"Blood flow simulation for clinical applications" by Dr Irene Vignon-Clementel, Directrice de recherche @Inria Abstract : The dynamics of how blood flows into our body can be numerically simulated. Such simulations provide an 'augmented intelligence' to better understand cardiovascular and organ disease and plan their treatment.

1. Blood flow simulation
for clinical applications
Irene Vignon-Clementel
Directrice de recherche, Inria - France
SIMBIOTX, Inria Saclay Ile-de-France research center
and many collaborators!
Women in Machine Learning and Data Science
L’Oreal Beauty Tech Square, April 5th 2022
In order to survey a potential micro metastatic spread of the disease, samples from bone marrow, peripheral
blood and portal blood will be obtained from all Ltx study subjects for later analyses. Tumour and normal tissue
samples from explanted liver and from hepatic lymph nodes will be obtained for determination of lymphocyte
infiltration (regulatory T-cells), micro-metastatic disease and micro-array analyses.
4.1. Combined liver resection and liver transplantation
Total hepatectomy will be performed in 2 steps. First, a resection of the liver segments 1-3 is performed,
carefully avoiding dividing through tumor affected liver tissue. If needed, additional resection into segment 4
may be perfomed The left portal, arterial and bile duct branches are identified and divided. The Right liver
remnant should be fully mobilized to facilitate the later second stage hepatectomy. The volume of the liver
remnant following resection should be ≥ 40%.of standard liver volume. Standard liver volume is calculated as:
SLV= 1072.8 * body surface area (m2)-345.7 (23) Directly following resection, the patients receive a liver
segments 2+3 from a deceased donor. The donor segments will be placed orthotropically. The graft liver vein
is anastomosed to the orifice of the left liver vein in the recipient with a triangulation technique. The graft
portal vein is anastomosed in an end to side fashion to the main portal trunk and the artery end to side to the
common hepatic artery (figure). The reason for this is that this will obviate the need for complex hilar
dissection at the second stage hepatectomy and also reduce the risk of complications to the liver remnant at
the first operation. Biliary reconstruction is performed as a Roux-en-Y hepatico-jejunostomy.
A t l e a s t 5 m i n u t e s a f t e r
revascularization a pressure
catheter is placed in the portal vein.
Pressure is monitored for 5 minutes
during basal conditions and during
portal clamping of the portal vein
d i s t a l t o t h e g r a f t p o r t a l
anastomosis. At least three repeated
measurements are performed. If the
pressure is stable < 20 mmHg, the
portal vein to the liver remnant is
closed. If the pressure is > 20
mmHg during clamping, the splenic
arery is ligated and pressure
measurements repeated. If the
pressure still exceeds 20 mmHg, a
banding of the portal vein to the liver remnant is performed by creation of a stenosis resulting in a stable portal
pressure of 10-20 mmHg. If this is not possible, e temporal portocaval shunt may be considered. This
provedure is however not very likely to be needed, since the cohort of patients with colorectal liver metastases
normally do not have portal hypertension and a hyperdynamic splanchnic circulation. The diversion of portal
flow to the graft is expected to result in enhanced proliferation of the graft during the course of 2-4 weeks after
combined liver resection and liver transplantation without causing graft injury and small-for-size syndrome due
to portal hyperperfusion (24, 25).
CT scans with volumetry of the transplanted segment is performed at postoperative day1, 7,14, 21 and 28. As
soon as the donor graft has obtained a size of approximately 0,75-0.80% of body weight,or > 35-40% of the
recipients standard liver volume (SLV) a second stage hepatectomy of the liver remnant is performed, leaving
only the donor segments in place.

