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Linking Molecular Scale Insights to Population Impacts Paul A

Linking Molecular Scale Insights to Population Impacts Paul A

unit 1. Unit 1 contextual framework for molecular 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 and clinical applications the imagination and creativity of the population level. It is also a by addressing the medical and medical and health 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 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 , to health is to evaluate and establish the epidemiology and how they link with problems that afflict relationship between a 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 . 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 , 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 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 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, , 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, and many subspecialties. Some by identifying the frequency of infectious disease epidemiology; subspecialties focus on the disease biological markers of exposure, and ; 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; (e.g. occupational, environmental Examples are population monitoring epidemiology; genetics, molecular or nutritional), and still others of blood lead concentrations, , 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 . 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 , (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 . 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 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 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 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 or prophylaxis. evidence base for demonstrating marker data can be used to prevent the efficacy and effectiveness of or reduce morbidity and mortality Understanding the solutions clinical and population interventions (1,2,21,22,46). Consequently, moved into practice (42). Molecular molecular epidemiology is the When potential solutions or epidemiologic knowledge can be means to obtain molecular- and interventions are identified, used in impact assessments to biochemical-level understanding in molecular epidemiological determine changes in of a population context. knowledge is useful in the the biomarkers as surrogates for The term molecular development and conduct of disease or as indicators of disease epidemiology is compelling. It clinical and intervention trials, risk. inspires the scientific imagination, and monitoring the efficacy of compelling thinking of incorporating policy interventions. Following the new resolving powers of

Unit 1 • Chapter 1. Molecular epidemiology: Linking molecular scale 3 , genetics and research in general. These Specifically, this expansive view and analytical chemistry into issues—lack of biological realism means not only thinking of causal epidemiology, and it stimulates or theoretical basis for research, mechanisms and being problem- hypothesis development and testing lack of consistency in results, and oriented, but also being solution- over a broader range of genetic worse still, in some cases lack of oriented. How can the findings of and environmental factors. The scientific rigor—are threats of which molecular epidemiologic research term also focuses on the population all epidemiology, indeed all scientific be used to address a problem both distributions and implications of research, must be wary (51,52). Too at the and population levels? molecular events. often the attempt to substantiate It is critical to focus on credibility, On the face of it, the fact that molecular epidemiologic results rather than statistical significance molecular epidemiology is focused by post-hoc searching through the of research findings; encourage both on biological processes in scientific literature has led to finding rigorous replication, not just individuals and their distribution biologic information that is not truly discovery; and build public trust by in populations makes the term corroborating but only appears to be communicating results honestly and sound contradictory (47). Yet this so (53). acknowledging the limitations of the tension between identifying causal Similarly, the criticism that evidence (43). pathways at an individual biological molecular epidemiologic results are If molecular epidemiology is to level and understanding the causes not consistent between studies, and make a major impact on population of disease in populations has always are even sometimes contradictory, health, it must have a global focus been present in epidemiology. This is partly due to the media and public as well as a local one. Too often, seemingly contradictory nature misinterpretation of the nature of the findings of research on genetic of the molecular epidemiological scientific investigations, but it is also biomarkers have been seen as endeavour may be most familiar partly due to the failure of molecular leading to expensive sophisticated as articulated by Geoffrey Rose, epidemiologists to say loud and tests and treatments for a few in that epidemiologists’ efforts are clear that their studies must be rather than for the many. Molecular concerned with unraveling both the repeated and confirmed in various epidemiologic researchers need determinants of individual cases populations and settings before a to be aware of this concern in the and the determinants of incidence causal link can be strongly inferred context of their work. The result rates (48). Although this tension (54,55). This is especially true when should be research and strategies to may be exemplified by molecular strong causal claims are made help develop affordable population- epidemiology, there is nothing following small studies. wide tools for combating common inherent in the actions of molecular To continue to serve as a hub diseases (56). epidemiologists per se that limits for health research, molecular the utility of their activities for public epidemiology will need to continue Nomenclature, taxonomics health. Of greater importance expanding its contribution to and approaches is that this tension itself, this surveillance, mechanistic research, struggle to reconcile two seemingly efficacy trials, translational Other disciplines and terms overlap contradictory objectives, has been research and health policy. with molecular epidemiology. productive and inspiring (49). In Critical for this holistic approach The terms genomics, population this vein, some have argued that is the ability to assemble and genomics, population genetics, and the integration of genomics into communicate information, and, epidemiology all epidemiology can been seen as a ultimately, evidence to decision- can involve molecular epidemiologic further challenge to epidemiologists makers, medical and health approaches. Critical in all of these to take seriously the contextual professionals, and the public. This approaches is the use of valid factors that bear on biological will involve fostering an evidence- epidemiological study designs, processes (37,50). based approach to research and methodologies, and perspectives In short, the relevance adopting vigorous and stringent with valid and reliable indicators and usefulness of molecular criteria for systematic integration of of susceptibility, genotype and epidemiologic research to confirmation from many disciplines phenotypes. public health depends on how (e.g. genomics, , Another term that merits successfully practitioners address exposure assessment, pathology, discussion and definition is challenges that face epidemiology medicine and public health)(43). “biomarker.” The term biologic

