Evaluation of a New Genetic Epidemiology Resource: The Intermountain Genealogy Registry.

BACKGROUND: Many landmark genetic breakthroughs, including the recent discovery of PCSK-9 inhibitor drugs, were accomplished with substantial contributions from evaluation of pedigrees. Finding and ascertaining high-value pedigrees is not trivial and requires considerable time and cost. Here, we describe the creation of the Intermountain Genealogy Registry for use in studying the genetics of cardiovascular and other diseases. METHODS: Using publicly available pedigree records and probabilistic linkage techniques, we created a genealogy of ≈23 million records that we linked to 3.9 million patient records in the Intermountain Healthcare system. Analytical tools were developed to support this registry, including calculation of genealogical index of familiality (GIF), testing of familial coaggregation of diseases, and extraction of high-risk pedigrees. RESULTS: A total of 658,822 (16.8%) patients were linked to a genealogy pedigree record. The average age of the linked patients was 53 years, the majority (89.0%) were Caucasian, and 50.5% were male. The GIFs for the leading cardiovascular conditions of atrial fibrillation, coronary artery disease, heart failure, and myocardial infarction (MI) were all 1.2 times greater than the GIFs of matched control sets (p < 0.001). For extreme values of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides, the GIFs were each 1.5 times greater than those of matched control sets (p < 0.001). There was coaggregation with MI and the extreme lipid traits with the largest coaggregation being for MI and triglycerides. CONCLUSION: The Intermountain Genealogy Registry is a multifaceted resource created to provide insights into the genetic components of cardiovascular and other diseases. This registry provides the means for easy identification and ascertainment of high-risk pedigrees for discovery of genetic susceptibility variants.

Hypermedia-based software architecture enables Test-Driven Development.

Objectives: Using agile software development practices, develop and evaluate an architecture and implementation for reliable and user-friendly self-service management of bioinformatic data stored in the cloud. Materials and methods: Comprehensive Oncology Research Environment (CORE) Browser is a new open-source web application for cancer researchers to manage sequencing data organized in a flexible format in Amazon Simple Storage Service (S3) buckets. It has a microservices- and hypermedia-based architecture, which we integrated with Test-Driven Development (TDD), the iterative writing of computable specifications for how software should work prior to development. Relying on repeating patterns found in hypermedia-based architectures, we hypothesized that hypermedia would permit developing test "templates" that can be parameterized and executed for each microservice, maximizing code coverage while minimizing effort. Results: After one-and-a-half years of development, the CORE Browser backend had 121 test templates and 875 custom tests that were parameterized and executed 3031 times, providing 78% code coverage. Discussion: Architecting to permit test reuse through a hypermedia approach was a key success factor for our testing efforts. CORE Browser's application of hypermedia and TDD illustrates one way to integrate software engineering methods into data-intensive networked applications. Separating bioinformatic data management from analysis distinguishes this platform from others in bioinformatics and may provide stable data management while permitting analysis methods to advance more rapidly. Conclusion: Software engineering practices are underutilized in informatics. Similar informatics projects will more likely succeed through application of good architecture and automated testing. Our approach is broadly applicable to data management tools involving cloud data storage.