dkNET New Investigator Pilot Program in Bioinformatics Awardee Webinar Series Presenter: Jack Virostko, Ph.D. Assistant Professor of Diagnostic Medicine, Dell Medical School, University of Texas at Austin; Appointments in Oncology, Oden Institute for Computational Engineering and Sciences, LIVESTRONG Cancer Institutes Abstract The pancreas is smaller in individuals with diabetes and those at risk for developing the disease. Furthermore, quantitative measures of pancreas morphology and composition are altered in individuals with diabetes and display longitudinal changes accompanying disease progression. This talk will introduce MRI techniques for interrogating the pancreas. I will also demonstrate how machine learning may improve our understanding of pancreas changes in individuals with diabetes. Upcoming webinars schedule: https://dknet.org/about/webinar

1. Machine Learning To Analyze
Pancreas Imaging In Diabetes
Jack Virostko, Ph.D., MSCI
4/22/2022

2. The Pancreas is First Affected in Type 1
Diabetes, but We Don’t Assay It
Virostko, et al. Mol Imaging Biol 2010.
Pancreas
Bladder
Liver
Intestines
Head
Virostko, et al. PNAS 2011.
Genetic
Susceptibility
Time (months or years)
Triggering Event
Autoimmune
Process
No Diabetes
Clinical Diabetes
100 %
10 %
Beta
Cells
• Interest in
measuring
beta cell
mass

3. Control T1D
Pancreas volume = 26.95 cm3
10 y.o. male, 64 lbs.
Pancreas volume = 14.28 cm3
10 y.o. male, 64 lbs.
People with Type 1 Diabetes (T1D) Have a
Smaller Pancreas
Reduced pancreas size also found in individuals with type 2 diabetes

4. p < 0.001
• 56 controls, 49 T1D
• Average 67 days
post T1D diagnosis
25
50
75
100
125
Control T1D
Pancreas
Volume
(ml)
Pancreas Size is Smaller in T1D
Virostko, et al. Diabetes Care 2019

5. Volume of Coke Can = 355 mL
Pancreas in Control = 48 mL
Pancreas in T1D = 30 mL
Pancreas Size is Smaller in T1D
Islet Volume = 0.48 mL
→ Exocrine
Involvement in
T1D Pathogenesis

6. Why is the Pancreas Smaller in T1D?
Pancreatic Islet
Pancreas
Autoimmune Destruction of Exocrine Pancreas Loss of Insulin as Trophic Factor
X
X
X
X
X
Pancreatic Islet
Pancreas
Beta Cell
(Insulin)
X
X
Trophism

7. 0
50
100
150
0 100 200 300
weight (lbs)
Pancreas
Volume
(ml)
• Age range 8 – 35 yrs
• Average age = 13.4 ± 4.1 yrs
• Pancreas volume index =
Pancreas Volume
Subject Weight
Pancreas Volume Proportional to Body
Weight

8. 0.4
0.8
1.2
1.6
Control T1D
Pancreas
Volume
Index
(ml/kg)
p < 0.001
• Pancreas volume index =
Pancreas Volume
Subject Weight
• 56 controls, 49 T1D
• p < 0.001 while adjusted
for age, gender, BMI
Pancreas Volume Index Lower in T1D

9. Genetic
Susceptibility
Time (months or years)
Progressive
Loss of Beta
Cells
No Diabetes
Clinical Diabetes
100 %
10 %
Beta Cells
Does the Size of the Pancreas Change?

10. 0.5
1.0
1.5
0 1 2 3 4 5
Duration of Diabetes [years]
Pancreas
Volume
Index
[ml/kg]
p < 0.001 P < 0.05
Pancreas Volume Declines After Diagnosis
Diagnosis with T1D
• Pancreas size
declines ~ 10%
in first year
after diagnosis
with T1D

11. Pancreas Volume Continues to Decline in
Longstanding T1D
0.5
1.0
1.5
20 40 60
Age [years]
Pancreas
Volume
Index
[ml/kg]
subject
T1D
Control

12. Genetic
Susceptibility
Time (months or years)
Triggering
Event
Autoimmune
Process
Window for
therapeutic
intervention
No Diabetes
Clinical Diabetes
100 %
10 %
Beta Cells
What about the pancreas prior to diagnosis?

