Deriving Drug Discovery Value from Large-Scale Genetic Bioresources Proceedings of a Workshop (2016) / Chapter Skim
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2 Maximizing Discovery Capabilities Through Cohort Design
2 Maximizing Discovery Capabilities Through Cohort Design
Pages 9-24
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From page 9... ...
(Stefánsson) Due to the large volume of patients seen at community health centers in the United States, these centers are an ideal venue for collecting and curating genetic data linked to longitudinal health information in electronic health records.
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From page 10... ...
Issues that arise when designing large cohort studies include challenges concerning sharing data, protecting individual privacy, and overcoming analytical and computational barriers. BIOBANK STUDIES IN FINLAND Several large cohort studies in northern European countries have demonstrated the potential of genetic bioresources to enhance drug discovery and development.
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From page 11... ...
"If you are interested in a specific phenotype, or a response to a specific medication, that information can not only be fleshed out over the life history of two individuals but over hundreds of thousands," Daly said. This enables new study designs that are difficult to do in a traditional academic environment, such as searching for adverse outcomes using prescription registry data, including adverse outcomes in people with specific genetic backgrounds, he said.
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Even though the studies required subjects to have a meal and then undergo numerous blood draws over 3 hours, more than 75 percent of the eligible individuals in the biobanks made themselves available for the recall study. The Finnish population tends to participate in recall studies because they have high levels of education, access to their own medical data, and a great deal of trust in their doctors and researchers, Daly said.
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GENETIC BIORESOURCES AND DISCOVERY EFFORTS IN ICELAND As in Finland, a great deal is known about the genetic diversity of the population in Iceland. deCODE genetics,3 a company based in Iceland, has been working to collect and curate genotypic and medical data on the Icelandic population, reported Kári Stefánsson, the chief executive officer and founder of deCODE genetics.
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Additional work using the Icelandic biobank samples has uncovered another variant that has a greater protective effect for coronary artery disease, he added (Nioi et al., 2016)
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(Baras) LONGITUDINAL STUDIES AT THE COMMUNITY HEALTH LEVEL Longitudinal health data from patient populations, in combination with genetic data, are another source of valuable information.
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GENETICS-GUIDED DRUG DEVELOPMENT AT REGENERON Studying human genetic data collected from longitudinal studies is one approach that Regeneron Pharmaceuticals is taking to accelerate the discovery and development of new drugs, said Aris Baras, the vice president and co-head of the Regeneron Genetics Center. Regeneron is incorporating human genetics into its research and development paradigm using a three-pronged approach:
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From page 17... ...
as targets for medicines, he said, and Regeneron is currently pursuing 200 different targets, with support from a variety of sectors, including human genetics, mouse genetics, molecular biology, biochemistry, and clinical pharmacology. The company also uses principles from human genetics to identify links that can help expand drug indications, and it uses pharmacogenetics to identify patients who may be more responsive or who may have a predictable adverse effect to a particular medicine.
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Using Genetics to Guide Drug Discovery Through general population cohort studies, including the DiscovEHR Study, it was found that loss-of-function mutations in the ANGPTL3 and ANGPTL4 genes result in lower levels of triglycerides and a lower risk of coronary artery disease than is found in noncarriers (Dewey et al., 2016; Helgadottir et al., 2016)
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"You cannot pursue modern drug discovery and development without incorporating human genetics into your R&D approaches," he said. DRUG DISCOVERY THROUGH DIRECT-TO-CONSUMER GENETICS Another source of genomic and phenotypic data is personal genetics companies that offer direct-to-consumer genetic tests.
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About 52 percent of customers are female, with a fairly even distribution of ages. The company uses a series of question to gather a wide variety of phenotypic data (see Box 2-1)
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, which, Scheller said, "is reassuring because I came to 23andMe to try to use this data to find drug targets." The database now contains large cohorts of people with specific conditions, including Parkinson's disease, cancer, depression, asthma, cardiovascular disease, and colorectal cancer, which are now the subject of genome-wide and phenome-wide association studies.
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"So we sent out an email to 80,000 of our customers [with] asthma, and in 2 weeks we set up a survey where 8,000 people will answer questions once a month for 6 months." PARTICIPATION, DATA SHARING, AND PRIVACY A major consideration in collecting information from large cohorts is assuring the participants that their data will remain private.
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"You have to find some sort of a middle ground, [such as] sharing summary-level data." To some extent, people have a tendency to overestimate the dangers posed by sharing genetic data.
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Another important issue with sharing of genotypic and phenotypic data is the quality of the data. Several international disease-focused consortia have addressed data quality challenges by agreeing on effective diagnostic and general criteria, Daly said, and those criteria have led to harmonious research tools that can be used across populations in the same disease state.
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