Physicians struggle to take Full advantage oF ehrsNew findings published in Annals of Internal Medicine show that the num-ber of physicians using basic electronic health records (EHR) increased by 10% in just over 1 year, but that only a small percentage of these physicians use the advanced EHR functions that have the most potential to increase pa-tient care quality while reducing costs. Under the Centers for Medicare and Medicaid Services (CMS) “meaning-ful use” standards for EHRs, providers meeting specific criteria for using EHRs to report their performance on quality measures are eligible to receive incentive payments from CMS.

Researchers for the Commonwealth Fund–supported study surveyed a ran-dom selection of approximately 2,000 primary care physicians (PCPs) and 1,400 specialists. From October 2011 to March 2012, the survey questioned participants about measures of EHR adoption previously developed by the Office of the National Coordinator for Health Information Technology, as well as care coordination, use of quality information, and participation in pay-ment incentive programs promoting EHR use.

During the study period, EHR use by participants increased from 34% to 44%. More than 40% of both PCPs and specialists now use a “basic EHR,” meaning that they use simple EHR functions, such as viewing lab results and X-rays, ordering prescription drugs electronically, and recording clinical notes. About 40% of PCPs and specialists also meet between eight and 10 of the 11 federal meaningful use criteria.

Overall, though, the survey results show that adoption of EHRs still has a long way to go before the full promise of this tool is realized. Only 9.8% of physicians reported meeting all 11 meaningful use criteria, and among those who came close, many experi-enced difficulty using more advanced EHR features that, for example, gener-ate quality metrics, provide patients with after-visit summaries, and facili-tate the electronic exchange of data with physicians outside the practice.

The authors concluded that ad-ditional training, as well as further research on usability, may be needed to help physicians reap the full benefits of EHRs.

ClinicalLaboratoryNews

n e w s b r i e fThe auThoriTaTive

source for The clinical laboraTorian

sepTember 2013volume 39, number 9

w w w . a a c c . o r g

Our Daily BloodHow Can Labs Tackle Utilization of High-Volume, Low-Cost Tests?By Bill Malone

With the growth of specialty genetic tests that can cost thousands of dollars, some large medical centers have become more aggressive in keeping tabs on physicians’ orders of expensive tests. But while reining in big ticket tests may offer a quick

fix to out-of-control sendout testing, another utilization problem often still lurks in plain sight: routine, low-cost tests that demand large amounts of real estate in the lab and on patients’ charts.

The cost savings from reducing unnecessary tests are well docu-mented, but a second and more important goal is patient safety. By cutting back on high-volume tests, hospitals can reduce the risk of iatrogenic anemia and transfusion for patients while also avoiding pouring human blood down the drain for no reason. Although a conservative approach to phlebotomy isn’t new, rising healthcare costs and government programs that measure patient satisfaction and safety are putting a new emphasis on this area.

Even at institutions like the prestigious Cleveland Clinic in Ohio, laboratorians have discovered that busy physicians often order daily or even repeat tests on the same day, simply out of habit and hurry. Dealing with these kinds of frequent, unnecessary tests is a way for laboratorians to have a more direct impact on patients’ experience of health-care, according to Gary W. Procop, MD, who leads the organization’s test utilization committee. “Decreas- ing unnecessary phlebotomy is a great way for laboratorians to show that they really care about patient

The Fast-Moving Realm of Prenatal DiagnosticsHow Long Will Microarrays Reign as the Preferred Method?By Genna Rollins

for nearly 50 years, karyotyping has been the backbone of prenatal diagnostic testing for congeni-tal anomalies, but rapid advances in genomic technologies are outpacing both this tried-and-true method and others poised to take its place. Pivotal research showing the superiority of microarrays in comparison to karyotyping is hastening the obsolescence of the latter; however, at the same time, microarrays also appear to be only a milestone along the path to even more sophisticated non-

invasive testing approaches. The growing pains of adopting these new technologies require diligence by medical teams and likely will spell changes for lab practice.

“There’s never a history of going backwards. This technology is here, it’s going to move forward and replace what we’re pres-ently doing, but we’re going to have to be very careful,” advised Ronald Wapner, MD, professor, director of reproductive genet-ics, and vice chair of research in the department of obstetrics and gynecology at Columbia University in New York City. “This is a giant revolution and it’s gotten very complicated for practicing physicians and patients. So as we transition the technology from the lab into clinical practice we really have to work as a team to use it appropriately.”

See Daily blood, continued on page 3

See prenatal Dx, continued on page 6

in This issueLab 2013

8 Total Analytic Error— How to Use It

11 Early Results— Pediatric Reference Ranges

12 Regulatory Profiles

13 Industry Profiles

13 Labs Are Vital Program Relaunched

14 Diagnostic Profiles

15 News From the FDA

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snapshoTEHR Use Among Physicians

Source: Ann Intern Med 2013;158:791–9

Primary care physicians Specialists

0% 10% 20% 30% 40% 50%

Use a basic EHR

Meet most meaningful-use

criteria

45% 41%

41% 37%

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satisfaction scores and patient experi-ence,” he said. “This is a great added value to improving test utilization of these tests beyond greater efficiency or cost savings.” Procop also is chair of molecular pathology at Cleveland Clinic, and medical director of the molecular microbiology, mycology, and parasitology laboratories.

Stop and ThinkEven when patients don’t have out-of-pocket expenses, they pay for lab results with something else—their own blood. Al-though the occasional prick in the arm for outpatients seems inconsequential, observ-ers have long expressed concern about how often inpatients have their blood drawn. In the hospital, patterns of routine or daily testing can drain patients past the point of discomfort.

In one example, Canadian research-ers asked doctors at St. Paul’s Hospital in Vancouver not to order complete blood counts (CBC) and metabolic panels when they didn’t have a specific indication in mind, the idea being to reduce unneces-sary routine CBCs and metabolic panels. Peter Dodek, MD, chair of the Critical Care Working Group at St. Paul’s Center for Health Evaluation and Outcome Sciences led this quality improvement study. Dodek also is a professor of medicine at the Uni-versity of British Columbia.

His team employed a handful of strate-gies aimed at getting physicians to consider whether the tests were necessary before ordering them. The first step was work-ing with ICU staff physicians to develop acceptable indications for ordering CBCs and metabolic panels, including suspected anemia, infection, thrombocytopenia, and kidney injury (See Box, p. 4).

Next the researchers introduced some educational strategies, including talking to rotating ICU residents about the indica-tions for ordering these tests and display-ing posters around the ICU that listed the indications along with the phrase, “THINK before you order!”

Dodek’s team also added an item to the ICU rounds checklist reminding staff about the initiative, and provided a rubber stamp for lab orders, nursing flow sheets, and progress notes that read, “Routine blood work NOT indicated for tomor-row”—meant to catch the attention of on-call staff. Finally, in the hospital’s com-puterized physician order entry (CPOE) system, a prompt for the tests in question read, “Please do not order without an in-dication.”

For the next 6 months, Dodek and his colleagues monitored how many tests doc-tors ordered and compared these num-bers to the year before the interventions. As they implemented each intervention in a step-wise fashion, they found that the number of CBC and metabolic panel or-ders dropped by 24% overall. However, the changes were not as dramatic over time. Across the 6-month study period, CBCs and metabolic panels per patient-day dropped by 7% and 5%, respectively. The researchers also checked to make sure that study participants didn’t have worse out-comes, and found no adverse effects from their having had fewer tests.

Notably, physicians went along with the initiative and lodged few complaints. “The criteria for ordering these tests were actu-ally not very strict,” Dodek said. “We sim-ply asked physicians to put down a reason. It seemed most of them saw this as a good thing—if we don’t need to draw blood from patients, we shouldn’t. On the other hand, some are quite stuck on routine test-ing and feel like they might miss something if they stop ordering them. They want to get a test ‘just in case.’”

The project won an award at St. Paul’s during a quality improvement project competition and was credited with proving that routine blood tests could be reduced with relatively simple interventions. How-ever, the researchers felt somewhat disap-

pointed that the project was not nearly as successful as a previous intervention that focused on unnecessary routine chest X-rays. Using similar educational interven-tions, the X-ray project reduced routine chest X-rays by more than 60%, an effect that has lasted long after the intervention ended.

The most recognizable barrier for edu-cational interventions such as these is sim-ply the distractions in the ICU, according to Dodek. “If a little complacency sets in, something like this can quickly fall off phy-sicians’ radar,” he said. “There are already so many things vying for our attention in the ICU. But I think the point to remember is that it is possible to reduce some routine tests without compromising patient care. It just requires continued attention.”

Dodek did not collaborate directly with St. Paul’s lab on the project, but he believes

that laboratorians should embrace these utilization challenges and play a role. “I’m sure that laboratorians would rather be do-ing tests that make a difference. So I think they should help inform those on the or-dering end that for their laboratory to be as efficient as possible, every test should be important and meaningful for the patient,” he said. “That’s the kind of wisdom that laboratory personnel can bring to the clini-cal scenario. If we’re doing a lot of tests that are unnecessary, we’re just cluttering up the lab’s workload. No one is better suited than laboratorians to speak to the value of this.”

Reducing unnecessary tests is about more than just efficiency, or even money, Dodek said. Rather, real risks like infection and anemia caused by phlebotomy wor-ries him more. “We do know that there is evidence that the more blood we draw,

See Daily blood, continued on page 4

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the more we will transfuse patients. We also know that the more we transfuse, the higher the risk of nosocomial infections and mortality,” he said. “So, given that link-age of drawing unnecessary blood, creating iatrogenic anemia, and then transfusing people, it does make sense to go right up-stream and decrease the amount of blood that we draw.”

Saying “No” to Same-Day RepeatsTaking on high-volume tests can mean more than just avoiding a daily order, and in fact Cleveland Clinic struggled before it was able to tamp down on same-day repeat testing. The medical center’s test utilization committee tried using CPOE best practice alerts to address this issue, but found a full electronic stop was the only way to reduce overutilization on some orders.

The committee started with pop-up windows in the CPOE that would alert physicians when they tried to order a test for the second time in the same day. But physicians apparently clicked through these pop-ups without noticing and ordered the tests anyway. While same-day repeats de-creased for a few molecular tests, the more common tests, such as C. difficile, contin-ued unabated. That’s when the committee took the next step: the hard-stop initiative.

