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 Dr. Lam dedicates this book to Jennifer, Jessica, and Derek;
Aunt Chee-Ming and Uncle Po-Hon; Mom and Dad.

Dr. Scott dedicates this book to Gillian, Camille, and Harvey.

This page intentionally left blank

     
 Contents

List of Contributors xiii Enzyme Genes 34

Preface xv Ion Channel Genotype 36
Conclusion 37
Questions for Discussion 37
References 37
1. Principles of Pharmacogenomics:
Pharmacokinetic, Pharmacodynamic, 2. Governmental and Academic
and Clinical Implications Efforts to Advance the Field of
Y. W. FRANCIS LAM Pharmacogenomics
KATHRYN M. MOMARY AND KATARZYNA DROZDA
Objectives 2
Introduction 2
Objectives 56
Polymorphisms in Cytochrome P450 Enzymes 3
Introduction 56
CYP2D6 4
The Role of Academic Institutions, the
CYP2C19 9
National Institutes of Health (NIH), and
CYP2C9 11
Other Government Agencies 57
CYP2C8 13
Historical Efforts 57
CYP3A4/5/7 13
International HapMap Project 58
CYP4F2 15
1000 Genomes Project 59
CYP2B6 15
The ENCyclopedia of DNA Elements (ENCODE)
CYP2A6 17
Project 60
CYP1A2 17
Genotype-Tissue Expression (GTEx) Project 61
Polymorphisms in Non-CYP450 Drug-Metabolizing
Therapeutics for Rare and Neglected Diseases
Enzymes 18
(TRND) Program 61
UDP-Glucuronosyl Transferase 18
Million Veterans Program (MVP) 62
Thiopurine-S-methyltransferase 19
Pharmacogenomics Research Network (PGRN) 62
Dihydropyrimidine Dehydrogenase (DYPD) 19
Pharmacogenomics Knowledge Base (PharmGKB) 63
N-acetyltransferase 20
Clinical Pharmacogenetics Implementation
Glutathione-S-transferase 20
Consortium (CPIC) 64
Polymorphisms in Drug-Transporter Genes 21
Pharmacogene Variation (PharmVar) Consortium 66
The ABC-Efflux Transporters 21
ClinGen 67
The SLC-Uptake Transporters 24
Electronic Medical Records and Genomics
OAT1B1 24
(eMERGE) Network 68
OATP2B1 26
Implementing Genomics in Practice (IGNITE) 69
OATP1B3 26
The 21st Century Cures Act 70
Polymorphisms in Drug-Target Genes 27
All of Us Research Program 70
Drug Target Receptor Genes in Oncology 28
The Role of the Food and Drug Administration
Drug Target Receptor Genes in Cardiology 30
and Other International Government Agencies 70
Drug Target Genes in Psychiatry 32
Critical Path Initiative (C-Path) 71
Drug Target Genes in Pain Management 32
Critical Path Innovation Meeting (CPIM) 71
Signal Transduction Proteins 33
Biomarker Qualification Program (BQP) 71

vii
viii Contents

Prescription Drug User Fee Act (PDUFA V) 72 Evaluation of Cost-Effectiveness 109

Guidance Development 72 Regulatory Approval of Pharmacogenomic
Pharmacogenomics Biomarkers in Drug Labeling 73 Diagnostic Tests 110
Diagnostic Approval/Clearance 74 Integration of Testing Within the Healthcare
Activities of Non-U.S. Agencies 76 Environment 111
European Medicines Agency (EMA), Reimbursement Issues 114
European Union 76 Ethical, Legal, and Social Issues 115
Pharmaceuticals and Medical Devices Incorporating Pharmacogenomics Into Drug
Agency (PMDA), Japan 77 Development 117
Conclusion 77 Conclusion 118
Questions for Discussion 77 Questions for Discussion 118
References 78 References 119

