Investigators
Natalia Trayanova, Johns Hopkins University (PI/PD); Hugh Calkins, Johns Hopkins Medicine (PI); Patrick Boyle, University of Washington (Co-I); Adityo Prakosa, Johns Hopkins University (Co-I)
Contact info (email)
ntrayanova@jhu.edu
1. Define context(s)
aid in clinical decision making
aid in clinical trial design
identify/explore new therapies
reveal new biological insights
Current Conformance Level / Target Conformance Level
Extensive
Primary goal of the model/tool/database
The overall objective of this application is to develop and validate a novel personalized multiscale modeling strategy for determining the optimal targets for catheter ablation of the fibrotic substrate in patients with persistent atrial fibrillation (PsAF). The project will culminate with a pilot prospective patient study, where PsAF ablation will be executed directly at simulation-predicted targets.
Biological domain of the model
cardiac electrophysiology
Structure(s) of interest in the model
human atria, cardiomyocytes, fibrosis
Spatial scales included in the model
sub-cellular, cellular, tissue, and organ-scale cardiac features
Time scales included in the model
sub-events of the cardiac action potential, with time courses on the order of 10s or 100s of µs; arrhythmia events at the organ-scale, which evolve over the course of several seconds of rapid electrical stimulation
2. Data for building and validating the model
| Data for building the model | Published? | Private? | How is credibility checked? | Current Conformance Level / Target Conformance Level |
|---|---|---|---|---|
| in vitro (primary cells cell, lines, etc.) | x | baseline model calibrated from literature sources (see: 10.1093/cvr/cvw073) | Adequate | |
| ex vivo (excised tissues) | ||||
| in vivo pre-clinical (lower-level organism or small animal) | ||||
| in vivo pre-clinical (large animal) | ||||
| Human subjects/clinical | x | baseline model calibrated from literature sources (see: 10.1093/cvr/cvw073) | Adequate | |
| Other: ________________________ |
| Data for validating the model | Published? | Private? | How is credibility checked? | Current Conformance Level / Target Conformance Level |
|---|---|---|---|---|
| in vitro (primary cells cell, lines, etc.) | x | Establish baseline ion channel expression levels (i.e., maximal conductances) by measuring mRNA levels | In Progress (Will be Extensive) | |
| ex vivo (excised tissues) | x | Adjust mathematical formulations for membrane kinetics to match action potential morphology observed via optical mapping | In Progress (Will be Extensive) | |
| in vivo pre-clinical (lower-level organism or small animal) | ||||
| in vivo pre-clinical (large animal) | ||||
| Human subjects/clinical | ||||
| Other: ________________________ |
3. Validate within context(s)
| Who does it? | When does it happen? | How is it done? | Current Conformance Level / Target Conformance Level | |
|---|---|---|---|---|
| Verification | Trayanova & Boyle Labs | Throughout project | convergence testing in tissue wedge models extracted from all atrial models; re-running simulations and analysis for a subset of models in a distinct software package | Extensive |
| Validation | Trayanova & Efimov Labs | Years 1-2 of project | Establish baseline ion channel expression levels (i.e., maximal conductances) by measuring mRNA levels; Adjust mathematical formulations for membrane kinetics to match action potential morphology observed via optical mapping; Calibrate conductivity tensor values to match conduction velocities observed via optical mapping | Extensive |
| Uncertainty quantification | Trayanova & Boyle Labs | Years 2-3 of project | Characterize the relationship between cell- and tissue-scale model parameters and primary model outputs (i.e., locations of persistent reentrant drivers within the fibrotic substrate) | Adequate |
| Sensitivity analysis | Trayanova & Boyle Labs | Years 1-2 of project | Calculate sensitivity of reentrant driver target estimation to locations of pacing sites used to elicit reentry (work already done) | Adequate |
