# US 2014/0156200 A1 · Assessment of cellular signaling pathway activity using probabilistic modeling of target gene expression

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- Number: US 2014/0156200 A1
- Document ID: US20140156200A1
- Status: Published application
- Kind: A1
- Application number: 14/233,546
- Filed: 2012-07-19
- Published: 2014-06-05
- Earliest claimed: 2011-07-19
- Assignees: Koninklijke Philips N.V.
- Applicants: Koninklijke Philips N.V.
- Inventors: Wilhelmus Franciscus Johannes Verhaegh; Anja Van De Stolpe; Hendrik Jan Van Ooijen; Kalyana Chakravarth Dulla; Marcia Alves De Inda; Ralf Hoffmann
- Web page: https://patentgrep.com/patent/US20140156200A1

## CPC

- G16B 5/20: Probabilistic models
- C12Q 1/6809: Methods for determination or identification of nucleic acids involving differential detection
- C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575)
- 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 20/00: ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
- G16B 20/20: Allele or variant detection, e.g. single nucleotide polymorphism [SNP] detection
- G16B 20/30: Detection of binding sites or motifs
- 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
- G16B 40/20: Supervised data analysis
- C12Q 2600/106: Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
- C12Q 2600/158: Expression markers
- 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
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES

## Abstract

The present application mainly relates to specific methods for inferring activity of one or more cellular signaling pathway(s) in tissue of a medical subject based at least on the expression level(s) of one or more target gene(s) of the cellular signaling pathway(s) measured in an extracted sample of the tissue of the medical subject, an apparatus comprising a digital compressor configured to perform such methods and a non-transitory storage medium storing instructions that are executable by a digital processing device to perform such methods.

## Claims

### Claim 1

A method comprising:
inferring activity of one or more cellular signaling pathway(s) in tissue of a medical subject based at least on the expression level(s) (20) of one or more target gene(s) of the cellular signaling pathway(s) measured in an extracted sample of the tissue of the medical subject, wherein the inferring comprises:
inferring activity of the cellular signaling pathway(s) in the tissue of the medical subject by evaluating at least a portion of a probabilistic model (40-1, . . . , 40-7), preferably a Bayesian network (40-1, . . . , 40-7), representing the cellular signaling pathway(s) for a set of inputs including at least the expression level(s) (20) of the one or more target genes of the cellular signaling pathway(s) measured in the extracted sample of the tissue of the medical subject;
estimating a level (46) in the tissue of the medical subject of at least one transcription factor (TF) element, the at least one TF element controlling transcription of the one or more target gene(s) of the cellular signaling pathway(s), the estimating being based at least in part on conditional probabilities relating the at least one TF element and the expression level(s) (20) of the one or more target gene(s) of the cellular signaling pathway(s) measured in the extracted sample of the tissue of the medical subject;
inferring activity of the cellular signaling pathway(s) based on the estimated level in the tissue sample of the transcription factor; and
determining whether the cellular signaling pathway(s) is/are operating abnormally in the tissue of the medical subject based on the inferred activity of the cellular signaling pathway(s) in the tissue of the medical subject;
wherein the inferring is performed by a digital processing device (12) using the probabilistic model (40-1, . . . , 40-7) of the cellular signaling pathway(s).

### Claim 2 (depends on 1)

A method according to claim 1, wherein the inferring comprises:
estimating a level (46) in the tissue of the medical subject of at least one transcription factor (TF) element represented by a TF node of the probabilistic model, the TF element controlling transcription of the one or more target gene(s) of the cellular signaling pathway(s), the estimating being based at least in part on conditional probabilities of the probabilistic model (40-1, . . . , 40-7) relating the TF node and nodes in the probabilistic model representing the one or more target gene(s) of the cellular signaling pathway(s) measured in the extracted sample of the tissue of the medical subject,
and wherein the inferring is preferably performed by using a Bayesian network (40-1, . . . , 40-7) comprising nodes representing information about the signaling pathway(s) and conditional probability relationships between connected nodes of the Bayesian network.

