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.

Replicative Instability Drives Cancer Progression.

In the past decade, defective DNA repair has been increasingly linked with cancer progression. Human tumors with markers of defective DNA repair and increased replication stress exhibit genomic instability and poor survival rates across tumor types. Seminal studies have demonstrated that genomic instability develops following inactivation of BRCA1, BRCA2, or BRCA-related genes. However, it is recognized that many tumors exhibit genomic instability but lack BRCA inactivation. We sought to identify a pan-cancer mechanism that underpins genomic instability and cancer progression in BRCA-wildtype tumors. Methods: Using multi-omics data from two independent consortia, we analyzed data from dozens of tumor types to identify patient cohorts characterized by poor outcomes, genomic instability, and wildtype BRCA genes. We developed several novel metrics to identify the genetic underpinnings of genomic instability in tumors with wildtype BRCA. Associated clinical data was mined to analyze patient responses to standard of care therapies and potential differences in metastatic dissemination. Results: Systematic analysis of the DNA repair landscape revealed that defective single-strand break repair, translesion synthesis, and non-homologous end-joining effectors drive genomic instability in tumors with wildtype BRCA and BRCA-related genes. Importantly, we find that loss of these effectors promotes replication stress, therapy resistance, and increased primary carcinoma to brain metastasis. Conclusions: Our results have defined a new pan-cancer class of tumors characterized by replicative instability (RIN). RIN is defined by the accumulation of intra-chromosomal, gene-level gain and loss events at replication stress sensitive (RSS) genome sites. We find that RIN accelerates cancer progression by driving copy number alterations and transcriptional program rewiring that promote tumor evolution. Clinically, we find that RIN drives therapy resistance and distant metastases across multiple tumor types.

Current and Emerging Informatics Initiatives Impactful to Cancer Registries.

Cancer surveillance at the population level is a highly labor-intensive process, with certified tumor registrars (CTRs) manually reviewing medical charts of cancer patients and entering information into local databases that are centrally merged and curated at state and national levels. Registries face considerable challenges in terms of constrained budgets, staffing shortages, and keeping pace with the evolving national and international data standards that are essential to cancer registration. Advanced informatics methods are needed to increase automation, reduce manual efforts, and to help address some of these challenges. The Cancer Informatics Advisory Group (CIAG) to the North American Association of Central Cancer Registries (NAACCR) board was established in 2019 to advise of external informatics activities and initiatives for long-term strategic planning. Reviewed here by the CIAG are current informatics initiatives that were either born out of the cancer registry field or have implications for expansion to cancer surveillance programs in the future. Several areas of notable activity are presented, including an overview of informatics initiatives and descriptions of 12 specific informatics projects with implications for cancer registries. Recommendations are also provided to the registry community for the continued tracking and impact of the projects and initiatives.

Enhancing research informatics core user satisfaction through agile practices.

OBJECTIVE: The Huntsman Cancer Institute Research Informatics Shared Resource (RISR), a software and database development core facility, sought to address a lack of published operational best practices for research informatics cores. It aimed to use those insights to enhance effectiveness after an increase in team size from 20 to 31 full-time equivalents coincided with a reduction in user satisfaction. MATERIALS AND METHODS: RISR migrated from a water-scrum-fall model of software development to agile software development practices, which emphasize iteration and collaboration. RISR's agile implementation emphasizes the product owner role, which is responsible for user engagement and may be particularly valuable in software development that requires close engagement with users like in science. RESULTS: All RISR's software development teams implemented agile practices in early 2020. All project teams are led by a product owner who serves as the voice of the user on the development team. Annual user survey scores for service quality and turnaround time recorded 9 months after implementation increased by 17% and 11%, respectively. DISCUSSION: RISR is illustrative of the increasing size of research informatics cores and the need to identify best practices for maintaining high effectiveness. Agile practices may address concerns about the fit of software engineering practices in science. The study had one time point after implementing agile practices and one site, limiting its generalizability. CONCLUSIONS: Agile software development may substantially increase a research informatics core facility's effectiveness and should be studied further as a potential best practice for how such cores are operated.

SHARE: system design and case studies for statistical health information release.

OBJECTIVES: We present SHARE, a new system for statistical health information release with differential privacy. We present two case studies that evaluate the software on real medical datasets and demonstrate the feasibility and utility of applying the differential privacy framework on biomedical data. MATERIALS AND METHODS: SHARE releases statistical information in electronic health records with differential privacy, a strong privacy framework for statistical data release. It includes a number of state-of-the-art methods for releasing multidimensional histograms and longitudinal patterns. We performed a variety of experiments on two real datasets, the surveillance, epidemiology and end results (SEER) breast cancer dataset and the Emory electronic medical record (EeMR) dataset, to demonstrate the feasibility and utility of SHARE. RESULTS: Experimental results indicate that SHARE can deal with heterogeneous data present in medical data, and that the released statistics are useful. The Kullback-Leibler divergence between the released multidimensional histograms and the original data distribution is below 0.5 and 0.01 for seven-dimensional and three-dimensional data cubes generated from the SEER dataset, respectively. The relative error for longitudinal pattern queries on the EeMR dataset varies between 0 and 0.3. While the results are promising, they also suggest that challenges remain in applying statistical data release using the differential privacy framework for higher dimensional data. CONCLUSIONS: SHARE is one of the first systems to provide a mechanism for custodians to release differentially private aggregate statistics for a variety of use cases in the medical domain. This proof-of-concept system is intended to be applied to large-scale medical data warehouses.