Molecular Diagnostics (eBook)

Front Cover 1
Molecular Diagnostics 4
Copyright Page 5
Contents 6
List of Contributors 10
Preface – First Edition 14
Preface – Second Edition 16
Foreword – First Edition 18
Chapter 1. Molecular Diagnostics: Past, Present, and Future 20
1.1 INTRODUCTION 20
1.2 HISTORY OF MOLECULAR DIAGNOSTICS: INVENTING THE WHEEL 20
1.3 THE PCR REVOLUTION: GETTING MORE OUT OF LESS 21
1.4 MOLECULAR DIAGNOSTICS IN THE POST-GENOMIC ERA 23
1.5 FUTURE PERSPECTIVES: WHAT LIES BEYOND 25
1.6 CONCLUSIONS 28
REFERENCES 28
Section I. Molecular Diagnostic Technology 32
Chapter 2. Allele-Specific Mutation Detection 34
2.1 INTRODUCTION 34
2.2 PCR-ARMS 34
2.3 PCR-ASO 37
2.4 THE COMPETITIVE OLIGOPRIMING ASSAY 40
2.5 CONCLUSIONS 44
REFERENCES 44
Chapter 3. Enzymatic and Chemical Cleavage Methods to Identify Genetic Variation 48
3.1 INTRODUCTION 48
3.2 CHEMICAL PROPERTIES OF MISMATCHES 48
3.3 CHEMICAL CLEAVAGE OF MISMATCH METHOD FOR MUTATION DETECTION 49
3.4 ADVANTAGES AND LIMITATIONS 54
3.5 ENZYMATIC CLEAVAGE OF MISMATCH METHODS 55
3.6 CONCLUSIONS 61
REFERENCES 62
Chapter 4. Mutation Detection by Single Strand Conformation Polymorphism and Heteroduplex Analysis 64
4.1 INTRODUCTION 64
4.2 PRINCIPLES OF SINGLE STRAND CONFORMATION POLYMORPHISM ANALYSIS 64
4.3 FLUORESCENT SINGLE STRAND CONFORMATION POLYMORPHISM ANALYSIS 65
4.4 PARAMETERS INFLUENCING SINGLE STRAND CONFORMATION POLYMORPHISM ANALYSIS 66
4.5 HETERODUPLEX ANALYSIS FOR MUTATION DETECTION 68
4.6 SENSITIVITY AND LIMITATIONS 69
4.7 DETECTION OF THE UNDERLYING GENOMIC VARIATION USING SSCP AND HDA 71
4.8 CONCLUSIONS AND FUTURE ASPECTS 74
REFERENCES 74
Chapter 5. Capillary Electrophoresis 78
5.1 INTRODUCTION 78
5.2 HISTORY, PRINCIPLE, AND POTENTIAL APPLICATIONS OF CAPILLARY ELECTROPHORESIS 78
5.3 CAPILLARY ELECTROPHORESIS IN MOLECULAR DIAGNOSTICS 80
5.4 MODES OF APPLICATION 80
5.5 SPECIFIC DIAGNOSTIC APPLICATIONS 81
5.6 FUTURE IMPROVEMENTS 88
REFERENCES 88
Chapter 6. Temperature and Denaturing Gradient Gel Electrophoresis 94
6.1 INTRODUCTION 94
6.2 THE THEORY OF TEMPERATURE-GRADIENT GEL ELECTROPHORESIS 94
6.3 THE PRACTICE OF TEMPERATURE GRADIENT GEL ELECTROPHORESIS 96
6.4 DENATURING GRADIENT GEL ELECTROPHORESIS (DGGE) 99
6.5 THE USE OF TGGE/DGGE FOR MUTATION DETECTION 100
6.6 DETECTION RATE AND SENSITIVITY 100
6.7 RELATED TECHNIQUES AND VARIANTS 101
6.8 TECHNICAL EQUIPMENT FOR TGGE/DGGE 101
6.9 APPLICATIONS OF TGGE/DGGE AND RELATED METHODS 102
6.10 CONCLUSIONS 102
ACKNOWLEDGEMENTS 102
REFERENCES 103
Chapter 7. Real-Time Polymerase Chain Reaction 106
7.1 HISTORY OF PCR 106
7.2 PRINCIPLE OF REAL-TIME PCR 107
7.3 REAL-TIME THERMAL CYCLERS 110
7.4 HOW DATA ARE OBTAINED 111
7.5 HOW DATA ARE QUANTIFIED 111
7.6 MULTIPLEX REAL-TIME PCR 116
7.7 APPLICATIONS IN MOLECULAR DIAGNOSTICS 116
