Abstract
Benefits of this report
- This report has evolved during the past 17 years, profiting from feedback
by numerous readers and experts.
- The most comprehensive and up-to-date one-stop source of information on
technical and commercial aspects of molecular diagnostics.
- Includes profiles of 333 companies, the largest number in any report on
this topic.
- 600 references, cited in the report are included in the bibliography.
- The text is supplemented by 101 tables and 16 figures.
Who should read this report? Chief executive officers of molecular diagnostic
companies. Business development executives of pharmaceutical and biotechnology
companies. Executives of companies involved in developing integration of
diagnosis and treatment as well as those interested in personalized medicine.
Officers of genomic and proteomic companies interested in diagnostic
technologies. Research scientists involved in application of molecular
diagnostic technologies. Planners of healthcare services.
Summary
This report describes and evaluates the molecular diagnostics technologies
that will play an important role in practice of medicine, public health,
pharmaceutical industry, forensics and biological warfare in the 21st century.
This includes several polymerase chain reaction (PCR)-based technologies,
fluorescent in situ hybridization (FISH), peptide nucleic acids (PNA),
electrochemical detection of DNA, sequencing, mitochondrial DNA, biochips,
nanotechnology and proteomic technologies.
Initial applications of molecular diagnostics were mostly for infections but
are now increasing in the areas of genetic disorders, preimplantation
screening and cancer. Genetic screening tests, despite some restrictions is a
promising area for future expansion of in vitro diagnostic market. Molecular
diagnostics is being combined with therapeutics and forms an important
component of integrated healthcare. Molecular diagnostic technologies are also
involved in development of personalized medicine based on pharmacogenetics and
pharmacogenomics. Currently, there has been a considerable interest in
developing rapid diagnostic methods for for point-of-care and biowarfare
agents such as anthrax.
The number of companies involved in molecular diagnostics has increased
remarkably during the past few years. More than 800 companies have been
identified to be involved in developing molecular diagnostics and 333 of these
are profiled in the report along with tabulation of 778 collaborations.
Despite the strict regulation, most of the development in molecular
diagnostics has taken place in the United States, which has the largest number
of companies.
The markets for molecular diagnostics technologies are difficult to estimate.
Molecular diagnostics markets overlap with markets for non-molecular
diagnostic technologies in the in vitro diagnostic market and are less well
defined than those for pharmaceuticals. Molecular diagnostic markets are
analyzed for 2012 according to technologies, applications and geographical
regions. Forecasts are made up to 2022. A major portion of the molecular
diagnostic market can be attributed to advances in genomics and proteomics.
Biochip and nanobiotechnology are expected to make a significant contribution
to the growth of molecular diagnostics.
This report was first published as DNA Diagnostics in 1995 by PJB
Publications, UK. It was updated in 1997 as Molecular Diagnostics and the next
edition, Molecular Diagnostics II, was published by Decision Resources Inc in
1999. All the three versions of the reports were well accepted and sold
widely.The report has been rewritten several times since then.
Table of Contents
Part I
0. Executive Summary 25
1. Introduction 27
- Definitions and scope of the subject 27
- Historical evolution of molecular diagnostics 27
- Molecular biology relevant to molecular diagnostics 28
- DNA 28
- DNA polymerases 28
- Restriction endonucleases 29
- RNA 29
- RNA polymerases 29
- Non-coding RNAs 30
- DNA transcription 30
- Chromosomes 30
- Telomeres 31
- Mitochondrial DNA 31
- Genes 32
- The genetic code 32
- Gene expression 32
- The human genome 33
- ENCODE 33
- Variations in the human genome 34
- Variations in DNA sequences 34
- Single nucleotide polymorphisms 34
- Haplotyping 35
- Copy number variations in the human genome 35
- Genotype and haplotypes 37
- Insertions and deletions in the human genome 37
- Complex chromosomal rearrangements 38
- Large scale variation in human genome 38
- Structural variations in the human genome 38
- Replication of the DNA helix 39
- Transposons 40
- Epigenetics 40
- DNA methylation 40
- Proteins 41
- Proteomics 41
- Monoclonal antibodies 41
- Aptamers 41
- Basics of molecular diagnostics 42
- Tracking DNA: the Southern blot 42
- Pulsed-field gel electrophoresis 43
- DNA Probes 43
- The polymerase chain reaction 43
- Basic Principles of PCR 44
- Target selection 44
- Detection of amplified DNA 44
- Impact of human genome project on molecular diagnostics 45
- Mapping and sequencing of structural variation from human genomes 45
- 1000 Genomes Project 46
- Human Variome Project 47
- Role of bioinformatics in molecular diagnostics 47
- Systems biology approach to molecular diagnostics 47
- Biomarkers 48
- Applications of molecular diagnostics 49
2. Molecular Diagnostic Technologies 51
- Introduction 51
- DNA sample collection and extraction 51
- Blood samples 51
- Buccal swabs and saliva 51
- Dried blood spots 52
- Formalin-fixed, paraffin-embedded tissues 52
- Manual vs automated DNA extraction 53
- Urine samples for transrenal DNA 53
- Sample preparation 54
- Pressure Cycling Technology 54
- Membrane immobilization of nucleic acids 54
- Automation of sample preparation in molecular diagnostics 55
- ABI PRISM 6700 Automated Nucleic Acid Workstation 55
- BioRobot technology 55
- COBAS AmpliPrep System 55
- GENESIS FE500 Workcell 55
- GeneMole 56
- PCR BioCube 56
- QIAsymphony 56
- Tigris instrument system 56
- Techniques for sample preparation that are suitable for automation 57
- Xtra Amp Genomic DNA Extraction 57
- Extraction of DNA from paraffin sections 57
- Dynabead technology 57
- SamPrep 57
- Use of magnetic particles for automation in genome analysis 58
- Companies involved in nucleic acid isolation 58
- Labeling and detection of nucleic acids 59
- Novel PCR methods 60
- Addressing limitations of PCR 60
- CAST-PCR 60
- Combined PCR-ELISA 60
- Convection PCR 61
- Digital PCR 61
- Emulsion PCR 62
- ExCyto PCR 63
- Fast PCR 63
- Long and accurate PCR 63
- Multiplex PCR 63
- Overlap extension PCR 64
- Real-time PCR systems 64
- Dyes used in real-time PCR 65
- Target-specific fluorogenic probes for monitoring real-time PCR 65
- Applications of real-time PCR 65
- Limitations of real-time PCR 66
- Quantitative PCR for accurate low level DNA analysis 66
- qPCR for quantification of circulating mtDNA 67
- Guidelines for real-time qPCR 67
- Future applications of real-time qPCR 67
- Commercially available real-time PCR systems 68
- 7500 Fast Dx Real-Time PCR Instrument 69
- LightCycler PCR system 69
- LightUp probes based on real-time PCR 69
- MNAzyme qPCR 70
- READ™ real-time PCR method 71
- StellARray™ technology 71
- Reverse hybridization PCR assays 71
- Reverse transcriptase (RT)-PCR 71
- Standardized reverse transcriptase PCR 72
- Single cell PCR 72
- LATE-PCR 72
- COLD-PCR 73
- AmpliGrid-System 74
- DNA melt analysis 74
- High-resolution DNA melt analysis for genotyping 74
- PCR device for DNA melt analysis in space 75
- Monitoring of gene amplification in molecular diagnostics 75
- Non-PCR nucleic acid amplification methods 75
- DNA probes with conjugated minor groove binder 75
- Dynamic Flux Amplification 76
- Isothermal nucleic acid amplifications 76
- Isothermal reaction for amplification of oligonucleotides 76
- Isothermal and chimeric primer-initiated amplification of nucleic acids
76
- Loop-mediated amplification 77
- Linked Linear Amplification 77
- Multiplex Ligation-Dependent Probe Amplification 77
