Molecular Diagnostics: Transforming Pharmaceuticals, Impacting New Markets (2nd Ed)

Molecular Diagnostics: Transforming Pharmaceuticals, Impacting New Markets (2nd Ed)

Publisher:	D&MD Publications Inc
Year of publication:	2004
Type of publication:	Management report
Publisher's reference (if any):	D&MD9147
Author(s):	Sreten Bogdanovic and Beata Langlands
Approximate page count:	420
Price when published:	$4,950
Remarks: Page numbers, where given, refer to the draft manuscript (which may differ from the published version). The copyright in this report is owned by the publisher, to whom any requests for copies should be addressed. The price shown is for a single copy of the print version. Multiple copies and electronic copies usually have different prices.
MOLECULAR DIAGNOSTICS Transforming Pharmaceuticals, Impacting New Markets (2nd Edition, 2004) TABLE OF CONTENTS CHAPTER 1 INTRODUCTION 1.1 Overview of the IVD industry 1.1.1 Introduction 1.1.2 Platform technologies 1.2 Molecular diagnostics in the IVD arena 1.2.1 Introduction 1.2.2 Platform technologies 1.2.2.1 Immunoassays 1.2.2.2 Nucleic acid testing 1.2.2.3 Multiplexing platforms 1.3 Uses of traditional IVDs in clinical settings 1.3.1 Unique uses of molecular diagnostics 1.4 ASRs, diagnostic kits and homebrew tests 1.4.1 New initiatives CHAPTER 2 TECHNOLOGY DEVELOPMENTS 2.1 Immunoassay technology 2.1.1 Introduction 2.1.2 Principles and terms 2.1.3 Immunoassay design 2.1.3.1 Competitive assays 2.1.3.2 Noncompetitive "sandwich" assays 2.1.4 Point-of-care formats 2.2 Proteomics technology 2.2.1 Introduction 2.2.2 Clinical sample types 2.2.3 Analytical methods 2.2.3.1 Mass spectrometry 2.2.3.2 Protein chips 2.2.3.3 Protein chips/mass spectrometry 2.3 Nucleic acid testing technology 2.3.1 Introduction 2.3.1.1 DNA sequencing 2.3.1.2 Probe-based NAT 2.3.2 DNA probes and their uses 2.3.3 Technologies for increasing NAT sensitivity 2.3.3.1 PCR-based amplification technologies 2.3.3.2 Alternative amplification technologies 2.3.3.3 Other approaches 2.3.4 Automation and integration 2.3.5 Multiplex assays 2.3.5.1 DNA microarrays 2.3.5.2 Lab-on-a-chip products 2.3.5.3 Bead-based technologies 2.3.6 Transcriptional profiling 2.3.7 Large-scale SNP genotyping 2.3.7.1 Genotyping platforms 2.4 Nanotechnology developments CHAPTER 3 COMMUNICABLE DISEASES 3.1 Introduction 3.1.1 Emerging infectious diseases 3.2 Protein-based molecular diagnostics 3.2.1 Introduction 3.2.2 Developments in immunoassays 3.2.2.1 HIV 3.2.2.2 HBV/HCV 3.2.2.3 Influenza and RSV 3.2.2.4 WNV 3.2.2.5 SARS 3.2.2.6 Bacteria 3.2.2.7 Fungi and parasites 3.3 NAT-based molecular diagnostics 3.3.1 Introduction 3.3.1.1 Arrival of automated NAT systems 3.3.1.2 Initiatives in microarray-based NAT 3.3.2 Detecting viral pathogens 3.3.2.1 HIV: viral load and drug resistance 2.3.2.2 HBV/HCV: viral load and drug resistance 3.3.2.3 HPV 3.3.2.4 SARS CoV 3.3.2.5 WNV 3.3.2.6 Other viruses 3.3.3 Detecting bacterial pathogens 3.3.3.1 Chlamydia and gonorrhea 3.3.3.2 Group B Strep 3.3.3.3 Mycobacteria 3.3.3.4 Atypical pneumonia bacteria 3.3.3.5 Other bacteria 3.3.3.6 Detection of antibiotic resistance 3.3.4 Detecting fungi and parasites 3.3.5 Screening of blood and blood products 3.3.5.1 Viral contamination 3.3.5.2 Bacterial contamination 3.3.5.3 Parasitic contamination 3.3.6 Susceptibility to infectious disease CHAPTER 4 CARDIOVASCULAR DISEASES 4.1 Introduction 4.1.1 Overview of cardiovascular diseases 4.1.2 Diagnostic approaches 4.2 Lipid and protein-based molecular diagnostics 4.2.1 Lipid and protein markers of cardiac risk . 4.2.1.1 Backgrounder on lipid profiling 4.2.1.2 Lipoprotein subclass particle analysis 4.2.1.3 ApoB and apoB/apoA-1 4.2.1.4 CRP 4.2.1.5 Lp-PLA2 4.2.1.6 Homocysteine 4.2.1.7 Lp(a) 4.2.1.8 Ox-LDL 4.2.1.9 Sphingolipids 4.2.1.10 ADMA 4.2.1.11 MPO 4.2.1.12 PAPP-A 4.2.1.13 Antibodies to pathogens 4.2.1.14 Other markers 4.2.1.15 Markers in metabolic syndrome/obesity 4.2.2 Markers of myocardial necrosis 4.2.2.1 Troponins, myoglobin and CK-MB 4.2.3 BNP and NT-proBNP 4.2.4 Multi marker strategies in acute syndromes 4.2.5 Protein markers in stroke 4.2.6 Initiatives in proteomic analysis 4.3 NAT-based molecular diagnostics 4.3.1 Overview 4.3.1.1 Monogenic diseases 4.3.1.2 Non-monogenic diseases 4.3.2 Genetic predisposition markers 4.3.2.1 Thrombophilia (Factor V/II genes) 4.3.2.2 Other gene markers of hemostasis 4.3.2.3 Gene markers of hypertension 4.3.2.4 MTHFR gene 4.3.2.5 ApoE gene 4.3.2.6 IL-1 gene 4.3.2.7 Genes identified by deCODE/Roche 4.3.2.8 Miscellaneous markers 4.3.3 Genetic markers of drug responses 4.3.3.1 Statins 4.3.3.2 Antihypertensives CHAPTER 5 CANCER 5.1 Introduction 5.1.1 Overview of cancer 5.1.2 Diagnosis of cancer 5.1.3 