CN109616152B - Method and device for establishing cancer-specific co-modulation network - Google Patents
Method and device for establishing cancer-specific co-modulation network Download PDFInfo
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Abstract
The invention provides a method and a device for establishing a cancer-specific co-regulation network, belonging to the technical field of establishment of cancer regulation networks. The method comprises the following steps: obtaining TF regulation information and miRNA regulation information of TF and miRNA on the target gene according to a public database; establishing a ternary regulation network according to the TF regulation information and the miRNA regulation information; identifying FFLs in the ternary regulation network to obtain FFLs identification results; and screening to obtain the miRNA-TF co-regulation network specific to the cancer according to the FFLs recognition result and the cancer genome expression amount information. The invention establishes a ternary regulation network of TF, miRNA and a target gene, and combines gene expression information to obtain an miRNA-TF co-regulation network, thereby improving the accuracy of the miRNA-TF co-regulation relationship.
Description
Technical Field
The invention relates to the field of establishment of cancer regulation and control networks, in particular to a method and a device for establishing a cancer-specific co-regulation network.
Background
Transcription Factors (TF) and micrornas (mirna) are regulatory factors having an important role in gene expression regulation. There is increasing evidence that TF and mirnas can work synergistically and their dysregulation is associated with many diseases including cancer. However, the existing research on the co-regulation relationship of miRNA-TF lacks specific analysis on diseases (such as cancer) and lacks combination with gene expression data, and the accuracy of the miRNA-TF co-regulation relationship conclusion needs to be improved.
Disclosure of Invention
In view of the above, the present invention aims to provide a method and an apparatus for establishing a cancer-specific co-regulation network, which establish a ternary regulation network of TF, miRNA and a target gene, and combine gene expression information to obtain a miRNA-TF co-regulation network, thereby improving the accuracy of miRNA-TF co-regulation relationship.
In a first aspect, the present invention provides a method for establishing a cancer-specific co-modulation network, comprising:
obtaining TF regulation information and miRNA regulation information of TF and miRNA on the target gene according to a public database;
establishing a ternary regulation network according to the TF regulation information and the miRNA regulation information;
identifying FFLs in the ternary regulation network to obtain FFLs identification results;
and screening to obtain the miRNA-TF co-regulation network specific to the cancer according to the FFLs recognition result and the cancer genome expression amount information.
In combination with the first aspect, the present embodiments provide a first possible implementation manner of the first aspect, wherein the TF regulatory information includes TF-miRNA regulatory information and TF-mRNA regulatory information.
In combination with the first aspect, the present embodiments provide a second possible implementation manner of the first aspect, wherein the miRNA regulation information includes miRNA-TF regulation information and miRNA-mRNA regulation information.
In combination with the first aspect, the present embodiments provide a third possible implementation manner of the first aspect, wherein the FFLs are in the form of miRNA and TF co-regulated target genes, and include three types of TF-FFLs, miRNA-FFLs, and complex FFLs;
among the TF-FFLs, TF is a main regulator;
among the miRNA-FFLs, miRNA is a main regulator;
in the composite FFLs, miRNA and TF are mutually regulated, and the composite FFLs are formed by combining the TF-FFLs and the miRNA-FFLs.
With reference to the first aspect, an embodiment of the present invention provides a fourth possible implementation manner of the first aspect, where the identifying FFLs in the ternary regulatory network and obtaining an FFLs identification result specifically includes:
and identifying the FFLs in the ternary regulation and control network according to a network motif mining algorithm to obtain FFLs identification results.
In combination with the first aspect, the present embodiments provide a fifth possible embodiment of the first aspect, wherein the cancer genome expression information includes mRNA expression level information and miRNA expression level information.
With reference to the first aspect, the present invention provides a sixth possible implementation manner of the first aspect, wherein the screening to obtain a cancer-specific miRNA-TF co-regulation network according to the FFLs recognition result and the cancer genome expression amount information specifically includes:
and obtaining the co-regulation relation of the miRNA and the TF to the target gene of the cancer genome by utilizing statistical test, a network reasoning algorithm or gene enrichment analysis according to the FFLs recognition result and the cancer genome expression quantity information, and establishing a cancer specific miRNA-TF co-regulation network according to the co-regulation relation.