2. Multi-level analysis, flow & transport modeling
Collaboration DKFZ, Heidelberg U. hosp – Inria
Congenital heart disease: surgical planning,
development
Collaboration Stanford U.
/ Children’s hosp. & Inria
Collaborations UCSD – Berkeley - Inria
& Air Liquide Santé International - Inria
Design of new percutaneous device (POD)
Collaboration Necker Children’s hosp.,
France & Inria
DWI
Cancer: model-based image analysis
Collaboration Cornell U.
& Inria
Respiratory flow & transport in diseases
50 µm
5 cm

3. 3
Cardiovascular system
heart beat (1s)
From Prof. Gunther Von
Hagens “Body Worlds”
exhibition catalogue
Property Density Viscosity
Blood 103 4 10-3
SI units Kg.m-3 Pa.s
I. Vignon-Clementel 3

4. MULTI-LEVEL MATHEMATICAL
MODELS & PATIENT-SPECIFIC
SIMULATIONS
Methods
100 000 km

5. Mathematical biofluid models: physics & IA
I. Vignon-Clementel 5
Math
&
numerical
complexity
Precision
rigid walls or FSI
0D
3D
1D
pressure voltage
flowrate current

6. To each biomedical application its model
I. Vignon-Clementel 6
Math
&
numerical
complexity
Précision
0D
3D
1D
In order to survey a potential micro metastatic spread of the disease, samples from bone marrow, peripheral
blood and portal blood will be obtained from all Ltx study subjects for later analyses. Tumour and normal tissue
samples from explanted liver and from hepatic lymph nodes will be obtained for determination of lymphocyte
infiltration (regulatory T-cells), micro-metastatic disease and micro-array analyses.
4.1. Combined liver resection and liver transplantation
Total hepatectomy will be performed in 2 steps. First, a resection of the liver segments 1-3 is performed,
carefully avoiding dividing through tumor affected liver tissue. If needed, additional resection into segment 4
may be perfomed The left portal, arterial and bile duct branches are identified and divided. The Right liver
remnant should be fully mobilized to facilitate the later second stage hepatectomy. The volume of the liver
remnant following resection should be ≥ 40%.of standard liver volume. Standard liver volume is calculated as:
SLV= 1072.8 * body surface area (m2)-345.7 (23) Directly following resection, the patients receive a liver
segments 2+3 from a deceased donor. The donor segments will be placed orthotropically. The graft liver vein
is anastomosed to the orifice of the left liver vein in the recipient with a triangulation technique. The graft
portal vein is anastomosed in an end to side fashion to the main portal trunk and the artery end to side to the
common hepatic artery (figure). The reason for this is that this will obviate the need for complex hilar
dissection at the second stage hepatectomy and also reduce the risk of complications to the liver remnant at
the first operation. Biliary reconstruction is performed as a Roux-en-Y hepatico-jejunostomy.
A t l e a s t 5 m i n u t e s a f t e r
revascularization a pressure
catheter is placed in the portal vein.
Pressure is monitored for 5 minutes
during basal conditions and during
portal clamping of the portal vein
d i s t a l t o t h e g r a f t p o r t a l
anastomosis. At least three repeated
measurements are performed. If the
pressure is stable < 20 mmHg, the
portal vein to the liver remnant is
closed. If the pressure is > 20
mmHg during clamping, the splenic
arery is ligated and pressure
measurements repeated. If the
pressure still exceeds 20 mmHg, a
banding of the portal vein to the liver remnant is performed by creation of a stenosis resulting in a stable portal
pressure of 10-20 mmHg. If this is not possible, e temporal portocaval shunt may be considered. This
provedure is however not very likely to be needed, since the cohort of patients with colorectal liver metastases
normally do not have portal hypertension and a hyperdynamic splanchnic circulation. The diversion of portal
flow to the graft is expected to result in enhanced proliferation of the graft during the course of 2-4 weeks after
combined liver resection and liver transplantation without causing graft injury and small-for-size syndrome due
to portal hyperperfusion (24, 25).
CT scans with volumetry of the transplanted segment is performed at postoperative day1, 7,14, 21 and 28. As
Precision

7. Parameterization: heterogeneous measurements
I. Vignon-Clementel 7
Direct or surrogate pressure, flow or velocity measurements
0
20
40
60
80
100
120
0 0.1 0.2 0.3 0.4 0.5 0.6
Time (s)
Volume
Flow
Rate
(cc/s)
Doppler ultrasound
(max) velocities Catheterization
PC-MRI flow rate

