, which has already begun with the purchase of an

automated streaker and MALDI-TOF for organism identifi cation. SLS is also looking into smart incuba-tors, digital plate reading, and conveyor belts to pull plates to reading stations, as well as an RFID solu-tion for specimen tracking and the implementation of digital pathology. Lab leaders will also be adding next generation sequencing (NGS) to the molecular diag-nostics laboratory and bedside barcode collection and labeling this year.

They are also considering technology advancements that will have major workfl ow impacts. Hematology will move to a diluent system for concentrated reagents, and sed rates will be automated. The Cytogenetics lab will implement an automated cell harvester, an automated FISH dropper, and a cell separator. Anatomic Pathology is presently validating Peloris processors for dual tissue type protocols and anticipates the use of auto-embed-ders. Molecular testing is already seeing a shift to primary tube-to-answer testing, automating molecular microbiology testing.

Lab inspectionsSLS has had many years of successful inspections, and is both AABB and CAP accredited. Its Lab Quality Department has developed a strong quality system manual.

The Lab Quality Team is responsible for the development and maintenance of a safety manual for lab services, internal audits (quality and safety), investigations, compilation of facility-specifi c and system performance and process monitors (including turn-around times), and involvement with process-improvement and problem-solving teams. They serve as regulatory and accredita-tion resources and liaisons with accreditation and regulatory agencies.

The team conducts internal audits for every laboratory disci-pline and follows up on every fi nding to ensure that all are re-solved and that actions are sustained. They develop LIS reports, and administer document control and competency programs. Members are certifi ed auditors through the American Society for Quality (ASQ) and maintain their expertise with CAP, AABB, CLIA, ISO, and COLA requirements.

“This lab quality program has enabled SLS to achieve high scores with our inspection agencies. We consider each fi nding an opportunity for improvement and work hard to not have a repeat fi nding,” notes Lou Ann Wyer, MS, MT(ASCP), CQA(ASQ), Labo-ratory Director. “We track the total number of standards reviewed with each assessment to monitor trends and types of fi ndings.”

Congratulations to allSentara Laboratory Services convinced the MLO judges that it was indeed the Lab of the Year for 2016, and we congratulate the lab and its leaders for delivering invaluable healthcare services to its patients. Congratulations, too, to the fi rst runner-up and second runner-up labs (see page 36)—and to all who submitted nomi-nations for their labs. Any lab that puts forth maximum effort to serve the public and the profession is a winner. In times of change for the healthcare delivery system in the United States, outstand-ing clinical laboratories are islands of excellence and stability in sometimes raging seas. MLO is proud to honor you all, and to be a voice for the profession.


Luz Thomas, Senior MT, observes Hematology results.

Sarah Holt, MLT, reads a MacCon-key agar plate.

Michelle Kline and Daniel Sanchez verify a specimen in Anatomic Pathology.


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First runner-up: Le Bonheur Children’s Hospital LaboratoryLe Bonheur Children’s Hospital is a 255-bed pediatric hospital located

in Memphis, Tennessee. The hospital and pediatric specialty programs

care for more than 250,000 patients each year. Le Bonheur’s outstand-

ing laboratory makes a vital and integral contribution to the institution’s

success. Here are some marks of particular distinction, in the words of

Le Bonheur’s Lab of the Year nomination:

• “Le Bonheur is a Level One Pediatric Trauma Center and phlebotomy

is an important part of the trauma team. We respond to all ‘Trauma Stats’

and assist the team by accurately and completely labeling the specimens

and personally delivering them to the blood bank and laboratory. This has

eliminated unlabeled and mislabeled samples from traumas and ensures

that the specimens arrive in the blood bank quickly.”

• “Every year our laboratory hosts a Symposium and invites all CLS

and MLTs from the surrounding area to attend. We alternate each year

between the Clinical Laboratory Symposium and the Laboratory Manage-

ment Symposium. The symposium assists the staff with their required

continuing education hours to maintain their license and, if desired, to obtain their Supervisor’s license.”

• “Our Blood Bank has accomplished some amazing things over the past few years. The TEGs were relocated into the blood bank

to provide increased customer service for both the ECMO [Extracorporeal Membrane Oxygenation] program and for the open

heart surgery program, and also in preparation of the cardiac failure/heart transplant program. Since the TEG is mandatory testing

for the Berlin Heart protocol, this helped prepare Le Bonheur for these expanded patient programs.”

• “The laboratory integrated outpatient samples from our pediatric specialty clinics into primarily our core services department.

These additional specimens increased our testing volume by 45 percent and were initially performed by current staff. As volumes

have continued to increase, we did add one FTE to support the OP testing. This additional volume increased our effi ciency and

stabilized our laboratory productivity. Our turnaround time, quality results, and consolidated EMR (patient results from IP and OP

testing are available to the physician) have increased physician satisfaction and patient safety.”

• “The Microbiology Department has implemented the Bruker MALDI TOF. We are now able to identify bacterial pathogens di-

rectly from a blood culture bottle within an hour of it becoming positive on the instrument. This enables the physician to prescribe

the correct antibiotic versus a broad spectrum or ineffective antibiotic. Starting the correct antibiotic quicker potentially shortens

the length of stay and improves outcomes. The MALDI identifi cation also aids the physicians in deciding if a discharged emer-

gency room patient needs to come back to the hospital for IV antibiotics immediately.”

• Our molecular diagnostics lab is designated one of two “Molecular Centers of Excellence” in the United States. We perform

molecular testing primarily for infectious diseases and are in the process of validating next-generation sequencing for cystic fi -

brosis. We support transplant patients across the city by performing testing for the BK virus, CMV, HCV, etc. Our transplant and GI

physicians have been very supportive of the gastric pathogen panel, which tests for 22 targets and results within an hour.”

Second runner-up: Cape Regional Medical Center LaboratoryCape Regional Medical Center (CRMC) is a 242-bed, acute-care facility located in

Cape May Court House, New Jersey. In lab leaders’ own words:

• “The Lab at Cape Regional employs 30 technicians/technologists, a team of

15 in-house Phlebotomists, 10 outreach Phlebotomists, and a professional sup-

port staff consisting of three Client Service Representatives, two transcription-

ists, and a dedicated courier for all our outreach clients.”

• “Our Lab may seem small, but it is quite a powerhouse! The number of re-

ported tests completed every year is approximately 1.5 million; for example, we

perform approximately 340,000 CBCs and more than one million Chemistry tests

annually. Our outpatient volume constitutes 60% of our total volume.”

• “All clinical staff is cross-trained to work in at least two sub-sections of the Lab, and fl exible scheduling occurs between the shifts to

help accommodate staffi ng needs. During morning phlebotomy rounds, clinical staff work alongside the phlebotomy team to have re-

sults available to the physicians during their AM rounds. Phlebotomists assist the technicians/technologists by helping to load specimens

on the robotics track systems in Hematology and Chemistry.”

• “The Lab has seen an expansion in patient-focused bedside testing by means of a collaborative and interdisciplinary team approach

among several departments and locations. In the Emergency Department, we offer point-of-care glucose, urinalysis, and urine pregnancy

testing. For our brain and heart rescue patients, we provide POC troponin and PT IN’s. In our GI Center, POC glucose and CLO testing is

performed. The Laboratory, Nursing, Pharmacy, Interventional Radiology, and Wound Care Teams work together to provide a POC pro-

gram that fi ts the needs of the department and patients it serves, as well as meeting all regulatory standards.”

