Personalized Medicine

Part I: Scientific & Commercial Aspects

by
Prof. K. K. Jain
MD, FRACS, FFPM

Jain PharmaBiotech
Basel, Switzerland

July 2012

A Jain PharmaBiotech Report

AUTHOR'S

BIOGRAPHY

Professor K. K. Jain is a neurologist/neurosurgeon by training and has been working in
the biotechnology/biopharmaceuticals industry for several years. He received graduate
training in both Europe and USA, has held academic positions in several countries, and is
a Fellow of the Faculty of Pharmaceutical Medicine of the Royal College of Physicians of
UK. Currently, he is a consultant at Jain PharmaBiotech.
Prof. Jain is the author of 440 publications including 21 books (4 as editor) and 50 special
reports which have covered important areas in biotechnology, gene therapy and
biopharmaceuticals. He has also written a textbook of gene therapy which is the first book
on this subject to be translated into the Chinese language. A book on gene therapy
companies was published in 2000 by John Wiley & Sons and the updated version of it is
incorporated in the 2010 edition of Gene Therapy published by Jain PharmaBiotech. The
most recent books include "Handbook of Nanomedicine" (Humana/Springer 2008;
Chinese edition, Peking University Press 2011, 2nd ed Springer 2012), “Textbook of
Personalized Medicine” (Springer 2009), "Handbook of Biomarkers" (Springer 2010),
"Handbook of Neuroprotection" (Springer 2011), “Applications of Biotechnology in
Cardiovascular Therapeutics” (Springer 2011), and “Applications of Biotechnology in
Neurology” (Springer 2012, in preparation).
Prof. Jain has been interested in using biotechnology to develop personalized medicine
since 1997. He has also lectured and conducted several workshops on personalized
medicine.

ABOUT

THIS

REPORT

Prof. Jain wrote the first report on Personalized Medicine in 1998, which was published
by Decision Resources Inc, USA. The second edition was published in 2001 by Informa
Publications, London. Since 2003, the report is published and continuously updated and
rewritten at Jain PharmaBiotech.

July 2012 (first edition published in 1998 by Decision Resources Inc)
Copyright  2012 by
Jain PharmaBiotech
Bläsiring 7
CH-4057 Basel
Switzerland
Tel & Fax:
Email:
Web site:

+4161-6924461
info@pharmabiotech.ch
http://pharmabiotech.ch/

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted
in any form or by any means, electronic, mechanical, photocopying, or otherwise without the prior written
permission of the Publisher. This report may not be lent, resold or otherwise traded in any manner without the
consent of the Publisher. While all reasonable steps have been taken to ensure the accuracy of the information
presented, the Publisher cannot accept responsibility for inadvertent errors or omissions.

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TABLE

OF

CONTENTS

0. Executive Summary .............................................................................. 19
1. Basic Aspects ........................................................................................ 21
Definition of personalized medicine ................................................................................... 21
History of medical concepts relevant to personalized medicine ......................................... 22
Molecular biological basis of personalized medicine .......................................................... 24
The human genome ......................................................................................................... 24
Chromosomes ................................................................................................................. 25
Genes............................................................................................................................. 25
The genetic code ......................................................................................................... 25
Gene expression ......................................................................................................... 26
DNA sequences and structure ....................................................................................... 26
Genetic variations in the human genome ............................................................................ 26
Single nucleotide polymorphisms .................................................................................. 27
Copy number variations in the human genome ............................................................... 27
Insertions and deletions in the human genome ............................................................... 29
Large scale variation in human genome ......................................................................... 30
Structural variations in the human genome .................................................................... 30
Mapping and sequencing of structural variation from human genomes ............................... 30
1000 Genomes Project ................................................................................................. 31
Role of DNA sequencing in the development of personalized medicine ............................... 33
Human Variome Project ............................................................................................... 33
Interconnected genetic and genomic patterns in human diseases ...................................... 33
Basics technologies for developing personalized medicine ................................................ 34
Definitions of technologies relevant to personalized medicine ................................................ 34
Problems with the ICH definitions of pharmacogenomcis and pharmacogenetics ...................... 35
Relationship of various technologies to personalized medicine ............................................... 35
Conventional medicine versus personalized medicine ........................................................ 36
Role of genetics in future approaches to healthcare .......................................................... 36
Genetic medicine ............................................................................................................. 36
Human disease and genes ................................................................................................. 36
Genetic and environmental interactions in etiology of human diseases .................................... 37
Role of genetics in development of personalized medicines.................................................... 37
Genetic databases ....................................................................................................... 38
Genetic epidemiology .................................................................................................. 38
Limitations of medical genetics and future prospects ....................................................... 38
Genetics vs. epigenetics ............................................................................................... 39
Role of systems biology in personalized medicine ............................................................. 39
Systems pharmacology ..................................................................................................... 40
Systems medicine ............................................................................................................ 41
Synthetic biology and development of personalized medicines .......................................... 42
A personalized approach to environmental factors in disease ............................................ 42
Reclassification of diseases ............................................................................................... 43

2. Molecular Diagnostics in Personalized Medicine ................................... 45
Introduction....................................................................................................................... 45
Molecular diagnostic technologies ..................................................................................... 45
PCR-based methods ......................................................................................................... 46
DirectLinear™ Analysis ................................................................................................ 46
Denaturing high-performance liquid chromatography ....................................................... 47
Multiplex Allele-Specific Diagnostic Assay ....................................................................... 47
Representational oligonucleotide microarray analysis ....................................................... 47
Restriction fragment length polymorphism (RFLP) ........................................................... 47
Real-time PCR for detection of CNVs .............................................................................. 47
Non-PCR methods ............................................................................................................ 48
Arrayed primer extension (APEX) .................................................................................. 48
Enzymatic Mutation Detection (EMD) ............................................................................. 48
DNA sequencing............................................................................................................... 48
Sanger-sequencing technology ..................................................................................... 49
ABI PRISM® 310 Genetic Analyzer ................................................................................ 50
High-throughput paired end transcriptome sequencing .................................................... 50
Emerging sequencing technologies ..................................................................................... 50
4300 DNA analyzer ..................................................................................................... 51
Apollo 100.................................................................................................................. 51
"Color blind" approach to DNA sequencing ..................................................................... 52
Cyclic array sequencing ............................................................................................... 52
CEQ™ 8000 ................................................................................................................ 52

