Front Cover

Precision Medicine: Tools and Quantitative Approaches

Copyright

Contents

Contributors

Preface

References

Chapter 1: Ethical Aspects of Precision Medicine: An Introduction to the Ethics and Concept of Clinical Innovation

1 Introduction

2 What Is Clinical Innovation?

2.1 Clinical Innovation Is Neither Clinical Research nor Validated Medical Practice

2.2 Clinical Innovation Is New Nonvalidated Practice

2.2.1 Novelty

2.2.2 Validation

2.2.3 Benefit for the Individual

3 What Is the Ethical Justification of Clinical Innovation?

4 How Should We Regulate Clinical Innovation?

5 What is the importance of clinical innovation in precision medicine?

6 Conclusion

Acknowledgments

References

Further Reading

Chapter 2: Issues and Challenges in the Systematic Evaluation of Biomarker Tests

1 Introduction

2 Terminology and Classifications

2.1 Definition: Biomarker

2.2 Differentiation of Functions of Biomarkers

2.2.1 Differentiation by Type of Information

2.2.2 Differentiation by the Context of Use

2.3 Medical Tests

2.4 Evaluation Framework

3 Context for Analysis

3.1 Developing an Analytical Framework

3.2 Formulation of Review Question With PICO

3.2.1 Population

3.2.2 Intervention

3.2.3 Comparator

Differentiation Between Reference Standard and Comparator

3.2.4 Outcomes

4 Study Designs and Study Selection

4.1 Literature Search

4.2 Hierarchies of Evidence

4.3 Diagnostic Accuracy Studies

4.4 Prognostic Studies

4.5 Randomized Clinical Trial Designs

5 Critical Appraisal-Specific Issues in Biomarker Studies

5.1 Diagnostic Accuracy Studies

5.2 Prognosis Studies

5.3 Linked-Evidence Evaluation of Co-dependent Technologies

References

Further Reading

Chapter 3: Statistical Learning in Precision Medicine

1 Introduction

2 Data

3 Types of Statistical Learning Algorithms

4 Steps in Supervised Learning

4.1 Preparation of Data

4.2 Handling Imbalanced Datasets

4.3 Imputation of Missing Data

4.4 Feature Selection

4.5 Learning Algorithms

4.6 Evaluating the Performance

4.7 Improving Model Performance

5 Sketch of the Workflow

6 Conclusion

Acknowledgment

References

Chapter 4: Biobanks as Basis of Individualized Medicine: Challenges Toward Harmonization

1 Introduction

2 Governance

3 Consent

4 Vulnerable Groups

4.1 Minors

4.2 Deceased Persons

5 From Individual Rights to Solidarity

6 Privacy

7 Access to Samples and Data

7.1 Public Trust

8 Sustainability

9 Quality Assurance Management (QAM)

10 Security

11 Biobanks for Precision Medicine

11.1 Return of results

11.2 Networking activities

11.2.1 BBMRI-ERIC

11.2.2 EuroBioBank

12 Future

13 Conclusion

References

Chapter 5: Sequencing in Precision Medicine

1 Sequencing Technologies

2 Meaning of Sequencing

3 First-Generation Sequencing

3.1 Maxam-Gilbert "Base-Specific Chemical Cleavage" Sequencing

3.1.1 Chemical Cleavage of Specific Bases

3.2 Sanger Chain-Termination Sequencing

3.2.1 dNTPS and ddNTPS

4 Next-Generation Sequencing

4.1 Roche 454 Pyrosequencing

4.2 Illumina/Solexa Sequencing

4.2.1 Basic Sequencing Principle

4.2.2 Reversible Terminators

4.2.3 Cluster Generation

4.2.4 Sequencing by Synthesis

4.3 SOliD (Sequencing by Oligonucleotide Ligation and Detection)

4.4 Ion Torrent (Ion Semiconductor) Sequencing

5 Third-Generation Sequencing

5.1 Pacific Biosciences "Single-Molecule Real-Time" Sequencing

5.2 Oxford Nanopore Technologies Nanopore Sequencing

5.2.1 Basic Sequencing Principle

5.2.2 Interaction of the Pore With the DNA Strand

5.2.3 Sequencing Adapters

5.2.4 Biological Nanopores for Sequencing

5.2.5 One Directional Read, Two Directional Read and One Directional Squared Read

6 Issues to be Improved for Obtaining an Optimal Sequencing Technology

References

Further Reading

Chapter 6: Workflow for Circulating miRNA Identification and Development in Cancer Research: Methodological Considerations