Leadership and associates of Le Bonheur Children’s show off their “Le Bonheur Proud” t-shirts.

Just a few of the dedicated personnel across all sections of the CRMC Department of Pathology and Lab Medicine--Histology, Microbiology, Phlebotomy, Core Lab, Blood Bank, and Client Services.

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SPECIAL FEATURE PL AT EL E T T ES TING

Solving the thrombocytopenia puzzle with immature platelet testingBy Maggie Fischer, RN, BSN, MS, and Krista Curcio, BS, MBA

management. For example, thrombocytopenic samples with low to normal IPF are often consistent with a platelet produc-tion disorder. This could be due to conditions such as aplastic anemia, leukemia, and bone marrow suppression, or the effect of drugs.

On the other hand, thrombocytopenic samples with higher than normal IPF are often consistent with platelet destruction disorders like immune thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), dissemi-nated intravascular coagulation (DIC), the effect of drugs or other causes.

Using IPF as a screening toolThe value of IPF has been proven as a screening tool for the clinician in the differential diagnosis of thrombocytopenia. IPF is most effective when the measurement is used serially and in-terpreted in conjunction with the platelet count.1 IPF can also be used as an early indicator of bone marrow recovery in patients who are undergoing a stem cell transplant or chemotherapy. In fact, IPF has been found to show recovery faster than absolute neutrophil recovery.2

Because immature platelets are usually larger in size, some technologies use the MPV, or mean platelet volume, as an in-dication of platelet immaturity. However, MPV may not be an accurate indication of immaturity because of interference from giant platelets, platelet clumps, microerythrocytes, and cell fragments. Due to these interferences, MPV is not necessarily the best method for assessing the immaturity of platelets.

In summary, IPF provides an automated, direct cellular mea-surement of thrombopoietic activity in bone marrow. Used in conjunction with platelet count and other patient information, IPF may help the clinician assess the mechanism of newly iden-tifi ed thrombocytopenias. Therefore, IPF is a valuable labora-tory parameter that may provide clinicians with the missing piece to the thrombocytopenia puzzle.

REFERENCES

1. Psaila B, Bussell JB, Frelinger AL, et al. Differences in platelet function in patients with acute myeloid leukemia and myelodysplasia compared to equally thrombocytope-nic patients with immune thrombocytopenia. J Thrombosis Hemostasis. 2011;9(11):2302-2310.

2. Zucker, M., Murphy CA, Rachel JM,et al. Immature Platelet Fraction as a predictor of platelet recovery following hematopoietic progenitor cell transplantation. Laboratory Hematology. 2006;12(3):125-130.

Thrombocytopenia, or low platelet (PLT) count, is a com-mon hematologic abnormality that may be associated with risk of severe bleeding. Understanding the cause of

thrombocytopenia can be a clinical puzzle for clinicians. While the PLT count is the most important parameter to diagnose thrombocytopenia, it doesn’t provide information regarding the underlying cause of low platelet count, which makes the differential diagnosis unclear. It is merely a snapshot in time, refl ecting PLT quantity and not the mechanism responsible for the low count.

Possible causes of thrombocytopenia may include decreased platelet production or increased platelet consumption. Clini-cians must determine the cause of thrombocytopenia because low platelet counts can be associated with spontaneous bleed-ing, even without injury. Patients with thrombocytopenia there-fore must be carefully monitored and treated based upon the underlying cause.

Rapid assessment of platelet production may aid clinicians in distinguishing between thrombocytopenia due to platelet destruction (such as immune thrombocytopenia [ITP]) and low platelet count due to aplastic disorders or other bone marrow failure syndromes.

Assessing the cause of thrombocytopenia Determining the cause of thrombocytopenia may require addi-tional laboratory tests and potentially invasive procedures. It is virtually impossible for the clinician to differentially diagnose thrombocytopenia from CBC results alone.

One non-invasive method of understanding the underlying cause of thrombocytopenia is to measure the immature platelet fraction (IPF), which indicates the presence of immature plate-lets in the peripheral blood.

The IPF is the automated measurement of reticulated, or im-mature, platelets. It refl ects the presence of nucleic acid material in the cell by using a combination of fl uorescent stains, fl ow cytometry and algorithms to separate immature from mature platelets. The more immature the platelet, the more it fl uoresc-es, thus allowing an accurate immature platelet count without requiring a separate reticulated platelet test performed by tra-ditional fl ow cytometry.

Using this test, physicians have immediate access to rel-evant data specifi c to platelet maturity for better patient

Maggie Fischer, RN, BSN, MS, has more than 25 years

of clinical and technical experience within the health-

care environment. For Sysmex America, Inc., she man-

ages a clinical support team that educates healthcare

providers about Sysmex’s novel clinical parameters.

Krista Curcio, BS, MBA, is a hematology product

manager at Sysmex, where she manages the XN-Series

product line as well as the RU-20 reagent unit system.

Krista has been with Sysmex for 10 years. She has 20

years of industry experience including managing a he-

matology laboratory and working at CAP. Krista holds a

BS in Medical Technology from Michigan State Univer-

sity and an MBA from Lake Forest Graduate School.

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MANAGEMENT MATTERS

CDC’s more restrictive policy CDC’s more restrictive policy on child lead testing means on child lead testing means more positives and high QCmore positives and high QCBy Robert Kapler

“We have not been able to identify a safe blood level for chil-dren,” says Mary Jean Brown, PhD, chief of the CDC’s Healthy Homes and Lead Poisoning Prevention Branch. “We only use 5 because it is the top 2.5 percent of the population distribution [for lead exposure], which means something different is going on with that child.”

The report recommended that CDC move from a poison identifi cation-based approach to a strict prevention-based ap-proach. In due course, the CDC lowered the reference level and decided to update it every four years based on the results of two national surveys on lead exposure. The fi rst cycle is about to end.3

A surge in positivesHashim Othman, PhD, director of Toxicology & Special Chem-istry at Bio-Reference Labs in northern New Jersey, says his facility has not done signifi cantly more lead testing since the cutoff change. “But the rate of positives has increased tremen-dously!” he exclaims. “In August, when kids are tested before school, we see more than double the rate of positives than be-fore. We used to have three, four, maybe fi ve positives a day. Now we have 20, 30, maybe 40.” Most of the year, the lab runs 425 to 475 lead tests daily; during the preschool spike, it runs 550 to 650 tests a day.

His lab’s rate of positives seems to mirror the national trend. Back in June 2012, the CDC predicted the new reference

level would increase the number of children affected nationwide from fewer than 100,000 to close to 373,000.1 Now it estimates that ap-proximately 535,000 children ages one to fi ve years have been found with blood lead at or above 5 μg/dL, says Bernadette Burden, a CDC spokeswoman. The estimate is based partly on the CDC’s biannual National Health and Nutrition Ex-amination Survey (NHANES) and partly on the agency’s Childhood Blood Lead Surveillance System, which includes data from 35 state and local health agencies, many of which receive CDC funding.

