An Overview of Basic Epidemiology Concepts, Randomization Techniques and Minimization for Clinical Trials

Download Article

Authors : Praneeth Kumar


This article will cover concepts of association and outcomes, introduce standard epidemiological concepts of incidence and prevalence, define and describe relative risk, absolute risk, attributable risk and the various methods for calculating those quantities in different observational research designs. Definitions of and methods for reducing bias are major components of this section.

Epidemiology is the study of disease in populations. It thus differs from the more conventional medical approaches to the study of disease that is normally concerned with the study of disease processes in affected individuals.Cohort, cross sectional, and case-control studies are collectively referred to as observational studies. Often these studies are the only practicable method of studying various problems, Cohort studies are used to study incidence, causes, and prognosis. Because they measure events in chronological order they can be used to distinguish between cause and effect. Cross sectional studies are used to determine prevalence. They are relatively quick and easy but do not permit distinction between cause and effect. Case controlled studies compare groups retrospectively. They seek to identify possible predictors of outcome and are useful for studying rare diseases or outcomes.

The crucial point of a clinical trial is the aim of investigating the difference of the patient groups caused only by the treatment procedures that are applied. If other kinds of differences exist (such as systematic differences) between the groups to be formed, then the outcomes are supposed to be biased. Forms of bias can corrupt a study at any phase, including patient selection (selection and membership bias), study performance (performance and information bias), patient follow-up (non responder and transfer bias), and outcome determination (detection, recall, acceptability, and interviewer bias).

The two common methods that are used to reduce the bias are randomization and blinding. The aim of randomization in clinical trials is the creation of groups that are comparable for any known or unknown, potentially confounding variables. Randomization, if done properly, ensures strengthening both the internal validity by minimizing selection bias and external validity by providing a correct basis for generalization. Simple randomization, weighted randomization, block randomization, stratified randomization, and minimization methods are discussed in this article.

Keywords: Epidemiology, simple randomization, block randomization, stratified randomization, minimization and blinding.


[1]. Heineken’s CH, Buring JE. Epidemiology in medicine. May rent SL, editor. Boston: Little, Brown; 1987.

[2]. Fowkes F, Fulton P. Critical appraisal of published research: introductory guidelines. BMJ 1991; 302:1136–40.

[3]. Doll R, Peto H. Mortality in relation to smoking. 40 years observation on female British doctors. BMJ 1989; 208:967–73.

[4]. Alberman ED, Butler NR, Sheridan MD. Visual acuity of a national sample (1958 cohort) at 7 years. Dev. Med Child Neural 1971; 13:9–14.

[5]. Davey Smith G, Hart C, Blane D, et al. Adverse socioeconomic conditions in childhood and cause specific mortality: prospective observational study. BMJ 1998; 316: 1631–5.

[6]. Goyder EC, Goodacre SW, Botha JL, et al. How do individuals with diabetes use the accident and emergency department? J Accid Emerg Med 1997; 14:371–4.

[7]. Jaffe HW, Bregman DJ, Selik RM. Acquired immune deficiency in the US: the first 1000 cases. J Info Dis 1983; 148:339–45.

[8]. Lerner DJ, Kennel WB. Patterns of coronary heart disease morbidity and mortality in the sexes: a 26 year follow-up of the Framingham population. Am Heart J 1986; 111:383–90.

[9]. van der Pol V, Rodgers H, Aitken P, et al. Does alcohol contribute to accident and emergency department attendance in elderly people? J Accid Emerge Med1996; 13:258–60.

[10]. Reidy A, Minassian DC, Vafadis G, et al. BMJ 1998;316:1643–7.

[11]. Karjaleinen, Kujala U, Kaprio J, et al. BMJ 1998; 316:1784–5.

[12]. Kunst A, Groenhof F, Mackenbach J. BMJ 1998; 316:1636–42.

[13]. Hill AB, Hill ID. Bradford Hills principles of medical statistics. 12th edn. London: Edward Arnold, 1991. 60 Mann www.emjonline.comDownloaded from on June 22, 2013 - Published by

[14]. John stone AJ, Zuberi SH, Scobie WH. Skull fractures in children: a population study. J Accid Emerge Med1996; 13:386–9.

[15]. Juni, P., Altman, D.G., and Egger, M. Assessing the quality of controlled clinical trials. British Medical Journal. 2001; 323: 42-46.

[16]. Checklist of items to include when reporting a randomized trial. In CONSORT statement.

[17]. Altman, D.G., and Bland, J.M. How to randomize. British Medical Journal. 1999; 319; 703-704.

[18]. Altman, D.G., and Bland, J.M. Treatment allocations by minimisation. British Medical Journal. 2005; 330: 843.

[19]. Singh, G. Minimisation may be viewed parallel to stratified randomisation though not equivalent. British Medical Journal. Rapid Responses;, [Accessed October 30, 2005]

[20]. Department of Health Services Research, Palo Alto Medical Foundation Research Institute, Palo Alto, CA, USA.