- Rapid analysis of gene expression 77
- Rolling circle amplification technology 78
- Gene-based diagnostics through RCAT 79
- RCAT-immunodiagnostics 79
- RCAT-pharmacogenomics 80
- Circle-to-circle amplification 80
- Ramification amplification method 80
- Single Primer Isothermal Amplification 81
- Transcription mediated amplification 81
- WAVE nucleic acid fragment analysis system 81
- Technologies for signal amplification 82
- 3 DNA dendrimer signal amplification 82
- Hybridization signal amplification method 83
- Signal mediated amplification of RNA technology 84
- Invader assays 84
- Hybrid Capture technology 86
- Branched DNA test 87
- Tyramide signal amplification 87
- Non-enzymatic signal amplification technologies 87
- Non-PCR methods for molecular diagnosis 88
- Direct molecular analysis without amplification 88
- Trilogy™ Platform 88
- Direct detection of dsDNA 89
- Multiplex assays 90
- Fluorescent in situ hybridization 90
- FISH technique 91
- Applications of FISH 91
- Modifications of FISH 92
- Direct visual in situ hybridization 92
- Direct labeled Satellite FISH probes 93
- Comparative genomic hybridization 93
- Primed in situ labeling 93
- Interphase FISH 94
- FISH with telomere-specific probes 94
- Multicolor FISH 94
- Simultaneous Ultrasensitive Subpopulation staining/Hybridization In situ
95
- Automation of FISH 95
- Companies involved in FISH diagnostics 95
- RNA diagnostics 96
- RNA isolation from tissue samples 96
- Commercially available tests for mRNA detection and quantitation 97
- Branched-chain DNA assay for measurement of RNA 97
- Cycling probe technology 98
- Invader RNA assays 98
- Linear RNA amplification 98
- Non-isotopic RNase cleavage assay 99
- Nucleic acid sequence-based amplification 99
- Q Beta replicase system 101
- RNAScope 101
- RNA expression profiling 101
- Visualization of mRNA expression in vivo 102
- Solid Phase Transcription Chain Reaction 102
- Transcriptome analysis 102
- MicroRNA diagnostics 103
- Microarray vs quantitative PCR for measuring miRNAs 103
- Microarrays for analysis of miRNA gene expression 103
- miR-TRAP to identify miRNA targets in vivo 104
- Modification of in situ hybridization for detection of miRNAs 105
- Nuclease Protection Assay to measure miRNA expression 105
- Real-time PCR for expression profiling of miRNAs 105
- Use of LNA to explore miRNA 106
- Whole genome amplification 106
- Companies that provide technologies for whole genome amplification 106
- QIAGEN's Repli-G system 107
- GenomePlex™ Whole Genome Amplification 107
- DNA sequencing 108
- Companies involved in sequencing 109
- Applications of next generation sequencing in molecular diagnostics
110
- Companies developing sequencing for molecular diagnostics 111
- Genome-wide approach for chromatin mapping 112
- Mitochondrial sequencing 112
- Identification of unknown DNA sequences 113
- Mitochondrial exome sequencing 113
- Optical mapping 114
- Gene expression analysis 114
- Gene expression profiling on whole blood samples 115
- Gene expression patterns of white blood cells 115
- Gene expression profiling based on alternative RNA splicing 116
- MAUI (MicroArray User Interface) hybridization 116
- Monitoring in vivo gene expression by molecular imaging 117
- Serial analysis of gene expression (SAGE) 117
- Single-cell gene expression analysis 117
- T cell receptor expression analysis 118
- Tangerine™ expression profiling 118
- Whole genome expression array 119
- Ziplex™ system 119
- Companies involved in gene expression analysis 120
- Peptide nucleic acid technology 121
- Use of PNA with fluorescence in situ hybridization 121
- PNA and PCR 122
- Use of PNA with biosensors 122
- PNA-based PD-loop technology 123
- PNA-DNA hybrid quadruplexes 123
- Companies involved in PNA diagnostics 123
- Locked nucleic acids 124
- Zip Nucleic Acids 124
- Electrochemical detection of DNA 125
- Mediated nucleic acid oxidation 125
- Detection of hybridized nucleic acid with cyclic voltametry 126
- Electrochemical detection based on Toshiba's CMOS technology 126
- Concluding remarks on electrochemical DNA detection 126
- Bead-based assay platforms 127
- Scorpions™ technology 128
- The Scorpions reaction 128
- Applications of Scorpions 128
- Nucleic acid lateral flow molecular diagnostics 129
- Omics-based tests 130
3. Biochips, Biosensors, and Nanobiotechnology 131
- Introduction to biochip technology 131
- Applications of biochips in diagnostics 131
- GeneChip 132
- GeneChip Human Genome Arrays 133
- AmpliChip CYP450 133
- Electronic detection of nucleic acids on microarrays 133
- Microchip capillary electrophoresis 134
- Strand displacement amplification on a biochip 134
- Rolling circle amplification on microarrays 134
- LiquiChip-RCAT 134
- Fast PCR biochip 135
- Multiplex microarray-enhanced PCR for DNA analysis 135
- Multiplexed Molecular Profiling 135
- Universal DNA microarray combining PCR and ligase detection reaction
136
- Genomewide association scans 136
- Whole genome chips/microarrays 137
- Transposon insertion site profiling chip 137
- Standardizing the microarrays 138
- Companies involved in developing biochip technology for diagnostics
138
- Future of biochip technology for molecular diagnostics 139
- Microfluidic chips 140
- Fish-on-chip 140
- Lab-on-a-chip 140
- LabCD 141
- Micronics' microfluidic technology 141
- Microfluidic chips/arrays using PCR 141
- Microfluidic automated DNA analysis using PCR 141
- Digital PCR Array 141
- Digital PCR on a SlipChip 142
- Microfluidic chips integrated with RCAT 142
- Microfluidic chips integrated with PET 142
- Companies developing microfluidic technologies 143
- Biosensor technologies 144
- Classification of biosensor technologies 144
- DNA-based biosensors 145
- DNA hybridization biosensor chips 145
- PCR-free DNA biosensor 145
- DNA based biosensor to detects metallic ions 146
- Genetically engineered B lymphocytes 146
- Biosensors immunoassays 146
- PNA (peptide nucleic acid)-based biosensors 147
- Protein-based biosensors 147
- Antibody biosensors 147
- Cell-based biosensors (cytosensors) 147
- Multicell biosensors 148
- Microbial biosensors 148
- Optical biosensors 149
- Surface plasmon resonance technology 149
- Label-free optical biosensor 150
- Microsensors using with nano/microelectronic communications technology
150
- Electrochemical sensors 150
- Enzyme electrodes for biosensing 151
- Conductometric sensors 151
- Electrochemical genosensors 151
- Electrochemical nanobiosensor 151
- Electrochemical microRNA biosensor 152
- Phototransistor biochip biosensor 153
- Ribozyme-based sensors 153
- RiboReporters 153
- Concluding remarks and future prospects of biosensor technology 154
- Companies developing biosensors for molecular diagnostics 155
- Molecular labels and detection 156
- Detection technologies for molecular labels 157
- Fluorescence and chemiluminescence 157
- Fluorescence technologies for label detection 157
- Companies with fluorescence and chemiluminescence products 158
- Molecular beacons 159
- The Green fluorescent protein 160
- Multiophoton detection radioimmunoassay 160
- Multi-pixel photon counter 161
- Enzyme labels and detection by fluorescence 161
- Phase-sensitive flow cytometry 161
- Microtransponder-based DNA diagnostics 162
- Laboratory Multiple Analyte Profile 163
- Multiple labels 163
- Protein-DNA chimeras for detection of small numbers of molecules 164
- Single molecule detection 164
- Atomic force microscopy 164
- Capillary electrophoresis 164
- Confocal laser scanning 164
- Time domain optical imaging technology 165
- nCounter Analysis System 165
- Spectrally resolved fluorescence lifetime imaging microscopy 166
- Molecular imaging 166
- Technologies for molecular imaging 166
- Basic research in molecular imaging 167
- Devices for molecular imaging 168
- Molecular imaging in clinical practice 168
- Challenges and future prospects of molecular imaging 168
- Companies involved in molecular imaging 168
- Nanobiotechnology for molecular diagnostics 169
