Drug discovery methods

• US 8,489,334 B2
• Filed: 02/03/2003
• Issued: 07/16/2013
• Est. Priority Date: 02/04/2002
• Status: Active Grant

• Current Assignee: Qiagen Redwood City, Inc. (Qiagen NV)
• Original Assignee: Ingenuity Systems, Inc. (Qiagen NV)
• Inventors: Cho, Raymond J., Felciano, Ramon M., Holley, Bret, Patel, Viresh, Richards, Daniel R., Steward, Keith, Schneider, Sara, Chen, Richard O., Selvarajan, Sushma
• Primary Examiner(s): Clow, Lori A
• Application Number:
  US10/502,420
• Publication Number:
  US 20060036368A1
• Time in Patent Office: 3,816 Days
• Field of Search: None
• US Class Current: 702/19
• CPC Class Codes: G16B 20/00 ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
• CPC Class Codes: G16B 25/00 ICT specially adapted for hybridisation; ICT specially adapted for gene or protein expression
• CPC Class Codes: G16B 25/10 Gene or protein expression profiling; Expression-ratio estimation or normalisation
• CPC Class Codes: G16B 40/00 ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding
• CPC Class Codes: G16B 45/00 ICT specially adapted for bioinformatics-related data visualisation, e.g. displaying of maps or networks
• CPC Class Codes: G16B 5/00 ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks
• CPC Class Codes: G16B 5/20 Probabilistic models
• CPC Class Codes: G16B 50/00 ICT programming tools or database systems specially adapted for bioinformatics
• CPC Class Codes: G16B 50/10 Ontologies; Annotations

Abstract

Method for identifying disease-related pathways that can used to identify discovery targets, to identify new uses for known drugs, to identify markers for drug response, and related purposes.

Claims

1. A computer system for evaluating user-supplied genomics data, the system comprising:

a computer comprising a structured database to store and access genomics information, wherein the structured database comprises stored genomics information, wherein the computer permits the computation of complex relationships among genes and/or gene products found within the genomics information;

wherein the computer is configured to;

(a) define one or more profile models based on one or more profile definition criteria;

(b) pre-generate a profile library by building a collection of profiles according to the profile models using the genomics information stored in the structured database;

(c) receive the user-supplied genomics data;

(d) identify one or more overlapped profiles from the profile library that overlap with at least a portion of the user-supplied genomics data;

(e) determine, for each of the one or more overlapped profiles, whether the overlap is statistically significant, wherein the determination permits all profiles to be compared in relative terms against each other; and

(f) analyze one or more statistically significant overlapped profiles together with the user-supplied genomics data including inspection of database-asserted biological interactions embodied in the one or more statistically significant overlapped profiles;

wherein the computer system is a stand alone computer, a multicomponent computer, or a networked computer, and wherein the computer system further comprises hardware for electronically searching the structured database.

2. The computer system of claim 1, wherein the computer is configured to pre-generate a profile library containing a profile for each one of a genomic information type in the database according to the profile model.

3. The computer system of claim 2, wherein the profiles are pre-generated from a graph structure.

4. The computer system of claim 3, wherein the determination of whether the overlap is statistical significant comprises the computation of a probability of overlap as a function of information contained in the structured database.

5. The computer system of claim 2, wherein the genomic information is a type of information selected from the group consisting of a gene, gene product or biological process.

6. The computer system of claim 2, wherein the pre-generation of a profile library comprises the selection of a node for a profile based on a number of similar findings in the structured database that link the node to a neighboring node.

7. The computer system of claim 2, wherein the pre-generation comprises generating a plurality of profile libraries and wherein each profile library corresponds to a different profile generation criterion.

8. The computer system of claim 1, wherein the computer is further configured to generate the profiles by querying the structured database for information matching the one or more profile definition criteria.

9. The computer system of claim 1, wherein the user-supplied genomics data comprises differential gene expression data.

10. The computer system of claim 9, wherein the differential gene expression data relates to a disease.

11. The computer system of claim 10, wherein the computer is further configured to analyze the user-supplied genomics data to identify a new use for a known therapy wherein the differential gene expression data relates to a pathway affected by the known therapy.

12. The computer system of claim 10, wherein the computer is further configured to analyze the user-supplied genomics data prioritizing candidate development compounds for further development by giving higher priority to development compounds on the basis of whether or not they are likely to result in an undesirable effect based on their involvement in other biological pathways as embodied in one of the one or more overlapped profiles.

13. The computer system of claim 10, wherein the computer is further configured to analyze the user-supplied genomics data to identify disease-related pathways wherein the disease is a side effect of drug therapy.

14. The computer system of claim 10, wherein the differential gene expression data relates to a particular disease, and wherein the analysis of one or more statistically significant overlapped profiles together with the user-supplied genomics data further comprises validating whether the differential gene expression data comprise genotypic markers for the disease according to whether a database-asserted biological association related to the disease, which is shared among a plurality of overlapped profiles, is statistically significant.

15. The computer system of claim 1, wherein the one or more profile generation criteria comprise one or more of a biological process, number of genes, organismal process, gene connectivity, edge connectivity, findings source type, experiment context, or tissue consistency criterion.

16. The computer system of claim 1, wherein the profiles are generated from a seed node and the inspection of database-asserted biological interactions focuses on the biological interactions emanating from the seed node.

17. The computer system of claim 16, wherein the seed is selected from the group of genomic data types consisting of a gene, gene product, and biological process.

18. The computer system of claim 1, wherein the computer is further configured to compute a statistical significance for a biological association in the one or more overlapped profiles that are determined to comprise a statistically significant overlap.

19. The computer system of claim 1, wherein the computer is further configured to display information related to the one or more overlapped profiles that are determined to comprise a statistically significant overlap and the user-supplied genomics data using a GUI.

20. The computer system of claim 1, wherein the computer is further configured to annotate the profiles with biological associations asserted by the structured database wherein the associations comprise one or more of a cellular process, molecular process, organismal process or disease process.

21. The computer system of claim 20, wherein the computer is further configured to display biological associations using one of a GUI or a report.

22. The computer system of claim 20, wherein the annotation of profiles comprises use of classification information found in an ontology.

23. The computer system of claim 1, wherein the determination of statistical significance comprises a test of a null hypothesis over a discrete probability distribution, the distribution being a function of a size of the structured database, sizes of profiles, a size of the user-supplied genomics data and expression values.

24. A computer system for evaluating user-supplied genomics data, the system comprising:

a computer comprising a structured database to store and access genomics information, wherein the computer permits the computation of complex relationships among genes and/or gene products found within the genomics information

wherein the computer is configured to;

(a) define a profile model based on one or more profile definition criteria;

(b) build a collection of profiles according to the profile model using the genomics information stored in the structured database, wherein each profile comprises a subset of the genomics information contained in the structured database comprising information relating to genes, their DNA sequences, their mRNA, proteins expressed from said genes and the biological effects of the expressed proteins;

(c) receive the user-supplied genomics data;

(d) identify a plurality of overlapped profiles from the collection of profiles that comprise an overlap with at least a portion of the user-supplied genomics data and

(e) rank at least a subset of the plurality of overlapped profiles, based on statistical significance of the overlap according to one or more metrics; and

wherein the computer system is a stand alone computer, a multicomponent computer, or a networked computer, and wherein the computer system further comprises hardware for electronically searching the knowledge base.

25. The computer system of claim 24, wherein the computer is further configured to analyze database asserted biological interactions embodied in at least a subset of the plurality of overlapped profiles with an overlap to the user-supplied genomics data that is above a threshold statistical significance.