Virtual models of complex systems
First Claim
1. A computer readable medium or media comprising a virtual model of a complex system implementable in a computer system, comprising a plurality of model elements and program instructions, wherein:
- i) the model elements include first elements representing pools of any number of entities of a given type, state and/or compartment, and a plurality of second elements representing processes of different types in which the pools of entities participate;
ii) there are a plurality of input, regulator and output references or links between a plurality of said first and second elements; and
iii) the program instructions comprise functions to integrate in the computer system said first and second elements according to said references or links, resulting in a network of one or more pathways, at least one of said first or second elements acting as junctions where different pathways merge or different pathways branch, or both, the network representing the topology of the interactions detected between the components of the complex system.
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Accused Products
Abstract
A computer based virtual models of complex systems, together with integrated systems and methods provide a development and execution framework for visual modeling and dynamic simulation of said models. The virtual models can be used for analysis, monitoring, or control of the operation of the complex systems modeled, as well as for information retrieval. More particularly, the virtual models in the present implementation relate to biological complex systems. In the current implementation the virtual models comprise building blocks representing physical, chemical, or biological processes, the pools of entities that participate in those processes, a hierarchy of compartments representing time-intervals or the spatial and/or functional structure of the complex system in which said entities are located and said processes take place, and the description of the composition of those entities. The building blocks encapsulate in different layers the information, data, and mathematical models that characterize and define each virtual model, and a plurality of methods is associated with their components. The models are built by linking instances of the building blocks in a predefined way, which, when integrated by the methods provided in this invention, result in multidimensional networks of pathways. A number of functions and graphical interfaces can be selected for said instances of building blocks, to extract in various forms the information contained in said models. Those functions include: a) on-the-fly creation of displays of interactive multidimensional networks of pathways, according to user selections; b) dynamic quantitative simulations of selected networks; and c) complex predefined queries based on the relative position of pools of entities in the pathways, the role that the pools play in different processes, the location in selected compartments, and/or the structural components of the entities of those pools. The system integrates inferential control with quantitative and scaled simulation methods, and provides a variety of alternatives to deal with complex dynamic systems and with incomplete and constantly evolving information and data.
435 Citations
119 Claims
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1. A computer readable medium or media comprising a virtual model of a complex system implementable in a computer system, comprising a plurality of model elements and program instructions, wherein:
- i) the model elements include first elements representing pools of any number of entities of a given type, state and/or compartment, and a plurality of second elements representing processes of different types in which the pools of entities participate;
ii) there are a plurality of input, regulator and output references or links between a plurality of said first and second elements; and
iii) the program instructions comprise functions to integrate in the computer system said first and second elements according to said references or links, resulting in a network of one or more pathways, at least one of said first or second elements acting as junctions where different pathways merge or different pathways branch, or both, the network representing the topology of the interactions detected between the components of the complex system. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69)
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2. The computer readable medium or media of claim 1, the program instructions further comprising functions to generate visual representations of said network of pathways on the display means of said computer system.
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3. The computer readable medium or media of claim 1, wherein said program instructions further comprise functions to generate on-the-fly visual representations of subsets of networks of pathways which meet user-defined criteria, including the selection of at least one of said first or second elements as starting nodes or a direction upstream or downstream from said starting nodes, or any combination thereof.
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4. The computer readable medium or media of claim 1, wherein said program instructions further comprise functions to display visual representations of said elements on the display means of said computer system, and navigation functions associated with said visual representations, enabling interactive navigation between related elements.
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5. The computer readable medium or media of claim 1, wherein at least one of said regulator references or links represents an activator, inhibitor, catalyst, ligand, agonist, antagonist, repressor, or promoter.
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6. The computer readable medium or media of claim 1, wherein a plurality of said elements are classified according to a semantically meaningful hierarchy.
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7. The computer readable medium or media of claim 1, further comprising an inference engine capable of data type reasoning over instances of said elements or over the values of properties or attributes of said instances.
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8. The computer readable medium or media of claim 1 wherein said program instructions comprise chaining functions to establish downstream or upstream relationships between chains of first or second elements, or any combination thereof, identified based on the sequential order of said first and second elements as defined by said references or links.
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9. The computer readable medium or media of claim 1 wherein said program instructions further comprise query functions in reference to one or more of said first or second elements, or any combination thereof, including criteria based on the upstream or downstream position within said network, or both, of any first or second element in relation to said one or more reference elements.
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10. The computer readable medium or media of claim 1, wherein said program instructions further comprise query functions to identify a downstream set of any number of said first or second elements, or any combination thereof, of said virtual model which represents a set of pools of entities or processes, or any combination thereof, of said complex system which are putatively affected by manipulating at least one other of said entities or processes represented by a reference query set of at least one of said first or second elements.
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11. The computer readable medium or media of claim 1, wherein said program instructions further comprise query functions to identify an upstream set of any number of said first or second elements, or any combination thereof, of said virtual model which represents a set of pools of entities or processes of said complex system which are putative targets for manipulation to achieve any desired outcome, including affecting entities or processes represented by a reference query set of at least one of said first or second elements.
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12. The computer readable medium or media of claim 1, the model elements further comprising a plurality of entity elements, each comprising descriptions of the common structure, composition or state, or any combination thereof, of the entities represented by one or more of said pools of entities.
