Informatics of Clinical Genomics

Transcription

1 Informatics of Clinical Genomics Lynn Bry, MD, PhD. Director, Center for Clinical and Translational Metagenomics Associate Pathologist, Center for Advanced Molecular Diagnostics Dept. Pathology, Brigham & Women s Hospital Harvard Medical School lbry@partners.org

2 Overview 1. Operational and IT components in workflows that lead to complex genetic testing 1. Germline testing 2. Cancer 3. Infectious agents 2. Maintaining bioinformatics/computational pipelines in a CLIA lab. 3. Points for inter-operability and integration with other healthcare systems

3 Information Flow for Clinical Genomic Testing Next Generation Sequencing Curated Variant Database Billing LIS Accessioning Raw Data Generation Analysis and Interpretation Reporting Reanalysis and Reuse NGS Instrument(s) Instrument or Other Software EHR Sample Patient Populations Alexis Carter, M.D., Emory

4 Integrating NextGen technologies into CLIA settings Frequently separate systems Wild-west/brave new world..

5 IT and Clinical Teams IT Team supporting Genomic Testing Clinical IT/LIS support personnel Bioinformatics Pipelines Project Manager Software Architect Analysts QA Analysts/Engineers Developers DBA SysAdmin Statistician Computational Biologist Bioinformaticians Data warehousing IT and ETL support team Computational staff for data mining and analysis; hypothesis generation and testing. Epidemiology and population effects. Clinical Interpretation Team Analysts Clinical Geneticists (MS) Medical Geneticists (PhD) Medical Geneticists (MD) Pathologists Other Medical Specialties Develop expert teams to both devise clinical use cases for complex genetic testing and assist with content development and interpretation of test s.

6 Items new to CLIA labs Lack of vendor tools: lab must become a software development company Degree of software documentation The need to establish a robust versioning system All components of the pipelines in use Open source tools, in-house scripts/applications, content databases, etc. Pipeline validation and development of complete test scripts and documentation Unit and full regression testing. Costs for bioinformatics, computational + IT infrastructure and personnel >>> technical costs for CLIA-grade genome analyses

7 IT/Computational Improvements Vendors are starting to provide CLIA-grade tools. Sequencing Vendors: initial processing/qc 3 rd -party vendor tools to assist in clinical reporting National and international efforts to develop CLIA-grade knowledge bases HIPAA-compliant clouds and computational clusters CAP NGS Accreditation Program Released in July 2012 as a new section in the Molecular Pathology Checklist Analytical Wet-Bench Processes Bioinformatics Pipelines for NGS HL-7 Genetic test report standard released 2/2013. Specification for communication of complex genetic test s.

8 Bioinformatics components (1) Process/Pipeline Documentation: The laboratory documents the bioinformatics process or pipeline(s) used to support the analysis, interpretation, and reporting of next generation sequencing based s. Documentation of all open source tools, vendor components, in-house developed scripts or applications. Validation/Revalidation: The laboratory has validated the bioinformatics process or pipeline(s) and revalidates after any changes or upgrades are made to any components used to generate next generation sequencing data. Includes any updates to the OS, database, application-layer components. Train bioinformatics staff that small tweaks can profoundly affect clinical s, and to make certain any change is discussed, documented, and signed off by the lab director or designee. QM Program: The laboratory has a documented Quality Management program for the bioinformatics process or pipeline used to support the analysis, interpretation and reporting of next generation sequencing based s. Have procedures in place for corrective measures if components fail laboratory standards.

