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Authors

Kexin Wang, Shuo Wang, Minghua Xiong, Chengyan Wang, He Wang

Abstract

Clinically significant portal hypertension (CSPH) is a severe complication of chronic liver disease associated with cirrhosis, which is diagnosed by the measurement of hepatic venous pressure gradient (HVPG). However, HVPG measurement is invasive and therefore difficult to be widely applied in clinical routines. There is no currently available technique to measure HVPG noninvasively. Computational fluid dynamics (CFD) has been used for noninvasive measurement of vascular pressure gradient in the intracranial and coronary arteries. However, it has been scarcely employed in the hepatic vessel system due to the difficulties in reconstructing precise vascular anatomies and setting appropriate boundary conditions. Several computer tomography and ultrasound based studies have verified the effectiveness of virtual HVPG (vHVPG) by directly connecting the portal veins and hepatic veins before CFD simulations \cite{CHESS1601,CHESS1701}. We apply the latest techniques of phase-contrast magnetic resonance imaging (PC-MRI) and DIXON to obtain the velocity and vessel anatomies at the same time. Besides, we improve the CFD pipeline in regards to the construction of vessel connections and reduction of calculation time. The proposed method shows high accuracy in the CSPH diagnosis in a study containing ten healthy volunteers and five patients. The MRI-based noninvasive HVPG measurement is promising in the clinical application of CSPH diagnosis.

Link to paper

DOI: https://doi.org/10.1007/978-3-030-87234-2_4

SharedIt: https://rdcu.be/cyl7Z

Link to the code repository

N/A

Link to the dataset(s)

N/A

Reviews

Review #1

Please describe the contribution of the paper

This study demonstrates the use of image-based computational fluid mechanics for retrospective measurement of pressure in the right hepatic vein—a measurement used to diagnose and monitor liver function abnormalities. Images are used to extract the geometry and velocity boundary condition, subject-specific model construction follows and then a model is used to calculate a pressure distribution along the major hepatic vessels (the outlet pressure boundary condition is drawn from accepted values and is the same across the cohort). The in silico results show a clear difference between patients and controls as well as pressure measurements that are similar to those encountered clinically.
Please list the main strengths of the paper; you should write about a novel formulation, an original way to use data, demonstration of clinical feasibility, a novel application, a particularly strong evaluation, or anything else that is a strong aspect of this work. Please provide details, for instance, if a method is novel, explain what aspect is novel and why this is interesting.
- Pressure measurements are difficult to obtain, and using noninvasive computational fluid mechanics may reduce the number of infections associated with invasive methods.
- The paper is well organized, and easy to follow.
- The results show that (subject to computational assumptions ignoring small capillaries) clinically-relevant pressure differences are reflected in large vessels, which could simplify detection and monitoring of liver problems.
Please list the main weaknesses of the paper. Please provide details, for instance, if you think a method is not novel, explain why and provide a reference to prior work.
- The manuscript contains a few typos and figures with small print, and this makes the paper a bit confusing at times, although one can still understand the paper as a whole.
- The authors could had addressed the limitations of the computational approach a bit better.
Please rate the clarity and organization of this paper

Very Good
Please comment on the reproducibility of the paper. Note, that authors have filled out a reproducibility checklist upon submission. Please be aware that authors are not required to meet all criteria on the checklist - for instance, providing code and data is a plus, but not a requirement for acceptance

With the exception of the imaging data itself, the paper seems to many details for another research group seeking to reproduce the original findings. It would be good to mention the exact solver package, whether commercial or custom, and where can it be found.
Please provide detailed and constructive comments for the authors. Please also refer to our Reviewer’s guide on what makes a good review: https://miccai2021.org/en/REVIEWER-GUIDELINES.html

Altogether this is a very good study with a clear and relevant clinical problem as well as a relatively large patient cohort. I have two comments to improve it: Correct or clarify some writing issues, and provide a more complete description of the computational mechanics part.

As for writing, the authors should proof read the paper and consider revising some of their expressions. One example of this is the word ‘besides’, which can express an additional fact either to support what was said or in passing. I believe the authors meant the former, case in which the ‘in addition’ could had been clearer. This occurs twice. The word ‘potentials’ may be confusing with flow potentials, but I think the authors meant ‘potential’ which means something has promise to work. Section 4 in the conclusion mentions that the proposed method can be used to obtain the ‘gold standard’ but the introduction says that this corresponds to direct pressure measurements. Perhaps the authors should consider using ‘an accurate estimate’ instead (perhaps this estimate will be the gold standard some day). In Section 3 the authors use the word ‘obviously’, but this result does not feel obvious, and perhaps the word ‘notably’ would fit better. There are other places where corrections and adequate proofreading are needed. Lastly, some of the labels in Figures 1 and 2 are two small to be read.