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13. The computer readable medium or media of claim 12, wherein said program instructions comprise query functions including criteria based on the structure, composition or state described in the entity elements.
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14. The computer readable medium or media of claim 1, the model elements further comprising a plurality of organizing elements representing compartments, including space, time-interval, or function compartments, or any combination thereof, organized in one or more levels of a hierarchy, each level representing a respective level of complexity, wherein said first and second elements have relationships with their corresponding organizing elements in the hierarchy.
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15. The computer readable medium or media of claim 14 wherein said program instructions further comprise query functions in reference to one or more of said first and second elements selected as reference elements, including criteria based on the upstream or downstream position within said network of any first or second element, the types of its references or links, its relationship with any organizing element, or any combination thereof.
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16. The computer readable medium or media of claim 14, wherein said complex system is a biological system, and said organizing elements comprise elements to represent compartments of biological organization.
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17. The computer readable medium or media of claim 16, wherein the biological organization represented by said organizing elements comprise organization at the molecular assembly, reaction cascade, subcellular, cellular or multi-cellular levels, or any combination thereof, in one or more levels of a hierarchy.
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18. The computer readable medium or media of claim 16, wherein said organizing elements comprise one or more elements to represent different stages during cell activation, cell cycle, apoptosis, differentiation, disease or life cycle, or any combination thereof, organized in one or more levels of a hierarchy.
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19. The computer readable medium or media of claim 1, wherein said virtual model represents a biological cellular system applicable to model the transduction of signals provided by ligands in their external environment to the interior of the cell, resulting in the execution of specific functions.
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21. The computer readable medium or media of claim 1, wherein at least one of said elements implements a lumped parameter system, black-box system, encapsulation or aggregation.
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22. The computer readable medium or media of claim 1 wherein a plurality of said second elements comprise stoichiometric coefficients relating said inputs and outputs.
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23. The computer readable medium or media of claim 1 wherein:
- a) a plurality of said second elements comprise rate variables representing quantitative or semi-quantitative rates of conversion of inputs into outputs; and
b) said program instructions comprise simulation functions to infer or compute, or any combination thereof, the value of said rate variables when simulating the behavior of said complex system.
- a) a plurality of said second elements comprise rate variables representing quantitative or semi-quantitative rates of conversion of inputs into outputs; and
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24. The computer readable medium or media of claim 23 wherein:
- a) said rate variables are of a plurality of different types, representing different types of processes; and
b) said simulation functions comprise a plurality of different types of functions to infer or compute, or any combination thereof, the value of the corresponding different types of rate variables.
- a) said rate variables are of a plurality of different types, representing different types of processes; and
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25. The computer readable medium or media of claim 1, wherein said complex system is a biological system and a plurality of the entities represented are of at least one of the following types:
- cell, gene, mRNA, protein or any assembly, complex or combination thereof.
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26. The computer readable medium or media of claim 25, wherein a plurality of said elements further comprise links to a plurality of databases, the model providing a mechanism for integration of data in said databases.
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27. The computer readable medium or media of claim 25, wherein said program instructions further comprise query functions in reference to a set of one or more of said first or second elements, or any combination thereof, selected as reference, including criteria based on the upstream or downstream position within said network, or both, of any first or second element, or the types of its references or links, or any combination thereof, the result set representing any number of pools of entities or processes which are putative targets for or affected by manipulation of said biological system.
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28. The computer readable medium or media of claim 27, wherein said query functions identify an upstream set of any number of said first or second elements, or any combination thereof, representing pools of entities or processes of said biological system which are putative targets for manipulation to achieve any desired outcome, including affecting the expression of any gene(s) or receptor(s), or the secretion of any substance(s), or any combination thereof, wherein the one or more pools of entities or processes which are biomarkers for the outcome are represented by the reference query set.
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29. A method for identifying desirable targets for screening agents or combination of agents to be further tested for the prevention or treatment of adverse conditions on a human or any other living organism, or any part thereof, comprising applying the virtual model and program instructions of the computer readable medium or media of claim 28 in a computer system to identify pools of entities or processes, represented by said upstream set, which are putative targets for manipulation in said human or other living organism, or any part thereof, to achieve any desired outcome known to affect the prevention or treatment of said adverse conditions, wherein said reference query set represents the one or more pools of entities or processes which are biomarkers for the desired outcome.
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30. A method for designing strategies for controlling the expansion or further differentiation of progenitor or other precursor living cells in a cell culture or reactor to produce outcome cells of one or more types having characteristic phenotypes, comprising:
- i) applying the virtual model and program instructions of the computer readable medium or media of claim 28 in a computer system to identify the upstream set of pools of entities or processes which are putative targets for putative inducing agents, the reference query set representing the pools of entities or processes which are biomarkers for the one or more phenotypes of the desired outcome cells; and
ii) applying the one or more of said identified targets for designing a strategy for controlling the expansion or further differentiation of said precursor cells in said cell culture medium.
- i) applying the virtual model and program instructions of the computer readable medium or media of claim 28 in a computer system to identify the upstream set of pools of entities or processes which are putative targets for putative inducing agents, the reference query set representing the pools of entities or processes which are biomarkers for the one or more phenotypes of the desired outcome cells; and
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31. A computerized storage and retrieval system of biological information comprising the virtual model and instructions of the computer readable medium or media of claim 27.
