CN103150467A - Method for detecting medicine adverse reaction with genome expression profiling - Google Patents

Method for detecting medicine adverse reaction with genome expression profiling Download PDF

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CN103150467A
CN103150467A CN2013100450297A CN201310045029A CN103150467A CN 103150467 A CN103150467 A CN 103150467A CN 2013100450297 A CN2013100450297 A CN 2013100450297A CN 201310045029 A CN201310045029 A CN 201310045029A CN 103150467 A CN103150467 A CN 103150467A
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genomic expression
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王可鉴
杨仑
贺林
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Shanghai Jiaotong University
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Abstract

The invention relates to a method for detecting medicine adverse reaction with a genome expression profiling, which comprises the following steps: inquiring and confirming known medicines that can trigger specifical adverse reaction, namely risk medicines; counting the frequency of the adverse reaction of the risk medicines; utilizing the risk medicines and target medicines to respectively process human or animal cell lines, and obtaining the whole genome expression profiling of the cell lines through a genome expression chip technical platform; and counting the similarity of the target medicines and the corresponding risk medicines on the genome expression profiling, and carrying out weighting calculation for the similarity of the expression profiling according to the relative frequency of the adverse reaction of the risk medicines so as to score and judge the risk of the target medicine triggering the adverse reaction. The detection method is suitable for all kinds of medicines, without limitation, is simple and easy to operate, can indirectly estimate the risk of the target medicine triggering the adverse reaction without at the cost of practical personal injury, and has excellent application prospect for clinical medicine risk assessment.

