e MERGE CLINICAL ANNOTATION WORKGROUP: Status & Accomplishments

e MERGE CLINICAL ANNOTATION WORKGROUP: Status &Accomplishments Co-Chairs: Gail Jarvik (KPW/UW) & Heidi Rehm (Partners/Broad) The Clinical Annotation work group will focus on activities that build consistency of approaches to the gene and variant interpretation across the eMERGE sequencing centers and study sites as well as support contribution to public knowledge bases. • Apply the ClinGen approach to gene-disease validity assessment to all genes on the eMERGE gene panel (including SNP genes), defining each associated condition and the strength of evidence • Develop consistency in variant interpretation approaches • Develop consensus on the most common clinically reportable variants in the eMERGE panel and whether to recommend return to patients • Facilitate regular ClinVar submissions for all variants interpreted for the eMERGE program • Work with the ROR/ELSI WG to develop an environment for ongoing discussion and sharing of challenging genes, cases and variants considered for return (prospective or retrospective) • Work jointly with the ROR/ELSI WG to gather feedback and develop consensus on standard language used in clinical reports • Lead publication summarizing incidental findings across the network (paper to be submitted shortly) √ √ √ ongoing √ √ √

Actionable Incidental Findings in eMERGE-III(N=21,915; Gordon et al.) Positive: 3.02% (n=661) ACMG59: 2.54% (n=556) Non-ACMG: 0.48% (n=105) Negative: 96.98% (N=21,254) e MERGE CLINICAL ANNOTATION WORKGROUP

Actionable Incidental Findings by Gene * C282Y/C282Y only * * * * * * *Non-ACMG e MERGE CLINICAL ANNOTATION WORKGROUP

e MERGE CLINICAL ANNOTATION WORKGROUP: Future Efforts Co-Chairs: Gail Jarvik (KPW/UW) & Heidi Rehm (Partners/Broad) Table: Penetrance order Network year 5 milestone 1: Expand the understanding of penetrance and the impact a variant has on clinical outcomes, using a variety of approaches including cascade testing and family history analyses. (Clinical Annotation & Genomics Workgroup): Collaborate to evaluate penetrance of P/LP variants in gene-disease pairs in participants NOT ascertained for a relevant phenotype. Aligned chart review for penetrance with that for outcomes using the same forms. Underway. Variant classification of variants with a higher probability of being reclassified across the clinically significant threshold (VUS/LP/P) • VUS-Favor Path : with potential to become LP CSGs identified a set of ~200 VUS-FP variants, a more frequent (>3Xs) subset of which have been shared (22 from LMM)/will be shared (<79 from Baylor) with sites for additional relevant clinical information from EHR data. Potential incorporation of functional data from available follow-up assays: • In vitro LDLR assay using plasma • BRCA 1/2 assay • Arrhythmia high throughout assays (SCN5A, KCNQ1, KCNE1) • Variants NOT reported (VUS and below): with potential to identify new reportable variants. CSGs are leveraging ClinVar data to identify variants that may be upgraded to LP/P. Baylor has prelim data showing >100 “newly pathogenic” in ClinVar but most of classifications were still only VUS by Baylor standards. • REPORTED Variants: with potential to be reclassified as VUS or below • Variants seen again and reanalyzed by CSGs: Prompt alerts in respective CSG reporting systems, consultation with sites for next steps wrt updated reports. • Variants NOT seen again: Comparison to ClinVar to identify any variants that should be reclassified. In progress

BRCA1 missense variants in eMERGE-III participants Deep mutational scanning predictions e MERGE CLINICAL ANNOTATION WORKGROUP

Variant bake-off 2 • Collected 160 “random variants” from sites • Next, distribute ~35 variants to each of 9 projects • Each variant interpreted by submitting project + 2 others • Blinded assignment of ACMG lines of evidence and interpretation • Use laboratory variant interpretation pipeline and sign-out process • Resolve discordance

e MERGE CLINICAL ANNOTATION WORKGROUP: Challenges & discussion points • What challenges has the WG faced competing Year 5 milestones? • Timeline of getting the genetic data back over time and late in grant cycle. Waiting for 6 month after return for outcomes data. • Communication, when incorporating penetrance analysis collection into outcomes forms, getting forms filled. • What can the Network help provide feedback on? • Sites can provide and verify penetrance questions for their respective outcomes form, and also define “non-responders” and “non-consenters”. • Are there any significant delays that may cause work to not be competed? • Initial technical issues with the forms and missing abstraction guides led to a delay in the completion of forms for several sites. e MERGE CLINICAL ANNOTATION WORKGROUP