3. Incorporating Pharmacogenomics 5. Pharmacogenomics in

in Drug Development: A Perspective Cancer Therapeutics
From Industry Y. W. FRANCIS LAM AND STUART A. SCOTT
OPHELIA YIN AND ALEXANDER VANDELL
Introduction 123
Objectives 82 Therapy for Non-small-Cell Lung Cancer 124
Introduction 82 Therapy for Chronic Myeloid Leukemia 125
Genetic Research and New Drug Target Therapy for Breast Cancer 125
Identification 83 Therapy for Metastatic Colorectal Cancer 126
Genetics and Preclinical Animal Toxicology Studies 85 Additional Biomarkers for Drug Toxicity 127
Pharmacogenomic/Pharmacokinetic Research 86 The Path Forward for Implementation of
Atomoxetine 87 Precision Oncology 128
Pharmacogenomic/Pharmacodynamic Research 87 References 129
Gefitinib 88
Imatinib 89 6. Pharmacogenetics in
Pharmacogenomic/Safety Research 90 Cardiovascular Diseases
Irinotecan 90 LARISA H. CAVALLARI AND KATHRYN M. MOMARY
Abacavir 92
Challenges in Applying Pharmacogenomics Objectives 134
to Drug Development 92 Introduction 134
Future Perspectives 95 Pharmacogenetics of Antiplatelet Agents 137
Discussion Questions 96 Background on Antiplatelet Agents 137
References 96 Overview of Clopidogrel Metabolism and
Pharmacodynamics 137
4. Translating Pharmacogenomic CYP2C19 Genotype and Clopidogrel
Research to Therapeutic Potentials Responsiveness 137
Y. W. FRANCIS LAM
ABCB1 Genotype and Clopidogrel
Responsiveness 140
Objectives 103 Paraoxonase-1 (PON1) Genotype and
Introduction 104 Clopidogrel Responsiveness 140
Implementation of Biomarkers in Clinical Practice 104 Genome-Wide Association Study (GWAS)
Complexity of Genetic Variabilities and Nongenetic of Clopidogrel Responsiveness 141
Influences 104 Alternative Treatment Approaches in Patients
Analytical Validity, Clinical Validity, and With a CYP2C19 Nonfunctional Allele 141
Clinical Utility 106 Clopidogrel Labeling Revisions 142
 Contents ix
Guidelines for the Clinical Use of CYP2C19 ADRB1 Genotype: A Case for Targeted
Genotyping With Clopidogrel 142 β-Blocker Therapy? 165
Randomized Controlled Trials Examining Pharmacogenetics of Nitrates/Hydralazine 166
Outcomes With CYP2C19-Guided Opportunity in Pharmacogenetics: Potential to
Antiplatelet Therapy 143 Streamline Heart-Failure Therapy 166
Clinical Implementation of CYP2C19-Guided Genetic Influences of Drug-Induced
Antiplatelet Therapy 144 Arrhythmia 167
Opportunities and Challenges With Clopidogrel Antiarrhythmic Medications 167
Pharmacogenetics 145 Pharmacogenetics of Drug-Induced Long QT
Warfarin Pharmacogenetics 145 Syndrome 167
Challenges With Warfarin 145 Opportunities in Pharmacogenetics: Potential
Genes Affecting Warfarin Pharmacokinetics and to Resurrect Old Drugs 169
Pharmacodynamics 146 Conclusion 169
CYP2C9 147 Discussion Points 169
VKORC1 148 Questions for Discussion 169
CYP4F2 149 References 170
CALU 149
Genome-Wide Association Studies 150 7. Pharmacogenomics in
Warfarin Pharmacogenetics Dosing Algorithms 150 Psychiatric Disorders
Warfarin Labeling Revisions 151
Y. W. FRANCIS LAM AND TOSHIYUKI SOMEYA
Early Studies of Genotype-Guided Warfarin
Dosing 151 Objectives 182
Large Randomized Clinical Trials of Introduction 182
Genotype-Guided Warfarin Therapy 152 Polymorphisms in Proteins that Affect Drug
Pharmacogenetic Guidelines 154 Concentrations 182
Opportunities and Challenges for Warfarin Genes Encoding Drug-Metabolizing Enzymes 182
Pharmacogenetics 155 Genes Encoding Drug Transporters 186
Trials and Tribulations of Pharmacogenetics Polymorphisms in Proteins that Mediate
of Agents Used to Treat Dyslipidemia 156 Drug Response 187
Overview of Statin Pharmacokinetics and Antidepressants 187
Pharmacodynamics 156 Antipsychotics 196
Pharmacogenetics of Statin Safety 156 Mood Stabilizer 202
Genetic Contributors to Plasma Lipid Levels 158 Application of Pharmacogenomics in Psychiatry 204
Pharmacogenetics of Statin Efficacy 158 Conclusions 211
Ezetimibe Pharmacogenetics and NPC1L1 Questions for Discussion 212
Genotype 159 References 212
Opportunity in Pharmacogenetics: Potential
to Improve Management of Dyslipidemia 160 8. Pharmacogenomic Considerations in
Tacrolimus Pharmacogenetics 160
Pharmacogenetics of Antihypertensives 161
the Treatment of HIV Infection
Genetic Determinants of β-Blocker Response 161 SURULIVELRAJAN MALLAYASAMY AND
SCOTT R. PENZAK
Genetic Determinants of Response to Thiazide
Diuretics 162 Introduction 227
Opportunity in Pharmacogenetics: A Look to Nucleoside and Nucleotide Reverse
the Future of Hypertension Management 163 Transcriptase Inhibitors 228
Pharmacogenetic Potential in Heart Failure 163 Abacavir 228
Current Approach to Heart-Failure Management 163 Tenofovir 231
Pharmacogenetics of ACE Inhibitors in Heart Zidovudine 232
Failure 164 Lamivudine 233
x Contents