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32. A method for identifying or characterizing candidates for agent development, including drugs or any other preventive, diagnostic, prognostic or therapeutic agents or procedures, or any combination thereof, comprising applying the virtual model and program instructions of the computer readable medium or media of claim 27 in a computer system to determine the pools of entities or processes in said biological system which are putatively affected by applying said at least one candidate agent or involved in attaining a desired outcome, wherein the model of the applicable biological system includes at least one first or second element representing at least one agent or its interaction with the biological system or a biomarker for the desired outcome in said biological system.
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33. The method of claim 32, wherein the virtual model and program instructions are applied to identifying any number of first or second elements which are downstream of the at least one first or second element representing in said virtual model at least one agent or its interaction with the biological system, and thereby identifying pools of entities or processes in said biological system which are putatively effected by said at least one agent acting upon said biological system.
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34. The method of claim 32, wherein the virtual model and program instructions are applied to:
- i) selecting a set of two or more of said first or second elements representing two or more agents or their interactions with their targets, ii) identifying a shared set of any number of first or second elements which are shared by the pathways downstream from the first or second elements of the selected set, and iii) identifying any outcome which would be affected by changes in the pools of entities or processes represented by the shared set as a result from manipulating the pools of entities or processes represented by the selected set, and thereby identifying or characterizing putative combined therapy regimes or harmful side effects of the combination of two or more selected agents.
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35. The method of claim 32, wherein the virtual model and program instructions are applied to identifying any number of first and second elements in said virtual model which are upstream of the at least one first or second element representing in said virtual model at least one pool of entities or process which are biomarkers for a desired outcome, and thereby identifying upstream candidate target entities or processes which when targeted by an agent would influence said desired outcome in said biological system.
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36. The method of claim 32, wherein the virtual model and program instructions are applied to identifying common first or second elements in said virtual model which are upstream of a plurality of first or second elements representing pools of entities or processes which are biomarkers for at least one desired outcome, and thereby identifying upstream candidate target entities or processes which when targeted by an agent would simultaneously influence the plurality of biomarkers for the at least one desired outcome.
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37. A method for identifying putative effects of an agent or combination of agents on a human or other living organism, or any part thereof, the agents including environmental agents, drugs or any combination thereof, comprising applying the virtual model and program instructions of the computer readable medium or media of claim 27 in a computer system to identify downstream pools of entities or processes which could be affected by exposing said human or other living organism, or any part thereof, to said agent or combination of agents, wherein the reference set of one or more first or second elements represents the agent or combination of agents to be tested and the interactions of the agents with their targets in said human or other living organism, or any part thereof.
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38. The computer readable medium or media of claim 25, wherein:
- a) a plurality of said first elements comprise first variables, representing the quantities or concentrations of the entities of said pools; and
b) said program instructions comprise simulation functions to infer or compute, or any combination thereof, the values of said first variables when simulating the quantitative behavior of said complex system.
- a) a plurality of said first elements comprise first variables, representing the quantities or concentrations of the entities of said pools; and
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39. The computer readable medium or media of claim 38, wherein:
- a) a plurality of said second elements comprise second variables representing the rates of conversion of inputs into outputs represented by said input and output references or links; and
b) said program instructions comprise simulation functions to infer or compute, or any combination thereof, the values of said second variables when simulating the quantitative behavior of said complex system.
- a) a plurality of said second elements comprise second variables representing the rates of conversion of inputs into outputs represented by said input and output references or links; and
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40. The computer readable medium or media of claim 39, the virtual model further comprising a plurality of organizing elements representing compartments, including space, time-interval, or function compartments, organized in one or more levels of a hierarchy, each level representing a respective level of complexity, wherein said first and second elements have relationships with their corresponding organizing elements in the hierarchy.
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41. The computer readable medium or media of claim 40, wherein said organizing elements comprise one or more elements to represent compartments of biological organization at the molecular assembly, reaction cascade, subcellular, cellular or multi-cellular levels, or any combination thereof, in one or more levels of a hierarchy.
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42. The computer readable medium or media of claim 40, wherein said organizing elements comprise a plurality of elements representing different stages of the cell, including phases of the cell cycle, apoptosis, differentiation, disease or life cycle, or any combination thereof, in one or more levels of a hierarchy.
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43. A method for simulating physiological or pathological states of a cell by using the computer readable medium or media of claim 40 in a computer system, comprising:
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a) implementing a virtual model of the cell comprising one or more first or second elements representing biomarkers for one or more phenotypes of one or more states of the cell, wherein one or more of said elements have a relationship with one or more of said organizing elements;
b) setting the values of one or more sets of parameters or initial conditions of said virtual model; and
c) executing the simulation functions over the variables of said virtual model to simulate a state or a succession of states of the cell.
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44. The computer readable medium or media of claim 39 applicable to testing different model scenarios, wherein said program instructions comprise functions to assign to at least one selected variable or parameter of said virtual model a plurality of initial values representative of different model scenarios.
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45. The computer readable medium or media of claim 39, wherein said program instructions comprise query functions for finding an upstream set of any number of said elements representing entities or processes of said biological system which are putative targets for manipulation to achieve any desired outcome, including affecting the expression of any gene(s) or receptor(s), or the secretion of any substance(s), the pools of entities or processes which are biomarkers for the outcome represented by a reference query set of any number of said elements.