Under this initiative, the CPOE blocked repeat orders of tests that the test utilization committee determined were never appro-priate more than once per day. Physicians who still insisted on ordering a test had to call the lab, Procop explained. “We began with 10 tests for which it was beyond medi-cal debate whether they were needed more than once per day, but with a ‘break-the-glass scenario,’ so to speak, where if the doc-tors really, really wanted one of these tests, they could still have it. If someone wanted a second test, they had to call the lab, tell us who they were, who they worked for, and why they wanted it,” he said. “That kind of initiative was never really tried here before. The previous culture was: if the doctor or-dered it, just do it. And this gave us an op-portunity to challenge the status quo. I give the leadership at the Cleveland Clinic a lot of credit for letting the test utilization team pilot this project.” The initiative started with tests such as HbA1C, basic lipid pan-els, C-reactive protein, hypercoagulation panels, reticulocyte count, and hepatitis C. Now with more than 1,200 tests on the list, the success of the hard-stop initiative has grown, with surprisingly few complaints from physicians.

The key to building an initiative like this in which the lab could essentially tell a physician “no” was a close relationship

with senior information technology (IT) staff, Procop noted. When physicians came to the test utilization committee with evi-dence that they did in fact need a test more than once a day, it was essential to promptly deal with it. “We had such a good relation-ship with the IT people that we were able to remove a test from the hard-stop list the same day if there was a valid objection,” he said. “That way I could write back to the doctor right away and say, ‘we heard you; it won’t be a problem anymore.’ That really helped build our credibility with our clini-cal colleagues.”

The hard-stop initiative saved Cleve-land Clinic approximately $116,000 in its first year, discontinuing more than 7,000 unnecessary duplicate tests. However, the biggest payoff has been in patient satisfac-tion, according to Procop, because it’s the high-volume tests that can be burdensome on patients.

“The motivator behind all of this was really a patient experience improvement initiative in that we felt like there was too much duplicate phlebotomy for inpa-tients,” Procop said. “Our chief phleboto-mist was pretty upset with patients being stuck twice for the same test, and rightly so.”

Unhide the Price TagEven though many overused lab tests are not expensive—at least compared to imaging tests or drugs—simply showing the ordering physician a dollar amount also has had some

Clinical Labs Can Say No to Test OrdersDaily blood, continued from page 3

peter Dodek, MD, and colleagues at st. paul’s Hospital in Vancouver tried several strategies for reducing unnecessary routine blood tests, including putting up posters like this one around the hospital’s intensive care unit. the poster highlights accepted indications for CbC and electrolyte tests.

THINK before you order!l suspected anemia

l suspected infection

l changes in IVF

l active correction of

electrolyte abnormalities

l suspected new electrolyte abnormalities

l suspected thrombocytopenia

l suspected/ongoing kidney injury

CliniCal laboratory news septeMBeR 2013 5

success in reducing over-testing. A study at The Johns Hopkins Hospital in Baltimore examined if the number of laboratory tests ordered could be reduced by presenting cli-nicians with test fees at the time they were entering the orders in the CPOE (JAMA Intern Med 2013;173:903–8).

All clinicians, including physicians and non-physicians, who ordered laboratory tests through the hospital’s CPOE were in-cluded in the study. Researchers randomly assigned 61 diagnostic laboratory tests to an active group with the fee displayed, or to a control group. Tests were randomly picked from two categories: the most fre-quently ordered tests and the most expen-sive. The expensive tests had to be ordered at least 50 times a year to be included.

No fee was displayed during a 6-month baseline period, November 2008–May 2009. During a 6-month intervention pe-riod 1 year later, fee data were displayed for active tests only. The fees shown to clini-cians in this case were based on the Medi-care allowable fee in the clinical laboratory fee schedule.

Physicians exposed to the test fees sig-nificantly trimmed their orders. Rates of test ordering declined from 3.72 tests per patient-day in the baseline period to 3.40 tests per patient-day in the intervention period, an 8.59% decrease. For the control group, ordering increased from 1.15 to 1.22 tests per patient-day from the baseline pe-riod to the intervention period, a 5.64% increase.

Daniel Brotman, MD, the senior author of the study, noted that orders of the more expensive tests did not make a significant difference in the study; instead, the fre-quent and relatively inexpensive tests took a significant dive. For example, there was a marked decrease in orders of compre-hensive metabolic panels. “We realized in looking at the data that the total aggregate cost for the frequent tests was a heck of a lot higher than the more expensive tests. So if you were to focus on only the expen-sive tests, you’d only get at the tip of the iceberg.” Brotman is an associate professor of medicine at the Johns Hopkins Univer-sity School of Medicine and director of the hospitalist program at The Johns Hopkins Hospital.

Compared to basic tests like metabolic panels, clinicians appear more likely to think through the reasoning for ordering expensive tests, and order them less often, according to Brotman. “Expensive tests are generally ordered on a single occasion for a patient based on a perceived true need. So if you want to make sure that you under-stand whether someone has HIV, there is only one way to do that, and you only do it once. You wouldn’t order it frequently throughout a hospitalization,” he said. “I think to some extent it’s reassuring that in our study the ordering of expensive tests didn’t change, which to my mind means clinicians had a real curiosity about what was going on with their patient.” Going forward, Brotman and his colleagues are working on a report card-style system for offering individualized feedback to clini-cians on diagnostic ordering.

Brotman also believes there could be a generational gap in how physicians re-spond to these types of interventions. “I’m sure that in our study some were slightly annoyed to have to think about costs, but I think younger physicians are going to feel

like it makes sense,” he said. “They tend to see a dark cloud of healthcare expenses looming in this country, and physicians of-ten don’t feel very empowered to do much about it.”

Let’s Not Do That AgainWhen studied on a large scale, overuse of common, low-cost tests can look surpris-ingly costly—both in dollars and in hours of patient and physician time. A recent Vet-erans Affairs (VA) study examined patients with coronary heart disease (CHD) who had reached their treatment goals of low-density lipoprotein cholesterol (LDL-C) <100 mg/dL or even <70 mg/dL, and found that about a third underwent re-peat lipid testing within 11 months with-out an identifiable aim (JAMA Intern Med 2013;doi:10.1001/jamainternmed.2013. 8198). Current performance measures for CHD, based on Adult Treatment Panel (ATP) III guidelines, recommend only one lipid test per year once a patient reaches his or her goal, unless the physician wants to intensify treatment or check for medica-tion non-compliance.

Salim Virani, MD, PhD, of the Michael E. DeBakey VA Medical Center in Houston, and colleagues analyzed a total of 35,191 patients with CHD in a VA network of seven medical centers. Of 27,947 patients with LDL-C levels <100 mg/dL, about 9,200—32.9%—had additional lipid tests without treatment intensification during the following 11 months. All together, these patients had more than 12,000 additional lipid panels performed, at a mean cost of $16.08 per person, or about $204,000 in annual costs for one VA network.

The study demonstrates that overuse of common, inexpensive tests can still make a big dent in healthcare costs due to their high frequency, according to Virani. “The reason that we looked at this was that, while a regular lipid panel is not very costly com-pared to the imaging tests that other groups are looking at in terms of healthcare over-use, we believe the most important thing is that these are high-frequency tests, and it’s the low-cost but high-frequency tests that go under the radar,” he said. “Although the cost per individual patient might be low, overall the frequency of overuse is so high that it can become a pretty big number.” Vi-rani is an investigator for both the Health Policy, Quality and Informatics Program, and the Houston VA Health Services Re-search and Development Center of Excel-lence, as well as a staff cardiologist at the Michael E. DeBakey VA Medical Center. Virani is an assistant professor at Baylor College of Medicine, and he chairs the Stra-tegic Planning Work Group the National Heart, Lung, and Blood Institute (NHLBI) National Program to Reduce Cardiovascu-lar Risk (NPRCR).

“This well-conceived study on a large clinical database, which has the advantage of containing pharmacy data for use in track-ing medication adherence, delivers an im-portant message regarding a type of waste that is likely widespread in healthcare and that goes under the radar because it involves a low-cost test,” wrote Joseph P. Drozda, Jr., in a commentary. “However, it is precisely these low-cost, high-volume tests and procedures that need to be addressed if significant sav-ings from reduction of waste are to be real-ized” (JAMA Intern Med 2013;doi:10.1001/jamainternmed.2013.6808).

Virani believes that VA physicians or-dered the additional lipid tests either out of routine or as a way to offer themselves reassurance, even when they did not plan on taking any action after seeing the results. In the study, Virani found a high correla-tion between primary care office visits and testing. “When a healthcare provider is go-ing to see a patient, it may provide them some comfort in ordering labs just before or after the visit, so they feel that they are taking good care of the patient by doing something,” Virani said.

In the future, additional lipid tests may become even less necessary if the ATP IV guidelines pivot and recommend a dose-based approach for statins versus the cur-rent treat-to-target approach that empha-sizes lipid testing. “Although we don’t know what the ATP guidelines will say, there is a

debate in the literature about the fact that all of the clinical trials for statins were per-formed with a fixed-dose approach—the dose of the statin was the target and not the LDL-C,” he said. “If ATP guidelines were to move in this direction, the need for follow-up with more lipid testing once a patient is on a stable statin dose would obviously go down.”

Although Virani was able to use VA data sources to very accurately gauge lab costs for the redundant tests, he emphasized that more intangible consequences for unnec-essary tests could be equally large. “The cost we estimated of course does not take into account the value of the patients’ time to go to the lab and have an additional test per-formed, or the value of a physician’s time to follow-up on these test results and notify patients,” he said. CLN

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Critical ComparisonsWapner was the principal investigator of a recent landmark clinical trial that com-pared microarray analysis against karyo-typing in more than 4,000 women referred for prenatal diagnosis based on maternal age, abnormal Down syndrome screen-ing results, anomalies identified on ultra-sound, or other indications (N Engl J Med 2012;367:2175–84). The participants, seen at 29 centers across the U.S., underwent chorionic villus sampling or amniocen-tesis. The study protocol involved halv-ing each specimen collected from these procedures, with a single cytogenetics lab performing all karyotyping. Four different labs completed the microarray analyses us-ing either Agilent or Affymetrix platforms. The arrays, designed to maximize detection of well-characterized microdeletions and duplications, also had probes for regions throughout the genome to identify other chromosomal imbalances.

