Abstract: The present invention provides methods for enhanced detection of biological response profiles. In particular, the methods of this invention allow for the detection of biological response patterns, such as gene expression patterns, in response to different drug treatments. The methods of the invention also allow the determination of a “consensus profile” which describes a particular class or type of biological response. In certain embodiments the consensus profile may describe the biological response of a particular group or class of drugs. In other embodiments, the consensus profile may describe an “ideal” biological response such as one associated with a desired therapeutic effect. The methods of the present invention also allow for the comparison of different biological responses. Thus, the methods of the invention may be used, e.g., to identify and/or study new drugs.

Abstract: The present invention relates to methods for determining the genetic causes of certain phenotypes. The present invention further relates to methods for predicting the phenotype of a organism from its genotype. In particular, the methods of the invention relate to the use of compendia of biological response profiles of cells having known genetic mutations for comparisons with the biological response profiles of cells having unknown phenotypes and genotypes. The methods of the present invention are particularly useful for monitoring the success of genetic engineering and cross-breeding of crops and livestock. The present invention further relates to a computer system for comparing biological response profiles to a compendium of biological response profiles and to kits for relating the phenotype of a cell type to its genotype or for predicting the phenotype of a cell type.

Abstract: The invention relates to methods and systems (e.g., computer systems and computer program products) for characterizing cellular constituents, particularly genes and gene products. In particular, the invention provides methods for assigning or determining the biological function of uncharacterized genes and gene products by using “response profiles,” i.e., measurements of pluralities of cellular constituents in cells having a modified gene or gene product, as phenotypic markers for the gene or gene product. Methods are provided for clustering such response profiles so that similar or correlated response profiles are organized into the same cluster. The invention also provides databases or “compendiums” of response profiles to which the response profile of an uncharacterized gene or gene product can compared.

Abstract: The present invention provides methods and systems, particularly computer systems, for determining the relative specificity with which a particular polynucleotide molecule hybridizes to a polynucleotide probe. For example, the methods and systems of the invention enable a user to compare the specificity with which different polynucleotides hybridize to a given probe and/or rank these polynucleotides according to their specificity to that probe. The methods and systems of the invention also enable a user to compare the specificity with which a particular polynucleotide hybridizes to different probes, and/or rank those different probes according to their specificity for that particular polynucleotide.

Abstract: Diagnostic methods that rely on the use of one or more assays that assess cellular activation are provided. The assays are performed on whole blood or leukocytes, and indicate individually or in combination the level of cardiovascular cell activation, which is pivotal in many chronic and acute disease states. These results of the assays are used within a clinical framework to support therapeutic decisions such as: further testing for infectious agents, anti-oxidant or anti-adhesion therapy, postponement and optimal re-scheduling of high-risk surgeries, classifying susceptibility to and progression rates of chronic disease such as diabetes, atherogenesis, and venous insufficiency; extreme interventions in trauma cases of particularly high risk and activation-lowering therapies. Also provided is as composition derived from a pancreatic homogenate that contains circulating cell activating factors, which can serve as targets for drug screening to identify drug candidates for use in activation lowering therapies.

Abstract: A method for fluorophore bias removal in microarray experiments in which the fluorophores used in microarray experiment pairs are reversed. Further, a method for calculating the individual errors associated with each measurement made in nominally repeated microarray experiments. This error measurement is optionally coupled with rank based methods in order to determine a probability that a cellular constituent is up or down regulated in response to a perturbation. Finally, a method for determining the confidence in the weighted average of the expression level of a cellular constituent in nominally repeated microarray experiments.

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 response with greatly enhanced sensitivity. In another embodiment of the invention, biological responses are grouped according to the similarity of their biological profile. The methods of the invention have many useful applications, particularly in the fields of drug development and discovery. For example, the methods of the invention may be used to compare biological responses with greatly enhanced sensitivity.

Abstract: The present invention relates to the characterization of genes and their gene products (i.e., proteins). In particular, the invention relates to novel systems and methods for characterizing the cellular function and/or activity of different cellular constituents such as different genes and/or their gene products. The invention also provides novel systems and methods for comparing different cellular constituents (e.g., novel genes and/or their gene products) from different cells, such as genes and/or gene products from cells of different species of organism or, alternatively, from different cells (e.g., of different cell types or from different tissues types) of the same organism. In particular, using the systems and methods of the invention, it is possible to identify different cellular constituents having common cellular functions.

Abstract: A method for fluorophore bias removal in microarray experiments in which the fluorophores used in microarray experiment pairs are reversed. Further, a method for calculating the individual errors associated with each measurement made in nominally repeated microarray experiments. This error measurement is optionally coupled with rank based methods in order to determine a probability that a cellular constituent is up or down regulated in response to a perturbation. Finally, a method for determining the confidence in the weighted average of the expression level of a cellular constituent in nominally repeated microarray experiments.

Abstract: The present invention provides methods for determining the level of protein activity in a cell by: (i) measuring abundances of cellular constituents in a cell in which the activity of a specific protein is to be determined so that a diagnostic profile is thus obtained; (ii) measuring abundances of cellular constituents that occur in a cell in response to perturbations in the activity of said protein to obtain response profiles and interpolating said response profiles to generate response curves; and (iii) determining a protein activity level at which the response profile extracted from the response curves best fits the measured diagnostic profile, according to some objective measure. In alternative embodiments, the present invention also provides methods for identifying individuals having genetic mutations or polymorphisms that disrupt protein activity, and methods for identifying drug activity in vivo by determining the activity levels of proteins which interact with said drugs.