9 Bioinformatics components (2) Updates: The laboratory has a policy for monitoring and implementing patchreleases, upgrades, and other updates to the bioinformatics process or pipeline. Open source and other third party tools, most of which are not developed with CLIA-level testing in mind. Input Storage: The laboratory has a policy regarding the storage of input, intermediate and final data files generated in the bioinformatics analyses performed on patient samples. What files to store?.fastq,.ban, others? Raw files from the sequencer frequently not stored long-term. If sequence data needs to be re-run on a new/updated bioinformatics pipeline is an adequate, initial starting dataset available for re-analysis. Consider local and state requirements for data storage. Version Traceability: The specific version(s) of the bioinformatics process or pipeline(s) used to generate next generation sequencing data are traceable for each patient report. Store log files on runs associated with each patient dataset. If there is an issue, does the lab have adequate data to replicate the original analysis? Important to capture all steps in the lab, including what bioinformaticians may undertake. Develop training programs for bioinformatics staff regarding the level of documentation required and need to always perform analyses to a defined SOP.

10 Bioinformatics (3) Exception Log: The laboratory maintains an exception log for patient cases where steps used in the bioinformatics process or pipeline deviate from laboratory SOPs. Cases where pipeline and/or tools need to be modified to evaluate a particular region or potentially significant variant. Appropriate sign off by the lab director. Data Transfer/Confidentiality: There are procedures in place to ensure that internal and external storage and transfer of sequencing data provides reasonable confidentiality and security, and conforms to patient confidentiality requirements. HIPAA-compliant storage; for external/cloud storage, robust encryption and insure protection of patient data and genome sequences.

11 Integrated Infrastructure within Pathology to Support Genomic Testing Data Information Knowledge Understanding Wisdom Instrument signals Sequences Lab analytes AP s Content & knowledge bases -Cancer -Germline -ID The practice of Pathology -Integrated reporting. -Bedside -> Bench -> Bedside - Collaboration with other medical specialities. -Training programs

12 Complex Genetic Testing: Exome or Genome Sequencing Order order Accessionin g Pre-analytical (accession, DNA extraction) Workflow QC Library Prep QC monitoring QC Sequencer Run Clinical LIS QC Level 1 Bioinformatics (QC filter, assemble, align..) QC Vars Level 2 Bioinformatics (Variant Calling) KB EHR Or ClientIS Reporting Billing Or XML Or XML Level 3 Bioinformatics (Reporting) Level 4 Informatics (Integrated Reporting) CDR Level 5 Informatics (Data Warehousing)

13 Germline: Data re-evaluation Order: Genome re-analysis order Accessionin g Workflow Retrieve patient s prior data (or sample?) QC monitoring QC Level 1 Bioinformatics (QC filter, assemble, align..) EHR Or ClientIS Clinical LIS Reporting QC Vars Or XML Level 2 Bioinformatics (Variant Calling) Level 3 Bioinformatics (Reporting) KB Billing Or XML Level 4 Informatics (Integrated Reporting) CDR Level 5 Informatics (Data Warehousing)

14 Workflow: Cancer Genome Analysis Procedure(s) Blood/Fluid Collection order order order Case Accession Pathology Case Accession OR/frozen sect Lab Accession Clinical Labs (Heme) Gross Report Prepare blocks or other preps Analytes, cellular markers Flow cytometry Microscopic Analysis IHC, slide FISH Addn l Reference Testing MolDx, Cytogenetics Genome Analysis (<<5% cases) LIS: Report/Integrated Report -Report: LIS and/or APLIS -Asynchronous receipt of data from days (Gross/Micro, IHC) to week+ for molecular and other types of data. - Integrated reporting: Variably supported among Pathology Information Systems and EHRs.

15 Genetic Home Integrate complex genetic testing with additional Anatomic and/or Clinical laboratory analyses. Define when to proceed to complex genetic testing. Validate new variants identified by testing. Integrated reporting. Warehouse s of clinical testing to support future analyses on other patients. Bedside -> bench -> bedside BMT if IL-10RA, other known loci Continued medical management Severe IBD <6yrs Clinical Workup AP and/or CP testing If etiology believed Immune defect CLIA Immunological Assay if available Targeted genome seq for loci to decide to move to BMT If other variant, potentially pathogenic CLIA (vs research) assay to validate Warehouse s

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