lecture 10: prediction system for pharmacogenetic response to drugs

CZ5225 Methods in Computational Biology

Lecture 10: Prediction system for pharmacogenetic response to drugs



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 drugsTherapeutic 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 polymorphismTranscriptional processing of proteins: altered methylations of genes, differential splicing of mRNASPost-transcriptional processing of proteins: differences in protein folding, glycosylation, turnover and trafficking.


Medicines are not Safe or Effective in all Patients

Source: CDER Report to the Nation: 2004--Drug Safety and Quality


Medicines are not Safe or Effective in all Patients

Drug Group Efficacy Incomplete/Absent

SSRI 10-25%Beta blockers 15-25%Statins 30-70%Beta2 agonists 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.


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.


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


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



ADME-associated proteins linked to reported drug response variations :Also by a comprehensive search of the abstracts of Medline database



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



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).


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…

HIV-1 genotype 3

…

Phenotype resistant : drug 2, drug 3, drug a…

Phenotype susceptible: drug b, drug c…

Phenotype resistant : drug 1, drug 3…

Phenotype susceptible: drug 2, drug a…

Phenotype resistant : …

Phenotype susceptible:…

Drug 1: Genotype1: phenotype (penalty / score); Genotype2: phenotype (penalty / score); …Drug 2: Genotype1: phenotype (penalty / score); Genotype2: phenotype (penalty / score); …


The approach of prediction of pharmacogenetic response to drugsExamples 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.


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


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]


Examples:

Statistical analysis and statistical learning methods used for pharmacogenetic prediction of drug responses


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”


A guide to the projectStep 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


Pharmacogenetics: to deliver Pharmacogenetics: to deliver ‘right medicine, ‘right medicine, right dose, to right patient’right dose, to right patient’

Physician Dx;clinical info

prediction system

Genetic profiles


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.

The primary goal is to reduce the time and cost of drug development.

Drug – Gene Interactions Optimal Dosing


Any questions?

Thank you

lecture 10: prediction system for pharmacogenetic response to drugs

Documents