# US 2019/0318802 A1 · Method and apparatus for improved determination of node influence in a network

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- Number: US 2019/0318802 A1
- Document ID: US20190318802A1
- Status: Published application
- Kind: A1
- Application number: 16/340,738
- Filed: 2017-10-13
- Published: 2019-10-17
- Earliest claimed: 2016-10-13
- Assignees: University of Florida Research Foundation, Inc.
- Applicants: University of Florida Research Foundation, Incorporated
- Inventors: David TRAN; Son Bang LE
- Web page: https://patentgrep.com/patent/US20190318802A1

## CPC

- G16B 25/10: Gene or protein expression profiling; Expression-ratio estimation or normalisation
- G16B 5/00: ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks
- G16B 25/00: ICT specially adapted for hybridisation; ICT specially adapted for gene or protein expression
- G16B: BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY

## Abstract

Example embodiments of the present invention address problems in computational biology and network theory. As mentioned above, example embodiments enable the determination of where to set a threshold cutoff level to maximize sensitivity of a gene expression profile while minimizing the false discovery rate (FDR). Some example embodiments exploit the filtered gene expression profile to discover potential master regulators that may be targetable by various perturbagen-based treatments. Other example embodiments facilitate the harvesting of meaningful data from other type of network and node statistics inputs, even those not related specifically to computational biology or the exploitation of inferred gene expression profiles.

## Claims

### Claim 1

A method for an analysis computing entity to utilize a computational pipeline to generate a highly reliable regulatory network from gene expression data, the method comprising:
receiving, by the analysis computing entity, an initial set of gene expression values;
generating, by the analysis computing entity, a real dataset and a number of randomized datasets from the initial set of gene expression values;
applying, by the analysis computing entity, a bootstrap procedure to the real dataset and the randomized datasets to create a series of bootstrap files corresponding to the datasets;
for each of the datasets, processing, by the analysis computing entity, the corresponding series of bootstrap files to generate a set of bootstrap adjacency matrix files, wherein each adjacency matrix file includes an entry for each hub-gene contained in the corresponding bootstrap file, wherein the entry for each hub-gene identifies corresponding edges, wherein each edge comprises a connection for the hub-gene along with mutual information corresponding to the connection;
performing, by the analysis computing entity, a consensus procedure that utilizes each set of bootstrap adjacency matrix files to generate a single consensus adjacency matrix file for the corresponding dataset, wherein each consensus adjacency matrix file identifies only a subset of the edges that occur in the set of bootstrap adjacency matrix files;
determining, by the analysis computing entity and based on the generated consensus adjacency matrix files, significance thresholds for the set of gene expression values; and
filtering, by the analysis computing entity, the consensus adjacency matrix file for the real dataset using the determined significance thresholds to produce a gene expression network stripped of low-significance edges.

### Claim 2 (depends on 1)

The method of claim 1, further comprising:
receiving, by the analysis computing entity, a user-specified number of bootstrap rounds and sample size, wherein the series of bootstrap files created in the bootstrap procedure are created based on the number of bootstrap rounds and the sample size.

### Claim 3 (depends on 1)

The method of claim 1, wherein processing the series of bootstrap files to generate the set of bootstrap adjacency matrix files utilizes a reverse engineering tool for reconstruction of cellular networks.

### Claim 4 (depends on 1)

The method of claim 1, further comprising determining the subset of the edges that occur in a particular set of bootstrap adjacency matrix files to identify in the consensus adjacency matrix for a corresponding dataset by:
calculating, by the analysis computing entity, a support level for each edge;
calculating, by the analysis computing entity, a false-positive rate (FPR) for each edge; and
selecting, by the analysis computing entity, only those edges having a support level and FPR above a predetermined value.

### Claim 5 (depends on 1)

The method of claim 1, wherein performing the consensus procedure further includes:
generating, by the analysis computing entity, a counts file for each consensus adjacency matrix, wherein the counts file identifies a support level of each edge in the consensus adjacency matrix; and
generating, by the analysis computing entity, a statistics file that records, for each edge in the consensus adjacency matrix, the support level of the edge, the FPR of the edge, and a sum of the mutual information of the edge, as taken from the bootstrap adjacency matrix files,
wherein the significance thresholds for the set of gene expression values are based on the counts file and the statistics file.

### Claim 6

A method for an analysis computing entity to calculate importance scores for nodes in a network, the method comprising:
(a) receiving, by the analysis computing entity, an initial dataset describing a network;
(b) extracting, by the analysis computing entity, one or more subnetworks from the initial dataset;
(c) calculating, by the analysis computing entity, individual scores for each node in the one or more subnetworks;
(d) calculating, by the analysis computing entity, neighborhood scores for each node in the one or more subnetworks;
(e) generating, by the analysis computing entity, a combined node score for each node in the one or more subnetworks; and
(f) iteratively refining, by the analysis computing entity, the combined node scores.

### Claim 7 (depends on 6)

The method of claim 6, wherein calculating an individual score (indscore) for a given node i comprises applying the formula:
indscorei=Πk=1istatik,
where statik is a k-th statistic selected from a list of gene statistics.

### Claim 8 (depends on 6)

The method of claim 6, wherein calculating a neighborhood score (nbhscore) for a given node i comprises applying the formula:
nbhscore
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where step represents a number of steps from node i to neighborhood noaes;
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comprises a weight penalty based on how far a given node s is from node i; wi,jp is a weight of closeness between nodes i and j; and ns is a number of neighbors of node i that require s steps to reach node i.

### Claim 9 (depends on 6)

The method of claim 6, wherein calculating a neighborhood score (nbhscore) for a given node i comprises applying the formula:
nbhscore
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where step represents a number of steps from node i to neighborhood nodes;
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comprises a weight penalty based on how far a given node s is from node i; wi,jp is a weight of closeness between nodes i and j; and ns is a number of neighbors of node i that require s steps to reach node i.

