System, method and apparatus for causal implication analysis in biological networks

• US 20050165594A1
• Filed: 11/19/2004
• Published: 07/28/2005
• Est. Priority Date: 11/26/2003
• Status: Active Grant

• Current Assignee: Selventa, Inc.
• Original Assignee: Selventa, Inc.
• Inventors: Pratt, Dexter, Chandra, Dundee Navin, Kightley, David, Chandra, Maria Fatima, Sun, Justin, Segaran, Suresh Toby
• Granted Patent: US 8,594,941 B2
• Time in Patent Office: Days
• US Class Current: 703/11
• CPC Class Codes: G16B 40/00 ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding
• CPC Class Codes: G16B 5/00 ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks
• CPC Class Codes: G16B 5/20 Probabilistic models

Abstract

Described are methods, systems and apparatus for hypothesizing a biological relationship in a biological system. A database of biological assertions is provided consisting of biological elements, relationships among the biological elements, and relationship descriptors characterizing the properties of the elements and relationships. A biological element may be selected from the database and a logical simulation may be performed within the biological database, from the selected biological element, through relationship descriptors, along a path defined by potentially causative biological elements to discern a biological element hypothetically responsible for the change in the selected biological element. The logical simulation may be either a backward logical simulation, performed upstream through the relationship descriptors to discern a hypothetical responsible biological element, or a forward logical simulation, performed downstream through the relationship descriptors to discern the extent to which the perturbation generates the observed change in the selected biological element.

Claims

1. A software implemented method for hypothesizing a biological relationship in a biological system, the method comprising:

(a) providing a database of biological assertions comprising a multiplicity of nodes representative of biological elements, relationship descriptors describing relationships between nodes, and characterizing properties of said nodes and relationships;

(b) selecting a target node in the database known from experimental observation to correspond to a biological element which increases in number or concentration, decreases in number or concentration, appears within, or disappears from a real biological system when it is perturbed; and

(c) performing a backward logical simulation within said database from said target node through said relationship descriptors upstream along a path defined by potentially causative nodes to discern a node hypothetically responsible for the experimentally observed change in said target node.

2. The method of claim 1 comprising the additional steps of:

(a) simulating perturbation of said hypothetically responsible nodes; and

(b) performing a forward logical simulation within said database from said hypothetically responsible nodes through said relationship descriptors downstream along a path defined by potentially affected nodes to discern the extent to which said simulated perturbation generates the experimentally observed change in said target node.

3. The method of claim 1 wherein the database comprises noisy data, erroneous data, or omits nodes representing structures, processes, or networks present in the real biological system.

4. The method of claim 1 further comprising applying a probability algorithm to plural hypotheses to assess which hypothetical relationship has the highest probability of representing real biology.

5. The method of claim 1 wherein said biological system is a mammalian biological system, and wherein the method further comprising determining the identity of a second hypothetically responsible node upstream of a said hypothetically responsible node, predicted to induce upon inhibition or stimulation a predetermined change in the biological system.

6. The method of claim 1 comprising the additional step of conducting an experiment on a specimen of said biological system to determine if said hypothetical relationship corresponds to said observed change.

7. The method of claim 1 comprising the additional step of conducting an experiment on a specimen of said biological system to attempt to induce said observed change.

8. The method of claim 1 wherein said biological system is a mammalian biological system in a biological state perturbed from stasis and wherein the perturbation is induced by a disease, toxicity, environmental exposure, abnormality, morbidity, aging, or other stimulus.

9. The method of claim 8 further comprising determining the state of a group of nodes reproducibly associated with the biological state of said mammal which can act as a marker set characteristic of said biological state.

10. The method of claim 1, wherein said relationship descriptors comprise descriptors of the condition, location, source, amount, or substructure of a molecule, biological structure, physiological condition, trait, phenotype, biological process, clinical data, medical data, or disease data and chemistry.

11. The method of claim 1, wherein one or more relationship descriptors correspond to an epistemological relationship between a pair of nodes.

12. The method of claim 1, wherein one or more of the relationship descriptors comprise a case frame.

13. The method of claim 1, wherein said database comprises at least 1,000 nodes.

14. The method of claim 1, wherein said database comprises at least 5,000 nodes.

15. The method of claim 1, wherein said database comprises at least 10,000 nodes.

16. The method of claim 1, wherein said database comprises at least 50,000 nodes.

17. The method of claim 1, wherein said database comprises at least 100,000 nodes.

18. A software implemented method for hypothesizing a biological relationship in a biological system, the method comprising:

(a) providing a database of biological assertions comprising a multiplicity of nodes representative of biological elements, relationship descriptors describing relationships between nodes, and characterizing properties of said nodes and relationships;

(b) selecting for investigation a target node in the database;

(c) specifying a perturbation of said target node comprising an effective increase in concentration or number, stimulation of activity, an effective decrease in concentration or number, inhibition of activity, or the appearance or disappearance thereof; and

(d) performing a logical simulation within said database from said target node, through said relationship descriptors;

(i) upstream along a path defined by nodes affecting the state of said target node directly or indirectly to discern a hypothesis potentially explanatory of a cause of the specified change in said target node within the system or a node hypothetically responsible for said specified change in said target node, or;

(ii) downstream along a path defined by nodes affected by said target node directly or indirectly to discern a hypothesis potentially explanatory of an effect of the specified change in said target node within the system or a node hypothetically affected by said specified change in said target node.

