Methods for modeling hepatic inflammation

Patent metadata

Field	Value
Publication number	US-11004543-B2
Application number	US-201615223367-A
Country	US
Kind code	B2
Filing date	Jul 29, 2016
Priority date	Jun 7, 2010
Publication date	May 11, 2021
Grant date	May 11, 2021

Abstract

Provided herein are in silico methods of modeling hepatic inflammation, fibrosis/cirrhosis, and cancer. The models are computer-implemented agent-based models and are useful in determining patient prognoses in hepatic conditions, including viral infections, damage, inflammation, and cancer. The modeling system also is useful in modeling the effects of active agents on normal hepatic tissue or hepatic tissue perturbed by inflammation, infection, damage, fibrosis/cirrhosis, and cancer.

First claim

We claim:

1. A computer-implemented method of modeling progression of at least one hepatic condition in a patient, comprising:
(i) receiving, with at least one processor, data relating to at least one first parameter of a plurality of parameters associated with a hepatic condition in a patient, the data relating to the at least one first parameter comprising data relating to hepatocytes, stellate cells, and Kupffer cells, and at least one of TNF-α, TGF-β1, and/or HMGB1 levels;
(ii) identifying, with at least one processor, at least one first rule from a rules database, the at least one first rule comprising:
(a) determining a level of TGF-β1 at a position associated with at least one hepatocyte;
(b) comparing the level of TGF-β1 at the position with a threshold TGF-β1 value;
(c) determining that the position is adjacent to a second position having free space; and
(d) creating a new hepatocyte in the second positon having free space when the level of TGF-β1 exceeds the threshold;

(iii) generating, with at least one processor, a simulated progression of the hepatic condition by applying the at least one first rule to the data relating to the at least one first parameter, thereby generating a progression of the hepatic condition based on the at least one first rule;
(iv) generating in a continuous space, using at least one processor and based on the simulated progression, image-based output providing predicted hepatic tissue structure, the image-based output comprising representations of hepatocytes, stellate cells, and Kupffer cells, and storing the image-based output in a database;
(v) repeating steps (i)-(iv) to generate a stochastic range of image-based output of the simulated progressions, the stochastic range of image-based output comprising a plurality of images generated based on interactions among hepatocytes, stellate cells, and Kupffer cells based at least in part on levels of TNF-α, TGF-β1, and/or HMGB1 and the at least one first rule;
(vi) comparing, using at least one processor, the stochastic range of image-based output of the simulated progressions with one or more liver biopsy images, the comparison comprising at least a comparison of one or more hepatocytes, stellate cells, and Kupffer cells; and
(vii) associating, using at least one processor, image-based output corresponding to a matched liver biopsy image and storing the associated data in the database.

2. The computer-implemented method of claim 1 , further comprising:
(viii), associating, using at least one processor, the associated data, and diagnostic information relating to the patient; and
(ix) storing, using at least one processor, the image-based output corresponding to the matched liver biopsy image and the diagnostic information relating to the patient.

3. The computer-implemented method of claim 1 , wherein the data further comprises an image of hepatic tissue and data relating to one or more biologic factors related to the hepatic condition.

4. The computer-implemented method of claim 3 , wherein the step of generating a simulated progression of the hepatic condition comprises a step of modifying the image of hepatic tissue.

5. The computer-implemented method of claim 1 , wherein the image-based output further comprises data relating to predicted hepatic inflammation state, inflammation-induced hepatic damage, hepatic viral load, virally-induced hepatic damage, hepatic tumor presence, hepatic tumor size, hepatic cancer presence, hepatic metastasis size, hepatic metastasis extent, hepatic fibrosis state, or any combination thereof.

6. The computer-implemented method of claim 1 , wherein the data and rule are associated with an active agent, and wherein the image-based output comprises a representation of the effect of the active agent on hepatic inflammation, fibrosis and/or cancer.

7. The computer-implemented method of claim 1 , wherein the data comprise data representing hepatocytes, macrophages, stellate cells, cancer cells, TNF-α, TGF-β1, and HMGB1.

8. The computer-implemented method of claim 1 , wherein the data further comprise data representing one or both of a hepatic lobule and a portal triad.

9. The computer-implemented method of claim 1 , wherein the data further comprise data representing one or more of septa, myofibroblasts, and collagen.

10. The computer-implemented method of claim 1 , wherein the data further comprise data representing hepatic septa, myofibroblasts, and collagen.

11. The computer-implemented method of claim 1 , wherein the data comprise data obtained from a patient.

12. The computer-implemented method of claim 1 , wherein the data further comprise data representing an effect of an active agent on the at least one parameter.

13. The computer-implemented method of claim 1 , wherein the data and rule are associated with simulating surgical removal of a simulated tumor with attendant tissue damage that stimulates further inflammation.

14. The computer-implemented method of claim 1 , wherein the data and rule are associated with simulating a chemotherapeutic cytotoxic drug, such that simulated death of both tumor cells and hepatocytes occurs.

15. The computer-implemented method of claim 1 , wherein the data and rule are associated with simulating an antiviral drug, such that both viral killing and inflammatory damage to the simulated liver tissue are simulated.

16. The computer-implemented method of claim 1 , wherein the data and rule are associated with simulating an anti-inflammatory drug, such that reduction in inflammation and subsequent inflammatory damage to simulated liver tissue, immunosuppression, and virus growth-stimulating effects, are simulated.

17. The computer-implemented method of claim 1 , wherein the data and rule are associated with simulating an anti-fibrotic drug, such that both reduction in fibrosis and subsequent inflammatory damage to simulated liver tissue, as well as suppression of tissue healing, are simulated.

18. The computer-implemented method of claim 1 , further comprising identifying and applying at least one second rule to the data relating to the at least one first parameter, the at least one second rule comprising:
(a) determining a level of TNF-α at a position associated with at least one hepatocyte;
(b) comparing the level of TNF-α at the position with a threshold TNF-α value; and
(c) converting the at least one hepatocyte to a dead cell when the level of TNF-α at the position exceeds the threshold.

19. A system comprising:
a display;
a processor; and
memory having stored thereon programming instructions that when executed by the processor cause the processor to:
(i) receive data relating to at least one first parameter of a plurality of parameters associated with a hepatic condition, the data relating to the at least one first parameter comprising data relating to hepatocytes, stellate cells, and Kupffer cells, and at least one of TNF-α, TGF-β1, and/or HMGB1 levels;
(ii) identify at least one first rule from a rules database, the at least one first rule comprising:
(a) determining a level of TGF-β1 at a position associated with at least one hepatocyte;
(b) comparing the level of TGF-β1 at the position with a threshold TGF-β1 value;
(c) determining that the position is adjacent to a second position having free space; and
(d) creating a new hepatocyte in the second positon having free space when the level of TGF-β1 exceeds the threshold;

(iii) generate a simulated progression of the hepatic condition by applying the at least one first rule to the data relating to the at

Assignees

• Univ Of Pittsburgh—Of The Commonwealth System Of Higher Education

Inventors

• Dutta-Moscato Joyeeta
• Kang Liang-I
• Mi Qi
• Nejak-Bowen Kari
• Vodovotz Yoram

Classifications

• G16H50/50 Primary

  for simulation or modelling of medical disorders · CPC title

• G16B50/00 Primary

  ICT programming tools or database systems specially adapted for bioinformatics · CPC title