NonNucleoside Reverse Transcriptase Inhibitors 233 Measuring Phenotypes 275

Efavirenz 233 Structuring Data for Sharing 275
Nevirapine 235 Genomic Data Standards 276
Etravirine 236 Drug Data Standards 276
Protease Inhibitors 236 Phenotype Data Standards 278
Atazanavir 236 Data Exchange Standards 279
Lopinavir 238 Discovering and Quantifying Pharmacogenomic
Integrase Strand Transfer Inhibitors 238 Interactions 280
Raltegravir 238 Federated Data Models 280
Dolutegravir 239 Primary Evidence 281
Conclusion 240 Secondary Evidence 282
References 241 Post Hoc Drug-Focused Randomized Clinical Trial 282
Tertiary Analysis 282
9. The Role of Pharmacogenomics Qualitative Summary Methods 283
in Diabetes Quantitative Summary Methods 283
Pharmacogenomics Forecasting 284
Y. W. FRANCIS LAM, RAVINDRANATH DUGGIRALA,
CHRISTOPHER P. JENKINSON, AND RECTOR ARYA Conclusion 284
References 285
Objectives 247
Diabetes Overview 248 11. The Importance of Ethnicity
Lessons From Diabetes-Susceptibility Genes 248 Definitions and Pharmacogenomics in
Type 2 Diabetes Pharmacogenomics 250 Ethnobridging and Pharmacovigilance
Sulfonylureas 250
WEI CHUEN TAN-KOI, MICHAEL LIMENTA,
Drug Metabolism 252 ELSA HANIFFAH MEJIA MOHAMED, AND
Drug Targets 252 EDMUND JON DEOON LEE
Diabetes-Risk Alleles 254
Metformin 255 Objectives 290
Drug Transporters 255 Introduction 290
Drug Targets 256 Ethnicity 291
Diabetes-Risk Alleles 257 Ethnicities Are Rarely Homogeneous in
Thiazolidinediones 257 Any Nation 292
Drug Metabolism 258 Ethnic Factors Affecting Drug Response 297
Drug Targets 258 Intrinsic Factor: (Pharmaco)genetics 297
Other Antidiabetic Drugs 259 Extrinsic Factors 301
Challenges and Opportunities of Conclusion 305
Pharmacogenomics in Diabetes 260 Acceptability of Foreign Clinical Data 307
Questions for Discussion 261 Ethnically Sensitive or Insensitive? 309
References 262 Acceptability of Foreign Clinical Data and Drug
Regulatory Procedures in East and
10. A Look to the Future: Southeast Asia 309
Pharmacogenomics and Data Global Drug Development and Pharmacogenomics 314
Pharmacogenomics and Ethnicity in Global Drug
Technologies of Today and Tomorrow
Development 315
ERICK R. SCOTT AND RICHARD L. WALLSTEN
Pharmacogenomics in Pharmacovigilance 317
Conclusion 317
Introduction 272
Discussion Questions 318
Measuring Genes 272
References 318
Measuring Drugs 274
 Contents xi

