Feature Story

Line backers—support grows for linearity Surveys

November 2002
Karen Southwick

The CAP’s linearity Surveys for quality assurance have proved so effective that a recently proposed NCCLS guideline is largely modeled on the College’s approach.

NCCLS guideline EP6-P2, "Evaluation of the linearity of quantitative analytical methods; proposed guideline—second edition," which was published in December 2001, awaits full approval. "They’re using essentially the same method as we’re doing for evaluating linearity," says Martin Kroll, MD, director of clinical chemistry at the Dallas VA Medical Center and associate professor at the University of Texas Southwestern Medical School. Dr. Kroll also co-chairs the CAP Standards and Instrumentation Resource Committee, which oversees what are commonly referred to as the LN Surveys.

The CAP offers 16 LN Surveys, and three more will be added for 2003. They help laboratories check the linearity of their instruments. But they can also be used to determine analytical measurement range and to verify calibration, thus satisfying CLIA as well as CAPinspection checklist requirements for accreditation.

Though linearity checks are not required under CLIA, they are an important part of overall quality assurance, Dr. Kroll says. "When you’re talking about linearity, you’re talking about the whole range [of values]," not just a midpoint.

"Linearity evaluations," he adds, "are the only ones that give you information about what’s occurring near the extremes," the high and low ends of the measurement range. Measuring those values accurately can be important in diagnosing or monitoring disease. "This is one of the strongest quality assurance tools you can use in the lab," Dr. Kroll says. "I don’t see how you can run a lab in good conscience and not do it."

Skeptics abound

When the CAP first offered the LNSurveys about a decade ago, not everyone was convinced of the need to check linearity. David A. Floering, MD, a member and later chair of what was then the CAP Instrumentation Committee, was skeptical. "A lot of people didn’t see the purpose of this, including me," he says. "In Ohio, we weren’t required to do this." Dr. Floering is a pathologist at Middletown (Ohio) Regional Hospital.

In the 1980s, the state of Florida was asking laboratories to perform linearity checks, but there was no readily available material with the right matrix and analyte concentration to perform the linearity and establish a reportable range. "There was an absolute lack of material for this purpose," says Tony Vazquez, MT(ASCP), who was then technical director of laboratories at Cedars Medical Center, Miami. "You had to go through all sorts of contortions to try to come up with a product. In some cases a high enough patient sample had to be used. Checking for linearity and reportable range is an integral part of method validation."

Because he was a consultant to the CAP committee, Vazquez turned to the committee members. "It took several years to get the LN Surveys off the ground," he says. "Some members didn’t see why there would be a need for this." In fact, the number of subscribers was unexpectedly high. "No question there was a need," he says.

Dr. Floering agrees. "When I started using the LNSurveys in my own lab, I found them very helpful in evaluating how a new test was running," he says. "I evolved from skeptic to champion." The CAP developed freeze-dried samples for linearity testing and analyzed the results. "One thing that showed us we were on the right track was that a cottage industry sprang up to provide linearity material as a commercial enterprise," Dr. Floering says.

Furthermore, laboratories became more aware of what kind of quality assurance would satisfy CLIAregulations. LN Surveys are particularly useful in calibration verification, Dr. Floering notes. "By having multiple points through the reportable range, you can learn a lot about your assay. Many times the Survey will pick up problems before they become noticeable in other ways. It’s like an early warning system."

Adds Dr. Kroll: "Linearity is a property of the entire system over the entire range. When your reagents age, when you have problems with instruments, the first thing to go is your upper or lower limit." Laboratories performing well on the LN Surveys, he says, tend to score better on proficiency testing.

Improving the Surveys

The LN Surveys have become more popular thanks in part to the growth of automation and point-of-care testing and the proliferation of new lab tests. Each time you begin using a new method or new machine, you want to check for linearity, Dr. Kroll says.

After analyzing the results for an individual laboratory, the CAP compares the results to those of a peer group culled from the 2,000 Surveys subscribers. "You have a material that many of the other labs are also running, so you can compare yourself with others," says Dr. Floering. The comparison helps pinpoint whether problems stem from method or machine.

The CAP has made its LN Surveys more user-friendly with regard to reporting results and handling material. In 1999, the College moved from freeze-dried to liquid samples, reducing the possibility of preparation error.

The labs had to reconstitute freeze-dried samples, Dr. Floering says. This led to matrix effects and possible user error in reconstituting the sample, yielding poor results. "Any time you have to add something, there’s a propensity for error," Vazquez says. The liquid-based samples are ready to use.

Dr. Kroll recalls a persistent case in which a particular dry-slide technique kept performing poorly on the LN Surveys: "When we moved from freeze-dried to liquid-based linearity specimens, those problems disappeared."

The CAP has also made its analysis easier to interpret. "We’ve been trying to simplify it so you don’t have to be a statistician to understand it," Vazquez says. "You can have the best Survey in the world but laboratories won’t use it if they don’t feel comfortable with it." Although medical technologists typically run the linearity Surveys, other professionals, such as nurses, can use them.

Generally, more than 90 percent of Surveys participants pass all their methods, Dr. Kroll says. Problems can range from old reagents to a defect in the instrument itself. That’s where the CAP’s peer-group comparison is so valuable, he says. "If everybody is coming up with non-linear results, the manufacturer probably needs to deal with it. If 95 percent are linear and you’re not, you have a problem with your assay system."

Failure commonly results from entering values incorrectly and imprecise results at the extremes. "Linearity helps you find out if you have an imprecision problem," Dr. Kroll says. About one to five percent of participants using any given method experience imprecision problems, he adds.

Another advantage of repeating LN Surveys is that this reduces the possibility of false-negatives. One nonlinear result could be due to chance or user error. "But if you’re nonlinear twice, you probably have a problem," Dr. Kroll says. For example, the false-negative rate for one LN Survey is 20 percent; with two Surveys, it drops to less than four percent, and with three to 0.8 percent.

Karen Southwick is a writer in San Francisco. For more information on the linearity Surveys, contact Sharon Burr at the CAP at 800-323-4040 ext. 7417 or at sburr@cap.org. To learn more about the upcoming changes to the CAPcalibration/calibration verification accreditation requirements, visit www.cap.org.