- Magnetic nanoparticles 170
- Gold nanoparticles 171
- Immunoliposome-PCR 171
- Quantum dot technology 172
- Nanotechnology on a chip 173
- Nanogen's NanoChip 173
- Fullerene photodetectors for chemiluminescence detection on microfluidic
chip 174
- Diagnostics based on nanopore technology 174
- Nanosensors 174
- Detection of cocaine molecules by nanoparticle-labeled aptasensors 175
- Nanosensors for glucose monitoring 175
- PEBBLE nanosensors 175
- Quartz nanobalance biosensor 175
- Cantilever arrays 176
- Resonance Light Scattering technology 176
- DNA nanomachines for molecular diagnostics 177
- Nanobarcodes technology for molecular diagnostics 177
- Qdot nanobarcode for multiplexed gene expression profiling 178
- Role of nanobiotechnology in improving molecular diagnostics 178
- Companies involved in nanomolecular diagnostics 178
- Concluding remarks about nanodiagnostics 181
- Future prospects of nanodiagnostics 182
4. Proteomic Technologies for Molecular Diagnostics 183
- Introduction 183
- Proteomic technologies 183
- Biomarkers of disease 183
- Proteomic tools for biomarkers 183
- Search for biomarkers in body fluids 184
- Captamers with proximity extension assay for proteins 184
- Cyclical amplification of proteins 184
- Detection of misfolded proteins by ELISA with exponential signal
amplification 185
- Detection of proteins by Western blot 185
- Diagnostics based on designed repeat proteins 185
- Differential Peptide Display 186
- Light-switching excimer probes 186
- MALDI-TOF MS 187
- Molecular beacon aptamer 187
- Molecular beacon assay 188
- Proteomic patterns 188
- Real-time PCR for protein quantification 189
- Protein biochip technologies 189
- ProteinChip 190
- LabChip for protein analysis 191
- TRINECTIN proteome chip 191
- Protein chips for antigen-antibody interactions molecular diagnostics
191
- Microfluidic devices for proteomics-based diagnostics 192
- Nanotechnology-based protein biochips/microarrays 192
- Nanoparticle protein chip 192
- Protein nanobiochip 192
- Protein biochips based on fluorescence planar wave guide technology 193
- New developments in protein chips/microarrays 193
- Antibody microarrays 194
- Aptamer-based protein biochip 194
- Multiplexed Protein Profiling on Microarrays 194
- Proteomic pattern analysis 195
- Single molecule array 195
- Viral protein chip 195
- Commercial development of protein chips for molecular diagnostics 196
- Proteome Identification Kit 197
- Laser capture microdissection (LCM) 197
- LCM technology 197
- Applications of LCM in molecular diagnostics 198
- Proteomic diagnosis of CNS disorders 198
- Cerebrospinal fluids tests based on proteomics 198
- Urine tests for CNS disorders based on proteins in urine 199
- Diagnosis of CNS disorders by examination of proteins in the blood 200
- Diagnosis of CNS disorders by examination of proteins in tears 200
- Role of proteomics in the diagnosis of Alzheimer's disease 201
- Role of proteomics in the diagnosis of Creutzfeldt-Jakob disease 201
- Future prospects of use of proteomics for diagnosis of CNS disorders
201
- Concluding remarks on the use of proteomics in diagnostics 202
5. Molecular Diagnosis of Genetic Disorders 203
- Introduction 203
- Cytogenetics 204
- FISH with probes to the telomeres 204
- Single copy FISH probes 204
- Comparative genomic hybridization 205
- Use of biochips in genetic disorders 205
- Representational oligonucleotide microarray analysis 206
- SignatureChip®-based diagnostics for cytogenetic abnormalities 206
- Diagnosis of genomic rearrangements by multiplex PCR 206
- Quantitative fluorescent PCR 206
- Mutation detection technologies 207
- PCR-based methods for mutation detection 208
- Cleavase Fragment Length Polymorphism 208
- Direct dideoxy DNA sequencing 208
- Digital Genetic Analysis (DGA) 208
- Fluorescence-based directed termination PCR 209
- Fluorescence melting curve analysis for multiplex mutation detection
209
- Heteroduplex analysis 210
- Restriction fragment length polymorphism 210
- Single-stranded conformation polymorphism (SSCP) analysis 210
- TaqMan real-time PCR 211
- Non-PCR methods for mutation detection 211
- Arrayed primer extension 211
- BEAMing (beads, emulsion, amplification, and magnetics) 212
- ELISA-protein truncation test 212
- Enzymatic mutation detection 212
- Specific anchor nucleotide incorporation 213
- Conversion analysis for mutation detection 213
- Biochip technologies for mutation detection 213
- Combination of FISH and gene chips 214
- Haplotype Specific Extraction 214
- Use of biosensors for detection of mutations 214
- Technologies for SNP analysis 215
- DNA sequencing 216
- Electrochemical DNA probes 216
- Use of NanoChip for detection of SNPs 217
- Single base extension-tag array 217
- Laboratory Multiple Analyte Profile 217
- SNP genotyping with gold nanoparticle probes 218
- PCR-CTPP (confronting two-pair primers) 218
- PCR using one primer amplification of PCR-CTPP products 218
- Peptide nucleic acid probes for SNP detection 218
- SNP genotyping on a genome-wide amplified DOP-PCR template 219
- Pyrosequencing 219
- Reversed enzyme activity DNA interrogation test 219
- Smart amplification process version 2 220
- Zinc finger proteins 220
- UCAN method (Takara Biomedical) 221
- Biochip and microarray-based detection of SNPs 221
- SNP genotyping by MassARRAY 221
- Electronic dot blot assay 221
- Biochip combining BeadArray and ZipCode technologies 222
- SNP-IT primer-extension technology 222
- OmniScan SNP genotyping 222
- Affymetrix SNP genotyping array 223
- Concluding remarks on SNP genotyping 223
- Limitations of SNP in genetic testing 223
- Haplotyping versus SNP genotyping 224
- Nanofluidics technology for high throughput SNP genotyping 224
- Companies involved in developing technologies/products for SNP analysis
224
- Role of copy number variations in genetic diagnostic testing 226
- CNVs in various diseases 226
- CNVs in genetic epilepsy syndromes 226
- CNVs associated with schizophrenia 227
- Methods for determination of CNVs 227
- Digital array for CNV detection 227
- Wellcome Trust Case Control Consortium CNV typing array 227
- CNVer algorithm for CNV detection 228
- Study of rare variants in pinpointing disease-causing genes 228
- Prenatal DNA diagnosis 229
- Invasive prenatal diagnostic procedures 229
- Amniocentesis 229
- Chorionic villus sampling 229
- Molecular methods for prenatal diagnosis 230
- aCGH for prenatal diagnosis 230
- BAC HD Scan test 230
- FISH for prenatal diagnosis 230
- PCR for prenatal diagnosis 230
- In vivo gene expression analysis of the living human fetus 231
- Non-invasive prenatal molecular diagnostic procedures 231
- Fetal cells separation from maternal blood for genetic diagnosis 231
- Digital relative mutation dosage in maternal plasma 232
- Prenatal testing based on transrenal DNA from urine 232
- Tests on fetal DNA in maternal blood 232
- Sequencing-based methods for prenatal diagnosis from maternal DNA 233
- Noninvasive WGS of the fetus 234
- Directed DNA analysis of maternal blood 235
- Applications of prenatal diagnosis 235
- Antenatal screening for Down's syndrome 237
- Diagnosis of congenital infections 237
- Diagnosis of eclampsia 237
- Preimplantation genetic diagnosis 238
- Technologies for preimplantation genetic diagnosis (PGD) 238
- PCR for preimplantation genetic diagnosis 238
- FISH for preimplantation genetic diagnosis 239
- Microarrays for preimplantation genetic diagnosis 239
- Conditions detected by preimplantation genetic diagnosis 239
- The future of preimplantation genetic diagnosis 240
- Companies involved in prenatal/preimplantation diagnosis 241
- Cystic fibrosis 242
- Detection of CFTR gene mutations 242
- CFTR technologies of various companies 243
- Genzyme's CF gene sequencing 243
- CF Plus™ Tag-It Cystic Fibrosis Kit 244
- Asuragen's bead array test 244
- The Ambry CF Test 245
- Biochip for CF diagnosis 245
- Identification of CF variants by PCR/Oligonucleotide Ligation Assay 245