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46. The computer readable medium or media of claim 39, wherein said program instructions comprise query functions for finding a downstream set of any number of said elements representing entities or processes of said complex system which are putatively affected by the manipulation of entities or processes represented by a reference query set of any number of said elements.
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47. A method for predicting putative beneficial or toxic effects of an agent or combination of agents on a human or other living organism, or any part thereof, the agents including drugs or any other preventive, diagnostic, prognostic or therapeutic agents or procedures, by applying the virtual model and program instructions of the computer readable medium or media of claim 39 in a computer system, comprising:
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a) implementing a virtual model representing said human or other living organism, or any part thereof, which comprises one or more sets of first and second elements representing the agent or combination of agents to be tested and the interactions of the agents with their targets in said human or other living organism, or any part thereof;
b) executing said virtual model under various sets of conditions to simulate the effects of manipulating the agent or combination of agents on the quantitative behavior of said human or other living organism, or any part thereof; and
c) identifying a set of any number of said first or second elements of said virtual model which represent pools of entities or processes of said human or other living organism, or any part thereof, which are putatively affected by exposing said human or other living organism, or any part thereof, to said agent or combination of agents, thereby identifying the beneficial or toxic effects of the agent or combination of agents.
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48. A method for predicting putative targets for manipulation for the prevention or treatment of adverse conditions on a human or any other living organism, or any part thereof, by applying the virtual model and program instructions of the computer readable medium or media of claim 39 in a computer system to, comprising:
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a) implementing in said computer system a virtual model of said human or other living organism, or any part thereof;
b) identifying, in reference to a query set, an upstream set of any number of said first or second elements of said virtual model representing pools of entities or processes which are putative targets for manipulation to achieve any desired outcome in said human or other living organism, or any part thereof, known to affect the prevention or treatment of said adverse conditions, including affecting the expression of any gene(s) or receptor(s), or the secretion of any substance(s), wherein the reference query set of one or more of said first or second elements represents pools of entities or processes which are biomarkers for the desired outcome; and
c) executing said virtual model under various sets of conditions to simulate the effects of manipulating the putative targets on achieving the desired outcome, and thereby characterizing the putative targets.
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49. A method for identifying one or more components of a cell as putative targets for interaction with one or more agents, the agents including drugs or any other preventive, diagnostic, prognostic or therapeutic agent or procedure, by applying the virtual model and program instructions of the computer readable medium or media of claim 39 in a computer system, comprising:
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a) implementing a virtual model of the cell comprising first and second elements representing components characteristic of a phenotype of the cell;
b) executing the simulation functions over the variables of said elements to simulate a first state of the cell;
c) perturbing the virtual model by deleting one or more elements thereof, changing the amount or concentration of one or more first elements thereof or modifying one or more simulation functions or the relationships between one or more elements thereof, or any combination thereof;
d) executing the simulation functions over the variables of said elements after said perturbation of the virtual model to simulate a second state of the cell; and
e) comparing said first and second simulated states of the virtual model to identify the effect of said perturbation on the state of the virtual model, and thereby identifying one or more components of said cell as desirable putative targets for interaction with one or more agents.
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50. The computer readable medium or media of claim 1 further enabling quantitative, semi-quantitative or mixed type simulations of said virtual models in said computer system, wherein:
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a) mathematical models characterizing the quantitative behavior of said complex system comprise a number of quantitative or semi-quantitative variables or parameters, or any combination thereof, distributed among said first and second elements, said variables or parameters representing characteristics of the components they represent; and
b) said program instructions further comprise inference or simulation functions, or any combination thereof, for computing the values of said variables during the execution of the model.
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51. The computer readable medium or media of claim 50 applicable to testing different model scenarios, wherein said inference or simulation functions comprise functions for assigning to at least one of said variables or parameters of said model a plurality of initial values representative of different model scenarios.
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52. The computer readable medium or media of claim 50 wherein said program instructions comprise functions to identify common upstream pools of entities or processes, or any combination thereof, which putatively exert influences on a plurality of selected pools of entities or processes, or any combination thereof, based on the sequential ordering of the first and second elements as defined by said references or links.
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53. The computer readable medium or media of claim 50 wherein said program instructions comprise functions to identify downstream pools of entities or processes, or any combination thereof, influenced by one or more selected pools of entities or processes, or any combination thereof, based on the sequential ordering of the first and second elements as defined by said references or links.
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54. The computer readable medium or media of claim 50 applicable in a computer system comprising monitoring capabilities for monitoring the operation of said complex system in conjunction with the virtual model, comprising means for mapping one or more monitored variables of any component of said complex system to the corresponding of said variables which represent them in said virtual model.
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55. The computer readable medium or media of claim 50 applicable in a computer system further comprising controlling means to developing strategies or generating instructions for controlling the operation of said complex system based on the simulation of said virtual model by modifying any component of said complex-system represented by any of said variables of said elements of the model.
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56. The computer readable medium or media of claim 50, wherein said complex system is a biological system and a plurality of the entities represented are of at least one of the following types:
- cell, gene, mRNA, protein or any assembly, complex or combination thereof.