This long-awaited National Institute of Child Health and Human Development (NICHD)-funded study demonstrated that single nucleotide polymorphism (SNP)-based and comparative genomic hybridiza-tion microarrays found all the aneuploidies and unbalanced rearrangements identified

by karyotyping. Additionally, microarrays detected clinically relevant deletions or du-plications in 6% of samples referred due to anomalies on ultrasound and in 1.7% re-ferred because of advanced maternal age or positive screening results, all of which had normal karyotype results.

Taiwanese researchers also recently re-ported similar findings, in a smaller popu-lation (BJOG 2012;119:614–25). After test-ing of more than 3,100 cases, the authors found that microarray analysis had an ad-ditional 8.2% diagnostic yield in compari-son to karyotyping.

A First-Line Test?These findings present a solid case for us-ing microarrays as the first-line prenatal di-agnostic test, according to Aaron Caughey, MD, PhD, chair of the department of ob-stetrics and gynecology and associate dean for women’s health research and policy at the Oregon Health and Science University in Portland, who was not involved in either study. “This is a big step forward, monu-mental even, because prenatal diagnostics have been focused for so long on Down syndrome detected by karyotyping, which is a very crude way to look at someone’s genome,” he explained. “However, there are so many genetic syndromes related to mi-

crodeletions or duplications that we’ve not been diagnosing prenatally for decades, and now with microarrays there’s a way to do so by looking at much smaller parts of DNA.”

The researchers also found that micro-array results generally were available sooner than those of karyotypes, owing to most microarray specimens not needing to be cultured, which is necessary for karyotyp-ing. Initially they performed microarray analysis on paired cultured and uncultured specimens to see whether the different pro-cedures led to different diagnostic yields, 259 in the case of chorionic villus sam-pling and 275 with amniotic fluid. Finding comparable results, the investigators subse-quently used culture with microarray only when they encountered difficulties with uncultured samples. They plan to publish a report about their lab methods.

Furthering the appeal of microarrays, the methods cost about the same, $1,500 to $2,000 for microarrays and $1,000 to $1,500 for karyotyping, according to one estimate.

The Problem With Balance Microarrays fell short of karyotyping only in detecting triploidies and balanced translocations, which the investigators an-ticipated going into the study, since these variations cause no gain or loss in genetic material and microarray technology is de-signed to detect copy number changes.

“We knew there might be cases where a balanced translocation would be iden-tified by karyotyping which microarray would not detect. But our study was trying to identify chromosome imbalances that could cause human disease, and if there’s no imbalance, most likely that wouldn’t cause any issues,” explained co-author Christa Lese Martin, PhD, FACMG, director and senior investigator of Geisinger Health Sys-tem’s Autism and Developmental Medicine Institute in Lewisburg, Penn.

She added that balanced transloca-tions usually don’t cause abnormal clinical outcomes. “It’s something we look for in couples with infertility, but that’s a differ-ent indication than what this study was be-ing done for. In fact, most cases of balanced translocations in our study were inherited from a normal parent, giving more evidence that they were not related to phenotype.”

At the time the study took place, Martin was an associate professor of human genet-ics at Emory University School of Medi-cine in Atlanta, and her lab was one of the four that performed the study’s microarray analysis.

The Troubling Issue of VOUSWhile microarrays came out looking pretty good in the studies, that does not mean they are a perfect diagnostic vehicle. One issue Wapner’s study brought to light is variants of unknown significance (VOUS). Because they are at significantly higher resolu-tion than karyotypes—50–200 Kb versus 3–10 Mb—microarrays detect submicro-scopic gains, losses, and rearrangements, compared with karyotypes’ broad brush look at chromosome size and structure.

With the genome far from completely annotated, microarray-detected VOUS were expected at the outset, and indeed, initially 3.4% of cases had VOUS that karyotyping also did not pick up. With ge-nomic variant data being added daily to the literature, the authors toward the end of the

study reanalyzed the original VOUS against updated databases and were able to whittle them down so that only 1.4% of cases had such findings. As genomic discoveries con-tinue, VOUS should be even less of an issue going forward, experts agreed.

In the meantime, VOUS pose challenges for clinicians and patients alike. Clinicians not only need to make sense of any VOUS themselves but also to educate patients about the likelihood of each method to de-tect VOUS. “The main concern is the po-tential anxiety that VOUS causes or the po-tential of patients making decisions about whether to continue a pregnancy based on diagnostic test results,” explained David T. Miller, MD, PhD, a clinical geneticist at Boston Children’s Hospital and assistant professor of medicine at Harvard Medical School. “If you’re delivering ambiguous re-sults it makes it very difficult for both the physicians and the patients themselves to make those management decisions.” (See Box, p. 7).

A Maturing TechnologyWhile Wapner and his colleagues made a big splash with microarrays in prenatal diagnostics, their findings in some ways merely reflect the maturation of this tech-nology. For several years, microarrays have been the preferred method of postnatal di-agnosis of genetic abnormalities involved in developmental delays, intellectual dis-ability, and autism spectrum disorders. In fact, the American College of Medical Genetics and Genomics (ACMG) in 2010 published a practice guideline endorsing microarray as the first-line test in the work up of anomalies not clearly tied to well-described syndromes, developmental de-lay and intellectual disabilities, and autism spectrum disorders.

Despite this positive view of microar-rays, the maternal-fetal medicine com-munity needed more robust evidence to use the method routinely in prenatal di-agnostics, according to Martin. “It became very clear from using microarrays in the postnatal setting that they could detect not only rearrangements or imbalances that were detectible by karyotype but also sub-microscopic rearrangements that weren’t readily noticeable or even detectible by karyotyping. But a person presenting with some phenotype is very different than the prenatal setting where there may be an ab-normal serum screen but not abnormal ul-trasound findings,” she explained. “Prenatal microarrays not only have a different in-dication, but also different specimen types than postnatal. With these differences, the field was ready to see whether microarrays would be superior to karyotyping in the prenatal setting.”

Whether this new evidence will lead the American College of Obstetricians and Gynecologists to change its prenatal testing recommendations remains to be seen. In 2009 the group endorsed microarray analy-sis as a second-line diagnostic when ultra-sound results are abnormal but karyotype is normal. Yet leading centers like Wapner’s already are offering microarray testing to all patients scheduled for invasive procedures, whether or not an abnormality has been detected on ultrasound.

Further evidence of the utility of micro-array technology was published in the same New England Journal of Medicine issue as Wapner’s and his colleagues’ study, in which

Microarrays Poised, But Not Perfectprenatal Dx, continued from page 1

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CliniCal laboratory news septeMBeR 2013 7

researchers at NICHD reported that micro-array testing outperformed karyotyping in providing genetic diagnosis in stillbirth (N Engl J Med 2012;367:2185–93). They found that microarrays had a higher di-agnostic yield than karyotyping—87.4% versus 70.5%—and detected more genetic abnormalities, including both aneuploidy and pathogenic copy-number variants, 8.3% versus 5.8%.

The End of Karyotyping?If these studies seem to sound the death knell for karyotyping, experts—Miller among them—cautioned not to count out this method anytime soon. “There are still going to be complex rearrangements that need to be evaluated with traditional tech-niques like karyotyping and fluorescence

in situ hybridization. There are going to be indications where a traditional karyo-type is still the best test for conditions like Turner syndrome, Down syndrome, and in couples with a history of multiple mis-carriages where you suspect there’s a rear-rangement that’s leading to an imbalance,” he explained.

Experts also emphasized that microar-rays are not a prenatal diagnostic pana-cea. In a third study published in the New England Journal of Medicine, Harvard re-searchers reported prenatal diagnosis of CHARGE syndrome—colomboma of the eye, heart anomaly, atresia of the choanae, retardation, and genital and ear anoma-lies—using whole genome sequencing (N Engl J Med 2012;367:2226–32). The au-thors emphasized that ultrasound, karyo-

typing, and microarray all would have missed this problem.

The Rise of Non-Invasive TestingIf microarrays with rare exceptions out-perform karyotyping in prenatal diagnosis, does this method have the same 5-decade staying power as karyotyping? In a word, no. The experts who spoke with CLN em-phasized that microarrays one day will be sidelined by non-invasive testing methods like the one pioneered by Y. M. Dennis Lo, DM, DPhil, which use massively parallel sequencing of cell-free fetal DNA in mater-nal plasma to detect trisomy 21 (CLN April 2011). Already, commercial tests based off this amazing technology are available, and all indications are that this form of testing has taken off like a rocket, to the chagrin of maternal-fetal medicine, laboratory, and genetics specialists. Their concern is that microarrays are being bypassed inap-propriately in favor of non-invasive testing. Rapid adoption of non-invasive prenatal testing prompted the ACMG in April to issue a policy statement, pointedly empha-sizing that these tests are screening, not di-agnostic, in nature, and identifying at least 10 limitations of the technology (CLN May 2013).

“Non-invasive prenatal testing is seduc-tive. Patients think they’ll be able to know all they want to learn about their fetus with-out having an invasive procedure. But with non-invasive testing right now we’re talk-ing about learning about just five chromo-somes versus with microarray getting the sub-microscopic changes and other copy number variants that we know are linked to disease,” said Martin. “A lot of people are calling non-invasive testing the new karyo-type, but it’s really a step backward. Micro-arrays are the new karyotype—for now.”

In a recent commentary on the new era of non-invasive prenatal testing authors Stephanie Morain, MPH, Michael Greene, MD, and Michelle Mello, JD, PhD, argued that cell-free fetal DNA testing “seems to be drifting into routine practice ahead of the evidence” (N Engl J Med 2013;doi:10.1056/NEJMp1304843). They suggested that this is partially due to test providers building up consumer demand for the tests in the absence of a requirement by the U.S. Food and Drug Administration to provide evi-dence of clinical utility.

