Molecular Diagnostics in Genetic Testing

  • November 2013
  • -
  • TriMark Publications
  • -
  • 185 pages

Molecular diagnostics in genetic testing brings advanced analytical techniques to the diagnosis and treatment of genetic disorders. The confluence of breakthroughs in genomics and proteomics and the development of microarray devices to measure analytes in the blood and various body tissues are driving significant growth in the segment. Major developments include the integration of specialty labs and gene expression profiling into clinical practice, the introduction and rapid growth of cell-free fetal DNA prenatal testing, the advancement of companion diagnostics for drug development, the widespread installed base of automated instruments for molecular testing and the development of personalized medicine. The genetic testing space is one of the most profitable sectors of molecular diagnostics and is expected to be an area of high growth and corporate change throughout the forecast period. This TriMark Publications report describes the emerging field of molecular diagnostics in genetic testing. This review analyzes the size and growth of the molecular diagnostics in genetic testing market, including the factors that influence the various market segments within it and the dollar volume of sales, both in the United States and worldwide. Moreover, this analysis profiles the leading companies focused on the molecular diagnostics for genetic testing sector.

Table Of Contents

TABLE OF CONTENTS

1. Overview 9
1.1 Statement of Report 9
1.2 About this Report 9
1.3 Scope of the Report 10
1.4 Objectives 11
1.5 Methodology 12
1.6 Executive Summary 13

2. Role of Molecular Diagnostics and Opportunities in the Genetic Testing Sector
15
2.1 Introduction to Molecular Diagnostics for Genetic Testing 15
2.1.1 Definition and Scope of Molecular Genetic Testing within this Report 15
2.1.2 Key Functions of Molecular Genetic Testing 15
2.1.3 Overview of Molecular Genetic Testing Laboratories 16
2.2 Diagnostic Testing of Genetic Disorders 16
2.2.1 Review of Genetic Disorders: Characterizations of Abnormalities and
Patterns of Inheritance 17
2.2.2 Common Genetic Disorders 19
2.3 Carrier Testing for Genetic Disorders 20
2.4 Preimplantation Genetic Diagnosis and Preimplantation Genetic Screening 20
2.5 Prenatal/In utero Genetic Testing 21
2.6 Newborn Genetic Screening Tests 23
2.6.1 Molecular Diagnostics for Newborn Genetic Testing 25
2.7 Pre-Symptomatic and Predictive Testing for Adult Onset Disorders 26
2.8 Pharmacogenetics and Pharmacogenomics 27
2.8.1 Current Applications for Pharmacogenetics and Pharmacogenomics 28
2.8.1.1 Warfarin and VKORC1 and CYP2C9 Testing 30
2.8.1.2 Trastuzumab and Lapatinib and HER2 Overexpression Testing 31
2.8.1.3 Clopidogrel and CYP2C19 Testing 32
2.8.1.4 Thiopurines and TPMT Testing 32
2.8.1.5 Cetuximab and EGFR Expression and KRAS Mutation Testing 33
2.8.1.6 Irinotecan and UGT1A1*28 Testing 33
2.8.1.7 Abacavir and HLA-B*5701 Testing 34
2.8.1.8 Carbamazepine and HLA-B*1502 Testing 34
2.9 Tissue and Blood Typing 34
2.9.1 HLA Determination 34
2.9.2 Rhesus D Factor Determination 37
2.10 Parentage/Relationship Testing (Paternity Testing) 38
2.11 Genealogical DNA Testing 38
2.12 Criminal and Forensics Testing 39

3. Introduction to Molecular Diagnostics Technology for Genetic Testing 40
3.1 Introduction to Genomics and Its Opportunity 40
3.1.1 Science Background: Structures and Functions of Nucleic Acids and Proteins
40
3.1.2 The Human Genome 41
3.1.3 Genomics: Opening Opportunities in Molecular Diagnostics 41
3.2 Genetic Variability and Disease 42
3.3 Impact of the Human Genome Project on Molecular Diagnostics 43
3.4 Key Considerations for Molecular Diagnostics 44
3.5 Molecular Diagnostics in the Post-Genomic Era 45
3.6 Advances in Molecular Diagnostics Technologies 48
3.7 Molecular Diagnostics Testing Technologies and Platforms 50
3.7.1 Amplification Technologies 50
3.7.1.1 PCR and PCR Derivative Platforms 50
3.7.1.2 Multiple Displacement Amplification 55
3.7.1.3 Multiple Annealing and Looping-Based Amplification Cycles 56
3.7.1.4 Whole Genome Amplification 57
3.7.1.5 Nucleic Acid Sequence-based Amplification 57
3.7.2 Detection of Amplified Gene Products 57
3.7.2.1 High Resolution Melting Analysis 58
3.7.2.2 Microparticle-based Flow Cytometry 59
3.7.3 DNA and Oligonucleotide Microarrays and Chips 59
3.7.3.1 Array Comparative Genomic Hybridization 62
3.7.4 Gene Sequencing 62
3.7.4.1 Sanger Sequencing 62
3.7.4.2 Next Generation Sequencing 63
3.7.5 Fluorescence In situ Hybridization 68