Description

A kind of method of composing the detection of drugs bad reaction by genomic expression
Technical field
The invention belongs to the assessment of clinical medicine drug safety detection field, particularly a kind of method of composing the detection of drugs bad reaction by genomic expression.
Background technology
Due to the serious adverse drug reaction that causes the pill taker, many medicines can be abandoned at the commitment of clinical development, or are subject to sale ban or the safety warning of supervision department after listing.Current, the prevention of adverse drug reaction and monitoring are mainly comprised the means of two aspects.On the one hand, at the commitment of drug development, can by the security risks of the means look-ahead medicines such as compound structure-activity relationship or animal toxicology experiment, abandon early high risk drug candidate.Yet facts have proved, research and develop the generation that early stage Risk Screening can not be avoided bad reaction fully, still have quite a few risk medicine to enter clinical trial and even enter the listing stage.On the other hand, can realize by the occurrence frequency of monitoring specific bad reaction secure alarm and the intervention of certain drug in clinical trial or after the medicine listing, but the retrospective monitoring means of this class often have obvious hysteresis quality, before safety issue was found, the personal injury of certain degree and economic loss often can't be avoided.
Summary of the invention
Technical matters to be solved by this invention is to provide a kind of method of composing the detection of drugs bad reaction by genomic expression, and detection method of the present invention can be common to all types of drugs, is not subjected to the restriction of medicament categories; This detection method is simple to operation, under the prerequisite take actual personal injury as cost not, and the bad reaction risk of scheduled target medicine indirectly, risk assessment has good application prospect to clinical medicine.
A kind of method of composing the detection of drugs bad reaction by genomic expression of the present invention comprises the steps:
(1) the known medicine that can cause specific bad reaction, i.e. risk medicine are confirmed in inquiry (as the FDA of Food and Drug Administration authoritative database etc.);
(2) the statistical risk medicine causes occurrence frequency (inquiry is as the Adverse Events Reporting System(AERS of the U.S. FDA management) database of bad reaction);
(3) application risk medicine and drug target are processed respectively the mankind or animal cell line, and obtain the full genomic expression spectrum of clone by genomic expression chip technology platform;
(4) calculate drug target and each risk medicine similarity on the genomic expression spectrum, and occurrence frequency relative to the bad reaction of risk medicine is weighted calculating to the express spectra similarity;
(5) weighing computation results of drug target and each risk medicine is carried out read group total, thereby obtain the risk factor that drug target causes bad reaction, sum formula is as follows:
Risk?Score＝∑(R i×P i)
Wherein, R iRepresent the relative occurrence frequency of bad reaction of i risk medicine; P iThe genomic expression spectrum similarity of representative check medicine and i risk medicine;
(6) according to the risk factor of drug target, judge this coefficient higher than risk medicine known more than 50%, can be considered and have potential security risk.
Described bad reaction refers to by in the prevention of normal usage, consumption drug application, diagnosis or treatment lysis, the adverse reaction irrelevant with therapeutic purposes occur, and includes but not limited to that myocardial infarction, liver poison, kidney are malicious, drug allergy etc.;
Described medicine refers to affect organism physiology, biochemistry and pathologic process, and the chemical substance in order to prevention, diagnosis, treatment disease and family planning comprises the Experimental agents of not going public, marketed drug or delisting medicine;
Described risk medicine refer to because of bad reaction by various countries safety of medicine regulator require to quit listing, in addition safety warning or the medicine of being pointed out to have the bad reaction risk in biology and medical research;
Described drug target refers to that the bad reaction risk is unknown or do not admitted by various countries safety of medicine regulator, thereby awaits the listing checked by this method or the medicine in research and development;
The occurrence frequency of described bad reaction refers to that the risk medicine causes the ratio of case number of cases and all numbers of taking medicine of target bad reaction, the ratio of the case number of cases of the case number of cases of perhaps target bad reaction (as myocardium bad reaction) and other bad reactions outside the target bad reaction (as other the various bad reactions except myocardium bad reaction);
Described clone refers to come from the cell colony that the primary cell culture of the mankind or animal is bred after going down to posterity successfully;
Described genomic expression chip refers to utilize the biological sample with mark to hybridize, thereby the genomic expression spectrum of sample is carried out the technical equipment of fast quantitative analysis, includes but not limited to the genetic chip that the companies such as Affymetrix and Luminex produce;
Described genomic expression spectrum similarity refers to the similarity degree on the expression of several genes between two genomic expression spectrums, and its criterion includes but not limited to Pearson's related coefficient and Euclidean distance etc.;
Described Pearson's related coefficient, its computing formula is:
P = 1 n - 1 Σ n = 1 500 ( X n - X ‾ s X ) ( Y n - Y ‾ s Y )
X wherein nAnd Y nRepresent that respectively the expression of n gene after drug target and risk drug treating in 500 genes changes multiple;
Figure BDA00002818411300022
With
Figure BDA00002818411300023
Represent that respectively the expression after drug target and risk drug treating changes the multiple average; s XAnd s YRepresentative represents that respectively the expression after drug target and risk drug treating changes the multiple standard deviation respectively; Wherein, described 500 genes refer in express spectra to be in harmonious proportion on expression and lower each the highest 250 genes of multiple.
Described weighted calculation refers to arrange according to the bad reaction occurrence frequency of each risk medicine the Weighted Average Algorithm of weight.
In order to replenish the deficiency of existing prediction adverse drug reaction method, the present invention proposes a kind of new method, at first confirm that a collection of regulator and academic institution find to cause the typical risk medicine of specific bad reaction, and obtain corresponding genomic expression spectrum by the clone of risk drug treating; Then obtain the genomic expression spectrum of drug target by same program; At last the express spectra of drug target and risk medicine is compared and is calculated, thus under the prerequisite take actual personal injury as cost not the bad reaction risk of scheduled target medicine indirectly.