My second suggestion deals with describing limitations associated with using computational methods. At the end of the Intro, the authors speculate that computational results are dependent on (1) the availability of anatomical and velocity data and (2) the lack of computational power. To this, it would be good to add that computational simulations are quite tricky to ‘set up’, meaning that an expert physicist is needed to construct the models. Note that this paper includes quite a bit of geometrical ‘polishing’ that while one day may be automated, it is currently painstakingly done manually by a technically proficient person.

By a similar token, we do not yet know the sensitivity of the simulations to important components, such as wall vessel deformation, constitutive properties of blood (which is actually non-Newtonian), and variations of boundary conditions that may reflect the actual population. The discriminative power of the method will be subject to all of these, and the results would ideally be consistent over a reasonable range of values. Until then, I see this as a limitation of the method that should be noted.

An interesting result of this study is that the results seem reasonable even when ignoring the small vessels. What was the size of the smallest vessel reconstructed? One reason this is interesting is that it could suggest a type of heuristic to provide pressure measurements in case where the full CFD simulation is not available. For instance, the pressure may be proportional to a function of the phase-contrast MRI input boundary condition and the volume of vessels.
Please state your overall opinion of the paper

accept (8)
Please justify your recommendation. What were the major factors that led you to your overall score for this paper?

The problem is relevant, the approach is sound both rationally and based on 10 subjects. The study suggests something interesting about the biology of the problem.
What is the ranking of this paper in your review stack?

1
Number of papers in your stack

4
Reviewer confidence

Confident but not absolutely certain

Review #2

Please describe the contribution of the paper

The authors investigated non-invasive CFD simulation-based measurements of hepatic venous pressure gradient for potential diagnosis of CSPH. The study used both the geometry and flow boundary conditions from MRI data for CFD simulations. The authors assessed the method in 10 healthy subjects and 5 patients.
Please list the main strengths of the paper; you should write about a novel formulation, an original way to use data, demonstration of clinical feasibility, a novel application, a particularly strong evaluation, or anything else that is a strong aspect of this work. Please provide details, for instance, if a method is novel, explain what aspect is novel and why this is interesting.

If successful, the methodology could mitigate the use of the invasive catheter for diagnosing patients hence limiting its potential risks.
Please list the main weaknesses of the paper. Please provide details, for instance, if you think a method is not novel, explain why and provide a reference to prior work.

• The biggest issue with this work is the improper validation/evaluation of the method feasibility. Particularly, the lack of comparison to a clinical gold standard (e.g. invasive cath) for pressure gradient measurements. Hence, the validations are substandard and could not be used to conclude the method accuracy. • Use of MRI for geometry as boundary conditions which has low spatial resolution. • The authors claim this is the study strength lies in the use of MRI alone. However, this is a limitation. A main reason why not to use MRI for anatomy is the poor spatial resolution (and SNR). • Hepatic and portal vein were extracted separately and an artificial geometry was constructed based on interpolation. Such critical step was not validated against the noninvasive measurements which could have a strong adverse impact on the simulated flow/ PG data. • The additional value of CFD for CSPH diagnosis is not convincing. How does the methodology compare to using PC-MRI alone for computing pressure gradient without CFD?
Please rate the clarity and organization of this paper

Satisfactory
Please comment on the reproducibility of the paper. Note, that authors have filled out a reproducibility checklist upon submission. Please be aware that authors are not required to meet all criteria on the checklist - for instance, providing code and data is a plus, but not a requirement for acceptance

Satisfactory.
Please provide detailed and constructive comments for the authors. Please also refer to our Reviewer’s guide on what makes a good review: https://miccai2021.org/en/REVIEWER-GUIDELINES.html
1. Why hepatic and portal vein were extracted separately? Is this related to an issue with the deep learning segmentation used? There is only 15 cases, why these were not segmented by expert observer manual or semi automatically to avoid such disconnection that required artificial interpolation to resolve (Fig. 3) which further affects the boundary conditions.
2. Given the small sample size, why not show the results of all studied cases for transparency since no statistical comparison was possible.
3. How does the methodology compare to using PC-MRI alone for computing pressure gradient without CFD?
4. How was the accuracy defined? What was the goal of the performed validation? This is unclear.
5. Boundary conditions are defined at a single location but propagated for all the vessels for the results in Fig. 3.
6. The authors are encouraged to revisit their validation strategy and perform more rigorous evaluation against an invasive clinical standard.
Please state your overall opinion of the paper

probably reject (4)
Please justify your recommendation. What were the major factors that led you to your overall score for this paper?