4. Business Landscape for Molecular Diagnostics in Genetic Testing 69
4.1 Market Analysis: Size, Growth, Share and Competitors 69
4.1.1 Worldwide Genetic Testing Markets 69
4.1.2 Market Structure and Competitive Situation 73
4.1.3 Primary Competitors 74
4.1.4 Commercialization Strategies for Molecular Diagnostic Products 74
4.1.5 Market Penetration Strategies for Genetic Testing 74
4.2 Growing Genetic Testing Market Segments 75
4.2.1 Personalized Medicine and Companion Diagnostics Market 75
4.2.2 Predictive Molecular Diagnostics Market 76
4.2.3 Parallel Genetic Tests for Drug Development 77
4.2.4 Direct-to-Consumer Genetic Testing Market 78
4.2.5 Detecting Genetic Disorders 79
4.2.6 Prenatal Screening 79
4.2.7 Neonatal Screening 79
4.2.8 Forensic Testing 80
4.2.9 Blood and Tissue Typing 80
4.2.10 Parentage Testing 82
4.2.11 DNA Sequencing 82
4.3 Market Drivers and Restraints 84
4.3.1 Market Drivers 84
4.3.2 Market Restraints 85
4.4 Market and Technology Trends 86
4.4.1 Market Trends 86
4.4.2 Technology Trends 86
4.5 Industry Challenges and Strategic Recommendations 87
4.6 Recent Industry Activity 88
4.6.1 Mandamp;A Activity 88
4.6.2 License Agreements and Partnerships 89
4.7 Business Models and Requirements for Successful Products in the Genetic
Testing Industry 90
4.7.1 Commercial Manufacturing of Genetic Testing Products: Requirements 90
4.7.1.1 Regulatory Requirements 90
4.7.1.2 Manufacturing Process Scale 90
4.7.1.3 In-House Manufacturing 91
4.7.1.4 Contract Manufacturing: Commercial and Academic 91

