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Fall 2018 Work Weekend Report

November 16-18, 2018

11th

floor Gilgan Learning Tower SickKids

Paul Devlin, the current Kirklin/Ashburn Fellow, gave a progress report as follows .

Accepted manuscripts AVSD Baseline Echo JTCVS Critical Left Heart Obstruction Baseline Echo European J CV Imaging Intervention for Arch Obstruction post Norwood JTCVS Under revision Myocardial Ischemia in AAOCA In Development CHSS Critical AS Calculator presented AHA TGA Late Survival & FH to be presented STS PAB for AVSD – Early Outcomes submitted to AATS Surgical Repair of AAOCA submitted to AATS In addition to the above, Paul is completing his course work at University of Toronto statistical analysis & computer programming, cardiac-focused courses in CV science (molecular biology & heart signal transduction and developmental CV physiology) and student seminars in translational research. Paul is on target to complete his MSc thesis. Paul then gave an update on CHSS cohort status focusing on AAOCA, AVSD, and Pulmonary Conduit. The data center has an important backlog of data entry and is emerging from a 2-year hiatus in cohort follow-up due to regulatory issues. Dr. Lofland recommends to members that spending time extracting data (as he did on several occasions) was a worthwhile experience & is very helpful to the CHSS. Among the problematic regulatory issues are institutional gaps in obtaining enrolled children’s assent (as early as age 7 years), continuing consent at age 18 years, and continuing IRB amendment updates in several studies that need re-submission to each institution’s IRB. The data center is planning to rebrand itself as a “Registry” focusing on Quality Assurance to overcome some of the ever-changing regulatory restrictions on clinical research and to move to a single (central) IRB system. Adoption of a single IRB (now mandated by NIH and to be added to the 2019 Common Rule) will require each CHSS institution to accept central approval and avoid delays inherent in each of 80 institution IRB reviews. The data center is also submitting to IRB a proposal to search the US National Death Registry. Overview of 5 of 11 CHSS Cohorts (LVOTO, TGA, AAOCA, AVSD & PC)

CHSS Cohort Enrolled Median Follow-up (yr.)

Critical Lt Heart Obstruction 1148 4.2

TGA 891 22.8

AAOCA 684 3.2

AVSD 527 1.6

PC 632 7.4

Updates of these cohorts was presented (see below) and members are encouraged to help explore research questions these cohorts can answer. Ideas from discussion: Follow-up is less complete recently. Why? (Caller ID? Different CHSS centers, lack of feedback to institutions, parents, patients, coordinators. Perhaps develop national patient portal? A handout pre-discharge as

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thank-you and to invite families to check-in once a year so families reach out to data center rather than vice versa) An App for that? Involve Lay group of family in DC/WW? Are questionnaires too complex rather than simply asking for clinical follow-up? (These will become more important as re-ops are done elsewhere.) Are there discrepancies between re-interventions? Liaison with other organizations to obtain follow-up (AARCC as below) To Do: Report to institutions re: follow-up/alert re: consent/assent performance appraisal CHSS Critical AS Calculator Paul Devlin presented his AHA analysis of the current (2005 –2013, n = 246) critical left heart obstruction outcomes. Compared to the Hickey era (1994-2001, n=362), current survival is better, and there is no longer a difference if management is not concordant with the calculator’s prediction.

Current risk factors are different and new management pathways are no longer binary but multiple. So the calculator is no longer predictive. In discussion, Dr. Mertens asked if the echo variables really are different. If so why? Perhaps MRI data is needed? Could the calculator be kept current with changing variables of significance, different treatment options, imaging techniques and post-op outcomes? Is this a project for machine learning? Is the calculator used enough to justify the effort? Should mitral atresia (where a BVR is not an option) be excluded? In conclusion, Dr. Kirklin suggests we develop an analysis leading to a paper, then decide if the data is worth updating the calculator To Do: Priority: draft Website disclaimer in withdrawing the calculator Ensure specific variables are entered into the dataset before re-analysis: For UVR (≥ mod TR & RV dysfunction, VSD size, length of apex) and for BVR (minimum LVOT diameter, EFE grade, LV dysfunction & diameter of mid-aortic arch) Re-do statistics with separate training sets (70/30 split) TGA Late survival & Functional Health Follow-up is a problem in this cohort now > 32 years post inception. But it is a valuable dataset. Previously we noted the Mustard group has a substantial rise in late hazard for death, whereas the ASO group continues to have a low constant hazard. The Senning patients are intermediate with a late hazard much higher than the ASO but, unlike the Mustard’s the hazard remains constant. Functional health has been assessed in 100 patients in 2018 and compared to a Danish population of controls. The ASO patients perform better than atrial repair patients.