- SensiGene (SEQUENOM) CF carrier screening test 245
- Serum proteomic signature for CF using antibody microarrays 246
- Guidelines for genetic screening for CF 246
- Congenital adrenal hyperplasia 246
- Primary immunodeficiencies 247
- Hematological disorders 248
- Hemoglobinopathies 248
- Sickle cell anemia 248
- Thalassemia 248
- Paroxysmal nocturnal hemoglobinuria 249
- Hemophilia 249
- Hereditary hemochromatosis 249
- Polycystic kidney disease 250
- Hereditary metabolic disorders 250
- Lesch-Nyhan Syndrome 250
- Gaucher's Disease 251
- Acute Intermittent Porphyria 251
- Phenylketonuria 251
- Hereditary periodic fever 252
- Achondroplasia 252
- Molecular diagnosis of eye diseases 252
- Molecular diagnosis of retinitis pigmentosa 252
- Genetic screening for glaucoma 253
- Role of molecular diagnostics in rheumatoid arthritis 253
- Molecular diagnosis of neurogenetic disorders 254
- Alzheimer's disease 255
- Autism spectrum disorders 256
- CNVs associated with autism 256
- Charcot-Marie Tooth disease 257
- Down syndrome 257
- Duchenne and Becker muscular dystrophy 258
- eNOS gene polymorphisms as predictor of cerebral aneurysm rupture 258
- Fragile X syndrome 259
- Huntington disease 259
- Hereditary neuropathy with liability to pressure palsies 260
- Mitochondrial disorders affecting the nervous system 260
- Parkinson's disease 261
- Pompe's disease 262
- Spinal muscular atrophy 262
- Triple repeat disorders 262
- Genetic testing for disease predisposition 263
- Direct-to-consumer genetic tests 263
6. Molecular diagnosis of cardiovascular disorders 265
- Introduction 265
- Coronary heart disease 266
- Genomics of coronary heart disease 266
- Cardiomyopathy 267
- Familial Hypertrophic Cardiomyopathy 267
- Idiopathic dilated cardiomyopathy 267
- Cardiac Arrhythmias 267
- Long Q-T Syndrome 267
- Familial atrial fibrillation 268
- Idiopathic ventricular fibrillation 268
- Congestive heart failure 268
- Hypertension 269
- Disturbances of blood lipids 269
- Familial dyslipoproteinemias 269
- Hypercholesterolemia 269
- Thrombotic disorders 270
- Factor V Leiden mutation 270
- Pulmonary embolism 271
- Hereditary thrombophilia 271
- Molecular diagnostics for monitoring heart transplant rejection 271
- AlloMap® molecular expression testing 271
- Commercial molecular diagnostics for cardiovascular disorders 272
7. Molecular Diagnosis of Infections 273
- Introduction 273
- Molecular techniques for the diagnosis of infections 273
- Antibody-enhanced microplate hybridization assays 274
- Bacteriophage-based methods for detection of bacteria 274
- Biochips/microarrays for detection of microorganisms 275
- Lawrence Livermore Microbial Detection Array 275
- Biosensors for detection of microorganisms 275
- Ibis T5000™ Biosensor System 275
- DNA enzyme immunoassay 275
- DNA biochip/microarray in diagnosis of infections 276
- DNA-based typing methods 277
- Restriction fragment length polymorphism analysis 277
- Ribotyping 277
- Random amplified polymorphic DNA 277
- Combinatorial DNA melting assay 277
- Electrochemical detection of pathogens 277
- FISH for detection of infections 278
- Helicase-dependent isothermal amplification for rapid detection of
pathogens 278
- High resolution melt analysis for diagnosis of infections 278
- Immunomagnetic cell capture 279
- Ligase chain reaction 279
- Multiplex PCR for detection of infections 279
- Metagenomic pyrosequencing 280
- Dual priming oligonucleotide for multiplex PCR 281
- Multiplex amplified nominal tandem repeat analysis 282
- Tests for sepsis 282
- LightCycler® SeptiFast Test 282
- NanoDx™ 283
- SeptiCyte Triage assay 283
- SepsiTest™ 283
- VYOO® Sepsis Test 283
- NASBA for detection of microorganisms 284
- Nucleic acid probes 284
- Neutrophil CD11b expression as a diagnostic marker 284
- Optical Mapping 284
- PNA-FISH for diagnosis of infections 285
- Proteomic technologies for diagnosis of infections 285
- Mass spectrometry for microbial identification 285
- QuantiFERON® technology for pre-molecular diagnosis of infections
286
- Quantitative reverse-transcription PCR for bacterial diagnostics 286
- Rupture event scanning 287
- Real-time single-molecule imaging of virus particles 287
- Single-strand conformational polymorphism 287
- SmartGene platform for identifying pathogens based on genetic sequences
287
- Tessera array technology 287
- Unyvero Solution 288
- Applications, advantages and limitations of molecular diagnostics 288
- Molecular diagnostics versus other microbial detection technologies
288
- Advantages of nucleic acid-based diagnostics in infections 288
- Drawbacks of nucleic acid-based diagnostics in infections 289
- Nanotechnology for detection of infectious agents 289
- Bacterial infections 290
- Mycobacterium tuberculosis 291
- Conventional diagnosis of tuberculosis 291
- Combined tuberculin testing and ELISpotPLUS assay 292
- Microscopic Observation Drug Susceptible Assay for tuberculosis 292
- Molecular diagnostics for tuberculosis 293
- Biomarker-based tests for tuberculosis 294
- Diagnosis of TB in a POC setting 295
- Diagnosis of drug-resistant MTB infection 295
- GeneXpert MTB/RIF (eXpert) automated molecular test for MTB 296
- Diagnosis of other mycobacteria 296
- Leprosy and M. leprae 297
- Chlamydial infections 297
- Neisseria gonorrhoeae 298
- Bacteria associated with bacterial vaginosis 299
- Streptococcal infections 299
- Group B Streptococci 299
- Streptococcus pyogenes and Streptococcus dysgalactiae 300
- Pseudomonas aeruginosa 300
- Helicobacter pylori 300
- Lyme disease 301
- Mycoplasmas 302
- Fungal infections 302
- PCR-based tests for fungal infections 303
- DNA barcode marker for fungi 303
- DNA sequencing for fungal infections 304
- MALDI-TOF MS for diagnosis of fungal infections 304
- Aspergillus 304
- Candida species 305
- Viral infections 305
- HIV/AIDS 306
- Diagnosis of HIV 306
- Detection of HIV provirus 307
- Global Surveillance of HIV-1 genetic variations 308
- Genotyping for drug-resistance in HIV 308
- Neonatal screening of infants of HIV-positive mothers 309
- Phenotyping as predictor of drug susceptibility/resistance in HIV 310
- POC testing for HIV 310
- PCR for resolution of indeterminate Western blot 311
- Screening of cadaveric tissue donors 311
- Tests used for quantification of HIV 311
- Conclusions about HIV diagnostics 312
- Hepatitis viruses 313
- Hepatitis A virus 313
- Hepatitis B virus 313
- Hepatitis C virus 314
- Detection and quantification of HCV RNA 314
- Quantification of HCV RNA levels as a guide to antiviral therapy 315
- Electrochemical DNA chip for diagnosis of HCV 315
- HCV Genotyping as a guide to therapy 315
- Enteroviruses 316
- Adenoviruses 317
- Rhinoviruses 317
- Herpes viruses 317
- Herpes simplex virus 318
- Genital and neonatal herpes simplex 318
- Human cytomegalovirus infections 319
- Epstein-Barr virus 319
- Human papilloma virus 320
- Molecular diagnostics for HPV 320
- Detection of encephalitis viruses 321
- West Nile and St. Louis encephalitis 321
- Venezuelan equine encephalitis virus 321
- Detection of noroviruses 322
- Detection of dengue virus 322
- Protozoal infections 322
- Amebiasis 322
- Cryptosporidium parvum 322
- Leishmaniasis 323
- Malaria 323
- Neurocysticercosis 323
- Pneumocystis carinii 324
- Toxoplasmosis 324
- Infections of various systems 325
- CNS infections 325
- Molecular diagnosis in bacterial meningitis 325
- Molecular diagnosis in herpes simplex encephalitis 325
- Diagnosis of transmissible spongiform encephalopathies 326
- Molecular diagnosis of respiratory viruses 327
- SARS-associated coronavirus 327
- Influenza viruses 328
- Avian influenza H5N1 330
- Avian influenza H7N9 334
- H1N1 influenza 334
- Gastrointestinal infections 337
- Periodontal infections 338
- Diagnosis of urinary infections by a biosensor 339
- Role of molecular diagnosis in sexually transmitted infections 339
- Role of molecular diagnostics in septicemia 339
- Limitations and needs of diagnostics for infections 340
