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US 6,203,987 B1Granted
Methods for using co-regulated genesets to enhance detection and classification of gene expression patterns
AssigneeRosetta Inpharmatics LLC
InventorsStephen H. Friend, Roland Stoughton
Life of this patent
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Abstract
The present invention provides methods for enhanced detection of biological response patterns. In one embodiment of the invention, genes are grouped into basis genesets according to the co-regulation of their expression. Expression of individual genes within a geneset is indicated with a single gene expression value for the geneset by a projection process. The expression values of genesets, rather than the expression of individual genes are then used as the basis for comparison and detection of biological responses with greatly enhanced sensitivity.
Claims61
A method for analyzing the values of cellular constituents in a biological sample comprising converting a first profile comprising measurements of a plurality of cellular constituents in said biological sample into a projected profile comprising a plurality of cellular constituent set values according to a definition of co-varying basis cellular constituent sets;
- wherein said definition is based upon co-variation of measurements of cellular constituents that comprise at least a portion of said plurality of cellular constituents, under a plurality of different perturbations;
- and wherein said converting comprises projecting said first profile onto said co-varying basis cellular constituent sets, thereby analyzing the values of cellular constituents in said biological sample.
A method for defining co-varying cellular constituent sets comprising defining co-varying cellular constituent sets based upon the co-variation of a plurality of measurements of cellular constituents in a biological sample under a plurality of perturbations.
A method for analyzing expression data from a biological sample comprising converting a first expression profile of a plurality of genes in said sample into a projected expression profile containing a plurality of geneset expression values according to a definition of basis genesets, wherein each of said basis genesets comprises genes having co-varying transcript levels under a plurality of different perturbations, and wherein said converting comprises projecting said first expression profile onto said basis genesets, thereby analyzing said expression data.
A method for comparing two expression profiles comprising
- (a) converting a first expression profile into a first projected expression profile according to a definition of basis genesets, wherein each of said basis genesets comprises genes having co-varying transcript levels under a plurality of different perturbations, and wherein said converting comprises projecting said first expression profile onto said basis genesets;
- (b) converting a second expression profile into a second projected expression profile according to said definition of basis genesets, wherein said converting comprises projecting said expression profile onto said basis genesets;
- and
- (c) determining the generalized angle cosine between the vector of said first projected expression profile and the vector of said second projected expression profile as a similarity metric, thereby comparing said first and second expression profiles.
1 more element
A method for determining the type of an unknown perturbation comprising:
- (a) converting a first expression profile from a biological sample subjected to an unknown perturbation into a first projected expression profile according to a definition of basis genesets, wherein each of said basis genesets comprises genes having co-varying transcript levels under a plurality of different perturbations, and wherein said converting comprises projecting said first expression profile onto said basis genesets;
- and
- (b) comparing said first projected expression profile with a plurality of reference projected expression profiles to determine the type of said perturbation, wherein each said reference projected expression profile is the product of a method comprising projecting a second expression profile from a biological sample subjected to a different, known perturbation onto basis genesets, wherein each of said basis genesets comprises genes having co-varying transcript levels under a plurality of different perturbations, wherein similarity of said first projected expression profile to one or more reference projected expression profiles indicates that said unknown perturbation is similar to the known one or more perturbations giving rise to said one or more reference projected profiles.
A method for analyzing expression data from a biological sample comprising:
- (a) selecting a geneset definition from a plurality of geneset definitions, wherein said geneset definitions are stored in a database management system, wherein said geneset definitions are based upon genes having co-varying transcript levels under a plurality of different perturbations;
- (b) inputting an expression profile of said biological sample;
- (c) converting said expression profile into a projected expression profile according to said selected geneset definition, wherein said converting comprises projecting said expression profile onto said geneset definition;
- and
- (d) displaying said projected expression profile, thereby analyzing expression data from said biological sample.
2 more elements
A computer system comprising
- (a) a processor,
- (b) storage media for storing a database, and
- (c) a program module, executable by said processor, said program module comprising computer readable program code for effecting the following steps within said computer system:
- (i)) retrieving a definition of basis genesets from said database, wherein said definition is based upon genes with co-varying transcript levels under a plurality of different perturbations;
- and
- (ii) converting a gene expression profile into a projected expression profile according to said definition, wherein said converting comprises projecting said gene expression profile onto said basis genesets.