5. Molecular Diagnostic Assays and Select Laboratories for Genetic Testing on
the Market 93
5.1 Select Diagnostic Tests for Genetic Disorders 93
5.1.1 CombiMatrix Diagnostics’ DNAarray Pediatric Microarray Oligo 105K 93
5.1.2 GeneDx’s Genetic Testing for Hereditary Disorders 93
5.1.3 Hologic’s Factor V Reagents 93
5.1.4 Progenika’s FH Test 93
5.2 Carrier Tests for Genetic Disorders 94
5.2.1 Abbott Molecular’s Cystic Fibrosis Genotyping Assay 94
5.2.2 Counsyl’s Universal Genetic Test 94
5.2.3 GenPath’s InheriGen and InheriGen Plus 95
5.2.4 Good Start Genetics’ Good Start Select 95
5.2.5 Hologic’s InPlex CF Molecular Test 95
5.2.6 Integrated Genetic’s Inheritest Carrier Screen 95
5.2.7 Luminex’s xTAG Cystic Fibrosis v2 Assays 96
5.2.8 Natera’s Natera One Multi-Disease Genetic Carrier Screening Panel 96
5.2.9 Sequenom’s Heredi-T Cystic Fibrosis Carrier Screen Test 97
5.3 Pre-implantation Genetic Tests 97
5.3.1 Natera’s Preimplantation Genetic Diagnosis Test 97
5.4 Prenatal/In utero Molecular Genetic Screening Tests 98
5.4.1 Cell-free Fetal DNA Testing 98
5.4.1.1 Ariosa Diagnostics’ Harmony Prenatal Test 98
5.4.1.2 Natera’s Panorama 99
5.4.1.3 Sequenom’s MaterniT21 PLUS Test 99
5.4.1.4 Verinata Health’s verifi Prenatal Test 100
5.4.2 Molecular Cytogenetic Tests 100
5.4.2.1 Abbott Molecular’s AneuVysion (Vysis CEP 18/X/Y-alpha satellite/LSI
13/21) Multicolor DNA
Probe Panel 100
5.4.2.2 CombiMatrix Diagnostics’ DNAarray™ Prenatal Microarrays 101
5.4.2.3 Signature Genomics’ Signature Precision Panel I Prenatal 102
5.4.2.4 Signature Genomics’ Signature PrenatalChip TE (Targeted Enhanced)
Microarray 102
5.4.2.5 Signature Genomics’ Signature PrenatalChip OS Microarray 103
5.5 Newborn Genetic Screening Tests 103
5.5.1 Screening for Cystic Fibrosis with Molecular Diagnostic Assays 103
5.5.2 Screening for SCID with the TREC Assay 103
5.5.2.1 PerkinElmer Genetics 104
5.6 Predictive and Presymptomatic Tests for Adult Onset Disorders 104
5.6.1 Sequenom’s RetnaGene AMD Test for Age-Related Macular Degeneration 104
5.7 Pharmacogenomics and Pharmacogenetics 104
5.7.1 Warfarin Sensitivity 105
5.7.2 EntroGen’s Mutation Analysis and Genotyping Kits 105
5.7.3 Qiagen’s Therascreen KRAS RGQ PCR Kit 106
5.7.4 Roche’s COBAS AmpliPrep/COBAS TaqMan HLA-B*5701 Screening Test 106
5.7.5 Genomic Health Oncotype Tests 107
5.7.6 Life Technologies 107
5.7.6.1 Life Technologies’ Pervenio Lung RS Test 108
5.7.7 Nanosphere’s Verigene Human Genetic Tests 108
5.7.8 Agendia’s SYMPHONY Personalized Breast Cancer Profile 109
5.7.9 CardioDx’s Corus CAD 110
5.7.10 Veracyte’s Afirma Thyroid FNA Analysis 110
5.8 Tissue and Blood Typing Tests 110
5.8.1 Immunocor’s LIFECODES HLA Typing Kits 110
5.8.1.1 LIFECODES HLA SSO Typing Kits 110
5.8.1.2 LIFECODES HLA SSP Typing 111
5.8.2 Life Technology/Invitrogen’s AllSet+ Gold HLA Typing Kits 112
5.8.3 Life Technology/Invitrogen’s SeCore HLA Sequence-Based Typing Kits 112
5.8.4 One Lambda’s LABType SSO 112
5.8.5 Progenika’s BLOODchip 113
5.8.6 Sequenom’s SensiGene Fetal RhD Genotyping Test 113
5.9 Paternity Tests 114
5.9.1 Natera’s Non-Invasive Prenatal Paternity Test 114
5.10 Criminal and Forensics Tests 114
5.10.1 IntengenX’s RapidHIT 200 Human DNA Identification System 114
5.10.2 NetBio’s and GE Healthcare Life Sciences’ DNAscan Rapid DNA Analysis
System 114
5.10.3 Sorenson Forensics 115
5.11 Direct-to-Consumer Genetic Tests 115
5.11.1 23andMe 115
5.11.2 Lumigenix 116
5.11.3 DNA DTC 116
5.11.4 Family Tree DNA 116
5.11.5 Gene by Gene 116
5.11.6 AncestryDNA Test 117
5.12 Select Laboratories Providing Genetic Testing Services 117
5.12.1 Ambry Genetics 117
5.12.2 ARUP Laboratories 118
5.12.3 GeneDx 118
5.12.4 LabCorp and Integrated Genetics 120
5.12.5 Mayo Medical Laboratories 120
5.12.6 Medical Genetics Laboratory at Baylor College of Medicine 121
5.12.7 Pathway Genomics 122
5.12.8 Quest Diagnostics 122
5.13 Major Technology Platforms for Genetic Testing on the Market 122
5.14 Product Launches and Introductions 123
5.14.1 Ariosa Diagnostics Introduces Y-Chromosome Analysis Test Option 123
5.14.2 Ariosa Diagnostics Expands Harmony Prenatal Test to Twin Pregnancies and
Launches New X,Y
Analysis Test 123
5.14.3 Natera Launches Panorama 124
5.14.4 Rubicon Genomics Launched Its New ThruPlex Technology and Partners with
Agendia 124
5.14.5 Sequenom Center for Molecular Medicine Launches New Cystic Fibrosis
Carrier Screen Test 124
5.14.6 Sequenom Launches the MaterniT21 PLUS 124
5.14.7 Next Generation Sequencing with Roche’s GS Junior System Approved for
Tissue Typing 125

