Pathology Informatics Summit

Pathology Informatics Summit Pathology Information Systems in Genomic Medicine May 5 th, 2015 Lynn Bry, MD, PhD Director, Center for Metagenomics and Crimson Core Associate Professor, Harvard Medical School Center for Advanced Molecular Diagnostics Brigham & Women s Hospital lbry@partners.org

Overview 1. Operational and IT components to support complex genetic testing. - Germline, Cancer/Somatic, Infectious agents 2. CLIA-grade computational processes. 3. Inter-operability with healthcare systems. 4. Models for structuring supporting systems. 5. Means to actively participate in institutional and national efforts.

Incorporating Population-based approaches in the practice of Pathology Clinical Event Order Accessioning Testing Resulting Reporting/ Billing Integrated Reporting Patient Case Decision Support Tools Decision Support Content Development, Knowledge Bases Population/Epi Metrics Data Warehousing (Clinical, Translational, Research, QI Programs) Population-Based Analyses

Next Generation Sequencing in CLIA Labs Research -> Clinical Realms Wild-west -> civilization..

Guiding Principles: Insure patient care remains the underlying driver for decisions What testing to offer, components that may be in-house vs outsourced. Work with clinicians on decision trees for ordering complex genetic/genomic tests. Integrate resources and expertise from research/genomics labs. Design of systems and their integration. Don t re-invent the wheel. Leverage existing systems and infrastructure where possible. Leverage standards in data formats, storage, and messaging. Be active in institutional planning. Insure needs of CLIA laboratory testing are met, provide leadership. Systems integration, decision support. Data warehousing planning, structuring, use. Computational resources and data storage. Participate in national efforts. Variant reporting (ClinVar) Crowd-sourced content development and curation (CAP, ACMG, others..). HL-7 structures for reporting complex genomic results

What CLIA Labs Bring Experience bringing new technologies and methods into diagnostic use. Resources: LIS for handling patient orders and samples. Reporting into the EHR and/or to physician clients Billing for services provided Insure robust quality processes to provide clinically useful information in patient care. Clinical-grade reporting of findings to be used in the delivery of patient care.

Items new to CLIA labs: Lack of vendor tools for bioinformatics and clinical reporting of genomic data: 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. Considerations for computing resources and data storage. Costs for bioinformatics, computational + IT infrastructure and personnel >>> technical costs for CLIA-grade genome analyses

IT vs. 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) Pathologists Medical Geneticists (PhD) Medical Geneticists (MD) Other Medical Specialties Librarians/MLIS background. Develop expert teams to both devise clinical use cases for complex genetic testing and assist with content development and interpretation of test results.

LIS vs LIMS LIS Information system supporting a CLIA Lab (AP and/or CP). Often lacks functions needed to support complex genomic testing. Sample/library prep. Monitoring of sequencing. Bioinformatics pipelines Knowledge base development and curation. Resulting and interpretation of complex genomic data. Data warehousing/storage LIMS More commonly found in research cores. May/may not have needed functions to support diagnostic testing and reporting. Test ordering on patients Patient/client-based login QC programs Resulting and interpretation Systems Integration Instruments (variable) Reporting to EHR and/or clients Clinical billing Integrate, replace vs purchase new system(s)

IT and Computational Improvements Vendors are starting to provide CLIA-grade tools. Sequencing Vendors: initial processing/qc 3 rd -party vendor tools to assist in knowledge base management and clinical reporting National and international efforts to develop CLIA-grade knowledge bases HIPAA-compliant clouds and computational clusters CAP NGS Accreditation Program (www.cap.org) Released in July 2012 as a new section in the Molecular Pathology Checklist Analytical Wet-Bench Processes Bioinformatics Pipelines for NGS Updated Dec 2014 Wet/dry bench PT and in silico PT (under development). 2015-2016: Expanding CAP offerings in proficiency testing for genomic studies. HL-7 Genetic Test Report (GTR) standard released 2/2013. Specification for communication of complex genetic test results. As with any standard, needs to be adapted for local needs..

