Download Prediction system for pharmacogenetic response to drugs

CZ5225 Methods in Computational Biology
CZ5225 Methods in Computational Biology
Lecture 10: Prediction system for pharmacogenetic
response to drugs
CZ5225 Methods in Computational Biology
Introduction
Individual variations in drug response are
frequently associated with three groups of protein:
ADME-associated proteins: proteins responsible for the absorption,
distribution, metabolism and excretion (ADME) of drugs
Therapeutic targets: proteins that can be modified by an external
stimulus (drug molecules).
ADR related proteins: drug adverse reaction related proteins
The factors in variations of drug responses:
Sequence polymorphism
Transcriptional processing of proteins: altered methylations of genes,
differential splicing of mRNAS
Post-transcriptional processing of proteins: differences in protein
folding, glycosylation, turnover and trafficking.
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Medicines are not Safe or Effective in all Patients
Source: CDER Report to the Nation: 2004--Drug Safety and Quality
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Medicines are not Safe or Effective in all Patients
Drug Group
SSRI
Beta blockers
Statins
Beta2 agonists
…
Efficacy Incomplete/Absent
10-25%
15-25%
30-70%
40-70%
…
when considered in further detail, we can see that efficacy of
some of our major drug classes vary from 10-70% incomplete
efficacy.
CZ5225 Methods in Computational Biology
The needs of prediction of pharmacogenetic
response to drugs
Pharmacogenetic prediction and mechanistic elucidation of
individual variations of drug responses is important for
facilitating the design of personalized drugs and optimum
dosages.
For most drugs, not all of the ADME-associated proteins
responsible for metabolism and disposition of pharmaceutical
agents are known.
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The feasibility of prediction of pharmacogenetic
response to drugs
A number of studies have explored the possibility of using
polymorphisms as indicators of specific drug responses.
Computational methods have been developed for analyzing
complex genetic, expression and environmental data to analyze
the association between drug response and the profiles of
polymorphism, expression and environmental factors and to
derive pharmacogenetic predictors of drug response
A number of Freely accessible internet resources
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The approach of prediction of pharmacogenetic
response to drugs
Reported polymorphisms of ADME-associated proteins:
By a comprehensive search of the abstracts of Medline
database
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The approach of prediction of pharmacogenetic
response to drugs
ADME-associated proteins linked to reported drug
response variations :
Also by a comprehensive search of the abstracts of Medline
database
CZ5225 Methods in Computational Biology
The approach of prediction of pharmacogenetic
response to drugs
Rule-based prediction of drug responses from the
polymorphisms of ADME-associated proteins
the analysis of clinical
samples of the variation of
drug responses
+
the results of genetic
analysis of the participating
patients
Used as indicators for
predicting individual
variations of drug response
CZ5225 Methods in Computational Biology
The approach of prediction of pharmacogenetic
response to drugs
Similar to the “Simple rules-based” method for using
HIV-1 genotype to predict antiretroviral drug
susceptibility (HIV drug resistant genotype
interpretation systems)*
*Comparative Evaluation of Three Computerized Algorithms for Prediction of Antiretroviral
Susceptibility from HIV Type 1 Genotype. J Antimicrob Chemother 53, 356-360 (2004).
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Basic idea of using HIV-1 genotype to predict
antiretroviral drug susceptibility
HIV-1 genotype 1
HIV-1 genotype 2
Phenotype resistant : drug 1, drug 2, drug 3…
Phenotype susceptible: drug a, drug b, drug c…
Phenotype resistant : drug 2, drug 3, drug a…
Phenotype susceptible: drug b, drug c…
Phenotype resistant : drug 1, drug 3…
HIV-1 genotype 3
…
Phenotype susceptible: drug 2, drug a…
Phenotype resistant : …
Phenotype susceptible:…
Drug 2:
1:
Genotype1: phenotype (penalty / score); Genotype2: phenotype (penalty / score); …
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The approach of prediction of pharmacogenetic
response to drugs
Examples of the ADME-associated proteins having a known pharmacogenetic
polymorphism and a sufficiently accurate rule for predicting responses to a
specific drug or drug group reported in the literature.
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Limitation of Simple rules based methods
Low predicting accuracies of simple rules based methods:
50%~100% (comparable to those of 81%~97% for predicting
HIV drug resistance mutations from the HIV resistant genotype
interpretation systems)
Variation of response to some drugs: associated with complex
interaction of polymorphisms in multiple proteins
Simple rules:
Limited predicting capacity for prediction of drug responses
 The basis for developing more sophisticated interpretation
systems like those of the HIV resistant genotype interpretation
systems
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Other methods
Computational methods for analysis and prediction of
pharmacogenetics of drug responses from the polymorphisms of
ADME-associated proteins
Examples recently explored for pharmacogenetic prediction of
drug responses:
Discriminant analysis (DA) [Chiang et al., 2003]
Unconditional logistic regression [Yu et al., 2000]
Random regression model [Zanardi et al., 2001]
Logistic regression, 2004 [Zheng et al., 2004b]
Artificial neural networks (ANN) [Chiang et al., 2003; Serretti et al., 2004]
Maximum likelihood context model from haplotype structure provided by
hapmap [Lin et al., 2005]
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Examples:
Statistical analysis and statistical learning methods used for
pharmacogenetic prediction of drug responses
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About the project:
Distinguish subgroups of patients who respond differently to
drug treatment.
The study of genome-derived data, including human genetic
variation, RNA and protein expression differences, to predict
drug response in individual patients or groups of patients by
using simple-rule based methods.
“Develop a simple rule-based computational drug
response prediction system”
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A guide to the project
Step 1: Choose the research object
- one protein with quite a lot of corresponding drugs
- several function relevant proteins
Step 2: Drug Response Data collection
- by extensive searching web-sources
- developing a database of the information collected
Step3: Design a simple rule-based computational drug response
prediction system
- using simply “penalty/score” to describe the simple rules
- comparing the variant sequence with wild type sequence
- predicting the possible drug responses
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Pharmacogenetics: to deliver ‘right medicine,
right dose, to right patient’
prediction system
Genetic profiles
Physician Dx;
clinical info
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Summary
Genetic profiles of new patients can be used to prescribe
drugs more effectively and avoid adverse reactions.
Can also speed clinical trials by testing on those who are
likely to respond well.
Drug – Gene Interactions  Optimal Dosing
The primary goal is to reduce the time and cost of drug
development.
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Any questions?
Thank you