Initiatives in bioinformatics 5.2 Protein-based molecular diagnostics 5.2.1 Overview 5.2.1.1 Proteomics initiatives 5.2.2 Established immunoassays 5.2.2.1 Circulating markers 5.2.2.2 Urine markers 5.2.3 Emerging tumor markers 5.2.3.1 Prostate cancer 5.2.3.2 Ovarian cancer 5.2.3.3 Colorectal cancer 5.2.3.4 Breast cancer 5.2.3.5 Mesothelioma 5.2.3.6 Pancreatic cancer 5.2.3.7 Cervical cancer 5.2.3.8 Liver cancer 5.2.3.9 All cancers 5.2.4 Immunomic analysis 5.2.5 Serum proteomic pattern diagnostics 5.2.5.1 Ovarian cancer 5.2.5.2 Prostate cancer 5.2.5.3 Miscellaneous cancers 5.3 DNA-based molecular diagnostics 5.3.1 Aproaches to predictive testing 5.3.1.1 Familial cancer syndromes 5.3.1.2 Susceptibility to breast cancer 5.3.1.3 Drug responsiveness 5.3.2 Analysis of nucleated tumor cells 5.3.2.1 Detecting residual tumor cells 5.3.2.2 Surveying the tumor genome 5.3.2.3 Detecting patterns of DNA-methylation 5.3.3 Analysis of nucleic acids shed by tumors 5.3.3.1 Circulating tumor nucleic acids 5.3.3.2 Stool-associated tumor nucleic acids 5.4 RNA-based molecular diagnostics 5.4.1 Gene expression profiling 5.4.1.1 Breast cancer 5.4.2 Alternative RNA splicing 5.4.3 Single marker gene expression CHAPTER 6 MISCELLANEOUS DISEASES AND CONDITIONS 6.1 Introduction 6.2 Protein-based molecular diagnostics 6.2.1 Maternal-fetal medicine 6.2.1.1 Markers of early pregnancy 6.2.1.2 Markers of Down Syndrome 6.2.1.3 Markers of pre-eclampsia 6.2.1.4 Other markers 6.2.2 Markers of Alzheimer's disease 6.2.3 Markers of diabetes risk 6.2.4 Markers of bone turnover 6.2.5 Miscellaneous markers 6.3 NAT-based molecular diagnostics 6.3.1 Congenital conditions 6.3.1.1 Chromosomal abnormalities 6.3.1.2 Monogenic diseases 6.3.2 Glaucoma 6.3.3 Alzheimer's and Parkinson's disease 6.3.4 Organ transplantation 6.3.5 Disease susceptibility testing 6.3.5.1 Osteoporosis 6.3.5.2 Diabetes and its complications 6.3.5.3 Periodontal disease 6.3.5.4 Rheumatoid arthritis 6.3.6 Pharmacogenomic tests 6.3.6.1 Prediction of adverse effects 6.3.6.2 Drug efficacy in Alzheimer's disease 6.3.6.3 Drug efficacy in asthma 6.3.6.4 Drug efficacy in rheumatoid arthritis 6.3.6.6 Drug efficacy in other conditions CHAPTER 7 NON-CLINICAL APPLICATIONS 7.1 Introduction 7.2 Bioterrorism 7.2.1 Bioterrorism preparedness initiatives 7.2.1.1 Role of molecular diagnostics 7.2.2 Bioterrorism agents 7.2.3 Focus on anthrax 7.2.3.1 Environmental testing 7.2.3.2 Diagnostic testing 7.2.4 Advances in biodetection technologies 7.2.4.1 Detecting proteins 7.2.4.2 Detecting nucleic acids 7.2.4.3 Detecting proteins and nucleic acids 7.2.4.4 Reagentless biosensors 7.2.4.5 Analyzing molecular signatures 7.3 Human identity testing 7.3.1 Parentage testing 7.4 Drugs of abuse testing 7.4.1 Rapid immunoassays 7.5 Veterinary market 7.5.1 Protein-based molecular diagnostics 7.5.1.1 Infectious diseases 7.5.2 NAT-based molecular diagnostics 7.5.2.1 Infectious diseases 7.5.2.2 Animal breeding industry 7.6 Food testing 7.6.1 Pathogenic bacteria 7.6.1.1 Immunoassays 7.6.1.2 NAT 7.6.3 Other applications of immunoassays 7.6.3.1 BSE 7.6.3.2 Drug residues 7.6.4 Other applications of NAT 7.6.4.1 Animal identity tracking 7.7 Water testing 7.7.1 Immunoassays 7.7.2 NAT 7.8 Anti-counterfeiting 7.8.1 Protein-based technologies 7.8.2 DNA-based technologies 7.8.2.1 Key proprietary technologies 7.9 Emerging opportunities in plant testing 7.9.1 Plant diagnostics 7.9.2 Plant breeding 7.9.3 Plant-based drug production CHAPTER 8 MARKET CONSIDERATIONS AND FORECASTS 8.1 Introduction 8.2 Outlook for the total immunoassay market 8.2.1 General Immunoassays 8.2.2 Infectious Disease Immunoassays 8.2.3 Cancer Immunoassays 8.2.4 Specialty (e.g. Cardiovascular) Immunoassays 8.3 Outlook for the total NAT market 8.3.1 Infectious Diseases 8.3.1.1 Bacterial tests 8.3.1.2 Viral detection and load 8.3.1.3 Viral and bacterial genotyping 8.3.1.3 Blood screening 8.3.2 Cancer 8.3.2.1 Cervical cancer (HPV) screening 8.3.2.2 Chromosomal abberations and shed nucleic acids 8.3.2.3 Gene expression profiling 8.3.3 Genetic testing and hereditary cancers 8.3.4 Predisposition and pharmacogenomic tests 8.3.5 Forensic and identity testing 8.4 Outlook for the proteomic assay market 8.5 Non-clinical applications 8.5.1 Veterinary diagnostics 8.5.2 Plant diagnostics 8.5.3 Food industry 8.6 Forecasts by geographical region CHAPTER 9 COMPANY PROFILES 9.1 Abbott Laboratories Inc 9.2 Agendia 9.3 Bayer AG 9.4 Biosite Diagnostics Inc 9.5 Cepheid 9.6 Chembio Diagnostic Systems Inc 9.7 Chiron Corporation 9.8 Ciphergen Biosystems Inc 9.9 Correlogic Systems 9.10 Diagnostic Products Corporation 9.11 DiagnoSwiss SA 9.12 Digene Corporation 9.13 Epigenomics AG 9.14 EXACT Sciences Corp 9.15 Genaissance