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INTRODUCTION Clinical epidemiology and biostatistics are the basic sciences of clinical research. This series of articles will provide a basic primer of clinical epidemiology and biostatistics for the orthopaedic surgeon. The evidence-based medicine and patient-derived outcomes assessment movements burst onto the scene of clinical medicine in the 1980s and 1990s as a result of contemporaneous medical, societal, and economic influences. Work by Wennberg and colleagues revealed large small-area variations in clinical practice, with some patients thirty times more likely to undergo an operative procedure than other patients with identical symptoms merely because of their geographic location1-6. Further critical research suggested that up to 40% of some surgical procedures might be inappropriate and that up to 85% of common medical treatments were not rigorously validated7-9. Meanwhile, the costs of health care were rapidly rising to over two billion dollars per day, increasing from 5.2% of the gross domestic product in 1960 to 16.2% in 199710. Health maintenance organizations and managed care emerged. In addition, increasing federal, state, and consumer oversight were brought to bear on the practice of clinical medicine. These forces have led to an increased focus on the clinical effectiveness of care. Clinical epidemiology provides the methodology to assess the clinical effectiveness of care. Part I of this series, presented here, provides an overview of the concepts of study design, hypothesis testing, measures of treatment effect, and diagnostic performance. Evidence-based medicine, outcomes assessment, data, and statistical analysis will be covered in Part II, to be published in next year’s edition of The Orthopaedic Journal at Harvard Medical School. Examples from the orthopaedic literature and a glossary of terminology are provided. STUDY DESIGN In observational studies researchers observe patient groups without allocation of the intervention, whereas in experimental studies researchers allocate the treatment. Experimental studies involving humans are called trials. Research studies may be retrospective, meaning that the direction of inquiry is backwards from the cases and that the events of interest transpired before the onset of the study, or they may be prospective, meaning that the direction of inquiry is forward from the cohort inception and that the events of interest transpire after the onset of the study (Fig. 1). Cross-sectional studies are used to survey one point in time. All research studies are susceptible to invalid conclusions due to bias, confounding, and chance. Bias is the nonrandom systematic error in the design or conduct of a study. Bias usually is not intentional; however, it is pervasive and insidious. Forms of bias can corrupt a study at any phase, including patient selection (selection and membership bias), study performance (performance, information, and nonresponder bias), and outcome determination (detection, recall, acceptability, and interviewer bias). A confounder is a variable having independent associations with both the independent (predictor) and dependent (outcome) variables, thus potentially distorting their relationship. Frequent confounders in clinical research include gender, age, socioeconomic status, and comorbidities. As discussed below in the section on hypothesis testing, chance may lead to invalid conclusions based on the probability of type-I and type-II errors, which are related to p values and power. The adverse effects of bias, confounding, and chance can be minimized by study design and statistical analysis. Prospective studies minimize selection, information, recall, and nonresponder bias. Randomization minimizes selection bias and equally distributes confounders. Blinding can decrease bias, and matching can decrease confounding. Confounders can sometimes be controlled post hoc with use of stratified analysis or multivariable methods. The effects of chance can be minimized by an adequate sample size based on power calculaDr. Kocher is an Instructor in Orthopaedic Surgery, Harvard Medical School, and Director of the Program in Clinical Effectiveness, Harvard School of Public Health and Department of Orthopaedics, Children’s Hospital, Boston MA