Assessment of cellular signaling pathway activity using probabilistic modeling of target gene expression

Abstract

The present application mainly relates to specific methods for inferring activity of one or more cellular signaling pathway(s) in tissue of a medical subject based at least on the expression level(s) of one or more target gene(s) of the cellular signaling pathway(s) measured in an extracted sample of the tissue of the medical subject, an apparatus comprising a digital compressor configured to perform such methods and a non-transitory storage medium storing instructions that are executable by a digital processing device to perform such methods.

1 - 7 . (canceled) 
     
     
         8 . A kit for determining abnormal operation of an AR cellular signaling pathway in a sample isolated from a subject suffering from a disease associated with an activated AR cellular signaling pathway, comprising:
 a set of primers directed to a plurality of AR cellular signaling pathway genes; and   a set of probes directed to the plurality of AR cellular signaling pathway target genes;   wherein the kit is configured to enable measurement of expression levels of a plurality of mRNA direct target genes of the AR cellular signaling pathway, the plurality of mRNA direct target genes of the AR cellular signaling pathway comprising at least nine target genes selected from the group consisting of KLK2, PMEPA1, TMPRSS2, NKX3-1, ABCC4, KLK3, FKBP5, ELL2, UGT2B15, DHCR24, PPAP2A, NDRG1, LRIG1, CREB3L4, LCP1, GUCY1A3, AR, and EAF2.   
     
     
         9 . The kit of  claim 8 , wherein the plurality of mRNA direct target genes of the AR cellular signaling pathway comprises of KLK2, PMEPA1, TMPRSS2, NKX3-1, ABCC4, KLK3, FKBP5, ELL2, UGT2B15, DHCR24, PPAP2A, NDRG1, LRIG1, CREB3L4, LCP1, GUCY1 A3, AR, and EAF2. 
     
     
         10 . The kit of  claim 8 , wherein the plurality of mRNA direct target genes of the AR cellular signaling pathway consists of KLK2, PMEPA1, TMPRSS2, NKX3-1, ABCC4, KLK3, FKBP5, ELL2, UGT2B15, DHCR24, PPAP2A, NDRG1, LRIG1, CREB3L4, LCP1, GUCY1A3, AR, and EAF2. 
     
     
         11 . The kit of  claim 8 , wherein the disease is a cancer. 
     
     
         12 . The kit of  claim 8 , further comprising a probabilistic model of the AR cellular signaling pathway, the probabilistic model representing the AR cellular signaling pathway for a set of inputs including at least the expression levels of the plurality of mRNA direct target genes of the AR cellular signaling pathway. 
     
     
         13 . The kit of  claim 8 , further comprising a processor configured to:
 calculate activity of the AR cellular signaling pathway in the sample by evaluating at least a portion of a probabilistic model of the AR cellular signaling pathway, the probabilistic model representing the AR cellular signaling pathway for a set of inputs including at least the expression levels of the plurality of mRNA direct target genes of the AR cellular signaling pathway;   determine a level in the sample of at least one transcription factor (TF) element, the at least one TF element controlling transcription of the plurality of mRNA direct target genes of the AR cellular signaling pathway, and the determining being based at least in part on conditional probabilities relating the at least one TF element and the expression levels of the plurality of mRNA direct target genes of the AR cellular signaling pathway;   determine the activity of the AR cellular signaling pathway based on the determined level in the sample of the at least one TF element; and   determine that the AR cellular signaling pathway is operating abnormally in the subject based on the determined activity of the AR cellular signaling pathway.   
     
     
         14 . The kit of  claim 13 , wherein the determined abnormal operation of the AR cellular signaling pathway is active or overactive. 
     
     
         15 . The kit of  claim 13 , wherein the determined abnormal operation of the AR cellular signaling pathway is active or overactive, and wherein the processor is further configured to:
 select, based on the determined abnormal operation of the AR cellular signaling pathway, a specific treatment configured to remedy the determined abnormal operation of the AR pathway.   
     
     
         16 . The kit of  claim 15 , wherein the selected specific treatment is an antagonist of the AR cellular signaling pathway. 
     
     
         17 . The kit of  claim 13 , wherein the determined abnormal operation of the AR cellular signaling pathway is inactive or reduced active, and wherein the processor is further configured to:
 select, based on the determined abnormal operation of the AR cellular signaling pathway, a specific treatment configured to remedy the determined abnormal operation of the AR pathway.   
     
     
         18 . The kit of  claim 17 , wherein the selected specific treatment is an agonist of the AR cellular signaling pathway. 
     