### Claim 3 (depends on 1)

The method of claim 1, wherein the cellular signaling pathway(s) comprise(s) a Wnt pathway, an ER pathway, an AR pathway and/or a Hedgehog pathway.

### Claim 4 (depends on 3)

The method of claim 3, wherein the inferring comprises:
inferring activity of a Wnt pathway in the tissue of the medical subject based at least on expression levels (20) of one or more, preferably at least three, target gene(s) of the Wnt pathway measured in the extracted sample of the tissue of the medical subject selected from the group comprising: KIAA1199, AXIN2, RNF43, TBX3, TDGF1, SOX9, ASCL2, IL8, SP5, ZNRF3, KLF6, CCND1, DEFA6 and FZD7.

### Claim 5 (depends on 3)

The method of claim 3, wherein the inferring (also) comprises:
inferring activity of an ER pathway in the tissue of the medical subject based at least on expression levels (20) of one or more, preferably at least three, target gene(s) of the ER pathway measured in the extracted sample of the tissue of the medical subject selected from the group comprising: CDH26, SGK3, PGR, GREB1, CA12, XBP1, CELSR2, WISP2, DSCAM, ERBB2, CTSD, TFF1 and NRIP1.

### Claim 6 (depends on 3)

The method of claim 3, wherein the inferring (also) comprises:
inferring activity of a Hedgehog pathway in the tissue of the medical subject based at least on expression levels (20) of one or more, preferably at least three, target gene(s) of the Hedgehog pathway measured in the extracted sample of the tissue of the medical subject selected from the group comprising: GLI1, PTCH1, PTCH2, IGFBP6, SPP1, CCND2, FST, FOXL1, CFLAR, TSC22D1, RAB34, S100A9, S100A7, MYCN, FOXM1, GLI3, TCEA2, FYN and CTSL1.

### Claim 7 (depends on 3)

The method of claim 3, wherein the inferring (also) comprises:
inferring activity of an AR pathway in the tissue of the medical subject based at least on expression levels (20) of one or more, preferably at least three, target gene(s) of the AR pathway measured in the extracted sample of the tissue of the medical subject selected from the group comprising: KLK2, PMEPA1, TMPRSS2, NKX3—1, ABCC4, KLK3, FKBP5, ELL2, UGT2B15, DHCR24, PPAP2A, NDRG1, LRIG1, CREB3L4, LCP1, GUCY1A3, AR and EAF2.

### Claim 8 (depends on 4)

The method of claim 4, wherein the inferring is further based on expression levels (20) of at least one target gene of the Wnt pathway measured in the extracted sample of the tissue of the medical subject selected from the group comprising: NKD1, OAT, FAT1, LEF1, GLUL, REG1B, TCF7L2, COL18A1, BMP7, SLC1A2, ADRA2C, PPARG, DKK1, HNF1A and LECT2.

### Claim 9 (depends on 5)

The method of claim 5, wherein the inferring is further based on expression levels (20) of at least one target gene of the ER pathway measured in the extracted sample of the tissue of the medical subject selected from the group comprising: AP1B1, ATP5J, COL18A1, COX7A2L, EBAG9, ESR1, HSPB1, IGFBP4, KRT19, MYC, NDUFV3, PISD, PREDM15, PTMA, RARA, SOD1 and TRIM25.

### Claim 10 (depends on 6)

The method of claim 6, wherein the inferring is further based on expression levels (20) of at least one target gene of the Hedgehog pathway measured in the extracted sample of the tissue of the medical subject selected from the group comprising: BCL2, FOXA2, FOXF1, H19, HHIP, IL1R2, JAG2, JUP, MIF, MYLK, NKX2.2, NKX2.8, PITRM1 and TOM1.

### Claim 11 (depends on 7)

The method of claim 7, wherein the inferring is further based on expression levels (20) of at least one target gene of the AR pathway measured in the extracted sample of the tissue of the medical subject selected from the group comprising: APP, NTS, PLAU, CDKN1A, DRG1, FGF8, IGF1, PRKACB, PTPN1, SGK1 and TACC2.

