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Clinical Genomics
1st Edition - November 7, 2014
Editors: Shashikant Kulkarni, Somak Roy
Language: English
Hardback ISBN:9780124047488
9 7 8 - 0 - 1 2 - 4 0 4 7 4 8 - 8
eBook ISBN:9780124051737
9 7 8 - 0 - 1 2 - 4 0 5 1 7 3 - 7
Clinical Genomics provides an overview of the various next-generation sequencing (NGS) technologies that are currently used in clinical diagnostic laboratories. It presents…Read more
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Clinical Genomics provides an overview of the various next-generation sequencing (NGS) technologies that are currently used in clinical diagnostic laboratories. It presents key bioinformatic challenges and the solutions that must be addressed by clinical genomicists and genomic pathologists, such as specific pipelines for identification of the full range of variants that are clinically important.
This book is also focused on the challenges of diagnostic interpretation of NGS results in a clinical setting. Its final sections are devoted to the emerging regulatory issues that will govern clinical use of NGS, and reimbursement paradigms that will affect the way in which laboratory professionals get paid for the testing.
Simplifies complexities of NGS technologies for rapid education of clinical genomicists and genomic pathologists towards genomic medicine paradigm
Tried and tested practice-based analysis for precision diagnosis and treatment plans
Specific pipelines and meta-analysis for full range of clinically important variants
Clinical Genomicists, Molecular Pathologists, molecular Geneticists, clinical Cytogeneticists, Clinical Geneticists, Primary Care Physicians (including Oncologists, Pediatricians, Neurologists, Cardiologists, and Neonatologists) and Genetic Counselors seeking to use or interpret Next Gen Sequencing in the diagnosis, prognosis, and management of inherited and somatic disorders in the era of precision medicine.
Dedication
List of Contributors
Foreword
Reference
Preface
Acknowledgments
Section I: Methods
Chapter 1. Overview of Technical Aspects and Chemistries of Next-Generation Sequencing
Clinical Molecular Testing: Finer and Finer Resolution
Sanger Sequencing
Cyclic Array Sequencing
Illumina Sequencing
SOLiD Sequencing
Ion Torrent Sequencing
Roche 454 Genome Sequencers
Third-Generation Sequencing Platforms
References
Chapter 2. Clinical Genome Sequencing
Key Concepts
Introduction
Applications and Test Information
Laboratory Process, Data Generation, and Quality Control
Conclusion
References
Chapter 3. Targeted Hybrid Capture Methods
Key Concepts
Introduction
Basic Principles of Hybrid Capture-Based NGS
Hybrid Capture-Based Target Enrichment Strategies
Clinical Applications of Target Capture Enrichment
Variant Detection
Practical and Operational Considerations
Conclusions
References
Chapter 4. Amplification-Based Methods
Introduction
Principles of Amplification-Based Targeted NGS
Nucleic Acids Preparation
Primer Design for Multiplex PCR
Library Preparation and Amplification
Other Amplification-Based Target Enrichment Approaches
Comparison of Amplification- and Capture-Based Methods
Clinical Applications
Conclusion
References
Chapter 5. Emerging DNA Sequencing Technologies
Key Concepts
Introduction
Third-Generation Sequencing Approaches
Fourth-Generation Sequencing
Selected Novel Technologies
Summary
References
Chapter 6. RNA-Sequencing and Methylome Analysis
Key Concepts
Introduction
Approaches to Analysis of RNA
Workflow
Utility of RNA-Seq to Characterize Alternative Splicing Events
Utility of RNA-Seq for Genomic Structural Variant Detection
RNA-Seq: Challenges, Pitfalls, and Opportunities in Clinical Applications
Methylome Sequencing
Conclusions
References
Section II: Bioinformatics
Chapter 7. Base Calling, Read Mapping, and Coverage Analysis
Key Concepts
Introduction
Platform-Specific Base Calling Methods
Read Mapping
Coverage Analysis: Metrics for Assessing Genotype Quality
Summary
References
Chapter 8. Single Nucleotide Variant Detection Using Next Generation Sequencing
Key Concepts
Introduction
Sources of SNVs
Consequences of SNVs
Technical Issues
Bioinformatic Approaches for SNV Calling
Interpretation of SNVs
Reporting
Summary
References
Chapter 9. Insertions and Deletions (Indels)
Key Concepts
Overview of Insertion/Deletion Events (Indels)
Sources, Frequency, and Consequences of Indels
Technical Issues That Impact Indel Detection by NGS
Specimen Issues That Impact Indel Detection by NGS
Bioinformatics Approaches to NGS Indel Detection
Summary
References
Chapter 10. Translocation Detection Using Next-Generation Sequencing
Key Concepts
Introduction to Translocations
Translocations in Human Disease
Translocation Detection
Informatic Approaches to Translocation Detection
Translocation Detection in Clinical Practice
Summary and Conclusion
References