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DeepCAGE sequencing ................................................................................................. 52
Electron microscope-based DNA sequencing ................................................................... 53
Genometrica sequencer ............................................................................................. 53
GS-FLEX system (Roche/454) ....................................................................................... 54
IBS sequencing technology........................................................................................... 55
Illumina Genome Analyzer System ................................................................................ 55
MegaBACE 500 ........................................................................................................... 56
Microdroplet-based PCR for large-scale targeted sequencing. ............................................ 56
Multiplex amplification of human DNA sequences ............................................................ 57
Nanoscale sequencing.................................................................................................. 57
Polonator sequencer .................................................................................................... 57
RainStorm™ microdroplet technology ............................................................................ 58
Sequential DEXAS ....................................................................................................... 58
SOLiD technology ........................................................................................................ 59
Sequencing by hybridization ......................................................................................... 60
Whole genome sequencing ........................................................................................... 60
Bioinformatic tools for analysis of genomic sequencing data ............................................. 60
Detection of single molecules in real time ....................................................................... 61
Direct observation of nucleotide incorporation................................................................. 61
Molecular Combing ...................................................................................................... 61
Nanopore sequencing .................................................................................................. 61
DNA sequence by use of nanoparticles ........................................................................... 62
Zero-mode waveguide nanostructure arrays ................................................................... 62
Future prospects of sequencing ..................................................................................... 62
Role of sequencing in development of personalized medicine ............................................ 63
Biochips and microarrays ................................................................................................... 64
Application of biochip technology in developing personalized medicine .................................... 64
Standardizing the microarrays ........................................................................................... 65
Biochip technologies ......................................................................................................... 65
GeneChip ................................................................................................................... 66
AmpliChip CYP450 ....................................................................................................... 66
Microfluidics .................................................................................................................... 67
Lab-on-a-chip ............................................................................................................. 68
Micronics' microfluidic technology .................................................................................. 68
LabCD ....................................................................................................................... 68
Microfluidic automated DNA analysis using PCR............................................................... 69
Integrated microfluidic bioassay chip ............................................................................. 69
Electronic detection of nucleic acids on microarrays .............................................................. 69
Strand displacement amplification on a biochip .................................................................... 70
Rolling circle amplification on DNA microarrays .................................................................... 70
Universal DNA microarray combining PCR and ligase detection reaction .................................. 70
Protein biochips ............................................................................................................... 71
ProteinChip ................................................................................................................ 71
LabChip for protein analysis ......................................................................................... 72
TRINECTIN proteome chip ............................................................................................ 72
Protein expression microarrays ..................................................................................... 73
Microfluidic devices for proteomics-based diagnostics ...................................................... 73
New developments in protein biochips/microarrays ......................................................... 73
Protein biochips/microarrays for personalized medicine .................................................... 74
SNP genotyping ................................................................................................................. 74
Genotyping and haplotyping .............................................................................................. 75
Haplotype Specific Extraction ........................................................................................ 76
Computation of haplotypes ........................................................................................... 76
HapMap project .......................................................................................................... 77
Haplotyping for whole genome sequencing ..................................................................... 78
Predictingdrug response with HapMap............................................................................ 78
Companies developing haplotyping technology ............................................................... 78
Technologies for SNP analysis ............................................................................................ 79
Biochip and microarray-based detection of SNPs .................................................................. 80
SNP genotyping by MassARRAY ..................................................................................... 80
Biochip combining BeadArray and ZipCode technologies ................................................... 80
SNP-IT primer-extension technology ............................................................................. 81
Affymetrix Variation Detection Arrays ............................................................................ 81
Use of NanoChip for detection of SNPs ........................................................................... 81
Electrochemical DNA probes .............................................................................................. 82
Single base extension-tag array ......................................................................................... 82
Laboratory Multiple Analyte Profile ..................................................................................... 82
PCR-CTPP (confronting two-pair primers) ............................................................................ 83
SNP genotyping on a genome-wide amplified DOP-PCR template ........................................... 83
TaqMan real-time PCR ...................................................................................................... 83
Non-Enzymatic Amplification Technology ............................................................................ 83

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SNP genotyping with gold nanoparticle probes ..................................................................... 84
Locked nucleic acid .......................................................................................................... 84
Molecular inversion probe based assays .............................................................................. 84
Pyrosequencing ............................................................................................................... 85
Reversed enzyme activity DNA interrogation test ................................................................. 85
Smart amplification process version 2................................................................................. 86
Zinc finger proteins .......................................................................................................... 86
UCAN method (Takara Biomedical) ..................................................................................... 86
Mitochondrial SNPs........................................................................................................... 87
Limitations of SNP in genetic testing ................................................................................... 87
Concluding remarks on SNP genotyping .............................................................................. 87
Companies involved in developing technologies/products for SNP analysis .............................. 88
Impact of SNPs on personalized medicine ........................................................................... 89
Detection of copy number variations ................................................................................. 90
Study of rare variants in pinpointing disease-causing genes ............................................. 90
Optical Mapping ................................................................................................................. 91
Role of nanobiotechnology in molecular diagnostics .......................................................... 91
Cantilevers for personalized medical diagnostics .................................................................. 92
Nanopore-based technology for single molecule identification ................................................ 92
Role of biomarkers in personalized medicine ..................................................................... 93
Biomarkers for diagnostics ................................................................................................ 93
Biomarkers for drug development ...................................................................................... 94
Application of proteomics in molecular diagnosis .............................................................. 94
Proteomic strategies for biomarker identification .................................................................. 94
Proteomic technologies for detection of biomarkers in body fluids ..................................... 94
Protein patterns ............................................................................................................... 95
Layered Gene Scanning .................................................................................................... 95
Comparison of proteomic and genomic approaches in personalized medicine ........................... 96
Gene expression profiling .................................................................................................. 96
DNA microarrays .............................................................................................................. 97
Analysis of single-cell gene expression................................................................................ 97
Gene expression profiling based on alternative RNA splicing .................................................. 98
Whole genome expression array ........................................................................................ 99
Tangerine™ expression profiling ........................................................................................ 99
Gene expression analysis on biopsy samples ..................................................................... 100
Profiling gene expression patterns of white blood cells ........................................................ 100
Serial analysis of gene expression (SAGE) ......................................................................... 101
Multiplexed Molecular Profiling ......................................................................................... 101
Gene expression analysis using competitive PCR and MALDI TOF MS .................................... 102
Monitoring in vivo gene expression by magnetic resonance imaging ..................................... 102
Companies involved in gene expression analysis ................................................................ 102
Monitoring in vivo gene expression by molecular imaging ............................................... 103
Molecular imaging and personalized medicine ................................................................. 104
Glycomics-based diagnostics ........................................................................................... 104
Combination of diagnostics and therapeutics................................................................... 104
Use of molecular diagnostics for stratification in clinical trials .............................................. 105
Companion diagnostics ................................................................................................... 105
Companies involved in companion diagnostics ................................................................... 106
Point-of-care diagnosis .................................................................................................... 108
Companies developing point-of-care diagnostic technologies ............................................... 109
Point-of-care diagnosis of infections ................................................................................. 111
Advantages versus disadvantages of point-of-care diagnosis ............................................... 111
Future prospects of point-of-care diagnosis ....................................................................... 112
Genetic testing for disease predisposition ....................................................................... 112
Preventive genetics by early diagnosis of mitochondrial diseases ......................................... 112
Direct-to-consumer genetic services ................................................................................. 113
Role of diagnostics in integrated healthcare .................................................................... 114
Concept of integrated healthcare ..................................................................................... 114
Components of integrated healthcare ............................................................................... 115
Screening................................................................................................................. 115
Disease prediction ..................................................................................................... 115
Early diagnosis ......................................................................................................... 115
Prevention................................................................................................................ 116
Therapy based on molecular diagnosis ......................................................................... 116
Monitoring of therapy ................................................................................................ 116
Advantages and limitations of integrated healthcare ........................................................... 116
Commercially available systems for integrated healthcare ................................................... 117
Future of molecular diagnostics in personalized medicine ............................................... 117

3. Pharmacogenetics .............................................................................. 119
Basics of pharmacogenetics ............................................................................................. 119