6. Reimbursement and Billing Landscape for Molecular Diagnostic Genetic Testing
126
6.1 Overview 126
6.2 Trends in Healthcare Reimbursement Practices 127
6.2.1 Molecular Genetics Testing Reimbursement 128
6.3 Medicare Reimbursement Program 129
6.4 Medicare Billing Procedure 130
6.5 CPT Coding Rules for Molecular Diagnostics 132
6.5.1 Former Coding Rules for Molecular Diagnostics 133
6.5.2 Current Coding Rules for Molecular Diagnostics 133
6.5.2.1 Gapfilling 133
6.5.2.2 Reimbursement Delays for Molecular Diagnostics 134
6.6 Revenue Threats 135
6.6.1 Medicare Payment Exceptions 137
6.6.2 Three Areas for Denial of Claims 137
6.7 Bundled Payments for Care Improvement Initiative 138

7. Regulatory Issues for Genetic Testing 139
7.1 U.S. Food and Drug Administration 140
7.1.1 FDA Labeling Requirements 140
7.1.2 U.S. Government Regulation of Medical Devices 140
7.1.3 FDA’s Qualification of Biomarkers 141
7.1.4 FDA’s Voluntary Genomic Data Submission 142
7.2 Clinical Laboratory Improvement Act 142
7.3 CLIA Regulations 144
7.4 State Licensing for Service Laboratories 144
7.5 Multivariate Index Assays 145
7.6 FDA Draft Guidance on In Vitro Companion Diagnostic Devices 146
7.7 Pre-Market Approval 146
7.7.1 510(k) Clearance 147
7.8 De Novo Classification 147
7.9 Laboratory Developed Tests 148
7.9.1 Analyte Specific Reagents 150
7.10 U.S. Patent and Trademark Office 151
7.11 IRB Approval in Clinical Trials 151
7.12 CE marking and European In Vitro Diagnostic Device Directive 151
7.13 Research Use Only Reagents 151
7.14 Regulatory Issues for Direct-to-Consumer Genetic Tests 152
7.15 The Genetic Information Nondiscrimination Act of 2008 153
7.16 Genetic Tests and Medical Records 153
7.17 Recommendations by the American College of Medical Genetics and Genomics
154

8. Business Decisions, Strategic Outlook and Recommendations Using Molecular
Diagnostic Tests in Genetic Testing 155
8.1 Key Opportunities in Genetic Testing Development and Commercialization 155
8.2 What are the Current Obstacles in Molecular Diagnostic Genetic Testing
Implementation? 155
8.3 How are Genetic Testing Products Driven by Business Strategies? 156
8.4 How might Novel Genetic Test Development Lead to Acquisition Strategies? 156
8.5 How can Genetic Tests Increase Value in Associated Drug Marketing Plans? 157
8.6 What Steps can be Taken in the Clinical Phases to Improve the Success Rate
of Genetic Tests in Development? 157
8.7 How can Regulatory Oversight Drive Approval and Adoption of New
Technologies? 157
8.8 What are the Noteworthy Deals? 158
8.9 How will Platform Technology Companies Enter the Space and Position
Themselves for Diagnostic Development? 159
8.10 Will Pharma Integrate with Diagnostics? 159
8.11 How will Partnering and Mandamp;As Alter the Competitive Landscape? 160
8.12 How will FDA Regulations Impact New Diagnostic Tests? 160
8.13 What is Necessary for Incorporating Promising Molecular Tests into Clinical
Practice 161
8.14 What is the Best Type of Business Model for Developing Genetic Testing
Biomarkers? 162
8.15 How have Genetic Biomarkers Provided the Most Benefit in Genetic Testing?
163
8.16 What are the Most Innovative Methods in Development of Molecular Diagnostic
Biomarkers? 163