Pharmaceuticals Inc 9.16 Gen-Probe Inc 9.17 HandyLab 9.18 Innogenetics N.V. 9.19 Interleukin Genetics 9.20 Matritech Inc 9.21 Myriad Genetics Inc 9.22 Nanogen 9.23 Nuvelo Inc. 9.24 Nymox Pharmaceutical 9.25 OXIS International Inc 9.26 Proteome Sciences plc 9.27 Roche Holding Ltd 9.28 Sequenom Inc 9.29 SomaLogic Inc 9.30 Third Wave Technologies Inc CHAPTER 10 TRENDS AND OPPORTUNITIES 10.1 Diagnostic insights grow with new research tools 10.2 Research tools evolve into ASRs and IVDs 10.3 Routine molecular tests move into POC settings 10.4 New molecular tests key to personalized medicine 10.5 Molecular diagnostics boosted by antibioterrorism 10.6 Human genetic and genomic testing gains acceptance 10.7 DNA microarrays show commercial potential 10.8 NAT: changing clinical diagnostics 10.9 NAT: impacting non-clinical markets 10.10 Towards tests based on multiple protein markers 10.11 A goldmine of protein markers becons 10.12 Proteomics: changing clinical diagnostics 10.13 Proteomics: impacting non-clinical markets 10.14 Molecular diagnostics and therapeutics converge 10.15 New approaches await further exploitation APPENDIX 1: ABBREVIATIONS - ORGANISATIONS AND REGULATORY APPENDIX 2: ABBREVIATIONS - TECHNOLOGIES, DISEASES, BIOMARKERS EXECUTIVE SUMMARY Molecular diagnostic tests analyze DNA, RNA or protein markers to characterize diseases. The first generation molecular diagnostics described in this Report are predominantly single-analyte assays, either nucleic acid probe-based tests (NATs) or immunoassays. There is increasing evidence that multiple markers and patterns of markers can provide more insight into a disease state than single-marker assays. In the recent years great strides have been made in developing mutiplexing testing platforms which permit the measurement of many parameters simultaneously. As research tools and technologies evolve, they are making possible diagnostic testing on a level of complexity that was unthinkable a decade ago. Emerging second generation molecular diagnostics based on molecular profiling are also described in this Report. Genomic, transcriptomic and proteomic profiling products hold the key to personalized medicine, which redefines diseases on the molecular level so that diagnostics and therapeutics can be targeted more precisely to specific patient populations. The world market for in vitro diagnostic products (IVDs) as a whole is forecast to increase from $24.2 billion in 2003 to $30.8 billion in 2009, a compound annual growth rate (CAGR) of 4.1%. Growth will be driven mainly by China, Latin America, and the developing countries (including Eastern Europe). CAGRs in the US, Western Europe, and Japan will be under 3% owing to long-running healthcare cost-containment pressures in those regions. However, the segments analysed in this report, about one-third of the global IVD market by dollar value, will considerably outperform the total market, growing at an average CAGR of 9.3% from $9.0 billion in 2003 to $15.3 billion in 2009. Only Japan and Italy are expected to lag behind significantly, and Latin America and Spain will be leading the field. Sales of nucleic acid-based tests are expected to grow much more quickly than immunoassays. Apart from their greater utility in many circumstances, NATs are starting from a lower baseline (13% vs 87% of total sales in 2003, rising to 25% vs 75% in 2009), and will to some extent displace immunoassay tests in applic- ations such as infectious disease testing. Expected CAGRs are 6.6% for immunoassays and 21.7% for NAT. However, the segments of infectious disease and specialty immunoassays, both of which include a small but growing number of second generation tests (e.g. antibody-based chips), are growing respectively three and four times faster than the immunoassay average. With annual sales of $3 billion in 2003, infectious disease tests are currently the largest group of immunoassays by sales volume, and the largest single test segment discussed in this report. Overall, the fastest-growing applications (all currently niche NATs) are viral and bacterial genotyping (44% CAGR), cervical cancer screening (34% CAGR), and disease prediction/theranostics (30% CAGR). This Report reviews technological developments which are leading to the development of improved molecular diagnostics. Growth in immunoassay-based molecular diagnostics has been enabled by the availability of rapid assay formats suitable for point-of-care (POC) applications, while developments in amplification techniques and genotyping methods have fueled the growth of NAT-based diagnostic testing. A number of companies have been developing multiplexing platforms for nucleic acid analysis suitable for clinical diagnostic