Chapter 11. Copy Number Variant Detection Using Next-Generation Sequencing
Key Concepts
Overview of Copy Number Variation and Detection via Clinical Next-Generation Sequencing
Sources, Frequency, and Functional Consequences of Copy Number Variation in Humans
CNV Detection in Clinical NGS Applications
Conceptual Approaches to NGS CNV Detection
Detection in the Clinic: Linking Application, Technical Approach, and Detection Methods
Reference Standards
Orthogonal CNV Validation
Summary and Conclusion
References
Section III: Interpretation
Chapter 12. Reference Databases for Disease Associations
Key Concepts
Introduction
Identification and Validation of Human Variation
Identification of Common Variation
Interpretation of Common Variation
Defining Diseases and Phenotypes
Representation of Variation Data in Public Databases
Data Access and Interpretation
Determination of Variant Pathogenicity
Global Data Sharing
Conclusion
References
Chapter 13. Reporting of Clinical Genomics Test Results
Key Concepts
Introduction
Components of the Written NGS Report
Beyond the Written Report: Other NGS Reporting Issues to Consider
Conclusion
References
Chapter 14. Reporting Software
Key Concepts
Introduction
Clinical Genomic Test Order Entry
Laboratory Information Management Systems (LIMS) Tracking
Analytics: From Reads to Variant Calls
Analytics: Variant Annotation and Classification
Variant Interpretation
Final Report Transmission to the EMR
Leveraging Standards in Clinical Genomics Software Systems
Introduction to Exome and Genome Sequencing in Cancer
Interpretative Considerations in Exome and Genome Cancer Sequencing
Analytic Considerations for Exome and Genome Sequencing in Cancer
Summary
References
Section IV: Regulation, Reimbursement, and Legal Issues
Chapter 21. Assay Validation
Key Concepts
Introduction
NGS Workflow
The Regulatory and Professional Framework for Assuring Quality
Assay Validation
Accuracy
Precision
Analytical Sensitivity and Analytical Specificity
Reportable and Reference Ranges
Quality Control
Reference Materials
Conclusion
Acknowledgment
References
Chapter 22. Regulatory Considerations Related to Clinical Next Generation Sequencing
Key Points
Introduction
Regulatory Standards
FDA Oversight of Clinical NGS
Total Quality Management: QC
Total Quality Management: QA
Conclusion
References
Chapter 23. Genomic Reference Materials for Clinical Applications
Introduction
Genome in a Bottle Consortium
Reference Data
Other Reference Materials for Genome-Scale Measurements
Conclusion
References
Chapter 24. Ethical Challenges to Next-Generation Sequencing
Key Concepts
Introduction
Challenging Existing Frameworks
Notifying of Results
Privacy and Confidentiality
Informed Consent
Conclusion
References
Chapter 25. Legal Issues
Introduction
Patent Overview
History of Gene Patents
Arguments for and Against Gene Patents
Important Legal Cases
Implication of Recent Court Decisions for Genetic Testing
Genetic Information Nondiscrimination Act
References
Chapter 26. Billing and Reimbursement
Key Concepts
Introduction
Insurance Payers
Reimbursement Processes
Test Design Factors That Impact Reimbursement
Patient Protection and Affordable Care Act
Cost Structure
Summary
References
Index
No. of pages: 488
Language: English
Edition: 1
Published: November 7, 2014
Imprint: Academic Press
Hardback ISBN: 9780124047488
eBook ISBN: 9780124051737
SK
Shashikant Kulkarni
Dr. Shashikant Kulkarni is the Head of Clinical Genomics, Genomics and Pathology Services and also the Director of Cytogenomics and Molecular Pathology at Washington University School of Medicine. In addition, he is Associate Professor of Pathology and Immunology, Pediatrics, and Genetics. His lab's principle research interest is delineation of novel genomic structural and single nucleotide variants in cancer.
Affiliations and expertise
Head of Clinical Genomics, Genomics and Pathology Services; Director of Cytogenomics and Molecular Pathology, Washington University School of Medicine, USA
SR
Somak Roy
Dr. Somak Roy is an Assistant Professor, in the division of Molecular and Genomic Pathology, at the University of Pittsburgh Medical Center, in Pittsburgh, PA. He is also Director of Molecular Informatics and the Director of the MGP Fellowship Program, and Associate Laboratory Director of the Division of Molecular and Genomic Pathology. Dr. Roy's research is focused on understanding mechanisms of urothelial carcinogenesis and metastasis using next generation sequencing and microarray technologies. He also develops biomedical informatics solutions for optimizing clinical laboratory operations and quality management.
Affiliations and expertise
Assistant Professor, Division of Molecular and Genomic Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; Director of Molecular Informatics and the Director of the MGP Fellowship Program, and Associate Laboratory Director of the Division of Molecular and Genomic Pathology