7.8 CRITERIA FOR DEVELOPING REAL-TIME PCR ASSAYS 119
7.9 CONCLUSIONS 121
REFERENCES 121
Chapter 8. Pyrosequencing 126
8.1 INTRODUCTION 126
8.2 TECHNOLOGY 126
8.3 APPLICATIONS 130
8.4 CONCLUSIONS 133
ACKNOWLEDGEMENTS 133
REFERENCES 133
Chapter 9. Application of Padlock and Selector Probes in Molecular Medicine 136
9.1 INTRODUCTION 136
9.2 PADLOCK AND SELECTOR PROBES 136
9.3 APPLICATION OF PADLOCK AND MOLECULAR INVERSION PROBES FOR GENOTYPING 138
9.4 APPLICATION OF PADLOCK PROBES FOR INFECTIOUS DISEASE DIAGNOSTICS 140
9.5 TARGETED MULTIPLEX CNV ANALYSIS USING SELECTOR PROBES 140
9.6 HIGH-THROUGHPUT TARGETED SEQUENCING USING SELECTORS AND GAP-FILL PADLOCK PROBES 141
9.7 BIOSENSOR APPROACHES BASED ON ROLLING-CIRCLE AMPLIFIED PADLOCK PROBES 143
9.8 IN SITU GENOTYPING USING PADLOCK PROBES 144
9.9 CONCLUSIONS 148
REFERENCES 148
Chapter 10. Molecular Cytogenetics in Molecular Diagnostics 152
10.1 INTRODUCTION 152
10.2 FROM CONVENTIONAL TO MOLECULAR CYTOGENETICS 153
10.3 FLUORESCENCE IN SITU HYBRIDIZATION 155
10.4 BASIC TECHNICAL ELEMENTS AND MATERIALS 155
10.5 TYPES OF FISH PROBES AND RECENT FISH APPROACHES FOR METAPHASE AND INTERPHASE FISH 157
10.6 MULTICOLOR FISH SCREENING ASSAYS 161
10.7 MULTICOLOR WHOLE METAPHASE SCANNING TECHNIQUES 163
10.8 MULTICOLOR CHROMOSOME BANDING TECHNIQUES 164
10.9 WHOLE GENOME SCANNING AND COMPARATIVE GENOMIC HYBRIDIZATION 164
10.10 MOLECULAR KARYOTYPING – ARRAY CGH 165
10.11 CONCLUSIONS AND PERSPECTIVES 167
REFERENCES 168
Chapter 11. Analysis of Human Splicing Defects Using Hybrid Minigenes 174
11.1 INTRODUCTION 174
11.2 BASIC PRE-mRNA SPLICING PROCESS AND ALTERNATIVE SPLICING 174
11.3 NOVEL CIS-ACTING ELEMENTS INVOLVED IN SPLICING REGULATION 175
11.4 HUMAN GENETIC DEFECTS INVOLVING PRE-mRNA SPLICING 176
11.5 GENERAL STRATEGY OF THE HYBRID MINIGENE ASSAY FOR THE IDENTIFICATION OF SPLICING DEFECTS 177
11.6. APPLICATIONS OF THE HYBRID MINIGENE ASSAY 178
11.7 CONCLUSIONS 187
REFERENCES 187
Chapter 12. Detection of Genomic Duplications and Deletions 190
12.1 INTRODUCTION 190
12.2 MECHANISMS 190
12.3 PATHOLOGICAL CONSEQUENCES 191
12.4 DIAGNOSTIC TECHNIQUES 192
12.5 NOMENCLATURE 196
12.6 GENE DOSAGE APPLICATIONS IN TUMOR PROFILING 196
12.7 SUMMARY AND FUTURE DEVELOPMENTS 197
REFERENCES 198
Chapter 13. Multiplex Ligation-Dependent Probe Amplification (MLPA) and Methylation-Specific (MS)-MLPA: Multiplex Detection of DNA/mRNA Copy Number and Methylation Changes 202
13.1 INTRODUCTION 202
13.2 PRINCIPLE OF MLPA 203
13.3 DETECTION METHODS FOR MLPA AMPLIFICATION PRODUCTS 206
13.4 ANALYSIS OF MLPA RESULTS 207
13.5 METHYLATION QUANTIFICATION BY MS-MLPA 208
13.6 RT-MLPA FOR mRNA PROFILING 209
13.7 DESIGN OF MLPA PROBE SETS 211
13.8 RELATED TECHNIQUES 212
13.9 PITFALLS OF MLPA REACTIONS 212
13.10 SUMMARY: ADVANTAGES AND LIMITATIONS OF MLPA 214
