Increases in molecular testing levels drive creation of many new products.

The attraction of diagnostics continues to increase among the nation’s clinical labs. The momentum is spreading beyond major instrument manufacturers and big hospitals to include specialty suppliers and even small hospital labs.

An independent news and information service that has chronicled health care industry trends for 3 decades, the Washington G-2 Report surveyed more than 300 clinical labs across the country. Officials found the average number of billable molecular tests performed by the labs increased almost 30% from January 2004 to December 2006.

Stephanie Murg, managing editor of the G-2 Diagnostic Testing & Technology Report, says interest was high for the June conference in the San Francisco area. Titled “From Bench to Bedside: Onco-Molecular Diagnostics,” the conference will address many issues, including optimizing efficiency in the diagnostic setting and validation challenges.

What’s driving the move to go molecular? “The increased sensitivity and specificity of molecular testing produces results that go beyond the simple yes and no of traditional testing to provide quantitative results frequently,” Murg says.

Access Genetics

Since 2001, privately held Access Genetics LLC, Minneapolis, has helped CLIA-certified, highly complex laboratories establish and operate in-house molecular genetic programs. Along with personnel training and complete setup support of molecular testing labs, Access Genetics’ certified medical technologists and ACMG-certified pathologists offer real-time, Web-based consultations on molecular test results for client labs across the nation. In addition, Access provides convenient supply packages for a variety of molecular tests to assist in inventory management.

“I think we were the first to take such a complete approach to molecular testing,” says Terri Poindexter, Access vice president for marketing and sales. “We deliver a molecular testing information system with Web-based support and interpretive services. We say to labs, ‘You keep the samples. We’ll assist you in getting up and running with a quality molecular program that includes DNA extraction through patient reporting, and we will stay connected through the Web for support as you need it.’ This collaborative effort produces results that really benefit patients.”

Sales at Access have increased more than 100% for each of the last 3 years, Poindexter says. Company revenues reached $4.4 million at the end of 2006. In a little more than 5 years, the company has built a core of more than 40 customer labs in 24 states. Poindexter says that while her company focuses on “expanding the entire molecular marketplace,” some molecular tests are not for every lab.

“We believe there will always be a place for reference labs,” she says. “Our business model actually encourages the development of the increasing number of esoteric tests available from reference laboratories as we help make the currently esoteric more commonplace. But without the right mix of volume and reimbursement, it may not be smart to bring some molecular tests in-house.”

Poindexter says that tests for infectious and inherited diseases, respiratory conditions, and tests using FISH (fluorescence in situ hybridization) technology continue to be among the most frequently performed assays. Included is the human papillomavirus, for which Access Genetics recommends a test that provides complete and specific genotyping. “We don’t sell a box, we sell a molecular platform. In the future, we hope to broaden its flexibility by supporting more industry-leading technologies and chemistries.”

bioMérieux Inc

Peter Kaspar, bioMérieux Inc corporate vice president of research and development, says the efficient preparation of samples is mandatory for high-sensitivity molecular assays. “The quality of extracted nucleic acid determines the quality of the final diagnostic result,” Kaspar says. “Sample preparation typically involves a large part of the labor resources that go into molecular testing; this issue is magnified, given the difficulty these laboratories have in finding skilled molecular testing personnel.”

These factors are driving development of novel approaches to automating nucleic acid extraction. The NucliSENS easyMAG and an enhanced version of its Boom technology (nucleic acid extraction chemistry) are two prominent examples of how bioMérieux is responding to molecular market needs.

This new platform offers automated extraction of nucleic acids from clinical samples based on bioMérieux’s proprietary Boom technology, which is based upon the nucleic acid binding property of silica. bioMérieux researchers further optimized this chemistry using magnetic particles to enhance automation and improve nucleic acid purity and concentration. The result: An even higher quality of extracts can be obtained from a widening variety of sample types.

Capable of extracting both RNA and DNA from many sample types— among them plasma, serum, whole blood, stool, sputum, and cerebrospinal fluid—the automated NucliSENS easyMAG system can process up to 24 biological samples in 1 hour. The instrument’s smart design also gives labs additional flexibility that is usually rare among automated systems.