EHRI Report Out Sandy Aaronson (Harvard/Partners) & Casey Overby Taylor (Hopkins/Geisinger) eMERGE SC Meeting Seattle, WA June 21, 2019

Status and Accomplishments • Supporting work to translate eMERGE xml format to FHIR • Continuing to monitor status of site technical implementations • First stage of CDS Hazard Analysis begun (todays presentation)

Future • Support completion of eMERGE xml translation to FHIR • Paper Under Development • Genomic Information for Clinicians in the Electronic Health Record: Lessons Learned from ClinGen and eMERGE • Lead by Marc Williams • Concept sheet under review • Lessons from eMERGE on readiness for genomic clinical decision support implementation • Lead by Casey Overby-Taylor • Determine feasibility of proceeding to deeper levels of the hazard analysis

eMERGE GENOMICS WORKGROUP: Status & Accomplishments Co-Chairs: Megan Roy-Puckelwartz (NU), Patrick Sleiman (CHOP) & David Crosslin (KPW/UW) • Manuscript detailing the genotyping and imputation of ~84,000 eMERGE subjects has been published in Genetic Epidemiology. • Merging and QC for ~15,000 (mostly Hispanic) are complete, bringing the total to ~105,000 imputed samples (data available) • There are multiple structural variation (SV) efforts ongoing in eMERGE. • The CC imputed the ~100k sample array data against a 1000Genomes SV reference set that contains both indels and larger events. • Includes ABO blood type calls. • Validating events against PennCNV calls; promising concordance. • Manuscript underway • These common events were validated against other orthogonal approaches including PennCNV and circular binary segmentation using B-allele frequency and log R ratio. • The eMERGE I (~18k) has already generated this data using PennCNV, and the Genomics Workgroup is leading efforts to secure more metadata (B-allele and log R-ratio) from eMERGE II and III sites. Patrick Sleiman and CHOP (along with the Genomics Workgroup) leads these efforts. • eMERGESeq data from the first ~15k subjects has been frozen, and the eMERGE CC has generated an ensemble-called multisample for discovery analyses. The entire ~25k is now available from the sequencing centers and realignment and variant calling has been completed by the CC. QC underway

e MERGE GENOMICS WORKGROUP: Future Efforts and Challenges Co-Chairs: Megan Roy-Puckelwartz (NU), Patrick Sleiman (CHOP) & David Crosslin (KPW/UW) Future efforts • The Genomics Workgroup has established a focus groups to help design the user interface and experience with the Electronic MEdical Records and GENomics Toolkit (eMERGENT), which will be built off the ideas surrounding the current SPHINX design. • The focus groups also include collaboration with the EHR Integration and Clinical Annotation Workgroups to provide FHIR CDS Hooks via the eMERGENT resource. • There will also be privacy security safeguards. • Three focus groups have taken place, with several more planned this summer • The Genomics Workgroup will assist CHOP and Vanderbilt with implementation of alternative methods of assessing penetrance and risk scores using Network-wide data. This will involve a collaboration with the Phenotyping Workgroup. • As always, the Genomics Workgroup will continue to emphasize manuscript submission and provide any and all necessary support for publication across the Network. • The Genomics eIII lessons learned manuscripts is in development Challenges • Collection of data from individual sites for CNV analysis • Defining clear discovery-based hypothesis • Analyzing all the data – not just the newest (we are looking at you PGRNSeq)

eMERGE OUTCOMES WORKGROUP: Status & Accomplishments Co-Chairs: Josh Peterson (VUMC), Marc Williams (Geisinger), & HakonHakonarson (CHOP) • Over 500 outcomes forms have been completed! • Abstraction Guides have been completed for all the top phenotypes. • Outcomes and Clinical Annotation workgroup collaboration on Penetrance Analysis • Data collection on subgroups of participants without returned results.