Picture may be brighterWhile the CDC estimate may sound dramatic, the exposure picture for children nationwide might not be as dire as the tragedy in Flint suggests. The percentage of children found with elevated blood levels (under the old reference level) has actually been falling steadily during the past

June will mark four years since the Centers for Disease Control and Prevention (CDC) halved its reference blood lead level (BLL) for children from 10 micrograms per deci-

liter (μg/dL) of blood to 5 μg/dL, the agency’s threshold for public health action.1 As the water supply contamination crisis in Flint, Michigan, illustrates, the spread of lead in the envi-ronment—as well as the resulting health impacts—has been insidious, perhaps even more so than public health agencies had anticipated just a few years ago. Labs play an increasingly important role in helping to detect higher levels of human ex-posure. This article will look at the reasons for the revised refer-ence level, the laboratory experience since the policy shift, how labs test and guard against contamination, and why lead will continue to be a public health problem long after the crisis in Flint is resolved.

Genesis of policy change The shift in policy came on the heels of a two-year investiga-tion by a work group of the Advisory Committee on Child-hood Lead Poisoning Prevention, which was chartered to pro-vide guidance to the CDC and the U.S. Department of Health and Human Services. The group’s report cited newer research showing that any level of lead exposure can be detrimental to children.2 Even moderate exposure to lead is associated with cognitive development problems and lowered IQ.

Table 1

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Robert Kapler spent nearly a decade

as a science writer, editor, and

government relations specialist at

America’s Blood Centers. He now

works as a freelance journalist and as

a copywriter and marketing

consultant for Bio-Rad Laboratories

decade. In fact, under the old reference level, the incidence rate has been below one percent since 2007 (Table 1).

One reason for the decline is the Residential Lead-Based Paint Hazard Reduction Act of 1992, which directs the Depart-ment of Housing and Urban Development (HUD) and the En-vironmental Protection Agency (EPA) to require disclosure of known lead-based paint and paint hazards before the sale or lease of houses built prior to 1978. While the EPA and HUD are charged with strict enforcement of the law, CDC tracks BLL exposures, provides technical and fi nancial assistance to state and local childhood lead poisoning prevention programs, and makes policy. Dr. Brown is proud of her agency’s efforts. “Our surveillance data have shown that, in many communities, a small number of houses repeatedly poison children,” she says. “And with that information we’ve been able to work with HUD and EPA to enforce the lead disclosure rule.”

Industry perspectiveThe Association of Public Health Laboratories (APHL), rep-resenting some 800 state and local public labs, has taken a keen interest in efforts to reduce childhood lead exposure. The APHL is confi dent that current instruments and methodolo-gies can detect lead concentrations below the current refer-ence level. But members have heard that the CDC is consider-ing lowering the level again, to 3μg/dL. With the growing use of point-of-care (POC) BLL testing instruments, the APHL is concerned that federal standards may outpace current POC technology.

“More clinicians are using point-of-care devices because they are quick, cheap, and easy,” says Sanwat Chaudhuri, PhD, chair of the APHL Environmental Health Committee. “But that technique is not as sensitive compared with the oth-er techniques. And when you’re pushing the regulatory limit so low, then you are challenging the instrument, and that may affect the data that you’re getting.”

The most common lead testing methodologies are graph-ite furnace atomic absorption spectrometry (GFAAS), an-odic stripping voltammetry (ASV), and inductively coupled plasma mass spectrometry (ICPMS). A portable device using ASV technology is also available for POC BL testing. Accord-ing the World Health Organization (WHO), ICPMS is the most sensitive method for detecting BLL levels as low as ~0.1 μg/dl. That’s followed by GFAAS (lower limit: <1–2 μg/dl); lab-based ASV instruments (lower limit: 2-3 μg/dl); and portable ASV instruments (lower limit: 3.3 μg/dl).4

Testing and precautionsTo determine lead exposure levels among children and adults, hospitals across the country send public and private labs blood samples each day. They are shipped in either tan- or lavender-capped vials—the colors indicate the level of assurance that the container holds an untainted blood sample. Othman says tan-capped vials are preferable; an extra preparatory step must be performed before lavender-topped vial samples are analyzed.

At his lab, samples are tested each night on three ICPMS in-struments to have results for doctors by morning. Each instru-ment ionizes the sample, sorts and separates the ions by mass and charge, detects and measures the ions, and displays the results graphically for the user. Labs employ quality measures to ensure that the sample is untainted and the analyzer has ac-curately read what ends up on a graphic display.

“Here we have samples and quality controls,” Othman says, as a robotic arm inserts a pipette into one of 90 sample tubes nestled in a bread loaf-size rack. Because of the ubiquity of en-vironmental lead, he says, labs like his across the nation must

take precautions—such as controls, standards, and redundan-cy—to keep the testing process free of contamination.

First, whole blood controls with concentrations of lead at three known levels—normal (6.1 μg/dL), critical (13.7 μg/dL), and toxic (37.6 μg/dL)—are introduced. (The child refer-ence level is <5 μg/dL and <25 μg/dL for adults). These are freeze-dried samples whose purity and lead concentration have been subjected to rigorous QC. The controls are processed and analyzed at the same time and in the same manner as pa-tient samples. The result is then compared against acceptable variance ranges.

“We dilute every sample and quality control 100 times with 0.5 percent nitric acid. We start the run with three controls, then alternate controls after every 30 samples. If we get fi ve posi-tives, those samples are run again on another rack. We do an-other dilution, add more controls—the same procedure. Then we compare the results. If they match, we release the original results. If they don’t match, we repeat the process a third time.”

Another critical measure involves the use of independently-validated blood-based NIST standard reference materials.5 The lab also adds a common internal standard for lead, bismuth, to each sample to ensure accuracy of results and instrument per-formance. Finally, a calibrator blank (0.5% HNO3) is included in each run. The system software uses the blank as a baseline for calculating the concentrations of all unknown samples.

Each sample is run three times, and the software then aver-ages the three readings and provides a mean concentration and standard deviation, which must be less than 10 percent to avoid retesting.

“Any deviation from controls will depend, in large part, on how careful the technologists are and how good the controls and calibrators are,” Othman says, adding that CLIA sets the allowable error for controls: +/- 4 mcg/dL (equal to three stan-dard deviations). “If you fail two controls, you have to do a corrective action. You either repeat a portion of the batch or the entire batch.”

Later the same morning, Othman is at his desk, sifting through a two-inch stack of BLL test reports. “Look at my cali-bration curve,” he says. “It’s almost perfect: 0.99999. And my calibration blank has only 129 counts of lead in it, which is con-sidered very low compared to my lowest standard and then standards 2, 3, 4 and 5. As you can see, it’s a perfect curve.”

Satisfi ed, he initials the report.

REFERENCES

1. Betts, KS. CDC updates guidelines for children’s lead exposure. Environ Health Perspect. 2012;120(7): a268.

2. CDC. Low-level lead exposure harms children: a renewed call for primary preven-tion. http://www.cdc.gov/nceh/lead/acclpp/fi nal_document_030712.pdf.

3. CDC. CDC response to advisory committee on childhood lead poisoning prevention recommendations. http://www.cdc.gov/nceh/lead/acclpp/cdc_response_lead_expo-sure_recs.pdf.

4. WHO. Brief guide to analytical methods for measuring lead in blood. http://www.who.int/ipcs/assessment/public_health/lead_blood.pdf.

5. Parsons PJ, Chisholm Jr JJ. The lead laboratory. http://www.cdc.gov/nceh/lead/publications/1997/pdf/c1.pdf.

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TIPS F ROM T HE CL INICA L E XPER TS

Pleural and peritoneal fl uids“TIPS” is an exclusive MLO feature that allows readers to ask technical questions and have them answered by our clinical experts. Please email your questions to: [email protected].

