Computer-Aided Discovery of Biomarker Profiles in Complex Biological Systems

• US 20090093969A1
• Filed: 08/28/2008
• Published: 04/09/2009
• Est. Priority Date: 08/29/2007
• Status: Active Grant

• Current Assignee: Alexion Pharmaceuticals Incorporated (Astrazeneca PLC), Qualcomm, Inc.
• Original Assignee: Selventa, Inc.
• Inventors: Loureiro, Joseph J., Elliston, Keith O., Ladd, William M.
• Granted Patent: US 8,082,109 B2
• Time in Patent Office: Days
• US Class Current: 702/19
• 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: Y10T 436/203332 Hydroxyl containing

Abstract

The invention relates to computational methods, systems and apparatus useful in the analysis of sets of biomolecules in an accessible body fluid or tissue sample from a patient, which biomolecules collectively or individually are candidates to serve as biomarkers, i.e., biomolecules which together or individually upon detection or change are indicative that the patient is in some biological state, such as a diseased state. The methods permit one to examine such potential biological markers to determine whether each one is indeed present as a consequence of the biological state, or as an artifact of the biomarker search protocol.

Claims

1. A software assisted method of discovering in a sample from an animal biomarkers indicative of a biological state of a cell, tissue, organ, organ system, or organism, the method comprising the steps of:

a) providing in a storage medium one or more models representative of one or more causative or characteristic biophysical or biochemical relationships underlying said biological state in said cell, tissue, organ, organ system, or organism and comprising nodes representing a biological entity, action, functional activity, or concept, and links between nodes indicative of there being a relationship therebetween, at least some of which include indicia of causal directionality;

b) providing a candidate set of data representative of biomolecules, or concentration relationships therebetween, determined by analysis of a sample from a animal in said biological state, and comprising lymph, tears, urine, blood, serum, plasma, saliva, amniotic fluid, cerebro-spinal fluid, stool, tissue lysate preparations, cell lysate preparations, or fractions thereof, which are hypothesized to be indicative of the biological state of said cell, tissue, organ, organ system, or organism;

c) comparing said candidate set of data with said model to discern which of said biomolecules or concentration relationships therebetween are indicative of the biological state or which are not directly related to said biological state, thereby to discern a candidate biomarker for said biological state; and

d) causing an electronic representation of the candidate biomarker to be physically stored on a computer-readable medium.

3. The method of claim 1 wherein the provided models are generated by a method comprising the steps of:

providing a knowledgebase of biological assertions concerning a selected biological state, the knowledgebase comprising a multiplicity of nodes representative of a network of biological entities, actions, functional activities, and concepts, and links between nodes indicative of there being a relationship between the nodes, wherein at least some of the links comprise indicia of causal directionality;

simulating in the network one or more perturbations of plural individual root nodes to initiate a cascade of virtual activity through said links between connected nodes to discern multiple branching paths within the knowledgebase;

mapping onto the knowledgebase operational data representative of a perturbation, associated with a biological state, of one or more nodes and optionally of experimentally observed or hypothesized changes in other nodes resulting from the one or more perturbations;

prioritizing said branching paths on the basis of how well they predict said operational data, thereby to define a set of models comprising said branching paths potentially explanatory of the molecular biology implied by the data;

applying logic based criteria to said set of models to reject models as not likely representative of real biology thereby to eliminate hypotheses and to identify from remaining models one or more active causative relationships.

4. The method of claim 3 comprising the additional step of harmonizing a plurality of said remaining models to produce a larger model comprising a model of a portion of the operation of said biological system.

5. The method of claim 1 wherein the sample is from a species different from the species used to prepare the model, the methods comprising the additional step of applying interspecies homological reasoning to discern biomolecules in the sample homologous to biological entities in the model.

6. The method of claim 1 wherein the biological state is a disease state, toxic state, homeostatic state, a drugged state, or an environmentally stressed state.

7. The method of claim 1 wherein the biological state is a cancer of an organ or tissue or a metabolic disease.

8. The method of claim 1 comprising the additional step of obtaining a sample from an patient presenting himself for a health checkup or diagnosis, and assaying said sample for the presence of said candidate biomarkers to discern a biological state of the patient.