eMERGE OUTCOMES WORKGROUP: Future Efforts & Challenges Co-Chairs: Josh Peterson (VUMC), Marc Williams (Geisinger), & HakonHakonarson (CHOP) • 6-month data collation and release for analysis • Data Freeze 1: > 50% completion; October 2019 • Data Freeze 2: > 90% completion; January 2020 • 12-month data collation and release for analysis by January 2020 • Determine incremental data with a subset of 6-month data • Criteria for ‘date of return’ • Site variability but should reflect date of return in EHR

e MERGE Phenotyping WORKGROUP: Year 5 Milestone & Progress updates Co-Chairs: Wei-Qi Wei (Vanderbilt) & Chunhua Weng (Columbia) Phenotype Development & Implementation eMERGE III phenotypes (as of June 2019): • Algorithm completed: 100% • Validation completed: 92% • Implementing across network: 88% • Everything Completed: 80% Natural Language Processing (NLP) Progress to Date: • Long QT- Arrthymias, Lupus Algorithms, and ACO have been developed Future Efforts: • Developing and implementing the selected five NLP phenotypes • Developing NLP-based e3 lessons learned manuscripts Year 5 NLP Phenotypes: • Lupus (NU/VUMC)-needed to power lupus subtype analyses • Chronic Rhinosinusitis (GHS/NU)-needed to improve algorithm PPV • Familial Hypercholesterolemia(Mayo/Geisinger)-needed to improve algorithm PPV • ACO-Asthma COPD(Harvard/KPW-UW)-needed to capture phenotype variants not reflected in quantitative measures • Long QT/Arrhythmias(VUMC/Mayo)-capture additional information for phenotyping and analyses eMERGE Datasets: • eRecord Counter refresh • eMERGEseq V2 dbGaP submission Publications: • Hripcsak et all. “Facilitating phenotype transfer using a common data model.” Revised. J Biomed Inform. • Shang et al. “Making work visible for electronic phenotype implementation: lessons learned from the eMERGE network.” Submitted. J Biomed Inform. • Zhao et al. “Detecting Time-Evolving Phenotypic Topics via Tensor Factorization on Electronic Health Records: Cardiovascular Disease Case Study.” Revised. J Biomed Inform. • Namjou et al. “GWAS and enrichment analyses of non-alcoholic fatty liver disease identify new trait-associated genes and pathways across eMERGE Network”. Published. BMC Medicine • Almoguera et al. “ Drug-resistant epilepsy classified by a phenotyping algorithm associates with NTRK2.” Published. Acta Neurol Scand.

e MERGE Phenotyping WORKGROUP: Challenges & discussion points Co-Chairs: Wei-Qi Wei (Vanderbilt) & Chunhua Weng (Columbia) • Facts: • Small sample sizes in algorithm development has compromised the validation of phenotypes. • Low PPV results on select phenotypes have delayed implementation on select sites. • Inadequate notes from specialty has delayed validation of algorithm development. • Lessons Learned: • Implementation of electronic phenotypes requires significant local customization from three key perspectives: i.e., knowledge conversion, clause interpretation, and programming. • The implementation of OMOP CDM enables reuse, improves efficiency and reduces human efforts for phenotyping. • The concordance between the OMOP query and the original eMERGE query varied from perfect to mediocre due to various reasons including errors in the original query, errors in the OMOP query, changes in data, and heterogeneity in the databases. • Areas for feedback: • Potential areas for development of lessons learned manuscripts with other Workgroups. • Needs of shared standards, annotated corpora, and best practices for increasing NLP-based phenotype portability.

e MERGE PGx WORKGROUP: Year 5 Milestone & Progress updates Co-Chairs: Cindy Prows, Laura Rasmussen-Torvik • Year 5 milestone progress • Initiated collaborations with CPIC • Call 1/10/19 with CPIC leadership; • eMERGEPGx prominently featured (particularly in area of PGx implementation) at June 2019 CPIC conference featuring Geisinger’s and Vanderbilt’s experience. • Identify network projects for SPHINX • Adam Gordon and Bob Freimuth received leadership approval for NT 335, Evaluating the ‘Star Allele’ PGx nomenclature standard in the context of automated interpretation of panel, exome and genome sequencing results. 1st meeting with coauthors 5/29/19 • Determine if PGx outcomes are feasible (ongoing) • Overall progress • eIII PGx results returned at VU and CHOP; integrated with CDS at VU • Collected site experiences with EPIC and PGx integration (not limited to e3 PGx reports); Laura and Sara to be on call with EPIC Friday. • Publication update • NT179, Pharmacogenetic variation identified via targeted next-generation sequencing among 9000 eMERGE subjects, Adam Gordon lead, under revision, resubmit to Pharmacogenetics and Genomics Summer 2019 • NT260, Association of CYP2D6 genotypes in eMERGE PGx Cohort with EHR-derived phenotypes, John Black lead – extensive work as PGRNseq different capture with less coverage of CYP2D6 than capture for Mayo samples which is requiring extensive adaptations to software Mayo uses to call genotypes. Once software development completed will test with subset of PGRNseq samples and decide whether or not to proceed with project. • NT273, parts 1 (Georgia Weisner lead) and 2 (Kathy Leppig lead)– Planned and actual return of PGx captured. Sites will be able to contribute lessons learned regarding PGx ROR • NT284: Validation of PharmCAT annotations, Anurag Verma lead - analysis complete and working on draft manuscript.