applications, including DNA microarrays, microfluidics and bead-based assays. This Report also discusses the gradual emergence of protein chips and mass spectroscopy into the realm of clinical diagnostics which can screen multiple biomarkers present in sera or other body fluids. This Report offers the most comprehensive coverage of molecular diagnostic products ever attempted in a single volume. All major clinical and non-clinical markets are reviewed, with particular emphasis on commercial products recently launched and those under development. Infectious diseases are the leading cause of death worldwide and take third place in the US. In the US and elsewhere, the recent emergence or re-emergence of infectious diseases has stimulated the rapid development of new immunoassays and NAT assays for pathogens such as West Nile virus, SARS virus, and the parasite T. cruzi. The need to bring rapid, inexpensive tests to high-risk populations led to rapid immunoassay products replacing lab-based HIV tests. During the last few years progress has been made in automation of NAT assays, with the launch of the first fully automated, high throughput instrument for the NAT marketplace. Concurrent with the steady growth in viral load testing, the last two years saw expanded use of NAT in cervical-cancer (HPV) screening, bacterial detection, genotyping to detect drug resistance, and screening of blood and blood products. Cardiovascular disease is the leading cause of death in the industrialized world. Although the principle modifiable risk factors for heart disease are well known, the inexorable rise in the prevalences of the metabolic syndrome and type 2 diabetes means that heart disease will remain a major cause of morbidity and mortality for the foreseeable future. Developments in the cardiovascular field are being driven by a host of new protein markers. Growth is anticipated in immunoassays, in particular POC products, based on protein biomarkers of cardiovascular risk, markers of cardiac necrosis, and markers of hemodynamic stress. Multibiomarker panels promise to be the best approach to risk stratification in acute coronary syndromes. The cardiovascular area boasts the first DNA-based test kit for an inherited disorder to be approved by the FDA. Tests based on molecular profiling are under development, but will require clinical validation. Cancer is the second leading cause of death in the US and most other developed countries. The development of the cancer molecular diagnostic field had lagged behind some of the other disease segments, but rapid advances have been made in the recent years. Although the market still consists predominantly of immunoassay-based methods, new markers identified through proteomics promise better specificities. A number of companies have developed tests to detect genomic abnormalities associated with early-stage cancer, including analysis of nucleic acids shed by tumors. Development continues of genetic predisposition and pharmacogenomic tests. In this area more than in any other, proteomic and transcriptional profiling is expected to radically alter the way patients are diagnosed, classified and treated. Serum proteomic pattern diagnostics may allow pre-symptomatic diagnosis, while transcriptional profiling may predict tumor aggressivenes, or response to therapy. Both types of tests are making their debuts on the market. Rapid POC immunoassays based on specific, often novel biomarkers are increasingly employed in prenatal diagnosis, and in the detection and management of a variety of medical conditions. There are indications that proteomic profiling may allow early diagnosis of diseases such as Alzheimer's disease and amyotrophic lateral sclerosis. NAT already plays an important role in prenatal and pre-implantation diagnosis. Genetic screening for the most common monogenic diseases is increasing as is pharmacogenomic testing for adverse drug reactions, with both areas witnessing the emergence of products based on microarrays and bead-arrays. In addition, genomic tests to predict drug efficacy are under development. Development of tests for susceptibility to non-monogenic diseases continues, although their scope is restricted at present. The impact of new molecular diagnostic technologies is being felt across a wide range of industries outside the clinical arena and the stage is set for further expansion. Non-clinical applications od molecular diagnostic techniques reviewed in this Report include: bioterrorism; human identity testing; drugs of abuse testing; veterinary market; food testing: water testing; anti-counterfeiting; and plant testing. All offer unique opportunities for developers of molecular diagnostics.

