Growth, complexity of molecular testing drive

May 1, 2010

Change occurs in the medical diagnostics industry
at a deliberate pace. New products and processes must undergo rigorous testing
and navigate regulations before being approved for use in the marketplace. Once
change takes place, however, there is often a scramble to adapt. Such is the
case with molecular genetic testing which has brought about new ways to diagnose
and treat illness, yet the rapid pace of adoption, combined with the growing
complexity of new molecular genetic testing techniques, has outpaced the
industry’s capacity to provide neede diagnostic quality controls (QC).

The reasons for eager adoption of molecular genetic testing are clear: As our knowledge of genetic causes behind illnesses and conditions grows, the ability to test for the causes has improved the medical community’s ability to diagnose accurately and quickly and to prescribe personalized treatments — sometimes even before symptoms manifest — all of which can greatly improve patient quality of life. Testing for a growing number of known genetic mutations, however, means that the controls used to ensure accuracy also become increasingly complex.

… genetic tests may be run only once in a lifetime
may affect the entire family.

Research for providing quality controls for cystic fibrosis, for
example, has seen test panels increase from 23 mutations to 79 in just a
few years. CLIA regulations dictate that controls be run for each
mutation or analyte. This is important for best practice because the
detection of each mutation is a unique test reaction, and test
manufacturers cannot optimize assays equally for all mutations.

A major dilemma for labs is lack of availability
of molecular genetic quality controls. Quality controls often emerge in
the marketplace after new laboratory tests are established; however,
controls for molecular testing have fallen far behind.

Molecular quality control manufacturers are
challenged by the complexities of working with DNA, evolving test
technologies, a need to provide controls for rare mutations, multiplex
and other complex test methods, a reluctance by labs to run many
controls on expensive tests, and a lack of software for traditional QC
statistical techniques (e.g., plotting QC results on Levey-Jennings
charts and application of Westgard Rules).

This situation sometimes forces the labs to use minimal QC, which is
risky considering that genetic tests may be run only once in a lifetime
and may affect the entire family. Expectations among all parties are too
high to risk an inaccurate test result.

As for all laboratory tests, the risk and sources
of test system variability of a molecular test should be assessed and a
QC plan developed. Best practice and CLIA regulations require that the
entire assay, including extraction and all analytes (mutations), be
monitored. There are insufficient extractable, multiplex controls
available to meet this need.

Also required is that the test system be monitored over time to detect
shifts or trends so performance can be continuously assessed and
troubleshooting procedures implemented as needed to prevent inaccurate
test results and failed runs. Now, numerical outputs such as genotype
ratios and fluorescence signal allow for monitoring and application of
statistical analysis, but software, such as that available for
multianalyte chemistry tests, is needed to make performance assessment
of multiplex molecular tests practical

The industry has recognized and responded to
these changes, and the resulting need for availability of better quality
controls and procedures to help laboratories implement better QC

A standard guide for the application of Westgard
Rules, for example, has been updated to reflect quality controls for
genetic testing (Basic QC Practices, 3rd ed., 2010), concluding that,
“even in new areas of testing, even when testing processes are as
standardized as clinical chemistry, and even when quality requirements
are hard to determine, these difficulties do not eliminate the need for
quality control and assurance. If anything, these emerging testing
methods demonstrate a need for greater emphasis on QC to guard against
the risk of incorrect test results.”

How do diagnostic test labs respond to the
challenges before them? First, by recognizing the need for adoption of
quality control programs appropriate for today’s genetic tests. The
Clinical and Laboratory Standards Institute, or CLSI (,
will soon issue updated guidelines for genetic testing in revised MM01
and new MM20. Understanding and adopting these new guidelines can help
to bring processes up to date.

Lab professionals are not on their own when it comes to keeping pace
with best practices. The Association for Molecular Pathology (AMP)
offers the support of the professional community, and a list of
FDA-cleared/approved tests and controls. More information is available

The Centers for Disease Control and Prevention has an initiative
specifically addressing quality control needs of genetic testing, the
Genetic Testing Reference Materials Program (GeT-RM), which can be found
online at

For testing facilities that wish to create their
own controls, Johns Hopkins has published a paper offering an outline to
help make the task easier.1

Joan Gordon, MT(ASCP), is
co-owner and president of Maine Molecular Quality Controls

Liang SL, Lin MT, Hafez MJ, Gocke CD, et al. Application of traditional
clinical pathology quality control techniques to molecular pathology.
J Mol Diagn. 2008;10(2):142-146.

Published: May 2010