12. Pharmacogenomics in Latin Direct-to-Consumer Pharmacogenomic Testing 376

American Populations History of Direct-To-Consumer Genetic Testing 378
Direct-To-Consumer Pharmacogenomics Testing
MARIANA R. BOTTON, KARLA CLAUDIO CAMPOS,
JORGE DUCONGE, AND STUART A. SCOTT
Regulatory Landscape 378
Advantages of Direct-To-Consumer
Introduction 330 Pharmacogenomics Testing 379
Latin Americas 330 Challenges of Direct-To-Consumer
Latin American Admixture and Population Pharmacogenomics Testing 380
Structure 330 Conclusion and Future Perspective 381
Latin America and Self-Reported Ethnicity 333 References 382
Latin American Pharmacogenomics 336
Pharmacogenomic Variants Among Latin 14. Economic Evaluation of
Americans 336 Pharmacogenomic Testing: Lessons
Pharmacogenomic Variants in the Brazilian From Psychiatric Pharmacogenomics
Population 344
Y. W. FRANCIS LAM
Pharmacogenomic Research in the Latin Americas 350
Pharmacogenomic Research Studies in Brazil 351 Introduction 385
Pharmacogenomic Implementation in the Latin Validity and Utility of Pharmacogenomic Testing 386
Americas 355 Combinatorial Pharmacogenomic Testing 386
Pharmacogenomic Implementation in Brazil 357 Cost-Effectiveness of Psychopharmacogenomic
Conclusion and Future Directions 357 Testing 389
References 358 Lessons Learned and Moving Forward 391
Further Reading 366 References 393

13. Reactive, Point-of-Care, Preemptive, 15. Pharmacogenomics Education

and Direct-to-Consumer and Clinical Practice Guidelines
Pharmacogenomics Testing ROSEANN S. GAMMAL, HENRY M. DUNNENBERGER,
ANIWAA OWUSU OBENG, MATTHIAS SAMWALD, KELLY E. CAUDLE, AND JESSE J. SWEN
AND STUART A. SCOTT
Clinical Practice Guidelines 396
Genetic Testing for Pharmacogenomics 370 Clinical Pharmacogenetics Implementation
Validity and Utility 370 Consortium (CPIC) Guidelines 396
Pharmacogenomic Testing Regulation 371 The Dutch Pharmacogenetics Working
Pharmacogenomic Testing Turnaround Time 371 Group (DPWG) Guidelines 401
Point-of–Care Pharmacogenomic Testing 371 Clinician Education 403
Preemptive Pharmacogenomic Testing 373 Clinician Education in the Healthcare Setting 403
Advantages of Preemptive Pharmacogenomics Clinician Education in Professional Schools 406
Testing 373 Patient Education 407
Challenges of Preemptive Pharmacogenomics Conclusion 411
Testing 373 References 411
Examples of Preemptive PGx Implementation 374
When and What to Test? 376 Index 415
     
 List of Contributors

Rector Arya South Texas Diabetes and Obesity Christopher P. Jenkinson South Texas Diabetes
Institute, University of Texas Rio Grande Valley and Obesity Institute, University of Texas Rio
School of Medicine, Edinburg, TX, United States Grande Valley School of Medicine, Edinburg, TX,
Mariana R. Botton Department of Genetics and United States
Genomic Sciences, Icahn School of Medicine at Y. W. Francis Lam Department of Pharmacology,
Mount Sinai, New York, NY, United States University of Texas Health Science Center at San
Karla Claudio Campos Department of Pharmaco­ Antonio, San Antonio, TX, United States; College
therapy and Translational Research, University of Pharmacy, University of Texas at Austin, Austin,
of Florida College of Pharmacy, Gainesville, FL, TX, United States
United States Edmund Jon Deoon Lee Pharmacogenetics
Kelly E. Caudle Pharmaceutical Sciences Department, Laboratory, Department of Pharmacology, Yong
St. Jude Children’s Research Hospital, Memphis, TN, Loo Lin School of Medicine, National University of
United States Singapore, Singapore
Larisa H. Cavallari Department of Pharmaco­ Michael Limenta Health Products Regulation
therapy and Translational Research and Center Group, Health Sciences Authority, Singapore
for Pharmacogenomics, University of Florida, Surulivelrajan Mallayasamy Post-Doctoral Research
Gainesville, FL, United States Associate, Department of Pharmaco­ therapy,
Katarzyna Drozda Office of Clinical Pharmacology, University of North Texas System College of
Food and Drug Administration, Silver Spring, MD, Pharmacy, Fort Worth, TX, United States; Department
United States of Pharmacy Practice, MCOPS, Manipal University,
Manipal, India
Jorge Duconge Department of Pharmaceutical
Sciences, School of Pharmacy, University of Puerto Elsa Haniffah Mejia Mohamed Pharmacogenomics
Rico Medical Sciences Campus, San Juan, PR, Laboratory, Department of Pharmacology,
United States University Malaya, Kuala Lumpur, Malaysia;
Pharmacogenetics Laboratory, Department of
Ravindranath Duggirala South Texas Diabetes
Pharmacology, National University of Singapore,
and Obesity Institute, University of Texas Rio
Singapore
Grande Valley School of Medicine, Edinburg, TX,
United States Kathryn M. Momary Department of Pharmacy
Practice, Mercer University, College of Pharmacy,
Henry M. Dunnenberger Pharmacogenomics, Center
Atlanta, GA, United States
for Molecular Medicine, NorthShore University
Health System, Evanston, IL, United States Aniwaa Owusu Obeng The Charles Bronfman
Institute for Personalized Medicine, Icahn School
Roseann S. Gammal Department of Pharmacy
of Medicine at Mount Sinai, Department of
Practice, MCPHS University, Boston, MA, United
Pharmacy, The Mount Sinai Hospital, New York,
States; Pharmaceutical Sciences Department, St.
NY, United States
Jude Children’s Research Hospital, Memphis, TN,
United States