e MERGE PGx WORKGROUP: Year 5 Milestone & Progress updates Co-Chairs: Cindy Prows, Laura Rasmussen-Torvik • Challenges with Year 5 Milestones • Parsing PGx results from reports and activating CDS in EPIC • Planning joint workgroup call with EHRI group before Oct SC meeting to strategize best way to influence EPIC to accommodate genomic data in a useful manner • Tracking PGx Outcomes across network • Only two sites returning results to date and only 1 of these tied to CDS • Outcomes forms focused on disease risk per network wide prioritization • Requested network feedback • Is meeting with EPIC leadership or publishing challenges and lessons learned specific to PGx more likely to influence change?

e MERGE RoR WORKGROUP: Year 5 Milestone & Progress updates Co-Chairs: Ingrid Holm, Iftikhar Kullo • Updates on Year 5 milestone progress RoR completed at 4 sites, anticipate completion in other sites within next few months Explore the challenges involved in identifying at-risk family members: Mayo CASH Study, MeTree Estimate the institutional impact of RoR: Various aspects of RoR being studied Disseminate lessons learned • Updates on overall workgroup progress RoR for both +ve and –ve results completed in majority of participants • Updates on lessons learned MCS & publications MCS: Returning genomic results to eMERGE participants, Operationalizing participant choices about genomic results, Patient summary letters, ROR for 25,000 eMERGE3 participants, Challenges in RoR in the eMERGE consortium, RoR in pediatrics, RoR of negative test results, Interactions with Sequencing Labs related to RoR

e MERGE RoR WORKGROUP: Challenges & discussion points Co-Chairs: Ingrid Holm, Iftikhar Kullo • What challenges has the WG faced competing Year 5 milestones Non responders, Decliners, deceased participants, transition to adulthood Lab: Gender mismatch, mosaicism, genotype-phenotype mismatch, variant reclassification, • What can the Network help provide feedback on Non-responder definition, total #, plan for RoR, assessing outcomes and penetrance in non-responders, Lessons learned Increase number for penetrance estimates: Non Responders + Decliners + VUS favoring P Factors associated with non responder status, Geocodes to be included • Are there any significant delays that may cause work to not be competed Need Labs to complete reclassification, VUS fav LP Need to decide on EHR review of VUS fav LP Need to decide prioritization of Factors associated with Non Responder status

Cases from the Outcomes Workgroup Maureen Smith Alanna Rahm Cindy Prows

Northwestern Participant • 59 year old male • No indication for genetic testing • Contacted the study himself to participate • Wife also participated • Heard about the study through word of mouth • PCP and ENT at Northwestern Medicine • Study results: 2 CFTR heterozygous gene mutations, F508del (pathogenic)/R117H/7T (likely pathogenic) • Results were returned by a genetic counselor over the phone • Participant reported the following personal medical history: • Congenital absence of the vas deferens (CAVD) • Chronic sinusitis that frequently tests positive for pseudomonas aeruginosa, history of two prior sinus surgeries • Digestive issues, including a dairy allergy that aggravates his sinuses, foul smelling stools, increased flatulence, and a lean BMI despite a large appetite • Reportedly very susceptible to illness