1 Introduction

2 Biomarkers

2.1 Definitions and Types

2.2 Workflow for Biomarker Identification and Development

3 Circulating miRNAs

3.1 Preanalytical Factors in miRNA Analysis

3.2 Analytical Factors in miRNA Analysis

3.3 Workflow for miRNA-Based Signature Development

4 Statistical Issues in miRNA-Based Signature Development

4.1 Data Normalization of High-Throughput qPCR Data

4.2 Composite Score Generation

4.2.1 Penalized Regression Models

4.2.2 Model Reduction

4.2.3 Model Evaluation

4.2.4 Model Validation

4.2.5 Model Updating and Extension

4.3 Assay-Oriented Steps

4.4 Clinical Validation and Implementation

5 Colorectal Cancer

5.1 Application

6 Conclusion

Acknowledgment

References

Chapter 7: Analyzing the Effects of Genetic Variation in Noncoding Genomic Regions

1 Introduction

2 SNPs and Disease

3 SNP Genotyping

3.1 Variant Detection Techniques

3.1.1 Primer Extension

3.1.2 Hybridization

3.1.3 Mismatch Repair Detection

3.1.4 BeadArray and SNPlex

3.2 Genome-Wide Association Studies

3.2.1 Minor Allele Frequency

3.2.2 Linkage Disequilibrium

3.2.3 Direct vs Indirect Associations

4 SNPs Associated With Gene Regulation

4.1 DNA Methylation

4.1.1 Sequence Specific Regulation of DNA Methylation

4.2 Histone Modifications

4.2.1 Loop Formation

4.2.2 Noncoding SNPs Affect Chromatin-Modifying Enzymes

4.3 Binding of TFs to Regulatory Elements

4.3.1 TFs and Histone Modifications

4.3.2 SNPs Affect TF Binding

4.4 Alternative Splicing

4.5 mRNA Stability

5 Diseases Affected by SNPs in Noncoding Regions

5.1 Cancer

5.1.1 Roles of Somatic Variants in Cancer

5.1.2 Roles of Germline Variants in Cancer

Promoter Mutations

SNPs in Enhancers

SNPs in ncRNAs and Their Binding Sites

Germline-Somatic Variants Interplay

5.2 Asthma

5.2.1 ORMDL3

5.2.2 CD14

5.2.3 Interleukin-18

6 Annotating the Genome With Noncoding Genomic Elements

6.1 RegulomeDB

6.2 HaploReg

6.3 FunciSNP

6.4 Enlight

6.5 GWAS3D

6.6 GREGOR

7 rSNP Classifiers Based on Machine-Learning Algorithms

7.1 GWAVA

7.2 CADD

7.3 DANN

7.4 FATHMM-MKL

8 Future Lines

Acknowledgments

References

Chapter 8: Synthesis of Magnetic Iron Oxide Nanoparticles

1 Introduction

2 Synthesis of Magnetic IONPs

2.1 Coprecipitation

2.2 Thermal Decomposition

2.3 Hydrothermal and Solvothermal Synthesis

2.4 Sol-Gel Reaction and Polyol Method

2.5 Synthesis by Microemulsion

2.6 Sonochemical Synthesis

2.7 Microwave-Assisted Synthesis

2.8 Biosynthesis by Magnetotactic and Iron Reducing Bacteria

2.9 Other Chemical or Physical Synthesis Routes

3 Surface Functionalization of Magnetic Nanoparticles

3.1 Fabricating Types of Magnetic Composite Nanomaterials

3.1.1 Core-Shell Structure

3.1.2 Matrix-Dispersed Structure

3.1.3 Janus Structure

3.1.4 Shell-Core-Shell Structure

3.2 Organic Materials

3.2.1 Small Molecules and Surfactants

3.2.2 Natural and Synthetic Polymer Coating

3.2.3 Functionalized Biomolecules as Targeting Ligands

3.3 Inorganic Materials

3.3.1 Silica Coatings

3.3.2 Carbon Coatings

3.3.3 Metallic and Metallic Oxides/Sulphides (Surface Functionalization of IONPs)