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A recent publication from the Cardiac Care Consortium used NDI to estimate long-term survival. Future plans: A trial has been approved to identify CHSS TGA patients seen in AARCA clinics. Two centers, Oregon and Philadelphia will invite participation if their patients were repaired within the 1985-89 era. In addition we seek an optional IRB waiver for an NDI search (cost approximately $1200). A manuscript is being prepared to submit at the January presentation at the STS. Re: STS TGA Presentation January 2019 Suggestions for presentation: Simplify objectives Do the NDI search to update follow-up A presentation is telling a story (EHB) Speculate on late mortality among Mustards. List PHT & get TGH paper on late deaths What is the rate of lost to follow-up? EHB Clarify Response rate: 100 of 169 (59%) of questionnaires sent vs 100 of 508 NNTHD (20%) Explain why Peds QL is used? Spans the transition to adulthood to allow consistent normative data and has cardiac specific module. FH status is all about self-perception Is there unequal variance between ASO & atrial repair Statistics Overview

Part II (Part I at the Spring WW) was presented by Gene Blackstone & Paul Devlin. A continuing review from the spring 2018 WW.

A) Structured approach to survival analysis: Critical left heart obstruction data was used to develop a parametric hazard model to identify risk factors using Bootstrapped Hazard Analysis of Baseline Echo Risk Factors for Death.

B) Random Forests Survival Analysis

Random Forests is an “ensemble” machine learning technique o Ensemble = Many “weak learners” can combine to create a “strong learner” o The decision tree is the weak learner building block of the random forest o Example Decision Tree: based upon the weather & whether to play baseball

Decision tree grown to completion = terminal nodes (play or don’t play) with uniform

distribution of the dependent variable Discussed the Bias-Variance Trade off and the importance of using a training and testing

dataset to avoid overfitting a model to the sample dataset More decision branches in a decision tree = more variance

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(Reference: Random survival forests. Ishwaran H, Kogalur UB, Blackstone EH, Lauer MS. Ann. Appl. Stat. 2008;2:841-860) (layman reference: https://medium.com/@williamkoehrsen/random-forest-simple-explanation-377895a60d2d) The interaction between survival and risk factors was then explored to develop algorithms for graphic representation of survival outcomes AAOCA Anusha Jegatheeswaran presented a preview of her AAOCA surgery analysis: Is Surgical Repair of Anomalous Aortic Origin of a Coronary Artery Benign? Problems: clarify muddles! 4 deaths; 3 in-hospital 2 of whom presented in extremis Discuss post-op re-operations (13 on same admission vs. 22 post discharge) vis. a vis. ischemia & ischemia testing Dr. Kirklin suggested discussing post-op failures: %, cause, op type associations. While not predictive, we should learn from the experience. Can we make recommendations from this experience re: post-op (& pre-op?) ischemia testing? Can these be developed by examining post-op failures? (There are 4 deaths & 18 post-op coronary re-ops & 10 post-op ischemia among ?? patients) Other suggestions: Use flow diagrams to show pre & post-op data comparisons & ischemia prevalence Simplify AI by using > mild as % Clarify the 4 deaths Break down early vs post discharge re-op for coronary ischemia Specify Index operations What’s next for AAOCA Registry? 1) Initiate follow-up in spite of incomplete regulatory compliance at every institution and gaps (assent & continuing consent) within each institutions. 2) Resolve CT/MRI core lab reviews of ischemia patients with a ‘control’ group 3) Feedback to institutions re: QA issues 4) Outcomes of medically managed patients Critical Left Heart Obstruction Summary of Cohort Issues: Of 1148 enrolled babies, 297 have not their data extracted into the Access database. Of 650 with baseline echos read by ICL, 287 have a diagnosis of isolated critical AS or AS/AI, among whom there are 57 deaths Baseline echos: Since Dr. Slieker’s ICL review of 650 baseline echos, and additional 337 have been received & 161 are missing. Is it worthwhile doing an ICL review of the additional echos? Possible Research question re: Impact of shunt size for Stage I palliation with specific focus on 650 with baseline echos showing ≥ moderate AVV Regurgitation:

n=27 23 underwent Glenn 19 underwent Fontan 5 Heart transplants (3 after DKS, 2 after Glenn) Only 1 tricuspid valve replacement No recorded tricuspid repairs

Given the low n (27), it is unlikely an analysis of the outcomes among babies presenting with important TR will be fruitful.

