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Module 2: Fundamentals of Epidemiology

Module 2: Fundamentals of Epidemiology. Experimental Studies. Developed through the APTR Initiative to Enhance Prevention and Population

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Module 2: Fundamentals of Epidemiology

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  1. Module 2:Fundamentals of Epidemiology Experimental Studies Developed through the APTR Initiative to Enhance Prevention and Population Health Education in collaboration with the Brody School of Medicine at East Carolina University with funding from the Centers for Disease Control and Prevention

  2. Acknowledgments This education module is made possible through the Centers for Disease Control and Prevention (CDC) and the Association for Prevention Teaching and Research (APTR) Cooperative Agreement, No. 5U50CD300860. The module represents the opinions of the author(s) and does not necessarily represent the views of the Centers for Disease Control and Prevention or the Association for Prevention Teaching and Research. APTR wishes to acknowledge the following individual that developed this module: Jeffrey Bethel, PhD Department of Public Health Brody School of Medicine at East Carolina University

  3. Presentation Objectives • Recognize use of experimental studies as an epidemiologic study design • Distinguish between types of experimental studies • Describe key features of conducting experimental studies • Recognize special considerations of experimental studies

  4. Analytic Study Designs • Experimental studies (experimental) • Researcher determines who is exposed (treatments received) • Cohort studies (observational) • Case-control studies (observational) • Cross-sectional studies (observational)

  5. Experimental StudiesBackground Goal of public health and clinical medicine is to modify natural history of disease and improve morbidity and mortality How do we select the best preventive and therapeutic measures? Carry out studies to determine value of various measures

  6. Smith, AH. The Epidemiologic Research Sequence. 1984

  7. Experimental Studies Most closely resemble controlled laboratory experiments Gold standard of epidemiological research High status and validity and can pick up small and modest effects

  8. Experimental StudiesScurvy James Lind identified symptoms of scurvy among sailors at sea after as little as a month Conducted early experimental study on treatment of scurvy in mid-1700’s among British sailors Small sample size (6 groups of 2 ill sailors) Group eating oranges and lemons were fit for duty in 6 days

  9. Experimental Studies Potential Uses Evaluate new drugs and other treatments for diseases Evaluate new medical and health care technology Evaluate new screening programs or techniques Evaluate new ways of organizing or delivering health services (e.g. home v. hospital care following myocardial infarction)

  10. Experimental Studies Preventive v. Therapeutic • Preventive • Does prophylactic agent given to healthy or high-risk individual to prevent disease? • Therapeutic • Does treatment given to diseased individual reduce risk of recurrence, improve survival, quality of life?

  11. Experimental Studies Individual- v. Community-Based • Individual • Do women with stage I breast cancer given a lumpectomy alone survive as long without recurrence of disease as women given a lumpectomy plus radiation? • Community • Does fluoride in the water supply decrease the frequency of dental caries in a community compared to a similar community without such water treatment?

  12. STUDY POPULATION RANDOM ASSIGNMENT CURRENT TREATMENT NEW TREATMENT IMPROVE DO NOT IMPROVE IMPROVE DO NOT IMPROVE

  13. Experimental Studies Overall Conduct • Hypothesis formed • Participants recruited based on specific criteria and their informed consent is sought • Eligible and willing subjects randomly allocated to receive one of the two or more interventions being compared • Study groups are monitored for outcome under study (recurrence of disease, first occurrence of disease, getting better, side effects) • Rates of the outcome in the various groups are compared

  14. Experimental StudiesHypothesis Women with stage I breast cancer given a lumpectomy alone will survive as long without recurrence of disease as women given a lumpectomy plus radiation Water supply with fluoride will decrease the frequency of dental caries in a community compared to a similar community without water treated with fluoride

  15. Experimental StudiesInclusion Criteria for Participants • Who will be in the study? • Must be defined specifically before study begins • Remove subjectivity • Reproducibility

  16. Experimental StudiesInclusion Criteria for Participants • NEJM 352;13:1293-1303 • Women’s Health Study • ≥ 45 years • No history of coronary heart disease, cerebrovascular disease, cancer, or other major chronic illness • No history of side effects to any of study medications • Were not taking any of following meds more than once per week: aspirin, NSAIDs, supplements of vitamin A, E, or beta-carotene • Were not taking anticoagulants or corticosteroids

  17. Experimental StudiesSample Size How many participants do we need to enroll in the study? Programs and tables exist to calculate sample size based on various parameters

  18. Type I and II errors can be reduced by increasing sample size

  19. Experimental StudiesSample Size Required Parameters • The difference in effect to be detected • Estimate of effect in one group • Level of significance (a) • Probability of concluding treatments differ when they do not differ • Level of power desired (1 - β) • Probability of concluding treatments differ when they do differ • 1-sided or 2-sided test

  20. Experimental Studies Participant Allocation Compare the outcome among “exposed” to what the outcome would have been if unexposed This comparison is counterfactual Instead, compare the outcome among “exposed” group to the outcome in a “substitute” population Validity of inference depends on finding a valid substitute population

  21. Experimental StudiesParticipant Allocation • Need to randomly assign participants to one of the intervention groups (test or control) • Randomization • Next assignment is unpredictable • Coin toss to determine group allocation • Random number table, opaque envelopes • Computer

  22. Experimental Studies Randomization • Main purpose • Reduces selection bias in the allocation of treatment • Each participant has an equal chance of being in test or control group • Secondary purpose • If large enough sample size, produce treatment and control groups with similar baseline characteristics • Control for known and unknown factors