xiii
xiv List of Contributors

Scott R. Penzak Department of Pharmacotherapy, Toshiyuki Someya Department of Psychiatry,

University of North Texas System College of Niigata University Graduate School of Medical and
Pharmacy, Fort Worth, TX, United States Dental Sciences, Niigata, Japan
Matthias Samwald Center for Medical Statistics, Jesse J. Swen Department of Clinical Pharmacy
Informatics, and Intelligent Systems, Medical and Toxicology, Leiden University Medical Center,
University of Vienna, Vienna, Austria Leiden, The Netherlands
Erick R. Scott Department of Genetics and Genomic Wei Chuen Tan-Koi Health Products Regulation
Sciences, Icahn School of Medicine at Mount Sinai, Group, Health Sciences Authority, Singapore
New York, NY, United States; Clinical Data Science, Alexander Vandell Daiichi Sankyo Pharma
Sema4, Stamford, CT, United States Development, Basking Ridge, NJ, United States
Stuart A. Scott Department of Genetics and Richard L. Wallsten Clinical Data Science, Sema4,
Genomic Sciences, Icahn School of Medicine at Stamford, CT, United States
Mount Sinai, New York, NY, United States; Sema4,
Ophelia Yin Daiichi Sankyo Pharma Development,
Stamford, CT, United States
Basking Ridge, NJ, United States
 Preface

Pharmacogenomics and pharmacogenetics book. In addition, we have included two chap-

are overlapping sciences, and, although the two ters that discuss the complexity of ethnicity in
terminologies have been used interchangeably pharmacogenomics studies and global drug
in the literature, pharmacogenomics reflects a development, and several chapters that discuss
progressive transition that has taken place over practical aspects of pharmacogenomics testing.
the years within the broad scope of personalized The book chapters are organized into three sec-
medicine. As a discipline, pharmacogenomics is tions. The first section (Chapters 1 to 4) provides
envisioned as a major societal benefit from all an introductory chapter on pharmacogenomics,
the scientific and technical advances related to one on industry perspective and insights for
the Human Genome Project. To date, much work the role of pharmacogenomics in drug develop-
remains to address the challenges with translat- ment, another on global academic and govern-
ing pharmacogenomics into clinical practice mental efforts to advance and apply the relevant
and drug development to achieve the ultimate genomic knowledge, and an overview chapter
goal envisioned many years ago. Nevertheless, on the challenges of moving the discipline into
examples of clinical applications of pharma- real-world settings over the last decade. The sec-
cogenomics knowledge have emerged at several ond section (Chapters 5 to 9) primarily focuses
major academic medical centers. on clinical areas in which the evidence supports
This book differs from available pharmacoge- direct pharmacogenetic applications to patient
nomics books in several aspects. It neither con- care. When appropriate, unsuccessful applica-
tains significant materials on molecular genetics tions are used to illustrate the challenges for the
nor lists all the theoretical pharmacogenomics discipline. The third section (Chapters 10 to 15)
applications organized by therapeutic special- is unique and covers diverse topics including
ties. Rather, the focus of the book is to provide looking to the future for pharmacogenomics
a timely discussion and viewpoints on a broad data technologies, pharmacogenomics issues in
range of topics; from the academic, regulatory, different ethnic populations, as well as different
pharmaceutical, clinical, socioethical, and eco- models and economic evaluations of pharma-
nomic perspectives that are relevant to the com- cogenomics testing. The final chapter provides a
plex processes in translating pharmacogenomics resource as to how this textbook can be useful for
findings into therapeutic applications. teaching pharmacogenomics to students in vari-
As with the first edition, our goal has been ous healthcare disciplines and graduate-level
to provide information that is not readily avail- students in health and pharmaceutical sciences,
able in other books covering the same topic. as well as how pharmacogenomics information
Although the processes and implementation can be integrated into clinical practice.
barriers are presented in depth in one chapter, Because the book details viewpoints on the
perspectives on challenges and limitations, as challenges of translating pharmacogenomics,
well as examples of successful direct therapeu- we intentionally did not “limit” our contribu-
tic applications, are presented throughout the tors with “organized content” for each chapter.