In a second aspect, an embodiment of the present invention provides a cancer-specific co-modulation network establishment apparatus, including:
the obtaining module is used for obtaining TF regulation information and miRNA regulation information of TF and miRNA on the target gene according to the public database;
the establishing module is used for establishing a ternary regulation network by a user according to the TF regulation information and the miRNA regulation information;
the identification module is used for identifying the FFLs in the ternary regulation and control network to obtain FFLs identification results;
and the screening module is used for screening the miRNA-TF co-regulation network specific to the cancer according to the FFLs recognition result and the cancer genome expression quantity information.
In a third aspect, an embodiment of the present invention provides an electronic device, including a memory and a processor, where the memory stores a computer program operable on the processor, and the processor executes the computer program to implement the steps of the method according to the first aspect.
In a fourth aspect, the present invention provides a computer-readable medium having non-volatile program code executable by a processor, where the program code causes the processor to execute the method according to the first aspect.
The invention brings the following beneficial effects: the invention provides a method and a device for establishing a cancer-specific co-modulation network. In the method, TF regulation information and miRNA regulation information of TF and miRNA on a target gene are obtained according to a public database; then establishing a ternary regulation network according to the TF regulation information and the miRNA regulation information; identifying the FFLs in the ternary regulation network to obtain an FFLs identification result; and finally, screening to obtain the miRNA-TF co-regulation network specific to the cancer according to the FFLs recognition result and the cancer genome expression amount information. The method establishes a ternary regulation network of TF, miRNA and a target gene, and combines gene expression information to obtain an miRNA-TF co-regulation network, thereby improving the accuracy of the miRNA-TF co-regulation relationship.
Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the invention as set forth above.
In order to make the aforementioned and other objects, features and advantages of the present invention comprehensible, preferred embodiments accompanied with figures are described in detail below.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 is a flowchart of a method for establishing a cancer-specific co-modulation network according to an embodiment of the present invention;
FIG. 2 is a schematic diagram of a cancer-specific co-tuned network establishment model according to an embodiment of the present invention;
fig. 3 is a structural diagram of a cancer-specific co-modulation network establishment apparatus according to a second embodiment of the present invention;
fig. 4 is a structural diagram of an electronic device according to a third embodiment of the present invention.
Icon: 31-obtaining a module; 32-establishing a module; 33-an identification module; 34-a screening module; 4-an electronic device; 41-a processor; 42-a memory; 43-a communication interface; 44-bus.
Detailed Description
To make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings, and it is apparent that the described embodiments are some, but not all embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The existing research on the miRNA-TF co-regulation relationship lacks specific analysis on diseases (such as cancer) and lacks combination with gene expression data, and the accuracy of the miRNA-TF co-regulation relationship conclusion is still to be improved. Based on this, the method and apparatus for establishing a cancer-specific co-modulation network provided by the embodiments of the present invention can be applied to establishing a cancer-specific co-modulation network.
To facilitate understanding of the present embodiment, a detailed description will be given of a cancer-specific co-modulation network establishment method disclosed in the present embodiment.
The first embodiment is as follows:
the embodiment of the invention provides a method for establishing a cancer-specific co-modulation network, which comprises the following steps as shown in figure 1:
s101: and obtaining TF regulation information and miRNA regulation information of the TF and the miRNA on the target gene according to a public database.
As shown in FIG. 2, TF regulatory information including TF-miRNA regulatory information and TF-mRNA regulatory information is obtained from public databases (e.g., TRRUST, TRED, HTRIdb).
miRNA regulatory information is obtained from public databases (e.g., mirtarBase, starBase, miRecords), including miRNA-TF regulatory information and miRNA-mRNA regulatory information.
S102: and establishing a ternary regulation network according to the TF regulation information and the miRNA regulation information.
