1. Design of Observational and Experimental Clinical Studies Kenneth F. Schulz, PhD

2. Epidemiology More than statistics; biostatistics; medical science - A specific research methodology More than statistics; biostatistics; medical science - A specific research methodology Methods conjures up what images? Methods conjures up what images? Connotation? Word association? Presentation? Connotation? Word association? Presentation? NEJM Methods Section NEJM Methods Section Bad Rap - really fun and exhilarating Bad Rap - really fun and exhilarating

3. Epidemiology of AIDS Before HIV Risk groups identified Risk groups identified MSM MSM Blood recipients Blood recipients IVDU IVDU > 100 partners/year > 100 partners/year (implying that 99 are safe…) Anal receptive intercourse/fist Anal receptive intercourse/fist Not using condoms Not using condoms Nash Herndon/FHI

4. AIDS Prevention Before HIV Exclusion of risk groups from blood donation Exclusion of risk groups from blood donation Education/recommendations on the risk factors Education/recommendations on the risk factors

5. AIDS Prevention Before HIV: Effects Transfusion associated, transmission dropped Transfusion associated, transmission dropped In certain areas, risk factor transmission dropped, witness the 90% reduction in syphilis in San Francisco In certain areas, risk factor transmission dropped, witness the 90% reduction in syphilis in San Francisco Supported by subsequent HIV analysis of banked blood Supported by subsequent HIV analysis of banked blood

6. Bacterial Vaginosis and Prematurity in Indonesia* Association between bacterial vaginosis diagnosed at 16 to 20 weeks and preterm delivery (gestational age <37 weeks) Association between bacterial vaginosis diagnosed at 16 to 20 weeks and preterm delivery (gestational age <37 weeks) OR = 2.0; 95% CI1.0 - 3.9 OR = 2.0; 95% CI1.0 - 3.9 Above OR adjusted for mothers age, education, smoking and Trichomonas Above OR adjusted for mothers age, education, smoking and Trichomonas *Joesoef et al. Am J Obstet Gynecol 1993;169:175-8.

7. Bacterial Vaginosis and Prematurity in Indonesia * (Cont.) Only bacterial vaginosis diagnosed early in the second trimester of pregnancy plays a major role as a risk factor for preterm delivery Only bacterial vaginosis diagnosed early in the second trimester of pregnancy plays a major role as a risk factor for preterm delivery Clindamycin vaginal cream - an effective treatment Clindamycin vaginal cream - an effective treatment *Joesoef et al. Am J Obstet Gynecol 1993;169:175-8. Nash Herndon/FHI

8. Begin Program in Indonesia? Begin Program in Indonesia? PPE PPE Corollary to PPE: SE Corollary to PPE: SE Conduct an RCT Conduct an RCT

9. OutcomeClindamycinPlaceboOR (95% CI) Preterm (<37)15.0%13.5%1.1 (0.7 – 1.7) Preterm (<32)4.7%2.6%1.8 (0.8 – 4.2) LBW (<2500gm)9.0%6.8%1.3 (0.8 – 2.4) Intravaginal Clindamycin for BV: Effects on Preterm Delivery and LBW* * Joesoef et al. Am J Obstet Gynecol 1995; 173:1527-31.

10. Study Design is Critical Reading the literature Reading the literature No study is perfect – the limitations MUST be understood No study is perfect – the limitations MUST be understood Conducting research Conducting research Serious mistakes in the study design stage cannot be corrected in subsequent stages Serious mistakes in the study design stage cannot be corrected in subsequent stages

11. Types of Epidemiologic Studies Observational:natural experience Descriptive: like newspaper reporting like newspaper reporting has no control or comparison group has no control or comparison groupAnalytic: has a control or comparison group has a control or comparison group Experimental:investigator controls has an exposed or experimental group plus a control or comparison group determined by investigator has an exposed or experimental group plus a control or comparison group determined by investigator complexity

12. Descriptive Studies Estimate frequency Estimate frequency Time trend Time trend Generate more specific etiologic hypotheses Generate more specific etiologic hypotheses

13. Descriptive Study of Women with PID Outcome (PID) SES (Age, Marital Status, Etc.) Exposure (STI, IUD) © Ruth C. Kennedy © Harvey Nelson

14. Observational Analytic Studies Cohort Exposure ExposedOutcome? Not ExposedOutcome? Case-Control Outcome Exposed?Outcome Exposed?Control

15. The Future Outcome No Outcome Prospective Cohort Design The Present Exposure present Exposure absent Sample Population

16. The Future Death No Death Example of a Prospective Cohort Design: Treatment of Severe Malaria in Children The Present Sample PTX present PTX absent Population

17. Case-Control Design The Past or PresentThe Present Exposure present present Exposure Sample of cases Population with disease (cases) Sample of controls Much larger population without disease (controls) NoOutcome Outcome Exposure absent absent Exposure

18. Example of Case-Control Design: OC Use and Breast Cancer The Past or PresentThe Present OC Use Sample of cases Population with disease (cases) Sample of controls Much larger population without disease (controls) No Breast Cancer OC Use absent

19. RCT Paradigm Outcome Assessment Unexposed Exposed Randomize Other allocation approach? Population of Interest Sample (Subset)

20. RCT Paradigm Outcome Assessment Recovered within 7 days New Antibiotic Ampicillin Randomize Sample (Subset) Women with Postpartum Febrile Morbidity

21. During the Emergence of Modern Epidemiology (around 1950) Sir Austin Bradford Hill, Sir Richard Doll and colleagues conducted: Sir Austin Bradford Hill, Sir Richard Doll and colleagues conducted: A case-control study of lung cancer A case-control study of lung cancer A cohort study of smoking and lung cancer A cohort study of smoking and lung cancer The first RCT in medicine, streptomycin for treatment of TB The first RCT in medicine, streptomycin for treatment of TB

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23. Epidemiologic Goals Read the literature more critically Read the literature more critically Ability to conceptualize EPI research designs Ability to conceptualize EPI research designs Implement simple designs Implement simple designs Seek assistance from the appropriate people and ask the right questions Seek assistance from the appropriate people and ask the right questions