Systems and methods for fault diagnosis in molecular networks

Abstract

The present disclosure provides advantageous systems and methods for identifying molecular vulnerabilities in biological pathways and networks. The present disclosure generally involves conceptualizing a disease/disorder at the molecular level as a faulty physiological system, wherein one or more molecules in the complex intracellular signaling network are dysfunctional. This is accomplished by modeling a given physiological system as a digital logic circuit. More particularly, in exemplarily embodiments, binary logic equations are derived by analyzing the interactions between the input and output nodes of a target biological system. These equations are then used to produce a digital circuit representation for the system. Once a digital circuit representation is created, this circuit may advantageously be analyzed, using fault analysis techniques, in order to determine the vulnerability levels of the molecules of the targeted system.

1 . A method for identifying molecular vulnerabilities in a biological system, the method comprising:
 a. specifying nodes for the biological system, including one or more input nodes and one or more output nodes;   b. identifying interactions between specified nodes;   c. deriving equations for the biological system using the identified interactions;   d. constructing a system representation of the equations; and   e. applying a fault diagnosis technique to determine vulnerability level for at least one specified node.   
     
     
         2 . The method of  claim 1 , wherein the one or more input nodes include ligands. 
     
     
         3 . The method of  claim 1 , wherein the one or more output nodes include transcription factors. 
     
     
         4 . The method of  claim 1 , wherein the identified interactions include at least one of: (i) a stimulatory interaction, and (ii) an inhibitory interaction. 
     
     
         5 . The method of  claim 1 , wherein, in deriving the equations for the biologic system:
 (i) a node affected by one or more inhibitory input nodes is considered inactive only if at least one of the one or more inhibitory input nodes is active, and   (ii) a node affected by only one or more stimulatory input nodes is considered active only if at least one of the one or more stimulatory nodes is active.   
     
     
         6 . The method of  claim 1 , wherein the derived equations are logic equations. 
     
     
         7 . The method of  claim 6 , wherein the derived logic equations are binary logic equations. 
     
     
         8 . The method of  claim 1 , wherein the system representation is a circuit representation. 
     
     
         9 . The method of  claim 8 , wherein the circuit representation is a digital circuit representation. 
     
     
         10 . The method of  claim 9 , wherein the digital circuit representation is constructed using combinations of AND, OR, NOT, and BUFFER logic operations. 
     
     
         11 . The method of  claim 10 , further comprising identifying feedback paths. 
     
     
         12 . The method of  claim 11 , wherein flip-flops are inserted in the identified feedback paths. 
     
     
         13 . The method of  claim 1 , wherein the fault diagnosis technique includes calculation of error propagation probability. 
     
     
         14 . The method of  claim 1 , wherein the fault diagnosis technique includes the steps of
 a. extracting all on-path signals and gates to every reachable primary output;   b. prioritizing signals on the paths based on their distance level; and   c. traversing the paths and applying propagation rules to compute the probability for each on-path node.   
     
     
         15 . The method of  claim 14 , wherein the on-path signals and gates are extracted using a forward depth-first search algorithm. 
     
     
         16 . The method of  claim 14 , wherein the signals on the paths are prioritized using a topological sorting algorithm and wherein the paths are traversed in a topological order. 
     
     
         17 . A system for identifying one or more molecular vulnerabilities in a biological network, the system comprising:
 a. a processor in communication with computer memory, and   b. a computer program interacting with the computer memory and operative on the processor, said computer program being adapted to:   i. access specified nodes for the biological network, including one or more input nodes and one or more output nodes; identified interactions between specified nodes; equations for the biological system derived using the identified interactions; and a system representation constructed of the derived equations; and   ii. apply a fault diagnosis technique to determine vulnerability level for at least one specified node.   
     
     
         18 . The system of  claim 17 , wherein the one or more input nodes include ligands. 
     
     
         19 . The system of  claim 17 , wherein the one or more output nodes include transcription factors. 
     
     
         20 . The system of  claim 17 , wherein the identified interactions include at least one of (i) a stimulatory interaction, and (ii) an inhibitory interaction. 
     
     
         21 - 32 . (canceled)