Dr. Szilard Voros, CEO and co-founder of Global Genomics Group (G3), is currently heading the international GLOBAL study, which will enroll up to 10,000 patients with coronary artery disease. The coronary atherosclerotic disease of each patient will be precisely phenotyped with advanced CT angiography; subsequently, each patient’s blood sample will undergo a panomic analysis that includes genomics, epigenomics, transcriptomics, proteomics, metabolomics, lipidomics, lipoprotein and proteomics. The trillions of data points collected from the phenotyping and the panomic analyses will be analyzed with specially designed bioinformatics techniques to identify novel pathways and factors contributing to atherosclerosis. We had a chance to speak with Dr. Voros about the project and what led to its development.
Tom Fowler, Medgadget: Dr. Voros, you have an impressive background in your work doing cardiology research. Can you share a unique project you enjoyed being a part of in the past?
Dr. Szilard Voros: There are several, and it is somewhat difficult to choose. However, I would like to highlight the ATLANTA project, for which I received on of my first large scale investigator initiated grants. This was very important for us, because it was instrumental in establishing cardiac CT as an outstanding phenotyping tool, which became a cornerstone of G3’s GLOBAL project. Another project I would like to mention is called iCARE, which utilized genomic information, biomarkers and cardiac imaging to better select preventive strategies for patients at risk for cardiac disease. All in all, we utilized bits and pieces of imaging, genomics and other methods from previous studies, and now we have combined them together in the GLOBAL study.
Medgadget: Tell us a little bit more about the GLOBAL study you are working on.
Dr. Szilard Voros: We initiated the GLOBAL study to uncover the root causes of global diseases, such as atherosclerosis, by deciphering the biological networks that underlie them, and the GLOBAL study is the most ambitious study ever undertaken to investigate the complex biological processes and systems underlying atherosclerosis. The study will gather and analyze trillions of data points from up to 7,000 to 7,500 patients.
We enrolled 5,000 patients in the discovery group, with approximately 2,500 patients each in the control group and the case group. We plan to enroll an additional 2,000 patients in the validation cohort, with approximately 1,000 patients each in the disease group and the control group.
The GLOBAL study is based on three pillars: next-generation phenotyping, pan-omics and systems-biology driven bioinformatics. We apply precision phenotyping with advanced cardiovascular imaging coupled with pan-omic analysis that includes whole genome sequencing, whole genome epigenomics, whole transcriptome sequencing, unbiased proteomics, metabolomics and lipidomics. The resulting data will be analyzed with systems-biology driven bioinformatics. The goal of the GLOBAL study is to identify and validate key biomarkers and central therapeutic targets to reduce the burden of global illnesses, in this case cardiovascular disease.
Medgadget: What inspired you to embark on the ambitiously large and comprehensive GLOBAL study?
Dr. Szilard Voros: We know that despite significant advances in molecular and cellular biology as well as population science, the biological processes behind the development of many diseases are still not well understood. In addition, recent genome wide association studies have been insufficient for the discovery of complex disease-relevant pathways. Especially for complex diseases such as cardiovascular disease, which are multifactorial, the biological pathways involved in their development are poorly understood. . For example, it is estimated that 50 percent of atherosclerosis is due to genetic factors while the other 50 percent can be attributed to environmental factors. One of the major insights that we found using our imaging technology with CT was that we were 30% more sensitive in picking up cardiovascular disease, compared to traditional invasive angiography.
It is noteworthy that the interest and support from the medical community is remarkable. Forty-eight institutions in 9 countries and across three continents are participating in the GLOBAL study, and we were able to complete the enrollment of the 5,000-patient discovery cohort well ahead of schedule. We hope to present the pilot data from the GLOBAL study later this year.
Medgadget: How have new imaging technologies and medical devices changed the research you are doing?
Dr. Szilard Voros: One of the most important factors for a comprehensive and integrated approach for biomarker and drug target discovery is accurate and precise phenotyping of the experimental and control groups. We use cardiovascular computed tomography (CT), including calcium scoring and CT angiography (CTA) to precisely characterize the disease. CTA is a noninvasive technique that can assess both calcified plaques and non-calcified plaques. It is able to show the lumen of the coronary arteries and the vessel wall, similar to intravascular sonography.
Many studies have shown that CTA is highly accurate for the estimation of luminal area, percentage of area stenosis and for detection of plaque including plaque area and plaque volume. G3 and our collaborators are the recognized experts in coronary CTA. We also know that coronary calcification is a marker for atherosclerotic disease with prognostic significance. In our study we are able to differentiate potentially unstable plaques that are characterized by high lipid content, and more likely to lead to an acute coronary event.
My laboratory has spent about 10 years establishing cardiovascular CT as the new gold standard for the evaluation of atherosclerotic cardiovascular disease. We worked out issues related to reproducibility, and then went on to establish its accuracy. We have done a great deal of work to validate cardiac CT against intravascular modalities such as intravascular ultrasound and near-infrared spectroscopy. This allowed us to utilize this technology for up to 10,000 patients around the world to evaluate cardiovascular disease. At the same time we will analyze the blood to understand genomic and other factors leading to heart disease.
Medgadget: What do you hope to learn and discover with this project?
Dr. Szilard Voros: We aim to identify novel biological pathways in cardiovascular diseases, creating an opportunity for the introduction of novel diagnostic biomarkers and therapeutic targets as well as providing a platform for early screening, continued monitoring of risk, prevention and early intervention.
Our three-pillared approach consisting of precise phenotyping, pan-omic analysis and bioinformatics also enables us to investigate biological systems involved in the diagnosis and development of other diseases such as diabetes and stroke as well as oncologic, neurodegenerative and psychiatric diseases.
Medgadget: How is your team preparing to work with the incredibly huge treasure trove of data that you will collect throughout the GLOBAL project?
Dr. Szilard Voros: We are working with renowned experts in systems-biology based bioinformatics and anticipate that the pilot data set will be available later this year.
The first major hurtle is just to establish the IT infrastructure even to house the data and to allow access for our bioinformatics groups from different parts of the globe. Second, we needed to develop a conceptual framework to evaluate the data set in a completely unbiased way, so that we can uncover previously unknown associations and relationships, in order to assemble the most comprehensive biological network related to heart disease. We have developed a very disciplined, targeted and focused bioinformatics approach which we will begin to execute over the next several months. We anticipate that we will have the first data from the initial patients by the end of 2014. Afterwards, of course, it will take several years to go through the data set and understand the major new insights and biology.
Medgadget: Do you have any tips for other medical entrepreneurs and scientists out there? What are three musts before starting a huge project like this?
Dr. Szilard Voros: First and foremost, one has to have a transformational idea; second, one needs passion in order to pursue that concept and dream. I would also say that one of the most important skills I learned over the past years is adaptation; when one embarks on a scientific and corporate journey, the only thing one knows in advance is that things will inevitably change over time. Therefore, I think it is essential to remain flexible and open-minded in order to adjust to changing circumstances, changing demands and changing directions.