Establishing a ternary regulation network by TF regulation information and miRNA regulation information:
and combining the regulation and control information obtained from the public databases to obtain a ternary mixed network consisting of miRNA, TF and Gene (Gene), wherein the network comprises the regulation and control relations of TF-miRNA, TF-miRNA, miRNA-TF and miRNA-Gene.
S103: and identifying the FFLs in the ternary regulation network to obtain an FFLs identification result.
As shown in fig. 2, the FFLs are identified in the ternary control network by using a network motif mining algorithm (which may also be called a network motif identification algorithm), and an FFLs identification result is obtained.
FFLs are the form of a target gene jointly regulated by miRNA and TF, and comprise three types of TF-FFLs, miRNA-FFLs and composite FFLs; among TF-FFLs, TF is the primary regulator; among miRNA-FFLs, miRNA is the primary regulator; in the composite FFLs, miRNA and TF are mutually regulated, and the composite FFLs are formed by combining TF-FFLs and miRNA-FFLs.
S104: and screening to obtain the miRNA-TF co-regulation network specific to the cancer according to the FFLs recognition result and the cancer genome expression amount information.
More accurate miRNA-TF co-regulation information is obtained by using expression data of a Cancer database TCGA (the Cancer Genome atlas). And calculating Spearman correlation coefficients of expression quantities among TFs, miRNA and genes pairwise, calculating a correlation coefficient rho value according to the correlation, and screening the FFLs.
Among them, Spearman's correlation coefficient, which is a Spearman's rank correlation coefficient named as charles Spearman. Often denoted by the greek letter p. It is a non-parametric indicator that measures the dependence of two variables. It evaluates the correlation of two statistical variables using a monotonic equation. If there are no repeated values in the data, and when the two variables are perfectly monotonically correlated, the spearman correlation coefficient is either +1 or-1.
As shown in fig. 2, according to the FFLs recognition result and the cancer genome expression amount information, the co-regulation relationship of miRNA and TF to the cancer genome target gene is obtained by using statistical test, network inference algorithm or gene enrichment analysis, and a cancer-specific miRNA-TF co-regulation network is established according to the co-regulation relationship.
The cancer genome expression information includes mRNA expression level information and miRNA expression level information.
The miRNA-TF co-regulation network constructed by the method can be used for analyzing diseases by combining the gene expression of specific diseases so as to find a correct disease treatment method.
For example, construction and analysis of THCA (thyroid tumor) miRNA-TF co-regulatory networks. THCA is a common endocrine malignancy, with increasing incidence worldwide. The cancer-specific co-regulation network establishment method provided by the embodiment is utilized to establish a complete miRNA-TF co-regulation network, establish a THCA-specific miRNA-TF co-regulation network consisting of 391 nodes and 520 edges, and find TF-FFLs 7 pairs, miRNA-FFLs 2 pairs and composite FFLs2 pairs in FFLs. Subsequently, key nodes in the co-regulatory network are scored by using network topology analysis to obtain five important genes (MELK, PIGR, SNX5, CLU, DAPK 2).
Comprehensive literature studies on these genes confirm their role in cancer diagnosis and therapy. MELK has been reported as a potential therapeutic target for malignancies. PIGR has the potential to be a candidate prognostic biomarker. The regulation of CLU by tumor genes and epigenetic factors has a major impact on mammalian tumorigenesis. Abnormal methylation and silencing of DAPK2 has been reported to play a key role in the development and progression of thyroid cancer. Finally, a reduction in SNX5 expression was recently demonstrated to be associated with promoting thyroid tumorigenesis, and SNX5 expression studies are useful for the pathological diagnosis of thyroid cancer. In addition, the functional enrichment analysis is carried out on the genes and TFs in the THCA specific miRNA-TF co-regulatory network. By KEGG pathway enrichment analysis, 11 significant pathways (as shown in the table below) were found, all associated with cancer.
