100,000 genomes RD Validation and Reporting Working Groups - Overview - Dom McMullan Chair Association for Clinical Genomic Science

Transcription

1 100,000 genomes RD Validation and Reporting Working Groups - Overview - Dom McMullan Chair Association for Clinical Genomic Science

2 What? More Working Groups? Post January 20 th meeting Volunteers for specific tasks/areas of work Teleconference to discuss process and progress Terms of reference and remit established NHSE commitment to support Administrative Minutes Teleconferencing.

3 Terms of Reference Name of group: GMC Designated Genetics Lab/Service RD Working Group (RGL-VRG) Title: 100,000 genomes RD Validation and Reporting Establishment of group: Following National RD V&R Workshop, January 2017 on request of NHSE Genomics Implementation Unit Membership: Co-opted Clinical Scientists and Clinical Geneticists from GMCs: flexible not fixed ACGS subcommittee members (Scientific/Technical and Quality) NHS Clinical Bioinformatics group rep Chair: Dom McMullan (ACGS Chair) / Deputy or Rotational Chair TBC Communication: Monthly teleconferencing initially; WebEx to follow NHSE to facilitate ACGS to facilitate potential physical meetings; slot reserved for Summer Meeting 26 th June Output: Produce briefing document capturing existing, planned future working practices developed by designated genetics laboratories Purpose: To develop emerging consensus practice guidance for centrally delivered WGS Validation and Reporting (100,000 genomes and beyond)

4 Purpose: To develop emerging consensus practice guidance for Validation and Reporting for centrally delivered WGS (100,000 genomes and beyond) 100K DDD + Research Established Service UK Clinical Genomic BPG

5 Purpose: To develop emerging consensus practice guidance for Validation and Reporting for centrally delivered WGS (100,000 genomes and beyond) 10 KEY ELEMENTS

6 1. Data Management Data-management pathways for genomic data reported to GMCs Reporting portal CIP interactions API interoperability.

7 2. GMC (lab) role Who does what and when? Receiving results Triggering Technical validation MDT meeting Interacting with CIPs Clinical reporting Distinct roles or shared?

8 3. Variant Triaging Triaging Genomic Variants into: 1. Immediate technical validation 2. MDT clinical validation and decision making prior to technical validation 3. Feedback to Validation & Feedback / Disease GeCIP (e.g Tier 3 RD variants)

9 4. Clinical Engagement Establishment of robust Clinician engagement Flexible to incorporate varying local practice Clinical Genetics Sub-specialities engaged in genetics (e.g neurology, cardiology, metabolics) Mainstream referrals

10 5. MDT working guidelines Core MDT Guidelines Agendas and time-allocations Who is present? What is presented, recorded and how? Compliance with Information Governance Drawing on existing practice

11 PAGE Clinical Review Panel (CRP) UK-wide virtual MDT 1x Clinical Scientist, 1x Clinical Geneticist per Centre Also: WTSI Scientists, Fetal Medicine, Midwifes, Pathologists Very few variants to review at CRP 30% of cases of 1 or more variants Agenda produced >2 weeks before review ~10 minutes per variant / case WebeX/Telecon mediated Sapientia (Congenica) used as Clinical Decision Support tool: Assessing + classifying variants Recording actions + evidence Producing clinical research report for downstream validations

12 is this gene associated with the disease? clinical validity is this variant causative? classification is this information actionable? ACMG SNV (+CNV) Guideline Adoption clinical utility

13 6. GMC Lab Responsibility Defining the limits of GMC RGL responsibility

14 7. Tech validation: current / future How long will validation be needed? Correct result / patient Evidence bases Validation Primer databases Best technologies for complex variants: CNV / SV / Mosaicism Centres as champions of expertise

15 8. Tech validation costing Costing Models UK variance Determining a generic model / price National tendering? Inclusion of analytical validation and MDT working in costing? Inclusion of Empty Test Result reporting

16 9. Turnaround Times (TATs) Defining realistic TATs for specific points in validation pathway When does the clock start/stop? How many points? review and revise all TATs Realistic and clinical priority motivated

17 10. Reporting Standardisation Genomic Report

18 NGS in the Clinic ESHG Workshop UK perspective - Dom McMullan Consultant Clinical Scientist Chair Association for Clinical Genomic Science

19 Is a detailed phenotype available to the Variable laboratory specialist? Locally delivered service largely via paper referral Some developed specifically for specific panels to ask specific questions National projects (100,000 Genomes /DDD) requiring mandatory e-submission of detailed phenotyping Key to Future UK Genomic Lab model Variant prioritisation MDT working Cohort and longitudinal analyses

20 Is a clinical geneticist or other clinician involved BEFORE the report goes out? Variable Not traditionally for single gene / small NGS panels / microarray Development of Genomic MDT In-house larger panels / WES Is the phenotype consistent with this gene? DDD/100,000 genomes experiences Increased Clinician / Clinical Scientist Working Clinical Reports largely signed by Clinical Scientists HCPC registered Accredited (UKAS)

21 Is a clinical geneticist or other clinician involved BEFORE the report goes out? Variable Not traditionally for single gene / small NGS panels / microarray Development of Genomic MDT In-house larger panels / WES Is the phenotype consistent with this gene? DDD/100,000 genomes experiences Increased Clinician / Clinical Scientist Working Clinical Reports largely signed by Clinical Scientists HCPC registered Accredited (UKAS)