  23. Experimental Studies Randomization

  24. Experimental Studies Randomization

  25. Experimental Studies Data Collection • Treatment • Keep track of which treatment group the participant was assigned • Keep track of which therapy received • Baseline data • Collect baseline demographic and other risk factor data • Compare treatment groups

  26. Experimental Studies Data Collection • Measuring outcome • Must be conducted in same fashion for all treatment groups • Preventive studies • Precursors of disease or first occurrence of disease • Therapeutic studies • Symptom improvement • Length of survival • Disease recurrence

  27. Women’s Health Study • Myocardial infarction • Symptoms met WHO criteria • Abnormal levels of cardiac enzymes or diagnostic electrocardiograms • Stroke • New neurologic deficit of sudden onset that persisted for at least 24 hours • Death from cardiovascular disease • Examination of autopsy reports, death certificates, medical records, and information obtained from the next of kin or other family members

  28. Experimental Studies Data Collection • Masking (Blinding) • Prevents conscious and subconscious bias in research • Use placebo to mask • Single blind: participants do not know which treatment they are receiving • Double blind: participants and observers (data collectors) do not know participant treatment status

  29. Experimental StudiesParallel v. Crossover • Parallel • Participants in each group simultaneously receive one study treatment • Treatment and comparison groups consist of different participants • Crossover • Planned reversal of intervention and control groups • Each participant can serve as his/her own control

  30. STUDY POPULATION RANDOMLY ASSIGNED NEW TREATMENT CURRENT TREATMENT Group 1 Group 2 Observe and Measure Effects Group 2 Group 1 Group 1 Group 2 Observe and Measure Effects Group 1 Group 2

  31. Experimental StudiesSimple v. Factorial • Simple • Each group receives a treatment consisting of one component (e.g. one drug) • Factorial • Use same study population to compare 2 or more treatments • 2 x 2 factorial design • Similar to 3 arms (drug A, drug B, and placebo) with fewer participants

  32. Experimental StudiesFactorial

  33. Experimental StudiesFactorial

  34. Experimental StudiesNoncompliance • Overt • Notify investigators he/she is dropping out of study • Drop outs • Covert • Stop taking assigned treatment without telling investigators • Need to build compliance checks in to the study (e.g. test urine, count pills, etc.)

  35. Experimental StudiesExpressing Results • Efficacy • Reduction in risk • Calculate risk of death, developing disease, complications in each group • Vaccine example = (Rate in placebo group) – (Rate in vaccine group) Rate in placebo group

  36. Experimental StudiesExpressing Results • Relative risk • Kaplan-Meier plot • Hazard ratio • Number of patients who would need to be treated (NNT) to prevent 1 adverse event • Number needed to harm (NNH) indicates number patients treated to cause harm in 1 patient who would not otherwise have been harmed

  37. Experimental StudiesValidity of Results • Internal validity • Extent to which the study groups are comparable • Comparability • Reflected by selection/randomization • External validity • Extent to which the results of a study can be applied to people not in it • Generalizability • Representativeness

  38. REFERENCE POPULATION External Validity STUDY POPULATION RANDOMLY ASSIGNED CURRENT TREATMENT NEW TREATMENT Internal Validity

  39. Experimental StudiesValidity of Results • Items affecting internal validity • Loss to follow-up • Lack of randomization • Items affecting external validity • Loss to follow-up • Low response rate • Narrow inclusion criteria

  40. Experimental StudiesEthical Considerations • Randomization • There must be genuine uncertainty about which treatment is better • Informed consent • Some trials enroll participants immediately after diagnosis • When to stop the study? • Harmful or beneficial effects of one treatment arm • Outside board monitors study

  41. Experimental StudiesDisadvantages Expensive and time-consuming Ethical concerns may arise A large number of participants may be required Participant exclusion may limit generalizability Compliance may be an issue Influence of sponsorship

  42. Experimental StudiesAdvantages Randomization tends to balance risk factors across study groups Blinding of participants can reduce bias in assessment of outcomes Prospective design Eliminate bias by comparing two otherwise identical groups Detailed information collected at baseline and throughout study period

  43. Summary Experimental studies top epidemiologic study design hierarchy in terms of validity Investigators assign treatment to participants (experimental) Randomization reduces selection bias in treatment allocation Data collection must be conducted systematically Noncompliance and drop-outs must be minimized to increase validity of results

  44. Collaborating Institutions Center for Public Health Continuing Education University at Albany School of Public Health Department of Community & Family Medicine Duke University School of Medicine

  45. Advisory Committee Mike Barry, CAE Lorrie Basnight, MD Nancy Bennett, MD, MS Ruth Gaare Bernheim, JD, MPH Amber Berrian, MPH James Cawley, MPH, PA-C Jack Dillenberg, DDS, MPH Kristine Gebbie, RN, DrPH Asim Jani, MD, MPH, FACP Denise Koo, MD, MPH Suzanne Lazorick, MD, MPH Rika Maeshiro, MD, MPH Dan Mareck, MD Steve McCurdy, MD, MPH Susan M. Meyer, PhD Sallie Rixey, MD, MEd Nawraz Shawir, MBBS

  46. APTR • Sharon Hull, MD, MPH President • Allison L. Lewis Executive Director • O. Kent Nordvig, MEd Project Representative

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