QWe are looking for information regarding reference ranges for Pleural Fluid for Total Protein, LD,

Glucose, Amylase, pH, Cholesterol, and Triglyceride, Peritoneal Body Fluids for Albumin, Total Protein, and Amylase. Do you have any published reference ranges for these body fl uids?

AThe standard format used in estab-lishing reference ranges for all vari-ous serous body fl uids has not been

well established. And of those references published, the literature shows some variation in what is considered “normal.” Unlike taking a blood sample that is ana-lyzed to see if there is some abnormality, the need to obtain other body fl uids for diagnostic reasons generally implies that there is an existing medical problem.

Pleural effusionsPleural Fluid (PF) is normally found in the space between the lung and the chest wall (normal amounts are estimated to be between 10 and 20mL) and is similar in biochemical composition to plasma.1 However, excess PF can accumulate due to a number of different disorders result-ing in a pleural effusion (PE) and is obtained through a procedure called thoracentesis. Approximately 1.3 million individuals in the United States are diagnosed with a PE each year.2

PEs may be classifi ed as a transudative PE or as an exudative PE. A transudative PE may occur during systemic illnesses such as heart failure, cirrhosis (with as-cites), or hypoalbuminemia (due to ne-phrotic syndrome), whereas exudative PE results from some abnormal local process, such as pneumonia, cancer, pulmonary embolism, and viral infection.1,3

While a reference range for PF is not as clear-cut as that seen with other clini-cal laboratory tests, in general, normal PF may show the following:

• Appearance: Mostly clear, straw-colored, and odorless

• pH of 7.60 to 7.64 • Protein content of less than 1 to 2 g/dL • Fewer than 1,000 WBC/μL • Glucose level similar to that of plasma

• Lactate dehydrogenase (LD) of less than half that found in plasma.4

Light’s criteria is commonly used in evaluating abnormal PEs.2,5 According to Light’s criteria, a PE exudate is present if one or more of the following exists:5

• PE protein: Serum protein ratio >0.5 • PE LD: Serum LD ratio >0.6 • PE LD: >2/3 of the upper limit of serum

LD reference rangeIf none of these criteria are present, the

PE is considered a transudate.1 In general, Light’s criteria correctly identify exudates but may misclassify 20 percent to 25 per-cent of transudates as exudates.1,3,4

Visual examination of exudative PEs may show turbidity and may be milky, hemorrhagic, or greenish in color. Evalu-ation of a PE exudative studies have shown:3,4,6

• LD levels >0.45 of the upper limit of nor-mal serum values

• Protein level >2.9 g/dL • Cholesterol level >45 mg/dL • Triglycerides >110 mg/dL • Albumin gradient (serum albumin mi-

nus PE albumin) <12g/L for exudates and >12g/L for transudates

• WBC >500 /μL • Hematocrit of PE is >50 percent of pe-

ripheral blood hematocrit, patient has hemothorax

• pH of 7.44 to 7.30 • PF Amylase: Serum amylase ratio >1 • PF Creatinine: Serum creatinine >1 • Transudate effusions: 6 • Appearance: Tends to be clear yellow in

color • Nucleated cells: Fewer than 500 nucle-

ated cells/μL • PE LD: Serum LD (upper normal limit):

Ratio is <0.67 • Glucose: Level similar to serum glucose

level • Cholesterol: Less than 520mg/L • pH of 7.45 to 7.55

Some additional analytes have also been noted to be of some value in evalu-ating pleural effusions. N-terminal pro-brain natriuretic peptide (NT-proBNP) has been shown to be elevated in heart failure (>1,300-4,000 ng/L). Effusions with elevated LD levels (>1,000IU/L) have been associated with empyema, ma-lignancies, rheumatoid effusions, para-gonimiasis (lung fl uke), and Pneumocystis jiroveci (formally P carinii). Decreased glu-cose levels in PE have been seen in malig-nancies, tuberculosis, esophageal rupture, and lupus.4

The presence of biomarkers, such as carcinoembryonic antigen (CEA), neu-ron-specifi c enolase (NSE), CA 125, CA 19-9, alpha-fetoprotein (AFP), CYFRA 21-1, and osteopontin, has been shown to dif-ferentiate between malignant and benign PE. Pancreatic disease may show elevated amylase level in PE and may reach levels of 100,000 IU/L.6

Lymphocytosis (>85 percent of nucle-ated cells) is seen in tuberculosis, lym-phoma, sarcoidosis, and several other disorders. Eosinophilia (>10 percent of nucleated cells) may be encountered in cases of pulmonary embolism, benign asbestos PE, parasitic diseases, fungal infections, and with certain medications. Other testing that might be done may in-clude cultures/Gram stains if infectious disease is involved or immunologic stud-ies (such as ANA, RF) when autoimmune processes may be involved.4

Peritoneal fl uidsThe peritoneum consists of serous mem-branes that line the peritoneal cavity through a network of mesothelial cells and collagen.8 Pathologic accumulation of peritoneal fl uid results in ascites fl uid (obtained through peritoneocentesis) that is generally submitted to the laboratory for evaluation.9 The amount of peritoneal fl uid normally present is 5mL to 20mL, but may be as much as 50mL, particularly in women during ovulation.8,9

Similar to PF, reference ranges are gen-erally not published as part of standard clinical laboratory guidelines. However, some cut-off values have been deter-mined as to what one might fi nd in nor-mal fl uids.9-12

• Specifi c gravity: <1.016 • Protein: 3g/dL • Glucose: similar to blood glucose • Amylase: similar to blood amylase • BUN: similar to blood BUN • WBC: <500/μL • pH of 7.5 to 8

Peritoneal fl uid is often clear and/or slightly yellowish in color. A cloudy, turbid color suggests an infection, while a milky color suggests an infl ammatory condition such as peritonitis, pancreatitis, or appendicitis. A red color is consistent with a traumatic tap (specimen has clots) or malignancy (non-traumatic tap has no clots). A greenish color has been associ-ated with a ruptured gall bladder, pancre-atitis, or intestinal perforation.10,11

Peritoneal fl uids may also be identifi ed

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TIPSF ROM T HE CL INICA L E XPER TS

as an exudate or a transudate. Exudates are most often associated with infections, neoplasms, trauma, pancreatitis, or rup-tured gall bladder. Transudates may be caused by congestive heart failure, hepat-ic cirrhosis, or hypoproteinemia (nephrot-ic syndrome). Peritoneal fl uid resulting from an infl ammatory condition general-ly contains an increased number of WBCs that are predominately neutrophils and reactive mesothelial cells. Transudates of-ten will show more lymphocytes.9,11

The serum-ascites albumin gradient (SAAG) is a reasonably reliable way to differentiate between transudate and exudate fl uids (serum albumin minus the ascitic albumen level). Transudates, as found in portal hypertension, exhibit a SAAG level of 1.1 g/dL or greater, where-as, values less than 1.1 g/dL are seen in patients with normal portal pressure and with ascitic exudates.7,9

Some additional tests to consider in the evaluation of ascites fl uids: 9,11,12

• Ascitic fl uid bilirubin/serum bilirubin ratio of 0.6 or greater is consistent with an exudate, generally due to the presence of bile.

• LD is greater than 130 U/L; fl uid LD/serum ratio >0.6 suggests a malignant effusion.