Beneficial effect
(1) detection method of the present invention can be common to all types of drugs, is not subjected to the restriction of medicament categories;
(2) this detection method is simple to operation, under the prerequisite take actual personal injury as cost not, and the bad reaction risk of scheduled target medicine indirectly, risk assessment has good application prospect to clinical medicine.
Description of drawings
Fig. 1 is detection method process flow diagram of the present invention, and wherein (A) obtains the genomic expression spectrum of the clone of risk medicine and drug target processing, and the adverse reaction rate of risk medicine, (B) calculates the risk marking value of drug target by weighting algorithm.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used for explanation the present invention and be not used in and limit the scope of the invention.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after the content of having read the present invention's instruction, these equivalent form of values fall within the application's appended claims limited range equally.
Term definition
1. clone: refer under given conditions through cultivate and go down to posterity after the cell colony of successful reproduction.Its primary cell separates usually from human body cancer tissue, such as Human Breast Cancer MCF-7 clone (separating from the pink toes of 69 years old in 1970) and human prostate cancer PC3 clone etc.But comprise that also other are take the clone of animal as the source, as rodent (as rat, mouse) and primate (as monkey) etc.Medicine adds in cell culture medium after being dissolved in other solvents of smuggled goods, thereby makes drug molecule enter the gene expression of the specific pharmacological action change of performance cell in cell.
2. genetic chip: refer to that the surface is fixed with the planar substrate of the probes such as oligonucleotides, genomic DNA or complementary DNA, utilize the nucleotide in stromal surface probe and biological sample to hybridize, can carry out fast qualitative and quantitative test to the gene expression profile biological information of sample.Based on all devices of this type of technology, as the genetic chip of the companies such as Affymetrix and Luminex product, and the genomic expression of customization separately spectrum quantitative analytical device is all in the covering scope of this concept.
Embodiment 1
The selection of the foundation of Drug Discovery express spectra and risk medicine
Use 1309 kinds of medicines to process separately human tumour cell line's (comprising MCF7, PC3, HL60 etc.), in order to contrast with the cell that is not subjected to drug treating.RNA (ribonucleic acid) in cell (english abbreviation RNA) is adjusted (english abbreviation cDNA) in order to synthetic complementary ribodesose after separating.By Affymetrix HG-U133A genetic chip, thereby cDNA and Probe Hybridization are determined the abundance of the corresponding RNA of each cDNA.Process the RNA abundance level of cell and untreated cell by drugs compared, can determine that totally 22283 kinds of RNA (are rise greater than one times because of the expression variation multiple that drug treating occurs; Be downward less than one times), namely genomic expression is composed (ConnectivityMap database).
In 1309 kinds are processed medicine, by inquiry medicine operation instructions (http://sideeffects.embl.de/), obtain Troglitazone, Atropine, 128 kinds of risk medicines that tend to cause miocardial infarction (Myocardial Infarction) such as Imatinib.In the Adverse Event Reporting System (english abbreviation AERS) of setting up by inquiry Food and Drug Administration (FDA), can obtain miocardial infarction number of reports and the bad reaction report sum of each risk medicine, ratio between the two is the weight (see the following form) of each risk medicine in forecast model.
Table: risk of myocardial infarction medicine and the weight in forecast model thereof
Figure BDA00002818411300041
Figure BDA00002818411300051
Embodiment 2
Compose the bad reaction risk of target of prediction medicine according to the genomic expression of risk medicine
Except 128 risk medicines, all the other 1181 medicines are as the check medicine.Similarity based on check medicine and risk medicine on genomic expression is composed (as Pearson's related coefficient etc.), and be weighted according to the miocardial infarction bad reaction report accounting to each risk medicine of similarity, can calculate the risk of myocardial infarction coefficient of check medicine.Its formula is as follows:
Score = Σ i = 1 128 R i × P i
R in above formula iRepresent the miocardial infarction bad reaction report accounting of i risk medicine, P iThe genomic expression spectrum Pearson related coefficient of representative check medicine and i risk medicine.
Take detection of drugs Clozapine as example, and i risk medicine is Alprostadil.We get to be in harmonious proportion on expression in the Clozapine express spectra and lower each the highest 250 genes of multiple, calculate the Pearson's related coefficient on these 500 gene expression doses between Clozapine and Alprostadil, and its computing formula is:
P = 1 n - 1 Σ n = 1 500 ( X n - X ‾ s X ) ( Y n - Y ‾ s Y )
X wherein nAnd Y nRepresent that respectively the expression of n gene after Clozapine and Alprostadil processing in 500 genes changes multiple;
Figure BDA00002818411300063
With
Figure BDA00002818411300064
Representative represents that respectively the expression after Clozapine and Alprostadil processing changes the multiple average respectively; s XAnd s YRepresentative represents that respectively the expression after Clozapine and Alprostadil processing changes the multiple standard deviation respectively.Pearson's related coefficient that can be got Clozapine and Alprostadil by above formula is 0.33923, and the miocardial infarction bad reaction of Alprostadil reports that accounting is that 2.876%(is 0.02876), can get R after weighting i* P i=0.33923 * 0.02876=0.00976; By that analogy, consider the whole risk of myocardial infarction coefficient 1.21636 that can get Clozapine after all 128 risk medicines.
In 1181 check medicines, some drug risk coefficient ranks of being warned by FDA owing to causing risk of myocardial infarction are forward, as Estradiol rank the 4th and Clozapine rank the 6th etc.This example explanation this method can effectively be predicted the adverse drug reaction risk to a certain extent.If certain medicine has the high risk factor for certain bad reaction, can be in medicament research and development, examine and the after-stage that goes on the market carries out emphasis monitoring to the risk of this bad reaction, to prevent the generation of safety of medicine problem.
Although the present invention discloses preferred embodiment as above; so it is not to limit content of the present invention; anyly be familiar with this skill person; within not breaking away from main spirits of the present invention and context; when doing various changes and retouching, therefore the protection domain of invention should be as the criterion with the basic right claimed range of applying for a patent.