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Kamal Pourmoghadam proposed an analysis of the impact of transplant-free survival among babies with Stage I B-T modification vs. RV-PA (Sano) presenting with ≥ moderate AVV regurgitation &/or ≥ RV dysfunction (separately or combined). The secondary question would be what is the best strategy for neonates with TR/RV dysfunction including the Hybrid Stage I option?

Priority: Luc re: Should the ICL do a focused echo review of > 500 not yet read? Kamal to write proposal to research committee to consider. AVSD PAB project: 50 of the 463 enrolled AVSD infants < 1-year have undergone PAB as the Index procedure Among the PAB infants, 25 were declared by their institution (n=28) to have balanced and 25 unbalanced AVSD. Among the balance, only one died pre-repair and 23 had subsequent BVR. Their repair risk was no different than primary repair of AVSD. In contract, those banded for unbalanced AVSD, there are 8 deaths, 2 BVR, 5 CPS and only 2 have had a Fontan. Changes in AVV regurgitation after PAB is binary and needs to be explored further. Conclusions: PAB is a successful strategy for 2-stage management of balanced AVSD. Outcomes among unbalance AVSD infants are poor. The effect of PAB on AVV function needs to be further explored. STS-CHSS link data. While we hoped to use STS data to define the denominator for the CHSS enrollment, we are unable to do so because the algorithm identified only AVSD-repaired patients. Dr. Devlin will explore fixing the identifying algorithm with Drs. Overman and J. Jacobs. The SickKids enrollment data revealed that only 24% of all eligible infants had been enrolled and among those enrolled the mortality was much higher than among those not enrolled (overall 14.6 vs. 3.7% ; and for repair 0.8% vs 6.5%). Reasons for this selection bias were discussed and the obvious solution is to enroll a greater % of eligible patients. Among the reasons for bias were regulatory restriction (since largely resolved) and the fact that consent is not required for dead patients. Sunday Updates: Sort out decision to PAB? Planned 2V (n=24);vs. planned UVR(n= 3); vs. deferral (n=23) (start here to

describe the indication vis a vis morphology)

Competing risks analysis of those with intended UVR vs. BVR (68% were repaired)

Assess changes in AVV regurgitation according to indication for PAB. (If done for volume overload vs. intrinsic valve defects) Does PAB mitigate risk for small patient size risk? (number may be too small)

Define limits of small size for VSD repair & compare those to PAB patients (age-related & size-related

survival for primary repair vs. PAB delayed repair)

Why surgeons do not do primary repair of AVSD with CoAo?

New concept: Hani Najm partitions the atrium by patch but leaves the VSD open in unbalance AVSD to see if

the ventricle will grow! (Good for heterotaxy!) I don’t think CHSS cohort has any of these?

Is our enrollment criteria (“ admitted for surgery…”) appropriate?