REFERENCES 215
Chapter 14. Molecular Techniques for DNA Methylation Studies 218
14.1 INTRODUCTION 218
14.2 CLINICAL APPLICATIONS OF DNA METHYLATION ANALYSIS 222
14.3 METHODS FOR DNA METHYLATION ANALYSIS 223
14.4 CONCLUSIONS 240
REFERENCES 240
Chapter 15. High-Resolution Melting Curve Analysis for Molecular Diagnostics 248
15.1 INTRODUCTION TO MELTING ANALYSIS 248
15.2 GENOTYPING BY HIGH-RESOLUTION MELTING 253
15.3 VARIANT (HETERODUPLEX) SCANNING BY HIGH-RESOLUTION MELTING 256
15.4 CONCLUSIONS 260
REFERENCES 260
Chapter 16. DNA Microarrays and Genetic Testing 266
16.1 INTRODUCTION 266
16.2 DNA MICROARRAYS AND GENE EXPRESSION PROFILING 266
16.3 APPLICATION OF CGH ARRAYS FOR STUDIES OF THE MALIGNANT CELL GENOME 274
16.4 WHOLE-GENOME SNP ARRAY ANALYSIS OF CANCER 275
16.5 DETECTION OF ALTERNATIVE SPLICING BY MICROARRAY ANALYSIS 279
16.6 RNAi ARRAYS – HIGH-THROUGHPUT FUNCTIONAL TESTING 280
16.7 FUTURE ASPECTS OF THE USE OF MICROARRAYS 280
REFERENCES 281
Chapter 17. Arrayed Primer Extension Microarrays for Molecular Diagnostics 286
17.1 INTRODUCTION 286
17.2 APEX TECHNOLOGY OVERVIEW 287
17.3 LARGE-SCALE MULTIPLEX ANALYSIS: APEX-2 289
17.4 APEX WITH IN SITU SYNTHESIZED OLIGONUCLEOTIDE MICROARRAYS 290
17.5 INTERNAL QUALITY CONTROL FOR APEX GENOTYPING 291
17.6 APEX IN DIAGNOSTIC APPLICATIONS 291
17.7 CONCLUSIONS 296
ACKNOWLEDGEMENTS 298
REFERENCES 298
Chapter 18. Application of Proteomics to Disease Diagnostics 304
18.1 INTRODUCTION 304
18.2 MASS SPECTROMETRY CENTRIC STRATEGIES 304
18.3 DISCOVERY APPROACHES VS. APPROACHES FOR VALIDATION AND CLINICAL IMPLEMENTATION 305
18.4 QUANTITATIVE APPROACHES TO PROFILING USING MASS SPECTROMETRY 306
18.5 MASS SPECTROMETRY-BASED PROFILING OF BIOLOGICAL FLUIDS TO IDENTIFY CANDIDATE BIOMARKERS 307
18.6 MICROARRAY-BASED PROFILING 307
18.7 CONCLUDING REMARKS 308
REFERENCES 308
Chapter 19. RNA-Based Variant Detection: The Protein Truncation Test 312
19.1 SUMMARY 312
19.2 INTRODUCTION 312
19.3 THE PROTEIN TRUNCATION TEST 313
19.4 METHODOLOGY 314
19.5 ALTERNATIVE DETECTION SYSTEMS 315
19.6 FALSE POSITIVES/FALSE NEGATIVES 315
19.7 APPLICATIONS 316
19.8 CONCLUSIONS 317
REFERENCES 317
Chapter 20. Protein Diagnostics by Proximity Ligation: Combining Multiple Recognition and DNA Amplification for Improved Protein Analyses 318
20.1 INTRODUCTION 318
20.2 BINDING THE PROTEOME 319
20.3 CURRENT AFFINITY-BASED PROTEIN DETECTION ASSAYS 319
20.4 PROXIMITY LIGATION ASSAYS FOR DETECTING PROTEINS IN SOLUTION 320
20.5 IN SITU PROXIMITY LIGATION ASSAYS 322
20.6 CONCLUSION AND FUTURE PERSPECTIVES 322
ACKNOWLEDGEMENTS 324
REFERENCES 324
Chapter 21. Mass Spectrometry and its Applications to Functional Proteomics 326
21.1 INTRODUCTION 326
21.2 FUNCTIONAL PROTEOMICS 328
21.3 SAMPLE PREPARATION AND SEPARATION TECHNOLOGIES 331
21.4 MASS SPECTROMETRY 333