9. The method of claim 3 wherein a said logic based criterion is based on a measure of consistency between:

the predictions resulting from simulation along multiple nodes of a model and known biology of said selected biological system;

the operational data and the predictions resulting from simulation within a model upstream from a root node to a node corresponding to an operational data point;

the operational data and the predictions resulting from simulation within a model downstream from a root node to a node corresponding to an operational data point.

10. The method of claim 3 comprising providing said data base by:

providing a data base of biological assertions comprising a multiplicity of nodes representative of biological elements and descriptors characterizing the elements or relationships among nodes;

extracting a subset of assertions from the knowledgebase that satisfy a set of biological criteria specified by a user to define a said selected biological system; and

compiling the extracted assertions to produce an assembly comprising a biological knowledge base of assertions potentially relevant to said selected biological system.

11. The method of claim 3 wherein the operational data comprises an effective increase or decrease in concentration or number of a biological element, stimulation or inhibition of activity of an element, alterations in the structure of an element, or the appearance or disappearance of an element.

12. The method of claim 3 wherein the operational data is experimentally determined data.

13. The method of claim 1 wherein the candidate set of data representative of biomolecules, or concentration relationships therebetween, comprise protein data, phosphorylation data, metabolite data, or polynucleotide data, including mRNA or the presence or absence of single nucleotide polymorphisms or other genetic characteristics.

14. The method of claim 1 comprising comparing candidate biomolecules identified from a body sample to biomolecules outside the model which the model predicts should appear in a body fluid.

2. A software assisted method of discovering biomarkers in a body fluid or tissue indicative of a biological state in a cell, tissue, organ or organ system of the body, the method comprising the steps of:

a) providing one or more models representative of one or more causative or characteristic relationships underlying said biological state in said cell, tissue, organ or organ system and comprising nodes representing a biological entity, action, functional activity, or concept, and

links between nodes indicative of there being a relationship therebetween, at least some of which include indicia of causal directionality;

b) examining said models to discern a set of biomolecules or concentration relationships therebetween hypothetically to be found in a biological sample and to be indicative of said biological state;

c) obtaining samples from individuals known to be in said biological state and confirming the presence of said set of biomolecules thereby to discern a candidate biomarker for said biological state; and

d) causing an electronic representation of the candidate biomarker to be physically stored on a computer-readable medium.

15. A method for discovery by an investigator in a biological sample of biomarkers indicative of a biological state of a cell, tissue, organ, organ system, or organism, such as a mammal, the method comprising the steps of causing a second party entity or entities to:

a) provide one or more models representative of one or more causative or characteristic relationships underlying said biological state in said cell, tissue, organ, organ system, or organism and comprising nodes representing a biological entity, action, functional activity, or concept, and links between nodes indicative of there being a relationship therebetween, at least some of which include indicia of causal directionality;

b) provide a candidate set of data representative of biomolecules or concentration relationships therebetween determined by analysis of a sample from a animal known to be in said biological state, and comprising lymph, urine, blood, serum, plasma, tears, sweat, saliva, amniotic fluid, cerebro-spinal fluid, stool, tissue lysate preparations, cell lysate preparations, or fractions thereof, which are hypothesized to be indicative of the biological state;

c) map said data onto said models to discern which of said biomolecules or concentration relationships therebetween are indicative of the biological state of the cell, tissue, organ, organ system, or organism which are unrelated to said biological state, thereby to discern candidate biomarkers for said biological state; and

d) physically storing an electronic representation of the candidate biomarkers on a computer-readable medium.

17. The method of claim 15 wherein said investigator is a pharmaceutical company and a said second entity is a discovery unit associated with the pharmaceutical company or an outside contractor.

16. A method for discovery by an investigator of biomarkers in an body fluid or tissue indicative of a biological state of a cell, tissue, organ, organ system or organism, the method comprising the steps of causing a second party entity or entities to:

a) providing one or more models representative of one or more causative or characteristic relationships underlying said biological state in said cell, tissue, organ, organ system, or organism and comprising nodes representing a biological entity, action, functional activity, or concept, and links between nodes indicative of there being a relationship therebetween, at least some of which include indicia of causal directionality;

b) examining said models to discern a set of biomolecules or concentration relationships therebetween hypothesized to be found in a body fluid or tissue and to be indicative of said biological state;

c) confirming the presence of said set of biomolecules in biological samples from individuals known to be in said biological state; and

d) physically storing an electronic representation of the candidate biomarkers on a computer-readable medium.