Cristóbal Rodero

Providing therapies tailored to each patient is the vision of precision medicine, enabled by the increasing ability to capture extensive data about individual patients. In this position paper, we argue that the second enabling pillar towards this vision is the increasing power of computers and algorithms to learn, reason, and build the 'digital twin' of a patient. Computational models are boosting the capacity to draw diagnosis and prognosis, and future treatments will be tailored not only to current health status and data, but also to an accurate projection of the pathways to restore health by model predictions. The early steps of the digital twin in the area of cardiovascular medicine are reviewed in this article, together with a discussion of the challenges and opportunities ahead. We emphasize the synergies between mechanistic and statistical models in accelerating cardiovascular research and enabling the vision of precision medicine.

Cardiac anatomy plays a crucial role in determining cardiac function. However, there is a poor understanding of how specific and localised anatomical changes affect different cardiac functional outputs. In this work, we test the hypothesis that in a statistical shape model (SSM), the modes that are most relevant for describing anatomy are also most important for determining the output of cardiac electromechanics simulations. We made patient-specific four-chamber heart meshes (n = 20) from cardiac CT images in asymptomatic subjects and created a SSM from 19 cases. Nine modes captured 90% of the anatomical variation in the SSM. Functional simulation outputs correlated best with modes 2, 3 and 9 on average (R = 0.49 ± 0.17, 0.37 ± 0.23 and 0.34 ± 0.17 respectively). We performed a global sensitivity analysis to identify the different modes responsible for different simulated electrical and mechanical measures of cardiac function. Modes 2 and 9 were the most important for determining simulated left ventricular mechanics and pressure-derived phenotypes. Mode 2 explained 28.56 ± 16.48% and 25.5 ± 20.85, and mode 9 explained 12.1 ± 8.74% and 13.54 ± 16.91% of the variances of mechanics and pressure-derived phenotypes, respectively. Electrophysiological biomarkers were explained by the interaction of 3 ± 1 modes. In the healthy adult human heart, shape modes that explain large portions of anatomical variance do not explain equivalent levels of electromechanical functional variation. As a result, in cardiac models, representing patient anatomy using a limited number of modes of anatomical variation can cause a loss in accuracy of simulated electromechanical function.

Deep learning can bring time savings and increased reproducibility to medical image analysis. However, acquiring training data is challenging due to the time-intensive nature of labeling and high inter-observer variability in annotations. Rather than labeling images, in this work we propose an alternative pipeline where images are generated from existing high-quality annotations using generative adversarial networks (GANs). Annotations are derived automatically from previously built anatomical models and are transformed into realistic synthetic ultrasound images with paired labels using a CycleGAN. We demonstrate the pipeline by generating synthetic 2D echocardiography images to compare with existing deep learning ultrasound segmentation datasets. A convolutional neural network is trained to segment the left ventricle and left atrium using only synthetic images. Networks trained with synthetic images were extensively tested on four different unseen datasets of real images with median Dice scores of 91, 90, 88, and 87 for left ventricle segmentation. These results match or are better than inter-observer results measured on real ultrasound datasets and are comparable to a network trained on a separate set of real images. Results demonstrate the images produced can effectively be used in place of real data for training. The proposed pipeline opens the door for automatic generation of training data for many tasks in medical imaging as the same process can be applied to other segmentation or landmark detection tasks in any modality. The source code and anatomical models are available to other researchers. <xref ref-type="fn" rid="fn1" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">¹</xref> <fn id="fn1" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><label>¹</label> <uri>https://adgilbert.github.io/data-generation/</uri> </fn>

Computational Fluid Dynamics (CFD) is used to assist in designing artificial valves and planning procedures, focusing on local flow features. However, assessing the impact on overall cardiovascular function or predicting longer-term outcomes may requires more comprehensive whole heart CFD models. Fitting such models to patient data requires numerous computationally expensive simulations, and depends on specific clinical measurements to constrain model parameters, hampering clinical adoption. Surrogate models can help to accelerate the fitting process while accounting for the added uncertainty. We create a validated patient-specific four-chamber heart CFD model based on the Navier-Stokes-Brinkman (NSB) equations and test Gaussian Process Emulators (GPEs) as a surrogate model for performing a variance-based global sensitivity analysis (GSA). GSA identified preload as the dominant driver of flow in both the right and left side of the heart, respectively. Left-right differences were seen in terms of vascular outflow resistances, with pulmonary artery resistance having a much larger impact on flow than aortic resistance. Our results suggest that GPEs can be used to identify parameters in personalized whole heart CFD models, and highlight the importance of accurate preload measurements.

Abstract Computational models of the heart are now being used to assess the effectiveness and feasibility of interventions through in-silico clinical trials (ISCTs). As the adoption and acceptance of ISCTs increases, best practices for reporting the methodology and analysing the results will emerge. Focusing in the area of cardiology, we aim to evaluate the types of ISCTs, their analysis methods and their reporting standards. To this end, we conducted a systematic review of cardiac ISCTs over the period of 1 January 2012–1 January 2022, following the preferred reporting items for systematic reviews and meta-analysis (PRISMA). We considered cardiac ISCTs of human patient cohorts, and excluded studies of single individuals and those in which models were used to guide a procedure without comparing against a control group. We identified 36 publications that described cardiac ISCTs, with most of the studies coming from the US and the UK. In <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:mn>75</mml:mn> <mml:mi mathvariant="normal">%</mml:mi> </mml:math> of the studies, a validation step was performed, although the specific type of validation varied between the studies. ANSYS FLUENT was the most commonly used software in <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:mn>19</mml:mn> <mml:mi mathvariant="normal">%</mml:mi> </mml:math> of ISCTs. The specific software used was not reported in <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:mn>14</mml:mn> <mml:mi mathvariant="normal">%</mml:mi> </mml:math> of the studies. Unlike clinical trials, we found a lack of consistent reporting of patient demographics, with <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:mn>28</mml:mn> <mml:mi mathvariant="normal">%</mml:mi> </mml:math> of the studies not reporting them. Uncertainty quantification was limited, with sensitivity analysis performed in only <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:mn>19</mml:mn> <mml:mi mathvariant="normal">%</mml:mi> </mml:math> of the studies. In <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:mn>97</mml:mn> <mml:mi mathvariant="normal">%</mml:mi> </mml:math> of the ISCTs, no link was provided to provide easy access to the data or models used in the study. There was no consistent naming of study types with a wide range of studies that could potentially be considered ISCTs. There is a clear need for community agreement on minimal reporting standards on patient demographics, accepted standards for ISCT cohort quality control, uncertainty quantification, and increased model and data sharing.