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57. A method for predicting a function of a component of a complex biological system, intrinsic or added to the system, comprising applying the virtual model and program instructions of the computer readable medium or media of claim 56 in a computer system to simulate perturbations of said component in said virtual model for testing the function of said component in said biological system, wherein the virtual model of the applicable biological system comprises at least one first or second elements representing the component or its interactions with one or more components of said biological system.
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58. A method for identifying or characterizing candidates for agent development, including drugs or any other preventive, diagnostic, prognostic or therapeutic agents or procedures, or any combination thereof, comprising applying the virtual model and program instructions of the computer readable medium or media of claim 56 in a computer system to identify the pools of entities or processes which are putatively affected by applying at least one candidate agent or involved in attaining a desired outcome in said biological system, wherein the model of the applicable biological system includes at least one first or second element representing the at said least one agent or its interaction with the biological system or at said least one biomarker for the desired outcome in said biological system.
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59. The method of claim 58 wherein the virtual model and program instructions are applied to simulating the effects of manipulating at least one first or second element in said virtual model, representing said at least one agent or its one or more interactions with its one or more targets on said biological system, on any number of downstream first or second elements, which represent the pools of entities or processes putatively affected by said at least one agent, and thereby predicting putative beneficial or harmful effects of said at least one agent.
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60. The method of claim 58 wherein the virtual model and program instructions are applied to simulating the effects of manipulating any combination of two or more first or second elements in said virtual model, representing a plurality of agents or their interactions with their targets, on a downstream set of any number of first or second elements which are shared by the downstream pathways from said plurality of first or second elements, the downstream set representing the entities or processes of said complex system affected by said combination, and thereby predicting putative effects of combined therapy regimes or harmful side effects for said combination of agents.
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61. A method for identifying or characterizing appropriate applications for an agent, including drugs or any other preventive, diagnostic, prognostic or therapeutic agents or procedures, or any combination thereof, comprising applying the virtual model and program instructions of the computer readable medium or media of claim 56 in a computer system to simulate and evaluate the effects of the agent on the biological system of interest at the subcellular, cellular, or multi-cellular level, or any combination thereof.
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62. A method for identifying one or more components of a cell as putative targets for interaction with one or more agents, the agents including drugs or any other preventive, diagnostic, prognostic or therapeutic agent or procedure, by applying the virtual model and program instructions of the computer readable medium or media of claim 56 in a computer system, comprising:
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a) implementing a virtual model of the cell comprising first and second elements representing components characteristic of a phenotype of the cell;
b) setting the parameters or initial conditions of said virtual model to correlate said phenotype to the state of the cell;
c) perturbing the virtual model by deleting one or more elements thereof, changing the parameters or initial conditions of one or more elements thereof or modifying one or more simulation functions or the relationships between one or more elements thereof; and
d) executing the simulation functions over the perturbed virtual model to determine whether said perturbation causes a desired transition of said cell from one phenotype to another, and thereby identifying one or more components of said cell as desirable putative targets for interaction with one or more agents.
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63. A method for identifying one or more components of a cell as putative targets for interaction with one or more agents, the agents including drugs or any other preventive, diagnostic, prognostic or therapeutic agent or procedure, by applying the virtual model and program instructions of the computer readable medium or media of claim 56 in a computer system, comprising:
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a) implementing a virtual model of the cell comprising first and second elements representing components believed to be intrinsic to a phenotype of the cell;
b) generating one or more expanded or perturbed virtual models by inferring new or modified first and second elements and their relationships to any of the elements of the virtual model subsystem using experimental data;
c) determining parameter values or constraining the virtual models by (i) sampling a set of one or more initial, expanded or perturbed virtual models and parameter values, (ii) simulating said virtual models by executing the simulation functions over the variables of the virtual models, and (iii) determining the initial values of variables and parameters which optimally fit a given set or sets of experimental data; and
d) comparing a plurality of simulated states of the initial or expanded or perturbed virtual models to identify the effect of said expansion or perturbation on the state of the virtual model, and thereby identifying the pertaining new or modified first or second elements representing the one or more targets for interaction with one or more agents.
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64. A method for designing or implementing a strategy for controlling the expansion or further differentiation of progenitor or other precursor living cells in a cell culture or reactor to produce outcome cells of one or more types having characteristic phenotypes, comprising applying the virtual model and program instructions of the computer readable medium or media of claim 56 in a computer system to:
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a) implementing a virtual model of the cellular system which comprises at least one first or second element representing at least one putative inducing agent or its interaction with at least one target in said precursor cell, or at least one pool of entities or process which is to be induced or modified to embody a characteristic phenotype of at least one outcome cell type, or any combination thereof;
b) executing said virtual model to simulate the putative effects of manipulating said one or more putative inducing agents in achieving said desired phenotypes of said outcome cell types; and
c) designing or implementing a strategy for controlling the expansion or further differentiation of said precursor cells in said cell culture medium or reactor based on one or more of said manipulations which result in the desired phenotypes.
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65. A method for designing or implementing a strategy for controlling the production in a living cellular system of one or more substances for preventive, therapeutic or diagnostic uses by applying the virtual model and program instructions of the computer readable medium or media of claim 56 in a computer system, wherein the living cellular system comprises the producing cells in a cell culture, reactor or a microorganism, plant or animal living environment, comprising:
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a) implementing a virtual model of the living cellular system which includes one or more first or second elements representing one or more pools of substances to be produced or their production processes within said producing cells;
b) executing said virtual model and any number of perturbations of said virtual model to simulate the putative effectiveness of said living cellular system and any number of manipulations of said living cellular system in achieving the desired production of said substances by said living cellular system; and
c) designing or implementing a strategy for controlling the production of said substances in said living cellular system based on the simulation of said virtual model or any number of said perturbations which result in the desired level of production of said one or more substances.