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Role of molecular diagnostics in pharmacogenetics ......................................................... 120
Role of pharmacogenetics in pharmaceutical industry ..................................................... 121
Study of the drug metabolism and pharmacological effects ................................................. 121
Causes of variations in drug metabolism ........................................................................... 121
Enzymes relevant to drug metabolism .............................................................................. 122
Pharmacogenetics of phase I metabolism .......................................................................... 122
CYP450 .................................................................................................................... 122
P450 CYP 2D6 inhibition by selective serotonin reuptake inhibitors .................................. 124
Cytochrome P450 polymorphisms and response to clopidogrel ........................................ 125
Lansoprazole and cytochrome P450 ............................................................................. 125
Glucose-6-phosphate dehydrogenase .......................................................................... 125
Pharmacogenetics of phase II metabolism ......................................................................... 126
N-Acetyltransferase ................................................................................................... 126
Uridine diphosphate-glucuronosyltransferase ................................................................ 127
Measurement of CYP isoforms.......................................................................................... 127
Polymorphism of drug transporters .................................................................................. 128
Genetic variation in drug targets ...................................................................................... 128
Polymorphisms of kinase genes .................................................................................. 129
Effect of genetic polymorphisms on disease response to drugs ............................................. 129
Ethnic differences in drug metabolism .............................................................................. 130
Gender differences in pharmacogenetics ........................................................................... 130
Role of pharmacogenetics in drug safety ........................................................................... 131
Adverse drug reactions .............................................................................................. 131
Adverse drug reactions in children ............................................................................... 132
Adverse drug reactions related to toxicity of chemotherapy ............................................ 132
Genetically determined adverse drug reactions ............................................................. 132
Malignant hyperthermia ............................................................................................. 134
Pharmacogenetics of clozapine-induced agranulocytosis ................................................. 134
Role of pharmacogenetics in warfarin therapy ............................................................... 134
Role of pharmacogenetics in antiplatelet therapy .......................................................... 135
Role of pharmacogenetics in carbamazepine therapy ..................................................... 137
Role of pharmacogenetics in statin therapy .................................................................. 137
FDA consortium linking genetic biomarkers to serious adverse events.............................. 138
Therapeutic drug monitoring, phenotyping, and genotyping ................................................ 138
Therapeutic drug monitoring ...................................................................................... 139
Phenotyping ............................................................................................................. 139
Genotyping .............................................................................................................. 140
Genotyping vs phenotyping ........................................................................................ 140
Phenomics .................................................................................................................... 141
Limitations of genotype-phenotype association studies .................................................. 142
Molecular toxicology in relation to personalized medicines ................................................... 142
Toxicogenomics ........................................................................................................ 142
Biomarkers of drug toxicity ........................................................................................ 142
Drug-induced mitochondrial toxicity ............................................................................ 143
Companies involved in molecular toxicology ................................................................. 143
Gene expression studies ............................................................................................ 144
Pharmacogenetics in clinical trials .................................................................................... 144
Postmarketing pharmacogenetics ..................................................................................... 145
Clinical implications of pharmacogenetics ....................................................................... 145
Application of CYP450 genotyping in clinical practice...................................................... 145
Pharmacogenomic biomarker information in drug labels ................................................. 145
Genotype-based drug dose adjustment ........................................................................ 146
Examples of use of pharmacogenetics in clinical pharmacology ............................................ 146
Genotyping for identifying responders to sulfasalazine ................................................... 146
HLA alleles associated with lumiracoxib-related liver injury ............................................. 146
Pharmacogenetic basis of thiopurine toxicity ................................................................. 147
Tranilast-induced hyperbilirubinemia due to gene polymorphism ..................................... 147
Linking pharmacogenetics with pharmacovigilance ............................................................. 147
Genetic susceptibility to ADRs ..................................................................................... 147
Linking genetic testing to postmarketing ADR surveillance.............................................. 148
Recommendations for the clinical use of pharmacogenetics ................................................. 148
Limitations of pharmacogenetics ..................................................................................... 149
Pharmacoepigenomics vs pharmacogenetics in drug safety............................................. 149
Future role of pharmacogenetics in personalized medicine .............................................. 150

4. Pharmacogenomics ............................................................................. 151
Introduction..................................................................................................................... 151
Basics of pharmacogenomics ........................................................................................... 152
Pharmacogenomics and drug discovery ........................................................................... 152
Preclinical prediction of drug efficacy ........................................................................... 154
Pharmacogenomics and clinical trials .............................................................................. 154

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Impact of genetic profiling on clinical studies ..................................................................... 155
Limitations of the pharmacogenomic-based clinical trials ..................................................... 156
Pharmacogenomic aspects of major therapeutic areas .................................................... 157
Oncogenomics ............................................................................................................... 157
Oncogenes ............................................................................................................... 157
Tumor suppressor genes ............................................................................................ 158
Cardiogenomics ............................................................................................................. 159
Neuropharmacogenomics ................................................................................................ 161
Pharmacogenomics of Alzheimer's disease ................................................................... 161
Pharmacogenomics of depression ................................................................................ 162
Pharmacogenomics of schizophrenia ............................................................................ 162
Companies involved in neurogenomics-based drug discovery .......................................... 163

5. Role of Pharmacoproteomics .............................................................. 165
Basics of proteomics ........................................................................................................ 165
Proteomic approaches to the study of pathophysiology of diseases................................. 165
Single cell proteomics for personalized medicine ................................................................ 166
Diseases due to misfolding of proteins .............................................................................. 166
Therapies for protein misfolding .................................................................................. 167
Significance of mitochondrial proteome in human disease ................................................... 168
Proteomic technologies for drug discovery and development .......................................... 168
Role of reverse-phase protein microarray in drug discovery ................................................. 168
Role of proteomics in clinical drug safety........................................................................... 168
Toxicoproteomics ........................................................................................................... 169
Application of pharmacoproteomics in personalized medicine ......................................... 170

6. Role of Metabolomics in Personalized Medicine .................................. 171
Metabolomics and metabonomics .................................................................................... 171
Metabolomics bridges the gap between genotype and phenotype ................................... 171
Metabolomics, biomarkers and personalized medicine .................................................... 172
Metabolomic technologies ................................................................................................ 172
Urinary profiling by capillary electrophoresis ...................................................................... 173
Lipid profiling ................................................................................................................ 173
Role of metabolomics in biomarker identification and pattern recognition .............................. 174
Validation of biomarkers in large-scale human metabolomics studies .................................... 174
Pharmacometabonomics .................................................................................................. 174
Metabonomic technologies for toxicology studies ............................................................ 175
Metabonomics/metabolomics and personalized nutrition ................................................ 175

7. Personalized Biological Therapies ....................................................... 177
Introduction..................................................................................................................... 177
Recombinant human proteins .......................................................................................... 177
Therapeutic monoclonal antibodies ................................................................................. 177
Cell therapy ..................................................................................................................... 178
Autologous tissue and cell transplants .............................................................................. 178
Stem cells ..................................................................................................................... 178
Role of stem cells derived from unfertilized embryos ..................................................... 178
Cloning and personalized cell therapy ............................................................................... 179
Use of stem cells for drug testing ..................................................................................... 179
Gene therapy ................................................................................................................... 179
Personalized vaccines ...................................................................................................... 180
Personalized vaccines for viral diseases ............................................................................ 180
Personalized cancer vaccines ........................................................................................... 180
Antisense therapy ............................................................................................................ 180
RNA interference ............................................................................................................ 181
MicroRNAs..................................................................................................................... 182

8. Personalized Medicine in Major Therapeutic Areas ............................. 183
Introduction..................................................................................................................... 183
Management of infections ................................................................................................ 184
Management of HIV ....................................................................................................... 184
CD4 counts as a guide to drug therapy for AIDS ........................................................... 184
Drug-resistance in HIV............................................................................................... 184
Genetics of human susceptibility to HIV infection .......................................................... 185
Measurement of Replication Capacity ........................................................................... 186
Personalized vaccine for HIV ....................................................................................... 186
Prevention of adverse reactions to antiviral drugs ......................................................... 186
Pharmacogenetics and HIV drug safety ........................................................................ 187
Pharmacogenomics of antiretroviral agents .................................................................. 187
Role of diagnostic testing in management of HIV........................................................... 188

