Clinical and Translational Science - 2nd Edition - ISBN: 9780128021019, 9780128021118

Clinical and Translational Science

2nd Edition

Principles of Human Research

Editors: David Robertson Gordon Williams
eBook ISBN: 9780128021118
Paperback ISBN: 9780128021019
Imprint: Academic Press
Published Date: 22nd December 2016
Page Count: 808
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Clinical and Translational Science: Principles of Human Research, Second Edition, is the most authoritative and timely resource for the broad range of investigators taking on the challenge of clinical and translational science, a field that is devoted to investigating human health and disease, interventions, and outcomes for the purposes of developing new treatment approaches, devices, and modalities to improve health.

This updated second edition has been prepared with an international perspective, beginning with fundamental principles, experimental design, epidemiology, traditional and new biostatistical approaches, and investigative tools. It presents complete instruction and guidance from fundamental principles, approaches, and infrastructure, especially for human genetics and genomics, human pharmacology, research in special populations, the societal context of human research, and the future of human research. The book moves on to discuss legal, social, and ethical issues, and concludes with a discussion of future prospects, providing readers with a comprehensive view of this rapidly developing area of science.

Key Features

  • Introduces novel physiological and therapeutic strategies for engaging the fastest growing scientific field in both the private sector and academic medicine
  • Brings insights from international leaders into the discipline of clinical and translational science
  • Addresses drug discovery, drug repurposing and development, innovative and improved approaches to go/no-go decisions in drug development, and traditional and innovative clinical trial designs


Investigators and clinicians involved in biomedical research across multiple fields; post-doctoral fellows and graduate researchers; instructors and trainees in national and international technical clinician and degree programs