Wapner agreed that non-invasive pre-natal testing is beginning to outpace its current diagnostic utility. However, he suggested that by the time this technology matures, experience gained from working with microarrays will have prepared the field to make the best use of it. “In the long run I believe that sequencing will replace microarrays. But we’ve learned from our study and from working with microar-rays all the problems, all the issues, so that as we move into sequencing we’ve begun to understand how introducing genomics information into prenatal testing should be done.”

The Role of Labs in Prenatal TestingThe shifting sands of prenatal diagnostics have enveloped the lab community as well as clinicians. Karyotyping traditionally has been the domain of cytogeneticists operat-ing in specialized labs, owing in part to the need to culture cells prior to staining them. Now Wapner’s team has demonstrated that nearly all microarray samples can be pro-cessed successfully without culture, and non-invasive prenatal testing has bolted out of the starting block. Does this mean that prenatal diagnostics might no longer be concentrated in cytogenetics? Sarah South, PhD, medical director of cytogenet-ics and microarray at ARUP Laboratories and associate professor of pediatrics at the University of Utah in Salt Lake City, envi-sions such a possibility.

“The technologies in this area and ge-nomics in general seem to be moving so quickly that we’re all students again. We will have to work more as teams, train each oth-er, share our expertise, and think outside the box of our respective fellowships and certifications,” she said. “In the past we’ve been defined by our technologies. But the technologies are moving so fast now that they’re taking us into different areas. This is causing us to think more about how our various colleagues understand biology and medicine and what we can teach each oth-er. Then we can apply that knowledge as a team to better utilize the technologies that are coming up.” CLN

Disclosures: Dr. Caughey receives salary/consultant fees and stock/bonds from Ariosa and Cellscape. Dr. Miller receives salary/consultant fees from Claritas Genomics.

microarrays versus Karyotyping in prenatal Diagnostics

What Should Expectant Parents Know?Microarrays have become the preferred lab method to help diagnose in infants and children developmental delays, intellectual disability, and autism spectrum disorders, and now research has demonstrated their utility in the prenatal realm. this technology, which has significantly higher resolution than the current diagnostic standard, karyotyping, raises the specter of expectant parents being informed about their fetus carrying genetic variants of unknown significance (Vous). as microarrays make their way into routine clinical practice, clinicians, labo-ratorians, and geneticists will need to collaborate closely about how to educate themselves and parents about this new wealth of information, according to experts.

“there needs to be a very active discussion of how much informa-tion one should get in a prenatal test because with microarrays you’ll begin to be able to identify adult-onset disorders, things that will have a much milder phenotype,” explained ronald wapner, MD, professor, director of reproductive genetics, and vice chair of research in the department of obstetrics and gynecology at Columbia university in new York City, and the principal investigator of a major study compar-ing microarrays against karyotyping in prenatal diagnosis of congenital anomalies.

although the microarray-versus-karyotype debate brings the Vous issue into sharper focus, it is not a new concern in prenatal diagnostics, said David t. Miller, MD, phD, a clinical geneticist at boston Children’s Hospital and assistant professor of medicine at Harvard Medical school. “there’s always going to be a little bit of that, the balance between maximum diagnostic yield and minimum Vous. that’s even true with karyotypes, and it doesn’t mean that people don’t use the test. it just means that with microarrays as with karyotyping, they’ll have to use it with their eyes wide open.”

even if the Vous issue did not arise solely from microarrays, the wealth of information available from this method calls out for an im-proved across-the-board understanding of genetics, contended aaron Caughey, MD, phD, chair of the department of obstetrics and gynecol-ogy and associate dean for women’s health research and policy at the oregon Health and science university in portland. “with microarrays and other ongoing genomic research, new microdeletions are going to be discovered every day. physicians will be faced with telling patients, ‘Your baby is missing a piece of Dna in the region where these seven genes are, but we don’t know what it means to have that missing Dna.’ there’s going to be a lot of that going on and it’s going to be very hard to deal with,” he suggested. “physicians barely understand this, so help-ing patients understand it is going to be very challenging. it calls out for genetic literacy for all.”

wapner suggested that while microarray technology brings out more Vous than karyotyping in the prenatal setting, it doesn’t funda-mentally change patients’ perception of or ability to process uncertain-ty. “the fear of giving people these unknown findings is it does create some anxiety. but it’s pretty amazing how smart people are and that they understand about not knowing things,” he observed. “so there’s absolutely no reason that we shouldn’t make the switch from karyo-typing to microarrays, but we have to do it taking into consideration not just the technical ability but all the other social, psychological, and practical implications.”

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8 CliniCal laboratory news septeMBeR 2013

The Basic ConceptIn 1974, Westgard, Carey, and Wold intro-duced the concept of TAE in an effort to provide a more quantitative approach for judging the acceptability of method perfor-mance (1). At that time, the practice used by laboratories considered precision (im-precision) and accuracy (inaccuracy, bias) as separate sources of errors and evaluated their acceptability individually.

This practice originated in conventional analytic laboratories in which replicate measurements were usually made to reduce the effects of imprecision, which left bias as the primary consideration for assessing the

quality of a test result. As we know, howev-er, clinical laboratories typically make only a single measurement on each patient spec-imen. Therefore, the analytical quality of a test result depends on the overall or total effect of a method’s precision and accuracy.

This difference in clinical laboratory practice prompted introduction of the TAE concept. In short, the authors recommend-ed that the acceptability of method perfor-

mance be judged on the sizes of the observed errors relative to a defined allowable total er-ror (ATE). Because terminology and abbre-viations sometime complicate discussions of this concept and because the Food and Drug Administration (FDA) favors TAE and ATE, these terms will be used in the rest of this discussion. Furthermore, these abbrevia-tions will likely become part of the standard lexicon in clinical laboratories.

Estimating Total Analytic Error In order to put the concept into practice, the authors recommended that laboratories estimate TAE by combining the estimate of

bias from a method comparison study and the estimate of precision from a replication study. Accordingly, using a multiple of the standard deviation (SD) or coefficient of variation (CV), TAE = bias + 2 SD (or TAE = bias + 1.65 SD for a one-sided estimate) for a 95% confidence interval or limit of the possible analytic error (Figure 1).

After Westgard, Carey, and Wold pro-posed these definitions, some analysts

argued that there were additional compo-nents of error that should be considered, such as interferences that affect individual patient samples, sometimes referred to as random biases. To include such effects, Krouwer recommended a direct estimation of TAE obtained by using a comparison with a reference method (2), and the Clini-cal Laboratory Standards Institute (CLSI) subsequently developed the EP21A guid-ance document using that approach (3).

This direct estimation approach re-quires a minimum of 120 patient samples, making it useful primarily for manufactur-ers that perform extensive validation stud-ies for new methods. For clinical labora-tories, Center for Medicare and Medicaid Services’ guidance for meeting the CLIA regulations recommends a minimum of 20 control samples to estimate precision and the same number of patient samples to verify a manufacturer’s claim for bias. Consequently, it is more practical to make an initial estimate of TAE by combining re-sults from the replication and comparison of methods experiments. Laboratories may also choose to make ongoing estimates by using long-term SQC data and periodic estimates of bias from proficiency testing (PT) or external quality assessment surveys (EQAS).

Today, assay manufacturers generally make claims for precision and bias but not for TAE. Therefore, clinical laboratories must make individual estimates of pre-cision and bias to verify manufacturers’ claims, with the exception of tests catego-rized by FDA as waived. For these tests, the agency recommends that manufacturers objectively evaluate each new method and device by establishing a criterion for the ATE before beginning clinical studies (4).

FDA currently recommends that manu-facturers evaluate TAE as “the combination of errors from all sources, both systematic and random, often expressed in terms of an interval that contains a specified pro-portion (e.g., 95%) of the observed differ-ences between the working method and the comparative method.” The agency further recommends at least 120 patient sample comparisons for each of three decision level concentrations, which means that manu-factures must perform a total of 360 patient comparisons.

Total Analytic Error From Concept to ApplicationBy JaMes o. WestGaRd, phd, and sten a. WestGaRd, Ms

Today clinical laboratories have come under increased pressure to implement quality systems and

new risk management guidelines for quality control in order to ensure timely and accurate deliv-

ery of test results. However, one issue that is often overlooked in these efforts is the actual quality

goal or requirement for a laboratory test. in simple terms, the question that laboratory professionals

should be asking is: how good does a test need to be? as laboratories attempt to answer this basic

question, other questions quickly become evident—how should the laboratory define the quality goal? how

should the laboratory validate the analytical methods to satisfy the goal? and what is the best way for the labora-

tory to assure those goals are achieved in routine testing?

an effective system for managing analytical quality can be developed based on the concept of total ana-

lytic error (tae), a useful metric both to assess laboratory assay quality and to set quality goals for assays. other

tools, such as sigma metrics, method decision charts, sigma statistical quality control (sQC) selection graphs,

and charts of operating specifications are also useful. in this article, we review the concept of tae, including its

estimation and application in managing the analytical quality of laboratory testing processes.

CLN’s

improviNgheaLthCare through LaboratorymediCiNe

series

CliniCal laboratory news septeMBeR 2013 9

Goals for Allowable Total Error Given that ATE is intended to be an es-timate of the quality of a measurement procedure, its practical value depends on a comparison to the quality required for the intended use of a test result. In other words, the definition refers to the amount of error that is allowable without invalidating the interpretation of a test result.

Laboratory professionals can find recommendations for ATE within many national and international PT and EQA programs. In addition, Ricos and col-leagues in Spain (5) have developed a database of biologic goals. Available at www.westgard.com, this database in-cludes more than 300 measurands based on published studies of biologic varia-tion. It also provides recommendations for allowable SDs, biases, and biologic total errors, in accordance with Fraser’s

guidelines for combining allowable SDs and biases (6).

Operating SpecificationsWhile laboratory professionals have no trouble setting a goal for the ATE of an assay, achieving that goal is a different story. The latter requires a practical strategy that can be implemented in the real world. For exam-ple, the College of American Pathologists’ (CAP) criterion for acceptable performance in a proficiency testing survey is 7.0% for HbA1c. To achieve that goal, laboratories must select a method that has appropriate stable performance in terms of precision and bias and apply the right SQC to detect analytic problems that cause instability.