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Role of genetic variations in susceptibility to HIV-1........................................................ 188
Personalized treatment of hepatitis B................................................................................ 188
Personalized treatment of hepatitis C ............................................................................... 189
Responders vs non-responders to treatment for hepatitis C ............................................ 189
Drug resistance in hepatitis C ..................................................................................... 190
Personalized management of tuberculosis ......................................................................... 191
Personalized management of fungal infections ................................................................... 191
Psychiatric disorders ....................................................................................................... 192
Psychopharmacogenetics/psychopharmacodynamics .......................................................... 192
Serotonin genes ........................................................................................................ 192
Calcium channel gene ................................................................................................ 193
Dopamine receptor genes .......................................................................................... 193
COMT genotype and response to amphetamine ............................................................. 193
Methylenetetrahydrofolate reductase ........................................................................... 193
Genotype and response to methylphenidate in children with ADHD.................................. 194
Personalized antipsychotic therapy ................................................................................... 194
Personalized antidepressant therapy................................................................................. 196
EEG to predict adverse effects and evaluate antidepressant efficacy ................................ 197
Individualization of SSRI treatment ............................................................................. 197
Treatment resistant depression ................................................................................... 198
Vilazodone with a test for personalized treatment of depression ...................................... 199
Neurological disorders ..................................................................................................... 199
Personalized management of Alzheimer's disease............................................................... 199
Personalized management of Parkinson's disease ............................................................... 201
Discovery of subgroup-selective drug targets in PD ....................................................... 201
Personalized management of Epilepsy .............................................................................. 202
Choice of the right AED .............................................................................................. 202
Pharmacogenetics of epilepsy ..................................................................................... 202
Pharmacogenomics of epilepsy ................................................................................... 202
Drug resistance in epilepsy ......................................................................................... 203
Future prospects for management of epilepsy ............................................................... 205
Personalized management of migraine .............................................................................. 205
Individualization of use of triptans for migraine ............................................................. 206
Multitarget therapeutics for personalized treatment of headache ..................................... 206
Personalized management of stroke ................................................................................. 206
Brain imaging in trials of restorative therapies for stroke................................................ 207
Decisions for evacuation of intracerebral hemorrhage .................................................... 207
Revascularization procedures in chronic post-stroke stage .............................................. 207
Personalized treatment of multiple sclerosis ...................................................................... 208
Immunopathological patterns of demyelination for assessing therapy .............................. 209
Personalizing mitoxantrone therapy of multiple sclerosis ................................................ 209
Fusokine method of personalized cell therapy of multiple sclerosis .................................. 209
MBP8298 ................................................................................................................. 210
Pharmacogenomics of IFN-β therapy in multiple sclerosis ............................................... 210
T cell-based personalized vaccine for MS ...................................................................... 211
Cardiovascular disorders ................................................................................................. 211
Role of diagnostics in personalized management of cardiovascular disease ............................ 212
Testing in coronary heart disease ................................................................................ 212
SNP genotyping in cardiovascular disorders .................................................................. 212
Cardiovascular disorders with a genetic component ....................................................... 213
Gene variant as a risk factor for sudden cardiac death ................................................... 214
KIF6 gene test as a guide to management of heart disease ............................................ 215
SNP Chip for study of cardiovascular diseases ............................................................... 215
Pharmacogenomics of cardiovascular disorders .................................................................. 216
Modifying the genetic risk for myocardial infarction ............................................................ 216
Management of heart failure............................................................................................ 216
-blockers ................................................................................................................ 216
Bucindolol ................................................................................................................ 217
BiDil ........................................................................................................................ 217
Management of hypertension........................................................................................... 218
Pharmacogenomics of diuretic drugs............................................................................ 218
Pharmacogenomics of ACE inhibitors ........................................................................... 219
Management of hypertension by personalized approach ................................................. 219
Prediction of antihypertensive activity of rostafuroxin .................................................... 220
Pharmacogenetics of lipid-lowering therapies ..................................................................... 220
Polymorphisms in genes involved in cholesterol metabolism ........................................... 221
Role of eNOS gene polymorphisms .............................................................................. 221
The STRENGTH study ............................................................................................... 222
Personalized management of women with hyperlipidemia............................................... 223
Thrombotic disorders ...................................................................................................... 223
Factor V Leiden mutation ........................................................................................... 223

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Anticoagulant therapy ................................................................................................ 224
Antiplatelet therapy ................................................................................................... 224
Nanotechnology-based personalized therapy of cardiovascular diseases ................................ 225
Project euHeart for personalized management of heart disease............................................ 225
Concluding remarks........................................................................................................ 226
Personalized management of pulmonary disorders.......................................................... 226
Role of genetic ancestory in lung function ......................................................................... 226
Personalized therapy of asthma ....................................................................................... 227
Biomarkers for predicting response to corticosteroid therapy .......................................... 227
Genetic polymorphism and response to β2-adrenergic agonists ....................................... 227
Genotyping in asthma ................................................................................................ 228
IgE as guide to dosing of omalizumab for asthma.......................................................... 229
Lebrikizumab for personalised treatment of asthma ....................................................... 229
Personalized management of chronic obstructive pulmonary disease .................................... 229
Personalized management of skin disorders .................................................................... 230
Genetic testing for personalized skin care ......................................................................... 230
Management of hair loss based on genetic testing .............................................................. 231
Personalized therapy of rheumatoid arthritis................................................................... 231
Biomarkers for personalizing therapy of rheumatoid arthritis ............................................... 232
DIATSTAT™ anti-cyclic citrullinated peptides in rheumatoid arthritis ..................................... 232
Personalization of COX-2 inhibitor therapy ........................................................................ 233
Personalization of infliximab therapy ................................................................................ 233
Personalized approaches in immunology ......................................................................... 233
Role of Mannose-binding lectin in personalized medicine ..................................................... 234
Pharmacogenetics and pharmacogenomics of immunosuppressive agents ............................. 234
Personalized management of patients with lupus erythematosus ................................... 234
Personalized management of pain ................................................................................... 235
Pharmacogenetics/pharmacogenomics of pain ................................................................... 236
Mechanism-specific management of pain .......................................................................... 237
Preoperative testing to tailor postoperative analgesic requirements ...................................... 237
Personalized analgesics................................................................................................... 238
Management of genetic disorders .................................................................................... 238
Personalized treatment of cystic fibrosis............................................................................ 238
Personalized management of gastrointestinal disorders.................................................. 239
Personalized therapy of inflammatory bowel disease .......................................................... 239
Personalized management of lactose intolerance ................................................................ 239
Personalized approaches to improve organ transplantation ............................................ 240
Personalization of kidney transplantation .......................................................................... 240
Personalization of cardiac transplantation .......................................................................... 240
Prediction of rejection to tailor anti-rejection medications ................................................... 241
Personalized immunosuppressant therapy in organ transplants ............................................ 241
Role of immunological biomarkers in monitoring grafted patients ......................................... 242
Improved matching of blood transfusion ........................................................................... 243
Personalized approach to addiction ................................................................................. 243
Pharmacogenetics of drug addiction ................................................................................. 243
Genetic polymorphism and management of alcoholism ....................................................... 243
Personalized therapy for smoking cessation ....................................................................... 244
Antidepressant therapy for smoking cessation .............................................................. 244
Effectiveness of nicotine patches in relation to genotype ................................................ 245
Personalized approaches to miscellaneous problems ....................................................... 245
Hormone replacement therapy in women .......................................................................... 245
Personalized treatment of malaria .................................................................................... 245
Personalized management of osteoporosis ........................................................................ 246
Personalized management of renal disease........................................................................ 246
Gene associated with end-stage renal disease .............................................................. 247
Personalized care of trauma patients ................................................................................ 247
Personalized anticoagulation............................................................................................ 248
Personalized hyperbaric oxygen therapy ......................................................................... 248
Personalized preventive medicine.................................................................................... 249
Personalized nutrition ...................................................................................................... 249
Nutrigenomics ............................................................................................................... 250
Genomics of vitamin D and calcium supplementation ..................................................... 250
Nutrigenomics and functional foods ............................................................................. 251
Nutrigenetics and personalized medicine ...................................................................... 251
Nutrigenomics and personalized medicine .................................................................... 252
Nutrition and proteomics ................................................................................................. 252
Personalized diet prescription .......................................................................................... 252