Improper validation and misinterpretation of the results as “proving” the accuracy of the technique for noninvasive assessment of CSPH. Methodological shortcomings e.g. the use of los resolution MRI for geometry boundary conditions and the consequent separate veins segmentation and invalidated artificial interpolation for imposing connected veins. These all question the validity of the results and conclusions.
What is the ranking of this paper in your review stack?

3
Number of papers in your stack

4
Reviewer confidence

Very confident

Review #3

Please describe the contribution of the paper

This article develops a model for estimating hepatic venous pressure gradient (HVPG) based on noninvasive evaluation for the prediction of clinically significant portal hypertension (CSPH) in patients with chronic liver disease. This represents an interesting and multidisciplinary subject. While the invasive procedure requires significant hospital resources, the presented approach is noninvasive and interlaces multi-contrast MRI and CFD simulations. A data set of ten healthy people and five patients with cirrhosis of the liver is considered to show the accuracy of the method.
Please list the main strengths of the paper; you should write about a novel formulation, an original way to use data, demonstration of clinical feasibility, a novel application, a particularly strong evaluation, or anything else that is a strong aspect of this work. Please provide details, for instance, if a method is novel, explain what aspect is novel and why this is interesting.
- A pipeline for estimating the hepatic venous pressure gradient (HVPG) by combining FEM CFD simulations and MRI.
- Good interdisciplinary work from image acquisition to simulations.
- A strategy for constructing the geometry is introduced and explained.
Please list the main weaknesses of the paper. Please provide details, for instance, if you think a method is not novel, explain why and provide a reference to prior work.
- I have some concerns about the efficiency of the approach which should take into account the velocity data in certain areas or parts of the computation domain (optimal control formalism). It is not enough to control the flow by setting only the inlet velocity boundary condition. The presented simulations are not enough and a quantitative validation is necessary.
- The idea of developing numerical approaches by interlacing CFD simulations and MRI data is not new. However, the problem remains difficult.
- This is an FSI issue where structural deformations are expected to have a large impact on the HVPG assessment. Why is it enough to only solve a fluid problem? The authors should comment on this.
- An overly simplified laminar and Newtonian CFD model ignoring various critical flow conditions (eg, turbulent losses, vortical / helical flow) is considered without discussing this choice. Authors must explain why this is sufficient and why a non-Newtonian model of blood flow is not necessary.
- Are there numerical instabilities resulting from reversal flows?
- The works lack novelty in terms of problem formulation and numerical aspects. Although a substantial effort has been made to set up the complete approach and in terms of mesh generation, I find that a fair evaluation of the numerical method is important eg. proof of mesh convergence, quantitative validation.
- Which FEM library is used?
- Provide more details on the size of the mesh and the corresponding computational cost in the case of a fully coupled direct solver.
- No statistical analysis is performed.
Please rate the clarity and organization of this paper

Very Good
Please comment on the reproducibility of the paper. Note, that authors have filled out a reproducibility checklist upon submission. Please be aware that authors are not required to meet all criteria on the checklist - for instance, providing code and data is a plus, but not a requirement for acceptance

Imaging parameters for multi-contrast MRI are provided. Details about the solver are provided.
Please provide detailed and constructive comments for the authors. Please also refer to our Reviewer’s guide on what makes a good review: https://miccai2021.org/en/REVIEWER-GUIDELINES.html

Address the major weaknesses of the paper.
Please state your overall opinion of the paper

accept (8)
Please justify your recommendation. What were the major factors that led you to your overall score for this paper?

The paper is clear. The topic is interesting but the non-invasive MRI-CFD approach is not novel. Only the boundary conditions of the CFD problem are extracted from the imaging data. The authors made efforts to put the various components together. The results are promising but a validation is required. A substantial effort has been made in the construction of the geometry and the approach is well explained.
What is the ranking of this paper in your review stack?