[21]. Ingersoll C.D. It's time for evidence. J Athl Train. 2006; 41:7. [PMC free article] [PubMed]

[22]. Request for proposals: evidence-based practice and outcomes of care in athletic training. National Athletic Trainers' Association Research & Education Foundation. Accessed December 24, 2006.

[23]. Singer J.D, Willett J.B. Applied Longitudinal Data Analysis: Modeling Change and Event Occurrence. New York, NY: Oxford University Press; 2003. pp. 3–15.

[24]. McEntegart D.J. The pursuit of balance using stratified and dynamic randomization techniques: an overview. Drug Info J. 2003; 37(3):293–308.

[25]. Altman D.G, Bland J.M. Statistics notes: treatment allocation in controlled trials. Why randomize? BMJ. 1999; 318(7192):1209. [PMC free article] [PubMed]

[26]. Hedden S.L, Woolson R.F, Malcolm R.J. Randomization in substance abuse clinical trials. Subst Abuse Treat Prev Policy. 2006; 1(1):6. [PMC free article] [PubMed]

[27]. Lachin J.M, Matts J.P, Wei L.J. Randomization in clinical trials: conclusions and recommendations. Control Cline Trials. 9 ;( 4):365–374. 1988.

[28]. Schulz K.F, Grimes D.A. Generation of allocation sequences in randomized trials: chance, not choice. Lancet. 2002; 359(9305):515–519. [PubMed]

[29]. Scott N.W, McPherson G.C, Ramsay C.R, Campbell M.K. The method of minimization for allocation to clinical trials: a review. Control Cline Trials. 2002; 23(6):662–674. [PubMed]

[30]. Altman D.G, Bland J.M. How to randomize. BMJ. 1999; 319(7211):703–704. [PMC free article][PubMed]

[31]. Pocock S.J, Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics. 1975; 31(1):103–115. [PubMed]

[32]. Fleiss J.L, Levin B, Paik M.C. Statistical Methods for Rates and Proportions. 3rd ed. Hoboken, NJ: John Wiley & Sons; 2003. How to randomize. pp. 86–94.

[33]. Simon S.D. Is the randomized clinical trial the gold standard of research? J Androl. 2001; 22(6):938–943. [PubMed]

[34]. Fisher R.A. The arrangement of field experiments. J Ministry Ag. 1926; 33:503–513.

[35]. Amberson J.B, McMahon B.T, Pinner M.A. Clinical trial of sanocrysin in pulmonary tuberculosis. Am Rev Tuberc. 1931; 24:401–435.

[36]. Kalish L.A, Begg C.B. Treatment allocation methods in clinical trials: a review. Stat Med.1985; 4(2):129–144. [PubMed]

[37]. Schulz K.F, Grimes D.A. Allocation concealment in randomized trials: defending against deciphering. Lancet. 2002; 359(9306):614–618. [PubMed]

[38]. Frane J.W. A method of biased coin randomization, its implementation, and its validation. Drug INF J. 1998; 32(2):423–432.

[39]. Lomax R.G. Statistical Concepts: A Second Course for Education and the Behavioral Sciences. Mahwah, NJ: Lawrence Erlbaum Assoc; 2001. pp. 186–199.

[40]. Weir C.J, Lees K.R. Comparison of stratification and adaptive methods for treatment allocation in an acute stroke clinical trial. Stat Med. 2003; 22(5):705–726. [PubMed]

[41]. Kaptchuk TJ. Intentional ignorance: a history of blind assessment and placebo controls in medicine. Bull Hist Med 1998; 72:389–433.

[42]. Devereaux PJ, Manns BJ, Ghali WA, et al. Physician interpretations and textbook definitions of blinding terminology in randomized controlled trials. JAMA 2001; 285: 2000–03.

[43]. Schulz KF, Chalmers I, Altman DG. The landscape and lexicon of blinding in randomized trials. Ann Intern Med 2002; 136: 254–59.

[44]. Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995; 273:408–12.

[45]. Schulz KF, Chalmers I, Grimes DA, Altman DG. Assessing the quality of randomization from reports of controlled trials published in obstetrics and gynaecology journals. JAMA 1994; 272:125–28.

[46]. Chalmers I. What is the prior probability of a proposed new treatment being superior to established treatments? BMJ 1997; 314:

[47]. Altman DG, Bland JM. Treatment allocation by minimisation. BMJ2005; 330:843.

[48]. Matts JP, Lachin JM. Properties of permuted-block randomization in clinical trials. Control Cline Trials1988; 9:327-44. CrossRefMedlineWeb of Science

[49]. ICH Harmonised Tripartite Guideline. Statistical principles for clinical trials. International Conference on Harmonisation E9 Expert Working Group. Stat Med1999; 18:1905-42.Medline Web

[50]. Kahan BC, Morris TP. Improper analysis of trials randomised using stratified blocks or minimisation. Stat Med2012; 31:328-40.CrossRefMedline