21.5 QUANTITATIVE PROTEOMICS 335
21.6 DATA INTERPRETATION, VALIDATION, STANDARDIZATION, AND BIOINFORMATIC ASPECTS 336
21.7 DATA VALIDATION AND INTERPRETATION 337
21.8 LIMITATIONS AND FUTURE PERSPECTIVE OF FUNCTIONAL PROTEOMICS 338
REFERENCES 338
Section II. Applications of Molecular Diagnostics and Related Issues 344
Chapter 22. Pharmacogenetics and Pharmacogenomics: Impact on Drug Discovery and Clinical Care 346
22.1 INTRODUCTION 346
22.2 DEFINITIONS AND HISTORY 346
22.3 PHARMACOGENETICS IN DRUG DEVELOPMENT 348
22.4 PHARMACOGENETICS IN CLINICAL CARE 349
22.5 USEFUL RESOURCES IN PHARMACOGENETICS 356
22.6 ETHICAL IMPLICATIONS 357
22.7 CONCLUSIONS AND FUTURE PERSPECTIVES 358
REFERENCES 358
Chapter 23. Nutrigenomics: Integrating Genomic Approaches into Nutrition Research 366
23.1 INTRODUCTION 366
23.2 THE NATURE OF GENETIC VARIATION 367
23.3 NUTRITIONAL EPIDEMIOLOGY 371
23.4 EXPERIMENTAL MODELS 372
23.5 DEFINING THE PHENOTYPE 377
23.6 INTEGRATING COMPLEX DATA SETS: DATA MANAGEMENT, BIOINFORMATICS, AND STATISTICS 379
23.7 CONCLUSIONS 380
ACKNOWLEDGEMENTS 380
REFERENCES 380
Chapter 24. Novel Next-Generation DNA Sequencing Techniques for Ultra High-Throughput Applications in Bio-Medicine 384
24.1 INTRODUCTION 384
24.2 NEXT-GENERATION DNA SEQUENCING PLATFORMS 385
24.3 PERSONAL GENOMICS AND THE 1,000 GENOMES PROJECT 393
24.4 RNA SEQUENCING, ANALYSIS OF GENE EXPRESSION 394
24.5 RNA-SEQ STUDY INTO ALTERNATIVE SPLICING IN HUMAN CELLS 394
24.6 SEQUENCING OF CHROMATIN IMMUNOPRECIPITATED FRAGMENTS (CHIP-SEQ) 395
24.7 GENOMICS AND MEDICINE, PROSPECTS FOR FUTURE DNA SEQUENCING 395
24.8 CONCLUSIONS 396
ACKNOWLEDGEMENTS 396
REFERENCES 396
Chapter 25. Locus-Specific and National/Ethnic Mutation Databases: Emerging Tools for Molecular Diagnostics 398
25.1 INTRODUCTION 398
25.2 MODELS FOR DATABASE MANAGEMENT 399
25.3 MUTATION DATABASE TYPES 399
25.4 LSDBs IN MOLECULAR GENETIC TESTING 400
25.5 NEMDBs: A NEW TREND 403
25.6 DATABASE MANAGEMENT SYSTEMS FOR LSDBs AND NEMDBs 405
25.7 FUTURE CHALLENGES 407
25.8 CONCLUSIONS 408
REFERENCES 408
Chapter 26. Molecular Diagnostic Applications in Forensic Science 412
26.1 INTRODUCTION 412
26.2 GENERAL CHARACTERISTICS OF Y-CHROMOSOME MARKERS 413
26.3 METHODOLOGY 414
26.4 CASE EXAMPLES 420
26.5 MITOCHONDRIAL DNA MARKERS ANALYSIS IN FORENSIC SCIENCE 420
26.6 LEGAL ADMISSIBILITY 421
26.7 CONCLUSIONS 422
ACKNOWLEDGEMENTS 422
REFERENCES 422
Chapter 27. Mass Disaster Victim Identification Assisted by DNA Typing 426
27.1 INTRODUCTION 426
27.2 CLASSIFICATION OF MASS FATALITIES AND DIVERSE SCENARIOS FOR HUMAN REMAINS RETRIEVAL 426
27.3 CONVENTIONAL IDENTIFICATION CRITERIA ROUTINELY USED FOR HUMAN IDENTIFICATION 428
27.4 CRITERIA FOR PRESERVATION OF REMAINS 428
27.5 DNA POLYMORPHISMS USED FOR TRACING KINSHIP BETWEEN FRAGMENTARY HUMAN REMAINS AND THEIR DEMANDING RELATIVES 429