9. Company Profiles 165
9.1 Abbott Laboratories 165
9.2 Beckman Coulter 168
9.3 CombiMatrix 171
9.4 EntroGen, Inc. 172
9.5 Genmark Diagnostics, Inc. 172
9.6 Genomic Health 172
9.7 Hologic, Inc. 173
9.8 Illumina, Inc. 178
9.9 IntegenX 178
9.10 Laboratory Corporation of America Holdings 179
9.11 Life Technologies Corporation 179
9.12 Luminex Corporation 181
9.13 Myriad Genetics, Inc. 181
9.14 Natera 183
9.15 NetBio 183
9.16 PerkinElmer Genetics 184
9.17 Progenika, Inc. 184
9.18 Roche Diagnostics 184
9.19 Sequenom, Inc. 185
9.20 Signature Genomics 186
9.21 Spartan Bioscience, Inc. 186
9.22 Transgenomic, Inc. 186


INDEX OF FIGURES

Figure 3.1: Segment of Double-Stranded DNA Showing the Base-Pair Relationship 40
Figure 3.2: Schematic of Molecular Diagnostics for Studying Gene Expression in
Patients 47
Figure 3.3: The PCR Cycle 50
Figure 3.4: Multiple Displacement Amplification 56
Figure 3.5: Using DNA Microassays to Measure Gene Expression 61
Figure 4.1: Overall Structure of Nucleic Acid Testing Market 70
Figure 4.2: Segmentation of the Biomarker Development Market 76
Figure 6.1: Reimbursement for Diagnostics in Healthcare Decision Making 128
Figure 6.2: MAC Jurisdiction Map, 2012 134
Figure 7.1: Current Regulations for Laboratory Testing 139
Figure 7.2: Existing Regulatory Framework for LDTs 150

INDEX OF TABLES

Table 2.1: Common Genetic Disorders 19
Table 2.2: Recommended Uniform Screening Panel by SACHDNC 24
Table 2.3: Potential Benefits of Pharmacogenetics 28
Table 2.4: Select Drugs with Commercially Available Pharmacogenetic Tests 29
Table 2.5: HLA Allele Nomenclature 36
Table 2.6: Comparison of HLA Typing Methods 37
Table 3.1: Key Assay Technologies for Molecular Diagnostics 49
Table 3.2: Emerging Molecular Diagnostic Technologies 49
Table 3.3: DNA Microarray Applications 60
Table 3.4: Companies Involved in Next Generation Sequencing Platforms 64
Table 3.5: Desired Characteristics for Clinical Versus Discovery Next Generation
Sequencing 66
Table 4.1: Summary of Molecular Diagnostics Testing Sectors 70
Table 4.2: Global Market for Molecular Diagnostics - Infectious Disease Testing,
Cancer Testing and Genetic Testing, 2008-2018 71
Table 4.3: Global Market for Molecular Diagnostics for Genetic Testing,
2008-2018 72
Table 4.4: U.S. Market for Molecular Diagnostics - Infectious Disease Testing,
Cancer Testing, and Genetic Testing, 2008-2018 72
Table 4.5: U.S. Market for Molecular Genetic Testing, 2008-2018 73
Table 4.6: Diagnostic Companies with Existing Pharma Relationships 75
Table 4.7: Use of Cancer Biomarkers in Drug Development 77
Table 4.8: Utility of Biomarkers as Companion Diagnostics to Drug Development 77
Table 4.9: Competitors in the Field of Forensic Testing 80
Table 4.10: Competitors in the Field of Identity, Family and Paternity Testing
82
Table 4.11: Comparison of Current Genetic Testing Protocols and Potential Use of
Whole Genome
Sequencing 83
Table 4.12: Molecular Diagnostics Market: Market Drivers Ranked in Order of
Impact 84
Table 4.13: Drivers of the Genetic Analysis Market 85
Table 4.14: Molecular Diagnostics Market: Market Restraints Ranked in Order of
Impact 85
Table 4.15: Total Molecular Genetic Testing Market: Impact of Top Industry
Challenges (U.S.) 87
Table 4.16: The Required Elements of a Manufacturing Facility 91
Table 4.17: CMO Qualification Audit: Points to Investigate 92
Table 6.1: Factors Determining Third-Party Payment for Molecular Diagnostic
Tests 135
Table 7.1: Regulatory Rules that Affect the Ability of a Diagnostic Testing
Reagent Company to
Conduct Business 139
Table 7.2: Strengths of the 510k Process 147
Table 7.3: Drawbacks of the 510k Process 147
Table 8.1: Effect of Regulation on MDx Infectious Disease Market Technology
Platforms, 2007 and 2015 157
Table 8.2: Impediments to Incorporating Promising Molecular Tests into Clinical
Practice 162

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