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G3 Enrolls 7,500 Participants in Project to Build Detailed 'Omics Map of CVD; Pilot Analysis Underway

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NEW YORK (GenomeWeb) – Global Genomics Group this week said it has finished enrolling a 7,500-patient cohort on which the company will collect and analyze 22 trillion data points, including omics data, and build a detailed network map of atherosclerotic cardiovascular disease (CVD).

The scientific aim of the project, according to G3 CEO Szilard Voros, is to "assemble the largest and most complete biological network of atherosclerotic cardiovascular disease." Launched in December 2012, the commercial aims of the effort are to commercialize novel biomarkers of CVD as diagnostics and advance targeted therapeutics through industry partners.

Toward these aims so far, G3 has finished enrolling its target 7,500 patient cohort at 49 sites in North America, Europe, and Australia several months ahead of schedule. Voros explained that G3 accomplished this by doing extensive due diligence before bringing any site on board with the project, making sure that the site could actually provide the number of patients necessary for the project. "That has worked," he said. "I don't think we had to terminate a single site from involvement."

With the study subjects enrolled, researchers will now turn their attention to the three components of the project – compiling a detailed phenotypic profile of participants, amassing a massive amount of 'omics data on them, and annotating this data using bioinformatics. In the first part of the study, which Voros has dubbed "next-generation phenotyping," researchers will use advanced cardiac imaging modalities to identify cases with CVD and those without.
 
Next, researchers will generate the molecular profile of subjects. They ambitiously plan to perform whole-genome sequencing on all 7,500 participants and to perform additional omics analysis on smaller cohorts, such as whole-genome methylation, transcriptome sequencing, mass spectrometry-based proteomics and metabolomics, lipidomics, and lipoprotein proteomics. "This is the single largest prospective study of whole-genome sequencing in CVD that we are aware of," Voros said. "We essentially want to create this really comprehensive dataset with every single omics that you can imagine."
 
Lastly, researchers will analyze the collected data by "systems biology-driven bioinformatics," Voros explained, which will enable researchers to assemble comprehensive networks of atherosclerotic CVD.

Although G3 just completed enrollment, the company's researchers are already working on analyzing a cohort of 360 study subjects for a bioinformatics pilot study that the company hopes to report as soon as the first half of next year. The participants in the pilot program have complete omics and phenotypic data sets. "We are already looking for signatures in the pilot study … and we already have intriguing data there," Voros said.
 
After this pilot phase, researchers will analyze data from a cohort of 2,000 subjects, then 5,000 subjects, and finally all 7,500, in order to validate findings in increasingly larger datasets.
 
G3 researchers are performing a variety of different omics tests, with the exception of WGS, on 700-subject cohorts, a size large enough to enable discovery and validation of biomarker signatures, Voros said. With regard to WGS, the discovery cohort will include 5,000 subjects and the validation cohort will involve 2,500 patients.

Illumina is providing WGS services for this project; Expression Analysis is providing transcriptome sequencing and methylation analysis; Metabolon is performing the metabolomics and lipidomics analysis; and Caprion is performing proteomics services.

Researchers have generated detailed phenotypic profiles on between 800 and 1,000 people so far, according to Voros. Advances in molecularly-guided personalized medicine for complex diseases, such as CVD, have been hindered by the lack of understanding of disease phenotypes. By applying advanced computerized tomographic (CT) imaging modalities, Voros is hoping in this study to establish clear subtypes of atherosclerotic CVD. "Typically, we use the analogy that by using this [next-generation phenotyping approach] we're going to do for cardiovascular disease what has been done for cancer," said Voros, who is an expert in non-invasive cardiovascular imaging and was among the first US physicians to obtain the highest certification in echocardiography, cardiovascular MRI, and cardiovascular CT.

CT, a technique that provides a detailed snapshot of the blood vessels and heart, provides advantages over traditional and more invasive angiography. Moreover, Voros noted that by using CT, G3 researchers have previously seen a 30 percent reclassification from traditional methods between cases and controls. "In the pilot study, as we are starting to look at imaging data and the molecular associations … the clustering we see is so much cleaner in this study than I've seen previously," he said.
 
In the phenotyping portion of the study, researchers will at first try to separate the participants into cases and controls by gauging if they have any atherosclerotic plaque versus none. Then, they will gather more detailed phenotypic data on 450 quantitative measurements, and from there establish subtypes of atherosclerotic disease.

"For example, on the basis of cardiac CT we divide plaques into non-calcified plaques, partially calcified plaques, and completely calcified plaques," Voros said. "That's a very simple three-bin classification system that actually speaks to progression of disease and outcomes." Previous studies suggest that patients with partially calcified plaques tend to have the highest rate of CVD events.
 
Voros did not reveal how much the study would cost, but said that the privately-held firm raised funds for the effort a few years ago, when it launched.

G3's business model is to partner with lab service providers and in vitro testing firms to develop biomarkers into diagnostics for the US and abroad. G3 has a joint venture with Health Diagnostic Laboratory, a large cardiovascular testing services lab also located in Richmond, and HDL can provide G3 an avenue to commercialize some of its findings from this effort in the US. In order to move into other countries, G3 will need to partner with other labs, and in partnerships with pharma to advance into the drug market.

Through an annual subscription fee, G3 intends to provide researchers and companies with the data being generated on the 7,500-patient cohort. G3 will also collaborate with parties interested in mining the database through fee-for service agreements, Voros said.

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