Computer-aided discovery of biomarker profiles in complex biological systems
First Claim
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 the biological state in the 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, wherein the one or more models are generated by the following sub-steps executed in a computing machine;
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;
b) providing a candidate set of data representative of biomolecules, or concentration relationships therebetween, determined by analysis of a sample from an 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 the candidate set of data with the model to discern which of the biomolecules or concentration relationships therebetween are indicative of the biological state or which are not directly related to the biological state, thereby to discern a candidate biomarker for the biological state; and
d) causing an electronic representation of the candidate biomarker to be physically stored on a computer-readable medium.
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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.
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Citations
13 Claims
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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:
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a) providing in a storage medium one or more models representative of one or more causative or characteristic biophysical or biochemical relationships underlying the biological state in the 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, wherein the one or more models are generated by the following sub-steps executed in a computing machine; 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; b) providing a candidate set of data representative of biomolecules, or concentration relationships therebetween, determined by analysis of a sample from an 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 the candidate set of data with the model to discern which of the biomolecules or concentration relationships therebetween are indicative of the biological state or which are not directly related to the biological state, thereby to discern a candidate biomarker for the biological state; and d) causing an electronic representation of the candidate biomarker to be physically stored on a computer-readable medium. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12)
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13. 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:
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a) providing in a storage medium one or more models representative of one or more causative or characteristic biophysical or biochemical relationships underlying the biological state in the 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 an 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 the candidate set of data with the model to discern which of the biomolecules or concentration relationships therebetween are indicative of the biological state or which are not directly related to the biological state, thereby to discern a candidate biomarker for the biological state; d) causing an electronic representation of the candidate biomarker to be physically stored on a computer-readable medium; and e) receiving a sample from a patient presenting for a health checkup or diagnosis, and assaying said the sample for the presence of the candidate biomarker to discern a biological state of the patient.
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Specification