9. Personalized Therapy of Cancer .......................................................... 255
Introduction..................................................................................................................... 255
Challenges of cancer classification .................................................................................... 255

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Relationships of technologies for personalized management of cancer .................................. 255
Impact of molecular diagnostics on the management of cancer ...................................... 256
Analysis of RNA splicing events in cancer .......................................................................... 257
Analysis of chromosomal alterations in cancer cells ............................................................ 257
Cancer classification using microarrays ............................................................................. 258
Detection of loss of heterozygosity ................................................................................... 258
Diagnosis of cancer of an unknown primary ....................................................................... 259
Diagnostics for detection of minimal residual disease .......................................................... 259
DNA repair biomarkers ................................................................................................... 260
Fluorescent in situ hybridization ....................................................................................... 260
Gene expression profiling ................................................................................................ 260
Gene expression profiles predict chromosomal instability in tumors ...................................... 261
Isolation and characterization of circulating tumor cells ...................................................... 262
Modulation of CYP450 activity for cancer therapy ............................................................... 262
Personalized therapies based on oncogenic pathways signatures .......................................... 263
Quantum dot-based test for DNA methylation .................................................................... 263
Role of molecular imaging in personalized therapy of cancer ............................................... 264
Functional diffusion MRI ............................................................................................. 264
FDG-PET/CT for personalizing cancer treatment ............................................................ 264
Image-guided personalized drug delivery in cancer ....................................................... 265
Tumor imaging and elimination by targeted gallium corrole ............................................ 265
Future prospects of molecular imaging in management of cancer .................................... 266
Unraveling the genetic code of cancer............................................................................... 266
Cancer prognosis ............................................................................................................. 266
Detection of mutations for risk assessment and prevention ............................................ 267
Impact of biomarkers on management of cancer ............................................................. 267
HER-2/neu oncogene as a biomarker for cancer ................................................................. 268
L-asparaginase treatment of cancer guided by a biomarker ................................................. 268
Oncogene GOLPH3 as a cancer biomarker ......................................................................... 268
Predictive biomarkers for cancer ...................................................................................... 269
Sequencing to discover biomarkers to personalize cancer treatment ..................................... 269
Systems biology approach to discovery of radiation sensitivity biomarkers ............................ 270
VeraTag™ assay system for cancer biomarkers .................................................................. 270
Determination of response to therapy ............................................................................. 270
Biomarker-based assays for predicting response to anticancer therapeutics........................... 271
ChemoFx cell culture assay for predicting anticancer drug response ..................................... 271
Ex vivo testing of tumor biopsy for chemotherapy sensitivity ............................................... 271
Genomic approaches to predict response to anticancer agents ............................................. 272
Gene expression patterns to predict response of cancer to therapy ................................. 272
Genomic analysis of tumor biopsies ............................................................................. 272
Genotype-dependent efficacy of pathway inhibition in cancer.......................................... 273
Mutation detection at molecular level........................................................................... 273
RNA Disruption Assay™ ............................................................................................. 273
Role of genetic variations in susceptibility to anticancer drugs ........................................ 273
Non-genetic factors for variations in response of cancer cells to drugs .................................. 274
Proteomic analysis of tumor biopsies to predict response to treatment ................................. 274
Real-time apoptosis monitoring ....................................................................................... 274
Serum nucleosomes as indicators of sensitivity to chemotherapy ......................................... 275
Targeted microbubbles to tumors for monitoring anticancer therapy ..................................... 275
PET imaging for determining response to chemotherapy ..................................................... 276
Tissue systems biology approach to personalized management of cancer .............................. 276
Molecular diagnostics combined with cancer therapeutics ............................................... 276
AmpliChip P53 as companion diagnostic for cancer ............................................................. 277
Aptamers for combined diagnosis and therapeutics of cancer............................................... 277
Monoclonal antibodies for combining diagnosis with therapy of cancer .................................. 278
Targeted cancer therapies ............................................................................................... 278
Targeting glycoproteins on cell surface ............................................................................. 278
Targeting pathways in cancer .......................................................................................... 278
Targeted personalized anticancer medicines in clinical use .................................................. 279
Functional antibody-based therapies ............................................................................... 279
Personalized cancer vaccines ........................................................................................... 281
Antigen-specific vaccines ................................................................................................ 281
Active immunotherapy based on antigen specific to the tumor ........................................ 281
Tumor-derived vaccines .................................................................................................. 282
MyVax ..................................................................................................................... 282
OncoVAX .................................................................................................................. 282
Tumor cells treated with dinitrophenyl ......................................................................... 283
Prophage ................................................................................................................. 283
Melacine .................................................................................................................. 283
Patient-specific cell-based vaccines .................................................................................. 284
Dendritic cell-based vaccines ...................................................................................... 284