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66. The computer readable medium or media of claim 1 wherein a plurality of said first elements comprise at least one input or output reference or link to second elements or their components, representing respectively an input to the represented pool of entities from the represented process or a contribution by the represented pool of entities to the represented process.
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67. The computer readable medium or media of claim 66 wherein said first elements comprise state variables and said program instructions comprise simulation functions to infer or compute, or any combination thereof, the value of any of said state variables over said inputs or outputs, or both.
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68. The computer readable medium or media of claim 67 wherein said second elements comprise rate variables representing the rate of conversion of said inputs into said outputs and said program instructions comprise simulation functions to infer or compute, or any combination thereof, the value of any of said rate variables.
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69. A computer system for implementing the virtual model and instructions of the computer readable medium or media of claim 1.
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2. The computer readable medium or media of claim 1, the program instructions further comprising functions to generate visual representations of said network of pathways on the display means of said computer system.
- i) the model elements include first elements representing pools of any number of entities of a given type, state and/or compartment, and a plurality of second elements representing processes of different types in which the pools of entities participate;
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20. A method for predicting pathways affected by a perturbation comprising applying the virtual model and program instructions of the computer readable medium or media of claim to identifying the signal cascades which occur through the pathways when stimuli are introduced to the complex system and dynamically generating results during execution of said model in a computer system.
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70. A method for implementing a virtual model of a complex system in a computer system comprising defining or selecting, or any combination thereof:
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a) a plurality of first and second variables, the first variables representing quantitatively, semi-quantitatively, or any combination thereof, pools of any number of entities of a given type, state and/or compartment, and the different types of second variables representing quantitatively, semi-quantitative, or any combination thereof;
the rates of different types of processes of said complex system where said entities participate;
b) a plurality of input, regulator and output relationships between a plurality of said first and second variables;
c) functions to integrate said variables and their relationships, resulting in a network of one or more pathways, a plurality of said variables acting as junctions where different pathways merge or different pathways branch, or both; and
d) functions to compute the values of said variables, to simulate the behavior of said complex system during execution of said model. - View Dependent Claims (71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88)
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71. The method of claim 70 further comprising defining or selecting, or any combination thereof, links between a plurality of said elements and a plurality of databases, thereby integrating data in said databases.
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72. The method of claim 70 further comprising defining or selecting, or any combination thereof, functions associated with any of said variables enabling the successive interactive navigation between related variables.
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73. The method of claim 70 further comprising defining or selecting, or any combination thereof, functions to generate visual representations of said network of pathways on the display means of said computer system.
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74. The method of claim 70 further comprising defining or selecting, or any combination thereof, functions to generate on-the-fly visual representations of subsets of the networks of pathways which meet user-defined criteria, including selection of one or more of said variables as starting nodes or a direction upstream or downstream from said starting nodes, or any combination thereof.
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75. The method of claim 70 further comprising defining or selecting, or any combination thereof, query functions in reference to one or more of said variables, including criteria based on the upstream or downstream position within said network of any first or second variable in relation to said reference one or more variables, or any combination thereof.
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76. The method of claim 70 applied to test different model scenarios, further comprising assigning to at least one selected variable or parameter of said virtual model a plurality of initial values representative of different model scenarios.
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77. The method of claim 70 wherein said computer system comprises monitoring capabilities applicable in conjunction with the virtual model, further comprising defining or selecting, or any combination thereof, program functions for i) mapping the one or more monitored variables of components of said complex system to their corresponding variables in said model, ii) comparing said monitored values to the simulated values of their corresponding variables;
- and iii) inferring or computing, or any combination thereof, any adjustments derived from said comparisons.
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78. A computer readable medium or media comprising instructions for implementing in a computer system the method of claim 77.
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79. The method of claim 70, wherein said computer system comprises controlling capabilities applicable in conjunction with the virtual model, further comprising defining or selecting, or any combination thereof, program functions to control the operation of said complex system by modifying any of its components based on the simulation of said model.
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80. A computer readable medium or media comprising instructions for implementing in a computer system the method of claim 79.
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81. The method of claim 70 further comprising defining or selecting, or any combination thereof, a plurality of organizing elements representing compartments, including space, time-interval, or function compartments, or any combination thereof, organized in one or more levels of a hierarchy, each level representing a respective level of complexity;
- and relationships between a plurality of said variables and their corresponding organizing elements in the hierarchy.
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82. The method of claim 81 further comprising defining or selecting, or any combination thereof, query functions in reference to one or more of said variables, including criteria based on the upstream or downstream position within said network of any first or second variable in relation to said reference one or more variables or the relationships between said variable and any of said organizing elements, or any combination thereof.
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83. The method of claim 70 wherein said regulator relationships comprise relationships of at least of the following types:
- activator, inhibitor, catalyst, ligand, agonist, antagonist, repressor or promoter.