Publisher:

D&MD Publications Inc

Year of publication:

2004

Type of publication:

Management report

Publisher's reference (if any):

D&MD9147

Author(s):

Sreten Bogdanovic and Beata Langlands

Approximate page count:

420

Price when published:

$4,950

Remarks:

Page numbers, where given, refer to the draft manuscript (which may differ from the published version).
The copyright in this report is owned by the publisher, to whom any requests for copies should be addressed.
The price shown is for a single copy of the print version. Multiple copies and electronic copies usually have different prices.

                              MOLECULAR DIAGNOSTICS
                 Transforming Pharmaceuticals, Impacting New Markets
                               (2nd Edition, 2004)
         
                                 TABLE OF CONTENTS
         
         CHAPTER 1 INTRODUCTION
         
           1.1 Overview of the IVD industry
              1.1.1 Introduction
              1.1.2 Platform technologies
           1.2 Molecular diagnostics in the IVD arena
              1.2.1 Introduction
              1.2.2 Platform technologies
                1.2.2.1 Immunoassays
                1.2.2.2 Nucleic acid testing
                1.2.2.3 Multiplexing platforms
           1.3 Uses of traditional IVDs in clinical settings
              1.3.1 Unique uses of molecular diagnostics
           1.4 ASRs, diagnostic kits and homebrew tests
              1.4.1 New initiatives
         
         CHAPTER 2 TECHNOLOGY DEVELOPMENTS
         
           2.1 Immunoassay technology
              2.1.1 Introduction
              2.1.2 Principles and terms
              2.1.3 Immunoassay design
                2.1.3.1 Competitive assays
                2.1.3.2 Noncompetitive "sandwich" assays
              2.1.4 Point-of-care formats
           2.2 Proteomics technology
              2.2.1 Introduction
              2.2.2 Clinical sample types
              2.2.3 Analytical methods
                2.2.3.1 Mass spectrometry
                2.2.3.2 Protein chips
                2.2.3.3 Protein chips/mass spectrometry
           2.3 Nucleic acid testing technology
              2.3.1 Introduction
                2.3.1.1 DNA sequencing
                2.3.1.2 Probe-based NAT
                2.3.2 DNA probes and their uses
              2.3.3 Technologies for increasing NAT sensitivity
                2.3.3.1 PCR-based amplification technologies
                2.3.3.2 Alternative amplification technologies 
                2.3.3.3 Other approaches
              2.3.4 Automation and integration
              2.3.5 Multiplex assays
                2.3.5.1 DNA microarrays
                2.3.5.2 Lab-on-a-chip products
                2.3.5.3 Bead-based technologies
              2.3.6 Transcriptional profiling
              2.3.7 Large-scale SNP genotyping
                2.3.7.1 Genotyping platforms
           2.4 Nanotechnology developments
         
         CHAPTER 3 COMMUNICABLE DISEASES
         
           3.1 Introduction
              3.1.1 Emerging infectious diseases
           3.2 Protein-based molecular diagnostics
              3.2.1 Introduction
              3.2.2 Developments in immunoassays
                3.2.2.1 HIV
                3.2.2.2 HBV/HCV
                3.2.2.3 Influenza and RSV
                3.2.2.4 WNV
                3.2.2.5 SARS
                3.2.2.6 Bacteria
                3.2.2.7 Fungi and parasites
           3.3 NAT-based molecular diagnostics
              3.3.1 Introduction
                3.3.1.1 Arrival of automated NAT systems
                3.3.1.2 Initiatives in microarray-based NAT
              3.3.2 Detecting viral pathogens
                3.3.2.1 HIV: viral load and drug resistance
                2.3.2.2 HBV/HCV: viral load and drug resistance
                3.3.2.3 HPV
                3.3.2.4 SARS CoV
                3.3.2.5 WNV
                3.3.2.6 Other viruses
              3.3.3 Detecting bacterial pathogens
                3.3.3.1 Chlamydia and gonorrhea
                3.3.3.2 Group B Strep
                3.3.3.3 Mycobacteria
                3.3.3.4 Atypical pneumonia bacteria
                3.3.3.5 Other bacteria
                3.3.3.6 Detection of antibiotic resistance
              3.3.4 Detecting fungi and parasites
              3.3.5 Screening of blood and blood products
                3.3.5.1 Viral contamination
                3.3.5.2 Bacterial contamination
                3.3.5.3 Parasitic contamination
              3.3.6 Susceptibility to infectious disease
         
         CHAPTER 4 CARDIOVASCULAR DISEASES
         
           4.1 Introduction
              4.1.1 Overview of cardiovascular diseases
              4.1.2 Diagnostic approaches
           4.2 Lipid and protein-based molecular diagnostics
              4.2.1 Lipid and protein markers of cardiac risk .
                4.2.1.1 Backgrounder on lipid profiling
                4.2.1.2 Lipoprotein subclass particle analysis 
                4.2.1.3 ApoB and apoB/apoA-1
                4.2.1.4 CRP
                4.2.1.5 Lp-PLA2
                4.2.1.6 Homocysteine
                4.2.1.7 Lp(a)
                4.2.1.8 Ox-LDL
                4.2.1.9 Sphingolipids
                4.2.1.10 ADMA
                4.2.1.11 MPO
                4.2.1.12 PAPP-A
                4.2.1.13 Antibodies to pathogens
                4.2.1.14 Other markers
                4.2.1.15 Markers in metabolic syndrome/obesity 
              4.2.2 Markers of myocardial necrosis
                4.2.2.1 Troponins, myoglobin and CK-MB
              4.2.3 BNP and NT-proBNP
              4.2.4 Multi marker strategies in acute syndromes 
              4.2.5 Protein markers in stroke
              4.2.6 Initiatives in proteomic analysis
           4.3 NAT-based molecular diagnostics
              4.3.1 Overview
                4.3.1.1 Monogenic diseases
                4.3.1.2 Non-monogenic diseases
              4.3.2 Genetic predisposition markers
                4.3.2.1 Thrombophilia (Factor V/II genes)
                4.3.2.2 Other gene markers of hemostasis
                4.3.2.3 Gene markers of hypertension
                4.3.2.4 MTHFR gene
                4.3.2.5 ApoE gene
                4.3.2.6 IL-1 gene
                4.3.2.7 Genes identified by deCODE/Roche
                4.3.2.8 Miscellaneous markers
              4.3.3 Genetic markers of drug responses
                4.3.3.1 Statins
                4.3.3.2 Antihypertensives
         