We use the term “operating specifica-tions” to describe the allowable precision and bias for a measurement procedure and the SQC, which includes control rules

and the number of control measurements necessary to monitor performance at the bench level and assure that the lab achieves a defined quality goal.

This approach is consistent with ISO 15189 requirements (7):5.5.1.1 “the laboratory shall select examina-tion procedures which have been validated for their intended use” and 5.6.2.1 “the laboratory shall design quality control procedures that verify the attainment of the intended quality of results.”

As used by ISO here, intended use and quality of results describe quality goals or requirements. Such quality goals are meant to guide selection of methods and design of SQC procedures. An appropriate combina-tion of precision, bias, and SQC becomes the ultimate strategy for achieving a de-fined quality goal.

Application ToolsFor waived tests, FDA requires manufac-turers to define ATE and to estimate TAE, but the CLIA regulations do not require laboratories to verify or validate method performance or to perform SQC, unless

specified in the manufacturer’s directions. For non-waived tests, which comprise the majority of testing in clinical laboratories, CLIA regulations also require that labora-tories verify manufacturers’ performance claims for precision and bias, implement a minimum SQC procedure with two levels of controls per day, and successfully per-form in periodic PT surveys.

We believe a more optimum system would require quality defined ATE goals for all methods, waived and non-waived. In ad-dition, laboratories would also be required to participate in PT for all methods, includ-ing waived methods. For now, laboratories would be well advised to implement more optimal management of analytical quality by defining their own quality goals and us-ing some of the following tools.

Sigma metrics. While the original rec-ommendation for a total error criterion was ATE ≥ bias + 2 SD, later papers recommend-ed ATE ≥ bias + 4 SD (8) and, with adoption of Six Sigma concepts (9), suggested ATE ≥ bias + 5 SD and ATE ≥ bias + 6 SD.

Applying Six Sigma tolerance limits corresponds to the laboratory limits for

figure 1

Total analytic error concept

the graph shows a representation of total analytic error or total error using the terminology of the original paper: random error (re), system-atic error (se), total analytic error (tae or te), bias (inaccuracy), and sD (standard deviation).

figure 2

sigma-metric calculation

the graph shows the six sigma concept of tolerance limits described in terms of allowable total error (ate or tea) and method performance illustrated by bias and standard deviation (sD).

figure 3

example of method Decision chart

this example of a methods decision chart shows allowable total error (ate) using Hba1c and the Cap pt criterion of 7%. allowable inaccuracy (% bias) is plotted on the y-axis versus allowable imprecision (% CV) on the x-axis. Diagonal lines represent, from left to right, 6-sigma, 5-sigma, 4-sigma, 3-sigma, and 2-sigma quality. operating point (a) shows a method having a bias of 1.0% and a CV of 1.5% that demonstrates 4-sigma quality.

figure 4

example of a sigma sQc selection graph

the probability for rejection is shown on the y-axis versus the size of systematic error on the lower x-axis (given in multiples of the sD or CV) and the sigma-metric of the method on the upper x-axis. the curves represent different sQC procedures, top to bottom, as shown in the key at the right, top to bottom. Vertical line represents a method having 4-sigma quality and illustrates selection of sQC procedures that have a total of four control measurements per run.

10 CliniCal laboratory news septeMBeR 2013

ATE and facilitates calculation of a sigma metric defined as, (ATE – bias)/SD or (% ATE – % bias)/% CV, to characterize test quality (Figure 2). The higher the sigma metric, the better the quality of the testing process. Industrial guidelines recommend a minimum of 3-sigma quality for a routine production process. As sigma increases, SQC becomes easier and more effective; therefore, methods with 5–6 sigma qual-ity are preferred when laboratories employ CLIA’s minimum requirement of two levels of controls per analytic run.

Method decision chart. A graphical tool for evaluating the quality of a labora-tory test on the sigma-scale, method deci-sion charts (10) are useful once laboratories have defined the ATE. To construct the chart, the scale of the y-axis (allowable bias) should be from 0 to the ATE value and the x-axis (allowable precision) from 0 to 0.5 ATE. The units for ATE, bias, and precision must be the same, either concentration or percentage. The lines are drawn represent-ing the various ATE criteria by locating the y-intercept at ATE and the x-intercept at ATE/m, where m is the multiple of the SD or CV in the total error criterion.

Figure 3 shows an example of a method decision chart for HbA1c based on the CAP PT criterion of 7.0%. To assess the quality

of a method, the laboratory should plot an operating point representing the observed bias as the y-coordinate and the observed SD or CV as the x-coordinate. For example, an HbA1c method with a bias of 1.0% and CV of 1.5% is shown as point A in Figure 3 and falls on the line corresponding to 4 sigma. To confirm this is correct, the labo-ratory should also calculate the sigma met-ric, where sigma = (7.0 – 1.0)/1.5 = 4.0.

Sigma SQC selection graph. Using SQC procedures, laboratories can employ statistical methods to monitor and evalu-ate systems, including several charting procedures for visually evaluating the con-sistency of key processes and identifying unusual circumstances that might merit attention. Using what is known as a power curve, it is possible to show the probability for rejection in relation to the size of the error that occurs. Figure 4 provides power curves for several different SQC procedures and shows as an example a sigma of 4.0. As expected, probability for error detection (Ped) increases as the error gets larger, the number of control measurements increase, and more control rules are put in place. The probability for false rejection (Pfr) also in-creases slightly, as shown by the y-intercepts of the power curves.

An appropriate SQC procedure pro-vides a high Ped for medically important errors and a low Pfr. Laboratories can also calculate the size of the medically important systematic error, called the critical system-atic error (DSEcrit), from the quality goal for the test and the bias and precision of the method using the formula: DSEcrit = [(ATE – bias)/SD] – 1.65, where the factor 1.65 is chosen to minimize the risk of erroneous test results at 5%. Note that the term (ATE – bias)/SD represents the sigma-metric for the testing process, which means that Sigma = DSEcrit + 1.65. That relationship allows the graph to be rescaled in terms of sigma, as shown by the horizontal scale at the top in Figure 4. To select an appropriate SQC pro-cedure, the laboratory draws a vertical line corresponding to the sigma metric of the testing process. For this example, the labo-ratory could select either a 12.5s single-rule with N=4 or a 13s/22s/R4s/41s multi-rule procedure with N=4. Directions for using

this sigma-metrics tool to select a SQC pro-cedure can be found in CLSI C24A3 (11).

Chart of operating specifications. This tool relates the precision and bias observed for a method to the desired SQC, employ-ing the same format as the method deci-sion chart. It uses mathematical equations in the form of “error budgets” to describe the relationship between the various error components and the defined quality goal. The starting point is the total error budget that is composed of bias plus a multiple of the SD or CV. Adding a factor that charac-terizes the sensitivity of the SQC procedure provides an analytical quality planning model (12). Further expansion to include pre-analytic variables and account for within-subject biologic variation provides a clinical quality planning model (13) that relates medically important changes in test results to precision, accuracy, and SQC.

Figure 5 shows how laboratories can display the results of these models, known as an OPSpecs chart. This chart uses a de-fined quality goal and displays the allow-able bias on the y-axis versus the allowable SD or CV on the x-axis. An operating point represents the observed method bias as the y-coordinate and observed method impre-cision as the x-coordinate. The lines on the chart show the allowable regions for the different SQC procedures.

Any line above the operating point iden-tifies an SQC procedure that will provide at least a 90% chance of detecting medically important systematic errors. The control rules and number of control measure-ments are identified in the key at the right, where the lines on the chart, top to bottom, match those in the key, top to bottom. For example, an HbA1c method that has a bias of 1.0% and a CV of 1.5%, as shown by point A, can be effectively controlled by a 12.5s single-rule procedure with N=4 or a 13s/22s/R4s/41s multi-rule procedure with N=4.

Normalized method decision and OP-Specs charts. Preparing method decision and OPSpecs charts for each test’s defined error goal is challenging. Alternatively, lab-oratories may also choose to prepare nor-malized charts that are scaled from 0–100% on the y-axis and 0–50% on the x-axis. The coordinates of the operating point are then calculated as a percent of the defined error goal. For example, a method with ATE of 7%, bias of 1.0%, and CV of 1.5% would have a y-coordinate of 14% and x- coordinate of 21%.

The advantage of normalized charts is that different tests with different qual-ity requirements can be presented on the same chart. For example, a point-of-care glucose (ATE=15%), a laboratory glucose (ATE=10%), and an HbA1c (ATE=7%) could all be presented on the same meth-od decision or OPSpecs chart. Moreover, the laboratory could present all tests on a multi-test analyzer on the same chart.

Achieving Quality in Laboratory TestingAs laboratorians, our mission is to provide accurate and useful information for clini-cians to use in making patient diagnostic and treatment decisions. Understanding how to set quality goals for tests and how to achieve those goals is essential to that mis-sion.

This review has only skimmed the sur-face of the TAE and ATE concepts. A more detailed version of this article is posted on

www.westgard.com, with links to other discussions of quality goals, tables of qual-ity goals, additional example applications, and more extensive references. CLN

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3. Clinical and Laboratory Standards In-stitute (CLSI). Estimation of total analytical error for clinical laboratory methods. CLSI EP21-A 2003.

4. Food and Drug Administration, Center for Devices and Radiological Health, Office of In Vitro Diagnostic Device Evaluation and Safety. Guidance for industry and FDA staff: Recommendations for clinical labora-tory improvement amendments of 1988 (CLIA) waiver applications for manufac-turers of in vitro diagnostic devices. 2008.

5. Ricos C, Alvarez F, Cava JV, et al. Cur-rent databases on biological variation: Pros, cons, and progress. Scand J Clin Lab Invest 1999;59:491–500.

6. Fraser CG. Biological variation: From principles to practice. Washington, D.C.: AACC Press; 2001.

7. International Organization for Stan-dardization (ISO). Medical laboratories—Requirements for quality and competence. International Standard 15189:2012. 3rd Ed. 2012.

8. Westgard JO, Burnett RW. Preci-sion requirements for cost-effective op-eration of analytical processes. Clin Chem 1990;36:1629–32.

9. Westgard JO. Six sigma quality design and control: Desirable precision and req-uisite QC for laboratory measurement pro-cesses. Madison, Wis.:Westgard QC; 2001.

