Mthodes du maximum de vraisemblance et alternatives Baysiennes pour - PowerPoint PPT Presentation

. Simulation study . . . . . . . . . Introduction Objectives Results . Conclusions Méthodes du maximum de vraisemblance et alternatives Bayésiennes pour le criblage à haut débit de marqueurs génétiques en modélisation pharmacocinétique Julie Bertrand Genetics Institute, University College London, London, UK 27 novembre 2014 j.bertrand@ucl.ac.uk Workshop Phon&Stat 2014 27/11/14 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 /18

. Results . . . . . . . . Introduction Objectives Simulation study Conclusions . Pharmacological and genetic variability Clinical pharmacology: study the interaction between the organism and the drug pharmacokinetics (PK) and pharmacodynamics (PD) Pharmacogenetics (PG): genetic part of the variability stratified medicine Genes coding for proteins involved in PK/PD processes metabolism enzymes (CYP450, NAT) single nucleotide polymorphism (SNP) j.bertrand@ucl.ac.uk Workshop Phon&Stat 2014 27/11/14 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 /18

. Results . . . . . . . . Introduction Objectives Simulation study Conclusions . Pharmacological and genetic variability Clinical pharmacology: study the interaction between the organism and the drug and its variability pharmacokinetics (PK) and pharmacodynamics (PD) Pharmacogenetics (PG): genetic part of the variability stratified medicine Genes coding for proteins involved in PK/PD processes metabolism enzymes (CYP450, NAT) single nucleotide polymorphism (SNP) j.bertrand@ucl.ac.uk Workshop Phon&Stat 2014 27/11/14 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 /18

. Results . . . . . . . . Introduction Objectives Simulation study Conclusions . Pharmacological and genetic variability Clinical pharmacology: study the interaction between the organism and the drug and its variability pharmacokinetics (PK) and pharmacodynamics (PD) Pharmacogenetics (PG): genetic part of the variability stratified medicine Genes coding for proteins involved in PK/PD processes metabolism enzymes (CYP450, NAT) single nucleotide polymorphism (SNP) j.bertrand@ucl.ac.uk Workshop Phon&Stat 2014 27/11/14 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 /18

. Semi-physiological models integrating the a priori . . . . . . Introduction Objectives Simulation study Results Conclusions Modelling in pharmacology knowledge on the drug . parameters characterizing each physiological processes model nonlinear in its parameters Mixed effect models all patients analyzed simultaneously parameter decomposed in fixed and random effects covariates identification Estimation methods Maximum likelihood: model linearization, Gaussian quadrature, SAEM Bayesian approaches j.bertrand@ucl.ac.uk Workshop Phon&Stat 2014 27/11/14 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 /18

. Semi-physiological models integrating the a priori . . . . . . Introduction Objectives Simulation study Results Conclusions Modelling in pharmacology knowledge on the drug . parameters characterizing each physiological processes model nonlinear in its parameters Mixed effect models all patients analyzed simultaneously parameter decomposed in fixed and random effects covariates identification Estimation methods Maximum likelihood: model linearization, Gaussian quadrature, SAEM Bayesian approaches j.bertrand@ucl.ac.uk Workshop Phon&Stat 2014 27/11/14 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 /18

. Modelling in pharmacology . . . . . . . Introduction Objectives Simulation study Results Conclusions Semi-physiological models integrating the a priori . knowledge on the drug parameters characterizing each physiological processes model nonlinear in its parameters Mixed effect models all patients analyzed simultaneously parameter decomposed in fixed and random effects Estimation methods Maximum likelihood: model linearization, Gaussian quadrature, SAEM Bayesian approaches j.bertrand@ucl.ac.uk Workshop Phon&Stat 2014 27/11/14 . . . . . . . . . . . . . . . . . . . . . . . . . 3 /18 . . . . . . ֒ → covariates identification Example : CL i = CL + β × SNP i + η i with SNP = { 0 , 1 , 2 }