         CHAPTER 5 CANCER
         
           5.1 Introduction
              5.1.1 Overview of cancer
              5.1.2 Diagnosis of cancer
              5.1.3 Initiatives in bioinformatics
           5.2 Protein-based molecular diagnostics
              5.2.1 Overview
                5.2.1.1 Proteomics initiatives
              5.2.2 Established immunoassays
                5.2.2.1 Circulating markers
                5.2.2.2 Urine markers
              5.2.3 Emerging tumor markers
                5.2.3.1 Prostate cancer
                5.2.3.2 Ovarian cancer
                5.2.3.3 Colorectal cancer
                5.2.3.4 Breast cancer
                5.2.3.5 Mesothelioma
                5.2.3.6 Pancreatic cancer
                5.2.3.7 Cervical cancer
                5.2.3.8 Liver cancer
                5.2.3.9 All cancers
              5.2.4 Immunomic analysis
              5.2.5 Serum proteomic pattern diagnostics
                5.2.5.1 Ovarian cancer
                5.2.5.2 Prostate cancer
                5.2.5.3 Miscellaneous cancers
           5.3 DNA-based molecular diagnostics
              5.3.1 Aproaches to predictive testing
                5.3.1.1 Familial cancer syndromes
                5.3.1.2 Susceptibility to breast cancer
                5.3.1.3 Drug responsiveness
              5.3.2 Analysis of nucleated tumor cells
                5.3.2.1 Detecting residual tumor cells
                5.3.2.2 Surveying the tumor genome
                5.3.2.3 Detecting patterns of DNA-methylation  
              5.3.3 Analysis of nucleic acids shed by tumors
                5.3.3.1 Circulating tumor nucleic acids
                5.3.3.2 Stool-associated tumor nucleic acids
           5.4 RNA-based molecular diagnostics
              5.4.1 Gene expression profiling
                5.4.1.1 Breast cancer
              5.4.2 Alternative RNA splicing
              5.4.3 Single marker gene expression
         
         CHAPTER 6 MISCELLANEOUS DISEASES AND CONDITIONS
         
           6.1 Introduction
           6.2 Protein-based molecular diagnostics
              6.2.1 Maternal-fetal medicine
                6.2.1.1 Markers of early pregnancy
                6.2.1.2 Markers of Down Syndrome
                6.2.1.3 Markers of pre-eclampsia
                6.2.1.4 Other markers
              6.2.2 Markers of Alzheimer's disease
              6.2.3 Markers of diabetes risk
              6.2.4 Markers of bone turnover
              6.2.5 Miscellaneous markers
           6.3 NAT-based molecular diagnostics
              6.3.1 Congenital conditions
                6.3.1.1 Chromosomal abnormalities
                6.3.1.2 Monogenic diseases
              6.3.2 Glaucoma
              6.3.3 Alzheimer's and Parkinson's disease
              6.3.4 Organ transplantation
              6.3.5 Disease susceptibility testing
                6.3.5.1 Osteoporosis
                6.3.5.2 Diabetes and its complications
                6.3.5.3 Periodontal disease
                6.3.5.4 Rheumatoid arthritis
              6.3.6 Pharmacogenomic tests
                6.3.6.1 Prediction of adverse effects
                6.3.6.2 Drug efficacy in Alzheimer's disease
                6.3.6.3 Drug efficacy in asthma
                6.3.6.4 Drug efficacy in rheumatoid arthritis  
                6.3.6.6 Drug efficacy in other conditions
         
         CHAPTER 7 NON-CLINICAL APPLICATIONS
         
           7.1 Introduction
           7.2 Bioterrorism
              7.2.1 Bioterrorism preparedness initiatives
                7.2.1.1 Role of molecular diagnostics
              7.2.2 Bioterrorism agents
              7.2.3 Focus on anthrax
                7.2.3.1 Environmental testing
                7.2.3.2 Diagnostic testing
              7.2.4 Advances in biodetection technologies
                7.2.4.1 Detecting proteins
                7.2.4.2 Detecting nucleic acids
                7.2.4.3 Detecting proteins and nucleic acids
                7.2.4.4 Reagentless biosensors
                7.2.4.5 Analyzing molecular signatures
           7.3 Human identity testing
              7.3.1 Parentage testing
           7.4 Drugs of abuse testing
              7.4.1 Rapid immunoassays
           7.5 Veterinary market
              7.5.1 Protein-based molecular diagnostics
                7.5.1.1 Infectious diseases
              7.5.2 NAT-based molecular diagnostics
                7.5.2.1 Infectious diseases
                7.5.2.2 Animal breeding industry
           7.6 Food testing
              7.6.1 Pathogenic bacteria
                7.6.1.1 Immunoassays
                7.6.1.2 NAT
              7.6.3 Other applications of immunoassays
                7.6.3.1 BSE
                7.6.3.2 Drug residues
              7.6.4 Other applications of NAT
                7.6.4.1 Animal identity tracking
           7.7 Water testing
              7.7.1 Immunoassays
              7.7.2 NAT
           7.8 Anti-counterfeiting
              7.8.1 Protein-based technologies
              7.8.2 DNA-based technologies
                7.8.2.1 Key proprietary technologies
           7.9 Emerging opportunities in plant testing
              7.9.1 Plant diagnostics
              7.9.2 Plant breeding
              7.9.3 Plant-based drug production
         
