Systems and methods for reverse engineering models of biological networks
First Claim
1. A method of constructing a model of a biological network comprising steps of:
- providing a biological system or a plurality of biological systems, each biological system comprising a biological network comprising a plurality of biochemical species having activities;
perturbing the activity of at least one of the biochemical species, thereby causing a response in the biological network;
allowing the biological network to reach a steady state;
determining the response of at least one of the biochemical species in the biological network; and
estimating parameters of the model.
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Abstract
The present invention provides methods and accompanying computer-based systems and computer-executable code stored on a computer-readable medium for constructing a model of a biological network. The invention further provides methods for performing sensitivity analysis on a biological network and for identifying major regulators of species in the network and of the network as a whole. In addition, the invention provides methods for identifying targets of a perturbation such as that resulting from exposure to a compound or an environmental change. The invention further provides methods for identifying phenotypic mediators that contribute to differences in phenotypes of biological systems.
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Citations
85 Claims
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1. A method of constructing a model of a biological network comprising steps of:
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providing a biological system or a plurality of biological systems, each biological system comprising a biological network comprising a plurality of biochemical species having activities;
perturbing the activity of at least one of the biochemical species, thereby causing a response in the biological network;
allowing the biological network to reach a steady state;
determining the response of at least one of the biochemical species in the biological network; and
estimating parameters of the model. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 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, 70, 71)
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72. A computer system for constructing a model of a biological network, the computer system comprising:
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memory that stores a program comprising computer-executable process steps; and
a processor which executes the process steps so as to construct a model of a biological network, the model comprising an approximation to a set of differential equations or a set of difference equations that represent evolution over time of activities of at least one biochemical species in a biological network. - View Dependent Claims (73, 74, 75)
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76. A computer system for performing sensitivity analysis of a biological network, the computer system comprising:
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memory that stores a program comprising computer-executable process steps; and
a processor which executes the process steps so as to (i) generate or receive a model of a biological network, the model comprising an approximation to a set of differential equations or a set of difference equations that represent evolution over time of activities of at least one biochemical species in a biological network; and
(ii) determine the sensitivity of the activities of a first set of one or more species in the network to a change in the activities of a second set of one or more species in the network using the model.
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77. A computer system for identifying a target of a perturbation comprising
memory that stores a program comprising computer-executable process steps; - and
a processor which executes the process steps so as to (i) construct or receive a model of a biological network, the model comprising an approximation to a set of differential equations or a set of difference equations that represent evolution over time of activities of at least one biochemical species in a biological network; and
(ii) receive data comprising responses of at least one of the biochemical species to the perturbation; and
(iii) calculate predicted perturbations of biochemical species in the biological network that would be expected to yield the determined responses according to the model.
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78. A computer system for identifying a phenotypic mediator, the computer system comprising:
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memory that stores a program comprising computer-executable process steps; and
a processor which executes the process steps so as to (i) compare parameters of models of biological networks for a plurality of biological systems, wherein the models comprise an approximation to a set of differential equations or a set of difference equations that represent evolution over time of activities of at least one biochemical species in a biological network, and wherein the biological networks comprise overlapping or substantially identical sets of biochemical species; and
(ii) identify one or more biochemical species for which associated parameters differ between the models as candidate phenotypic mediators.
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79. Computer-executable process steps stored on a computer-readable medium, the computer-executable process steps to construct a model of a biological network, the computer-executable process steps comprising:
code to construct a model of a biological network, the model comprising an approximation to a set of differential equations or a set of difference equations that represent evolution over time of activities of at least one biochemical species in a biological network. - View Dependent Claims (80, 81, 82)
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83. Computer-executable process steps stored on a computer-readable medium, the computer-executable process steps to perform sensitivity analysis of a biological network, the computer-executable process steps comprising:
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(i) code to generate or receive a model of a biological network, the model comprising an approximation to a set of differential equations or a set of difference equations that represent evolution over time of activities of at least one biochemical species in a biological network; and
(ii) code to determine the sensitivity of the activities of a first set of one or more species in the network to a change in the activities of a second set of one or more species in the network using the model.
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84. Computer-executable process steps stored on a computer-readable medium, the computer-executable process steps to identify a target of a perturbation, the computer-executable process steps comprising:
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(i) code to estimate parameters of and select a structure for a model of a biological network or to receive estimated parameters of and a structure for a model of a biological network, the model comprising an approximation to a set of differential equations or a set of difference equations that represent evolution over time of activities of at least one biochemical species in a biological network;
(ii) code to receive data comprising responses of at least one of the biochemical species to the perturbation; and
(iii) code to calculate predicted perturbations of biochemical species in the biological network that would be expected to yield the determined responses according to the model.
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85. Computer-executable process steps stored on a computer-readable medium, the computer-executable process steps to identify a phenotypic mediator, the computer-executable process steps comprising:
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(i) code to compare parameters of models of biological networks for a plurality of biological systems, wherein the models comprise an approximation to a set of differential equations or a set of difference equations that represent evolution over time of activities of at least one biochemical species in a biological network, and wherein the biological networks comprise overlapping or substantially identical sets of biochemical species; and
(ii) code to identify one or more biochemical species for which associated parameters differ between the models as candidate phenotypic mediators.
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Specification