3 more elements
A computer-usable medium having computer readable program code embodied thereon for effecting the following steps within a computer system:
- (a) retrieving a definition of basis genesets from a database, wherein said definition is based upon genes with co-varying transcript levels under a plurality of different perturbations;
- and
- (b) converting a gene expression profile into a projected expression profile according to said definition, wherein said converting comprises projecting said gene expression profile onto said basis genesets.
A method for analyzing expression data from a biological sample comprising causing a computer system to execute the following steps:
- (a) retrieving a definition of genesets from a database, wherein said definition is based upon genes with co-varying transcript levels under a plurality of different perturbations;
- and
- (b) converting a gene expression profile into a projected expression profile according to said definition, wherein said converting comprises projecting said gene expression profile onto said basis genesets.
A method for analyzing the values of cellular constituents in a biological sample comprising:
- (a) measuring a plurality of cellular constituents in said biological sample to produce a first profile;
- (b) converting said first profile into a projected profile comprising a plurality of cellular constituent set values according to a definition of co-varying basis cellular constituent sets;
- wherein said definition is based upon co-variation of measurements of cellular constituents that comprise at least a portion of said plurality of cellular constituents, under a plurality of different perturbations;
- and wherein said converting comprises projecting said first profile onto said co-varying basis cellular constituent sets, thereby analyzing the values of cellular constituents in said biological sample.
1 more element
A method for analyzing the values of cellular constituents in a biological sample comprising:
- (a) selecting a definition of co-varying basis cellular constituent sets from a plurality of definitions of co-varying basis cellular constituent sets, wherein said definitions are stored in a database management system, and wherein said definitions are based upon co-variation of cellular constituents under a plurality of different perturbations;
- (b) inputting a profile comprising measurements of a plurality of cellular constituents in said biological sample;
- (c) converting said profile into a projected profile according to said selected definition of co-varying basis cellular constituent sets;
- wherein said converting comprises projecting said profile onto said co-varying basis cellular constituent sets;
- and
- (d) displaying said projected profile.
3 more elements
A computer system comprising
- (a) a processor,
- (b) storage media for storing a database, and
- (c) a program module, executable by said processor, said program module comprising computer readable program code for effecting the following steps within said computer system:
- (i) retrieving a definition of co-varying basis cellular constituent sets from said database, wherein said definition is based upon co-variation of measurements of cellular constituents under a plurality of different perturbations;
- and
- (ii) converting a first profile into a projected profile according to said definition, wherein said first profile comprises measurements of a plurality of cellular constituents in a biological sample, and wherein said converting comprises projecting said first profile onto said co-varying basis cellular constituent sets.
3 more elements
A computer-usable medium having computer readable program code embodied thereon for effecting the following steps within a computer system:
- (a) retrieving a definition of co-varying basis cellular constituent sets from a database, wherein said definition is based upon co-variation of measurements of cellular constituents under a plurality of different perturbations;
- and
- (b) converting a first profile into a projected profile according to said definition, wherein said first profile comprises measurements of a plurality of cellular constituents in a biological sample, and wherein said converting comprises projecting said first profile onto said co-varying basis cellular constituent sets.
A method for analyzing the values of cellular constituents in a biological sample comprising causing a computer system to execute the following steps:
- (a) retrieving a definition of co-varying basis cellular constituent sets from a database, wherein said definition is based upon co-variation of measurements of cellular constituents under a plurality of different perturbations;
- and
- (b) converting a first profile into a projected expression profile according to said definition, wherein said first profile comprises measurements of a plurality of cellular constituents in a biological sample, and wherein said converting comprises projecting said first profile onto said co-varying basis cellular constituent sets.
