Case–cohort studies: A variant of the nested case–control study design, in which cases occurring in a study cohort are compared to a sample of the whole cohort (which may include some cases).
6. METHODS FOR COMBINING THE RESULTS
investigation of spatial clustering of 13,351 cases of childhood leukemia in 17 European countries between 1980 and 1989 found evidence of clustering of total childhood leukemia within small census areas, but the magnitude of the clustering was small (81). No specific cell type, age group, or etiology was highlighted.
Although the study of cancer clusters has not had direct applicability to regulatory risk assessment to date, knowledge and perspective on this topic are of considerable value to the public health and medical practitioner.
The U.S. Centers for Disease Control and Prevention has provided recom-mendations for local and state health departments in the management and investigation of cancer and other disease clusters reported by the public (82). A scientific publication of the International Agency for Research on Cancer provides information on choices of statistical methods for investigat-ing localized clusterinvestigat-ing of disease (83).
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3
Epidemiological Approaches to Studying Cancer II: Molecular Epidemiology
Loı¨c Le Marchand
Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii, U.S.A.
1. INTRODUCTION
It is thought that most cancers result from the combined effects of environmen-tal factors and inherited susceptibilities and that only few cancers (5–10%) are due to purely genetic or endogenous factors (1,2). Thus substantial prevention opportunities should result from the identification of key environmental risk factors (i.e., lifestyle factors, environmental pollutants, drugs, radiation, and infectious agents) and the characterization of genetic susceptibilities involved in the process. Epidemiology has already played a crucial role in identifying important causes of cancer in populations, such as smoking in lung cancer, hepatitis B virus in liver cancer, and UV radiation in skin cancer. However, the traditional epidemiologic approach, relying mainly on record and ques-tionnaire information, has had difficulty detecting weak or attenuated associ-ations. Studies have often been inconsistent when the relative risk associated with exposure has been smaller than 2.0. For example, despite 20 years of intense effort, only few specific dietary components have been convincingly demonstrated to be risk factors for cancer (3). Difficulty in measuring exposure accurately and the inability to distinguish susceptible from resistant indivi-duals have been major impediments to the study of cancer risk.
The field of epidemiology has dramatically changed in the past 10 years and, as a result, is poised to make new major contributions to our
39
understanding of cancer etiology, risk assessment and prevention. Taking advantage of new advances in laboratory methods, epidemiologists and laboratory scientists have worked toward refining measurement of study variables through the use of biomarkers. The widespread incorporation of biological measurements at the cellular and molecular levels into large-scale studies has given rise to the term molecular epidemiology, which characterizes more an evolutionary step than the birth of a new discipline. In this regard, an analogy can be drawn with the effects of the computer revolution in the 1980s and the 1990s on the field of epidemiology. Enhanced computational power has made possible the application of sophisticated statistical tech-niques (e.g., logistic regression, proportional hazards regression, generalized estimating equation) aimed at identifying new risk factors from an intricate web of causal factors, confounders, and effect modifiers. These methods have allowed the investigation of inter-related exposures (e.g., lifestyle factors) in the etiology of complex diseases, such as cancer and coronary heart disease.
The sequencing of the human genome and the genomics=proteomics revolu-tion that is currently unfolding, and other technical advances, such as in ana-lytical chemistry, are providing epidemiologists with the capability for an even greater methodological leap based on increasingly sensitive and accurate measurements of susceptibility, exposure, and disease. With some of these scientific advances, however, come social and ethical issues that need to be addressed before the potential benefits can be fully realized.
This chapter provides an overview of the opportunities offered by the use of biomarkers in cancer epidemiology and risk assessment, as well as summarizes the main categories of biomarkers and the issues related to their application. For further exploration of these topics, we refer the reader to recent textbooks on molecular epidemiology (4–6).