Microarray technology, long beset by widely differing data standards, may be one step closer to becoming a mainstream component of pharmacogenomics.
The External RNA Controls Consortium, an ad hoc group of 70 partners from industry, government, and academia seeking to develop a list of microarray and RT-PCR experimental controls, has published a draft of approximately 100 standard controls and a plan to test them, and is now seeking public comment on the draft before it becomes finalized at an ERCC meeting next month.
The development of the draft is noteworthy because it comes at a time when US regulators are becoming increasingly interested in the utility of microarray data as components in pharmacogenomics-based drug and diagnostics discovery.
To be sure, though the ERCC had planned to make the final controls available in mid-2006, it made early-access protocols available to commercial users earlier this quarter, which raises the question of whether the final controls will be any different from the current ones.
| "It's a priority because people are coming out with tests. So even if people aren't using the standard controls, it's something. End users need the controls, need to know how to use them, and need the software tools to analyze them."
According to a statement from the National Institute of Standards and Technology — the federal body hosting the ERCC — the consortium has agreed upon 100 RNA samples that can be added to QRT-PCR assays and microarray experiments as spike-in controls to "check the performance of the measurement system."
Ideally, investigators will use the samples "to deliver comparable results across the range of available microarray and QRT-PCR systems," NIST said in a statement released last week.
In addition, "because selecting a set of RNA controls that perform consistently is essential to the success of the project, the ERCC is planning extensive experimental qualification of the set," NIST said.
Michael Baum, a NIST spokesperson, told Pharmacogenomics Reporter sister publication BioArray News last week that the ERCC expects to begin validating the RNA samples across platforms "in [the] fourth quarter of 2005." However, before it can begin testing the RNA controls, the consortium has opened a month of public review, soliciting comment on the draft test plan, accessible on NIST's website.
"There is no rigid format. Appropriate forms for comments would include a narrative discussion or comments in a mark-up of the PDF document," he said.
According to Baum, the public review period will be capped off with a public meeting to be held at Lister Auditorium on the National Institutes of Health's campus in Bethesda, Md., Oct. 4-5.
"Comments will be discussed and reviewed publicly at the workshop, either in a general discussion section or, as appropriate, in the sections devoted to document elements," Baum said.
The final plan, which is to be adopted by consensus, is "intended to refine the test plan, by identifying gaps or opportunities to streamline the testing to obtain a useful, functional, proven set of reference sequences for external RNA controls," Baum said. Once adopted, testing is set to begin in the fourth quarter, he added.
Some users have already had access to the controls, however. Early-access ERCC controls became available in the third quarter of this year from the Clinical Laboratory Standards Institute, a global non-profit standards organization, Lois Schmidt, a CLSI official, told BioArray News in June (see BAN 6/15/2005). According to CLSI, which is an ERCC member, these controls were made available in July.
Schmidt, the director of standards and development at CLSI, said at the time that the document, entitled, "Use of External RNA Controls in Gene Expression Assays; Proposed Guidelines," would cost CLSI members $60, and non-CLSI members $120.
Janet Warrington, vice president of R&D at Affymetrix and an ERCC leader, told BioArray News at the Northwest Gene Expression Conference in May that the final controls would be available in mid-2006, but in the meantime, the ERCC understood that some users could not wait a year for the final controls to be released.
"It's a priority because people are coming out with tests," Warrington said at the time. "So even if people aren't using the standard controls, it's something. End users need the controls, need to know how to use them, and need the software tools to analyze them" (see BAN 6/1/2005).
When Warrington spoke in May, the ERCC had just finished collecting 140 RNA sequences following a consortium meeting in Boulder, Colo. She also said that the ERCC was founded two years ago to pool interest from array manufacturers like Affymetrix, Applied Biosystems, and Agilent with academic partners such as Cambridge, Northwestern, and Tokyo Universities, government members such as the Centers for Disease Control and Prevention and the US Department of Agriculture, and pharmaceutical members such as Bristol-Myers Squibb and Eli Lilly — all of whom make up the "community" that is expected to approve the plan for testing the controls in October
"Once we get the blessing of the community, we will work to do the testing. If everything goes well in the October meeting, testing could go forward in the fourth quarter of [this year], [which means] that we could have the controls in 2006," Warrington said in May.
Warrington said testing would be "undertaken by microarray manufacturers, such as Affymetrix, so-called 'neutral' sites like NIST and the CDC, and by diagnostic firms." The main impetus is to provide the US Food and Drug Administration with more reliable data.
"The FDA wants to have some reference point on understanding probes and array data or RT-PCR data," Warrington said.
Warrington did not respond to requests for comment for this article by press time.
However, if a user can just buy the early-access RNA controls from CLSI, wouldn't the ERCC be reluctant to institute major changes following the review of the draft in October.
Not so, according to NIST's Baum.
"Commentary has been, and will continue to be, encouraged throughout the process," Baum said last week.
"The ERCC, as an ad hoc group, operates in an open, consensus process, with the belief that such a process will yield the strongest, most broadly useful, and widely adopted standards," he said.
Baum also said that the test plan, when adopted, "will be made available in an open-access form to the community as part of a package of all development information, documentation, test results, informatics tools." He said these and "reference material specifications" are being developed by Agilent and Affymetrix.
— Justin Petrone ([email protected])