- Differentiation between live and antibiotic-killed bacteria 340
- Cell-based methods for identifying pathogenic microorganisms 341
- Cell-based virus assays 341
- Cell-based detection of host response to infection 341
- Role of molecular diagnostics in hospital acquired infections 341
- Detection of hospital-acquired bacterial infections 342
- Detection of methicillin-resistant S. aureus 342
- Whole-genome sequencing for investigation of MRSA outbreaks 343
- Detection of vancomycin-resistant enterococci 344
- Detection of hospital-acquired C. difficile 344
- Integrated device for rapid detection of organisms associated HAI 346
- Bacterial genome sequencing in antimicrobial resistance 346
- Detection of hospital-acquired viral infections 346
- Molecular diagnosis of BK virus 346
- Diagnosis of hospital-acquired rotavirus gastroenteritis 347
- Molecular diagnostics and the microbiome 347
- Human Microbiome Project 347
- Application of metagenomics to study of the microbiome 348
- MicroBiome Analysis Center 348
- Concluding remarks and future prospects of diagnosis of infections 349
- Rapid point-of-care diagnosis of infections 349
- Diagnosis of viruses using protein fingerprinting 351
- QIAplex PCR multiplex technology 352
- Role of PCR vs sequencing for diagnosis of infections 352
- Companies involved in molecular diagnosis of infectious diseases 353
8. Molecular Diagnosis of Cancer 357
- Introduction 357
- Cancer genomics 357
- Cancer genes 358
- Oncogenes 358
- Tumor Suppressor Genes 358
- p53 359
- p16 360
- CNVs in cancer 360
- Allele-specific copy number analysis of tumors 361
- Viruses and cancer 361
- Detecting viral agents in cancer 362
- Conventional cancer diagnosis 363
- Molecular techniques for cancer diagnosis 363
- Genome analysis at the molecular level 365
- Mutation detection at molecular level 365
- Expression profiling of tumor cells sorted by flow cytometry 366
- MicroRNA expression profiling for cancer diagnostics 366
- Biomarkers in cancer 366
- Circulating nucleic acids as potential biomarkers of cancer 367
- Circulating nucleosomes in serum of cancer patients 367
- Detection of DNA methylation 367
- eTag assay system for cancer biomarkers 369
- HAAH as a biomarker for cancer 370
- LigAmp for detection of gene mutations in cancer 370
- Mitochondrial DNA as a cancer biomarker 370
- Oncoproteins as biomarkers for cancer 371
- Sequencing-based approaches for detection of cancer biomarkers 371
- Molecular fingerprinting of cancer 372
- Fluorescent in situ hybridization 372
- Genetic analysis of cancer 373
- Comparative genomic hybridization in cancer diagnostics 373
- Loss of heterozygosity 373
- Digital karyotyping 374
- Gene expression profiles predict chromosomal instability in tumors 374
- PCR Techniques 374
- Cold-PCR 375
- Real-time qPCR for diagnosis of cancer 375
- Real-time PCR with myT™ Primer reagents 375
- Antibody-based diagnosis of cancer 376
- Monoclonal antibodies for diagnosis of cancer 376
- Recombinant antibodies as a novel approach to cancer diagnosis 376
- Combined immunological and nucleic acid tests 376
- Combination of MAbs and RT-PCR 376
- Immunobead RT-PCR 377
- Assays for determining susceptibility to cancer 377
- Gene expression profiling in cancer 377
- Microarrays for gene expression profiling in cancer 378
- Serial analysis of gene expression (SAGE) 378
- DNA tags for finding genes expressed in cancer 379
- Suppression subtractive hybridization 379
- Cancer tests based on gene expression profiling 379
- Measurement of telomerase activity 380
- Detection of circulating tumor cells in blood 381
- BEAMing technology for quantification of circulating tumor DNA 381
- Biochips/microfluidics for detection of CTCs 381
- CellSearch 382
- CellTracks® AutoPrep® System 382
- CTCscope system for detection of CTCs 382
- CTChip™ 383
- Fiber-optic array scanning technology 383
- IsoFlux System 383
- Lab-on-chip for the isolation and detection of CTCs 383
- MagSweeper 384
- Nano-Velcro to capture CTCs for diagnosis of cancer 384
- Future prospects of detection of cancer cells in blood 384
- Epithelial aggregate separation and isolation 385
- Proteomic technologies for the molecular diagnosis of cancer 385
- Proteomic technologies for tumor biomarkers 385
- Affibodies as contrast agents for imaging in cancer 386
- Aptamer-based technology for protein signatures of cancer cells 386
- Aptamer probes for in vivo diagnosis of cancer 386
- Aptamers for combined diagnosis and therapeutics of cancer 387
- Automated image analysis of nuclear protein distribution 387
- Laser capture microdissection in oncology 388
- Layered expression scanning 388
- Membrane-type serine protease-1 388
- Survivin and molecular diagnosis of cancer 389
- Biochip/microarrays for cancer diagnosis 389
- Role of DNA microarrays in gene expression profiling 390
- Biochip detection of FHIT gene 390
- Nanobiotechnology for early detection of cancer 390
- Detection of nanoparticle self assembly in tumors by MRI 391
- Differentiation between normal and cancer cells by nanosensors 391
- Magnetic nanoparticle probes 391
- Quantum dots for early detection of cancer 391
- Molecular imaging of cancer 392
- In vivo tumor illumination by adenoviral-GFP 392
- PET for in vivo molecular diagnosis of cancer 393
- Radiolabeled peptide-based targeting probes for cancer imaging 393
- Xenon-enhanced MRI 393
- Optical systems for in vivo molecular imaging of cancer 393
- Detection of micrometastases 394
- Detection of origin in cancers of unknown primary 395
- Molecular diagnosis of cancers of various organs 395
- Brain tumors 395
- Molecular diagnostic methods for brain tumors 396
- Glioblastoma multiforme 396
- Circulating microvesicles as biomarkers of glioblastoma 397
- Combination of neuroimaging and DNA microarray analysis in GBM 397
- Medulloblastoma 397
- Multigene predictor of outcome in GBM 398
- Oligodendroglioma 398
- Advantages and limitations of molecular diagnosis of brain tumors 398
- Breast cancer 399
- Breast cancer genes 399
- Circulating nucleic acid biomarkers of breast cancer 400
- Molecular diagnostic tests for breast cancer 400
- Mouse ESC-based assays to evaluate mutations in BRCA2 404
- Genomic profiles of breast cancer 404
- Role of molecular diagnostics in management of breast cancer 405
- Tests for prognosis of breast cancer 409
- Prediction of recurrence in breast cancer for personalizing therapy 411
- Cervical cancer 412
- Colorectal cancer 413
- ColoVantage CRC test 414
- Detection of familial adenomatous polyposis coli 414
- Detection of CRC at precancerous state 414
- Detection of circulating tumor cells in colorectal cancer 414
- Diagnosis of hereditary nonpolyposis colorectal cancer 415
- Diagnosis of colorectal cancer from DNA in stools 415
- Early diagnosis of colorectal cancer from blood samples 416
- Guanylyl cyclase C tests for colorectal cancer 416
- Minimally invasive screening for colorectal cancer 417
- Gastric cancer 417
- Head and neck cancer 417
- Nanobiochip sensor technique for analysis of oral cancer biomarkers 417
- ProteinChip for diagnosis of head and neck cancer 418
- Hematological malignancies 418
- Chromosome translocations 418
- Flow cytometry in diagnosis of leukemia 418
- Gene chip technology 419
- Hairy-cell leukemia 419
- Laboratory assessment of leukemia 419
- Molecular probes 420
- Minimal residual disease 421
- Screening of gene mutations in chronic myeloproliferative diseases 421
- Lung cancer 422
- Molecular subtyping of lung cancer 424
- Melanoma 424
- Ovarian cancer 425
- Mutation of genes 425
- Relevance of genetic testing to management of ovarian cancer 425
- Serum biomarkers for early detection of ovarian cancer 426
- Biomarkers of ovarian cancer 426
- Concluding remarks on testing for ovarian cancer 427
- Pancreatic cancer 427
- Proteomic techniques for diagnosis of pancreatic cancer 427
- Detection of KRAS mutations in pancreatic cancer 427
- Prostate cancer 428