. Modelling in pharmacology . . . . . . . Introduction Objectives Simulation study Results Conclusions Semi-physiological models integrating the a priori . knowledge on the drug parameters characterizing each physiological processes model nonlinear in its parameters Mixed effect models all patients analyzed simultaneously parameter decomposed in fixed and random effects Estimation methods Maximum likelihood: model linearization, Gaussian quadrature, SAEM Bayesian approaches j.bertrand@ucl.ac.uk Workshop Phon&Stat 2014 27/11/14 . . . . . . . . . . . . . . . . . . . . . . . . . 3 /18 . . . . . . ֒ → covariates identification Example : CL i = CL + β × SNP i + η i with SNP = { 0 , 1 , 2 }

. Simulation study . . . . . . . . . Introduction Objectives Results . Conclusions Methodological challenges in PGx data : plasma or insulin concentrations, ... Variable informativeness of genetic markers uneven distribution, small sample size of some genotypes Increased size of the genetic data sets toward high throughput screening structural correlation along the genome (linkage disequilibrium) j.bertrand@ucl.ac.uk Workshop Phon&Stat 2014 27/11/14 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 /18 PK/PD phenotype → not observed → dynamical models ֒ → mixed effect models ֒ dimensionality curse N << p → statistical genetics ֒

. Stepwise procedure . . . . . . Introduction Objectives Simulation study Results Conclusions Genetic association analyses in model-based PK commonly used for covariate model building . Lehr et al. (2010) adaptation for high throughput screening Penalized regression-based approach established in animal and plant genetics Lasso (Tibshirani. 1996) HLasso (Hoggart et al. 2008) developed for genome-wise association studies higher effect size once included in the model Bayesian variable selection KWII parsimonious interaction metric (Knights et al. 2013) j.bertrand@ucl.ac.uk Workshop Phon&Stat 2014 27/11/14 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 /18

. . . . . . . . . . . . Introduction . Objectives Simulation study Results Conclusions Stepwise procedure SNP selection after estimation of model parameters SNP considered independently j.bertrand@ucl.ac.uk Workshop Phon&Stat 2014 27/11/14 . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 /18

. . . . . . . . . . . . Introduction . Objectives Simulation study Results Conclusions Stepwise procedure SNP selection after estimation of model parameters SNP considered independently j.bertrand@ucl.ac.uk Workshop Phon&Stat 2014 27/11/14 . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 /18

. . . . . . . . . . . . Introduction . Objectives Simulation study Results Conclusions Stepwise procedure SNP selection after estimation of model parameters SNP considered independently j.bertrand@ucl.ac.uk Workshop Phon&Stat 2014 27/11/14 . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 /18

. . . . . . . . . . . . Introduction . Objectives Simulation study Results Conclusions Stepwise procedure SNP selection after estimation of model parameters SNP considered independently j.bertrand@ucl.ac.uk Workshop Phon&Stat 2014 27/11/14 . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 /18

. . . . . . . . . . . . . . Introduction Objectives Simulation study Results Conclusions Stepwise procedure j.bertrand@ucl.ac.uk Workshop Phon&Stat 2014 27/11/14 . . . . . . . . . . . . . . . . . . . . . . . . . . 6 /18 → SNP selection after estimation of model parameters ֒ → SNP considered independently ֒

. . . . . . . . . . . . Introduction . Objectives Simulation study Results Conclusions Integrated appr. with penalized regression Simultaneous SNP selection and estimation of model parameters All parameter-SNP associations considered simultaneously j.bertrand@ucl.ac.uk Workshop Phon&Stat 2014 27/11/14 . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 /18

. . . . . . . . . . . . Introduction . Objectives Simulation study Results Conclusions Integrated appr. with penalized regression Simultaneous SNP selection and estimation of model parameters All parameter-SNP associations considered simultaneously j.bertrand@ucl.ac.uk Workshop Phon&Stat 2014 27/11/14 . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 /18