Table of Contents

  • List of Contributors
  • Section I. Fundamental Principles
    • Chapter 1. Introduction to Clinical Research
      • Historical Background
      • Organization of This Book
      • Note
    • Chapter 2. Patient-Oriented Research
      • Introduction
      • Types of Patient-Oriented Research
      • The Role of Patient-Oriented Research in Translational Research
      • The Role of the Patient in Patient-Oriented Research
      • Sequence of Investigation
      • Tools of the Patient-Oriented Researcher
      • Funding for Patient-Oriented Research
      • Conclusions
    • Chapter 3. Clinical Trials
      • Introduction
      • History
      • Phases of Evaluation of Therapies
      • Critical General Concepts
      • Expressing Clinical Trial Results
      • Concepts Underlying Trial Design
      • General Design Considerations
      • Legal and Ethical Issues
      • Hypothesis Formulation
      • Publication Bias
      • Statistical Considerations
      • Metaanalysis and Systematic Overviews
      • Understanding Covariates and Subgroups
      • Therapeutic Truisms
      • Study Organization
      • Integration Into Practice
      • The Future
    • Chapter 4. Introduction to Epidemiology
      • Introduction: Definition and Role of Epidemiology
      • Measuring Occurrence of Disease
      • Measuring Risk and Association
      • Types of Epidemiological Studies
      • Threats to Validity and Reliability
      • Moving From Association to Causation
      • Clinical Epidemiology
      • Sex, Gender, Race, and Ethnicity in Epidemiology
      • Conclusion
    • Chapter 5. The Patient-Centered Outcomes Research Institute: Current Approach to Funding Clinical Research and Future Directions
      • Introduction: The Patient-Centered Outcomes Research Institute
      • Patient-Centered Comparative Effectiveness Research
      • Patient and Stakeholder Engagement in Research
      • Methodology Standards for Patient-Centered Comparative Effectiveness Research
      • Pragmatic Research
      • Integrating Research Into the Learning Health-Care System
      • Conclusion: Vision of Clinical Research in the 21st Century
      • Glossary
      • List of Acronyms and Abbreviations
    • Chapter 6. Health-Care Technology Assessment (HTA)
      • Summary
      • Introduction
      • The Evaluation of New Medical Technology: The Producer's Perspective
      • The Evaluation of New Medical Technology: The End User's Perspective
      • The Evaluation of New Medical Technology: Society's Perspective
      • Cost–Benefit, Cost-Effectiveness, and Cost–Utility Analysis
      • Can One Ever Avoid Putting Monetary Values on Health Benefits?
      • Unresolved Controversies on Economic Valuations in Health Care
    • Chapter 7. Health Services Research: Translating Discovery and Research Into Practice and Policy
      • Introduction
      • What Is Health Services Research and What Are Its Goals?
      • Assessing Medical Interventions: Outcomes, Effectiveness, and Cost-Effectiveness
      • Conclusions
  • Section II. Approaches
    • Chapter 8. Measurement of Biological Materials
      • Introduction
      • Immunoassays and Immunochemistry
      • Mass Spectrometry and Chromatography
      • Genomics
      • Proteomics, Lipidomics, Metabolomics, and Multiomics
      • Conclusion
    • Chapter 9. Imaging Tools in Clinical Research: Focus on Imaging Technologies
      • Introduction
      • Imaging Technologies
      • Conclusion
    • Chapter 10. Imaging Tools in Human Research: Focus on Image-Guided Intervention
      • Introduction
      • Image-Guided Biopsy
      • Image-Guided Therapy
      • Conclusion
    • Chapter 11. Nanotechnology in Clinical and Translational Research
      • Introduction and Historical Perspective
      • Nanotechnology in Basic Research Applications Supporting Clinical Translation
      • Clinical Applications of Nanotechnology for Research
      • Conclusion and Future Directions in Nanomedicine
    • Chapter 12. The Use of Questionnaires and Surveys
      • Introduction
      • The Practice of Questionnaire and Survey Measurement
      • Statistical and Analysis Considerations
      • Summary and Conclusions
      • Glossary
      • List of Acronyms and Abbreviations
    • Chapter 13. Information Technology
      • Introduction
      • Clinical Data Repositories
      • Information Technology Support of Participant Recruitment
      • Principles of Data Collection
      • Data Standards
      • Clinical Trial Management Systems
      • Publicly Available Databases
      • The Growing Impact of Big Data and the Cloud
      • Conclusion
    • Chapter 14. Principles of Biostatistics
      • Introduction
      • Types of Data
      • Descriptive Statistics
      • Testing and Summarizing Relationship Between Two Variables
      • Baseline Comparisons and Primary Outcome Analysis
      • Generalized Linear Models
      • Model Building
      • Multiple Comparisons
      • Missing Data
      • Linear Mixed-Effects Models (Clustered or Longitudinal Studies)
      • Conclusion
    • Chapter 15. Good Clinical Practice and Good Laboratory Practice
      • Overview
      • Good Clinical Practice
      • Good Laboratory Practice
      • Glossary
