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Cleveland Clinic to Evaluate IntegraGen's Autism SNP Panel in 600-Patient Prospective Study

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By Molika Ashford

Cleveland Clinic researchers have launched a 600-patient prospective study evaluating a SNP panel for predicting autism risk developed by French biotech firm IntegraGen.

IntegraGen's panel is intended to help identify children at risk of developing autism spectrum disorder. Initial work by the company has focused on familial autism, but IntegraGen is now working to expand to patients without an affected sibling but with other symptoms suggesting potentially higher risk.

According to Larry Yost, head of IntegraGen's US operations, the Cleveland Clinic team will be working with a larger panel than what has been represented in the company's published studies thus far, and will be investigating both familial and non-familial groups. IntegraGen has invested more than half a million dollars over two years for the project, Yost told BioArray News.

IntegraGen hopes to bring a test based on the panel to market near the end of the first quarter or during the second quarter of this year, he said. He declined to provide details on the company's commercial plans, but said the assay will be made available as laboratory-developed test through partnership with a CLIA-compliant laboratory.

The company hopes the test will be able to add to current risk-assessment strategies, helping to identify children at a higher risk who can be followed more closely or referred sooner to therapeutic intervention.

"If you look at the some of the latest reports, the average age of diagnosis of autism is four to four and a half … And there's now research out there that shows that if you start early intervention at a year to 18 months or at two or three years, there is so much benefit to a child of doing that as opposed to waiting until they're older," Yost said.

Thomas Frazier of the Cleveland Clinic's center for autism and Charis Eng, chair of the clinic's genomic medicine institute, are leading the new prospective study looking at the panel's predictive power in a group of children with an autism diagnosis, along with other developmental disorders and normal controls.

Cleveland Clinic will process cheek swab samples from the study participants, using equipment provided by IntegraGen.

The team will be using the Fluidigm EP-1 system to test blood samples with IntegraGen's predictive SNP panel to assess risk in a total cohort of at least 600 patients. Yost said that IntegraGen has a longstanding partnership with Fluidigm and felt the company's dynamic chip technology best fit its needs.

"When we looked at which system would be best for genotyping the large number of SNPs for our autism risk assessment test, we felt that Fluidigm … provided us with an approach which was easy to operate, allowing us flexibility in the number of SNPs and the number of samples interrogated, while also allowing the use of multiple chemistries," Yost explained.

Fluidigm launched the EP1 System in 2008. Users can conduct low- to mid-multiplex SNP genotyping on the company's Dynamic Array integrated fluidic circuit chips.

Frazier and Eng plan to evaluate about 300 patients who come through the Cleveland Clinic's autism clinic, another 75 who are enrolled with suspicion of ADHD or another developmental disorder, 100 healthy siblings, and 125 unrelated control subjects, according to an abstract describing the project.

"We wanted a heterogeneous population," Frazier told BioArray News. "Often in science you want really clean comparison groups, but in this case if you are testing the validity of an assay …you actually want groups that are going to potentially mimic the group of interest.”

Frazier said that the Cleveland Clinic team hopes to be able to replicate the predictive power IntegraGen has shown in earlier published work, as well as a more recent study that has not yet been released.

"Essentially what they've shown is that if you stratify by sex, the panel does a pretty good job separating folks who have autism from their unaffected siblings," he said. "When I say it does a pretty good job, it's not diagnostic, but it's definitely in the range of having clinical utility, so it changes the risk or the likelihood of having autism by two, three, or maybe even four times.

"That's a pretty good discrimination," Frazier said. "We know that unaffected siblings tend to have a higher autism symptom profile, at least in some families, so that's a tough group to discriminate."

In other cases, he said, the panel could also help to rule out autism in individuals, which is also very important.

"We haven't really gotten into that yet, but I think the panel will probably have some validity there as well," Frazier said.

Eng emphasized that the group is not evaluating the panel as a standalone method for establishing risk. Both IntegraGen and the Cleveland Clinic group see the test as one piece among many in the risk evaluation of suspected autism cases.

Eng said the team sees the SNP panel working "in conjunction with … clinical features to come up with an evidence-based risk calculator for ASD risk.”

"With accurate risk assessment and subsetting comes early tailored clinical and behavioral management," key for effective intervention in the disorder, she wrote in an e-mail to BioArray News.

"[Many] think that using only SNPs or only one kind of test will be the answer, but it is not. The most powerful risk assessment tools will be interdisciplinary," Eng said.

As part of the study, Frazier and Eng's team also plan to study whether genetic changes measured by the panel may be associated with attention deficit/hyperactivity disorder, and to "examine whether genetic differences and changes may predict which individuals benefit from medicine used to treat attention problems or other psychiatric difficulties," according to the project abstract.

"From my perspective as a scientist, I'm mainly interested in seeing if it works. We don't have a dog in the fight really," Frazer said.

"If it works, [that's] great. If it doesn't we should know that. It'll give us a sense that combining SNPs may not be the way to go in terms of finding out whether somebody has this condition," he added.

Yost said IntegraGen expects to release an initial version of the familial autism panel in the first half of this year.

"It is our plan to have something available in the US specifically for children who have an older sibling with autism," he said.

He said the company plans to partner with another firm to offer the panel as an LDT through a CLIA-compliant laboratory, but declined to elaborate.


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