3
Number of papers in your stack

5
Reviewer confidence

Very confident

Primary Meta-Review

Please provide your assessment of this work, taking into account all reviews. Summarize the key strengths and weaknesses of the paper and justify your recommendation. In case you deviate from the reviewers’ recommendations, explain in detail the reasons why. In case of an invitation for rebuttal, clarify which points are important to address in the rebuttal.

This manuscript is clear and very well structured. The assessment by the reviewers is positive and they indicate that the manuscript is reproducible. Comparison with catheter measurements is suggested by the most critic reviewer, which are costly and hard to get, but would certainly raise the value of the work. The use os statistical tools to assess and evaluate the results would certainly improve the contribution of the work.
What is the ranking of this paper in your stack? Use a number between 1 (best paper in your stack) and n (worst paper in your stack of n papers).

2

Author Feedback

Thank you very much for your thorough review of our manuscript as well as the recommendations for improvement of our study. Here we describe the changes that we have made and present our explanations in response to the reviewer’s major comments:

Comparision with the clinical gold standard We agree that comparing the calculated HVPG directly with the clinical measurement using an invasive catheter is the best way for validation. However, currently it is not a clinical routine to perform PC-MRI and DIXON MRI scan before the invasive HVPG measurement. Instead, we attempted to validate our method by differentiating pathologically confirmed liver cirrhosis patients from healthy volunteers based on our virtual HVPG. The limitation is added to the discussion. We are performing prospective studies in our collaborated hospitals to further validate our method.

Statistical evaluation We have added the detailed accuracy analysis in our revised manuscript for better demonstration. The definition of the clinical significant portal hypertension (CSPH) for the statistical analysis is clarified (larger than 10 mmHg). The kappa test has shown substantial consistency (k=0.7) between the diagnosis based on histopathology and our virtual HVPG measurements.

Spatial resolution of MRI We agree that the spatial resolution of CT is usually higher than MRI for liver imaging. Thus in this study, we used a high-resolution 3D GRE sequence for imaging and achieved a resolution of 0.87 × 0.87 × 2.0 mm^3. We believe that the resolution is comparable to conventional CT and adequate for CFD modelling. In addition, the advantage of MRI based CFD is obvious since flow information of multiple inlets/outlets can be measured simultaneously with geometry reconstruction, which can not be done with CT or US alone. The one-stop imaging solution will be more clinical available and can provide more accurate information for CFD modelling.

MRI vessel segmentation We used two separate pre-trained deep neural networks (DNNs) to obtain the portal veins and hepatic veins automatically. The DNNs were trained on an additional dataset including 30 manually labelled cases in our previous work. The measurement of inlet velocity was manually done by an experienced radiologist on the PC-MRI images. Details have been added to the revised manuscript.

Influence of small vessels It has been reported that the side branches do affect some specific wall variables of CFD simulation results, e.g. wall shear stress, although it is in the cardiovascular system [1-3]. However, it was suggested that including side blood vessels up to 1 mm in diameter is enough [3]. While the smallest vessel diameter in our study is no less than 0.87 mm due to the spatial resolution, we believe such simplification has a limited effect on our study of the pressure gradient.

Assumption of CFD model We calculated the Reynolds number and found it to be 27, which means that applying laminar physics and Newtonian fluid model is acceptable rather than the turbulence or non-Newtonian modelling. On the other hand, the geometry of vessels counts a lot in the CFD model and it will be more accurate if we use FSI (Fluid-Structure Interaction) model. However, considering that the patients who suffered from CSPH experienced significantly reduced wall compliance, we believe our assumption of rigid wall reasonable and computational efficient.

Softwares used in the study We used commercial software (COMSOL MULTIPHYSICS) for finite element simulation with the Laminar Fluid module.

[1]. G. AA, et al. Quantifying the effect of side branches in endothelial shear stress estimates. Atherosclerosis. [2]. Li Y, et al. Impact of Side Branch Modeling on Computation of Endothelial Shear Stress in Coronary Artery Disease: Coronary Tree Reconstruction by Fusion of 3D Angiography and OCT. [3]. V. M, et al. The importance of side branches in modeling 3D hemodynamics from angiograms for patients with coronary artery

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Non-invasive Assessment of Hepatic Venous Pressure Gradient (HVPG) Based on MR Flow Imaging and Computational Fluid Dynamics