• If total protein is greater than 3.0 g/dL (ascitic fl uid/serum ratio is >0.4-0.5), then an exudate is considered to be the cause.

• Amylase level three times greater than the plasma level suggests a pancreatic ascites.

• Alkaline phosphatase of >10 U/L is seen in hollow visceral injury; >240 U/L is seen in secondary peritonitis.

• BUN and creatinine levels that are greater than blood levels may be a result of intraperitoneal leakage of urine out-side of the urinary tract.

• Cholesterol >45-48 mg/dL has been used to differentiate between malignant and non-malignant ascites.

• Triglycerides >199 mg/dL or higher than blood level would be a concern.

• Glucose that is <50 mg/dL is consistent with secondary bacterial peritonitis.

Tumor markers (CEA, CA 19-9, CA 15-3, PSA) may also be of some value when evaluating ascites fl uid for the presence of certain malignant cells. CA-125 may be elevated in peritoneal fl uid samples from patients with ovarian, fallopian, or endo-metrial carcinomas. It should be noted that it may also be positive in certain non-malignant disorders such as cardiovascu-lar or chronic liver diseases.9

Each laboratory should carefully re-view the literature and make individual determinations in developing guidelines in assessing all body fl uids. Collaboration

with clinicians is often the best approach in establishing these guidelines so that ap-propriate diagnostic algorithms are devel-oped to include laboratory testing, imag-ing studies, and the clinical presentation when diagnosing and managing patients with effusions.

REFERENCES

1. Kaplan JL, Porter RS, eds. Mediastinal and Pleural Disorders. In: Merck Manual of Diagnosis and Therapy, 19th ed. (2011) Whitehouse Station, NJ. Merck Sharp & Dohme Corp. Chapter 204.

2. Sahn SA, Huggins JT, San Jose E, et al. The art of pleural fl uid analysis. Clin Pulmon Med. 2013; 20(2):77-96.

3. Light RW. Disorders of the Pleura. In: . Harrison’s Principles of Internal Medicine, 19th ed. (2015). Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. eds. New York, NY: McGraw-Hill; Chap 316.

4. Rubins J. Pleural effusion work-up. Medscape. 2014. http://emedicine.medscape.com/article/299959-workup.

5. Lamberg JJ. Light’s criteria. Medscape. 2014. http://emedicine.medscape.com/article/2172232-overview. Accessed February 28,, 2016.

6. Sahn SA. Getting the most from pleural fl uid analysis. Review. Respirol. 2012;17:270-277.

7. Kopcinovic LM, Culej J. Pleural, peritoneal, and peri-cardial effusions – a biochemical approach. Biochemia Medica. 2014;24(1):123-137.http://www.biochemia-medi-ca.com/2014/24/123.

Editor’s note: Anthony Kurec,

MS, H(ASCP)DLM, is Clinical

Associate Professor, Emeritus,

at SUNY Upstate Medical

University in Syracuse, NY. He

is also a member of the MLO

Editorial Advisory Board.

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8. Brady M, Mahoney E. Peritoneal Cavity. In: Doherty GM. eds. CURRENT Diagnosis & Treatment: Surgery, 14 ed.(2015) New York, NY: McGraw-Hill; Chapter 22.

9. Karcher DS, McPherson RA. Cerebrospinal, syno-vial, serous body fl uids, and alternative specimens. In: Henry’s Clinical Diagnosis and Management by Labora-tory Methods, 22nd ed. (2011) Philidelphia:Elsevier/Saun-ders. Chapter 29.

10. Shah R. Ascites workup. Medscape. http://emedi-cine.medscape.com/article/170907-workup#c3.

11. Bhutta RA, Syed NA, Ahmad A. Peritoneal fl uid anal-ysis: Ascitic fl uid analysis, Peritoneal tap or abdominal paracentesis, or abdominal tap, part 3. http://www.lab-pedia.net/test/227.

12. 2015-2016 Clinical Laboratory Reference. MLO. http://www.clr-online.com/. .

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FUTURE BUZZ PATIEN T-CEN T ERED CA RE

The laboratory’s role in the transformation to patient-centered careBy Donna Beasley, DLM(ASCP)

ber, this patient identifi er stays with the patient throughout his or her lifetime, regardless of where the service is performed or what IT system is being utilized. Without it, true data information exchange will not be complete.

However, there are numerous challenges attached to this solu-tion. At the top of that list is assuring patient privacy. In addition, the adoption of the patient identifi er must receive Congressional approval before it can be implemented. In the meantime many health systems have adopted an Enterprise Master Patient Index (EMPI), in which the patient has the same identifi er regardless of which hospital or service within the health system the patient originates.

The central data repository must be inclusive of clinical infor-mation. A longitudinal record for the patient would represent a complete medical history and all clinical data for the patient regardless of place of service. The comprehensive record is achieved via Health Information Exchange (HIE) connectivity which brings together multiple disparate systems. As an exam-ple, if a patient has testing as an outpatient, or in an emergency department, has an ambulatory surgery procedure, or was re-cently hospitalized in another hospital within the system, all of the results associated with those encounters must be available to the practitioner in one longitudinal record. This is value-add in patient-centered care, and the lab plays a role in its contribu-tion. The EMPI is essential to overcome the patient type chal-lenge. With the EMPI, it will be easier to manage and optimize care by tracking all tests in the data repository. The integration of the data from various disparate systems requires connectiv-ity solutions that cross these boundaries. There are challenges with varied terminologies within each system, but solutions to cross-map the translations are possible.

Patient-centered care: the lab’s contributionKnowing this, what can the laboratory do to contribute to patient-centered care?

• Start by eliminating or signifi cantly reducing paper test order-ing requisitions and replacing them with electronic order entry to signifi cantly reduce errors and streamline effi ciencies to add value. Evaluate the connectivity that currently exists with order-ing provider systems and work to extend connectivity to other providers that currently are still on paper. Consider a middle-ware provider to connect EHRs to your LIS instead of individual proprietary interfacing. It is faster to deploy and should be a less expensive route.

• Be involved with clinical decision support committees to help further develop the Computerized Physician Order Entry (CPOE) capabilities and maximize right test, right time automated

The “Patient.” The patient has fi nal-ly re-emerged as the focal point in healthcare, after decades of being

shunted aside by other major systemic concerns. It is a heartening develop-ment, and it is one in which the clinical laboratory is critical. Laboratories play a crucial role in caring for the patient; over 50 percent of electronic medical record (EMR) information is coming from lab data. In the context of the challenges of healthcare reform and payment changes which will reward value over volume, lab information is vital to providers in the management of their patients. Patient-centered care is the integration of all healthcare and clinical information for a patient, which is then portable to all providers of that patient’s care. The fundamental goal of patient-centered care is a higher quality of care that produces improved patient outcomes.

The challenge for laboratories, then, is how to adapt their business model to accommodate this new patient-centric model when all of their experiences have driven them to focus on vol-ume/accessions. Accountable Care Organizations (ACOs) are structured to focus on the patient and all activities that involve cost management while adding value to patient care. Payment methodology impacts patient-centered care by paying for all services in the patient’s episode of care, which would include lab testing. In some risk-sharing or bundled payment models, this can be dangerous for labs if they do not demonstrate value beyond a reduced cost of the testing. Labs have an opportunity to contribute to improved value for the patient-centered care in many ways.