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0.5
1.0
1.5
2.0
Control AAb+ T1D
Pancreas
Volume
Index
(ml/kg)
Number of Ab
●
2
3
4
5
0
NA
26 subjects with
multiple AAb+
Average age
16.1 ± 8.1 yrs
54% male
p < 0.0001
p < 0.05
Intermediate Pancreas Volume in AAb+ Individuals

14. 256 x 198 voxels x 30 slices
~ 3 MB of data
Pancreas volume = 40.5 ml
40.5 stored as a double data type
8 bytes data
(<300,000 fold loss of information)
A Picture is Worth 1000 Words

15. An Analogy to Histology
• Size
• Shape
• Different contrasts
• Spatial relationships

16. T1D
Control
Bounding Box Bounding Convex Hull Principal Axes
Pancreas Shape Can Be Quantitatively Characterized

17. p < 0.005 p < 0.005 p < 0.005 p < 0.005
p < 0.005 p < 0.005 p < 0.005 p < 0.01
Pancreas Morphometry is Altered in T1D

18. 0.00
0.25
0.50
0.75
1.00
0.00 0.25 0.50 0.75 1.00
1−Specificity
Sensitivity
Pancreas Volume Index
AUC = 0.83
Pancreas Volume Index + Shape Metrics
AUC = 0.91
Pancreas Shape Improves Discrimination of
Pancreas Changes in T1D

19. T1-weighted Image T2-weighted Image
MRI Contrast Can Be Tuned

20. Multiparametric MRI Acquired in Single Scan
Healthy Pancreas Diabetic Pancreas
Pancreas alteration MRI metric sensitive to alteration
Reduced volume Volumetric MRI
Changes in cell density Diffusion-weighted MRI
Ectopic fat accumulation Proton density fat fraction
Reduced protein content T1 relaxation time maps
Fibrosis Magnetization transfer MRI, T1 map
Inflammation T2 relaxation time maps
Fibrosis
Inflammation
Altered Cell Density
Ectopic fat
Protein content
• No contrast agent
required
• Spatially resolved
• Intrinsically co-
registered

21. Control
T1D
ADC Maps from Diffusion-weighted MRI
Pancreas Microstructure is Altered in T1D

22. Can AI Distinguish the Pancreas of an Individual
with T1D from a Control?
Control
T1D
Images Only
Images +
Demographic Data +
Summary Imaging
Metrics

23. The Pancreas is Also Altered in Type 2
Diabetes (T2D)
PLoS One. 2015 May 7;10(5):e0126825.
• The multimodal
imaging signature of
the pancreas in T2D
likely differs from T1D
– Shape
– Fat content
– Inflammation

24. Time (months or years)
100 %
10 %
Beta Cells
Type 1 Diabetes
(T1D)
Type 2
Diabetes (T2D)
Prediabetes Diabetes
Putative Natural History of Type 2 Diabetes
(T2D)
Insulin
Resistance
Difficulty Identifying
and/or Timing
Precipitating Events

25. Pancreas Dynamics After Liver
Transplantation
• A2ALL Study: Adult Living Donor Liver Transplantation Studies
– NIDDK abdominal image repository of liver transplant donors and recipients
• 30% of liver transplant recipients develop diabetes
• dkNET Pilot Grant: ‘Machine Learning of Abdominal MRI and CT in the
A2ALL Liver Transplant Study’

26. • Imaging performed before and
after liver transplantation
• Recipients and donors
• 9 clinical centers
– 559 CT scans
– 476 MRI scans
A2ALL Study Details

27. Pancreas Declines in Size in Liver
Transplant Recipients
1 week pre liver transplantation 2 months post liver transplantation

28. Pancreas Shrinks in Liver Transplant
Recipients
• 71 pre/post
measurements
• May reflect altered
metabolic demand and
increased risk of
diabetes
P
r
e
T
r
a
n
s
p
l
a
n
t
P
o
s
t
T
r
a
n
s
p
l
a
n
t
0
50
100
150
200
Pancreas
Volume
[ml]
✱✱✱✱