27.6 CHALLENGES CONCERNING DNA DEGRADATION AND CONTAMINATION 429
27.7 CRITERIA EVOLUTION AND TECHNICAL APPROACHES APPLIED TO DNA-BASED VICTIM IDENTIFICATION IN MASS DISASTERS FROM THE EARLY 1990s TO DATE 431
27.8 DESCRIPTION OF ANALYZED CASES 431
27.9 FUTURE PROSPECTS 433
REFERENCES 433
Chapter 28. Detection of Highly Pathogenic Viral Agents: Implications for Therapeutics, Vaccines and Biodefense 436
28.1 INTRODUCTION 436
28.2 OVERVIEW OF HEMORRHAGIC FEVER VIRUSES 436
28.3 DETECTION METHODS 438
28.4 IMPLICATIONS FOR THERAPEUTICS, VACCINES, AND BIODEFENSE 444
28.5 CONCLUSIONS 446
REFERENCES 446
Chapter 29. Identification of Genetically Modified Organisms 450
29.1 INTRODUCTION AND HISTORICAL PERSPECTIVE 450
29.2 SAMPLING PLANS 451
29.3 CERTIFIED REFERENCE MATERIAL 452
29.4 PROTEIN-BASED TESTING METHODS 453
29.5 DNA-Based Testing Methods 455
29.6 NEAR-INFRARED (NIR) TECHNOLOGY 460
29.7 CONCLUSIONS 461
REFERENCES 462
Chapter 30. Molecular Diagnostics and Comparative Genomics in Clinical Microbiology 464
30.1 INTRODUCTION 464
30.2 TECHNOLOGICAL IMPROVEMENTS 466
30.3 PERSISTING PROBLEMS WITH MOLECULAR DIAGNOSTICS 467
30.4 MOLECULAR VIRUS DETECTION 468
30.5 EXAMPLES FROM BACTERIOLOGY 469
30.6 FUTURE PERSPECTIVES 474
30.7 CONCLUDING REMARKS 475
REFERENCES 475
Chapter 31. Genetic Monitoring of Laboratory Rodents 480
31.1 INTRODUCTION 480
31.2 THE GENETIC STRUCTURE OF LABORATORY STRAINS AND STOCKS OF RODENTS 480
31.3 MONITORING THE GENETIC QUALITY OF INBRED STRAINS 483
31.4 PRESERVING THE GENETIC PURITY OF INBRED STRAINS 486
31.5 ASSESSING THE GENETIC STANDARD OF OUTBRED STOCKS 486
31.6 THE CONTROL OF HEALTH STATUS 487
31.7 CONCLUSIONS 487
REFERENCES 487
Chapter 32. Safety Analysis in Retroviral Gene Therapy: Identifying Virus Integration Sites in Gene-Modified Cells 490
32.1 INTRODUCTION 490
32.2 METHODS USED TO DETECT RETROVIRAL INTEGRATION SITES 491
32.3 IDENTIFYING VIRUS INTEGRATION SITES BY FLUORESCENCE IN SITU HYBRIDIZATION 491
32.4 IDENTIFYING VIRUS INTEGRATION SITES USING PCR-BASED METHODS 492
32.5 IDENTIFYING VIRUS INTEGRATION SITES USING LINKER-MEDIATED PCR METHODS 494
32.6 CONCLUSIONS 498
ACKNOWLEDGEMENTS 500
REFERENCES 500
Chapter 33. Preimplantation Genetic Diagnosis 504
33.1 WHAT IS PREIMPLANTATION GENETIC DIAGNOSIS? 504
33.2 INDICATIONS FOR PGD 504
33.3 TECHNOLOGIES USED IN PGD 506
33.4 OUTCOME OF PGD 513
33.5 CONCLUSIONS 514
REFERENCES 514
Chapter 34. Automated DNA Hybridization and Detection 520
34.1. INTRODUCTION 520
34.2. DNA HYBRIDIZATION 520
34.3. DNA EXTRACTION 522
34.4. QUANTIFYING DNA 522
34.5. ROBOTICS 524
34.6. REVERSE DOT-BLOT 524
34.7. 5' NUCLEOTIDASE (TAQMAN) ASSAYS 525
34.8. CAPILLARY THERMAL CYCLER 526
34.9. ELECTRONIC HYBRIDIZATION 526
34.10. HYBRIDIZATION ARRAYS 526