resources Genetic Test Report (GTR) Variants (VCF), cytogenetics Germline reports and improved methods for somatic testing. Infectious disease: Formats for viral genotyping. Deployment Guides Integrate HGVS and other nomenclature systems in reporting. Active group Two systems separated by a common standard Deployment will require local analysis and plans for implementation and ongoing support. http://www.hl7.org/special/committees/clingenomics/index.cfm

Data Warehousing Develop a plan for warehousing genomic data Frequently requires institutional commitment. Beyond the scope of what most Pathology Depts can manage alone. EHR-provided solutions What is stored (clinical report vs VCF vs raw sequence)? ETL processes, ongoing support and maintenance. Leverage in support of the testing lab, clinical interpretation and reporting. Research-focused tools: open source vs commercial i2b2 (http://i2b2.org/)/garlic module Open source tools will commonly cost $e^6-7 to implement Not designed for clinical use, but can be a starting point to store the information and make it available to research programs.

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

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 result result Reporting Billing Or XML Or XML Level 3 Bioinformatics (Reporting) Level 4 Informatics (Integrated Reporting) CDR result Level 5 Informatics (Data Warehousing)

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 result Level 5 Informatics (Data Warehousing)

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 result result Analytes, cellular markers result Flow cytometry result Microscopic Analysis IHC, slide FISH Addn l Reference Testing MolDx, Cytogenetics Genome Analysis result 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.

CAP NGS Accreditation Program: Bioinformatics components (1) Process/Pipeline Documentation: The laboratory documents the bioinformatics process or pipeline(s) used. 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 changes or upgrades are made. Includes any updates to the OS, database, application-layer components. Train bioinformatics staff that small tweaks can profoundly affect clinical results, 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 pipeline(s) used to support the analysis, interpretation and reporting of next generation sequencing based results. Have procedures in place for corrective measures if components fail laboratory standards.

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. 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.

Bioinformatics (3) Exception Log: The laboratory maintains an exception log for patient cases where steps used in the bioinformatics pipeline(s) 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: Lab procedures 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.

Models for Structuring Supporting Systems

Sandwiched integration Separate Systems

Hand-off from the Clinical -> Genomic LIS Clinical and Genomic LIS are integrated

Integration with External CLIA Labs External CLIA Laboratory

Institutional Considerations Define institutional ROI for developing local resources for clinical genomic testing. Integrate with broader institutional and research initiatives. Costs and resources for warehousing and computing resources are commonly outside of what a Pathology Dept can fund and support. Take an active role at your institution.

National Efforts ClinVar (NCBI): http://www.ncbi.nlm.nih.gov/clinvar/ HL-7 Clinical Genomics http://www.hl7.org/special/committees/clingenomics/ind ex.cfm CAP NGS Accreditation Program http://www.cap.org/ http://www.cap.org/apps/docs/laboratory_accreditation/c hecklists/new/molecular_pathology_checklist.pdf. CAP Molecular Oncology Programs http://www.cap.org/ Cancer Genome Panel

Acknowledgements BWH Pathology - Jonathan Nowak, MD, PhD - Bill Lane, MD, PhD - Nicole Pecora, MD, PhD - Neil Herring, MBA - Neal Lindeman, MD CAP NGS Accreditation Committee - Karl Voelkerding, MD - Qin Zhao, PhD - Many others -Clinical Genomics Committee - Mollie Ulman-Cullere (DFCI) - Many others Funding - R01-LM010100 - BWH Clinical Laboratories - BWH CAMD - BWH CCTM Partners LMM -Birgit Funke, PhD -Heidi Rehm, PhD -Sandy Aronson -Eugene Clarke Partners ERIS Team - Allan Harris - Joe Jackson - Aaron Zschau - Brent Richter Questions?