xv
xvi Preface

In essence, each chapter simply follows a gen- specific materials covered in the book would be
eral approach of including an overview of the useful resources for teaching graduate students
potentials or opportunities within the context in academic disciplines such as pharmacology,
of the respective chapter, but the emphasis is on neuroscience, structural and cellular biology,
discussion of barriers with perspectives on how and molecular medicine. It is our sincere hope
to move pharmacogenomics forward. Realizing that after completing the textbook, the readers
that overlap is inevitable in a book with multiple not only have a critical awareness of the value of
authors, we took measures to minimize unnec- pharmacogenomic implementation with actual
essary duplicated materials, and cross-reference versus potential applications, but also a broad
chapters whenever appropriate. knowledge of the pertinent issues and chal-
This book is intended not only as a reference lenges for pharmacogenomics before advances
book for scientists in academia and the pharma- in scientific findings can be broadly and practi-
ceutical industry involved in pharmacogenomics cally applied to patient care.
research, but also for healthcare clinicians work-
ing or interested in the field. In addition, this text Y. W. Francis Lam
is useful as a textbook for teaching clinicians and Stuart A. Scott
students in different healthcare disciplines, and
 C H A P T E R

1
Principles of Pharmacogenomics:
Pharmacokinetic, Pharmacodynamic,
and Clinical Implications
Y. W. Francis Lam1,2
1Department of Pharmacology, University of Texas Health Science Center at San Antonio,
San Antonio, TX, United States; 2College of Pharmacy, University of Texas at Austin,
Austin, TX, United States

O U T L I N E

Objectives2 Polymorphisms in Drug-Transporter Genes 21

The ABC-Efflux Transporters 21
Introduction2
ABCB121
Polymorphisms in Cytochrome P450 Enzymes 3 ABCC1 and ABCC2 23
CYP2D64 ABCG223
CYP2C199 The SLC-Uptake Transporters 24
CYP2C911 Organic Anion Transporting Polypeptides 24
CYP2C813 OAT1B124
CYP3A4/5/713 OATP2B126
CYP4F215 OATP1B326
CYP2B615 Organic Cation Transporters 26
CYP2A617 Organic Anion Transporters 27
CYP1A217
Polymorphisms in Drug-Target Genes 27
Polymorphisms in Non-CYP450 Drug- Drug Target Receptor Genes in Oncology 28
Metabolizing Enzymes 18 Drug Target Receptor Genes in Cardiology 30
UDP-Glucuronosyl Transferase 18 Drug Target Genes in Psychiatry 32
Thiopurine-S-methyltransferase19 Drug Target Genes in Pain Management 32
Dihydropyrimidine Dehydrogenase (DYPD) 19 Signal Transduction Proteins 33
N-acetyltransferase20 Enzyme Genes 34
Glutathione-S-transferase20 Ion Channel Genotype 36

Pharmacogenomics, Second Edition

https://doi.org/10.1016/B978-0-12-812626-4.00001-2 1 © 2019 Elsevier Inc. All rights reserved.