4 Biomedical Applications

4.1 In Vitro Applications

4.1.1 Biosensors

4.1.2 Bioseparation

4.1.3 Detoxification of Biological Fluids

4.1.4 Magnetofection

4.1.5 Tissue Repair

4.2 In Vivo Applications

4.2.1 Chemotherapy and Drug Delivery

4.2.2 Magnetic Resonance Imaging

4.2.3 Magnetic Hyperthermia or Thermoablation

5 Conclusion Remarks and Further Directions

References

Chapter 9: Magnetic Particle Imaging

1 Introduction

2 Basic Imaging Principles

2.1 Signal Generation and Encoding

2.2 Spatial Encoding

2.3 Volume Sampling

2.4 Current Limitations

3 Magnetic Nanoparticles

3.1 Synthesis

3.2 Magnetic Properties

3.2.1 Ferromagnetism, Superparamagnetism, and Hysteresis Effects

3.2.2 Langevin Theory of Paramagnetism

3.2.3 Relaxation Processes

3.3 Analytical Tools

3.3.1 Regarding Structure, Chemical Composition, and Size Determination

3.3.2 Regarding Applications

3.3.3 Regarding the Magnetic Behavior

3.4 Particle Analysis in MPI

3.4.1 Theoretical Analysis

3.4.2 Measurement-Based Analysis With Magnetic Particle Spectrometry

4 MPI Scanner

4.1 Basic Technical Components of an MPI Scanner

4.1.1 The Drive Field and Receive Path

4.1.2 The Selection Field Path

4.2 FFP Scanner With Closed Bore Geometry

4.3 FFP Scanner With a Single Sided Geometry

4.4 FFL Scanner

4.5 Traveling Wave Scanner

4.6 Industrial Scanner Development

5 Image Reconstruction

5.1 The Reconstruction Problem

5.2 Reconstruction via Solving a Linear System of Equations

5.2.1 System Matrix Acquisition

5.2.2 Solving the Linear System of Equations

5.3 Reconstruction via a Direct Approach

5.4 Particular Challenges

6 Applications of MPI

6.1 Diagnostics and Interventions With MPI

6.2 Color MPI

6.3 Multimodality With MPI

6.4 Cellular Imaging With MPI

6.5 Thermo-Therapy With MPI

6.6 Magnetic Manipulation and Drug Targeting With MPI

Acknowledgments

References

Chapter 10: Nanoparticles and Nanosized Structures in Diagnostics and Therapy

1 Different Functionalities of Nanoparticles

1.1 Optical Functionalities

1.1.1 Surface Plasmon Resonance

1.1.2 Raman Scattering

1.1.3 Fluorescence

1.1.4 Förster Resonance Energy Transfer

1.2 Magnetic Functionalities

1.2.1 Paramagnetism

1.2.2 Ferromagnetism

1.2.3 Superparamagnetism

1.3 Thermal Functionalities

1.4 Targeting Functionalities

1.4.1 Enhanced Permeability and Retention

1.5 Pharmakokinetic/Pharmacodynamic Functionalities

1.6 Multiple Functionalities

2 Nanoparticle-Based Diagnostic Therapy and Theranostics

2.1 Fluorescence-Linked Immunosorbent Assay

2.2 Western Blot

2.3 Lateral Flow Immunoassays

2.3.1 LFIAs With Colored Nanoparticles

2.3.2 LFIAs With Fluorescent Nanoparticles

2.3.3 LFIAs With Magnetic Nanoparticles

2.4 Immunohistochemistry

2.5 Liquid Biopsy

2.6 Nanoparticles as Bioprobes In Vivo

2.6.1 NIRF Imaging

2.6.2 X-ray and CT

2.6.3 Positron Emission Tomography

2.6.4 Magnetic Resonance Imaging

2.6.5 Ultrasound

2.7 Nanopharmacotherapy

2.8 Photothermal Therapy

2.9 Nanoparticles and Theranostics

References

Chapter 11: Interaction of Nanoparticles With Biomolecules, Protein, Enzymes, and Its Applications