“bioMérieux dedicated a broad range of development resources to the NucliSENS easyMAG,” Kaspar says. “It represents a precise combination of different projects such as reagents, robotics, hardware, and software.” Market response has made the new system a huge success since its introduction nearly 2 years ago, he says.

Kaspar says that laboratories must be judicious when adopting any new testing. “Molecular tests are chosen for reasons of sensitivity, specificity, and the rapid time to result. In many critical clinical situations the cost benefit of using molecular methods has been clearly demonstrated.”

Or sometimes, there are virtually no alternative methods available. An example: measuring HIV viral load in case of treatment monitoring in AIDS patients. bioMérieux, he says, is focused on molecular testing for those situations where clear benefits are established, and where traditional methods may fall short in terms of accuracy, speed, or both.

Because of the complexity of classical methods to culture viruses, molecular testing today is predominantly used for virology assays. Genetic testing is an evolving field.

“When time is of the essence in critical clinical situations, the use of molecular methods to determine bacterial targets is gaining momentum,” Kaspar says. “Broad antibiotic resistance testing is probably the least developed field of molecular testing, due to the complexity of the genetic mechanisms involved in antibiotic susceptibility.”

bioMérieux believes it is in a unique position as an infectious-disease diagnostic company with a technology portfolio in the core disciplines of culture, immunoassay, and molecular biology. “We have the advantage of viewing the diagnostic world through multiple portals,” Kaspar says. “We can then target a specific health care challenge using the most appropriate diagnostic tool, or even approach it with a suite of tools from a broad cost/value perspective.”

Nanogen Inc

The NanoChip 400 microarray, Nanogen’s second-generation multiplexing instrument, has been specifically designed to meet the needs of molecular labs, says Suzanne Clancy, PhD, the company’s director of corporate communications.

“The key feature of the NC400 system is the ability to analyze multiple samples for multiple sequences across multiple assay runs,” she says. “Electronic control of the microarray enables nucleic acid to be directed to specific sites or pads so that unused sites are available for other samples and other runs.” Use of cartridges makes the microarray an open system, enabling customers to develop their own applications.

Laboratories can use the NC400 automated, multiplexing platform to detect genetic sequences. Labs can perform the testing with Nanogen-supplied reagents or develop home-brew assays. The system features Nanogen’s core microarray technology, which employs patented microfluidics and electronic technology to automate sample handling and detection of results.

“The highly automated NanoChip platform can run multiple samples simultaneously, and arrays used in one application can be stored for future use,” Clancy says. Molecular technology is the basis for all of Nanogen’s testing products. In addition to multiplexing products, the firm supplies real-time PCR reagents and point-of-care rapid immunoassay tests for the detection of heart attack.

The current premarket notification request to the FDA is the first for the company’s proprietary electronic microarray technology. Receiving FDA clearance will mark an important milestone and lead to wider use of Nanogen’s multiplexing technology within clinical laboratories.

Beckman Coulter

Beckman Coulter has focused on ways to streamline sample preparation. The company’s Vidiera NsP Nucleic Sample Preparation Platform isolates, quantifies, normalizes, and sets up the downstream PCR reaction (with or without assays of choice) using nucleic acid templates, says Kimberly Klein, strategic product marketing manager for Beckman’s Molecular Diagnostics Business Center.

“The platform is flexible enough to enable end users to apply prevalidated methods and user-defined methods,” Klein says. “Key differences over competitors are that it isolates directly from primary tubes and has onboard quantification, normalization, and PCR setup.” The result: faster sample prep and less hands-on time for higher throughput and improved reproducibility.

According to Klein, the NsP system reduces laboratory functions. It can replace a spectrophotometer in sample quantification and normalization, something that could require an hour of lab tech attention to process 96 samples. Its prevalidated methods are designed to set up PCR reactions in various formats — the Light cycler, Taqman 48 (Roche), and 96 well formats.

Beckman, Klein says, views genetic testing as an increasingly viable tool for effective and more thorough patient diagnosis. The company’s philosophy is to offer prevalidated methods that simplify the lab validation process. Such simplification consistently yields good value for a lab, whether of high or moderate complexity.