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84. The method of claim 70, wherein said complex system is a biological system and the model is applied to identifying putative targets for manipulation to achieve any desired outcome, including affecting the expression of any gene or receptor, or the secretion of any substance, or any combination thereof, in various types of applications, including treatment of disease, improvement of livestock or food crops, or improvement of the environment, further comprising defining or selecting, or any combination thereof, functions to identify a target set of first or second variables, or any combination thereof, representing the putative target pools of entities or processes, which are upstream of a reference query set of one or more first or second variables, or any combination thereof, representing the pools of entities or processes which are biomarkers for said outcome.
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85. A computer readable medium or media comprising instructions for implementing in a computer system the method of claim 84.
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86. The method of claim 70, wherein said complex system is a biological system and the model is applied to identifying the putative effects of manipulation strategies for said biological system in various types of applications, including treatment of disease, improvement of livestock or food crops, or improvement of the environment, further comprising defining or selecting, or any combination thereof, functions to identify a downstream set of first or second variables, or any combination thereof, representing the pools of entities or processes of said biological system which are putatively affected by manipulating the entities or processes represented by a reference query set of one or more of said first or second variables, or any combination thereof.
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87. A computer readable medium or media comprising instructions for implementing in a computer system the method of claim 86.
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88. A computer readable medium or media comprising instructions for implementing in a computer system the method of claim 70.
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71. The method of claim 70 further comprising defining or selecting, or any combination thereof, links between a plurality of said elements and a plurality of databases, thereby integrating data in said databases.
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89. A method for implementing models of biological complex systems in a computer system comprising aggregating a plurality of modules representing components of a complex system, wherein:
- i) a plurality of the modules comprise one or more terminals allowing the module to exchange signals with other modules;
ii) the modules include process modules representing different types of processes;
iii) a plurality of the process modules comprise input, regulator and output terminals;
iv) the aggregating comprises establishing references or links, or any combination thereof, between the terminals of different modules resulting in a network of one or more crossing pathways which describes the topology of the complex system. - View Dependent Claims (90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119)
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90. The method of claim 89, further comprising defining or selecting links between a plurality of said modules and a plurality of databases, thereby integrating data in said databases.
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91. The method of claim 89, further comprising applying libraries of predefined and reusable modules in at least one of the composition or extension of said models, the libraries comprising different types of said modules, their components, or any combination thereof.
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92. The method of claim 89, wherein said modules have references to or containment relationships with at least one compartment module in a hierarchy of at least one level representing at least one physical or conceptual compartment of the complex system.
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93. The method of claim 89 wherein the modules comprise first modules representing pools of any number of entities of a given type, state and/or compartment and the references or links are references or links between the terminals of said first modules and the terminals of said process modules.
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94. The method of claim 93, further comprising applying chaining functions to establish downstream or upstream relationships between chains of first modules and process modules, or any combination thereof, identified based on the sequential order of said first modules and process modules as defined by said references or links.
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95. The method of claim 93, further comprising generating visual representations of said model on the display means of said computer system, with nodes representing a plurality of said modules linked according to said references or links resulting in a network of crossing pathways.
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96. The method of claim 93 wherein a plurality of the entities represented are of at least one of the following types:
- cell, gene, mRNA, protein or any assembly, complex or combination thereof.
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97. The method of claim 96 applied to the development of agents, the agents including drugs or any other preventive, diagnostic, prognostic or therapeutic agents or procedures, further comprising:
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a) including in the model of the applicable biological system at least one first module or process module representing at least one putative agent or its interaction with at least one target in said biological system, or biomarker for a desired outcome in said biological system; and
b) applying said model to identify any number of pools of entities or processes affected as a result of applying said at least one putative agent or involved in achieving said desired outcome in said biological system.
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98. The method of claim 97, wherein the method is applied to identifying putative beneficial or harmful effects of at least one agent acting upon said biological system, comprising identifying any number of first modules or process modules in said virtual model which are downstream of the at least one first module or process module representing the at least one agent or its interaction with the at least one target in said biological system.
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99. The method of claim 97, wherein the method is applied to characterizing putative combined therapy regimes or putative harmful side effects resulting from interactions between the effects of two or more agents, comprising identifying any number of first modules or process modules in said virtual model which are shared by the pathways downstream from the two or more of said first modules or process modules representing said two or more agents or their interactions with their targets in said biological system.
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100. The method of claim 97, wherein the method is applied to characterizing candidate target pools of entities or processes applicable in the selection of agents to influence at least one desired outcome in said biological system, comprising identifying any number of first modules or process modules in said virtual model which are upstream of the at least one first module or process module representing at least one pool of entities or process which is a biomarker for said desired outcome, wherein said upstream elements represent pools of entities or processes which are putative targets for manipulation in said biological system to achieve said desired outcome.
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101. A computer readable medium or media comprising instructions for implementing in a computer system the method of claim 97.
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102. The method of claim 96 applied to designing a strategy for controlling the expansion or further differentiation of progenitor or other precursor living cell in a cell culture or reactor to produce outcome cells of one or more types having characteristic phenotypes, further comprising:
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a) including in the model of the applicable cellular system at least one first module or process module representing at least one pool of entities or process which is a biomarker to be induced or modified to embody a characteristic an outcome cell phenotype;
b) defining or selecting functions to identify at least one candidate target for putative inducing agents represented by at least one first module or process module in said model which is upstream of the at least one first module or process module representing said phenotype biomarker; and
c) designing a strategy for controlling the expansion or further differentiation of said precursor cells in said cell culture or reactor based on at least one of said identified candidate targets for putative inducing agents which would induce the desired outcome cell phenotype.