         CHAPTER 8  MARKET CONSIDERATIONS AND FORECASTS
         
           8.1 Introduction
           8.2 Outlook for the total immunoassay market
             8.2.1 General Immunoassays
             8.2.2 Infectious Disease Immunoassays
             8.2.3 Cancer Immunoassays
             8.2.4 Specialty (e.g. Cardiovascular) Immunoassays
           8.3 Outlook for the total NAT market
             8.3.1 Infectious Diseases
                8.3.1.1 Bacterial tests
                8.3.1.2 Viral detection and load
                8.3.1.3 Viral and bacterial genotyping
                8.3.1.3 Blood screening
             8.3.2 Cancer
                8.3.2.1 Cervical cancer (HPV) screening
                8.3.2.2 Chromosomal abberations and shed nucleic acids
                8.3.2.3 Gene expression profiling
             8.3.3 Genetic testing and hereditary cancers
             8.3.4 Predisposition and pharmacogenomic tests
             8.3.5 Forensic and identity testing
           8.4 Outlook for the proteomic assay market
           8.5 Non-clinical applications
             8.5.1 Veterinary diagnostics
             8.5.2 Plant diagnostics
             8.5.3 Food industry
           8.6 Forecasts by geographical region
         
         CHAPTER 9  COMPANY PROFILES
         
           9.1 Abbott Laboratories Inc
           9.2 Agendia
           9.3 Bayer AG
           9.4 Biosite Diagnostics Inc
           9.5 Cepheid
           9.6 Chembio Diagnostic Systems Inc
           9.7 Chiron Corporation
           9.8 Ciphergen Biosystems Inc
           9.9 Correlogic Systems
           9.10 Diagnostic Products Corporation
           9.11 DiagnoSwiss SA
           9.12 Digene Corporation
           9.13 Epigenomics AG
           9.14 EXACT Sciences Corp
           9.15 Genaissance Pharmaceuticals Inc
           9.16 Gen-Probe Inc
           9.17 HandyLab
           9.18 Innogenetics N.V.
           9.19 Interleukin Genetics
           9.20 Matritech Inc
           9.21 Myriad Genetics Inc
           9.22 Nanogen
           9.23 Nuvelo Inc.
           9.24 Nymox Pharmaceutical
           9.25 OXIS International Inc
           9.26 Proteome Sciences plc
           9.27 Roche Holding Ltd
           9.28 Sequenom Inc
           9.29 SomaLogic Inc
           9.30 Third Wave Technologies Inc
         
         CHAPTER 10 TRENDS AND OPPORTUNITIES
         
           10.1 Diagnostic insights grow with new research tools
           10.2 Research tools evolve into ASRs and IVDs
           10.3 Routine molecular tests move into POC settings
           10.4 New molecular tests key to personalized medicine
           10.5 Molecular diagnostics boosted by antibioterrorism
           10.6 Human genetic and genomic testing gains acceptance
           10.7 DNA microarrays show commercial potential
           10.8 NAT: changing clinical diagnostics
           10.9 NAT: impacting non-clinical markets
           10.10 Towards tests based on multiple protein markers
           10.11 A goldmine of protein markers becons
           10.12 Proteomics: changing clinical diagnostics
           10.13 Proteomics: impacting non-clinical markets
           10.14 Molecular diagnostics and therapeutics converge
           10.15 New approaches await further exploitation
         
         APPENDIX 1: ABBREVIATIONS - ORGANISATIONS AND REGULATORY
         APPENDIX 2: ABBREVIATIONS - TECHNOLOGIES, DISEASES, BIOMARKERS