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Adoptive cell therapy ...................................................................................................... 285
Combination of antiangiogenic agents with ACT ............................................................ 287
Genetically targeted T cells for treating B cell malignancies ............................................ 287
Genetic engineering of tumor cells .............................................................................. 287
Hybrid cell vaccination ............................................................................................... 288
Personalized peptide cancer vaccines................................................................................ 288
Current status and future prospects of personalized cancer vaccines .................................... 288
Personalized radiation therapy ........................................................................................ 290
Role of nanobiotechnology in personalized management of cancer ................................. 291
Design of future cancer therapies .................................................................................... 292
Screening for personalized anticancer drugs ...................................................................... 292
Role of epigenetics in development of personalized cancer therapies .................................... 292
Personalized therapy of cancer based on cancer stem cells .................................................. 293
Role of oncoproteomics in personalized therapy of cancer .............................................. 293
Cancer tissue proteomics ................................................................................................ 294
Role of sequencing in personalized therapy of cancer...................................................... 294
Pharmacogenomic-based chemotherapy.......................................................................... 295
Whole genome technology to predict drug resistance.......................................................... 295
Anticancer drug selection based on molecular characteristics of tumor .................................. 295
Testing microsatellite-instability for response to chemotherapy ............................................ 295
Pharmacogenetics of cancer chemotherapy ..................................................................... 296
CYP 1A2........................................................................................................................ 296
Thiopurine methyltransferase .......................................................................................... 297
Dihydropyrimidine dehydrogenase ................................................................................... 297
UGT1A1 test as guide to irinotecan therapy ....................................................................... 298
Role of computational models in personalized anticancer therapy ................................... 298
A computational model of kinetically tailored treatment ...................................................... 298
Mathematical modeling of tumor mivroenvironments .......................................................... 299
Molecular profiling of cancer ............................................................................................ 299
Drug resistance in cancer ................................................................................................ 300
Detection of drug resistance in cancer by metabolic profiling ............................................... 300
Determination of chemotherapy response by topoisomerase levels ....................................... 301
Anaplastic lymphoma kinase ....................................................................................... 301
Management of drug resistance in leukemia ...................................................................... 301
Overexpression of multidrug resistance gene ..................................................................... 302
P53 mutations ............................................................................................................... 302
A chemogenomic approach to drug resistance ................................................................... 302
Systems biology approach to personalizing therapy for drug-resistant cancer ........................ 303
Personalized therapy of cancer metastases ..................................................................... 303
Personalized management of cancers of various organs .................................................. 303
Personalized management of brain cancer ......................................................................... 303
Biosimulation approach to personalizing treatment of brain cancer .................................. 304
Companion diagnostic for viral gene therapy of brain cancer .......................................... 304
Genetics and genomics of brain cancer ........................................................................ 304
Prognosis of glioblastoma multiforme based on its genetic landscape ............................... 306
Molecular diagnostics for personalized management of brain cancer ................................ 306
Personalized chemotherapy of brain tumors ................................................................. 308
Personalized therapy of oligodendroglial tumors (OTs) ................................................... 309
Personalized therapy of neuroblastomas ...................................................................... 310
Personalized therapy of medulloblastomas ................................................................... 310
Personalized management of germ cell brain tumors ..................................................... 311
Personalized management of breast cancer ....................................................................... 311
Developing personalized drugs for breast cancer ........................................................... 311
Gene expression plus conventional predictors of breast cancer ....................................... 312
Her2 testing in breast cancer as a guide to treatment .................................................... 313
HER2/neu-derived peptide vaccine for breast cancer ..................................................... 315
Molecular diagnostics in breast cancer ......................................................................... 315
Pharmacogenetics of breast cancer.............................................................................. 316
Proteomics-based personalized management of breast cancer ........................................ 316
Predicting response to chemotherapy in breast cancer ................................................... 317
Prediction of resistance to chemotherapy in breast cancer .............................................. 320
Prediction of adverse reaction to radiotherapy in breast cancer ....................................... 321
Prediction of recurrence in breast cancer for personalizing therapy .................................. 321
Prognosistic tests for breast cancer ............................................................................. 322
Racial factors in the management of breast cancer ........................................................ 325
RATHER consortium to study personalized approach to breast cancer .............................. 325
TAILORx (Trial Assigning Individualized Options for Treatment) ...................................... 325
Trends and future prospects of breast cancer research .................................................. 326
Understanding tumor diversity in mouse mammary cancer model ................................... 326
Personalized management of ovarian cancer ..................................................................... 327
Early diagnosis of ovarian cancer ................................................................................ 327

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Determining response to chemotherapy in ovarian cancer .............................................. 327
Recurrent and drug-resistant ovarian cancer ................................................................ 328
Pathway targeted therapies for ovarian cancer.............................................................. 328
Personalized management of hematological malignancies ................................................... 329
Personalized management of acute lymphoblastic leukemia ............................................ 330
Personalized management of acute myeloid leukemia .................................................... 331
Personalized management of chronic lymphocytic leukemia ............................................ 331
Personalized management of multiple myeloma ............................................................ 332
Personalized management of myelodysplastic syndrome ................................................ 333
Personalized management of lymphomas .......................................................................... 334
Personalized management B cell lymphomas ................................................................ 334
Personalized vaccine for follicular lymphoma ................................................................ 334
Companion diagnostic for treatment of lymphoma with Adcentris™ ................................. 335
Personalized management of hepatocellular carcinoma ....................................................... 335
Personalized management of gastrointestinal cancer .......................................................... 335
Personalized management of esophageal cancer ........................................................... 335
Personalized management of gastric cancer ................................................................. 336
Personalized management of colorectal cancer ............................................................. 336
A systems biology approach to drug resistance in colorectal cancer ................................. 339
Personalized management of liver cancer .......................................................................... 340
Personalized management of lung cancer .......................................................................... 340
Determination of outcome of EGFR tyrosine kinase inhibitor treatment ............................ 340
Crizotinib for personalized management of NSCLC......................................................... 342
Testing for response to chemotherapy in lung cancer..................................................... 342
Testing for prognosis of lung cancer ............................................................................ 343
Testing for recurrence of lung cancer ........................................................................... 343
Role of a new classification system in the management of lung cancer ............................. 344
Personalized therapy of NSCLC based on KIF5B/RET fusion oncogene .............................. 344
Personalized management of malignant melanoma ............................................................ 344
Therapy for inhibiting BRAF mutation in melanoma ....................................................... 345
Vaccine for malignant melanoma based on heat shock protein ........................................ 345
Personalized management of pancreatic cancer ................................................................. 345
Biomarkers of pancreatic cancer ................................................................................. 346
Histone modifications predict treatment response in pancreatic cancer ............................ 346
Personlized management of prostate cancer ...................................................................... 347
Diagnostics for guiding therapy of prostate cancer ........................................................ 347
Prolaris assay for determining prognosis in prostate cancer ............................................ 347
Detection of prostate cancer metastases ...................................................................... 348
Early detection of cancer recurrence and guiding treatment ............................................ 348
Effects of of lifestyle changes shown by gene expression studies ..................................... 348
Personalized peptide vaccine for prostate cancer ........................................................... 349
Future of cancer therapy .................................................................................................. 349
Challenges for developing personalized cancer therapies ..................................................... 349
Cancer Genome Atlas ..................................................................................................... 350
COLTHERES consortium .................................................................................................. 350
Computer and imaging technologies for personalizing cancer treatment ................................ 350
Genomic Cancer Care Alliance ......................................................................................... 351
Integrated genome-wide analysis of cancer for personalized therapy .................................... 351
International Cancer Genome Consortium ......................................................................... 351
PREDICT Consortium ...................................................................................................... 352
Companies involved in developing personalized cancer therapy ...................................... 353

10.

Development of Personalized Medicine ....................................... 357

Introduction..................................................................................................................... 357
Non-genomic factors in the development of personalized medicine ................................. 357
Personalized medicine based on circadian rhythms ............................................................. 357
Cytomics as a basis for personalized medicine ................................................................... 358
Intestinal microflora ....................................................................................................... 358
Gut microbiome compared to human genome ............................................................... 358
Metabolic interactions of the host and the intestinal microflora ....................................... 359
Role of drug delivery in personalized medicine ................................................................... 359
Personalized approach to clinical trials .............................................................................. 360
Use of Bayesian approach in clinical trials..................................................................... 360
Individualzing risks and benefits in clinical trials............................................................ 360
Clinical trials of therapeutics and companion diagnostics ................................................ 361
Players in the development of personalized medicine ...................................................... 361
Personalized Medicine Coalition ........................................................................................ 362
European Personalized Medicine Diagnostics Association ................................................ 363
Role of pharmaceutical industry ....................................................................................... 363
Production and distribution of personalized medicines .................................................... 363
Role of biotechnology companies ..................................................................................... 364