Patient-centered care: some relevant contextsThis begins with optimized workfl ow to collect correct patient demographics and insurance information, which is crucial to support health information exchange throughout the continuum of care. Laboratories have the opportunity to play a large role in data exchange with physician offi ces. The elimination of pa-per requisitions in favor of electronic connectivity helps in the containment of costs and error reduction. Errors can slow down processes and affect the entire patient encounter, not to mention negatively affect the fi ling of clean claims.

The communication of clinical information is less valuable if it doesn’t refl ect accurate patient information. Errors create cost down the service line and can affect quality as well. For this rea-son the electronic health records’ (EHRs’) bi-directional connec-tivity to and from the lab/hospital system is vital to patient-cen-tered care. The data repository of results helps to contribute to improved patient outcomes when this data is used as expanded clinical intelligence. Outreach programs help to drive the data exchange with physician offi ces while aligning physicians to the healthcare system. Without this connectivity, physicians will look elsewhere, to other labs that make ordering simpler and resulting into their EHRs a possibility.

The movement to adopt a unique master patient identi-fi er that is utilized from any service source is another positive industry-wide consideration. Similar to a Social Security num-

PopulationHealth

AccountabilityHealthyLifestyle

PhysicianGuided

TripleAimChronicCareMeasurement

CareCoordination EvidenceBased

Behavioral

Wellness

DiseaseManagement

Quality Preventative

ClinicalGuidlinesImprovementEng

agement

Interventions

PatientCentered

Outcomes

CaseManagement

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ordering aids. Often the lab and pathologist are not a part of order set formulation. Explore what committees exist and insert a lab representative where applicable.

• Know that test utilization management is a key component of patient-centered care, and have a formal program in place to aid providers. Improve the testing performed for the patient while reducing costs by utilizing algorithms: clinical pathways based on data. Again, pathologists need to be involved with variation of care solutions.

• Review front-end error processing reports to better understand the type and source of ordering errors. Work with your Informa-tion Technology (IT) team to build rules that minimize errors such as duplicate test orders, date-of-birth issues, and demographic issues, or purchase third-party connectivity solutions that have robust rules already built into their software. Additionally, work with your staffed Patient Service Centers (PSCs) to hold them ac-countable for getting accurate and complete information upfront. Take every advantage of having the patient available, and get the data correct. Tie in an eligibility check to this process as well.

• Be aware of having duplicate patient records and work to mini-mize and eliminate this. Utilize multiple identifi ers that match to confi rm a particular patient record to include components other than just name and date of birth.

• Have a mechanism for the PSC staff to view patient balances within the health system, and develop stringent co-pay collection policies, which further extends to patient-centered care to pull in billing capabilities.

• With regard to the actual Lab report, be sure to include all recent encounters regardless of patient type for a longitudinal view of the record. Have this data contribute to the central repository of the patient record, which is visible from all operational workfl ows.

• Utilize the test results in advanced strategies to add value to pro-viders. Focus on alerts to help better predict the potential for read-mission. Help providers and case managers determine if any ad-ditional testing or abnormal results have occurred post discharge.

• Use technology and data to deliver value: Help your providers by fl agging patients at risk. Offer special questionnaires around disease states within

your ordering template. Support clinical intelligence

dashboards that go beyond the test result itself, which will help to reduce costs and translate into better care.

Use your test report formats to educate for appropri-ate test utilization and new testing.

Develop actionable insight data sets to improve quality of care at the patient level.

From a global perspective, utilize data to contribute to proactive population health considerations. Key to data sharing for population health is “big data” manage-ment; the Lab contributes signifi cantly to that volume of data (Figure 1).

• Know that a patient portal is an excellent resource for patient-centered care that allows patients to access to their results, review and correct their information, and even pay their bills.

• “Lean” processes to elimi-nate waste and reduce costs by

minimizing variation to be better positioned within the ACO environment.

• Have a seat at the table with ACO formation to demonstrate the value of the Lab in the patient-centered care focus.

Patient satisfaction is also an important component of patient-centered care. Patients have more tools today to stay informed and contribute to their care. Labs should look for ways to en-hance the patient experience, either online or in person, by pro-viding more information and streamlining processes. Consider…how can the registration process be improved? How does the pa-tient bill look? Is it understandable, accurate, and consolidated? Multiple bills can be confusing to patients and decrease their sat-isfaction, although the practice today is very prevalent. Patients themselves, and their contribution to their own care, cannot be an overlooked component of patient-centered care.

All of these building blocks will contribute to a developed patient-centered care focus and help any laboratory move in the right direction for the future while ultimately impacting the quality of patient care. The laboratory plays a pivotal role in the creation of meaningful clinical information, impacting the diagnosis and treatment of patients. Labs should help to build upon a solid patient-centered care foundation by decreasing er-rors, contributing to improving quality outcomes, and operation-ally modifying workfl ow processes to reduce costs and improve patient and provider satisfaction. Successful labs will plan and position for the future reimbursement changes, leveraging pro-vider relations and current connectivity to defi ne their value in the shift to patient-centered care model.

Figure 1

Donna Beasley, DLM(ASCP), serves

as director of Chicago-based Huron Consulting Group. She is a member

of the MLO Editorial Advisory Board.

MLO201604-FutureBuzz_FINAL.indd 47MLO201604-FutureBuzz_FINAL.indd 47 3/14/2016 1:01:49 PM3/14/2016 1:01:49 PM


FUTURE BUZZ

In pursuit of patient-centered careBy Chrystal Adams

as well as the methodology used in their development. The program has begun to spread internationally to Canada, the United Kingdom, Australia, and other countries.

Seven multi-stakeholder alliances were recently formed to focus on the lo-cal implementation of Choosing Wisely at health systems, hospitals, and medical groups across the United States to achieve measurable reductions of at least three Choosing Wisely recommendations.

Motivated by the campaign, and to advance both patient-centered and value-based care initiatives, healthcare organiza-tions are developing their own evidence-based best practices for laboratory testing and clinical procedures as a resource to help clinicians better understand and im-prove their ordering practices to better serve patients.

As laboratory test recommendations are developed and implemented through these types of emerging evidence-based best practices, laboratory professionals will play an important role in educating clinicians and patients and consulting with them on how to improve the diagnostic value of laboratory tests while preventing the overutilization of laboratory resources.

II. Implementing clinical decision support to guide genetic testingThe growth of genetic testing is transform-ing the standard of care for some diseases, and clinicians will increasingly be able to pursue targeted, patient-specifi c therapies in the future based on the presence of spe-cifi c biomarkers and molecular mecha-nisms causing a disease.2

According to the National Center for Biotechnology Information’s Genetic Test-ing Registry, there are currently more than 32,000 genetic tests for 5,800 medical con-ditions and 3,900 genes. This vast volume of available genetic diagnostic tests makes it virtually impossible for physicians to keep current and know when to order a specifi c genetic test, or which one to order based on the patient’s medical history and other factors.

To help clinicians order appropriate ge-netic tests, interpret test results, and make the best treatment decisions for patient-centered care, labs should take a proactive role in supporting the development and integration of clinical decision support tools and genetic-based knowledge bases into clinical workfl ow. These tools evalu-ate and interpret the patient’s personal history, medication list, and genetic pro-fi le to analyze and guide clinical decisions about which tests and drugs are most rel-evant for the patient. Clinicians can review

Enhancing the patient experience through a patient-centered approach to care is a growing priority for health-

care organizations. The primary objective of patient-centered care is to ensure a con-tinuing relationship between the patient and his or her healthcare team with a focus on prevention and detection, diagnostic accuracy, and team-based, multi-disciplin-ary information sharing and collaboration.

