Network models of complex systems

Abstract

This invention describes computer based virtual models of complex systems, together with integrated systems and methods providing 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.

156 . A system for designing, simulating and/or analyzing in a computer models of complex biological networks, the system comprising: 
 a) one or more submodels comprising connected networks of discrete components, wherein said components are functional units of the physical or logical compartments represented by the submodels, said components comprise attributes or variables, or any combination thereof, and said connections represent mappings between the connected components or their attributes or variables; and    b) means for grouping components in order to encapsulate complexity;    c) means for specifying a plurality of different types of relationships that may exist between components or their attributes or variables; and    d) means for expressing the relationships between said components or their attributes or variables.    
   
   
       157 . The system of  claim 156 , wherein said components include first components, each used to store a) any type of information or data associated with at least a single process, such as a reaction, b) second components of said first components, or c) any combination thereof.  
   
   
       158 . The system of  claim 157 , wherein each of said first components comprises or references one or more variables that represent absolute or relative quantities of the participants in the process.  
   
   
       159 . The system of  claim 157 , wherein said second components are defined to play different types of roles as participants in the process, such as reactant, product, catalyst, activator, inhibitor, modifier, or any combination thereof.  
   
   
       160 . The system of  claim 157 , wherein each of said first components comprises or references a variable that represents the rate at which the process occurs.  
   
   
       190 . A method of creating a computer-implemented model for modeling a dynamic multi-variable biological system, wherein the biological system is controlled by a plurality of interrelated biologic processes defining functions occurring within the biological system, comprising: 
 a) creating a first class of objects representing state variables holding a scalar real number value, wherein the set of values of all first class objects in a simulation model defines the state of the model at a certain point in time;    b) creating a second class of objects representing processes in the simulation model that result in changes in the values of one or more first class objects, wherein the way of change of the values of the first class objects can be either discrete or continuous;    c) establishing references between certain of said first class objects and certain of said second class of objects, to indicate which second class of objects affect changes in which first class objects in the simulation model;    d) implementing equation solvers of one or more type; and    e) executing said dynamic model by applying said equation solvers to change the values of said first class objects.    
   
   
       191 . The method of  claim 190  further comprising the step of creating a third class of objects representing overall structure of the model, wherein the third class objects can contain sets of said three classes of objects, that is first class objects, second class objects and/or third class objects, wherein when the third class objects contain other third class objects, said third class objects can form a hierarchical or tree-like structure.  
   
   
       192 - 195 . (canceled)  
   
   
       208 . A method of interactively or dynamically generating by a computer program a display, on a display device, of a complex biological system model built using a plurality of reusable discrete components, each conforming to an interface specification, wherein one or more of said discrete components is a composite component, the method comprising: 
 a) displaying a set of reusable respective node representations for the plurality of discrete components;    b) displaying a set of reusable respective link representations for the plurality of relationships between the plurality of discrete components, such as cause-effect, conversion, association, or translocation relationships;    c) determining user or program selection of a number of said node representations; and    d) determining user or program selection of a number of said link representations to represent the relationships between said selected node representations; and    e) displaying the linked representation of the selected corresponding node and link representation instances to represent the relationships between the plurality of instances of the discrete components.    
   
   
       209 . A method of dynamically generating by a computer program a display, on a display device, of a complex biological system model built using a plurality of reusable discrete components, each conforming to an interface specification, wherein one or more of said discrete components is a composite component, the method comprising: 
 a) selecting, in response to a user selection of a complex system configuration to be modeled, a set of respective node representations for the plurality of discrete components and a set of respective link representations for the plurality of relationships between said selected node representations, such as cause-effect, conversion, association, or translocation relationships, necessary to represent the model of the complex system configuration; and    b) displaying the linked representation of the selected corresponding node and link representations to represent the plurality of instances of the discrete components and the plurality of relationships between the plurality of instances of the discrete components.    
   
   
       240 . A method for generating a model of a complex biological system in a computer system, the computer system comprising: 
 i) one or more defined classes of typed symbols representing different elements of the complex biological system,    ii) one or more defined classes of typed relations between at least two of the symbols for expressing the corresponding one or more types of relationships between at least two of the elements, including one or more relationships selected from the group of downstream, upstream, composition, linkage, association, regulation and containment relationships;    iii) one or more defined rules or procedures comprising an operator for establishing one or more of said typed relations between at least two symbols;    iii) one or more defined inference rules comprising an operator to reason about said symbols and their relations, the rules being expressed in a manner that enables use by an inference engine; and    the method comprising the steps of:    a) applying said one or more rules or procedures for establishing said typed relations between at least one symbol to at least another symbol;    b) using the inference engine to infer alternative results from the system based on at least some of said symbols and their relations, given an initial hypothetical state or set of conditions.    
   
   
       241 . The method of  claim 240  wherein said computer system further comprises: 
 a) one or more of said classes of typed symbols further comprising quantitative variables with associated mathematical equations to compute their values in said computer system;    b) simulation instructions to compute the values of said quantitative variables;    c) one or more inference rules comprising an operator to reason about the values of said quantitative variables; and    wherein said using the inference engine further comprises inferring said alternative results based further on the values of at least one of said quantitative variables.    
   