### Claim 10 (depends on 6)

The method of claim 6, wherein generating the combined node score for a given node includes one of:
setting the combined node score equal to the individual score for the node;
setting the combined node score equal to the neighborhood score for the node;
setting the combined node score equal to the neighborhood score for the node plus a product produced by multiplying the individual score for the node by a value comprising a number of other nodes in the neighborhood of the node; or
setting the combined node score equal to the individual score for the node multiplied by the neighborhood score for the node.

### Claim 11 (depends on 6)

The method of claim 6, wherein iteratively refining the combined node scores includes:
repeating steps (b), (c), (d), and (e) a predetermined number of time or until convergence is reached.

### Claim 12

A method for identifying and validating one or more master regulators and biomarkers, the method comprising:
generating, by an analysis computing entity, a gene expression network;
calculating, by the analysis computing entity, importance scores for the genes in the gene expression network;
identifying a predetermined number of genes having the highest calculated importance scores;
selecting a set of core master regulators based on the predetermined number of genes having the highest calculated importance scores;
testing candidate perturbagens to identify a best combination of perturbagens based on the selected set of core master regulators; and
developing a predictive test to forecast a response to the best combination of perturbagens.

### Claim 13

An apparatus comprising at least one processor and at least one memory storing computer program code, the at least one memory and the computer program code configured to, with the processor, cause the apparatus to at least:
receive an initial set of gene expression values;
generate a real dataset and a number of randomized datasets from the initial set of gene expression values;
apply a bootstrap procedure to the real dataset and the randomized datasets to create a series of bootstrap files corresponding to the datasets;
for each of the datasets, process the corresponding series of bootstrap files to generate a set of bootstrap adjacency matrix files, wherein each adjacency matrix file includes an entry for each hub-gene contained in the corresponding bootstrap file, wherein the entry for each hub-gene identifies corresponding edges, wherein each edge comprises a connection for the hub-gene along with mutual information corresponding to the connection;
perform a consensus procedure that utilizes each set of bootstrap adjacency matrix files to generate a single consensus adjacency matrix file for the corresponding dataset, wherein each consensus adjacency matrix file identifies only a subset of the edges that occur in the set of bootstrap adjacency matrix files;
determine, based on the generated consensus adjacency matrix files, significance thresholds for the set of gene expression values; and
filter the consensus adjacency matrix file for the real dataset using the determined significance thresholds to produce a gene expression network stripped of low-significance edges.

### Claim 14

A computer program product comprising at least one non-transitory computer-readable storage medium having computer-executable program code instructions stored therein, the computer-executable program code instructions comprising program code instructions that, when executed, cause a computer to at least:
receive an initial set of gene expression values;
generate a real dataset and a number of randomized datasets from the initial set of gene expression values;
apply a bootstrap procedure to the real dataset and the randomized datasets to create a series of bootstrap files corresponding to the datasets;
for each of the datasets, process the corresponding series of bootstrap files to generate a set of bootstrap adjacency matrix files, wherein each adjacency matrix file includes an entry for each hub-gene contained in the corresponding bootstrap file, wherein the entry for each hub-gene identifies corresponding edges, wherein each edge comprises a connection for the hub-gene along with mutual information corresponding to the connection;
perform a consensus procedure that utilizes each set of bootstrap adjacency matrix files to generate a single consensus adjacency matrix file for the corresponding dataset, wherein each consensus adjacency matrix file identifies only a subset of the edges that occur in the set of bootstrap adjacency matrix files;
determine, based on the generated consensus adjacency matrix files, significance thresholds for the set of gene expression values; and
filter the consensus adjacency matrix file for the real dataset using the determined significance thresholds to produce a gene expression network stripped of low-significance edges.

### Claim 15 (depends on 13)

The apparatus of claim 13, wherein the at least one memory and the computer program code are further configured to, with the processor, cause the apparatus to at least receive a user-specified number of bootstrap rounds and sample size, wherein the series of bootstrap files created in the bootstrap procedure are created based on the number of bootstrap rounds and the sample size.

### Claim 16 (depends on 13)

The apparatus of claim 13, wherein processing the series of bootstrap files to generate the set of bootstrap adjacency matrix files utilizes a reverse engineering tool for reconstruction of cellular networks.

### Claim 17 (depends on 13)

The apparatus of claim 13, wherein the at least one memory and the computer program code are further configured to, with the processor, cause the apparatus to at least determine the subset of the edges that occur in a particular set of bootstrap adjacency matrix files to identify in the consensus adjacency matrix for a corresponding dataset by:
calculating a support level for each edge;
calculating a false-positive rate (FPR) for each edge; and
selecting only those edges having a support level and FPR above a predetermined value.

### Claim 18 (depends on 14)

The computer program product of claim 14, wherein the computer-executable program code instructions further comprise program code instructions that, when executed, cause the computer to at least receive a user-specified number of bootstrap rounds and sample size, wherein the series of bootstrap files created in the bootstrap procedure are created based on the number of bootstrap rounds and the sample size.

### Claim 19 (depends on 14)

The computer program product of claim 14, wherein processing the series of bootstrap files to generate the set of bootstrap adjacency matrix files utilizes a reverse engineering tool for reconstruction of cellular networks.

### Claim 20 (depends on 14)

The computer program product of claim 14, wherein the computer-executable program code instructions further comprise program code instructions that, when executed, cause the computer to at least determine the subset of the edges that occur in a particular set of bootstrap adjacency matrix files to identify in the consensus adjacency matrix for a corresponding dataset by:
calculating a support level for each edge;
calculating a false-positive rate (FPR) for each edge; and
selecting only those edges having a support level and FPR above a predetermined value.