- Early detection of prostate cancer recurrence by nanotechnology 428
- Gene expression analysis of prostate cancer 428
- Huntingtin Interacting Protein 1 429
- Integrative genomic and proteomic profiling of prostate cancer 429
- LCM for diagnosis of prostate cancer 429
- PCA3 gene detection in urine 430
- PCR assay for assessing silencing of protein cadherin 13 gene 430
- Prolaris test 431
- Prostate biopsy for detection of prostatic intraepithelial neoplasia
431
- Prostate Core Mitomic Test™ 431
- Prostat Health Index 431
- Screening of multiple SNPs for risk of prostate cancer 432
- Semen testing for prostate cancer biomarkers 432
- Serum-protein fingerprinting in prostate cancer 433
- Thyroid cancer 433
- Afirma gene expression classifier for inconclusive thyroid biopsies 433
- Gene expression biomarkers of thyroid cancer 434
- Multiple endocrine neoplasia type 2B as risk factor for thyroid cancer
434
- miRNA expression profiling in thyroid cancer 434
- Urinary bladder cancer 435
- Role of molecular diagnostics in the management of cancer 435
- Risk assessment and prevention of cancer 435
- Role of molecular diagnosis in the design of future cancer therapies
436
- Molecular classification of cancer 436
- Determination of cancer prognosis 437
- Prognosis by tumor classification 437
- Prognosis by cancer gene expression 437
- Selection of anticancer drugs based on molecular diagnosis 437
- Integrated genome-wide analysis of cancer for diagnosis and therapy 438
- Personalized therapy for cancer patients 438
- Pharmacogenetics and cancer therapy 438
- Molecular diagnostics as an aid to selection of cancer therapy 439
- Drug resistance in cancer 440
- Role of organizatons in molecular diagnosis of cancer 440
- Role of NCI in molecular diagnosis of cancer 440
- Molecular profiling of cancer 440
- Cancer Genome Atlas 441
- Cancer Genetic Markers of Susceptibility Project 441
- Support for future research in molecular diagnosis of cancer 442
- Role of the International Cancer Genome Consortium 442
- Future prospects of molecular diagnosis of cancer 443
- Companies involved in molecular diagnosis of cancer 443
9. Molecular Diagnostics in Biopharmaceutical Industry & Healthcare 449
- Introduction 449
- Molecular diagnostics in biopharmaceutical industry 449
- Molecular diagnostic technologies and drug discovery 450
- Molecular diagnostics and pharmacogenetics 450
- Molecular toxicology 451
- Gene expression studies for toxicology 452
- Toxicogenomics 452
- Toxicoproteomics 452
- Mitochondrial assays 454
- MetaChip/Datachip 454
- Molecular diagnostics and pharmacogenomics 455
- Molecular diagnostics and therapeutic drug monitoring 456
- Applications molecular diagnostics in gene therapy 456
- Use of PCR to study biodistribution of gene therapy vectors 456
- PCR for verification of the transcription of DNA 457
- In situ PCR for direct quantification of gene transfer into cells 457
- Detection of retroviruses by reverse transcriptase (RT)-PCR 457
- Assessment of safety issues of gene transfer 457
- Quantitative PCR for monitoring the effectiveness of gene therapy 457
- Use of FISH for analysis of adeno-associated viral vector integration
458
- Monitoring of gene expression by green fluorescent protein 458
- Quality control of protein therapeutics and vaccines 458
- Detection of microbial contamination in biopharmaceutical manufacturing
459
- Role of PCR in detecting contamination 459
- Systems for rapid detection of contaminants 459
- Contamination of biopharmaceuticals with prions 460
- DNA tagging for control and tracing of drug distribution channels 460
- Molecular diagnostics for organ transplantation 460
- HLA typing 460
- Sequencing for HLA typing 462
- Commercial products for transplant molecular diagnostics 462
- Post-cardiac transplant patient monitoring for rejection 464
- Application of molecular diagnostics in blood transfusion 465
- Molecular diagnostics for testing transfusion compatibility 465
- Transmission of infections in blood transfusion 465
- Molecular tests for screening of blood supply for viruses 466
- Commercial molecular diagnostic technologies for blood screening 466
- Bridge amplification technology 467
- COBAS AmpliScreen HCV and HIV Assays 467
- INACTINE 468
- NucliSens Extractor system 468
- Pall's enhanced Bacteria Detection System 468
- PCR combined with algorithm method 469
- Prions detection in human blood 469
- PRISM® automated system 470
- Procleix HIV-1/HCV Assay 470
- West Nile virus detection in human blood 471
- Advantages and limitations of molecular diagnostics for blood screening
471
- Molecular epidemiology 472
- Molecular epidemiology of genetic diseases 472
- Role of CNVs in study of genetic epidemiology 472
- Accumulation of CNVs with aging 473
- Monogenic versus polygenic disorders 474
- Critical issues facing genetic epidemiology 474
- Molecular epidemiology of infectious diseases 474
- Methods and purposes 474
- Emerging infections 475
- Human vs. non-human infections 475
- Genetics and susceptibility to infectious disease 476
- Molecular epidemiology of cancer 476
- Molecular epidemiology of p53 gene mutations 477
- Molecular epidemiology of link between virus and cancer 477
- Molecular epidemiology and cancer prevention 477
- SNPs and molecular epidemiology 477
- Molecular diagnostics for identification of food-borne pathogens 477
- Introduction 477
- Molecular diagnostic methods used in food-borne infections 478
- Limitations of use of molecular probes in food analysis 479
- Detection of Listeria-contaminated foods 479
- Optical biosensor for detection of Listeria 480
- Real-time PCR for detection of Listeria 480
- Detection of Salmonella 480
- MicroSEQ® Salmonella Detection Kit 480
- E. Coli detection 481
- MicroSEQ® E. Coli Detection Kit 481
- DuPont Bax system 481
- MLG method for detection of multiple STEC strains 481
- Detection of rare strains of E. Coli 481
- Companies with technologies for food pathogen detection 482
- Transmissible spongiform encephalopathies (TSEs) 483
- Basis of molecular diagnosis of prion diseases 484
- Molecular diagnosis of TSEs 484
- Companies involved in developing molecular diagnostics for TSEs 487
- Detection of genetically modified food 488
- Molecular diagnostics for detection of doping in sports 489
- Screening of synthetic glucocorticosteroids in human urine 489
- Detection of gene doping 490
- Role of molecular diagnostics in future healthcare 490
- Translation of genomic research into genetic testing for healthcare
490
- Molecular diagnostics and disease management 491
- Role of genetic biomarkers in disease management 491
- Role of molecular diagnostics in personalized medicine 492
- Integrated healthcare 492
- Screening 492
- Early diagnosis 493
- Prevention 493
- Therapy based on molecular diagnosis 493
- Monitoring of therapy 493
- Advantages and limitations of integrated healthcare 494
- Commercially available systems for integrated healthcare 494
- Combination of diagnostics and therapeutics 494
- Companion diagnostics 495
- Companies involved in companion diagnostics 495
- Point-of-care diagnosis 497
- Technologies for point-of-care diagnosis 498
- Biochips for POC diagnosis 499
- Advantages versus disadvantages of POC diagnosis 500
- POC Diagnostic Initiative 501
- Future prospects of POC testing 501
- Companies developing POC diagnosis 501
- The impact of molecular diagnostics on clinical laboratory practice
504
- 10. Molecular Diagnostics in Forensic Medicine and Biological Warfare 505
- Application of molecular diagnostics in forensic medicine 505
- Technologies 505
- ABO genotyping 505
- DNA analysis for identification of ancient or historical specimens 506
- DNA processing of forensic samples 506
- Fluorescent detection systems 507
- Genome wide association studies linking genes to facial features 507
- Mitochondrial DNA analysis 507
- Pressure cycling technology for forensic applications 507
- Polymorphic Alu insertions 508
- Single Nucleotide Polymorphisms (SNP) analysis 508