   
       242 . The method of  claim 240  wherein the classes of typed symbols are organized in a hierarchy.  
   
   
       243 . The method of  claim 240  wherein at least one of the rules is conditional.  
   
   
       244 . The method of  claim 240  further comprising expressing the rules graphically by representing a plurality of the symbols as icons.  
   
   
       245 - 250 . (canceled)  
   
   
       251 . A method for generating (recording) computable knowledge in a complex domain, to facilitate the computerized analysis and integration of the large amount of knowledge in such domain, comprising: 
 a) defining a hierarchy of different classes of domain-specific typed symbols representing an ontology of the different elements and concepts of the complex domain, wherein at least some general knowledge about the pertinent elements and concepts in such domain is incorporated in the definitions of said typed symbols;    b) defining one or more classes of typed relations between at least two of the classes of typed symbols for expressing the corresponding one or more types of relationships between at least two of the elements and concepts in the complex domain, including one or more relationships selected from the group of downstream, upstream, composition, linkage, association, regulation and containment relationships;    c) defining one or more rules or procedures comprising an operator for establishing one or more of said defined typed relations between at least two typed symbols;    d) applying said one or more rules or procedures for establishing said typed relations between at least one symbol to at least another symbol; and    e) defining one or more rules or procedures comprising an operator to traverse the network formed by said symbols and their relations, thereby making the knowledge contained in said network available for further computations.    
   
   
       252 . The method of  claim 251 , further comprising expressing the knowledge graphically by representing at least some of the typed symbols as different types of icons and at least some of the typed relations as different types of lines interconnecting the icons, wherein each icon can be interconnected to any number of other icons to represent multiple relations thereby making the knowledge contained in said network available for navigation and further interactive exploration.  
   
   
       269 - 271 . (canceled)  
   
   
       394 . The system of  claim 156 , wherein said components include first components, each storing: a) any type of information or data associated with at least one or more biological entities of a given type, b) second components of said first components, or c) any combination thereof  
   
   
       395 . The system of  claim 394 , wherein at least one of the biological entities is a cell or a protein.  
   
   
       396 . The system of  claim 394 , wherein each of said first components comprises or references at least one variable that represents an absolute or relative quantity of said biological entity of a given type.  
   
   
       397 . The system of  claim 156 , wherein said types of relationships comprise at least one type selected from the group of quantitative or semi-quantitative.  
   
   
       398 . The system of  claim 156 , wherein said types of relationships comprise at least one type selected from the group of conversion, association, translocation, activation, inhibition, modification, and regulation.  
   
   
       399 . The system of  claim 156 , wherein said types of relationships comprise at least one type selected from the group of downstream, upstream, composition, linkage and containment.  
   
   
       400 . The system of  claim 156 , further comprising a database from which said components or the values of their attributes or variables are selected.  
   
   
       401 . The system of  claim 156 , further comprising an inference engine capable of reasoning over said components, their relationships, or any combination thereof  
   
   
       402 . The system of  claim 156 , wherein a rule set specifies how said components may be related to other components.  
   
   
       403 . The system of  claim 156 , further comprising a simulator to dynamically simulate networks of processes, such as networks of genetic, metabolic, or signal transduction pathways, or any combination thereof.  
   
   
       404 . The system of  claim 156 , wherein at least one submodel or discrete component is reusable to compose at least other model or submodel.  
   
   
       405 . The system of  claim 156 , wherein at least one submodel is defined through modification of at least one attribute or variable of at least one component of a preexisting submodel.  
   
   
       406 . The system of  claim 156 , wherein at least one discrete component is defined as a prototype that can be instantiated and configured dynamically.  
   
   
       407 . The system of  claim 156 , wherein the discrete components are defined as a hierarchy representing an ontology of the different functional units of a biological domain.  
   
   
       408 . The system of  claim 156 , wherein at least one discrete component is defined as a lumped parameter system or black-box system.  
   
   
       409 . The system of  claim 156 , wherein a plurality of discrete components comprise at least one input element, output element, or regulator element.  
   
   
       410 . The system of  claim 156 , wherein a plurality of discrete components comprise stoichiometric coefficients.  
   
   
       411 . The system of  claim 156 , wherein a plurality of discrete components comprise symbolic parameters.  
   
   
       412 . The system of  claim 156 , wherein a plurality of discrete components comprise each at least one variable which values over time are computed dynamically.  
   
   
       413 . The system of  claim 156 , wherein a plurality of said one or more submodels form a hierarchical or tree-like structure.  
   
   
       414 . The system of  claim 156 , wherein a plurality of discrete components have associated visual representations.  
   
   
       415 . The system of  claim 414 , wherein a plurality of said visual representations further comprise at least one associated rule or function that can be called programmatically or interactively to be executed.  
   
   
       416 . The system of  claim 414 , further comprising methods to generate and display multidimensional networks, wherein the nodes are said visual representations of the discrete components.  
   
   
       417 . The system of  claim 156 , wherein said components comprise variables with associated equations to compute their values, said network of discrete components representing the topology of the complex biological network and the variables representing its behavior.