Northwestern Participant: Post Results • Participant contacted PCP and ENT regarding results; reported he was happy to get explanation of infertility and expressed anxiety regarding future pancreatic and infectious implications. • Changed urologist to see physician at Northwestern Medicine (all NM physicians) • Genetic Counselor referred participant to Adult CF clinic (located at children’s hospital), full workup including the following findings: • Sweat chloride; Left arm: 38 mmol/L, Right arm: 36 mmol/L (30-59 intermediate range) • Lung imaging; revealed mild air trapping, predominantly in the lower lobes without bronchiectasis and several groundglass nodules that could be infectious and/or inflammatory. Recommended follow-up noncontrast CT chest in 3-6 months. • Chest x-ray; no acute cardiopulmonary process, some mild bronchial wall thickening seen in the lower lobes bilaterally which suggests reactive airway disease • Chest CT; revealed secondary findings in thyroid (calcifications) and kidney (hypodense lesion). Recommended ultrasound for each and both found to be benign. Repeat thyroid US in one year. • Vitamin-D levels low (pulmonology)- 13 (ref range 30-100); after intervention levels were retested and normal. . • IgE levels elevated: 425 kU/L (ref range: <115) • Therapies initiated: • Ergocalciferol (Vitamin D2) for treatment of Vitamin D deficiency which can be related to pancreatic insufficiency; • Kalydeco, a proton-pump inhibitor specific to his R117H/7T variant; Treatment with Kalydeco impacted dermatology and urology care requiring him to switch from ketoconazole shampoo to ciclopirox shampoo and discontinue Cialis respectively. • Albuterol and tobramycin via a nebulizer. • Overwhelmed by new medications and chose to discontinue his Clomid. CF clinic records kept at Children’s hospital-we do not have direct access; all f/u second hand from PCP/ENT office visit notes, phone calls and other communications

Geisinger Participant • 61 year old Female • MyCode participant. Consented August 8, 2014 in Internal Med. • Multiple comorbidities: DM type 2 with diabetic peripheral neuropathy, stage 3 chronic kidney disease ,proliferative diabetic retinopathy with macular edema, bilateral, hypothyroid, former smoker, angina pectoris, hypertensive heart disease, peripheral artery disease, obesity, anemia. • June 2009 right breast lumpectomy due to grade 3 invasive ductal carcinoma with chemo and radiation therapy. • Amputation of right foot June 5, 2017 with complications including an ischemic stroke. • Result: LDLR. ROR on August 30, 2017 while patient was in care facility recovering from amputation. • ROR Call: Patient stated she was in nursing home for rehabilitation following amputation surgery of right foot, stated she had stroke after surgery and is wondering if can be related to result. Scheduled appointment to see GC and requested result info packet sent to rehab facility where recovering • ROR appointment: no-show, patient called to say was in ambulance will call back when home. Patient eventually rescheduled and discussed result with GC

Geisinger Participant – post result • Further amputation complications led to another stroke 1 month post ROR. • Amputation of left foot 4 months post ROR. Additional CAD diagnosis post ROR. • Unable to tolerate statins • Specialist followups including stress test – modified due to double amputation • After 1 year now has breast cancer diagnosis, further amputations of leg. • Concerned for son having similar experiences who “doesn’t take care of himself” – heart attack at 39. she is concerned he has the condition but so far no notes in chart on cascade testing • Patient now residing in nursing home outside of system – no additional records available for review, other than ED visits and some CareEverywhere encounters visible in EPIC.

CCHMC Adolescent Cohort: CACNA1A • Enrolled without clinical indication • Adolescent and parent independently and jointly chose to learn all possible results • Family history screen at study visit • Father & sister with migraine, temporary muscle weakness / paralysis • Adolescent’s Result: Het c.6321+1G>A, Intron 44, LP • Risk – episodic ataxia type 2 • Telephone disclosure to mother and adolescent; summary letter with report to family & primary care provider; discrete results entered into EPIC (viewable in MyChart); CCHMC specialists sent staff message alerting them to result placed in EPIC.

CCHMC Adolescent Cohort: CACNA1A • 1 month later, evaluated in genetics clinic • Adolescent ROS negative, Medical history negative, cleared for wrestling • Targeted variant testing: Mother, father and younger twin siblings • Mother periodic numbness, falling, word choice issues. Previous neurology evaluations negative • Father: hemiplegic migraines with strenuous exercise when younger • Siblings with migraines (possibly hemiplegic) after strenuous exercise • Sister followed by pediatric neurologist • “I could have avoided spending thousands of dollars on MRIs and EEGs if I had known gene result.” • Requesting neurologist that specializes in CACNA1A related ataxia

e MERGE CLINICAL ANNOTATION WORKGROUP: Status & Accomplishments