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ClinGen ActionabilityWorking Group TrainingUpdated 03.21.2018, JEH

Table of ContentsTraining Steps for New Scorers ClinGen Overview Actionability Working Group (AWG) Overview General AWG Methods Generation of a Summary Report Scoring a Topic Scoring Process Dissemination of AWG Reports and Scores Using the AWG Interface How to Access Confluence Additional Resources Slide34710152122303141502

Training Steps for New AWG Scorers Review the following materials: ClinGen Project Summary Report Protocol AWG Scoring Protocol Manuscript on AWG methods development and scoringof the ACMG56 Review these training slides Orientation call with Kristy Lee Listen in on a couple of AWG calls and practicescoring without entering scores into interface3

ClinGen: Clinical Genome Resource Launched in 2013 Co-funded by NHGRI, NICHD, and NCI Collaboration with NCBI’s ClinVar 250 researchers and clinicians from 75institutionsPurpose: To build an authoritative central resourcethat defines the clinical relevance of genes andvariants for use in precision medicine and research.4

ClinGen OverviewKey Goals Share genomic and phenotypic data provided byclinicians, researchers, and patients throughcentralized databases for clinical and research use Standardize clinical annotation and interpretationof genomic variants Implement evidence-based expert consensus forcurating genes and variants Improve understanding of variation in diversepopulations to realize interpretation of genetictesting on a global scale Develop machine-learning algorithms to improvethe throughput of variant interpretation Assess the “medical actionability” of genes andvariants Structure and provide access to genomicknowledge for use in EHR ecosystems Disseminate the collective knowledge andresources for unrestricted use in the communityClinGen Website: https://www.clinicalgenome.org/5

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AWG: Actionability Working GroupThe overarching goal of the AWG is to identify those human genes that,when significantly altered, confer a high risk of serious disease that could beprevented or mitigated if the risk were known.Goals:1. Develop rigorous and standardized procedures for categoricallydefining “clinical actionability”; a concept that includes a knownability to intervene and thereby avert a poor outcome due to apreviously unsuspected high risk of disease2. Nominate genes and diseases to score for “clinical actionability”3. Produce evidence-based reports and semi-quantitative metricscores using a standardized method for nominated gene diseasepairs4. Make these reports and actionability scores publicly available toaid broad efforts for prioritizing those human genes with thegreatest relevance for clinical intervention.7

Clinical Context There are many points during a person’s life whengenomic information may be acted upon For the purposes of the AWG, the clinical context hasbeen defined as: An adult with an incidental or secondary finding identified viagenome-scale sequencing This person has not been previously diagnosed with thegenetic disorder However, this person may have signs or symptoms of thegenetic condition (e.g., the person may have high cholesteroland may be undergoing treatment for it, but does not knowthat they have familial hypercholesterolemia)8

Clinical Actionability There are many actions a person cantake afterreceiving genetic risk information For the purposes of the AWG, “clinical actionability” hasbeen defined as: Well-established, clinically prescribed interventions Interventions that are specific to the genetic disorder underconsideration (we do not consider general lifestyle and behavioralchanges that are recommended to the general population, with theexception of special cases, such as smoking cessation in a1antitrypsin deficiency) Lead to disease prevention or delayed onset, lowered clinicalburden, or improved clinical outcomes Though important, we do not current consider factors suchas personal utility, reproductive decision-making, andending the diagnostic odyssey9

Overview of the AWG WorkflowStep 1AWG selectsgenephenotype pairfor evaluationStep 2KSTassessesrapidrule-outcriteriaAWG decides ifan exceptionwill be madeYesStep 3KST preparessummaryreportNoSTOPStep 4AWG reviewspreliminary reportto determinewhether to provideother sources andselects outcomeintervention pairsfor scoringYesStep 6AWG: Actionability Working GroupKST: Knowledge Synthesis Team, asubset of AWG that curatesactionability evidence in summaryreportsAWG applies semiquantitative metricto generate scoresfor outcomeintervention pairsusing information inthe reportStep 5KST abstracts datafromsupplementalsources andincorporates intothe report10

Step 1:Selecting Gene-Disorder Pairs The pairings can include a single gene (e.g., APC and familialadenomatous polyposis) or bundles of genes that areassociated with the same disorder (e.g., MLH1, MSH2,MSH6, and PMS2 and Lynch syndrome) The AWG started with the list of genes recommended by theAmerican College of Medical Genetics and Genomics(ACMG) for return as secondary findings (e.g., ACMG56 andACMG 2.0 SF) Additional gene-disorder pairs assessed by the AWG havebeen nominated by AWG members and non-AWGstakeholders11

Step 2:KST Performs a Rapid Rule-Out AssessmentThe purpose of the rapid rule-out step is to quicklyrule-out from further consideration any genedisorder pair that does not meet 3 criteria:1. Actionability: Is the result actionable in an undiagnosedadult?2. Penetrance: Is there a pathogenic variant with at leastmoderate penetrance ( 40%)? [Penetrance is allowed tobe “unknown.”]3. Burden of disease: Is this an important health problem?12