      • List of Acronyms and Abbreviations
  • Section III. Human Genetics
    • Chapter 16. Introduction to Human Genetics
      • Introduction
      • Basic Molecular Genetics
      • Patterns of Genetic Transmission
      • Cytogenetics and Chromosomal Disorders
      • The Human Genome
      • Genetic Variation
      • Medical Applications
      • Genetic Counseling
      • Phenotyping and Clinical Research
      • Conclusion
    • Chapter 17. Epidemiologic and Population Genetic Studies
      • Introduction
      • Design Issues in Genetic Association Studies
      • Epidemiologic Study Design
      • Genetic Study Design: Genome-Wide Association Study Versus Hypothesis-Driven (Candidate Gene) Approaches
      • Interpreting Results of Genetic Association Studies
      • Future Directions
      • Conclusion
    • Chapter 18. Pharmacogenetics of Drug Metabolism
      • Introduction
      • Pharmacogenetics of Drug Metabolism: Historical Aspects
      • Genetic Polymorphisms of Individual Drug-Metabolizing Genes
      • CYP2B6
      • CYP2C8
      • CYP2C9
      • CYP2C19
      • CYP2D6
      • CYP3A5
      • N-acetyltransferase 2
      • Thiopurine Methyltransferase
      • UDP-Glucuronosyltransferase
      • Butyrylcholinesterase
      • Conclusions
    • Chapter 19. Statistical Techniques for Genetic Analysis
      • Introduction
      • Genetic Determination of Complex Disease
      • Genetic Linkage Studies
      • Common Genetic Study Designs and Statistical Tests
      • Genomewide Association Studies
      • Next-Generation Sequencing
      • Metaanalysis Techniques
      • Gene-by-Environment Analysis
      • Multivariant Approaches
      • Network Medicine
      • Integrative Omics
      • Phenotypic Limitations
      • Computer Programs
      • Summary and Conclusions
      • Glossary
      • List of Acronyms and Abbreviations
  • Section IV. Human Pharmacology
    • Chapter 20. Introduction to Clinical Pharmacology
      • Introduction: Mechanisms of Drug Disposition and Interactions
      • Transporters and Drug Absorption, Distribution, and Excretion
      • Drug-Metabolizing Enzymes
      • Drug–Drug Interactions
      • Induction and Regulation of Drug-Metabolizing Enzymes and Transporters
      • Principles of Pharmacokinetics
      • Conclusion
    • Chapter 21. Adverse Drug Events
      • The Multifactorial Nature of Adverse Drug Events
      • Types of Adverse Drug Events
      • Genetics to Genomics
  • Section V. Societal Context of Human Research
    • Chapter 22. Translating Science to the Bedside: The Innovation Pipeline
      • Realities of the Marketplace
      • Ideas and Innovations
      • Working With Industry
      • Entrepreneurship
      • Clinical Evaluation of Innovative Products
      • Conflicts of Interest
      • Translating Science to the Bedside Cores in Academic Health Centers
      • Summary
      • Statutes and Federal Regulations
      • Cases
    • Chapter 23. Regulatory Environment
      • Introduction
      • The US Food and Drug Administration
      • Other Regulatory Agencies
      • Conclusions
      • Glossary
      • List of Acronyms and Abbreviations
    • Chapter 24. Ethical Issues in Translational Research and Clinical Investigation
      • Introduction
      • Responsibility in Science and Society
      • Ethics and Translational Research
      • Guiding Principles for the Responsible Translational Investigator
      • Justice, Beneficence, and Respect for Persons: From Principles to Practice
      • Regulation of Research and Protection of Subjects
      • Individuals and the Clinical Research Process
      • Professionalism in Clinical Research
    • Chapter 25. Clinical Research in the Public Eye
      • Introduction
      • The Cultural Context of Research
      • Science and Politics
      • Conclusion
  • Section VI. Research in Special Populations
    • Chapter 26. Research in Special Populations: Acute Illnesses; Critical Care; and Surgical Patients
      • Introduction
      • Trial Design
      • Usual Care in Critically Ill Patients
      • Informed Consent
      • Outcomes
      • Adverse Events
      • Conclusion
    • Chapter 27. Research in the Emergency Care Environment
      • Introduction
      • The Environment and Unique Challenges of Emergency Care Research
      • Examples of Early Success
      • Building an Emergency Care Research Site
      • Funding of Infrastructure in the Emergency Care Environment
      • The Role of Industry
      • Implementation of Emergency Care Research
      • Conclusion
    • Chapter 28. Psychiatric Disorders
      • Introduction
      • Diagnostic Issues
      • Types of Studies
      • Tools
      • Statistical and Design Issues
      • Special Issues
      • A Practical Schematic Approach
      • Summary
    • Chapter 29. Research in Special Populations: Geriatrics
      • Introduction
      • What Is Different About Aging Research?
      • How an Aging Perspective Affects Research Topics and Approaches
      • The Effect of Aging on the Pragmatics of Research
      • Conclusions and Recommendations
    • Chapter 30. Clinical Research in Neurology
      • Introduction
      • Features Unique to Neurologic Diseases
      • Disease Examples
      • Conclusion