22 How often do laboratory specialists and Clinical Geneticists discuss patients? Frequent Growth of the Genomic MDT Some by Specialism Clinical Scientist / Geneticist /specialism input Neurology, Cardiology, Fetal Medicine,.. Standardisation via 100,000 genomes project Development of virtual MDTs for UK wide working Prenatal Assessment Exomes and Genomes (PAGE) project

23 Are all patients discussed in these meetings? NO If not, what percentage? Definite pathogenic findings reported directly Heterogeneous conditions require more discourse Is the observed phenotype consistent with those reported for this gene? E.g. from DDD review?50% of the reported findings go to MDT review (>1400 gene panel ID /DD / MCA)

24 Legacy of 100K UK is clearly ahead of the curve in vision for a future Clinical Genomic service 100K has galvanised increased dialogue between GMC labs Increased Clinician / Scientist working Future (modular/platform agnostic) Clinical Genomic BPGs SNV CNV Reporting (UK NOT LOCAL PRACTICE?) Increased ACMG collaborations

25 Clinical Genome Resource Structural Variation Interpretation Working Group Working with ACMG to revise CNV guidelines (Platform agnostic) Co-ordinator: Erin Rooney-Riggs

26 ACMG CNV scoring framework Currently DELETIONS only Significantly revised since November 2015 Currently being road-tested by ClinGen lab consortia Opportunity for ACGS labs to get involved Duplications to follow More uncertainty Less rules, simpler framework Finished Guidelines expected Mid-2017

27 Draft ACMG Score Ranges (Nov2016) Classification Score Benign -9 and less Likely benign -5 to -8 Variant of Uncertain Significance (VUS) -4 to +4 Likely Pathogenic +5 to +8 Pathogenic +9 and more

28 Section 1: Evaluation of Deletion Overlap with Known Genomic Regions Known bencnv region complete o/lap: STOP Known bencnv o/lap but with additional noncoding sequence bencnv o/lap but with additional protein coding Known pathcnv region partial o/lap; unclear if results in LOF or includes HI gene Known pathcnv region complete o/lap: STOP and CNV is NOT adjacent to a known HI gene: STOP and CNV is adjacent to known HI gene i/frame del = 4 o/frame del = 5 Known pathcnv region partial o/lap; still result in LOF or includes HI gene or critical region: STOP KEEP GOING!!

29 Cancer Validation and Reporting Working Group - Overview - Chris Wragg Co-Chair ACGS Science and Technology Subcommittee

30 8 KEY ELEMENTS 1. Data Management - Jan Taylor, JooWook Ahn 2. Communication/Stakeholder Engagement - Jane Moorhead, Shirley Henderson 3. Variant triaging and technical validation - Graham Taylor, Mary Alikian, Chris Wragg 4. Validation; current and future needs - Hing Shirley Henderson, Sandra 5. Cancer pertinent germline findings - Clare Turnbull, Jo Mason 6. MDT/Tumour Board/Molecular Disease Meeting - Salvador Diaz- Cano, Ellen Copson, Yvonne Wallis, Victoria Hewitt, Catherine Carpenter-Clawson 7. Integrated reporting/report standardisation - Emily Shaw, Angela Hamblin, Helen Dickinson, Sara Dyer 8. Turnaround Times - Shirley Henderson, Sandra Hing, Sandi Deans

31 8 KEY ELEMENTS 1. Data Management 2. Communication/Stakeholder 3. Variant triaging and technical validation 4. Validation; current and future needs 5. Pertinent germline findings 6. MDT/Tumour Board/Molecular Disease Meeting 7. Integrated reporting/report standardisation 8. Turnaround Times

32 3a) Variant Triaging Triaging of variants into: When to validate: Clinically actionable finding Not already confirmed by other methods Includes a clinically relevant negative result When not to validate: Not clinically actionable Patient not eligible for indicated intervention When the finding will be validated through a clinical trial MDT clinical validation and decision making prior to technical validation

33 5. Cancer Pertinent Germline Findings Proposal for increase in return of germline findings Decision on validation of WGS finding in the context of current patient information Drawing on existing practice - National/International Flexible guidance to recognise differing geographies Who should be present? What is presented, recorded and how? Compliance with Information Governance (e.g multi-trust patient reviews) Relationships with disease MDTs/Mainstreaming GeCIP escalation How is it funded?

34 6. MDT guidelines Tumour Board/Molecular Disease Meeting Decision on validation and reporting of WGS finding in the context of current patient information Drawing on existing good practice - National/International Flexible guidance to recognise differing geographies Who should be present? What is presented, recorded and how? Compliance with Information Governance (e.g multi-trust patient reviews) Relationships with disease MDTs/Mainstreaming GeCIP escalation How is it funded?

35 7. Reporting Integrated Standardised Empty/negative/nothing clinically actionable report Reporting actionable findings One size fits all? Modified per specialism? Understood by Clinician and Patient

36 Next steps Summary guidance document Established working groups Establish overlap with Rare Disease V&R Group Identify and review existing good practice First draft of guidance for next V&F meeting (26 th July) IDEAS / INPUT/VOLUNTEERS WELCOME: MUST BE COMMUNITY DRIVEN