Artel Inc

For more information, search for “molecular diagnostics” in our online archives.

The molecular market presents opportunities to lesser-known product developers, too. Westbrook, Maine–based Artel offers two instruments that help lab techs measure small amounts of liquids at the benchtop level. Lab accuracy is important, considering that today’s molecular labs routinely work with volumes in the 10-µL to 20-µL range and rely on liquid-handling instruments.

Compact and portable, the Artel Pipette Calibration System provides automatically documented National Institute of Standards and Technology–traceable pipette calibration for volumes as small as 0.1 µL in about 3 minutes. To verify performance of multichannel liquid-handling equipment, the company’s Multichannel Verification System uses patented ratiometric photometry to generate precise information on automated multichannel equipment in less than 10 minutes.

Nicholas Borgert is a contributing writer to CLP.

A Lab Pioneer’s Perspective: The Future of Molecular Diagnostics

Daniel H. Farkas, PhD, HCLD, serves as executive director of the Center for Molecular Medicine (CMM), in Grand Rapids, Mich. CMM is an advanced molecular pathology laboratory focused on advancing 21st-century diagnostics, translational research, and clinical trials. The center is a first-of-its kind joint venture between the independent medical research group Van Andel Institute and Spectrum Health.

A widely published author and frequent lecturer, Farkas has spent almost 20 years in the molecular diagnostics field. He has served on faculties at Cornell, Baylor College of Medicine, and Michigan State, and has established hospital-based molecular diagnostics laboratories in New Jersey, Michigan, and Houston.

Farkas is a member of the FDA’s Clinical and Molecular Genetics Advisory panel. Awarded the Association for Molecular Pathology’s 2007 Leadership Award, he was the first person certified in molecular diagnostics by the American Board of Bioanalysis.

He says the most widespread misperception about molecular testing is that it is new. “While it is cutting-edge technology, and new assays are coming out all the time, molecular diagnostics has been in place in the hospital pathology setting for over 20 years now,” Farkas says. “I still hear that molecular diagnostics in general is new. There are dozens of FDA-approved tests dating back to the late 1980s. While molecular testing is among the newest technologies, the field of molecular diagnostics, at this point, should be considered an established mainstay of clinical laboratory medicine.”

According to Farkas, molecular diagnostics now represents about 10% of the worldwide IVD market, one he estimates at between $25 billion and $30 billion. “That’s pretty good for a technology that was responsible for zero percent of the worldwide IVD market about 20 years ago,” he says.

For facilities considering a move into molecular testing, Farkas suggests that they work with their administrators to understand expectations for volumes, profitability, menus, and other concerns. “Many tests are money losers; a key few, however, generate enough income to underwrite a much larger test menu, so ensure that those few ‘golden goose’ tests will stay with your lab if there is expectation of profitability,” he says.

Farkas also cautions hospitals to be prepared to educate their medical staff on utility. “Seek new-lab discounts from vendors; many options for key platforms exist—explore them all; promote competition for your scarce capital equipment dollars,” he advises. “And remember my maxim: If the test doesn’t make a difference in the way a physician is going to manage his or her patient, the test will not be ordered.”

Molecular tools are first and foremost tools, Farkas says. “As we learn more about how to apply those tools to complex diseases, including cancer and cardiovascular disease, we should not hesitate to exploit those tools to improve diagnostics and health care in general,” he says.

Farkas has heard the skeptics. To those who complain that molecular testing is too slow, too esoteric, Farkas lists high-volume, nonesoteric tests for chlamydia detection, HIV viral load, monitoring, hepatitis B virus quantitation, human papillomavirus detection and typing, cytomegalovirus viral load, and cystic fibrosis mutation detection. For others who reject molecular testing as too research focused, Farkas mentions the rapid, potentially life-saving, real-time polymerase chain reaction for herpes simplex virus; a potentially life-saving test for leukemia therapy choice; Factor V Leiden genotyping; and FDA-approved, real-time PCR test for Methicilllin-resistant Staphylococcus aureus detection.

—NB