10. Westgard JO. Basic method validation, 3rd ed. Madison, Wis.:Westgard QC; 2008.

11. Clinical and Laboratory Standards In-stitute (CLSI). Statistical quality control for quantitative measurement procedures: Prin-ciples and definitions. CLSI C24A3 2006.

12. Westgard JO. Charts of operational process specifications (“OPSpecs Charts”) for assessing the precision, accuracy, and quality control needed to satisfy proficiency testing criteria. Clin Chem 1992;38:1226–33.

13. Westgard JO, Hyltoft Petersen P, Wiebe DA. Laboratory process specifications for assuring quality in the U. S. National Cho-lesterol Education Program. Clin Chem 1991;37:656–61.

14. Westgard JO. Managing quality vs. measuring uncertainty in the medical labo-ratory. Clin Chem Lab Med 2010;48:31–40.

James O. Westgard, PhD, is emeritus profes-sor, Department of Pathology and Labora-tory Medicine, University of Wisconsin, Madison, and principal of Westgard QC, Inc., Madison.

Sten A. Westgard , MS, is principal, West-gard QC, Inc., Madison, Wisc.

Disclosures: The authors receive salary/ consultant fees and stocks/bonds from Westguard QC, Inc.

next month in CLN

news from the 2013

aacc annual meeting

and expo

figure 5

example of an opspecs chart

this example of a chart of operating specifications uses Hba1c with the Cap pt criterion of 7.0%. allowable inaccuracy (% bias) is shown on the y-axis versus allowable imprecision (% CV) on the x-axis. the lines below the 3.0 sigma line represent different sQC procedures, as identi-fied in the key at the right. point a shows a method having a 1.0% bias and 1.5% CV and illustrates the selection of sQC procedures that have a total of 4 control measurements per run.

CliniCal laboratory news September 2013 11

The Quest to Define Normal Values in ChildrenResearchers Begin Data Collection for Pediatric Reference Ranges by NaNcy SaSavage, phD

The first analyses of blood spot samples from the National In-stitutes of Health’s National Children’s Study are now un-derway in the laboratories of

two members of AACC’s Pediatric Ref-erence Range Committee (PRRC), Patti Jones, PhD, and Dennis Dietzen, PhD. Using tandem mass spectrometry, the re-searchers are conducting studies of the precious samples collected from healthy newborns to define age-specific reference ranges for steroid hormones and amino acids that impact children’s development.

“It took a decade for the National Chil-dren’s Study to get to where it is now,” said Michael Bennett, PhD, FRCPath, referring to the efforts that are aimed at enlisting a diverse population of 100,000 healthy chil-dren at birth and following them for 21 years. As the study kicked off, a contingent of AACC members sought to collaborate with the NIH researchers in order to ac-cess blood samples from the participants. Bennett chairs the PRRC and is director of the Michael J. Palmieri Metabolic Labora-tory at Children’s Hospital of Philadelphia and professor of pathology and laboratory medicine at the University of Pennsylvania Perelman School of Medicine.

At a press conference held during the AACC Annual Meeting in Houston, Jones and Dietzen described early results from their research. Jones, who is clinical direc-tor of the chemistry and metabolic disease labs at Children’s Medical Center of Dal-las and professor of pathology and medi-cal laboratory science at UT Southwest-ern Medical Center, is leading the arm of the study focused on steroid hormones, including 17-OH progesterone, dehydro-epiandrosterone, dehydroepiandrosterone-sulfate, androstenedione, and testosterone.

“The reason we picked these steroids is that they are the tests that are ordered to diagnose and monitor congenital adrenal hyperplasia. This disorder in kids can have a serious effect on the development of their primary and secondary sexual character-istics. In addition, lack of production of some steroids in this pathway are involved in a very serious illness called salt wasting, where the body can’t regulate and maintain the amount of sodium,” Jones explained. “Having well-defined reference ranges is therefore important to interpreting these tests.”

In the first studies of 17-OH progester-one, Jones found concentrations in new-borns span a large range: 5 – >1,000 ng/dL. An early observation is that there are some differences between male and female new-borns, but Jones was particularly curious about the samples from the high end of the range. It turns out that these were from babies less than 24 hours old; however, by 48 hours, the levels of this steroid hormone drop down to the low end of the range. If this observation holds up, it would mean that babies with levels at the high end of the range who are >48 hours of age would be abnormal and require medical interven-tions, Jones said. “That’s why this study is

so near and dear to my heart. I want to be able to have those ranges to interpret test results.” So far, she has analyzed about 300 samples by tandem mass spectrometry and will continue studies to analyze the other targeted steroid hormones.

Dietzen is analyzing the same newborn blood spots for amino acids. “I like to think of amino acids as the canary in the coal mine because they are key components of multiple metabolic processes,” he said. In addition to protein synthesis, amino acids play a role in providing energy, participate

in signaling systems involved in blood pres-sure regulation, and serve as neurotrans-mitters in the brain. Using a tandem mass spectrometry method developed in his lab, Dietzen can simultaneously analyze and quantitate 32 amino acids from a single sample in 15–20 minutes. While some of the 32 are analyzed in newborn screening programs, many are not.

In the 160 samples analyzed so far, Di-etzen rejected two that showed evidence of inborn errors of metabolism. He also found that six amino acids normally picked up by

the analysis—alloisoleucine, homocystine, cystathionine, cystine, argininosuccinate, and alpha-aminoadipic acid—are unde-tectable in the spots as their concentrations are too low. In time and with more sam-ples, Dietzen aims to develop ranges for 26 amino acids.

Looking toward the future, Dietzen is hopeful that following study participants will provide not only a picture of group variability, but also individual variability that can be related to genetic and environ-mental factors. CLN

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12 CliniCal laboratory news septeMBeR 2013

hhs: insurance marketplace Will be ready

The new health insurance exchanges mandated by the Affordable Care Act

will be ready to go live in just a few weeks, with open enrollment beginning as sched-uled, according to Department of Health and Human Services (HHS) Secretary Kathleen Sebelius. “We are on target and ready to flip the switch on October 1,” she said. The government website for health insurance, www.heathcare.gov, is already operational, and consumers can log on and create an account ahead of the October 1 deadline for insurers to begin offering plans via the website. Insurance purchased this year will go into effect as early as January 2014.

Sebelius also announced a new report that found that premiums in the govern-ment’s Health Insurance Marketplace will be nearly 20% lower in 2014 than previ-ously expected. The Affordable Care Act requires health insurers in every state to publicly justify any premium rate increases of 10% or more. Health insurance compa-nies now generally have to spend at least 80 cents of every premium dollar on health-care or improvements to care, or provide a rebate to their policy holders. In addition, when the Health Insurance Marketplace opens for enrollment, consumers will be able to make “apples to apples” compari-sons of quality health insurance plans, Se-belius said.

The HHS report noted that preliminary premiums appear to be affordable even for young men, who traditionally pay high rates. For example, in Los Angeles—the county with the largest number of unin-sured Americans in the nation—the lowest cost plan in 2014 for a 25-year-old indi-vidual costs $174 per month without a tax credit, and $34 per month for an individual whose income is $17,235. This plan offers a catastrophic coverage for $117 per month for an individual.

More information about how the Health Insurance Marketplace will work is available from www.healthcare.gov.

more regional sharing of lab Data

prodded onward by the government’s meaningful use requirements for elec-

tronic health records (EHR), health infor-mation exchange between hospitals and other providers jumped 41% between 2008 and 2012, according to new research from the Office of the National Coordinator for Health Information Technology (ONC), Farzad Mostashari, MD, and other ONC researchers (Health Affairs 2013;32:1346–54). In 2012, 80% of hospitals with at least a basic EHR and a connection to a regional health information organization (HIO) were exchanging data on laboratory re-sults, making lab information number one among types of data hospitals share. Other

types include radiology reports, clinical care summaries, and medication lists.

The research indicates that in 2012, six in 10 hospitals actively exchanged elec-tronic health information with providers and hospitals outside their organization. Meaningful use, which requires eligible hospitals to exchange data with outside organizations using different EHR systems and share summary-of-care records during transitions of care, can help accelerate hos-pital use of health information exchange as a means to enhance care quality and safety, according to Mostashari. “We know that the exchange of health information is inte-gral to the ongoing efforts to transform the nation’s healthcare system and we will con-tinue to see that grow as more hospitals and other providers adopt and use health IT to improve patient health and care,” he said. “Our new research is crystal clear: health information exchange is happening and it is growing. But we still have a long road ahead toward universal interoperability.”

Highlights of the new study show that 58% of hospitals exchanged data with pro-viders outside their organization in 2012, more than doubling during the study pe-riod. In addition, the proportion of hospi-tals that adopted at least a basic EHR and participated in an HIO grew more than fivefold from 2008 to 2012. One area that the research found needs more attention is that of care summaries and medication lists. The research found that only about one-third of hospitals exchanged clinical care summaries or medication lists with outside providers.

State-level and other data collected in the study is available from ONC’s Health IT Adoption and Use dashboard, http://dashboard.healthit.gov.

in Wellpoint settlement, a Warning on hipaa

The managed care company WellPoint will pay the Department of Health and

Human Services (HHS) $1.7 million for leaving social security numbers and other information accessible over the Internet, according to HHS. The settlement stems from alleged violations of the Health Insur-ance Portability and Accountability Act of 1996 (HIPAA) Privacy and Security Rules.

In announcing the settlement, HHS said the case should serve as a warning to HIPAA-covered entities to take caution when implementing changes to their in-formation systems, especially when those changes involve updates to web-based ap-plications or portals that are used to pro-vide access to consumers’ health data using the Internet. The case also highlights the fact that, beginning this month, liability for many of HIPAA’s requirements will extend directly to business associates that receive or store protected health information, such as contractors and subcontractors.

In the case of WellPoint, the HHS Office

for Civil Rights (OCR) began its investiga-tion following a breach report submitted by WellPoint as required by the Health In-formation Technology for Economic and Clinical Health, or HITECH Act. The HI-TECH Breach Notification Rule requires HIPAA-covered entities to notify HHS of a breach of unsecured protected health information. WellPoint’s report indicated that security weaknesses in an online appli-cation database left the electronic protected health information of 612,402 individuals accessible over the Internet. OCR’s inves-tigation indicated that WellPoint did not implement appropriate administrative and technical safeguards as required under the HIPAA Security Rule.