Improving health outcomes by provid-ing “the right test for the right patient at the right time” is a popular credo in labo-ratory medicine that is becoming more achievable every day due to advances in genetic testing and pharmacogenetics, and the systems that support their implemen-tation. A personalized approach to medi-cine based on a patient’s genetic profi le not only accelerates patient diagnosis, but also helps determine response to medications to help guide the best possible treatment and health outcomes.

Toward this end, the laboratory is a criti-cal link and information source across the entire diagnostic process, from the initial lab order through guided clinical decision support to help ensure targeted patient therapies for the best clinical outcomes.

Progressive labs are able to expand their role in support of patient-centered care in three distinct ways:

I. Developing evidence-based testing algorithmsWhile lab professionals routinely consult with clinicians on laboratory test selection, labs need to expand evidence-based best practices to help both patients and their physicians better understand lab testing options and their impact on personalized, cost-effective medicine.

To promote patient-centered care and help physicians and patients engage in discussions about choosing care that is truly necessary, supported by evidence, and not duplicative of other tests or pro-cedures already received, in April 2012 the American Board of Internal Medicine Foundation, Consumer Reports, and nine medical specialty societies launched the Choosing Wisely campaign. Participating medical specialty organizations each de-veloped lists of fi ve recommendations for preventing overuse of a treatment in their fi eld whose necessity physicians and patients should question.1

To date, more than 50 specialty societies have joined the campaign and developed more than 250 evidence-based recom-mendations to help make the most appro-priate care-based decisions at the patient level and provide information on when tests and procedures may be appropriate,

Chrystal Adams is an Associate Vice

President with XIFIN, Inc. Chrystal has

an extensive background in digital

pathology and product strategy for

several innovative technology products.

treatment implications and weigh trade-offs among medication alternatives based on known gene-drug interactions.

III. Supporting multi-disciplinary team collaborationThe multi-disciplinary care team is now widely recognized as an essential mecha-nism to achieve a more patient-centered, coordinated, and effective healthcare de-livery system. Healthcare providers col-laborate with patients and their families and share information within and across healthcare settings to deliver higher-quality and lower-cost care.

Technology is driving the ability of care teams to coordinate care and communi-cate through use of web-based healthcare portals, collaborative networking tools, electronic health records, or other hospital-based information and cloud-based sys-tems, many of which can be accessed by the patient as well.

Laboratories and other diagnostic ser-vice providers are also leveraging tech-nology to enable specialists such as ra-diologists, pathologists, and oncologists to access information and expertise from remote locations to facilitate consultation and collaboration on diffi cult or challeng-ing cases. By having the ability to discuss a patient’s case in real time and share case information and digital images with the patient care team regardless of geograph-ic location, labs support more effi cient coordination of care and maximize the interpretation of diagnostics.

Integrated diagnostic reporting between pathology and radiology also provides an opportunity for the multi-disciplinary team to collaborate and bridge the in-formation and diagnostic gap. Technol-ogy advancements and platforms are now making it possible to integrate diagnostic fi ndings, results, digital images, and other relevant data into a combined diagnostic report to help determine a more accurate diagnosis and treatment plan.

Labs that are proactive in developing and communicating evidence-based test-ing algorithms, supporting tools for effec-tive clinical decision making, and ensur-ing a collaborative care team environment with specialists from both inside and out-side the existing network will be better po-sitioned to elevate and cement their role in the patient-centered care model.

Please see references online.

PATIEN T-CEN T ERED CA RE

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LETTERS

A “fi fth generation” HIV assay?

166 cases of HIV-2 infection were reported in the United States by the Centers for Disease Control and Prevention (CDC), while in 2011 alone, the CDC estimated that the number of HIV-infected individuals was 1.2 million.1,2

The reduction in the window period of up to fi ve days by fourth-generation HIV assays has been achieved by the de-velopment of an HIV “combo” assay that detects both HIV antibodies and the HIV p24 antigen. The serologic profi le of p24 antigen in the time-course of HIV infection demonstrates an earlier rise and peak in plasma concentration than occurs with HIV antibodies (Figure 1).

The principal difference between the BioPlex 2000 HIV Ag-Ab assay and currently available fourth-generation HIV as-says is the ability to discriminate between HIV-1 and HIV-2 infection in a single assay. Notably, Mr. Kapler’s article pro-vides information on the window period for fi rst-, second-, third-, and fourth-generation HIV assays, yet no information, data, or reference citations are provided indicating the win-

dow period for the BioPlex 2000 HIV assay. In my view, and for reasons indicated above, ear-lier detection of HIV infection, HIV-1 or HIV-2, is a more important characteristic of an HIV screening assay than the ability to differentiate simultaneously whether a positive HIV test re-sult is due to HIV-1 or HIV-2, especially given the markedly low prevalence of HIV-2 infection in the United States.

I suggest that we reserve the defi nition of a new and improved HIV assay, deserving of the moniker fi fth-generation, for an HIV assay that reduces the window period below that achieved with a fourth-generation assay. If that can be achieved with the ability to simultaneously dif-ferentiate in a single assay between HIV-1 and HIV-2, then this is an added bonus of such an assay; otherwise, we need to change the current-ly prevailing defi nition of a new “generation” of an HIV assay. However, a change in defi ni-tion based solely (assuming there are no data indicating a reduction in the window period for the BioPlex 2000 HIV assay versus current fourth-generation HIV assays) on an analytical characteristic of any HIV assay (e.g., the type of instrument, the principle of the method, etc.) is not consistent with our current usage of new “generation” of an HIV assay.

--Frank H. Wians, Jr., PhD, AT(ASCP), MASCP, DABCC, FACB

Professor of PathologyPaul L. Foster School of Medicine

Texas Tech University Health Sciences Center, and Technical Director, Clinical Chemistry,

University Medical CenterEl Paso, TX

The article, “Understanding the CDC’s updated HIV test protocol,” identifi es the BioPlex2200 HIV Ag-Ab assay as “the fi rst fi fth-generation (HIV) assay.” Clearly, the single

most important defi ning characteristic for each new genera-tion of HIV assays is a reduction in the window period [i.e., the time period between HIV infection and the presence of de-tectable HIV-RNA or HIV antibodies/antigen (p24)], not the ability to differentiate between HIV-1 and HIV-2 infection in a single assay. Discriminating between HIV-1 and HIV-2 infec-tion is clinically important, despite the fact that the prevalence of HIV-2 infection in the U.S. is low compared to HIV-1 sub-type M infection. During the 22-year period, 1987-2009, only

Figure 1. Time course of HIV-1 RNA, HIV antibodies, and HIV p24 antigen detection for 1st-, 2nd-, 3rd-, and 4th-generation HIV assays.3

Editor’s note: Frank Wians, PhD, raises an issue about the February 2016 Continuing Education article “Understanding the CDC’s updated HIV test protocol” (MLO. 2016;48(2):8-13). Here is Dr. Wians’ letter, followed by a response from the article’s author, Robert Kapler.

REFERENCES1. MMWR 2011;60(29):985-988.2. MMWR 2015;64(24):657-662.3. Wians, FH Jr, Moore HA, Briscoe D, Anderson KM, et al. Evalu-ation of four qualitative third-generation HIV antibody assays and the fourth-generation Abbott HIV Ag/Ab Combo Test. Lab Med 2011;42(9):523-535.