34.11. MICRO-WELL PLATE ARRAYS 528
34.12. MICROARRAY PRINTING 528
34.13. SUMMARY 528
ACKNOWLEDGEMENTS 528
REFERENCES 529
Chapter 35. The Use of Microelectronic-Based Techniques in Molecular Diagnostic Assays 532
35.1 INTRODUCTION 532
35.2 MICROFABRICATION 532
35.3 CHIPS FOR SAMPLE PREPARATION 533
35.4 DNA AND RNA AMPLIFICATION IN MICROCHIP FORMAT 536
35.5 COMMERCIAL IMPLEMENTATION OF MOLECULAR ASSAYS WITH THE USE OF MICROELECTRONICS 538
35.6 CONCLUSIONS 543
REFERENCES 543
Chapter 36. Human Gene Patents and Genetic Testing 546
36.1 INTRODUCTION 546
36.2 BENEFITS FROM PATENTS 546
36.3 PATENTABILITY 547
36.4 GENERAL CONCERNS 548
36.5 CONCERNS RELATED TO THE PROVISION OF HEALTH CARE 549
36.6 SUGGESTED REFORMS 551
36.7 CONCLUSIONS 552
ACKNOWLEDGEMENTS 553
REFERENCES 553
Chapter 37. Genetic Counseling and Ethics in Molecular Diagnostics 556
37.1 INTRODUCTION 556
37.2 PROBLEMS IN GENETIC COUNSELING 557
37.3 OPTIONS AVAILABLE TO PEOPLE WITH A REPRODUCTIVE RISK 559
37.4 PREMARITAL SCREENING 560
37.5 CAN PREVENTION PROGRAMS BE CONSIDERED EUGENICS? 562
37.6 ETHICS AND RELIGION IN GENETIC COUNSELING 562
37.7 CONSANGUINEOUS MARRIAGE 564
37.8 WHY COUSIN MARRIAGE IS FAVORED BY SOME COMMUNITIES 564
37.9 CONCLUSIONS 565
REFERENCES 565
Chapter 38. Genetic Testing and Psychology 568
38.1 INTRODUCTION 568
38.2 GETTING TO THE TEST: AWARENESS, ACCESS, AND ADVERTISING 569
38.3 INDIVIDUAL FACTORS INFLUENCING UTILIZATION OF GENETIC TESTING 571
38.4 GETTING THE GENETIC TEST RESULT: PERSONAL IMPACT AND PROFESSIONAL COMMUNICATION 574
38.5 FAMILY COMMUNICATION 576
38.6 FUTURE CHALLENGES: MORE GENES, LESS CLARITY 577
REFERENCES 577
Chapter 39. General Considerations Concerning Safety in Biomedical Research Laboratories 582
39.1 INTRODUCTION 582
39.2 HELP IN UNDERSTANDING REGULATORY ISSUES AND GUIDELINES IN LABORATORY SAFETY: INTERNATIONAL, NATIONAL, REGIONAL, AND LOCAL 582
39.3 GENERAL CONSIDERATIONS IN LABORATORY SAFETY 584
39.4 TRAINING IN SAFETY 584
39.5 SAFETY INFRASTRUCTURE 585
39.6 CONCLUSIONS 591
ACKNOWLEDGEMENTS 591
REFERENCES 591
Chapter 40. Quality Management in the Laboratory 592
40.1 INTRODUCTION 592
40.2 INTERNATIONAL STANDARDS AND THEIR ROLE IN ACCREDITATION 592
40.3 A PROCESS-BASED APPROACH TO QUALITY MANAGEMENT SYSTEMS 593
40.4 BUILDING A QUALITY MANAGEMENT SYSTEM 594
40.5 ESTABLISHMENT AND CONTROL 595
40.6 REVIEW AND IMPROVEMENT 598
REFERENCES 600
Glossary 602
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D 603
E 603
F 603
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I 604
K 604
L 604
M 604
N 605
O 605
P 606
Q 606
R 606
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W 608
Y 608
Z 608
Index 610
A 610
B 610
C 610
D 611
E 612
F 612
G 612
H 612
I 613
L 613
M 613
N 614
O 614
P 614
Q 615
R 616
S 616
T 616
U 617
V 617
W 617
Y 617