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Linking Molecular Scale Insights to Population Impacts Paul A UNIT 1. UNIT 1 CONTEXTUAL FRAMEWORK FOR MOLECULAR EPIDEMIOLOGY CHAPTER 1 CHAPTER CHAPTER 1. Molecular epidemiology: Linking molecular scale insights to population impacts Paul A. Schulte, Nathaniel Rothman, Pierre Hainaut, Martyn T. Smith, Paolo Boffetta, and Frederica P. Perera Summary In a broad sense, molecular trials. It can then contribute to of using these and other tools to epidemiology is the axis that unites the translation of biomedical prevent, control, and treat chronic insights at the molecular level research into practical public and infectious diseases stimulates and understanding of disease at health and clinical applications the imagination and creativity of the population level. It is also a by addressing the medical and medical and health scientists and partnership between epidemiologists population implications of molecular practitioners. The challenge is and laboratory scientists in which phenomena in terms of reducing to effectively apply these tools, investigations are conducted using risk of disease. This chapter and knowledge from genetics, the principles of both disciplines. A summarizes the contributions and exposure assessment, population key trait of molecular epidemiology research endeavours of molecular health and medicine, to health is to evaluate and establish the epidemiology and how they link with problems that afflict 21st century relationship between a biomarker public health initiatives and clinical people. The means of meeting and important exogenous practice. that challenge is the widespread and endogenous exposures, conduct of molecular epidemiologic susceptibility, or disease, providing Introduction research. Driven by discoveries understanding that can be used in of basic biological phenomena future research and public health This is a unique and exciting at the molecular and genetic and clinical practice. When potential period in the health sciences. levels, molecular epidemiology solutions or interventions are For the first time, it is possible to is able to translate discovery of identified, molecular epidemiology look at both nature and nurture essential scientific knowledge into is also useful in developing and with sophisticated and molecular- determination and quantification conducting clinical and intervention level tools (1–12). The promise of hazards and risks, and then to Unit 1 • Chapter 1. Molecular epidemiology: Linking molecular scale 1 investigate useful approaches for comprehensive framework for the which brings together molecular- prevention, control, and treatment of use of biomarkers of internal dose, level thinking and population-level disease and dysfunction (9,12–15). biologically effective dose, early understanding. These insights can To fully appreciate the potential biologic effect and susceptibility be useful in characterizing a health contributions of molecular within a molecular epidemiological problem, conducting mechanistic epidemiology, it is important framework (2). In 1987, the National research (at the molecular and to understand how it fits into Research Council (NRC) adopted population levels), understanding the context of epidemiology this basic conceptual framework the solutions, and contributing and public health. Molecular for molecular epidemiology and to the clinical and public health epidemiology is a partnership subsequently published a series practice. These four functions and between epidemiologists and of reports on biological markers the research that supports them are laboratory scientists that conducts (20–22). In the 1980s through the illustrated in Figure 1.1. investigations using the principles mid-1990s, a series of important of both laboratory and population papers and books were published Characterizing research (1,2,16). This is a message describing the evolution and a public health problem that merits restatement as powerful progress of molecular epidemiology genetic and analytic technologies (1,17,23–36). More recently, the Surveillance, the sentinel activity of become available to epidemiologists. changing face of epidemiology in public health and clinical practice, is Historically, molecular epidemiology the genomics and epigenetic eras the ongoing collection, analysis and was derived from those disciplines has been described (9,12,36–39). interpretation of data on rates and that made contributions to relating In the past, molecular trends of disease, injury, death and biological measurements to health epidemiology was sometimes hazards. Molecular epidemiology and disease (1,2). These include viewed as one of epidemiology’s plays an important role in surveillance bacteriology, immunology and many subspecialties. Some by identifying the frequency of infectious disease epidemiology; subspecialties focus on the disease biological markers of exposure, pathology and clinical chemistry; type (e.g. chronic, infectious, disease or susceptibility in various carcinogenesis and oncology; reproductive or cardiovascular), population groups and in monitoring occupational medicine and some on the origin of the hazard trends of biomarkers over time. toxicology; cardiovascular disease (e.g. occupational, environmental Examples are population monitoring epidemiology; genetics, molecular or nutritional), and still others of blood lead concentrations, biology, and genetic epidemiology; focus on the approach to the neonatal screening for genetic and traditional epidemiology and disease (e.g. clinical, serological or disease, and molecular typing of biostatistics. The term “molecular analytical). Viewed in this context, viruses in a geographical area. epidemiology” was first used in molecular epidemiology may best The validation of those biomarkers the infectious disease literature by fit into the category of subspecialty and the analysis of the data involve Kilbourne to describe the “molecular defined by the approach that is molecular epidemiologic skills and determinants of epidemiologic applicable to all of these areas. knowledge. Increasingly, biological events” (17). In 1977, Higginson used Molecular epidemiology is the use specimen banks are being used as the term in the context of pathology of all types of biological markers public health surveillance systems in a paper entitled “The role of in the investigation of the cause, (40) and can play an important role the pathologist in environmental distribution, prevention and in etiologic research (41). medicine and public health” (18). treatment of disease, in which Lower’s landmark 1979 publication biological markers are used to Mechanistic research introduced genetic effect modifiers represent exposures, intervening and brought attention to the factors, susceptibility, intermediate Establishing the relationship importance of external exposure, pathological events, preclinical and between a biomarker and exposure, individual susceptibility and biologic clinical disease, or prognosis. disease or susceptibility is the markers in terms of phenotype (19). More broadly, molecular hallmark of molecular epidemiology, In a seminal paper in 1982, Perera epidemiology can be viewed as a hub and leads to developing the and Weinstein coined the term that links various aspects of health knowledge that will eventually be “molecular cancer epidemiology” research. Even the term molecular used in further research and in and first proposed a formal and epidemiology is a linking term clinical and public health practice. 2 Figure 1.1. Molecular epidemiology can serve as a hub for other components of Clinical UNIT 1 health research and practice. Adapted from (74). and public health practice CHAPTER 1 CHAPTER Translation of biomedical research to useful clinical and public health applications is clearly a major challenge (15,42–44). Molecular epidemiologists can accept that challenge and contribute to the translation of knowledge from research endeavours. This entails a more expansive view of molecular epidemiology beyond a tool in etiologic research to a discipline Figure not available that addresses the medical and population ramifications of molecular phenomena in terms of reducing risk of disease (45). Translation is a multifaceted process that has been described as involving four phases: 1) discovery to candidate health application; 2) health application to evidence-based practice guidelines; 3) practice guidelines to health practice; and 4) practice to population health impact (44). At times, molecular epidemiology has been portrayed as a reductionist approach that merely identifies molecular To achieve this progression, there assessment in trials, there is a risk factors and indicators in is a need for parallel laboratory and need for research on the translation individuals. However, molecular population research to understand of findings to clinical and public epidemiology is first and foremost the mechanisms through which health practitioners. This involves a means to gain sufficient environmental exposures interact identifying the potential uses of the biological understanding at the with host susceptibility factors to findings, the plan for communicating molecular and biochemical level of increase the risk of disease. The key and disseminating this information, the process of disease causation mechanisms can then be blocked and ways to measure the impact to protect public health. From its by interventions, such as exposure of their use. Epidemiologists have outset, molecular epidemiology reduction, behaviour modification, a long history of providing the has had the vision that biological chemoprevention
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