Priority: Manuscript& presentation in progress

Prep for Overall AVSD outcomes project

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Coarctation of aorta Drs. Nancy Poirier & Ismail Bouhout received approval from Montreal Ethics Department for an Internet-based follow-up of selected Coarctation patients. The application stressed the potential benefit to contacted patients, given their risk for late complications (Risk vs Health Benefit; AHA guidelines) Among Internet programs surveyed are: PeekYou.org and Anywho.com and Arti Singh’s trial project with Facebook Dr Poirier also gave an update on how these searches could be facilitated by Artificial Intelligence programs. Priority: Dr. Poirier to send REB submission & approval FOR data center TO SUBMIT TO OUR REB. Request EHB’s find program. Test programs. Gore PC Project Paul Devlin outlined progress towards a collaborative effort with Gore to study the pathology of failed valved pulmonary artery explants. The Pathology Core Lab will be at Columbia University, directed by Giovanni Ferrari. A joint proposal between CHSS & Columbia has been submitted. 18 CHSS institutions have expressed interest in participating. The study will include explanted PC valved conduits sent from participating CHSS institutions directly to Dr. Ferrari’s lab. Retrospective clinical & echo data for explanted conduits will be entered into REDCap by institutional data coordinators who will be paid for their time and effort. No prospective data is required. Proposal update (Dec 2018) tentative approval of submission by Gore. Priority: Should we program the PC dataset into RedCap NOW? Operations Manual for data coordinators being completed Data Center to prepare for IRB submission. Risky Business presentation (https://www.riskybusiness.events/toronto.php) Dr. W.D. DeCampli gave his lecture he presented as an invited speaker at the 2018 Risky Business symposium; a business conference that began in 2006, dedicated to: Learning from high risk industries to improve the quality and safety of healthcare. How is the CV OR like a Space Shuttle Program? Dr. DeCampli related a comparison of parallel disasters in space – the disintegration of Columbia Spaceship during re-entry February 1, 2003 - and in the operating room – insertion of aortic valve prosthesis upside down! Both fatal events were errors in process. Events that may not have happened before or, if happened, caused no harm. The heat panels on Columbia were damaged by foam insulation during launch. While that had happened previously, no harm had followed. The damaged wing could not be seen by the crew of 7 who were assured by Mission Control that all was well. The ‘upside down’ AVR was a result of inadequate labelling of a prosthetic valve package resulting in a mitral prosthesis being handed to the surgeon. Intra-op severe LV distension was mistaken for myocardial stunning when an echo provided misleading reassurance that the prosthetic leaflets moved freely. Mitigation of both events would have been possible by a fool-proof system process and by open-minded approach to consider all potential untoward outcomes

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NIH UG3/UH3 Grant Application: Project synopsis Review of NIH requirements Prospective controlled trial Requires a data processing center and a clinical coordinating center Must include letters of support from all participating institutions. To illustrate the application process, Drs. Blackstone and Karamlou made use of the CHSS coarctation data as an example. Potential topic identified in CHSS membership pole:

Discussion of proposed topics: Balloon vs surgery of critical AS (15 Ross vs non-Ross (10): Ductal stent vs AP shunt: ToF initial PV management: Late Fontan management: Failing Fontan: Cath vs. surgery for infant CoAo Issues: Equipoise not critical AS: Maybe Ductal stent vs AP shunt: not Infant CoAo Research Question? ToF initial management of PV requires surgical expertise & too rare: No obvious question re: AVSD Fontan? Late management &/or failing Fontan; A Registry? NPC & PHN & PCORI might co-investigate Proposal: An International Fontan Registry? Multiple research questions But is it a trial? 1. Connections based on computational flow characteristics (precision medicine! 3-D modelling pre repair) 2. Fenestration yes/no indications for randomization? For closure? 3. Impeller device trial (phase I exclusion) 4. Medical strategies for Fontan management-anticoagulants-exercise rehab - afterload reduction- respiratory muscle training – (natural history surveillance strategies) 5. 1 ½ V repair vs. Fontan PA in continuity or not (pulsatile flow) 6. Transplant vs. Fontan? 7. Fontan assist strategies 8. Use of computational methods to “surgically plan” complex Fontans There was some consensus that some sort of Fontan trial would be interesting. The development would involve creating an international registry utilizing the Australia-New Zealand and perhaps European Fontan registries.

Leading Topics from Membership Survey

1. Balloon valvuloplasty vs. surgery for infant AS 15

2. Ross vs. non-Ross for AVR 11

3. Aortopulmonary shunt vs. ductal stent 10

4. Aortic valve: repair vs. replacement 8

5. Fontan management trial 8

6. TOF: management of the valve in infancy 4

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Priority: Finalize research questions for Fontan research writing group. Specify mandates: 1) Data coordinator 2) Cardiology 3) Increase patient engagement 4) Get out from SickKids burden 5) Single IRB will be mandated so institutional IRBs will be compliant of not be eligible for funding. (Will required to be specified in letters from participating institutions as part of U grant.) 6) Identify key stakeholders ( 7) NIH evaluates the DC budget & manager of DC 8) 2-week time crunch to get started! For submission in June 2019, response in October & re-submission spring 2020

Ebstein Cohort Chris Knott-Craig/J Dearani/C Pizarro/K Holtz Kim Holtz presented a summary of the submitted protocol: The protocol received approval from the data center IRB submission in November 2018. However 2 amendments have been submitted before sending the IRB template to CHSS participating institutions. These amendments cover use of National Death Registry and use of Internet searches to find missing patients. Both these additional amendments are to facilitate follow-up and are therefore critical important in conducting the study. We are hopeful the amendments will be accepted by January, at which point they will be included in the IRB template for each institution to submit to their IRB. Identification of Key Questions: Analyses’ Priorities: # 1 Description of retrospective data to understand what already has been done: i.e. who comes to surgery, when and for what?

