Uncertainty Quantification in Prospective and Predictive Patient Specific Cardiac Models

Lead Research Organisation: King's College London
Department Name: Imaging & Biomedical Engineering

Abstract

Clinical diagnosis is seldom definitive. Clinical data are noisy and sparse, and often support multiple diagnoses and potential therapies. To decide how best to treat a patient requires identifying the many possible outcomes for an individual and their corresponding probabilities. In this project we will apply the mathematics of uncertainty quantification, developed for automotive, geological and meteorological predictions, combined with biophysical models of individual patient physiology and pathophysiology to predict patient outcomes and their corresponding probabilities. This will demonstrate how patient specific computational models can be used to make prospective predictions to guide procedures and inform uncertain clinical decisions.

The use of uncertainty quantification and predictive patient specific models will be applied to patients with atrial fibrillation. Atrial fibrillation (AF) is the most common cardiac arrhythmia in the UK. In patients who do not respond to drug treatment, the pathological regions of the atria are removed or isolated through catheter ablation. However, up to 40% of patients with advanced (persistent) AF require further ablations to treat atrial tachycardia (pathological but regular activation) that develops after they have had an initial ablation to treat their AF. To reduce the number of additional procedures, this project will predict the probability that a patient will develop atrial tachycardia and the path that the atrial tachycardia will take, based on measurements recorded at the time of the initial persistent AF ablation procedure. If successful this approach would guide preventative ablations during the initial procedure to reduce the need for repeat procedures.

Planned Impact

The UK has a long history in developing cardiac electrophysiology models and this proposed research aims to continue this trajectory, moving computational models of cardiac electrophysiology into clinical applications. This project builds on the EPSRC investment at KCL in the Medical Engineering Centre, Medical Imaging Doctoral Training Centre and Fellowships and in Sheffield in the QUINTET project and POEMS network. Development of personalised models of the heart interacts with and integrates research across the EPSRC research portfolio. Primarily this work will support and develop the UK as an international leader in the clinical translation of cardiac modelling, contributing to the clinical technologies research area (RA). The process of creating quantitative and validated models of in-vivo cardiac tissue properties will contribute towards the biomaterials and tissue engineering RA, the need to better inform model parameters and improved understanding and quantification of cardiac physiology both motivate and exploit results from the medical imaging RA and the need for improved simulations times and robustness exploits, and drives, developments in the continuum mechanics RA and high performance computing. The adoption and development of statistical parameter inference and uncertainty quantification will feed into statistics and applied probability RA. This study will support the emergent industries using models as a healthcare service to guide procedures, improving patient outcomes and reducing costs, and for creating virtual patient cohorts for designing medical devices and improving cardio-toxicity screening. This project falls within the Clinical Technologies RA and in line with EPSRC guidance is focused heavily on translation to clinical impact and engaging with clinical end users. In light of this, the primary goal of this project is:
To move computational models of the heart from deterministic models that predict a single outcome for a patient to statistical tools that predict all of the possible outcomes and their likelihoods given the underlying uncertainty and sparsity in the available clinical data.

This transformative project will bring computational biophysical models from a position of a novel deterministic analysis tool to a predictive clinical application over 4 years. At the end of the project we will have:

1) Demonstrated the ability to create statistical patient specific biophysical models of the atria to predict the outcome and guide ablation procedures. This approach will be applicable to the ventricle and across other organ systems.
2) Applied supervoxel segmentation and uncertain marching cube algorithms to generate and visualise uncertain anatomical surfaces. These ideas can be extended to interpreting and visualising segmentation uncertainty in general.
3) Shown a novel role for uncertainty quantification within the clinic, giving mathematicians new avenues to apply and translate their research and deliver impact.
4) Predicted where to optimally ablate atrial fibrillation patients to minimize atrial tachycardia following an ablation to reduce the financial and social burden of repeat ablation procedures. This will provide clinical and basic science researchers with new understanding of atrial fibrillation and how this disease responds to treatment.
5) Generated clinical pilot data necessary to underpin the application for funding for the first biophysical patient specific model-guided atrial fibrillation ablation clinical trial.
6) Created a software platform that will enable other researchers to access patient specific model creation and statistical tools and demonstrate the value of these techniques to the healthcare technology industry.
7) Created a cohort of virtual patients for performing in-silico clinical trials. This will benefit clinical research by providing a test bed for new treatments and for device companies aiming to evaluate new technologies on virtual patients.