29. • Performed for 247
images
• Time consuming!
– Pancreas present on
~20 slices per MRI
– Some images have >40
slices with pancreas
Manual Pancreas Segmentation

30. 0 20 40 60 80 100
0
20
40
60
80
100
Manual Pancreas Volume [ml]
Automatic
Pancreas
Volume
[ml]
T1D
Control
Manual
Manual
Automatic
Automatic
T1D
Control
Manual / Automatic
Manual / Automatic
Segmentation of the Pancreas Using AI
Mean Dice Coefficient = 0.81 BMC Med Imaging. 2022 Jan 5;22(1):5.

31. A2ALL Images: Multisite & Multimodal
Pancreas Images to Train Segmentation

32. Performing Quantitative Pancreas MRI in
Multisite Trials
Kovler Diabetes Center, University of
Chicago, Chicago, IL
Siri Atma W. Greeley, M.D., Ph.D.
Louis H. Philipson, M.D., Ph.D.
St. Vincent’s Institute of
Medical Research,
Melbourne, AUS
Thomas Kay, MBBS, Ph.D.
Helen Thomas, Ph.D.
Vanderbilt University Medical
Center, Nashville, TN
Alvin C. Powers, M.D.
Daniel J. Moore, M.D., Ph.D.
William E. Russell, M.D.
Melissa Hilmes, M.D.
Dell Medical School,
University of Texas, Austin, TX
John Virostko, Ph.D.
Barbara Davis Center for
Diabetes, University of Colorado
School of Medicine, Aurora, CO
Andrea K. Steck, M.D.

33. Different MRI Hardware and Software Can
Affect Images
Vendor MRI Scanner Software RF Coil
Vanderbilt
University
Philips 3T Ingenia CX R5.3
Torso + Posterior
(32 channels total)
University of
Colorado Denver
Siemens 3T Skyra VE11C 16 channel torso
University of
Chicago
Philips
3T Ingenia / 3T
Achieva TX dStream
R5.4.1(Ingenia)/R5.3.1(Ac
hieva)
Torso + Posterior
(32 channels total)
University of
Melbourne
Siemens 3T Prisma VE11C 16 channel torso
University of
Texas Austin
Siemens
3T Skyra /
3T Vida
VE11C 16 channel torso
Vanderbilt
Philips
Texas
Siemens

34. Healthy
Volunteers
x5
Phantom & Volunteer Imaging

35. 1 2 3 4 5
0.0
0.5
1.0
1.5
Subject Number
Pancreas
Volume
Index
[ml/kg]
Nashville
Austin
Denver
Chicago
1 2 3 4 5
0
500
1000
1500
Subject Number
Pancreas
T1
[ms]
Nashville
Austin
Denver
Chicago
1 2 3 4 5
0.00
0.05
0.10
0.15
Subject Number
Surface
Area
to
Volume
[cm
-1
]
Nashville
Austin
Denver
Chicago
1 2 3 4 5
0.0000
0.0005
0.0010
0.0015
0.0020
Subject Number
Pancreas
ADC
[mm
2
/s]
Nashville
Austin
Denver
Chicago
Harmonized Pancreas MRI Protocol is
Reproducible

36. Conclusions
• The pancreas displays progressive reduction in size during the development
of diabetes
• The pancreas declines in size after liver transplantation
• MRI can characterize an array of pancreas alterations in diabetes
– Size
– Shape
– Structure / Composition
• Machine learning can characterize alterations in pancreas MRI
accompanying diabetes

37. Vanderbilt University
Dan Moore, MD, PhD
Al Powers, MD
Melissa Hilmes, MD Jon Williams, PhD
Dell Medical School UT Austin
Barbara Davis Center
St. Vincent’s Institute
Kovler Diabetes Center
Jack Virostko, PhD
Siri Greeley, MD, PhD Lou Philipson, MD, PhD Mariko Pusinelli, FNP-BC
Tom Kay, MBBS, PhD Helen Thomas, PhD
Andrea Steck, MD Hali Broncucia, MA Taylor Triola, MD
Chandrajit Bajaj, PhD