1. Living on the Edge (of Translational Informatics) Opportunities and Challenges for Integrating Bioinformatics into the Clinical Realm Russ B. Altman (Stanford U.) Samuel Volchenboum (U. Chicago) Robert R. Freimuth (Mayo Clinic) Casey Overby (Johns Hopkins) Subha Madhavan (Georgetown) Lewis Frey (Medical U. of South Carolina) Jessie Tenenbaum (Duke)

2. Goals Review trends in integrating bioinformatics into clinical care Focus on interfaces: tools, systems, processes for bench to beside translation Broad range of issues from basic informatics systems for clinical data analysis to issues of ethics and patient engagement.

3. Process 1.A brief journal club review of 1-2 publications that set stage for speaker. These have been chosen by speaker, and will be presented in abbreviated fashion. 2.Speaker will present on relevant topic (30 minutes) 3.If not DONE, loop to (1.)

4. Volchenboum: Informatics techniques used in clinical practice

5. “Detection of Circulating Tumor DNA in Early- and Late-Stage Human Malignancies” (Bettegowda et al, Sci. Trans. Med, 2014) Goal: Develop new methods to detect and monitor cancer. Method: Digital PCR to detect circulating tumor DNA (ctDNA) in 640 cancer patients. Result: ctDNA was detected in 82% of patients with metastatic non-brain tumors and 55% of localized tumors. Conclusion: ctDNA is broadly applicable, and shows promise as significant biomarker for clinical cancer management. 24553385

8. “A Hybridization Capture-Based Next-Generation Sequencing Clinical Assay for Solid Tumor Molecular Oncology” (Cheng et al, J. Mol. Diag, 2015) Goal: Develop Next generation sequencing (NGS) method for assessing mutational status on key cancer genes. Method: “Capture” technology for panel of 341 cancer genes (from formalin-paraffin samples). Result: Able to detect most known mutations in 284 samples and 48 exons, including SNPs, indels, copy number alterations, structural arrangements. Conclusion: NGS can provide reliable information about cancer gene mutational status. 25801821

10. Freimuth: Utilizing genomic data in clinical systems

11. “Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology” (Richards et al, Gen in Med, 2015) Goal: Create standards for communicating information about sequence variants. Summary: Specific definitions for “pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign” + evidence levels. Conclusion: ACMG made important contribution by creating discrete codes and definitions that can be used on a large scale. 25741868

13. Overby: Increasing the reach of clinical genomics research and genomics-informed care

14. “Convergence of Implementation Science, Precision Medicine, and the Learning Health Care System: A New Model for Biomedical Research” (Chambers et al, JAMA, 2016) Goal: Describe the great opportunities with convergence of data from omics, wearables, EMR. Summary: Learning healthcare system will bring ongoing systematic improvement of medicine. Implementation science studies best practices in the translation of research into practice. Conclusion: The triad of implementation science, precision medicine and learning health care is potent. 27163980

16. Madhavan: Practical Precision Medicine: Integration of clinical and genomic data to support cancer care

17. “The cancer biomarker problem” (Sawyers, Nature, 2008) Goal: Identify chief barriers to identifying useful biomarkers for assessing drug response. Summary: Describe prognostic and predictive biomarker types for cancer. Review challenges in discovery and commericialization. Conclusion: Biomarker discovery and validation is expensive and should be done through public-private collaborations. 18385728

19. Frey: Collection of data for research

20. “The immortal life of Henrietta Lacks” (Skloot & Bahni, 2010) Goal: Tell the story of HeLa cells, how they were derived and used, and the story of the family of Henrietta Lacks, from whom they were derived. Summary: There was no culture of informed consent for research purposes, cells potentiated much valuable science, patient and family were not aware. Conclusion: We need to do better in engaging patients as informed participants in science. No PMID = Book

22. Tenenbaum: Ethical, legal, and social implications of genomic testing

23. “23andMe, the Food and Drug Administration, and the Future of Genetic Testing” (Zettler et al, JAMA Int. Med, 2014) “23andMe and the FDA” (Annas & Elias, NEJM, 2014) Goal: Discuss FDA letter to Direct-to-Consumer genetic testing asking it to cease/desist. Key argument: When reports for high disease risk of 3 DTC companies were compared, they did not match. Summary: A milestone, since it ended the FDA’s silence on genetic testing regulation, and signalled more involvement in quality control of genetic testing. 24535082 & 2452093624520936