19. The method of claim 18 comprising the additional steps of:

(a) simulating perturbation of a node hypothetically responsible for said specified change in said target node; and

(b) performing a backward logical simulation within said database from said hypothetical target node through said relationship descriptors upstream along a path defined by potentially affecting nodes to discern the extent to which said simulated perturbation causes the specified change in said target node.

20. The method of claim 19 comprising the additional step of conducting an experiment on a specimen of said biological system to confirm or refute said hypothesized cause.

21. The method of claim 18 comprising the additional steps of

(a) simulating perturbation of said target node;

and

(b) performing a forward logical simulation within said database from said target node through said relationship descriptors downstream along a path defined by potentially affected nodes to discern the extent to which said simulated perturbation generates the hypothesized effects of the specified change in said target node.

22. The method of claim 21 comprising the additional step of conducting an experiment on a specimen of said biological system to confirm or refute said hypothesized consequence.

23. The method of claim 18 wherein the database comprises noisy data, erroneous data, or omits nodes representing structures, processes, or networks present in the biological system.

24. The method of claim 18 further comprising applying a probability algorithm to plural hypotheses to assess which hypothetical relationship has the highest probability of representing real biology.

25. The method of claim 18 wherein said biological system is a mammalian biological system, and wherein the method further comprising determining the identity of a second node hypothetically responsible for said specified perturbation or a node upstream of a said hypothetically responsible node predicted to induce upon inhibition or stimulation said specified perturbation.

26. The method of claim 25 comprising the additional step of conducting an experiment on a specimen of said biological system to determine if said identified node hypothetically responsible for said specified perturbation or a node upstream of said hypothetically responsible node induces said specified perturbation.

27. The method of claim 18 wherein said biological system is a mammalian biological system and the specified perturbation of said target node is selected to simulate a perturbation suspected to be present in said mammalian biological system when said system is in a state of disease, toxicity, environmental exposure, abnormality, morbidity, aging, or response to other stimulus.

28. The method of claim 18, wherein said relationship descriptors comprise descriptors of the condition, location, source, amount, or substructure of a molecule, biological structure, physiological condition, trait, phenotype, biological process, clinical data, medical data, or disease data and chemistry.

29. The method of claim 18, wherein one or more relationship descriptors correspond to an epistemological relationship between a pair of nodes.

30. The method of claim 18, wherein one or more of the relationship descriptors comprise a case frame.

31. The method of claim 18, wherein said database comprises at least 1,000 nodes.

32. The method of claim 18, wherein said database comprises at least 5,000 nodes.

33. The method of claim 18, wherein said database comprises at least 10,000 nodes.

34. The method of claim 18, wherein said database comprises at least 50,000 nodes.

35. The method of claim 18, wherein said database comprises at least 100,000 nodes.

36. A software implemented method for hypothesizing a biological relationship in a biological system, the method comprising:

(a) providing a database of biological assertions comprising a multiplicity of nodes representative of biological elements, relationship descriptors describing relationships between nodes, and characterizing properties of said nodes and relationships;

(b) selecting at least a pair of target nodes in the database; and

(c) performing a logical simulation within said database between said target nodes through said relationship descriptors along a path defined by at least one potentially causative node or at least one potential effector node to discern one or a group of pathways hypothetically linking said target nodes.

37. The method of claim 36 comprising the additional steps of:

(a) simulating perturbation of one of said pair of nodes; and

(b) performing a forward logical simulation within said database through said relationship descriptors from said virtually perturbed node downstream along a path defined by potentially affected nodes to discern the extent to which said simulated perturbation generates a predicted effect on the other of said pair of nodes.

38. The method of claim 36 wherein the database comprises noisy data, erroneous data, or omits nodes representing structures, processes, or networks present in the biological system.

39. The method of claim 38 further comprising applying a probability algorithm to plural hypothetical pathways to assess which pathway has the highest probability of representing real biology.

40. The method of claim 36 comprising the additional step of conducting an experiment on a specimen of said biological system to determine the existence or operability of said hypothetical pathway.

41. The method of claim 36, wherein said relationship descriptors comprise descriptors of the condition, location, source, amount, or substructure of a molecule, biological structure, physiological condition, trait, phenotype, biological process, clinical data, medical data, or disease data and chemistry.

42. The method of claim 36, wherein one or more relationship descriptors correspond to an epistemological relationship between a pair of nodes.

43. The method of claim 36, wherein one or more of the relationship descriptors comprise a case frame.

44. The method of claim 36, wherein said database comprises at least 1000 nodes.

45. The method of claim 36, wherein said database comprises at least 5000 nodes.

46. The method of claim 36, wherein said database comprises at least 10,000 nodes.

47. The method of claim 36, wherein said database comprises at least 50,000 nodes.

48. The method of claim 36, wherein said database comprises at least 100,000 nodes.