8. Challenges of subject-specific parameterization
• Hemodynamics data (pressure, flow) are not necessarily acquired
where boundary (forcing) conditions need to be prescribed
• Uncertainty in their acquisition
• Often too few to identify all parameters
• Usually not taken simultaneously: not synchronized in time and at
different heart rates
• Computational complexity for parameter identification need to be
coherent with available amount of information
I. Vignon-Clementel 8

9. COMBINING SIMULATIONS &
MACHINE LEARNING
Acquired aortic disease

10. Abdominal aortic aneurysms: clinical overview
I. Vignon-Clementel 10
• Localized expansion of the arterial wall
• Usually asymptomatic
• If ruptures: mortality > 80% (US CDC)
• Prevalence : ~4% of the population
• 14th leading cause of death in the USA
• Male (↘incidence for women but ↗ rupture risk)
• Hypertension
• …
Treatment (ideally only for high risk patients)
• Stent-graft
• Open-surgery
Can we predict AAA progression?
(mm)

11. Process of AAA development
I. Vignon-Clementel 11
DEFORMATION
• Mecano-adaptation
• Shift of elastin to collagen ratio
WALL DEGRADATION
• ILT promotes arterial cell hypoxia
and inflammation
INTRALUMINAL THROMBUS (ILT)
GROWTH
• Platelet activation in high shear zones
• Platelet deposition in stagnation zones
• Increased platelet adhesion on ILT and
low WSS zones
FLOW ALTERATION
• Transport topology
• Wall Shear Stress
AAA follow-up on 2 patients: ~ 6 months between each

12. Methods
• 138 scans (32 patients with >3 consecutive scans)
• Lumen & thrombus (ILT) segmentations
• CFD
• Pulsatile 3D-0D simulations
• Rigid walls (ok for diseased)
• Postprocessing (global and local patch-wise quantities)
• Morphology
• Hemodynamics
I. Vignon-Clementel 12

13. Building a risk predictor: classifier
13
PCA Repeated
k-fold
Neural-network1
1Multi-Layer Perceptron
(sknn : Theano + Scikit-learn)
• Definition of risk (time n+1)
Dmax (n+1) > 50 mm (55 mm )
Dmax(n+1) −Dmax(n)
∆t
> 5 mm/year
OR
Joly, Soulez, Lessard, Kauffman, VC – Annals of Biomed Eng. 2020, collaboration with CHUM Canada
• Goal: prediction of risk change from low risk to high risk based on current data (n)
• Machine learning process
HIGH RISK else LOW RISK

14. Classification evaluation with current clinical metric
I. Vignon-Clementel 14
Classification using only Dmax as learning feature
Fillinger & al. 2002
A receiver operating characteristic curve, or ROC curve, is a graphical plot that illustrates
the diagnostic ability of a binary classifier system as its discrimination threshold is varied.
Trade-off between sensitivity and specificity. x= false positive rate, y = true positive rate.

15. Features: different sets beyond clinical Dmax
Clinical metrics
• Age
• Sex
• BMI
• Sys- and diastolics BP
• Dyslipidemia
• Statins Morphological metrics
• Dmax
• Volume of ILT
• ILT thickness (max, min , mean, std)
• % lumen covered in ILT
• Lumen centerline curvature and
tortuosity
• Shape index of the lumen (deviation
from a sphere)
Hemodynamics metrics
(max, min , mean, std)
• TAWSS
• OSI
• RRT
• ECAP
• WSSG
I. Vignon-Clementel 15

16. AI results: classification evaluation
I. Vignon-Clementel 16
Clinical features only
Morphological features only
Hemodynamical features only
All features combined
p-values between AUCs according to DeLong & a
method.
Significant values ( <0.05) are in orange cells.