    • Chapter 31. Research in Pediatrics
      • Introduction
      • What Is Different About Pediatric Research?
      • Orphan (Rare) Diseases
      • Pediatric Conditions as Focus of Inquiry
      • Regulatory and Ethical Environment for Pediatric Research
      • Conclusion
      • Statutes and Regulations
      • Cases
    • Chapter 32. Cancer as a Paradigm for Translational and Clinical Biomedical Research
      • Introduction
      • Cancer: From the Edwin Smith Papyrus to the Molecular Genetic Era
      • Cancer Drivers and Personalized Medicine
      • From the Bench to the Bedside
      • The Crusade to Overcome Drug Resistance in Cancer
      • List of Acronyms and Abbreviations
    • Chapter 33. Maintaining an Emphasis on Rare Diseases With Research Initiatives and Resources at the National Center for Advancing Translational Sciences
      • Introduction
      • Translational Science Spectrum
      • Definition of Rare Diseases
      • International Classification of Diseases
      • Evolving Approaches to Rare Diseases Research
      • Translational Research Efforts and Resources at NCATS and Other NIH Institutes
      • The Rare Diseases Clinical Research Network Program—A Model for Collaboration
      • Rare Diseases Research and Orphan Product Development
      • RDCRN and Clinical and Translational Science Awards Programs on Education and Training Resources
      • Assessment of Unmet Medical Device Needs for Rare Diseases
      • An Even Brighter Path Forward
  • Section VII. Infrastructure
    • Chapter 34. Clinical and Translational Science Infrastructure
      • Introduction
      • Reinventing the Clinical Research Infrastructure
      • Clinical and Translational Science Institutes
      • National Center for Advancing Translational Sciences
      • Human Genome Project
      • Clinical and Translational Science Award
      • Conclusion
  • Section VIII. Education, Training and Career Choices
    • Chapter 35. Education, Training and Career Choices: Training Basic, Clinical, and Translational Investigators
      • Introduction
      • Overview
      • Didactic Curriculum
      • Degree-Granting Programs in Clinical or Translational Research
      • The Mentored Research Experience
      • Career Development Resources
      • Funding for Training Clinical and Translational Investigators
    • Chapter 36. A Stepwise Approach to a Career in Translational Research
      • Definitional Issues
      • Historical Perspective
      • Step 1: The Starting Point
      • Step 2: The Need for Normative Data and Control Populations
      • Step 3: Engaging Relevant Basic Researchers and Their Technologies
      • Step 4: Identifying Tractable Problems
      • Step 5: Identifying Appropriate Mentors Across a Career
      • Step 6: Obtaining Successful Independent Funding
      • Step 7: The Perils of Senior Leadership
      • Summary
    • Chapter 37. Physician Careers in the Pharmaceutical Industry
      • Introduction
      • Medical-Scientific Positions in the Pharmaceutical Industry
      • A Pharmaceutical Career
      • Summary
  • Section IX. Research in Academia
    • Chapter 38. Industry-Sponsored Clinical Research in Academia
      • Introduction
      • The Public Perspective
      • The Academic Health Center Perspective
      • The Industry Perspective
      • The Investigators' Perspective
      • Matching Industry Needs and Academic Health Center Priorities
      • Conclusion
    • Chapter 39. Governmental Support of Research
      • Introduction
      • Overview
      • United States Government Scientific Programs
      • Scientific Programs in Europe, Canada, and Australia/New Zealand
      • Scientific Programs in Asia, Africa and South/Central America and the Caribbean
      • Current Support for Clinical and Translational Research
      • Conclusion
    • Chapter 40. The Role of Nonprofit, Nongovernmental Funding in Support of Biomedical Research
      • Introduction
      • Overview of Philanthropic Funding on Biomedical Research
      • Distinctions Between Different Types of Philanthropic Funders
      • Funding Type
      • Recipient Type
      • Foundations Attached to Government Agencies
      • Concepts in Nonprofit Funding
      • Conclusion
      • Problem Set
    • Chapter 41. Modern Drug Discovery and Development
      • Introduction
      • The Origins of Drug Discovery
      • Drug Discovery in the 21st Century
      • Preclinical Development
      • Clinical Development
      • New Drug Discovery Paradigms
      • Conclusion
    • Chapter 42. Pharmaceutical and Biotechnology Sector Support of Research
      • Introduction
      • The Drug Development Process
      • Basic Science Within the Pharmaceutical and Biotechnology Sectors
      • Developmental Research—A Contrast to Academia and Government
      • Clinical Research and Development
      • Marketed Product Research
      • Conclusion
  • Section X. Prospectus
    • Chapter 43. The Future of Clinical Research
      • Definition of Translational Human Research
      • Subgrouping of Biological Scientists
      • The Patient-Oriented Scientist at the Beginning of the 21st Century
      • The 21st Century and the Future
      • Novel New Approaches: Big Data and N-of-One
      • Summary
  • Index


