Array-based methods are now being applied in a diagnostic setting and offer the possibility of analysing multiple analytes (and even multiple samples) in a highly parallel and high-throughput manner. In diagnosis, however, the tolerance for error is very low: it is important to get the right answer not just occasionally but all of the time, under stringent conditions and with varying sample quality. Nevertheless, important milestones have been achieved in the past year as array-based diagnostic tests begin to trickle onto the market.

Agendia of Amsterdam, The Netherlands, offers MammaPrint, a diagnostic test for assessing the risk of breast cancer progression. The test predicts the future development of metastases on the basis of a 70-gene expression signature discovered by scientists at the Netherlands Cancer Institute and Antoni van Leeuwenhoek Hospital in Amsterdam. Its use should improve the quality of treatment decisions for cancer patients by distinguishing those individuals who would, and who would not, benefit from further treatment.

In May, Tm Bioscience of Toronto, Canada, received FDA clearance for its Tag-It cystic fibrosis (CF) kit to be used as an in vitro device for diagnostic use. The test, which identifies a group of mutations in the CF transmembrane conductance regulator (CFTR) gene, is based on the bead-based xMAP multiplexing technology developed by Luminex of Austin, Texas. xMAP allows multiplexing of up to 100 assays within a single sample. In addition to human genetic disorders, Tm Bioscience is developing products aimed at pharmacogenetics and infectious diseases.

The NanoChip electronic microarray goes diagnostic. Credit: NANOGEN

Last year, Affymetrix of Santa Clara, California, received clearance by regulatory authorities in the United States and Europe for the in vitro diagnostic use of its GeneChip System 3000Dx. Affymetrix's strategy for developing new array-based diagnostic tests on its GeneChip platform is to work alongside partners from the diagnostics industry, such as Roche Diagnostics of Basel, Switzerland, bioMérieux of Marcy l'Etoile, France, and Veridex of Warren, New Jersey. “We are a technology-driven company,” says Robert Lipshutz, senior vice-president of molecular diagnostics and emerging markets at Affymetrix. “We did not have a large regulatory or commercial presence in the diagnostics industry.”

The first microarray product to be launched through the partnership with Roche is the AmpliChip CYP450 test, which identifies variations in two drug-metabolism genes that can affect the rate at which an individual metabolizes many common drugs.

Other companies are taking a different approach. CombiMatrix of Mukilteo, Washington, formed a diagnostic subsidiary, CombiMatrix Molecular Diagnostics, in May, now led by former senior executives from the diagnostics industry. “We want to capture revenue not just from the chip but from the test itself,” says Michael Tognotti, vice-president of sales and marketing at CombiMatrix.

“We didn't feel that high-density arrays are the way to go for clinical utility,” says Graham Lidgard, senior vice-president of research and development at Nanogen of San Diego, California. The company is targeting the clinical and diagnostic market with its NanoChip electronic microarray system. “If you want to do one or two targets, then reverse transcription–PCR is really the way to go, but if you want to look at four or five single-nucleotide polymorphisms to 100 targets across a number of patients, our technology is probably best suited to that application,” Lidgard says.

The company's NanoChip 400 platform for multiplexed mutation detection, out later this year, features increased automation and will offer a 400-site cartridge for increased throughput; the original version has 100 electrodes, or test sites.

An equity investment in Jurilab of Kuopio, Finland, announced in July, gives Nanogen certain rights to develop diagnostic products based on genes and gene markers discovered by Jurilab. The initial focus will be on cardiovascular and metabolic diseases, including adult-onset diabetes.

Microfluidics: Metrigenix's TipChip platform for RNA and DNA. Credit: METRIGENIX

BioArray Solutions of Warren, New Jersey, has developed a novel twist on traditional bead-based systems where beads displaying proteins or DNA capture probes are in suspension and assays are performed ‘in-tube’. BioArray's BeadChip format provides a bead array in the form of a single pre-assembled layer of colour-coded beads in random configuration on a small silicon chip. The company is initially developing BeadChip assays to screen carriers for CF and Tay–Sachs disease, as well as for transfusion and transplantation medicine.

“It's a very diverse set of applications that we've already developed and deliver on a complete platform,” says Michael Seul, president of BioArray Solutions. “As a small company, we've chosen to focus on certain areas where we can have a large impact because they have been largely unexplored.”

MetriGenix of Toronto, Canada, is developing genomic biomarker panels and genomics instrumentation for the diagnostic market. In the company's Flow-thru chip technology, molecular interactions occur within 3D microchannels rather than on a planar surface.

The company's TipChip technology is provided as part of the MGX8 automated system, which can process eight 1×1-cm silicon TipChips in parallel with up to 1,600 biomolecular targets or ‘spots’ per chip. The system is suitable for RNA, DNA or protein targets.

Sample preparation is still a time-consuming process in all platforms. Further automation on the front end would improve robustness and reduce costs.

D.G.