17. SIMULATIONS TO BETTER
UNDERSTAND & PREDICT
SURGERIES
Liver disease

18. Medical context: liver surgery
I. Vignon-Clementel 18
• 25% cardiac output
• regeneration capacity
• metabolism and storage
• drugs and hormones processing
Liver volume
Liver
hemodynamics
Liver function
Liver cancer
Chronic liver disease
Liver transplantation (total liver or split liver)
Partial liver resection (partial hepatectomy)
10 y Collab. with E Vibert & col., APHP-hôpital Paul Brousse

19. Digital twin concept to anticipate portal hypertens.
Intraoperative data
collection + preoperative
volumetric data
Patient requiring major
hepatectomy
Preoperative concern about
postoperative risk of portal
hypertension
EASL risk assessment: intermediate or
high risk of decompensation
Liver function: discrepancy between
current tools available (i.e. normal
indocyanine clearance but elevated liver
stiffness)
High-risk patient (comorbidities)
Golse, …,Vibert, Vignon-Clementel, J Hepatology 2021
erfomed The left portal, arterial and bile duct branches are identified and divided. The Right liver
hould be fully mobilized to facilitate the later second stage hepatectomy. The volume of the liver
ollowing resection should be ≥ 40%.of standard liver volume. Standard liver volume is calculated as:
2.8 * body surface area (m2)-345.7 (23) Directly following resection, the patients receive a liver
2+3 from a deceased donor. The donor segments will be placed orthotropically. The graft liver vein
mosed to the orifice of the left liver vein in the recipient with a triangulation technique. The graft
n is anastomosed in an end to side fashion to the main portal trunk and the artery end to side to the
hepatic artery (figure). The reason for this is that this will obviate the need for complex hilar
at the second stage hepatectomy and also reduce the risk of complications to the liver remnant at
peration. Biliary reconstruction is performed as a Roux-en-Y hepatico-jejunostomy.
t 5 m i n u t e s a f t e r
arization a pressure
s placed in the portal vein.
s monitored for 5 minutes
sal conditions and during
mping of the portal vein
o t h e g r a f t p o r t a l
sis. At least three repeated
ments are performed. If the
s stable < 20 mmHg, the
n to the liver remnant is
If the pressure is > 20
ring clamping, the splenic
ligated and pressure
ments repeated. If the
still exceeds 20 mmHg, a
f the portal vein to the liver remnant is performed by creation of a stenosis resulting in a stable portal
of 10-20 mmHg. If this is not possible, e temporal portocaval shunt may be considered. This
is however not very likely to be needed, since the cohort of patients with colorectal liver metastases
do not have portal hypertension and a hyperdynamic splanchnic circulation. The diversion of portal
graft is expected to result in enhanced proliferation of the graft during the course of 2-4 weeks after
liver resection and liver transplantation without causing graft injury and small-for-size syndrome due
yperperfusion (24, 25).
with volumetry of the transplanted segment is performed at postoperative day1, 7,14, 21 and 28. As
he donor graft has obtained a size of approximately 0,75-0.80% of body weight,or > 35-40% of the
standard liver volume (SLV) a second stage hepatectomy of the liver remnant is performed, leaving
onor segments in place.
Version no. 1.1– 1. August 2013 Page ! of !
11 22
I. Vignon-Clementel 19

20. Digital twin concept to anticipate portal hypertens.
Intraoperative data
collection + preoperative
volumetric data
Patient requiring major
hepatectomy
Preoperative concern about
postoperative risk of portal
hypertension
EASL risk assessment: intermediate or
high risk of decompensation
Liver function: discrepancy between
current tools available (i.e. normal
indocyanine clearance but elevated liver
stiffness)
High-risk patient (comorbidities)
Anticipation of
postoperative
portal/central
pressures + flows
Validation
of simulations
on a cohort of
47 patients
Golse, …,Vibert, Vignon-Clementel, J Hepatology 2021

21. Conclusions on hemodynamic digital twins
• Interactions between local changes and the global circulation
• Biofluid simulations :
• To understand the system/a disease/a treatment
• To predict/plan an intervention for a specific patient
• To test new treatment ideas of clinicians

22. Conclusions on hemodynamic digital twins
• Machine learning can be complementary to biophysical modeling:
palliate the lack of mechanistic equations / speed up simulations
• Great tool progress…
but validation remains an issue
• Data acquisition
• Data standardization
• Access to large cohorts
• More impact on patients
Digital
twin
Patient
data
Biophysical
model
Machine
learning