HHS advised healthcare providers, in-surers, and other HIPAA-covered entities that whether systems upgrades are con-ducted by covered entities or their business associates, HHS expects organizations to have in place reasonable and appropriate technical, administrative, and physical safe-guards to protect the confidentiality, integ-rity, and availability of electronic protected health information—especially informa-tion that is accessible over the Internet.

More information is available from the OCR HIPAA website, www.hhs.gov/ocr/privacy/hipaa.

congressional committee approves “Doc fix”

Taking a big step toward the so-called doc fix, a remedy to the infamous sustain-

able growth rate (SGR) formula for physi-cian payment, the House Energy and Com-merce Committee has unanimously passed a bill repealing and replacing the SGR. This formula was meant to limit how much Medicare pays physicians by tethering it to the nation’s overall economic growth, but now has failed to keep pace with the rapid increase in the cost of healthcare compared to other elements of the economy. Observ-ers are now waiting to see how Congress will decide to pay for the measure if both houses pass it: in prior years, congressional advisers have floated the idea of cutting the Medicare payment rates for lab tests as a way to pay for a permanent fix.

Established in 1996, the SGR formula is widely recognized as deeply flawed, and Congress has had to act each year to in-tervene to prevent massive cuts to physi-cians under Medicare. If Congress wants a long-term solution for the SGR problem, it needs to come up with money elsewhere to keep physician payment at a reasonable level, more than $10 billion a year. The Medicare Payment Advisory Commission (MedPAC), an advisory group to Congress on Medicare payment, has several times recommended cutting the clinical lab fee schedule by up to 10% as a way out.

House Energy and Commerce Com-mittee members emphasized their intent to finally end the SGR conundrum, and noted that their bill is also aimed at improving the quality of care provided by physicians un-der Medicare by moving away from the fee-for-service paradigm. “The time of tem-porary fixes and kicking the can down the road has ended. The bipartisan commit-tee draft we approved today permanently

repeals the SGR and places us on a path to paying for innovation and quality, not vol-ume of services, and puts doctors, not bu-reaucrats, back in charge of medicine,” said Health Subcommittee Chairman Joe Pitts (R-Pa.). “It is the first meaningful reform policy to repeal the SGR since it was created and a product of over two years of work by this committee.”

Quality reforms under the bill would come in several phases that together her-ald the long-anticipated move away from volume-based reimbursement to value-based reimbursement. At first, the bill would stabilize physician reimbursement and cap increases. Then, payment formulas would begin including quality measures in order for physicians to receive full payment. Finally, physicians could choose to switch to capitated reimbursement models and drop fee-for-service completely. Physicians who refuse to leave a fee-for-service system would be punished with a permanent 5% pay cut.

More information about the bill is avail-able on the committee’s website, http:// energycommerce.house.gov.

Device Tax payments surpass $1 billion mark

medical device manufacturers, in-cluding those that serve the in vitro

diagnostics industry, have now paid an estimated $1 billion to the Internal Rev-enue Service for the medical device excise tax that came into effect this year as part of the Affordable Care Act, according to a coalition of industry groups including the Advanced Medical Technology Associa-tion, the Medical Imaging and Technology Alliance (MITA), and the Medical Device Manufacturers Association.

“The $1 billion threshold is frightening as every dollar spent paying for this medi-cal device tax threatens medical innova-tion and American jobs,” said Gail Rodri-guez, executive director of MITA. “MITA is pleased to see bipartisan support for repeal of the tax building in both the House and the Senate, but Congress cannot wait any longer to repeal this burdensome tax and protect jobs and essential research and de-velopment funding.”

Under the 2.3% tax, device manufactur-ers are required to pay an estimated aver-age of $194 million per month in medical device tax payments. The U.S. medical device industry helps employ 2 million nationwide and invests nearly $10 billion in research and development annually, the companies noted.

Bipartisan majorities in the House of Representatives and Senate have supported repeal of the device tax. In March, a biparti-san coalition of 79 Senators voted to adopt an amendment to the Fiscal Year 2014 Sen-ate Budget Resolution to repeal the tax. In the House, Reps. Erik Paulsen (R-Minn.) and Ron Kind (D-Wis.) introduced the “Protect Medical Innovation Act,” garner-ing a bipartisan group that has grown to 253 co-sponsors, including 34 Democrats, since introduction.

More information about medical de-vice tax repeal efforts is available from AdvaMed, www.advamed.org.

p r o f i L e sp r o f i L e s

r e g u L at o r y

CliniCal laboratory news septeMBeR 2013 13

genisphere licenses signal amplification Technology to chembio

chembio Diagnostics, Inc. has signed an agreement for Genisphere’s 3DNA

Signal Amplification technology that could help the company broaden the potential ap-plications of its Dual Path Platform (DPP) rapid diagnostic pipeline tests by improv-ing their detection limits. According to the company, the 3DNA Dendrimer technol-ogy increases an assay’s sensitivity 100-fold without making the assay more complex. To date, this technology has been used to enhance the performance of many test plat-forms for protein and nucleic acid detection, including microarrays, ELISAs, bead-based flow cytometry, and lateral flow assays.

Prior to this agreement, the two compa-nies conducted a feasibility study together to show that 3DNA Dendrimer technology can be adapted to Chembio’s DPP. “Sensi-tivity, specificity, and reproducibility are important features for all diagnostic tests,” said Lawrence Siebert, Chembio’s chief executive officer.

life Technologies, merck serono form co-Diagnostics partnership

life Technologies and Merck Serono have inked a non-exclusive agreement

to collaborate on current and future com-panion diagnostics projects. This marks the first time the two companies have worked together. Initially, they will focus on an on-cology project, then will branch out across a potentially wide range of therapeutic areas and Life instrument systems. Among the targets are co-diagnostics for Merck drugs.

“The Life Technologies combination of platforms and capabilities are unique in the companion diagnostics space, particu-larly in oncology,” said Ronnie Andrews, president of Genetic and Medical Sciences at Life. “With our recent acquisition of Compendia Bioscience, we possess bio- informatics solutions and cancer biomark-er expertise to collaborate with pharma on each phase of the drug development pro-cess, from biomarker hypothesis to assay development concurrently with drugs to approved diagnostic tests.”

If this collaboration between Life and Merck succeeds, the two companies will follow it with an additional agreement that allows Life to commercialize the co- diagnostics.

cell signaling Technology, cepheid collaborate on lung cancer Test

cell Signaling Technology, Inc. (CST) has licensed patent rights to Cepheid,

Inc. that will allow Cepheid to develop a PCR-based diagnostic test to identify non-small cell lung cancer (NSCLC) patients with anaplastic lymphoma kinase (ALK) gene rearrangements. CST and one of its

partners own dominant intellectual prop-erty rights for EML4-ALK translocations in NSCLC that cover research through di-agnosis and therapy. These patent rights include method claims for the detection of EML4-ALK through immunohistochemis-try, PCR, gene sequencing platforms, and molecular-based methods, as well as inhib-iting the progression of lung cancers that express the EML4-ALK fusion gene.

paml forms collaboration With cleveland clinic laboratories

pAML signed a letter of intent with Cleveland Clinic Laboratories to ex-

plore ways to collaborate in the areas of test development, value-based care, analytical tools, and companion diagnostics for better therapeutic decision making. “In the age of healthcare reform, we have a responsibil-ity to improve the delivery of laboratory diagnostic services and increase clinical efficiency and outcomes,” said Francisco Velazquez, MD, president and chief execu-tive officer of PAML. Based in Spokane, Wash., PAML specializes in reference lab testing and information technology, while Cleveland Clinic Laboratories offers state-of-the-art testing to clients nationwide.

bio-reference to maintain free genetic laboratory service

bio-Reference Laboratories, Inc. and the University of Washington, Se-

attle, forged a deal to make GeneTests.org, GeneClinics.org, and all related properties a business unit of Bio-Reference. Founded in 1992, GeneTests.org provides physicians, geneticists, and genetic counselors with comprehensive information about testing for inherited disorders and genetic counsel-ing services. The public, as well as partici-pating labs and clinics, can access the site’s directories of international labs and clinics offering genetic testing and counseling free of charge.

Under the new licensing agreement, GeneTests.org has improved its search function and plans to enhance data-entry capabilities, as well as add new services and information, particularly on multi-gene panels. The website will continue to link to GeneReviews, a collection of peer-reviewed chapters written by experts describing in-herited diseases and the use of genetic test-ing in diagnosis, management, and genetic counseling.

“As the field of genetics has grown more complex and specialized, GeneTests.org has become one of the most indispens-able tools of the trade as a single source of information on genetic test availabil-ity,” said GeneTests.org founder Roberta Pagon, MD. “Initially, the lab directory was used primarily by geneticists, but today clinicians in all specialties, such as cardiol-ogy, endocrinology, and neurology, rely on GeneTests.org.

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labsarevital renews efforts to raise awareness, attract students

the newly relaunched LabsareVital program made its debut at the 2013 aaCC annual Meeting and expo in July, showcasing a new website with posts on current laboratory topics by world-renowned experts and an online toolkit of resources for instructors and students.

“the aaCC is the perfect opportunity for us to explain how laboratory professionals, publishers, and industry sponsors can get involved,” said graham beastall, phD, a long-time LabsareVital supporter and president of the international federation of Clinical Chemistry and Laboratory Medicine.

originally founded by abbott in 2006, ownership of LabsareVital recently passed to the laboratory community, with an international con-sortium of laboratory organizations taking the lead. the american society for Clinical pathology, ifCC, and world association of societies of pathol-ogy and Laboratory Medicine now run the program with some continued financial support from abbott. the consortium is also seeking additional sponsors to help further their goals.

“too many lab professionals feel that their profession is undervalued, underappreciated, and underfunded. we want to make LabsareVital a powerful voice to emphasize that laboratory medicine is part of the multi-disciplinary team at the heart of patient care,” beastall said.

in addition to its website, www.labsarevital.com, the program, which is open to anyone, will emphasize shared communities, work culture, and career choices for laboratory professionals.