| Other:__________ | ||||
| Additional Comments |
4. Limitations
| Disclaimer statement (explain key limitations) | Who needs to know about this disclaimer? | How is this disclaimer shared with that audience? | Current Conformance Level / Target Conformance Level |
|---|---|---|---|
| an intrinsic limitation of any image-based model is that it can only incorporate what can be imaged (i.e., limitations of the MRI scanner limit the information that can be used to constrain the model) | all relevant stakeholders | through dissemination in papers, abstracts, and public lectures | Adequate |
5. Version control
| Current Conformance Level / Target Conformance Level |
|---|
| Adequate |
| Naming Conventions? | Repository? | Code Review? | |
|---|---|---|---|
| individual modeler | yes | yes | peers |
| within the lab | yes | yes | peers |
| collaborators | yes | yes | via regular Skype calls |
6. Documentation
| Current Conformance Level / Target Conformance Level | |
|---|---|
| Code commented? | Adequate |
| Scope and intended use described? | Adequate |
| User’s guide? | Extensive |
| Developer’s guide? | Extensive |
7. Dissemination
| Current Conformance Level / Target Conformance Level |
|---|
| Extensive |
| Target Audience(s): | “Inner circle” | Scientific community | Public |
|---|---|---|---|
| Simulations | 10.1161/CIRCEP.119.008213 – (pre-procedure machine-learning + simulations) | ||
| Models | doi:10.1016/j.media.2019.04.004 - (UAC: modeling methodology) doi:10.3389/fphys.2018.01151 - (FIRM vs. modeling: validation methodology) 10.1007/s10439-020-02525-w – (human atrial fibre atlas) | ||
| Software | doi:10.1016/j.jacep.2018.08.016 - (jet vent: analysis tools relevant to project) doi:10.1038/s41551-018-0282-2 - (VAAT: analysis tools relevant to project) doi:10.3389/fphys.2019.00628 - (VT parameter variability: analysis tools relevant to project) doi:10.1016/j.bpj.2019.07.024 - (Characterizing Conduction Channels: analysis tools relevant to project) | ||
| Results | doi:10.1038/s41551-019-0437-9 (OPTIMA) doi:10.1093/cvr/cvz083 (pre/post MRI) doi:10.1093/europace/euy234 - (post-ablation reentry dynamics) | ||
| Implications of results | doi:10.1016/j.ijcard.2019.01.096 (personalized atrial modeling) 10.1016/j.ccep.2020.02.006 – (utility of cMRI in AF Management) | doi:10.1038/s41569-018-0149-y (developments in precision cardiology) doi:10.1038/s41569-018-0104-y (Computational models in cardiology) |
8. Independent reviews
| Current Conformance Level / Target Conformance Level |
|---|
| In Progress (Will be Extensive) |
| Reviewer(s) name & affiliation: | TBD; the emergence of a new software platform for cardiac EP simulations (OpenCARP: https://opencarp.org/) will pave the way towards identification of new outside groups to validate modeling and simulation methodology developed and used in this project |
|---|---|
| When was review performed? | TBD |
| How was review performed and outcomes of the review? | Comprehensive reproduction of modeling, simulations, and analysis steps of workflow by a different group using a different software platform |
9. Test competing implementations
| Current Conformance Level / Target Conformance Level |
|---|
| In Progress (Will be Extensive) |
| Yes or No (briefly summarize) | |
|---|---|
| Were competing implementations tested? | Not yet; however, the emergence of OpenCARP discussed above is a step towards feasibility of comprehensive testing in an alternative platform |
| Did this lead to model refinement or improvement? | n/a |
10. Conform to standards
| Current Conformance Level / Target Conformance Level |
|---|
| In Progress (Will be Extensive) |
| Yes or No (briefly summarize) | |
|---|---|
| Are there operating procedures, guidelines, or standards for this type of multiscale modeling? | Yes |
| How do your modeling efforts conform? | We have not yet carried out this part of the work; eventually, independent assessment of our modeling strategy in consultation with IMAG and the MSM consortium will lend additional credibility to simulation predictions |