Medical prognosis and prediction of treatment response using multiple cellular signalling pathway activities

A technology of cell signaling and pathways, applied in the field of genome processing and bioinformatics

Active Publication Date: 2015-12-02
KONINKLJIJKE PHILIPS NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, interpreting these complex data to extract relevant clinical information has proven challenging and remains largely unsolved

Method used

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  • Medical prognosis and prediction of treatment response using multiple cellular signalling pathway activities
  • Medical prognosis and prediction of treatment response using multiple cellular signalling pathway activities
  • Medical prognosis and prediction of treatment response using multiple cellular signalling pathway activities

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0092] Example 1: Inferring the activity of two or more cell signaling pathways

[0093] As described in detail in published European patent application EP2549399A1 ("Assessment of Wnt pathway activity using probabilistic modeling of target gene expressions"), and in particular published international patent application WO2013 / 011479A2 ("Assessment of cellular signaling pathway activity using probabilistic modeling of target gene expressions") and incorporating a Bayesian model, for example by constructing a probabilistic model ( Such models of the conditional probabilistic relationship between the expression levels of many different target genes and the activity of cell signaling pathways can be used to determine the activity of cell signaling pathways with high accuracy. Furthermore, the probabilistic model can be easily updated to incorporate additional knowledge gained through subsequent clinical studies by adjusting conditional probabilities and / or adding new nodes to the ...

Embodiment 2

[0212] Example 2: Determining Risk Score

[0213] In general, many different formulas can be devised for determining a risk score that indicates the risk that a clinical event will occur within a certain time period and is based at least in part on tissue and / or cell and / or The putative active combination of two or more cell signaling pathways in a body fluid, namely:

[0214]

[0215] in MPS is the risk score (the term " MPS ” is used herein as an abbreviation for “multi-pathway score” in order to indicate that the risk score is affected by the inferred activity of two or more cell signaling pathways), P i is a cell signaling pathway i activity score, N is the total number of cell signaling pathways under consideration, and Xare placeholders for possible further factors or parameters that may enter into the equation. Such formulas may more specifically be polynomials of some degree in a given variable, or linear combinations of variables. The weighting coefficien...

Embodiment 3

[0252] Example 3: Assay Development

[0253] Instead of applying e.g. the described Bayesian or (pseudo)linear models to mRNA input data from microarrays or RNA-sequencing, it may be advantageous in clinical applications to develop dedicated assays that perform sample measurements, e.g. using qPCR on an integrated platform to determine it as MPS The mRNA levels of the target genes in the section. The published RNA / DNA sequence of the target gene can then be used to determine which primers and probes to choose on such platforms.

[0254] Such dedicated MPS Validation of an assay can be accomplished by using a microarray-based Bayesian or (pseudo)linear model as a reference model, and verifying that the developed assay gives similar results for a set of validation samples. Next to dedicated assays, this can also be done using mRNA sequencing data as input measurements to construct and calibrate similar Bayesian or (pseudo)linear models.

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Abstract

The present application relates to a method for determining a risk score that indicates a risk that a clinical event will occur within a certain period of time. The risk score is based at least in part on a combination of inferred activities of two or more cellular signaling pathways in a tissue and / or cells and / or a body fluid of a subject. The cellular signaling pathways comprise a Wnt pathway, an ER pathway, an HH pathway, and / or an AR pathway. The risk score is defined such that the indicated risk that the clinical event will occur within the certain period of time decreases with an increasing P ER and increases with an increasing max(P Wnt, P HH ), wherein P ER , P wnt , and P HH denote the inferred activity of the ER pathway, the Wnt pathway, and the HH pathway, respectively.

Description

field of invention [0001] The topics described in this paper relate primarily to the fields of bioinformatics, genome processing, proteomics processing, and related fields. Background of the invention [0002] Genomic and proteomic analysis has largely been achieved and presents potential promise for clinical applications in medical fields such as oncology, where various cancers are known to be associated with specific combinations of genomic mutations / variations / abnormal methylation patterns and / or specific High or low expression levels of sex genes that play a role in cancer growth and evolution such as cell proliferation and metastasis. For example, the Wnt signaling pathway affects the regulation of cell proliferation and is highly regulated. High Wnt pathway activity due to loss of regulation has been associated with cancer, among which are malignant colon tumors. While not being limited to any particular theory of operation, it is believed that dysregulation of the W...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/68G16B5/20G16B20/20G16B25/10
CPCC12Q1/6886C12Q2600/118C12Q2600/158G06F19/12G06F19/18G06F19/20G16H50/30G16B25/00G16B5/00G16B20/00G16B20/20G16B25/10G16B5/20G01N33/48
Inventor W.F.J.维哈伊格H.J.范奧詹A.范德斯托佩M.阿维斯德恩达
Owner KONINKLJIJKE PHILIPS NV
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