14 CliniCal laboratory news septeMBeR 2013

Direct naaT for suspected pulmonary Tb Yields many health system benefits

Direct nucleic acid amplification test-ing (MTD) for suspected pulmonary

tuberculosis results in significant positive health system benefits, particularly for pa-tients with HIV infection or homelessness (Clin Infect Dis 2013;57:532–42). In com-parison to not performing MTD, MTD sig-nificantly decreased the time to diagnosis in patients with acid-fast-bascilli-smear-positive specimens, reduced the number of days of unnecessary tuberculosis treatment among non-hospitalized patients, and re-duced resources expended on contact in-vestigation. Although diagnostic workups that included MTD generally cost more than those that did not, MTD testing was associated with incremental cost savings in diagnosing or excluding tuberculosis among patients with HIV or homelessness, and in excluding tuberculosis among those with substance abuse who also had smear-negative specimens.

The researchers conducted the study because MTD use is not universal, despite being recommended for use by CDC since 1996 on smear-positive specimens and since 2009 on smear-negative specimens from patients in whom the test result would alter tuberculosis case management. MTD testing can provide results within 24–48 hours, whereas sputum-smear microscopy is simple and inexpensive to perform but detects <50% of cultured-confirmed cases and has poor positive-predictive value (PPV) in individuals with HIV. The gold

standard, culture, takes 2–8 weeks for re-sults.

The authors found the PPV of MTD was 98% in patients who also had smear-positive specimens, while the negative- predictive value (NPV) was 94%. Among patients with smear-negative specimens, the PPV of MTD was 90% and NPV was 88%. Among patients suspected of hav-ing tuberculosis whose specimens did not undergo MTD, the PPV of smear was 77% and NPV was 78%.

elevated bilirubin levels, bilirubin genotype associated With gallstone Disease

long-term elevated bilirubin levels are associated with symptomatic gallstone

disease (JAMA Intern Med 2013;173: 1222–8). The findings have significance both clinically and scientifically, according to the authors. From a clinical standpoint, routine measurement of plasma bilirubin levels could signal physicians about patients at risk for developing gallstone disease. Sci-entifically, this study aids in understanding the pathways that lead to gallstone disease, possibly providing targets for treatment or prevention.

Calcium bilirubinate salts have been hypothesized to act as a nucleating fac-tor for the precipitation of biliary choles-terol, thereby directly facilitating devel-opment of cholesterol gallstones. At the same time, increased production of bili-rubin has been associated with increased risk of gallstone disease, but whether elevated bilirubin levels per se are associ-

ated with higher risk of gallstone disease is unclear.

The study had four aims: to test wheth-er plasma bilirubin levels predict risk of symptomatic gallstone disease; to observe whether a variant in the bilirubin glucoro-nidating enzyme, UGT1A1, is associated with increased plasma bilirubin levels; to discern whether the UGT1A1 genotype is associated with increased risk of symp-tomatic gallstone disease; and to determine whether these genetic risks are similar to the estimated risk of observed plasma bili-rubin levels.

During 34 years of follow-up, 3,374 out of 61,212 subjects developed symptomatic gallstone disease. Those with plasma biliru-bin levels in the top decile had an increased risk of symptomatic gallstone disease in comparison to those in lower deciles, with a 1.57 hazard ratio overall. The authors found that the UGT1A1 genotype explained 20% of the total variation in bilirubin levels.

elevated nT-probnp, cTn linked to sub-clinical brain Disease

n-terminal brain natriuretic peptide (NT-proBNP) and cardiac troponin

T (cTn) are independently associated with subclinical brain disease and might be useful in identifying individuals with asymptomatic brain injury (Stroke 2013; 44:1803–8). The authors suggest that mea-surement of these biomarkers followed by magnetic resonance imaging (MRI) of the brain might facilitate interventions that could forestall cognitive decline in patients with brain injury.

The findings are from the Athero-sclerosis Risk in Communities studies, a prospective study of 15,792 middle-aged individuals in four U.S. communities who had baseline examinations and testing be-tween 1987–1989. At the third follow-up visit, which took place between 1993–1995,

a subset of participants had brain MRIs, and a subsection of these individuals had a second MRI approximately 10 years later. In addition, NT-proBNP and cTn were analyzed from blood samples collected at the fourth follow-up visit from 1996–1998. The researchers established quartiles of NT-proBNP values, with >119.1 pg/mL as the cutoff for the highest and 2.5 – ≤29.6 pg/mL as the cutoff for the lowest, and quintiles for cTn, with the cutoff for the highest being ≥0.014 µg/L and the lowest being <0.003 µg/L.

After adjusting for risk factors, the re-searchers found that individuals in the highest NT-proBNP quartile had signifi-cantly more brain infarcts (BI) in compari-son to those in the lowest quartile, with a 3.50 odds ratio. They also had more white matter lesions (WML), with a ß-coefficient of 0.09. Comparison of the follow-up MRI 10 years later revealed that individu-als in the highest NT-proBNP quartile also had significantly more incident BIs and WML progression than those in the low-est quartile, with a 2.18 odds ratio and 0.22 ß-coefficient, respectively.

The findings were similar for cTn. In-dividuals in the highest quintile had more BI and WML on the initial MRI in com-parison to those in the lowest quintile, with a 3.03 odds ratio and 0.11 ß-coefficient, respectively. At the time of the follow-up MRI, individuals in the highest cTn quin-tile also had more WML progression, with a ß-coefficient of 0.43.

markers of inflammation associated With pre-eclampsia in Type 1 Diabetics

a longitudinal study of pregnant women with type 1 diabetes found elevated C-

reactive protein (CRP), soluble E-selectin (sE-selectin), interleukin-1 receptor antag-onist (IL-1ra), and interferon-γ-inducible protein-10 (IP-10), and lower eotaxin to be associated with development of pre- eclampsia (Diabetes Care 2012;36:2054–61). The findings support the need for larger studies to confirm the role of inflammation in pre-eclampsia and to define the utility of these markers in screening for pre-eclampsia and in developing preventive and thera-peutic strategies for the disorder.

The study involved 151 pregnant wom-en with established type 1 diabetes and 24 nondiabetic pregnant women recruited during their first trimester and followed throughout pregnancy. The investigators collected clinical data and blood and urine specimens from the women at weeks 12, 21, and 31, and defined pre-eclampsia as new-onset hypertension >140/90 mmHg accompanied by proteinuria >300 mg/24 h after 20 weeks’ gestation in women who previously were normotensive. The study included at least 27 markers of inflamma-tion.

After analysis and covariate adjustment, the researchers found that higher CRP, sE-selectin, and the cytokines IL-1ra and IP10, along with lower eotaxin, remained signifi-cantly associated with development of pre-eclampsia. These findings suggest that exac-erbated maternal inflammatory responses confer susceptibility to pre-eclampsia.

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CliniCal laboratory news September 2013 15

Cepheid Receives FDA Nod for Rapid Tuberculosis Test

The U.S. Food and Drug Administra-tion (FDA) has cleared Cepheid’s Xpert

MTB/RIF test for the identification of tuberculosis (TB)-positive patients. Designed for use on Cepheid’s GeneXpert Systems, this new assay performs rapid molecular detection of Mycobacterium tuberculosis complex (MTB-complex) DNA, reduc-ing the wait for results from 6 weeks to 2 hours. When MTB-complex DNA is de-tected in a specimen, Xpert MTB/RIF can also detect rifampin-resistance associated with mutations of the rpoB gene. Rifampin is an important TB drug, and strains that show resistance to it are often multidrug-resistant as well, requiring more intensive drug therapy.

Use of HPV Assay on Hologic’s Panther System Granted FDA Approval

FDA approved Hologic, Inc.’s Aptima HPV assay for use on the company’s

fully automated Panther system. Using a Hologic ThinPrep liquid cytology speci-men, this mRNA-based assay detects 14 high-risk strains of human papillomavirus (HPV) associated with cervical cancer and precancerous lesions by nucleic acid ampli-fication. Its addition to the Panther menu expands the ability of low- to high-volume laboratories to run multiple tests from a single specimen on this platform.

FDA Approves Qiagen’s Lung Cancer Co-Diagnostic

Qiagen received FDA approval for its therascreen EGFR test as a compan-

ion diagnostic for Gilotrif, a new thera-peutic from Boehringer Ingelheim that tar-gets metastatic non-small cell lung cancer (NSCLC) tumors with the most common EGFR gene mutations. These include EGFR exon 19 deletions and exon 21 L858R sub-stitution mutations. The test also features the ability to detect EGFR mutations in separate tubes. Developed through a col-laboration with Boehringer Ingelheim, this is the third assay approved or cleared for use on the Rotor-Gene Q MDx, a real-time PCR platform in the QIAsymphony line.

Luminex Gets FDA Clearance for Updated Drug Metabolism Assay

FDA granted Luminex Corporation clearance for a new version of the xTAG

CYP2D6 Kit that determines a patient’s cy-tochrome P450 2D6 (CYP2D6) genotype by analyzing DNA extracted from blood. According to the company, this test can help guide treatment decisions involving the more than 25% of drugs metabolized by CYP2D6. Designed to run on the Lu-minex 100/200 instrument, the new version of this assay optimizes performance on the *17 allele and features an updated software algorithm that detects all 17 genotypes for which the assay is cleared.

Randox Immunoassay Controls Cleared by FDA

FDA cleared Randox’s Acusera Immu-noassay Speciality 1 control, a quality

control (QC) that contains the following nine complex immunoassays: I-25-(OH)2– vitamin D, 25-OH-vitamin D, C pep-tide, insulin, insulin like growth factor 1, procalcitonin, parathyroid hormone, anti- thyroglobulin, and anti-thyroperoxidase. This control works with most immunoas-

say analyzers, and according to the com-pany’s press release, it is the only multi-analyte immunoassay QC on the market that contains clinically relevant levels of vitamin D. To enhance its stability, the con-trol is lyophilized, and when reconstituted it remains stable for up to 5 days at 2–8°C and 4 weeks at -20°C. It is manufactured in-dependently using 100% human serum to minimize antibody cross reactivity and can be used with Acusera 24.7.

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