2013 Introduction to Molecular Diagnostics THE ESSENTIALS OF DIAGNOSTICS SERIES AdvaMedDx and DxInsights Present INTRODUCTION TO MOLECULAR DIAGNOSTICS Abstract Diagnostic tests are the foundation of Increasing automation is enabling a successful health care system, sophisticated molecular tests to be providing critical information that health performed in the full scope of health care providers and patients need to make care settings, bringing state of the art the right medical decisions. Diagnostics diagnostics to all areas of the world. often provide objective, quantitative This report provides an overview of measurements that inform every stage the current landscape for molecular of care—prevention, detection, diagnosis, diagnostics, explains the key technologies treatment, and successful management that are driving the molecular revolution, of health conditions. illustrates the power of molecular Molecular diagnostics is a dynamic diagnostics with some specific examples, and transformative area of diagnostics, and concludes by noting several leading to insights in research and challenges that have the potential to treatment in many disease states that influence progress in this critical field are revolutionizing health care. Molecular of medicine. diagnostics detect and measure the presence of genetic material or proteins associated with a specific health condition or disease, helping to uncover the underlying mechanisms of disease and enabling clinicians to tailor care at an individual level – facilitating the practice of “personalized medicine.” Continuous innovation in technology is increasing the speed and performance of molecular diagnostics, and a future in which whole genome sequencing is routinely performed is not far away. THE ESSENTIALS OF DIAGNOSTICS SERIES: INTRODUCTION 2 Table of Contents Introduction to Molecular Diagnostics THE ESSENTIALS OF DIAGNOSTICS SERIES Introduction 2 Molecular Diagnostics 4 The Molecular Diagnostics Field 6 Molecular Biology – Genomics and Proteomics 7 Technology of Molecular Diagnostics 9 DNA Sequence Detection using Polymerase Chain Reaction (PCR) 10 The Clinical Role 12 Screening Test Example: HPV 13 Screening/Diagnostic Test Example: Cystic Fibrosis 13 Diagnostic Test Example: Chlamydia/Gonorrhea 14 Therapeutic Decision-Making Example: KRAS 14 Therapeutic Monitoring Example: HIV 15 The Future of Molecular Diagnostics 15 Conclusion 17 Acknowledgments 17 Glossary of Common Molecular Diagnostic Terms 18-19 THE ESSENTIALS OF DIAGNOSTICS SERIES: MOLECULAR DIAGNOSTICS 3 Introduction Diagnostics are an integral and critical part of our provide critical insights at every stage of medical health care system, as the results of these tests care—prevention, detection, diagnosis, treatment and inform a wide range of medical decision making. From successful management of health conditions. Figure the genetic tests that inform personalized cancer 1 illustrates the roles of diagnostics throughout this treatment to the microbial culture that identifies the continuum of health care. right antibiotic to fight an infection, diagnostic tests Comprehensive Role of Diagnostics Diagnostics can help clinicians optimally manage patients through the continuum of care. Risk Screening Diagnosis Staging and Therapy Monitoring Assessment Prognosis Selection Description Diagnostic Applied to Use for Assess Used to Recurrence tests to high-risk definitive severity predict monitoring complement patient to diagnosis and/or risk efficacy Monotoring traditional identify and general of recurrence or safety for treatment risk factors disease typing Inform response efficacy early adjuvent to specific therapy treatments decision Clinical Implement Nip disease Refer to the Determine Do not waste Control disease Implications wellness in the bud appropriate whether unproductive progression programs with early specialist treatment is therapy with changes in proactively treatment necessary treatment SOURCE: DxInsights White Paper January 2012 FIGURE 1: Role of diagnostics through the continuum of health care. Broadly speaking, two primary areas of health care While the traditional laboratory remains a mainstay diagnostics are “in vivo” imaging and “in vitro” for diagnostic testing, significant testing is done diagnostics, often referred to as IVDs. Imaging outside the laboratory, in such point of care settings encompasses such technologies as X-Rays, ultrasonic as hospitals, physicians’ offices, and clinics, and for waves, magnetic resonance, or radio-nuclear methods personnel in the field, such as emergency responders that produce images of the body and its organs and and soldiers. Pregnancy tests and diabetes test other structures. IVDs are tests performed on a strips are familiar examples of diagnostics