### Claim 12

(canceled)

### Claim 13

(canceled)

### Claim 14 (depends on 1)

The method of claim 1 comprising:
inferring activity of a Wnt pathway in tissue of a medical subject based at least on expression levels (20) of two, three or more target genes of a set of target genes of the Wnt pathway measured in an extracted sample of the tissue of the medical subject
and/or
inferring activity of an ER pathway in tissue of a medical subject based at least on expression levels (20) of two, three or more target genes of a set of target genes of the ER pathway measured in an extracted sample of the tissue of the medical subject
and/or
inferring activity of a Hedgehog pathway in tissue of a medical subject based at least on expression levels (20) of two, three or more target genes of a set of target genes of the Hedgehog pathway measured in an extracted sample of the tissue of the medical subject,
and/or
inferring activity of an AR pathway in tissue of a medical subject based at least on expression levels (20) of two, three or more target genes of a set of target genes of the AR pathway measured in an extracted sample of the tissue of the medical subject.

### Claim 15 (depends on 14)

The method of claim 14, wherein
the set of target genes of the Wnt pathway includes at least nine, preferably all target genes selected from the group comprising: KIAA1199, AXIN2, RNF43, TBX3, TDGF1, SOX9, ASCL2, IL8, SP5, ZNRF3, KLF6, CCND1, DEFA6 and FZD7,
and/or
the set of target genes of the ER pathway includes at least nine, preferably all target genes selected from the group comprising: CDH26, SGK3, PGR, GREB1, CA12, XBP1, CELSR2, WISP2, DSCAM, ERBB2, CTSD, TFF1 and NRIP1,
and/or
the set of target genes of the Hedgehog pathway includes at least nine, preferably all target genes selected from the group comprising: GLI1, PTCH1, PTCH2, IGFBP6, SPP1, CCND2, FST, FOXL1, CFLAR, TSC22D1, RAB34, S100A9, S100A7, MYCN, FOXM1, GLI3, TCEA2, FYN and CTSL1,
and/or
the set of target genes of the AR pathway includes at least nine, preferably all target genes selected from the group comprising: KLK2, PMEPA1, TMPRSS2, NKX3—1, ABCC4, KLK3, FKBP5, ELL2, UGT2B15, DHCR24, PPAP2A, NDRG1, LRIG1, CREB3L4, LCP1, GUCY1A3, AR and EAF2.

### Claim 16 (depends on 15)

The method of claim 15, wherein
the set of target genes of the Wnt pathway further includes at least one target gene selected from the group comprising: NKD1, OAT, FAT1, LEF1, GLUL, REG1B, TCF7L2, COL18A1, BMP7, SLC1A2, ADRA2C, PPARG, DKK1, HNF1A, and LECT2,
and/or
the set of target genes of the ER pathway further includes at least one target gene selected from the group comprising: AP1B1, ATP5J, COL18A1, COX7A2L, EBAG9, ESR1, HSPB1, IGFBP4, KRT19, MYC, NDUFV3, PISD, PREDM15, PTMA, RARA, SOD1 and TRIM25,
and/or
the set of target genes of the Hedgehog pathway further includes at least one target gene selected from the group comprising: BCL2, FOXA2, FOXF1, G19, HHIP, IL1R2, JAG2, JUP, MIF, MYLK, NKX2.2, NKX2.8, PITRM1 and TOM1,
and/or
the set of target genes of the AR pathway further includes at least one target gene selected from the group comprising: APP, NTS, PLAU, CDKN1A, DRG1, FGF8, IGF1, PRKACB, PTPN1, SGK1 and TACC2.

### Claim 17 (depends on 1)

An apparatus comprising a digital processor (12) configured to perform a method as set forth in claim 1.

### Claim 18 (depends on 1)

A non-transitory storage medium storing instructions that are executable by a digital processing device (12) to perform a method as set forth in claim 1.

### Claim 19 (depends on 1)

A computer program comprising program code means for causing a digital processing device (12) to perform a method as set forth in claim 1.

### Claim 20

(canceled)