     
         19 . The kit of  claim 13 , wherein determining comprises:
 estimating the level in the sample of the subject of the at least one TF element represented by a TF node of the probabilistic model, the TF element controlling transcription of the plurality of mRNA direct target genes of the AR cellular signaling pathway, the estimating being based at least in part on conditional probabilities of the probabilistic model relating the TF node and nodes in the probabilistic model representing the plurality of mRNA direct target genes of the AR cellular signaling pathway;   wherein the determining by evaluating at least a portion of a probabilistic model is performed by using a Bayesian network comprising nodes representing information about the AR cellular signaling pathway and conditional probability relationships between connected nodes of the Bayesian network.   
     
     
         20 . A method for detecting abnormal operation of an AR cellular signaling pathway in a sample isolated from a subject suffering from a disease associated with an activated AR cellular signaling pathway, comprising:
 receiving a biological sample from the subject;   analyzing, using the kit of  claim 8 , expression levels of the plurality of mRNA direct target genes of the AR cellular signaling pathway by contacting the biological sample with the set of set of primers directed to the plurality of AR cellular signaling pathway genes and the set of probes directed to the plurality of AR cellular signaling pathway target genes.   
     
     
         21 . The method of  claim 20 , wherein the disease is a cancer. 
     
     
         22 . The method of  claim 20 , wherein detecting abnormal operation of an AR cellular signaling pathway further comprises:
 calculating activity of the AR cellular signaling pathway in the sample by evaluating at least a portion of a probabilistic model of the AR cellular signaling pathway, the probabilistic model representing the AR cellular signaling pathway for a set of inputs including at least the expression levels of the plurality of mRNA direct target genes of the AR cellular signaling pathway;   determining a level in the sample of at least one transcription factor (TF) element, the at least one TF element controlling transcription of the plurality of mRNA direct target genes of the AR cellular signaling pathway, and the determining being based at least in part on conditional probabilities relating the at least one TF element and the expression levels of the plurality of mRNA direct target genes of the AR cellular signaling pathway;   determining the activity of the AR cellular signaling pathway based on the determined level in the sample of the at least one TF element; and   determining that the AR cellular signaling pathway is operating abnormally in the subject based on the determined activity of the AR cellular signaling pathway.   
     
     
         23 . The method of  claim 20 , wherein the determined abnormal operation of the AR cellular signaling pathway is active or overactive. 
     
     
         24 . The method of  claim 20 , wherein the determined abnormal operation of the AR cellular signaling pathway is active or overactive, and wherein detecting abnormal operation of an AR cellular signaling pathway further comprises selecting, based on the determined abnormal operation of the AR cellular signaling pathway, a specific treatment configured to remedy the determined abnormal operation of the AR pathway. 
     
     
         25 . The method of  claim 24 , wherein the selected specific treatment is an antagonist of the AR cellular signaling pathway. 
     
     
         26 . The method of  claim 20 , wherein the determined abnormal operation of the AR cellular signaling pathway is inactive or less active. 
     
     
         27 . The method of  claim 20 , wherein the determined abnormal operation of the AR cellular signaling pathway is inactive or less active, and wherein detecting abnormal operation of an AR cellular signaling pathway further comprises selecting, based on the determined abnormal operation of the AR cellular signaling pathway, a specific treatment configured to remedy the determined abnormal operation of the AR pathway. 
     
     
         28 . The method of  claim 27 , wherein the selected specific treatment is an agonist of the AR cellular signaling pathway. 
     
     
         29 . The method of  claim 20 , wherein determining comprises:
 estimating the level in the sample of the subject of the at least one TF element represented by a TF node of the probabilistic model, the TF element controlling transcription of the plurality of mRNA direct target genes of the AR cellular signaling pathway, the estimating being based at least in part on conditional probabilities of the probabilistic model relating the TF node and nodes in the probabilistic model representing the plurality of mRNA direct target genes of the AR cellular signaling pathway;   wherein the determining by evaluating at least a portion of a probabilistic model is performed by using a Bayesian network comprising nodes representing information about the AR cellular signaling pathway and conditional probability relationships between connected nodes of the Bayesian network.   
     
     
         30 . The method of  claim 20 , further comprising one or more of:
 diagnosing based on the determined activity of the AR cellular signaling pathway;   preparing a prognosis based on the determined activity of the AR cellular signaling pathway;   drug prescribing based on the determined activity of the AR cellular signaling pathway;   predicting drug efficacy based on the determined activity of AR cellular signaling pathway;   predicting adverse effects based on the determined activity of the AR cellular signaling pathway;   monitoring of drug efficacy;   developing one or more drugs;   developing one or more assays;   researching one or more cellular pathways;   cancer staging;   enrolling the subject in a clinical trial based on the determined activity of the AR cellular signaling pathway;   selecting a subsequent test to be performed, and   selecting one or more companion diagnostics tests.