The embodiment of the invention provides a method for establishing a cancer-specific co-regulation network, which establishes a ternary regulation network of TF, miRNA and a target gene, and combines gene expression information to obtain the miRNA-TF co-regulation network, thereby improving the accuracy of the miRNA-TF co-regulation relationship.
Example two:
the cancer-specific co-modulation network establishment apparatus provided in the embodiment of the present invention, as shown in fig. 3, includes:
an obtaining module 31, configured to obtain TF regulation information and miRNA regulation information of the TF and the miRNA on the target gene according to the public database. TF regulatory information is obtained from public databases (e.g., TRRUST, TRED, HTRIdb), and includes TF-miRNA regulatory information and TF-mRNA regulatory information. miRNA regulatory information is obtained from public databases (e.g., mirtarBase, starBase, miRecords), including miRNA-TF regulatory information and miRNA-mRNA regulatory information.
And the establishing module 32 is used for establishing a ternary regulation and control network by the user according to the TF regulation and control information and the miRNA regulation and control information. And combining the regulation and control information obtained from the public databases to obtain a ternary mixed network consisting of miRNA, TF and Gene (Gene), wherein the network comprises the regulation and control relations of TF-miRNA, TF-miRNA, miRNA-TF and miRNA-Gene.
And the identification module 33 is configured to identify the FFLs in the ternary regulation and control network, and obtain an FFLs identification result. And identifying the FFLs in the ternary regulation network by utilizing a network motif mining algorithm to obtain an FFLs identification result.
And the screening module 34 is used for screening the miRNA-TF co-regulation network specific to the cancer according to the FFLs recognition result and the cancer genome expression quantity information. More accurate miRNA-TF co-regulation information is obtained by using expression data of a Cancer database TCGA (the Cancer Genome atlas). And calculating Spearman correlation coefficients of expression quantities among TFs, miRNA and genes pairwise, calculating a correlation coefficient rho value according to the correlation, and screening the FFLs.
And (3) obtaining the co-regulation relation of miRNA and TF to the target gene of the cancer genome by utilizing statistical test, a network reasoning algorithm or gene enrichment analysis according to the FFLs recognition result and the cancer genome expression quantity information, and establishing a cancer specific miRNA-TF co-regulation network according to the co-regulation relation.
The cancer-specific co-modulation network establishment apparatus provided in the embodiment of the present invention has the same technical features as the cancer-specific co-modulation network establishment method provided in the first embodiment, so that the same technical problems can be solved, and the same technical effects can be achieved.
Example three:
as shown in fig. 4, the electronic device 4 includes a processor 41 and a memory 42, where the memory stores a computer program that can run on the processor, and the processor executes the computer program to implement the steps of the method provided in the first embodiment.
Referring to fig. 4, the electronic device further includes: a bus 44 and a communication interface 43, and the processor 41, the communication interface 43 and the memory 42 are connected by the bus 44. The processor 41 is arranged to execute executable modules, such as computer programs, stored in the memory 42.
The Memory 42 may include a high-speed Random Access Memory (RAM) and may also include a non-volatile Memory (non-volatile Memory), such as at least one disk Memory. The communication connection between the network element of the system and at least one other network element is realized through at least one communication interface 43 (which may be wired or wireless), and the internet, a wide area network, a local network, a metropolitan area network, etc. may be used.
The bus 44 may be an ISA bus, a PCI bus, an EISA bus, or the like. The bus may be divided into an address bus, a data bus, a control bus, etc. For ease of illustration, only one double-headed arrow is shown in FIG. 4, but that does not indicate only one bus or one type of bus.
The memory 42 is configured to store a program, and the processor 41 executes the program after receiving an execution instruction, and the method executed by the apparatus defined by the flow process disclosed in any of the foregoing embodiments of the present invention may be applied to the processor 41, or implemented by the processor 41.