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Role of life sciences industries ......................................................................................... 364
Role of molecular imaging in personalized medicine............................................................ 365
Molecular imaging for personalized drug development in oncology .................................. 365
Molecular imaging and CNS drug development .............................................................. 367
Companies involved in molecular imaging .................................................................... 368
Role of the clinical laboratories ........................................................................................ 368
Role of the US government in personalized medicine .......................................................... 369
Department of Health and Human Services and personalized medicine ............................ 370
Agency for Healthcare Research and Quality ................................................................. 371
Comparative effectiveness research............................................................................. 371
Role of the US Government agencies in personalized medicine ............................................ 373
NIH's Roadmap Initiative for Medical Research.............................................................. 373
NIH and personalized medicine ................................................................................... 373
NIH collaboration with the FDA ................................................................................... 374
NIH and Genetic Testing Registry ................................................................................ 374
National Institute of General Medical Sciences .............................................................. 374
National Institute of Standards and Technology ............................................................ 376
Role of the Centers for Disease Control ........................................................................ 377
Role of academic institutions in the US and Canada ............................................................ 377
Clinical Proteomics Program of NCI & FDA .................................................................... 377
Coriell Personalized Medicine Collaborative™ ................................................................ 377
Delaware Valley Personalized Medicine Project .............................................................. 378
Duke University Medical Center and genomic medicine .................................................. 378
Evaluation of genetic tests and genomic applications ..................................................... 379
Ignite Institute ......................................................................................................... 380
Indiana University Institute for Personalized Medicine .................................................... 380
Institute of Medicine’s role in personalized medicine ...................................................... 381
Jackson Laboratory for Genomic Medicine .................................................................... 381
Johns Hopkins Center for Personalized Cancer Medicine Research ................................... 381
Mayo Clinic’s Center for Individualized Medicine ............................................................ 382
Mt. Sinai Medical Center’s Personalized Medicine Research Program ................................ 382
P4 Medicine Institute ................................................................................................. 382
Personalized Medicine Partnership of Florida ................................................................. 383
Personalized medicine at Ontario Institute for Cancer Research ...................................... 383
Personalized oncology at Massachusetts General Hospital............................................... 385
Personalized oncology at Oregon Health & Science University ......................................... 385
Pharmacogenetics Research Network and Knowledge Base ............................................. 385
Quebec Center of Excellence in Personalized Medicine.................................................... 386
Southeast Nebraska Cancer Center's Personalized Medicine Network ............................... 386
Stanford Center for Genomics and Personalized Medicine ............................................... 386
UNC Institute for Pharmacogenomics and Individualized Therapy .................................... 387
Wisconsin Genomics Initiative ..................................................................................... 387
Role of academic collaborations with companies................................................................. 387
New York Genome Center .......................................................................................... 387
Role of healthcare organizations and hospitals ................................................................... 388
Signature Genetics .................................................................................................... 388
Role of the medical profession ......................................................................................... 388
The American Medical Association and personalized medicine ......................................... 389
Education of the physicians ........................................................................................ 389
Off-label prescribing and personalized medicine ............................................................ 389
Medical education ..................................................................................................... 390
Role of patients ............................................................................................................. 390
Public attitude towards personalized medicine .............................................................. 390
Role of genetic banking systems and databases .............................................................. 391
Role of biobanks in development of personalized medicine .................................................. 391
UK Biobank ................................................................................................................... 391
Biobanking and development of personalized medicine in EU ............................................... 392
CARTaGENE for biobanks in Canada ................................................................................. 392
Personalized medicine based on PhysioGenomics™ technology ............................................ 393
Role of bioinformatics in development of personalized medicine ..................................... 393
Exploration of disease-gene relationship ........................................................................... 395
Biosimulation techniques for developing personalized medicine ............................................ 395
Health information management ...................................................................................... 395
Electronic health records ............................................................................................ 395
Linking patient medical records and genetic information ................................................ 396
Management of personal genomic data ........................................................................ 397
Use of EMRs for genetic research ................................................................................ 397
Personalized prognosis of disease .................................................................................... 398
Integration of technologies for development of personalized medicine .................................. 399
Global scope of personalized medicine............................................................................. 399
Personalized medicine in the developed countries .............................................................. 399

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Personalized medicine in the US .................................................................................. 399
Personalized medicine in the EU .................................................................................. 400
UK National Health Service and medical genetics .......................................................... 400
Personalized medicine in Germany .............................................................................. 401
Personalized medicine in the developing countries.............................................................. 401
Advantages and limitations of personalized medicine ...................................................... 402
Limitations of personalized medicine ............................................................................... 403
Future of personalized medicine ...................................................................................... 404
Ongoing genomic projects ............................................................................................... 404
Understanding the genetic basis of diseases ................................................................. 404
Personal Genome Project ........................................................................................... 405
Genome-wide association studies ................................................................................ 405
The 1000 Genomes Project......................................................................................... 406
Genomics of aging in a genetically homogeneous population .......................................... 406
Translational science and personalized medicine ................................................................ 407
Translation of genomic research into genetic testing for healthcare ................................. 407
Long-term behavioral effects of personal genetic testing ................................................ 408
Personalized predictive medicine ...................................................................................... 408
Opportunities and challenges ........................................................................................... 409
Prospects and limitations of genetic testing .................................................................. 409
Genetic testing and concerns about equality of healthcare .............................................. 410
Pharmacotyping ........................................................................................................ 410
Comparative-effectiveness research and personalized medicine ...................................... 411
Medicine in the year 2015 .......................................................................................... 411
Concluding remarks about the future of personalized medicine ............................................ 412

11.

Ethical and Regulatory Aspects of Personalized Medicine ........... 415

12.

Commercial Aspects of Personalized Medicine ............................ 433

Introduction to ethical issues .......................................................................................... 415
Ethical issues of pharmacogenetics................................................................................... 415
Ethical aspects of genetic information ............................................................................... 415
Ethical issues of whole genome analysis ....................................................................... 415
Ethical aspects of direct-to-consumer genetic services ................................................... 416
Privacy issues in personalized medicine ....................................................................... 417
Genetic Information Nondiscrimination Act in the US ..................................................... 418
Genotype-specific clinical trials ........................................................................................ 418
Social issues in personalized medicine .............................................................................. 418
Race and personalized medicine .................................................................................. 419
Regulatory aspects .......................................................................................................... 420
CLSI guideline for the use of RNA controls in gene expression assays ................................... 421
MicroArray Quality Control Project .................................................................................... 421
Regulatory aspects of pharmacogenetics ........................................................................... 422
Regulation of direct-to-consumer genetic testing ............................................................... 423
Need for regulatory oversight of DTC ........................................................................... 423
FDA and pharmacogenomics............................................................................................ 426
FDA guidance for pharmacogenomic data submissions ................................................... 426
Joint guidelines of the FDA and EU regulators for pharmacogenomics .............................. 427
Pharmacogenomic/pharmacogenetic information in drug labels ....................................... 427
FDA guidelines for pharmacogenomics-based dosing ..................................................... 428
FDA and validation of biomarkers ................................................................................ 428
FDA and predictive medicine....................................................................................... 429
FDA regulation of multivariate index assays.................................................................. 429
Evaluation of companion diagnostics/therapeutic .......................................................... 431

Introduction..................................................................................................................... 433
Perceived financial concerns ............................................................................................ 433
Personalized medicine and orphan drug syndrome ............................................................. 433
Commercial aspects of pharmacogenomics ...................................................................... 433
Cost of DNA testing ........................................................................................................ 433
Cost of sequencing the human genome............................................................................. 434
Cost of genotyping ......................................................................................................... 436
Cost of pharmacogenomics-based clinical trials .................................................................. 436
Business development of pharmacogenomic companies ...................................................... 437
Cost of personalized healthcare ....................................................................................... 437
The rising healthcare costs in the US ................................................................................ 437
Reducing healthcare costs by combining diagnostics with therapeutics.................................. 438
Cost-effectiveness of pharmacogenetic testing .............................................................. 438
Cost-effectiveness of CYP genotyping-based pharmacotherapy ....................................... 439
Cost effectiveness of HIV genotyping in treatment of AIDS ............................................. 439
Cost-effectiveness of warfarin pharmacogenomics ......................................................... 440
Lowering the high costs of cancer chemotherapy .......................................................... 440