- Short tandem repeat (STR) 508
- Applications 509
- Applications in criminology 509
- Identification of remains of military personnel 511
- Identification of remains of victims of mass disasters 511
- Parentage testing 512
- Gender determination 513
- Companies developing molecular diagnostics for forensic science 514
- Molecular detection of biological warfare agents 515
- Introduction to biological warfare agents 515
- Role of PCR in the diagnosis of biological warfare agents 516
- Multiplex PCR microarray assay to detect bioterror pathogens in blood
516
- Laboratory diagnosis of Anthrax 516
- Challenges in diagnosis of biological warfare agents 517
- US government efforts for detection of biological warfare agents 518
- The US Army Medical Research Institute of Infectious Diseases 518
- Homeland Security Advance Research Projects Agency 519
- Handheld Isothermal Silver Standard Sensor 519
- Hapten mediated display and pairing of rAbs for biothreat assays 519
- Commercial development of diagnostic devices for biological agents 520
- Companies developing diagnostic devices for biological agents 520
- Biodefence microarray 522
- Identification of genetic markers of individual pathogens 523
- Microbial Identification System based on OptiChip™ 523
- Hand-Held Advanced Nucleic Acid Analyzer 523
- Nanogen's portable detection device 524
- Nanode Array Sensor Microchips 524
- MicroChemLab 524
- BioThreat Alert Test Strip 525
- Benchtop living cell biosensor 525
- BioForce NanoArray sensor technology 525
- QTL handheld biosensor 526
- Analyte 2000 biosensor 526
- Airborne bacterial spore detection technology 526
- Destruction and detection of anthrax by lysin 526
- Biosensor based on mass spectrometry of microorganisms's RNA 527
- Bead ARray Counter 527
- ProteinChip-based detection of bioterroism agents 527
- TIGER biosensor 528
- The PathAlert™ Detection System 528
- VereThreat™ 528
- Concluding remarks about biodefense applications of diagnostics 528
11. References 531
Tables
- Table 1-1: Landmarks in development of molecular technology and its
application to diagnosis 27
- Table 1-2: Applications of molecular diagnostics 49
- Table 2-1: Companies with products for nucleic acid isolation 58
- Table 2-2: Applications of real-time PCR 66
- Table 2-3: Some commercially available real-time PCR systems 68
- Table 2-4: A selection of companies with commercially available FISH
diagnostics 95
- Table 2-5: Selected companies with RNA diagnostic tests 97
- Table 2-6: Companies involved in whole genome amplification 106
- Table 2-7: Companies involved in sequencing 109
- Table 2-8: Companies involved in application of sequencing in molecular
diagnostics 111
- Table 2-9: Comparison of methods of identification of unknown DNA
sequences 113
- Table 2-10: Classification of methods of gene expression analysis 114
- Table 2-11: A selection of companies with gene expression technologies
120
- Table 2-12: Companies involved in developing PNA diagnostics 123
- Table 2-13: Companies with bead-based diagnostic assay platforms 127
- Table 2-14: Companies developing nucleic acid lateral flow molecular
diagnostics 129
- Table 3-1: Applications of biochip technology in relation to molecular
diagnostics 131
- Table 3-2: Companies developing whole genome chips/microarrays 137
- Table 3-3: Companies involved in biochips for molecular diagnostics
138
- Table 3-4: Companies developing microfluidic technologies 143
- Table 3-5: Biosensor technologies with potential applications in molecular
diagnostics 144
- Table 3-6: Important applications of biosensors 154
- Table 3-7: Companies involved in application of biosensors in molecular
diagnostics 155
- Table 3-8: Selected labels for nucleic acid detection 156
- Table 3-9: Selected companies with fluorescence and chemiluminescence
products 158
- Table 3-10: Companies involved in molecular beacon manufacture and
research 160
- Table 3-11: Selected companies involved in molecular imaging 169
- Table 3-12: Nanotechnologies with potential applications in molecular
diagnostics 170
- Table 3-13: Companies developing nanomolecular diagnostics 178
- Table 4-1: Applications of protein biochips/microarrays 189
- Table 4-2: Companies involved in developing diagnostic applications of
protein biochips 196
- Table 4-3: Disease-specific proteins in the cerebrospinal fluid of
patients 199
- Table 5-1: Mutation detection technologies 207
- Table 5-2: Technologies for SNP analysis 215
- Table 5-3: A sampling of companies involved in technologies for SNP
genotyping 225
- Table 5-4: Application of preimplantation genetic diagnosis in monogenic
disorders 240
- Table 5-5: Companies involved in prenatal/preimplantation diagnostics
241
- Table 5-6: CFTR genotyping in cystic fibrosis - companies and technologies
243
- Table 5-7: X-linked immunodeficiency disorders 247
- Table 5-8: Available molecular diagnostics for neurogenetic diseases
254
- Table 5-9: Companies offering genetic screening tests directly to
consumers 263
- Table 6-1: Genes that cause cardiovascular diseases 265
- Table 6-2: Molecular diagnostics for cardiovascular diseases: commercial
development 272
- Table 7-1: Molecular techniques for the diagnosis of infections 273
- Table 7-2: Commercially available molecular diagnostics for sepsis
282
- Table 7-3: Bacteria that can be detected by molecular diagnostic tests
290
- Table 7-4: Commercially available molecular diagnostics for fungal
infections 303
- Table 7-5: Viruses that can be detected by recombinant DNA methods 306
- Table 7-6: Companies with molecular diagnostics for avian influenza virus
H5N1 331
- Table 7-7: Companies with molecular diagnostics for influenza virus H1N1
335
- Table 7-8: Commercially available molecular diagnostics for C. difficile
345
- Table 7-9: Companies developing POC tests for the diagnosis of infections
350
- Table 7-10: Selected companies involved in molecular diagnosis of
infections 353
- Table 8-1: Estimated new cases of cancer in the US of most involved organs
- 2011 357
- Table 8-2: Tumor suppressor genes, their chromosomal location, function,
and associated tumors 359
- Table 8-3: Viruses linked to human cancer 361
- Table 8-4: A classification of molecular diagnostic methods in cancer
364
- Table 8-5: Desirable characteristics of biomarkers for cancer 366
- Table 8-6: Approved monoclonal antibodies for cancer diagnosis 376
- Table 8-7: Methods for comparison of gene-expression profilling in tumor
specimens 378
- Table 8-8: Important cancer tests based on gene signatures 379
- Table 8-9: Impact of in vivo molecular imaging of cancer on oncology
practice 394
- Table 8-10: Molecular diagnostic tests for breast cancer 400
- Table 8-11: Companies developing cancer molecular diagnostics 443
- Table 9-1: Applications of molecular diagnostics in the biopharmaceutical
industry 449
- Table 9-2: Molecular diagnostic technologies for drug discovery 450
- Table 9-3: Molecular diagnostic technologies used for pharmacogenetic
studies 450
- Table 9-4: Companies with novel molecular toxicology technologies 451
- Table 9-5: Applications of molecular diagnostics in gene therapy 456
- Table 9-6: Companies involved in transplant molecular diagnostics 462
- Table 9-7: Companies involved in molecular diagnostics of blood
transfusions 467
- Table 9-8: Pathogenic bacteria in food and targets for molecular
diagnostic probes 478
- Table 9-9: Companies involved in molecular diagnostics for food-borne
infections 482
- Table 9-10: Testing for harmful prions in brain tissue from dead cattle
485
- Table 9-11: Companies involved in developing molecular diagnostics for
TSEs 487
- Table 9-12: Companies involved in detection of genetically modified food
488
- Table 9-13: Companies involved in companion diagnostics 496
- Table 9-14: Applications of point-of-care diagnosis 497
- Table 9-15: Companies developing point-of-care diagnostic tests 502
- Table 10-1: Forensic and legal applications of molecular diagnostics.