Deadlines

• Contact with NIH Section March 13 (at least!)

• LOI May 12, 2019

• Full Apps June 13, 2019

Questions (Blackstone)

• CHSS alone, or with PHN?

• CHSS Data Center would be CCC

• Brian says wait to link with PHN until we are well along the way with a proposal

• Should we use NERI (New England Research Institutes) as the DCC

• ? Use C5Research at CCF as the DCC

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#2 imaging classification of morphology (& physiology) #3 EPS #4 Future studies? From the prospective cohort? Risk prediction/late outcomes # 5 Develop Project Timelines/Plan Priority: Complete the Ebstein Operational Manual. (Add enrollment process). Form an ICL working group? (& obtain remote ICL access) Define retrospective end-point Priority: Sort out ICL access without the requirement of needing a SickKids appointment. Review and Summary of Work Weekend Discussions Work Weekend Recap Paul Devlin

TR in Norwood Survival: Additional thoughts: If > Mild TR? (5 of 27 pts) subsequently 23 had Glenn, 19 Fontan & 5 heart Tx (disproportionate # of Tx) Only 1 child had TV repair Maybe progression of TR is different compared to babies without initial TR? Maybe selection of Stage I is different (covered extensively in Travis Wilder’s JTCVS paper) Maybe look at all TV repairs and look at their TR development AVSD & STS link Can we change Duke’s algorithm? 271 pts enrolled in 2018 at SickKids several hours per patient Patient follow-up issues: Igor’s problem is legal department, not REB per se. They deny his access to cardiology & image databases. Cardiology is key to his enrollment What is CHSS goal for enrollment? PHN demands enrollment for their trials but are paying. CHSS has no obligation to enroll except that institutions are required to pay for the DC Tier system for recognition of participation? Could be linked to institutional tithe? Other models: EHB. Access to Epic in each institution by the coordinator center for real-time records? Data extraction at Cleveland Clinic connect to dozens of DB but EHB not sure how it’s transferred but they do have nurse extractors (about 40!) Priority: Draft response to STS algorithm to Drs. Overman & J. Jacobs Re STS algorithm to request selection by diagnosis not by procedure (STS data is for repair of AVSD only) CoAo and AVSD Reference Shuhaiber* 1990-2009 31 pts primary repair 26% in-hospital M @ repair 57% survival after initial repair 35 pts staged repair 9% M in-hospital @ repair and 85% survival after initial palliation Staged repair of neonates with CoAo and AVSD has better survival and lower morbidity than primary repair.

* Reference: The Annals of Thoracic Surgery.2013;95:2071-2077

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CHSS Data Center Logistics: Operationalizing Data Entry

Abstraction Backlog

Future of Follow-up

Death Registries

New Kirklin/Ashburn onboarding Connor Callahan

Do the NDI search now to update TGA follow-up for all patients except deaths, but include a few of

those for QA

Appendix: Attendees List

First Name Last Name

Nabi Aghaei

Eugene H. Blackstone

Igor Bondarenko

Ismail Bouhout

Sally Cai

Connor Callahan

Brenda Chow

William DeCampli

Paul Devlin

Anusha Jegatheeswaran

Michael Jiang

Tara Karamlou

Linda Lambert

Julia Lo

Amine Mazine

Brian W. McCrindle

Luc Mertens

Hani K. Najm

Tharini Paramananthan

Kate Pearson

Nancy Poirier

Rodolfo Rocha

Arti Singh

Anna Wasiak

William G. Williams

James Kirklin

Ellen Brinza

Julie Brothers

Ali Dodge-Khatami

Craig Fleishman

Stephanie Fuller

Rajesh Krishnamurthy

Gary K. Lofland

Meena Nathan

Kamal K. Pourmoghadam

Shubhika Srivastava

Robert Tunks

Richard Kim

Angelika Muter

Marshall Jacobs