Claims (10)

1. a method of composing the detection of drugs bad reaction by genomic expression, comprise the steps:
(1) the known medicine that can cause specific bad reaction of acknowledgment of your inquiry, i.e. risk medicine;
(2) the statistical risk medicine causes the occurrence frequency of bad reaction;
(3) application risk medicine and drug target are processed respectively the mankind or animal cell line, and obtain the full genomic expression spectrum of clone by genomic expression chip technology platform;
(4) calculate drug target and each risk medicine similarity on the genomic expression spectrum, and occurrence frequency relative to the bad reaction of risk medicine is weighted calculating to the express spectra similarity;
(5) weighing computation results of drug target and each risk medicine is carried out read group total, thereby obtain the risk factor that drug target causes bad reaction;
(6) according to the risk factor of drug target, judge this coefficient higher than risk medicine known more than 50%, can be considered and have potential security risk.
2. a kind of method of composing the detection of drugs bad reaction by genomic expression according to claim 1, it is characterized in that: described bad reaction refers to by in normal usage, the prevention of consumption drug application, diagnosis or treatment lysis, the adverse reaction irrelevant with therapeutic purposes occur.
3. a kind of method of composing the detection of drugs bad reaction by genomic expression according to claim 2 is characterized in that: described bad reaction is myocardial infarction, liver poison, kidney is malicious or drug allergy.
4. a kind of method of composing the detection of drugs bad reaction by genomic expression according to claim 1 is characterized in that: described risk medicine refer to because of bad reaction by various countries safety of medicine regulator require to quit listing, in addition safety warning or the medicine of being pointed out to have the bad reaction risk in biology and medical research.
5. a kind of method of composing the detection of drugs bad reaction by genomic expression according to claim 1, it is characterized in that: described drug target refers to that the bad reaction risk is unknown or do not admitted by various countries safety of medicine regulator, thereby awaits the listing checked by this method or the medicine in research and development.
6. a kind of method of composing the detection of drugs bad reaction by genomic expression according to claim 1, it is characterized in that: the occurrence frequency of described bad reaction refers to that the risk medicine causes the ratio of case number of cases and all numbers of taking medicine of target bad reaction, perhaps the ratio of the case number of cases of the case number of cases of target bad reaction and other bad reactions outside the target bad reaction.
7. a kind of method of composing the detection of drugs bad reaction by genomic expression according to claim 1 is characterized in that: described clone refers to come from the cell colony that the primary cell culture of the mankind or animal is bred after going down to posterity successfully.
8. a kind of method of composing the detection of drugs bad reaction by genomic expression according to claim 1, it is characterized in that: described genomic expression spectrum similarity refers to the similarity degree on the expression of several genes between two genomic expression spectrums, and its criterion includes but not limited to Pearson's related coefficient and Euclidean distance.
9. a kind of method of composing the detection of drugs bad reaction by genomic expression according to claim 8 is characterized in that: described Pearson's related coefficient, and its computing formula is:
P = 1 n - 1 Σ n = 1 500 ( X n - X ‾ s X ) ( Y n - Y ‾ s Y )
X wherein nAnd Y nRepresent that respectively the expression of n gene after drug target and risk drug treating in 500 genes changes multiple;
Figure FDA00002818411200022
With Represent that respectively the expression after drug target and risk drug treating changes the multiple average; s XAnd s YRepresentative represents that respectively the expression after drug target and risk drug treating changes the multiple standard deviation respectively; Wherein, described 500 genes refer in express spectra to be in harmonious proportion on expression and lower each the highest 250 genes of multiple.
10. a kind of method of composing the detection of drugs bad reaction by genomic expression according to claim 1, it is characterized in that: described weighted calculation refers to arrange according to the bad reaction occurrence frequency of each risk medicine the Weighted Average Algorithm of weight.
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CN106611094A (en) * 2015-10-15 2017-05-03 北京寻因生物科技有限公司 Method for carrying out prediction and intervention on toxic and side effect of chemotherapy drug on the basis of intestinal tract microbial flora
CN106611094B (en) * 2015-10-15 2021-08-06 北京寻因生物科技有限公司 System for predicting and intervening chemotherapeutic drug toxic and side effects based on intestinal microbial flora

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