EXECUTIVE SUMMARY
Molecular diagnostic tests analyze DNA, RNA or protein markers to characterize diseases. The first generation molecular diagnostics described in this Report are predominantly single-analyte assays, either nucleic acid probe-based tests (NATs) or immunoassays. There is increasing evidence that multiple markers and patterns of markers can provide more insight into a disease state than single-marker assays. In the recent years great strides have been made in developing mutiplexing testing platforms which permit the measurement of many parameters simultaneously. As research tools and technologies evolve, they are making possible diagnostic testing on a level of complexity that was unthinkable a decade ago.
Emerging second generation molecular diagnostics based on molecular profiling are also described in this Report. Genomic, transcriptomic and proteomic profiling products hold the key to personalized medicine, which redefines diseases on the molecular level so that diagnostics and therapeutics can be targeted more precisely to specific patient populations.
The world market for in vitro diagnostic products (IVDs) as a whole is forecast to increase from $24.2 billion in 2003 to $30.8 billion in 2009, a compound annual growth rate (CAGR) of 4.1%. Growth will be driven mainly by China, Latin America, and the developing countries (including Eastern Europe). CAGRs in the US, Western Europe, and Japan will be under 3% owing to long-running healthcare cost-containment pressures in those regions.
However, the segments analysed in this report, about one-third of the global IVD market by dollar value, will considerably outperform the total market, growing at an average CAGR of 9.3% from $9.0 billion in 2003 to $15.3 billion in 2009. Only Japan and Italy are expected to lag behind significantly, and Latin America and Spain will be leading the field.
Sales of nucleic acid-based tests are expected to grow much more quickly than immunoassays. Apart from their greater utility in many circumstances, NATs are starting from a lower baseline (13% vs 87% of total sales in 2003, rising to 25% vs 75% in 2009), and will to some extent displace immunoassay tests in applic- ations such as infectious disease testing. Expected CAGRs are 6.6% for immunoassays and 21.7% for NAT. However, the segments of infectious disease and specialty immunoassays, both of which include a small but growing number of second generation tests (e.g. antibody-based chips), are growing respectively three and four times faster than the immunoassay average. With annual sales of $3 billion in 2003, infectious disease tests are currently the largest group of immunoassays by sales volume, and the largest single test segment discussed in this report. Overall, the fastest-growing applications (all currently niche NATs) are viral and bacterial genotyping (44% CAGR), cervical cancer screening (34% CAGR), and disease prediction/theranostics (30% CAGR).
This Report reviews technological developments which are leading to the development of improved molecular diagnostics. Growth in immunoassay-based molecular diagnostics has been enabled by the availability of rapid assay formats suitable for point-of-care (POC) applications, while developments in amplification techniques and genotyping methods have fueled the growth of NAT-based diagnostic testing. A number of companies have been developing multiplexing platforms for nucleic acid analysis suitable for clinical diagnostic applications, including DNA microarrays, microfluidics and bead-based assays. This Report also discusses the gradual emergence of protein chips and mass spectroscopy into the realm of clinical diagnostics which can screen multiple biomarkers present in sera or other body fluids.
This Report offers the most comprehensive coverage of molecular diagnostic products ever attempted in a single volume. All major clinical and non-clinical markets are reviewed, with particular emphasis on commercial products recently launched and those under development.
Infectious diseases are the leading cause of death worldwide and take third place in the US. In the US and elsewhere, the recent emergence or re-emergence of infectious diseases has stimulated the rapid development of new immunoassays and NAT assays for pathogens such as West Nile virus, SARS virus, and the parasite T. cruzi. The need to bring rapid, inexpensive tests to high-risk populations led to rapid immunoassay products replacing lab-based HIV tests. During the last few years progress has been made in automation of NAT assays, with the launch of the first fully automated, high throughput instrument for the NAT marketplace. Concurrent with the steady growth in viral load testing, the last two years saw expanded use of NAT in cervical-cancer (HPV) screening, bacterial detection, genotyping to detect drug resistance, and screening of blood and blood products.
Cardiovascular disease is the leading cause of death in the industrialized world. Although the principle modifiable risk factors for heart disease are well known, the inexorable rise in the prevalences of the metabolic syndrome and type 2 diabetes means that heart disease will remain a major cause of morbidity and mortality for the foreseeable future. Developments in the cardiovascular field are being driven by a host of new protein markers. Growth is anticipated in immunoassays, in particular POC products, based on protein biomarkers of cardiovascular risk, markers of cardiac necrosis, and markers of hemodynamic stress. Multibiomarker panels promise to be the best approach to risk stratification in acute coronary syndromes. The cardiovascular area boasts the first DNA-based test kit for an inherited disorder to be approved by the FDA. Tests based on molecular profiling are under development, but will require clinical validation.
Cancer is the second leading cause of death in the US and most other developed countries. The development of the cancer molecular diagnostic field had lagged behind some of the other disease segments, but rapid advances have been made in the recent years. Although the market still consists predominantly of immunoassay-based methods, new markers identified through proteomics promise better specificities. A number of companies have developed tests to detect genomic abnormalities associated with early-stage cancer, including analysis of nucleic acids shed by tumors. Development continues of genetic predisposition and pharmacogenomic tests. In this area more than in any other, proteomic and transcriptional profiling is expected to radically alter the way patients are diagnosed, classified and treated. Serum proteomic pattern diagnostics may allow pre-symptomatic diagnosis, while transcriptional profiling may predict tumor aggressivenes, or response to therapy. Both types of tests are making their debuts on the market.
Rapid POC immunoassays based on specific, often novel biomarkers are increasingly employed in prenatal diagnosis, and in the detection and management of a variety of medical conditions. There are indications that proteomic profiling may allow early diagnosis of diseases such as Alzheimer's disease and amyotrophic lateral sclerosis. NAT already plays an important role in prenatal and pre-implantation diagnosis. Genetic screening for the most common monogenic diseases is increasing as is pharmacogenomic testing for adverse drug reactions, with both areas witnessing the emergence of products based on microarrays and bead-arrays. In addition, genomic tests to predict drug efficacy are under development. Development of tests for susceptibility to non-monogenic diseases continues, although their scope is restricted at present.
The impact of new molecular diagnostic technologies is being felt across a wide range of industries outside the clinical arena and the stage is set for further expansion. Non-clinical applications od molecular diagnostic techniques reviewed in this Report include: bioterrorism; human identity testing; drugs of abuse testing; veterinary market; food testing: water testing; anti-counterfeiting; and plant testing. All offer unique opportunities for developers of molecular diagnostics.