that are sample taken from the body (blood, tissue, sputum, available directly to consumers. urine, etc.). “In vitro” is from Latin, meaning “on glass”, The main categories of diagnostics are clinical in reference to the glassware used to hold bodily chemistry, immunology, hematology, microbiology samples during culture or examination. Molecular and molecular diagnostics. The diagnostics industry diagnostics, the topic of this report, is a subset of in continues to innovate in all of these important areas, vitro diagnostics, and, therefore, the scope of this and molecular diagnostics has captured particular report is confined to this field, which is hereafter attention in recent years because of the deep insights referred to as “diagnostics” for the sake these types of tests bring to diagnosis and treatment. of convenience. THE ESSENTIALS OF DIAGNOSTICS SERIES: MOLECULAR DIAGNOSTICS 4 Molecular Diagnostics Molecular diagnostics is one of the most dynamic a specific gene mutation in their cancer that is and transformative areas of diagnostics, leading associated with a specific type of lung cancer). to advances in research and treatment that are Of course, the ultimate power of personalized revolutionizing health care across a wide range of medicine is the ability to treat these smaller groups diseases and health conditions. with therapies tailored to the molecular profile of their “Molecular diagnostics” is a broad term describing individual cancer. When specific proteins or genetic a class of diagnostic tests that assess a person’s health sequences have a known association with a specific literally at a molecular level, detecting and measuring health condition or disease, they are often referred specific genetic sequences in deoxyribonucleic acid to as “biomarkers”” because they are markers of (DNA) or ribonucleic acid (RNA) or the proteins they that condition or disease. express. Molecular diagnostics identify gene, RNA, Molecular diagnostics are the tools that are driving and protein variations that shed light on whether the continuing discovery of biomarkers at the research a specific person is predisposed to have a disease, level, which in turn leads to treatments designed whether they actually have a disease, or whether a around these biomarkers. Then molecular diagnostics certain treatment option is likely to be effective for play an additional critical role by ensuring that these a specific disease. These tests also can detect and new therapies are delivered to the right patients quantify the presence of specific viruses, bacteria, through more accurate diagnosis of the exact nature or types of cells. of their individual disease. This has led to the Sequencing the entire human genome is a feat emerging field of companion diagnostics, in which a that, when it was first accomplished by the Human molecular diagnostic test is used to identify whether Genome Project, took an international, government- a specific therapy (a companion to the diagnostic) led research consortium over 10 years and $2.7 is likely to be effective for an individual patient. billion. (An initial draft of the entire genome sequence Molecular diagnostic tests can help a woman was published in 2001, ten years after the project understand the likelihood that her breast cancer will was initiated, and an essentially complete version reoccur later in life, or tell a doctor what drug is the was published in 2003.) Remarkably, molecular right treatment for a late-stage melanoma patient. diagnostics now can sequence a person’s entire They can make it possible for couples considering a genome for a cost that is rapidly declining and now family to know if they are carriers of a cystic fibrosis approaches $1,000. gene mutation and therefore at risk of having a child Many of our bodily processes, both normal and affected by cystic fibrosis. Molecular diagnostics abnormal, as well as health or disease states, are can identify multiple strains of respiratory viruses in driven by the interaction of our genes and the a single test, or monitor the level of HIV virus in a proteins they produce that carry out specific patient’s blood to determine how well their treatment functions within the body. Therefore, the ability is working. In these and many other ways, molecular to quickly and accurately assess an individual’s diagnostics are transforming health care. health at this molecular level is truly transforming Molecular diagnostics today are routinely used in the practice of medicine. hospitals, reference labs, and blood banks. In the The term “personalized medicine” has arisen from latter, molecular tests are used to screen donated this field of molecular discovery. The term means that blood products for infectious diseases like hepatitis understanding