1 Introduction

1.1 Nanotechnology

2 Types of NPs

2.1 Liposomes

2.2 Nanocrystals and Nanosuspension

2.3 Solid Lipid Nanoparticles

2.4 Dendrimers

2.5 Silicon-Based Structures

2.6 Carbon Nanostructures

2.7 Metal Nanostructures

3 Surface Charge of NP

4 NP Material

5 NP and Protein Corona

5.1 Structure and Composition of Corona

5.2 Probing the Interactions of Proteins and NPs

6 NPs Have a Very Large Surface-to-Volume Ratio

7 Effects on Protein Conformation of Binding to NPs

8 Increased Protein Stability/Activity Upon Binding to NPs (Enzymes)

9 Plant Mediated Synthesis of Metal NPs

10 Influence of the Size of NPs on the Activity of Adsorbed Enzymes

11 NP-Aptamer Bioconjugates for Cancer Targeting

12 Analytical Methods to Study Protein-NP Interactions

12.1 Spectroscopy Methods

12.1.1 UV/Vis

12.1.2 Fluorescence

12.1.3 FTIR and Raman Spectroscopy

12.1.4 Circular Dichroism

12.1.5 Centrifugation

12.1.6 Differential Centrifugation Sedimentation

12.1.7 Isothermal Titration Calorimetry

12.1.8 Mass Spectrometry

12.1.9 NMR

13 Simulation Methods to Study NP-Protein Interactions

13.1 Au(111)-His (and His-Derived Peptide) Interactions

13.2 Hydroxylated Fullerene-Ubiquitin

13.3 CNT-Protein Interactions

13.4 NP-Albumin Interactions

References

Further Reading

Chapter 12: Modeling and Simulating Carcinogenesis

1 Introduction

1.1 Background, Rationale and Approach

1.2 Analytical and Simulation Models

1.3 Modeling Evolution

1.4 Modeling Cancer

1.5 Simulating and Visualizing Cancer

2 Materials and Methods

2.1 Balancing—Visual Validation

2.2 Regression Analysis—Statistical Validation

3 Results

3.1 Modeling and Simulation

3.1.1 Simulating Carcinogenesis and Cancer Therapy

Approaches—Primary Models

Simulating Cancer Treatment

Simulating Carcinogenesis

Logical Background and Programming

Color

Position

Velocity

Direction Vector

Hayflick-Limit

Immune Attack

The Simulation Process

The Validation Process

3.1.2 Simulating Hematopoiesis and Acute Myeloid Leukemia

Normal Hematopoiesis

Simulating Leukemogenesis: Acute Myeloid Leukemia

4 The Hallmark Concept Revisited

5 Discussion

Acknowledgments

References

Chapter 13: Sepsis: A Challenging Disease With New Promises for Personalized Medicine and Biomarker Discovery

1 Introduction

2 Epidemiology and Burden of Disease

3 Definitions and Diagnosis of Sepsis

4 Management

5 Prognosis

6 Pathobiology Draws the Roadmap for Biomarker Discovery

7 Classical and Novel Biomarkers

7.1 Microbiological Documentation

7.2 C-Reactive Protein

7.3 Procalcitonin

7.4 Lactate

7.5 Circulating Immunoglobulins

7.6 Cytokines

7.7 Dendritic Cells

7.8 Endothelial Biomarkers

7.9 Endothelins

7.10 Presepsin

7.11 Neutrophil Gelatinase Associated Lipocalin

7.12 Cholesterol

7.13 Genetic Variants

7.14 Cell Free DNA

7.15 MicroRNA

8 Composite Systems and Point-of-Care Tests

9 Data Management

10 Perspective

References

Further Reading

Chapter 14: Asphyxia Diagnosis: An Example of Translational Precision Medicine

1 Introduction

2 The PM Approach

3 Examples for Successful PM Application

4 Metabolites in PM Diagnostics

5 The Global Burden of Perinatal Asphyxia

6 Perinatal Asphyxia—The Diagnostic Gap

7 Asphyxia Markers

8 Strategies for the POC Diagnosis of Perinatal Asphyxia

9 Antibodies

10 Aptamers

11 Enzymes

12 POC Devices

12.1 Paper Based Analytical Devices

12.2 Microfluidic Systems

13 Outlook

References

Chapter 15: Biomarker for Alzheimer's Disease

1 Introduction

2 Definition "Biomarker"

3 Classification of Biomarkers

3.1 Trait Markers

3.2 State Markers

4 Clinic and Pathogenesis of Alzheimer’s Disease

4.1 Amyloid Precursor Protein and the Production of Aβ

4.2 Tau Proteins

5 Current Status of Research: Potential Biomarkers for Alzheimer’s Disease

5.1 Genetic Biomarkers

5.2 Protein Biomarkers

5.2.1 APP Metabolism

Aβ42

Bace1

Bin1

5.2.2 T-Tau/P-Tau Proteins

α-Synuclein

5.2.3 Neurofilaments

5.2.4 sNRG-1

5.2.5 YKL-40

5.3 Metabolic Biomarkers

5.3.1 Glucose Metabolism and Plasma Acylcarnitines

5.3.2 Insulin Metabolism

5.3.3 Cholesterol Metabolism and 24-Hydroxycholesterol/27-Hydroxycholesterol

5.4 Immunologic Biomarker

5.4.1 Autoantibodies Against Aβ

5.4.2 Autoantibodies Against Anti-CAPS

5.5 Transcriptomic Biomarkers

5.6 Overview

6 Barriers Between the Brain and the Blood Circulation

7 Outlook

References

Index

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