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Overall impact of personalized medicine on healthcare ....................................................... 441
Drivers for the development of personalized medicine .................................................... 441
Evolution of medicine as a driver for personalized therapy markets ...................................... 441
Collaboration between the industry and the academia .................................................... 442
Personalized medicine and drug markets......................................................................... 443
Segmentation of therapeutic drug markets ........................................................................ 443
Reasons for increase of market values of personalized medicines ......................................... 443
Growth of markets relevant to personalized medicine ......................................................... 444
SNP market .............................................................................................................. 444
Pharmacogenomics ................................................................................................... 444
Pharmacogenetics ..................................................................................................... 445
Pharmacoproteomics ................................................................................................. 445
Biochips ................................................................................................................... 445
Point-of-Care ............................................................................................................ 445
Markets for personalized medicines according to therapeutic areas....................................... 445
Market for personalized cancer therapy ........................................................................ 446
Markets for personalized medicines according to geographical regions .................................. 446
Market opportunities for personalization of medicine .......................................................... 446
Impact of personalized medicine on other industries........................................................... 447
Strategies for developing and marketing personalized medicine ........................................... 448
Education of the public .............................................................................................. 448
Role of the Internet in development of personalized medicine ......................................... 449
Marketing companion diagnostics for personalized medicine ........................................... 449

13.

References .................................................................................. 451
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1-1: Selected terms relevant to the concept of personalized medicine ...................................... 21
1-2: Landmarks in the historical development of personalized medicine ................................... 22
1-3: Genetic variations in the human genome ....................................................................... 27
2-1: Molecular diagnostic technologies used for personalized medicine..................................... 45
2-2: Applications of biochip technology relevant to personalized medicine ................................ 64
2-3: Companies developing haplotying technology ................................................................ 79
2-4: Technologies for SNP analysis ...................................................................................... 79
2-5: A sampling of companies involved in technologies for SNP genotyping .............................. 88
2-6: Comparison of proteomic and genomic approaches in personalized medicine ..................... 96
2-7: Selected methods for gene expression profiling .............................................................. 97
2-8: A selection of companies with gene expression technologies .......................................... 102
2-9: Drugs requiring biomarker/companion diagnostic information in the label........................ 105
2-10: Companies involved in companion diagnostics ............................................................ 106
2-11: Applications of point-of-care diagnosis ...................................................................... 108
2-12: Companies developing point-of-care diagnostic tests .................................................. 109
2-13: Companies offering genetic screening tests directly to consumers................................. 113
3-1: Pharmacogenetic vs. pharmacogenomic studies ........................................................... 120
3-2: Enzymes relevant to drug metabolism ........................................................................ 122
3-3: Examples of mutation of the enzyme CYP450............................................................... 123
3-4: Frequency distribution of drugs metabolized by major isoforms of CYP450. ..................... 123
3-5: Commonly prescribed medications, which are metabolized by CYP2D6 ............................ 123
3-6: Polymorphisms in drug target genes that can influence drug response ............................ 129
3-7: Effect of genetic polymorphisms on disease response to drugs ....................................... 130
3-8: Examples of genetically determined adverse reactions to drugs...................................... 133
3-9: Examples of genotyping and phenotyping in some diseases ........................................... 141
3-10: Companies with novel molecular toxicology technology .................................................. 143
4-1: Role of pharmacogenomics in variable therapy targets .................................................. 151
4-2: Role of pharmacogenomics in clinical trials .................................................................. 154
4-3: Examples of pharmacogenomics-based clinical studies .................................................. 155
4-4: Tumor suppressor genes, their chromosomal location, function and associated tumors. .... 158
4-5: Gene polymorphisms relevant to cardiovascular disease management ............................ 159
4-6: Companies involved in cardiovascular genomics ........................................................... 161
4-7: A sampling of companies involved in neuropharmacogenomics....................................... 163
8-1: Important therapeutic areas for personalized medicine ................................................. 183
8-2: Enzymes that metabolize antipsychotics ...................................................................... 195
8-3: Enzymes that metabolize antidepressants ................................................................... 196
8-4: Biomarkers of response to interferon- in multiple sclerosis ........................................... 211
8-5: Genes that cause cardiovascular diseases.................................................................... 213
9-1: Factors that drive the development of personalized therapy in cancer ............................. 255
9-2: Impact of molecular diagnostics on the management of cancer ...................................... 256
9-3: Marketed anticancer personalized medicines ................................................................ 279
9-4: Clinical trials of personalized cancer vaccines ............................................................... 289

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9-5: Selected companies involved in developing personalized cancer therapies ....................... 353
10-1: Players in the development of personalized medicine .................................................. 361
10-2: Members of the Personalized Medicine Coalition ......................................................... 362
10-3: Biobanks relevant to personalized medicine ............................................................... 391
10-4: Role of bioinformatics in the development of personalized medicine .............................. 393
10-5: Advantages of personalized medicine for the biopharmaceutical industry ....................... 402
10-6: Advantages of personalized medicine for the patients ................................................. 402
10-7: Advantage of personalized medicine for the physicians ................................................ 403
10-8: Advantage of personalized medicine for the healthcare providers ................................. 403
10-9: Limitations of personalized medicine ......................................................................... 403
10-10: Methods of translational science that are relvant to personalized medicine ................... 407
10-11: Companies involved in predictive healthcare ............................................................ 409
11-1: Drugs with genetic information in their labels ............................................................. 427
12-1: Drivers for the development of personalized medicine ................................................. 441
12-2: Growth of markets relevant to personalized medicine 2011-2021 ................................. 444
12-3: Markets for personalized medicine according to therapeutic area 2011-2021 .................. 446
12-4: Markets for personalized medicine in major regions 2011-2021 .................................... 446
12-5: Lack of efficacy in current therapy ............................................................................ 447
12-6: Impact of personalized medicine on other industries ................................................... 447
12-7: Strategies to develop personalized medicine .............................................................. 448
12-8: Role of the Internet in development of personalized medicine ...................................... 449

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1-1: Relation of personalized medicine to other technologies ................................................. 35
1-2: Relation of systems pharmacology to personalized medicine ........................................... 41
2-1:Role of sequencing in personalized medicine .................................................................. 63
2-2: Role of biochips/microarrays in personalized medicine ................................................... 65
2-3: Affymetrix GeneChip technology ................................................................................. 66
2-4: Role of CYP450 genotyping in development of personalized medicine............................... 67
2-5: Role of SNPs in personalized medicine ......................................................................... 75
2-6: A scheme of integrated healthcare and personalized medicine ...................................... 115
3-1: Pharmacogenetics as a link between genotype and phenotype ...................................... 119
3-2: Role of pharmacogenetic technologies in personalized medicine .................................... 120
4-1: Impact of new technologies at various stages of the drug discovery process ................... 153
4-2: Steps in the application of pharmacogenomics in clinical trials ...................................... 155
7-1: Role RNAi in development of personalized medicine ..................................................... 181
8-1: A scheme of personalized approach to management of hypertension ............................. 219
8-2: A scheme of personalized management of pain ........................................................... 236
9-1: Relationships of technologies for personalized management of cancer ........................... 256
10-1: Integration of technologies for the development of personalized medicine .................... 399
12-1: Evolution of personalized medicine as a market driver ............................................... 442

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