The processor 41 may be an integrated circuit chip having signal processing capabilities. In implementation, the steps of the above method may be performed by integrated logic circuits of hardware or instructions in the form of software in the processor 41. The Processor 41 may be a general-purpose Processor, and includes a Central Processing Unit (CPU), a Network Processor (NP), and the like. The device can also be a Digital Signal Processor (DSP), an Application Specific Integrated Circuit (ASIC), a Field-Programmable Gate Array (FPGA) or other Programmable logic device, a discrete Gate or transistor logic device, or a discrete hardware component. The various methods, steps and logic blocks disclosed in the embodiments of the present invention may be implemented or performed. A general purpose processor may be a microprocessor or the processor may be any conventional processor or the like. The steps of the method disclosed in connection with the embodiments of the present invention may be directly implemented by a hardware decoding processor, or implemented by a combination of hardware and software modules in the decoding processor. The software module may be located in ram, flash memory, rom, prom, or eprom, registers, etc. storage media as is well known in the art. The storage medium is located in the memory 42, and the processor 41 reads the information in the memory 42 and performs the steps of the above method in combination with the hardware thereof.
Example four:
the computer readable medium provided by the embodiment of the invention has a non-volatile program code executable by a processor, and the program code causes the processor to execute the method provided by the first embodiment.
Unless specifically stated otherwise, the relative steps, numerical expressions, and values of the components and steps set forth in these embodiments do not limit the scope of the present invention.
It is clear to those skilled in the art that, for convenience and brevity of description, the specific working processes of the system and the apparatus described above may refer to the corresponding processes in the foregoing method embodiments, and are not described herein again.
In all examples shown and described herein, any particular value should be construed as merely exemplary, and not as a limitation, and thus other examples of example embodiments may have different values.
The flowchart and block diagrams in the figures illustrate the architecture, functionality, and operation of possible implementations of systems, methods and computer program products according to various embodiments of the present invention. In this regard, each block in the flowchart or block diagrams may represent a module, segment, or portion of code, which comprises one or more executable instructions for implementing the specified logical function(s). It should also be noted that, in some alternative implementations, the functions noted in the block may occur out of the order noted in the figures. For example, two blocks shown in succession may, in fact, be executed substantially concurrently, or the blocks may sometimes be executed in the reverse order, depending upon the functionality involved. It will also be noted that each block of the block diagrams and/or flowchart illustration, and combinations of blocks in the block diagrams and/or flowchart illustration, can be implemented by special purpose hardware-based systems which perform the specified functions or acts, or combinations of special purpose hardware and computer instructions.
In the several embodiments provided in the present application, it should be understood that the disclosed system, apparatus and method may be implemented in other ways. The above-described embodiments of the apparatus are merely illustrative, and for example, the division of the units is only one logical division, and there may be other divisions when actually implemented, and for example, a plurality of units or components may be combined or integrated into another system, or some features may be omitted, or not executed. In addition, the shown or discussed mutual coupling or direct coupling or communication connection may be an indirect coupling or communication connection of devices or units through some communication interfaces, and may be in an electrical, mechanical or other form.
The units described as separate parts may or may not be physically separate, and parts displayed as units may or may not be physical units, may be located in one place, or may be distributed on a plurality of network units. Some or all of the units can be selected according to actual needs to achieve the purpose of the solution of the embodiment.
In addition, functional units in the embodiments of the present invention may be integrated into one processing unit, or each unit may exist alone physically, or two or more units are integrated into one unit.
The functions, if implemented in the form of software functional units and sold or used as a stand-alone product, may be stored in a computer readable storage medium. Based on such understanding, the technical solution of the present invention may be embodied in the form of a software product, which is stored in a storage medium and includes instructions for causing a computer device (which may be a personal computer, a server, or a network device) to execute all or part of the steps of the method according to the embodiments of the present invention. And the aforementioned storage medium includes: a U-disk, a removable hard disk, a Read-Only Memory (ROM), a Random Access Memory (RAM), a magnetic disk or an optical disk, and other various media capable of storing program codes.