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About the Editor

David Robertson

Dr. Robertson graduated from Vanderbilt University in 1969, with a B.A. in Germanic and Slavic Languages. He attended the Arnamagnaen Institute in Copenhagen, Denmark before receiving his medical degree from Vanderbilt University Medical School in 1973. He went on to complete an internship and residency in Medicine at Johns Hopkins Hospital. Robertson was a postdoctoral fellow in Clinical Pharmacology at Vanderbilt for two years before accepting a position as assistant chief of Service in Medicine and instructor in Medicine at Johns Hopkins in 1977.

In 1978, Robertson returned to Vanderbilt as assistant professor of Medicine and Pharmacology, became an associate professor in 1982, then rose to professor in 1986. He spent one year as a visiting professor in the Department of Molecular Endocrinology at National, then served as a visiting professor in the Department of Anatomy and Embryology at University College in London. In 1993, Robertson became director of the Medical Scientist Training Program at Vanderbilt University and also took the position of director of the Division of Movement Disorders in the Department of Neurology, which he held until 2000.

Along with his current roles as professor of Medicine and Pharmacology and professor of Neurology, Robertson is currently the Elton Yates Professor of Autonomic Disorders, director of the General Clinical Research Center and director of the Center for Space Physiology and Medicine for Vanderbilt University.

Robertson currently serves on the Board of Advisors for the World Life Foundation, the NASA Microgravity Human Research Committee, the Merck Advisory Board, and the editorial boards of American Journal of Medicine, Autonomic Neuroscience and Clinical Autnomic Research. He is also associate editor for the Journal of Pharmacology and Experimental Therapeutics.

Affiliations and Expertise

Departments of Medicine, Pharmacology, and Neurology, Clinical Research Center, Vanderbilt University, Nashville, TN, USA

Gordon Williams

Dr. Williams’ group’s first major goal is the identification of the genetic underpinnings of endocrine factors related to cardiovascular (CV) risk in hypertension and diabetes with the ultimate goal of using genetic markers to develop individualized, personal treatment programs for patients with these diseases. His is a translational research group with interdisciplinary focus in humans and at the bench. The group's major focus in human studies is on careful phenotyping of patients with hypertension and diabetes relative to cardiovascular risk factors. The research focuses on evaluating hormones that can modify vascular contractility and/or salt handling. The major current thrusts are the renin-angiotensin-aldosterone system (RAAS), kallikrein, cortisol, adducin, the beta-2 adrenergic receptor and ion transport systems. The second major goal is to determine the role of aldosterone in producing CV disease at molecular, cellular, organ, whole animal and clinical levels. Recent studies suggest that aldosterone has a wide range of effects including inducing microvascular ischemia, thrombosis, fibrosis, and inflammatory responses many of them potentially mediated by aldosterone’s interaction with caveolins and two recently discovered proteins---striatin and lysine specific demethylase 1 (LSD1). Techniques employed include whole animal physiological studies using normal animals, those made hypertensive and those genetically modified (e.g. knock-outs and transgenics). Molecular and cellular techniques include gene arrays using chip technology, proteomics, confocal microscopy, electrophysiology and in situ hybridization. Finally, the group has just begin the first proof of concept clinical trial for using genetic information to provide personalized medicine.

Affiliations and Expertise

Chief, Endocrine Hypertension Division, Brigham and Women's Hospital, Boston, MA, USA