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103. A computer readable medium or media comprising instructions for implementing in a computer system the method of claim 102.
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104. The method of claim 93 further comprising the step of defining or selecting stoichiometric coefficients for said process modules which relate said inputs and outputs.
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105. The method of claim 93 wherein a plurality of said modules comprise quantitative or semi-quantitative variables or parameters, or any combination thereof, and the aggregating comprises applying functions over said variables or parameters to infer or simulate the behavioral model of the complex system.
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106. The method of claim 105 applied to the analysis, dynamic simulation, steady state simulation, or optimization of the biological complex models, or any combination thereof.
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107. The method of claim 105 wherein at least one of said modules is implemented as lumped parameter system, black-box system, abstraction, encapsulation, aggregation, or any combination thereof.
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108. The method of claim 105, wherein the variables of said process modules comprise rate variables representing the rate of conversion of said inputs into said outputs.
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109. The method of claim 105 applied to modeling of a set of related biological complex systems or their states, further comprising creating one or more network topologies corresponding to models or submodels representing the biological system or its subsystems;
- wherein one of said network topologies of said set is a master network topology representing a base biological system or state; and
the difference between any of two said biological systems or their states is described through changes in;
i) the values of one, or more parameters, ii) the initial values of one or more variables, iii) the topology derived from the references or links, iv) the exclusion or additional inclusion of one or more modules of the master network topology, or v) any combination thereof.
- wherein one of said network topologies of said set is a master network topology representing a base biological system or state; and
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110. The method of claim 109, wherein said network topologies are abstract modules which can be reused as submodels to compose a plurality of more complex models or alternative implementation models.
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111. The method of claim 105 further comprising applying said model to designing manipulation strategies or for controlling the operation of said complex system based on the behavior of the simulated model.
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112. The method of claim 105 applied to monitoring or controlling the operation of said complex system, further comprising:
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b) mapping one or more monitored or controlled variables of any component of said complex system to the corresponding of said variables which represent them in said model;
c) executing the model and comparing the values of the said monitored or controlled variables to the corresponding simulated values of the variables which represent them in said model;
c) inferring or computing any corrective adjustments derived from said comparisons; and
b) applying any of said corrective adjustments to modify the corresponding simulated or controlled variables.
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113. A computer readable medium or media comprising instructions for implementing in a computer system the method of claim 112.
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114. The method of claim 105 applied to testing different model scenarios, further comprising assigning to at least one of said variables or parameters of said model a plurality of initial values representative of different model scenarios.
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115. The method of claim 105 applied to studying the operation of said biological system or to design manipulation strategies to control said operation for various applications, including those in the areas of disease prevention or treatment, therapeutics, diagnostics, drug production, livestock, food crops, food production or the environment, wherein the model of the biological system is at the subcellular, cellular, or multi-cellular level, or any combination thereof.
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116. The method of claim 105 applied to agent development, including drugs or any other preventive, diagnostic, prognostic or therapeutic agents or procedures, or any combination thereof, further comprising identifying the pools of entities or processes which are putatively affected by applying at least one candidate agent or involved in attaining a desired outcome in said biological system, wherein the model of the applicable biological system, at the subcellular, cellular or multi-cellular, or any combination thereof, includes at least one first or second element representing the at least one agent or its interaction with the biological system, or a biomarker for the desired outcome in said biological system.
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117. The method of claim 105 applied to predicting in a computer system a behavior of a biochemical system, further comprising comparing two or more models of a biochemical system under different conditions, and identifying correlative changes of the values of one or more of said variables between said two models with said different conditions, wherein said correlative changes predict a behavior of said biochemical system.
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118. A computer readable medium or media comprising instructions for implementing in a computer system the method of claim 105.
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119. A computer readable medium or media comprising instructions for implementing in a computer system the method of claim 93.
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90. The method of claim 89, further comprising defining or selecting links between a plurality of said modules and a plurality of databases, thereby integrating data in said databases.
- i) a plurality of the modules comprise one or more terminals allowing the module to exchange signals with other modules;
Specification
- Resources
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Current AssigneeIntertech Ventures Limited
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Original AssigneeIntertech Ventures Limited
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InventorsThalhammer-Reyero, Cristina
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Primary Examiner(s)PHAN, THAI Q
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Application NumberUS08/860,975Time in Patent Office3,639 DaysField of Search703/2, 703/11, 703/12, 715/700, 345/419, 345/335, 345/346, 345/349, 395/500.33, 395/500.32, 395/500.35, 706/11, 706/53, 706/4, 706/6, 706/10, 707/103, 707/10US Class Current703/2CPC Class CodesG05B 17/02 electricG06F 2111/08 Probabilistic or stochastic...G06F 30/20 Design optimisation, verifi...G16B 45/00 ICT specially adapted for b...G16B 5/00 ICT specially adapted for m...G16B 5/30 Dynamic-time modelsG16B 50/00 ICT programming tools or da...G16B 50/20 Heterogeneous data integrationY02A 90/10 Information and communicati...