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Step 2:KST Performs a Rapid Rule-Out Assessment If the gene-disorder pair passes the rule-out criteria, itmoves automatically to generation of a summary report If the gene-disorder pair does not pass the rule-outcriteria, the AWG may decide that an exception shouldbe made to proceed to generation of a summary report An example may be if the penetrance is known to be low andis below the penetrance threshold, yet there are compellingreasons to consider it for scoring (e.g., Brugada syndrome didnot meet the penetrance threshold, but the outcome wasconsidered severe enough that an exception was made) If an exception is not made, the gene-disorder pair is notconsidered further at that time, but may be reassessedat a later time when additional evidence comesavailable14

Step 3:KST Generates the Summary ReportThe purpose of the summary report is to document andsummarize the available evidence related to key featuresof actionability KST evidence sources: The KST uses a detailed protocol to systematically identifyrelevant literature to make the process standardized andreproducible across curators The protocol to identify evidence is limited in scope to makethe process feasible: Evidence included: Clinical practice guidelines, systematicreviews, meta-analyses, OMIM, GeneReviews, OrphaNet,and Clinical Utility Gene Cards Evidence not included: Narrative reviews and primaryliterature15

Step 3:KST Generates the Summary ReportAll evidence identified by the KST for a gene-disorder pair istiered base on quality:Tier 1: Evidence from a systematic review, meta-analysis, orpractice guideline based on a systematic reviewTier 2: Evidence from a practice guideline or expert consensuswith some level of evidence reviewTier 3: Evidence from a non-systematic evidence review (e.g.,GeneReview or OMIM entry) with primary literature citedTier 4: Evidence from a non-systematic review of evidence(e.g., GeneReview or OMIM entry) with no citations toprimary data sourcesTier 5: Evidence from a non-systematically identified source(see slides 18 and 19)16

Step 3:KST Generates the Summary ReportThe KST abstracts data from the highest tiered sourcesavailable for 5 domains associated with clinicalactionability:1. Nature of the genetic disorder: Prevalence, clinicalfeatures, natural history2. Actionability: Patient management, surveillance,family management, and circumstances to avoid3. Likelihood: Prevalence of the associated geneticvariants, penetrance/relative risk, variable expressivity4. Nature of the intervention: risk and burden5. Chance to escape clinical detection prior to harm inthe clinical setting17

Step 3:KST Generates the Summary ReportTo ensure that the summary report contains all relevantinformation required to assign a score based on the SQM,additional sources may be identified by the KST tosupplement the report using a non-systematic method: These sources may include such sources as primaryliterature, references cited in MedGen, and websites ofrelevant major health organizations such as the CDC,American Cancer Society, or other trusted website Any information from these supplementary sourcesincluded in the summary report will be assigned a Tier 5(i.e., evidence not identified by the systematic evidencesearch)18

Step 4:AWG Reviews the Summary ReportOnce the KST generates a preliminary report, it is postedon Confluence for AWG review and comment with thegoals of: Assessment for accuracy Nomination of additional references References nominated by AWG members to incorporate intothe report are designated as Tier 5 Suggest specific outcomes and associated interventionsto be scored for actionability All topics are scored for specific outcome-intervention pairs,rather than the condition as a whole (e.g., colorectal cancerand colonoscopy for Lynch syndrome) See slides 39-47 on how to access Confluence19

Step 5:The KST Revises the Summary ReportAfter the AWG review, the KST revises the report to: Incorporate any suggested edits or nominatedreferences from the AWG Ensure there is sufficient evidence for theeffectiveness of interventions selected for scoring,if available20

Step 6:The AWG Applies the SQM to Generate Scores(Scoring is done in the AWG interface, see slides 28-38 on how to access the scoring interface)SEVERITYWhat is the nature of threat to health to individual carrying a clearly deleterious allele in this gene?3 Sudden death (e.g., Long QT syndrome)2 Death or major morbidity (e.g., Lynch syndrome)1 Modest morbidity0 Minimal or no morbidityLIKELIHOODWhat is the chance a serious outcome will materialize given a deleterious variant?3 40% chanceA Substantial evidence (Tier 1)2 5-39% chanceB Moderate evidence (Tier 2)1 1-4% chanceC Minimal evidence (Tier 3 or 4)0 1% chanceD Poor evidence, or missingE Expert contributions (Tier 5)EFFECTIVENESS How effective is intervention for preventing or significantly diminishing the risk of harm?3 Highly effectiveA Substantial evidence (Tier 1)2 Moderately effectiveB Moderate evidence (Tier 2)1 Minimally effectiveC Minimal evidence (Tier 3 or 4)0 Controversial or unknownD Poor evidence, or missingeffectivenessE Expert contributions (Tier 5)IN Ineffective*NATURE OFHow risky, medically burdensome or intensive is the intervention?INTERVENTION 3 Low risk, medically acceptable, and low intensity2 Moderate risk, moderately acceptable or intensive1 Greater risk, less acceptable and substantial0 High risk, poorly acceptable, or intensive21* If a score of IN is given, no scores are given for the other categories.

Scoring ProcessScorers are allowed to changetheir score after discussion withthe rest of the AWG scorersEach scorerprovides apreliminaryscoreScorediscussion onAWG callEach scorerprovides afinal scoreConsensusScoreThe consensus score isthe majority, but theindividual final scoresdon’t have to agree22