Publications

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Campbell SG (2020) KBTBD13 and the ever-expanding sarcomeric universe. in The Journal of clinical investigation

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Corrado C (2017) Personalized Models of Human Atrial Electrophysiology Derived From Endocardial Electrograms. in IEEE transactions on bio-medical engineering

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Coveney S (2020) Probabilistic Interpolation of Uncertain Local Activation Times on Human Atrial Manifolds. in IEEE transactions on bio-medical engineering

 
Description We have developed computational tools for measuring error in images of the heart and in electrical measurements fo the heart that can now be used to constrain models of the heart
Exploitation Route I have presented our results to Siemens, IBM and Abbott. I will also visit with medtronic later this year. All of these companies may be interested in these methods.
Sectors Aerospace, Defence and Marine,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description Atrial cardiac magnetic resonance imaging in patients with embolic stroke of unknown source without documented atrial fibrillation
Amount £184,072 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2019 
End 10/2021
 
Description Development of a real time, patient-specific computational catheter ablation guidance tool utilising personalised structural and functional measurements
Amount £354,064 (GBP)
Funding ID 213342/Z/18/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2019 
End 09/2021
 
Description Turing 
Organisation Alan Turing Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution We have worked with researchers at the Turing (Professor Chris Oates, Professor Mark Girolami and Jon Cockayne) on this BHF project.
Collaborator Contribution They have employed the people we are collaborating with.
Impact We received a BHF-Turing grant and a BHF programme grant. We have submitted two conference abstracts and have two papers in draft.
Start Year 2018
 
Description University of Sheffield 
Organisation University of Sheffield
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaborating on running uncertainty quantification workshops and jointly funded on this grant.
Collaborator Contribution collaborating on grant
Impact We have run multiple workshops together, done media presentations together and written papers together
Start Year 2017
 
Description Isaac Newton Meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Organised meeting and presentation at Isaac Newton Meeting
Year(s) Of Engagement Activity 2019
URL https://www.newton.ac.uk/event/fht
 
Description John Hopkins University 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited talk John Hopkins University
Year(s) Of Engagement Activity 2019
URL https://icm.jhu.edu/events/steven-niederer-kings-college-london-applying-cardiac-modelling-to-study-...
 
Description Lange Symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited presentation at Lange Symposium
Year(s) Of Engagement Activity 2019
URL https://www.dhzb.de/fileadmin/user_upload/relaunch/02_medizin_pflege/AHF/Langesymposium/2019/Program...
 
Description Mox invited talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact invited presentation to numerics group in Milan
Year(s) Of Engagement Activity 2019
URL https://mox.polimi.it/elenco-seminari/?id_evento=1919&t=763721&ricerca=
 
Description Murdoch Children's Research Institute 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited presentation at Murdoch Children's Research Institute,
Year(s) Of Engagement Activity 2019
 
Description Oslo University Hospital 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited presentation
Year(s) Of Engagement Activity 2020
 
Description Oxford talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Invited talk at physiology department oxford
Year(s) Of Engagement Activity 2019
 
Description Pfizer 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Invited talk at Pfizer
Year(s) Of Engagement Activity 2019
 
Description Philips 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Invited talk at Philips to discuss how we are developing digital twins.
Year(s) Of Engagement Activity 2019
 
Description Prince Alfred Hospital 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited presentation at Prince Alfred Hospital
Year(s) Of Engagement Activity 2019
 
Description Simula talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact I gave a presentation at Simula a norwegian research institute to about 40+ researchers.
Year(s) Of Engagement Activity 2020
URL https://www.simula.no/simula-seminars-scientific-computing
 
Description St Vincent's Hospital 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited talk at St Vincent's Hospital
Year(s) Of Engagement Activity 2019
 
Description TRM Lugano 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited presentation to biomedical engineering and clinical research workshop.
Year(s) Of Engagement Activity 2019
 
Description UCSD 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited presentation at UCSD Biomedical Engineering department
Year(s) Of Engagement Activity 2019
 
Description University of Auckland 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited presentation at University of Auckland
Year(s) Of Engagement Activity 2019
 
Description Victor Chang Sydney 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited presentation at victor chang institute
Year(s) Of Engagement Activity 2019
 
Description Yale 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited presentation at the Biomedical Engineering deparmtent in Yale
Year(s) Of Engagement Activity 2019
 
Description Youtube 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact youtube interview for Newton Institute meeting
Year(s) Of Engagement Activity 2019
URL https://www.youtube.com/watch?v=MSGaojtXcEA