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Author’s responseDr. Wians makes the case that the BioPlex 2200 HIV Ag-Ab assay does not deserve fi fth-generation status because it does not signifi cantly reduce the window period of infectivity de-tection. I appreciate his close reading, but that argument miss-es the mark. The assay in question deserves next-generation status because it is the fi rst assay that can simultaneously de-tect and differentiate the p24 antigen and antibodies to HIV-1 and HIV-2—in one set of results. Therefore, the assay can tell a clinician not only the type of HIV infection but also the pa-tient’s stage of infectivity (acute vs. established). This should signifi cantly reduce what I might call the “treatment win-dow”— the time period between overall HIV detection and the initiation of correct treatment. For the record, the assay’s window period is ~12 days. (Disclosure: I work part time for its maker, Bio-Rad, through an outside consulting fi rm).

He further suggests that earlier detection of HIV infec-tion of either type “is a more important characteristic of an HIV screening assay” than whether the type of infection is HIV-1 or HIV-2, because of the rarity of HIV-2 in the U.S. He concedes elsewhere, however, that distinguishing between HIV-1 and HIV-2 is “clinically important.” In this regard he is trying to have it both ways. Either it is important or it isn’t, whether the type is revealed during the initial screen-ing phase or the differentiating phase of the algorithm. As he knows, the CDC—like the FDA—takes actions based largely on the precautionary principle, which has been a component of public health policy since the AIDS epidemic began. Two of the CDC’s stated objectives in changing the algorithm were to identify infections earlier and to more accurately diagnose HIV-2 because it had been misdiagnosed under the former testing paradigm. Certainly, there were only 166 cases of HIV-2 in 22 years. That doesn’t mean much statistically. It only matters to the person infected with HIV-2 who is desperately seeking the right medicine.

More generally, his argument sits atop two faulty prem-ises: that some offi cial entity confers generational status on HIV assays, and that such status is based solely on the crite-rion of the infection-detection window. I have found no evi-dence that the CDC, or any other agency, body, or authority, confers generational status on new HIV assays. That status, like the criteria used to determine a new generation, fi lters up from the laboratory/research/manufacturing community itself. And fi lter it has. None other than Bernard Branson, MD, former Associate Director for Laboratory Diagnostics in the CDC’s Division of HIV/AIDS Prevention, has in at least one public presentation referred to the assay in question as a fi fth-generation assay.

--Robert Kapler

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By A lan Lenhof f, Edi torEXECUTIVE SNAPSHOT

If you were explaining Oncimmune to someone who is not familiar with the organization, how would you characterize its areas of exper-tise? What major categories of so-lutions does Oncimmune provide for its customers? Oncimmune is a biotech company specializing in blood biomarker tests for the early detection of various cancers. The fi rst major focus has been on the early detection of lung can-cer. More specifi cally, Oncimmune spe-cializes in detection of autoantibodies against cancer antigens in order to build a panel of autoantibodies that serve as a

JAMES R. JETT, MD

Chief Medical Offi cer

Oncimmune

ProfessionalNational Jewish Health, Denver, CO—

fi ve years.

Mayo Clinic, Rochester, MN—28 years.

Memberships: American Society of

Clinical Oncology; International

Association for the Study of Lung Cancer;

American Thoracic Society; American

College of Chest Physicians.

EducationBS: Southeast Missouri State University

MD: University of Missouri, Columbia

Mayo Clinic: Internal Medicine specialty

and Pulmonary Medicine subspecialty.

PersonalVolunteer: Co-chair Lung Cancer Task

Force, State of Colorado; National

Scientifi c Advisory Committee for

American Lung Association.

Hobbies and interests: International and

adventure travel, biking, and hiking.

blood biomarker test for early detection of specifi c cancers. Its fi rst autoantibody biomarker panel is for the detection of lung cancer before it becomes symp-tomatic, and it is called EarlyCDT-Lung. This test is a panel of seven autoantibod-ies to cancer antigens. If one or more of the autoantibody levels is elevated, then the test is considered positive.

You became Chief Medical Offi cer for Oncimmune in January. What will be your primary responsibilities and challenges in your new posi-tion? My major focus will be to assist in the further development and refi nement of the EarlyCDT-Lung biomarker test for use in screening of high-risk individu-als for lung cancer, and for assessing the risk of malignancy in non-calcifi ed or indeterminate pulmonary nodules. The challenge of any biomarker is to make sure that it is sensitive and specifi c enough that it aids practicing physicians in their decision-making over and above the clinical risk profi les. Equally chal-lenging will be the education of practic-ing physicians as to how the biomarker test can optimally assist them in the decision-making process.

Prior to your appointment as Oncimmune CMO, you worked on a clinical trial offered at National Jew-ish Health utilizing the EarlyCDT-Lung test. Can you tell us about this trial? I was the principal investiga-tor on a clinical trial that was assessing the utility of adding the EarlyCDT-Lung blood test to low-dose CT scan screening of high-risk individuals. That trial is on-going and has more than 1,000 individu-als enrolled to date. The plan is to enroll a total of 1600 participants.

What were the results of the tri-als? What insights were gained that may enhance their value to oncolo-gists and to the clinical laboratory? The results to date are preliminary but suggest that the risk of lung cancer is elevated approximately fi vefold if the blood test is positive. This is in a cohort of individuals who are already at high risk for lung cancer due to their age and smoking history. These early results support the results of a previously pub-lished clinical use audit which showed a fi vefold increased risk of lung cancer in individuals with a positive test.

Developing blood biomarker tests for the detection of cancer

The autoantibodies in the EarlyCDT-Lung blood test have been shown to be positive in all stages of lung cancer in-cluding the earliest, Stage I. Preliminary data has shown the blood test to be posi-tive one to two years before the clinical diagnosis of lung cancer in some cases. Two ongoing prospective clinical tri-als are in progress to further clarify the ability of the test to detect lung cancer before individuals develop signs and symptoms of disease.

Will the approach be applicable to other kinds of solid-tumor cancers as well? Is Oncimmune developing blood autoantibodies assays for other cancers? The EarlyCDT-Lung autoantibody biomarker approach is theoretically applicable to most cancers. However, the cancer antigens expressed on different cancers can vary greatly. Also, the extent of their expression for developing an autoantibody response will vary. Additional autoantibody blood tests for early detection of other cancers are in development. Oncim-mune is in the process of developing a blood autoantibodies test for hepatocel-lular carcinoma (liver cancer), and pre-liminary work is underway for ovarian cancer.

You spent many years serving at the Mayo Clinic (Rochester) be-fore moving on to National Jewish Health and now Oncimmune. How does your career as a top clinician and researcher help you function more effectively in your industry capacity? For more than 30 years the focus of my career has been on early detection, diagnosis, and treatment of lung cancer as well as other malignan-cies of the chest. During this time period I have been privileged to interact and collaborate with top physicians in the lung cancer fi eld. Through this exposure to critical thinkers and my own clinical practice, I have become aware of the high bar set for biomarkers to be of clini-cal usefulness. Additionally, I have cred-ibility and contacts within the lung can-cer fi eld. This will allow Oncimmune to develop a registry study for indetermi-nate pulmonary nodules and other po-tentially necessary prospective clinical trials. The acquired knowledge gained from these lung cancer clinical trials will translate to other malignancies.

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