Abstract: This invention provides methods for detecting and predicting drug interaction. In one embodiment of the invention, a plurality of cellular constituents in a biological sample is monitored as the sample is subject to various drug treatments. The response of the cellular constituents are analyzed to detect interactions. This method is particularly useful for predicting drug interaction using a model organism. It is also useful for analyzing interaction between any perturbations to a biological system.

Abstract: A method for fluorophore bias removal in microarray experiments in which the fluorophores used in microarray experiment pairs are reversed. Further, a method for calculating the individual errors associated with each measurement made in nominally repeated microarray experiments. This error measurement is optionally coupled with rank based methods in order to determine a probability that a cellular constituent is up or down regulated in response to a perturbation. Finally, a method for determining the confidence in the weighted average of the expression level of a cellular constituent in nominally repeated microarray experiments.

Abstract: The present invention provides methods for determining the level of protein activity in a cell by: (i) measuring abundances of cellular constituents in a cell in which the activity of a specific protein is to be determined so that a diagnostic profile is thus obtained; (ii) measuring abundances of cellular constituents that occur in a cell in response to perturbations in the activity of said protein to obtain response profiles and interpolating said response profiles to generate response curves; and (iii) determining a protein activity level at which the response profile extracted from the response curves best fits the measured diagnostic profile, according to some objective measure. In alternative embodiments, the present invention also provides methods for identifying individuals having genetic mutations or polymorphisms that disrupt protein activity, and methods for identifying drug activity in vivo by determining the activity levels of proteins which interact with said drugs.

Abstract: This invention relates to methods and systems for characterizing the actions of drugs in cells. In particular, the invention provides methods for identifying multiple primary targets through which a drug, drug candidate, or other compound of interest acts on a cell. Thus, the invention also relates to methods for drug development based on the disclosed methods for identifying multiple primary targets of a drug. The methods of the invention involve: (i) measuring responses of cellular constituents to graded exposures of the cell to a drug of interest; (ii) identifying an “inflection concentration” of the drug for each cellular constituent measured; and (iii) identifying “expression sets” of cellular constituents from the distribution of the inflection drug concentrations. Each expression set corresponds to a particular primary target of the drug. The invention also provides computer systems which identify multiple targets of a drug by executing the disclosed methods.

Abstract: This invention relates to methods and systems for characterizing the actions of drugs in cells. In particular, the invention provides methods for identifying multiple primary targets through which a drug, drug candidate, or other compound of interest acts on a cell. Thus, the invention also relates to methods for drug development based on the disclosed methods for identifying multiple primary targets of a drug. The methods of the invention involve: (i) measuring responses of cellular constituents to graded exposures of the cell to a drug of interest; (ii) identifying an “inflection concentration” of the drug for each cellular constituent measured; and (iii) identifying “expression sets” of cellular constituents from the distribution of the inflection drug concentrations. Each expression set corresponds to a particular primary target of the drug. The invention also provides computer systems which identify multiple targets of a drug by executing the disclosed methods.

Abstract: The present invention provides methods for monitoring disease states in a subject, as well as methods for monitoring the levels of effect of therapies upon a subject having one or more disease states. The methods involve: (i) measuring abundances of cellular constituents in a cell from a subject so that a diagnostic profile is obtained, (ii) measuring abundances of cellular constituents in a cell of one or more analogous subjects so that perturbation response profiles are obtained which correlate to a particular disease or therapy, and (iii) determining the interpolated perturbation response profile or profiles which best fit the diagnostic profile according to some objective measure.

Abstract: This invention provides methods for determining drug specificity, therapeutic index and effective doses for individual patients. According to the methods of the invention, graded levels of drug are applied to a biological sample or a patient. A plurality of cellular constituents are measured to determine the activity of the drug on a target pathway and at least one off-target pathway. A drug specificity is determined by comparing the target and off target activities of the drug. A therapeutic concentration (or dose) is defined as a concentration (or dose) of the drug that induces certain response in the target pathway. A toxic concentration (or dose) is defined as a concentration (or dose) of the drug that induces certain response in the off target pathway. Therapeutic index is the ratio of the toxic concentration over therapeutic concentration. Methods are also provided to determine an effective dose of a drug for a patient by measuring the activity of the drug on the particular patient.

Abstract: This invention provides methods for determining drug specificity, therapeutic index and effective doses for individual patients. According to the methods of the invention, graded levels of drug are applied to a biological sample or a patient. A plurality of cellular constituents are measured to determine the activity of the drug on a target pathway and at least one off-target pathway. A drug specificity is determined by comparing the target and off target activities of the drug. A therapeutic concentration (or dose) is defined as a concentration (or dose) of the drug that induces certain response in the target pathway. A toxic concentration (or dose) is defined as a concentration (or dose) of the drug that induces certain response in the off target pathway. Therapeutic index is the ratio of the toxic concentration over therapeutic concentration. Methods are also provided to determine an effective dose of a drug for a patient by measuring the activity of the drug on the particular patient.

Abstract: The present invention provides methods for monitoring disease states in a subject, as well as methods for monitoring the levels of effect of therapies upon a subject having one or more disease states. The methods involve: (i) measuring abundances of cellular constituents in a cell from a subject so that a diagnostic profile is obtained, (ii) measuring abundances of cellular constituents in a cell of one or more analogous subjects so that perturbation response profiles are obtained which correlate to a particular disease or therapy, and (iii) determining the interpolated perturbation response profile or profiles which best fit the diagnostic profile according to some objective measure.

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.