4 marker, or biomarker, is broadly tools in decision-making, regulation, the convergence of classical and Unit 1 defined to include any type of diagnostics, , molecular epidemiology applications measurement made in a biologic therapeutics, pharmacology, public in a practical approach for disease 1 Chapter sample and includes measurements and environmental health, and prevention. of exogenous and endogenous as dependent and independent exposures, as well as any variables in molecular epidemiologic On the horizon phenomena in biologic systems at research. the biochemical, molecular, genetic, Implicit in biomarker-based The great investment in biomedical immunologic or physiologic level research is the collection of biological research made in the past 50 (1,20). specimens from individuals within years could yield many benefits Historically, biomarkers have an epidemiologic framework, in the next 50 years if the results been used for many decades in analysis of those specimens and of that research can be used and etiologic and , the amassing of the results in translated into practical advances beginning with seminal studies databases. The emergence of (see the following chapters that of infectious diseases followed large-scale networks, multicentre discuss these advances). The skills, by research on chronic diseases, collaborations and formal consortia tools and insights of molecular such as cardiovascular disease has increasingly been observed epidemiology can contribute to (1,57–59). Over time, an and has been advanced as an that effort. Knowledge is the basis appreciation of the heterogeneity approach to complex disease of action. Serving as the linking in biomarkers developed with research efforts (12,61–63). hub for laboratory and population regard to the different aspects of Although there is a strong rationale research, molecular epidemiology the disease process reflected by for using consortia for exploring the can help translate it to practice. them. Emerging from the seminal role of environmental exposures To do this, there will be a need works in the 1980s and 1990s, and genetic variants in disease, to maintain current trends in the three types of biomarkers were this does not mean that smaller, discipline and establish new ones. defined: biomarkers of exposure/ single investigative approaches Continuation of the trend towards dose (internal and biologically are without merit. Such studies large-scale networks and biobanks, effective dose), biomarkers of still may provide useful leads, use of bioinformatics, and attention effect (generally indicators of hypotheses, mechanistic insights to individual and collective ethical damage, alteration in homeostatic and identification of risk factors; issues will serve to move the field mechanisms, molecular or they are also helpful for validation forward. But more powerful effects biochemical dysfunction, preclinical of biomarkers. Nonetheless, large- will be achieved by incorporating effects of early disease, and clinically scale consortia provide a powerful epigenetic and biological systems apparent disease), and biomarkers approach to achieve adequate theory in research, expanding skill of susceptibility (either inherited or statistical power (particularly in sets and professional knowledge acquired) (2,20–22,29,30). These studies of individual genetic variants to complement translation research have been linked in a continuum and gene-environment interactions) and risk communication, and by that is applicable to many exposure- to identify effects and avoid false- fostering public health perspectives disease relationships and have been positive reports and to address (35,72,73). A broad population-wide further characterized with regard to complex research problems (64–69). vision for using biological markers the advantages and limitations of One unique, global collaboration, is required to leverage the power their application within the spectrum the Human Genome Epidemiology of molecular scale insight to give of epidemiologic studies (1,2,33,39). Network (HuGE Net), combines beneficial macro-scale impacts on The discovery of new biomarkers the traditional methodology of public health. for medical, environmental and population-level investigation with epidemiologic research is of molecular and genetic epidemiology Disclaimer: The findings and conclusions growing importance. The global data. HuGE Net is focused on the in this chapter are those of the author and do not necessarily represent the biomarkers market is projected post-gene discovery phase and views of the Centers for Disease Control to reach about $20.5 billion by interpretation of epidemiologic and Prevention. 2014 (60). Increasingly, there are information on human genes for developments in a broad range of the purpose of health promotion areas that include: biomarkers as (70,71). This is one example of

Unit 1 • Chapter 1. Molecular epidemiology: Linking molecular scale 5 References

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