509
- Table 10-2: Molecular technologies used for forensic applications 514
- Table 10-3: Biological and chemical agents used as weapons of mass
destruction 515
- Table 10-4: Biological warfare agents that can be identified by PCR
methods 516
- Table 10-5: Companies developing detection devices for biological warfare
agents 520
Figures
- Figure 1-1: Relation of molecular diagnostics to other technologies
50
- Figure 2-1: MNAzyme qPCR 70
- Figure 2-2: Rolling circle amplification technology 78
- Figure 2-3: A schematic view of the Invader operating system 86
- Figure 2-4: Principle of fluorescent in situ hybridization 90
- Figure 2-5: Repli-G system of QIAGEN 107
- Figure 2-6: DNA sequencing process 108
- Figure 2-7: Electrochemical detection of DNA 126
- Figure 2-8: Elements of a Scorpions primer 128
- Figure 3-1: Affymetrix GeneChip technology 132
- Figure 3-2: Basic principle of a biosensor 144
- Figure 3-3: Surface plasmon resonance (SPR) technology 149
- Figure 7-1: Use of DNA chips in diagnosing microbial infections 276
- Figure 7-2: High throughput DNA pyrosequencing for pathogen discovery
281
Part II
12. Ethics, Patents and Regulatory issues 6
- Introduction 6
- Ethical concerns about genetic diagnosis 6
- Ethical guidelines for molecular diagnostics 7
- Ethical aspects of direct-to-consumer genetic services 8
- US public attitudes about genetic testing 9
- Opinion of European geneticists about DTC genetic testing 9
- Genetic testing for susceptibility to adult-onset cancer 9
- Ethics of preimplantation genetic diagnosis 10
- Preimplantation genetic diagnosis to screen for hereditary diseases 10
- PGD to test for susceptibiliy to cancer 10
- PGD and stem cells 11
- Genetic research on stored tissues 11
- Informed consent in clinical trials of in vitro devices 12
- Concluding remarks about ethical issues 12
- Insurance underwriting and gene tests 12
- Should genetic information be available to health insurers? 13
- A need for the re-examination of current views 13
- Genetic Information Nondiscrimination Act of US 14
- Impact of the US health care reform bill on genetic testing issues 14
- Patents for molecular diagnostics 14
- PCR patents 14
- Patenting DNA sequences 14
- US policy on gene patenting relevant to molecular diagnostics 15
- The impact of disease gene patents on molecular diagnostics 16
- Licensing problems associated with genetic testing 16
- BRCA1 and BRCA2 gene patents 16
- Role of the WHO in genetic testing standards 17
- NIH's Genetic Testing Registry 18
- Regulatory issues in the US 18
- Assay Migration Studies for In Vitro Diagnostic Devices 18
- Assessment of diagnostic accuracy 18
- Sensitivity and specificity 19
- Documentation of diagnostic accuracy 19
- Discovery of incidental findings on genetic screening 20
- Evaluation of companion diagnostics/therapeutic for cancer 21
- FDA regulation of multivariate index assays 21
- FDA guidance for IVDs to detect pathogens 22
- FDA guidelines for devices to detect and differentiate HPV 23
- FDA's Microarray Quality Control 23
- FDA and point-of-care diagnosis 24
- Genetic testing of rare disorders 24
- Guidelines for developing omics-based tests 25
- Shared responsibility on oversight of omics-based tests 25
- Guidelines for use of sequencing for diagnosis 26
- Quality control of molecular diagnostic laboratory procedures 27
- Quality assurance of RNA expression profiling 27
- Quality control of point-of-care tests 28
- Regulation of IVD by the FDA 28
- Regulation of in vitro companion diagnostics by the FDA 29
- Regulation of in vivo diagnostics by the FDA 30
- Regulation of laboratory developed tests 31
- Home-brew tests 31
- Laboratory-developed tests used by Medicare recipients 31
- Oversight of LDTs by the FDA 32
- Regulatory aspects of FISH 32
- Regulation of genetic testing 32
- Role of the FDA in genetic testing 32
- Regulation of direct-to-consumer genetic testing 33
- Need for regulatory oversight of DTC 33
- Regulatory issues concerning blood and plasma products 35
- United States Diagnostics Standards 35
- Regulation of in vitro diagnostics in the EU 36
- EU regulations for testing of blood products 36
- Regulation of genetic testing in EU 36
- Evaluation of diagnostic laboratory tests in the UK 38
- Pre-implantation genetic diagnosis in the UK 38
13. Markets for Molecular Diagnostics 40
- Introduction 40
- Methods for study of molecular diagnostic markets 40
- The overall market for diagnostic technologies 41
- Molecular diagnostic markets according to technologies 41
- Marketing strategies according to technologies 42
- Nucleic acid isolation market 42
- Market for PCR-based tests 42
- Markets for PCR instrumentation 42
- Markets for real-time PCR and qRT-PCR 43
- PCR market players 43
- DNA sequencing market 44
- Cytogenetic market 44
- Market for FISH technologies 44
- Biochip/microarray market 45
- Biosensor market 45
- Nanobiotechnology for molecular diagnostics 46
- Markets for gene expression technologies 46
- Reagents and other disposable laboratory materials 46
- Market for immunochemistry diagnostic 46
- Markets for tissue diagnostics 46
- Molecular diagnostic markets according to therapeutic areas 46
- Genetic disorders 47
- Prenatal testing 48
- Cancer 48
- Potential markets for cancer diagnosis according to type of cancer 49
- Infectious diseases 50
- Sexually transmitted diseases 52
- Hospital-acquired infections 52
- Testing for HIV drug resistance 53
- Potential markets for avian influenza diagnostics 54
- Cardiovascular diseases 54
- Neurological disorders 54
- Food testing 54
- Screening of blood for transfusion 55
- Tissue typing for transplantation 55
- Molecular diagnostic markets relevant to pharmaceutical industry 55
- Molecular diagnosis and personalized medicine markets 55
- Growth of markets relevant to personalized medicine 56
- Marketing opportunities according to geographic areas 56
- Unmet needs in molecular diagnostics 57
- Major market trends 57
- Markets according to home-brew and FDA-approved tests 57
- Decentralization of molecular diagnostics 58
- Point-of-care testing 59
- Development of personalized medicine 59
- Cost of sequencing the human genome 59
- Cost of genotyping 60
- Marketing companion diagnostics for personalized medicine 60
- Development of low-cost tests 61
- Simplification of test procedures 61
- Increasing role of proteomics in clinical diagnostics 62
- Forensic and legal applications 62
- Veterinary molecular diagnostics 62
- Marketing strategies 62
- Role of alliances in commercialization of molecular diagnostics 63
- Acquisitions vs collaborations 63
- Analysis of collaborations in molecular diagnostics 67
- Licensing of the technologies 68
- Strategies related to laboratory facilities and technologies 68
- Strategies relevant to the healthcare system 69
- Cost-Benefit studies 69
- Genetic susceptibility testing 69
- Preventive medicine strategies 70
- Targeting treatable and common diseases 70
- Information/education 70
- Physician education 70
- Patient education 71
- European diagnostic information platform 71
- Regulatory strategies 72
- Merger of in vitro and in vivo diagnostics 72
- Integration of diagnostics with therapeutics 72
- Diagnostic applications in clinical trials 72
- Prospects for development of new technologies 73
- Drivers for the development of molecular diagnostics 73
- Factors slowing the development of molecular diagnostics 73
- Cost of sequencing the human genome 74
- Challenges and future prospects for diagnostic applications of sequencing
75
- European projects for improving molecular diagnostics 75
- European Consortium for developing new DNA analysis tools 75
- EU project for improvement of IVD tools procedures 76
- Genetic knowledge parks in the UK 76
- Molecular diagnostic opportunities in defense against bioterrorism 76
- Molecular diagnostics for food safety 77
- POC diagnostics for the developing countries 77
14. Companies involved in molecular diagnostics 78
- Introduction 78
- Major players in molecular diagnostics 78
- Profiles of selected companies 79
- Collaborations 494
Tables
- Table 13-1: Share of in vitro diagnostics in the global diagnostic market
2012-2022 41
- Table 13-2: Molecular diagnostics markets according to technologies from
2012-2022 41
- Table 13-3: PCR market 2012-2022 42
- Table 13-4: Molecular diagnostics markets according to applications
2012-2022 47
- Table 13-5: Markets in 2012 for tests to screen healthy persons for
genetic disorders 48
- Table 13-6: Markets in 2012 for molecular diagnostic screening tests for
cancer 49
- Table 13-7: Molecular diagnostic markets for selected cancers 2012-2022
49
- Table 13-8: Markets value in 2012 for molecular diagnostic screening for
infections 51
- Table 13-9: Future markets for molecular diagnosis of infections 2012-2017
51
- Table 13-10: Future markets for HAI diagnostics 2012-2017 53
- Table 13-11: Growth of markets relevant to personalized medicine 2012-2022
56
- Table 13-12: Molecular diagnostic markets according to geographical areas
2012-2022 56
- Table 13-13: Molecular diagnostic markets according to home-brew and
approved tests 58
- Table 13-14: Marketing strategies for molecular diagnostics 63
- Table 13-15: Acquisitions of molecular diagnostic companies 64
- Table 13-16: Advantages of the integration of diagnostics with
therapeutics 72
- Table 14-1: Top ten players in molecular diagnostics 78
- Table 14-2: Collaborations of companies in molecular diagnostics 494
Figures
- Figure 13-1: Unmet needs in applications of molecular diagnostics 57
- Figure 13-2: Proportion of various areas in molecular diagnostic
collaborations 67
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