A method for identifying the cellular pathway affected by a drug comprising
- (a) converting a first expression profile from a biological sample subjected to said drug into a first projected expression profile according to a definition of basis genesets, wherein each of said basis genesets comprises genes having co-varying transcript levels under a plurality of different perturbations, and wherein said converting comprises projecting said first expression profile onto said basis genesets;
- and
- (b) comparing said first projected expression profile with a plurality of reference projected expression profiles to determine the cellular pathway affected by said drug, wherein each said reference projected expression profile is the product of a method comprising projecting a second expression profile from a biological sample subjected to a different perturbation known to be affecting a particular cellular pathway onto basis genesets, wherein each of said basis genesets comprises genes having co-varying transcript levels under a plurality of different perturbations, wherein similarity of said first projected expression profile to one or more reference projected expression profiles indicates that said drug affects a cellular pathway known to be affected by the one or more perturbations giving rise to said one or more reference projected profiles.
A method for determining whether a drug candidate has an activity similar to a known drug comprising:
- (a) converting a first expression profile from a biological sample subjected to said drug candidate into a first projected expression profile according to a definition of basis genesets, wherein each of said basis genesets comprises genes having co-varying transcript levels under a plurality of different perturbations, and wherein said converting comprises projecting said first expression profile onto said basis genesets;
- and
- (b) comparing said first projected expression profile with a plurality of reference projected expression profiles to determine whether said drug candidate has an activity similar to a known drug, wherein each said reference projected expression profile is the product of a method comprising projecting a second expression profile from a biological sample subjected to a different known drug onto basis genesets, wherein each of said basis genesets comprises genes having co-varying transcript levels under a plurality of different perturbations, wherein similarity of said first projected expression profile to one or more reference projected expression profiles indicates that said drug candidate has an activity similar to the known one or more drugs giving rise to said one or more reference projected profiles.
A method for identifying the cellular pathway affected by a drug comprising
- (a) converting a first profile from a biological sample subjected to said drug into a first projected profile according to a first definition of co-varying basis cellular constituent sets, wherein said first profile comprises measurements of a plurality of cellular constituents in said biological sample, and wherein said first definition is based upon co-variation of measurements of cellular constituents under a plurality of different perturbations, and wherein said converting comprises projecting said first profile onto said co-varying basis cellular constituent sets;
- and
- (b) comparing said first projected profile with a plurality of reference projected profiles to determine the cellular pathway affected by said drug, wherein each said reference projected profile is the product of a method comprising converting a second profile into said reference projected profile according to a second definition of co-varying basis cellular constituent sets, wherein said second profile comprises measurements of a plurality of cellular constituents from a biological sample subjected to a different perturbation known to be affecting a particular cellular pathway, and wherein said second definition is based upon co-variation of measurements of cellular constituents under a plurality of different perturbations, and wherein said converting comprises projecting said second profile onto said co-varying basis cellular constituent sets, wherein similarity of said first projected profile to one or more reference projected profiles indicates that said drug affects a cellular pathway known to be affected by the one or more perturbations giving rise to said one or more reference projected profiles.
A method for determining whether a drug candidate has an activity similar to a known drug comprising:
- (a) converting a first profile from a biological sample subjected to said drug candidate into a first projected profile according to a first definition of co-varying basis cellular constituent sets, wherein said first profile comprises measurements of a plurality of cellular constituents in said biological sample, and wherein said first definition is based upon co-variation of measurements of cellular constituents under a plurality of different perturbations, and wherein said converting comprises projecting said first profile onto said co-varying basis cellular constituent sets;
- and
- (b) comparing said first projected profile with a plurality of reference projected profiles to determine whether said drug candidate has an activity similar to a known drug, wherein each said reference projected profile is the product of a method comprising converting a second profile into said reference projected profile according to a second definition of co-varying basis cellular constituent sets, wherein said second profile comprises measurements of a plurality of cellular constituents from a biological sample subjected to a different known drug, and wherein said second definition is based upon co-variation of measurements of cellular constituents under a plurality of different perturbations, and wherein said converting comprises projecting said second profile onto said co-varying basis cellular constituent sets, wherein similarity of said first projected profile to one or more reference projected profiles indicates that said drug candidate has an activity similar to the known one or more drugs giving rise to said one or more reference projected profiles.
Dependencies are inferred from the claim text.