Finally, it should be noted that: the above-mentioned embodiments are only specific embodiments of the present invention, which are used for illustrating the technical solutions of the present invention and not for limiting the same, and the protection scope of the present invention is not limited thereto, although the present invention is described in detail with reference to the foregoing embodiments, those skilled in the art should understand that: any person skilled in the art can modify or easily conceive the technical solutions described in the foregoing embodiments or equivalent substitutes for some technical features within the technical scope of the present disclosure; such modifications, changes or substitutions do not depart from the spirit and scope of the embodiments of the present invention, and they should be construed as being included therein. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (7)
1. A method for establishing a cancer-specific co-tuned network, comprising:
obtaining TF regulation information and miRNA regulation information of TF and miRNA on the target gene according to a public database;
establishing a ternary regulation network according to the TF regulation information and the miRNA regulation information;
identifying FFLs in the ternary regulation network to obtain FFLs identification results;
screening to obtain a cancer specific miRNA-TF co-regulation network according to the FFLs recognition result and the cancer genome expression amount information;
the FFLs are in a form of regulating and controlling a target gene by miRNA and TF together, and comprise three types of TF-FFLs, miRNA-FFLs and composite FFLs;
among the TF-FFLs, TF is a main regulator;
among the miRNA-FFLs, miRNA is a main regulator;
in the composite FFLs, miRNA and TF are mutually regulated, and the composite FFLs are formed by combining the TF-FFLs and the miRNA-FFLs;
the identifying the FFLs in the ternary regulation and control network to obtain an FFLs identification result specifically comprises the following steps:
FFLs are identified in the ternary regulation and control network according to a network motif mining algorithm, and FFLs identification results are obtained;
the method comprises the following steps of screening and obtaining a cancer specific miRNA-TF co-regulation network according to FFLs recognition results and cancer genome expression quantity information, and specifically comprises the following steps:
and obtaining the co-regulation relation of the miRNA and the TF to the target gene of the cancer genome by utilizing statistical test, a network reasoning algorithm or gene enrichment analysis according to the FFLs recognition result and the cancer genome expression quantity information, and establishing a cancer specific miRNA-TF co-regulation network according to the co-regulation relation.
2. The method of claim 1, wherein the TF regulatory information comprises TF-miRNA regulatory information and TF-mRNA regulatory information.
3. The method of claim 1, wherein the miRNA regulatory information comprises miRNA-TF regulatory information and miRNA-mRNA regulatory information.
4. The method of claim 1, wherein the cancer genome expression information includes mRNA expression level information and miRNA expression level information.
5. A cancer-specific co-modulation network establishment apparatus, comprising:
the obtaining module is used for obtaining TF regulation information and miRNA regulation information of TF and miRNA on the target gene according to the public database;
the establishing module is used for establishing a ternary regulation network by a user according to the TF regulation information and the miRNA regulation information;
the identification module is used for identifying the FFLs in the ternary regulation and control network to obtain FFLs identification results; the FFLs are in a form of regulating and controlling a target gene by miRNA and TF together, and comprise three types of TF-FFLs, miRNA-FFLs and composite FFLs; among the TF-FFLs, TF is a main regulator; among the miRNA-FFLs, miRNA is a main regulator; in the composite FFLs, miRNA and TF are mutually regulated, and the composite FFLs are formed by combining the TF-FFLs and the miRNA-FFLs; identifying FFLs in a ternary regulation network by utilizing a network motif mining algorithm to obtain FFLs identification results;
the screening module is used for screening and obtaining a cancer specific miRNA-TF co-regulation network according to the FFLs recognition result and the cancer genome expression quantity information; and (3) obtaining the co-regulation relation of miRNA and TF to the target gene of the cancer genome by utilizing statistical test, a network reasoning algorithm or gene enrichment analysis according to the FFLs recognition result and the cancer genome expression quantity information, and establishing a cancer specific miRNA-TF co-regulation network according to the co-regulation relation.
6. An electronic device comprising a memory and a processor, wherein the memory stores a computer program operable on the processor, and wherein the processor implements the steps of the method of any of claims 1 to 4 when executing the computer program.
7. A computer-readable medium having non-volatile program code executable by a processor, wherein the program code causes the processor to perform the method of any of claims 1 to 4.
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