1. Introduction, Objectives, and an Alternative

The results of nonrandomized epidemiologic investigations have a direct impact on all aspects of health interventions. Studies of social, environmental, behavioral, and molecular risk factors associated with the incidence of particular diseases lead to primary public health interventions aimed at preventing the disease from occurring. Few studies of etiologic relations allow for the exposure to be assigned by randomization because of ethical constraints; participants cannot be randomized ethically to an exposure that might cause harm. Secondary interventions aim to reduce the disease burden by detecting disease before symptoms manifest, so that treatments can more effectively cure the disease or reduce its morbidity. While many studies of disease-screening programs are conducted by randomized designs, some have been conducted using nonrandomized designs (Weiss, 1994). In addition, the efficacy of screening programs established by randomized designs is often compared with its effectiveness measured by nonrandomized designs (Weiss, 1994), and history of screening can be an important confounder of etiologic relations (Weiss, 2003). Tertiary interventions, or medical interventions, aim to reduce the disease burden by curing the disease or by reducing its morbidity. Ideally, the efficacy of medical interventions is established by randomized study designs. However, such designs are sometimes unethical when patients cannot be assigned to a valid comparison group. For example, patients cannot be assigned to receive a placebo or to receive no therapy when there are accepted medical interventions available. When such a comparison group is required, nonrandomized designs are the only alternative. The medical literature contains a continuous and vigorous discussion about the advantages and disadvantages of nonrandomized versus randomized controlled trial evidence (Barton, 2000; Ioannidis et al., 2001a, b) and about the role of both in evidence-based medicine. Randomized controlled trials and nonrandomized studies have complementary roles (Sorensen et al., 2006), particularly when external validity, feasibility, and ethical concerns are paramount. Furthermore, nonrandomized designs provide a measure of the effectiveness of therapies – for which efficacy has been established by randomized designs – in clinical practice settings that involve patients with characteristics that differ from the clinical trial subjects (e.g., the elderly or other underserved subpopulations). Thus, nonrandomized epidemiologic research contributes to the knowledge base for disease prevention, early detection, and treatment.