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US Research Network Uses Microarrays To Develop IVDs for Trauma Patients


A nationwide network of scientists, physicians, and researchers has developed a protocol for collecting, sharing, and analyzing genomic data taken from trauma patients that organizers hope will yield an array-based in vitro diagnostic and potential anti-inflammatory therapeutics for the intensive care unit.

The Inflammation and Host Response to Injury Network is a collaboration of 70 investigators from 20 research and medical facilities in the United States. It is funded with a five-year, $37 million NIH grant. In a Proceedings of the National Academy of Sciences article this week, the group discusses the ways in which the protocol collects samples from critically injured patients and shares the resulting microarray data within the disparate network.

Though this project is still in its early stages, and an array-based molecular diagnostic is still years away from being used in the ICU, the investigators feel confident that they can move forward in their quest to develop an IVD for trauma patients.

"This acts as a springboard," J. Perren Cobb, the lead author of the article and an associate professor of surgery and genetics at Washington University School of Medicine, told BioArray News last week. "Now that we've validated our methods, we can with great confidence go into the clinic, into the ICU, and start collecting samples, and collect those data and analyze [them]."

For investigators like Cobb who deal regularly with patients in the ICU, the creation of the IHRIN and the validation of microarrays as a new methodology for testing trauma patients are two significant events for a component of medical care that has changed very little in the past few decades.

According to 2003 figures from the Center for Disease Control, some 5 million critically injured Americans are admitted to the ICU each year, and trauma is the number one cause of death for Americans aged 2 to 40. Trauma is also the No. 5 cause of death overall.

However, there is no national network for creating collaborative diagnostics or even therapeutics, and the IHRIN's attempt is, by all accounts, the first of its kind. And it comes at a time when physicians in the ICU are growing frustrated with the limited technological options available to them.

"It's a very exciting time because our field has experienced such frustration with some of these questions, many of which have important ramifications for how we treat patients," Cobb said in a statement.

The study was funded by a $37 million grant from the National Institute of General Medical Sciences, and Cobb said that it is about halfway through its work with the network. The first half of the study has been devoted to the creation of the network and protocol; the second half will create expression profiles for diagnosis in the ICU and identify possible drug targets for curbing inflammation in trauma patients. The network plans to use the total funding it received from the NIGMS to finance the second, five-year study.

Cobb added that the network was running all of its samples on the Affymetrix platform. Ronald Tompkins, a leading trauma investigator from Massachusetts General Hospital and professor of surgery at Harvard Medical School, who has led the team of 70 over the past five years since it received the grant money, said that the network chose Affymetrix "because of its comprehensive coverage and quality control characteristics."

"The genomic signal that we are evaluating requires very high precision that cannot be achieved using other systems," Tompkins said.

It was unclear what role Affymetrix played in the study other than being the primary chip vendor, although both Cobb and Tompkins said the firm had provided their program with some technical assistance and had been interested in the methodology being advanced by the network.

"It is of mutual benefit to advance the application of microarray technologies into clinical medicine and research," Tompkins wrote in an e-mail to BioArray News.

Affy did not return e-mails and phone calls to comment on the study.

According to information on the group's website, the network has so far used a variety of Affy chips to perform its preliminary studies, which compared gene-expression profiles of 34 critically injured patients with 20 controls.

Cobb said that the study is in its earliest phases, but ideally, over the coming decade, the use of tools created from genomic information will allow physicians in the ICU to determine what kind of prognosis their patients have, and will give them new treatment options to prevent massive, lethal inflammation.

As part of the collaboration, consortium participants developed strategies for sharing noise-free data and developed a protocol for isolating white blood cells — a key component for determining which biomarkers they will hope to target in order to suppress over-inflammation in trauma patients.

Cobb said that for the follow-up study his group plans to collect samples from 250 additional individuals to begin the process of identifying markers. The group has already collected data from 100 trauma patients. The final goal is to develop new IVDs and drug therapies that can be used in the ICU within 5 to 10 years, although Cobb admits it is an uphill battle to get to that point.

"My hope is that we can get the biomarkers in the near future. Understanding the biology and tweaking individual drugs is going to be a lot more difficult," he said.

Added Tompkins: "In my opinion, usage of microarray technologies in the clinical setting is still very early in its development.

Other Trauma Studies in Progress

While most experts dealing with inflammation in the trauma setting agree that Tompkins and Cobb's network is the only group working on developing diagnostic tools from genomic data, there are others in the US and abroad studying inflammation and working towards similar goals.

"The NIGMS study is one of the big studies," said Anthony Suffredini, an investigator from the National Institutes of Health, referring to the work being done by the Inflammation and Host Response to Injury Network, "but there's also one that's being done in children sponsored by NIGMS, and then there's one or two of them being done in Europe, in Germany particularly — where people are trying to use signatures and profiles in genes and how they relate in the ICU."

The second NIGMS-funded project for using microarrays to investigate the genomics of trauma is being led by Hector Wong, director of the Cincinnati Children's Hospital Medical Center in Ohio. Wong could not be reached by press time for an interview about his study, but Suffredini said "their interest is basically profiling children who have severe infections and are trying" to identify the biomarkers responsible.

Wong's study differs from Cobb's study because researchers are limited by what kind of data they can collect from pediatric trauma patients. It is unclear on which platform Wong's studies are being conducted.

The European studies of inflammation in response to injury are based out of the Giessen Research Center in Infectious Diseases in Giessen, Germany, which is part of that country's larger research network for infection and inflammation.

Trinad Chakraborty, the director of the center, wrote in an e-mail to BioArray News that his center is currently using GE Healthcare's CodeLink bioarrays to analyze sepsis. Chakraborty also sent a copy of a presentation he will give when he meets with Suffredini, Cobb, Wong, Tompkins, and others at the third annual Functional Genomics in Critical Injury conference at the NIH in April.

Chakraborty said that, as in the US, mortality due to sepsis and septic shock has remained unchanged over the past two decades and that "the interplay between microbial attack and host immune and inflammatory response is incompletely understood."

He pointed to statistics that show that nearly 100,000 people in Germany die from response to critical injury each year. Like his American colleagues, he too has turned to using microarrays to develop new methods for treating trauma patients.

"These tools provide a means to discover novel gene functions and relationships and to identify potential therapeutic targets," he wrote in the presentation.

— JP

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