Study Designs in HIV Research Colette Smith (based on slides from Fiona Lampe) UK CAB meeting Thursday 17th August 2017 Main types of research studies Cross-sectional Ecological Observational Cohort Case-control Systematic review of observational studies Experimental Randomised controlled trial (RCT) (Intervention) Non randomised intervention study Systematic review of experimental studies 2 Research ques3on and study design • A research ques,on always relates to a specific populaon • Different study designs are suited to different types of research ques,on • O<en several study designs can be used to provide evidence to answer a specific ques,on Does male circumcision influence the risk of acquisi4on of HIV infecon? 3 Exposures and Outcomes EXPOSURE EFFECT OUTCOME (also referred to as “risk/ (typically disease) protec3ve factor”; or it could be an intervenon) Does male circumcision influence the risk of acquisi4on of HIV infecon, among men in countries with high levels of HIV? What is the exposure, outcome, and populaon of interest, in this research ques,on? 4 Session Overview • Ecological study • Cross sec,onal study • Cohort study • Case-control study • Randomized controlled trial • Systemac review of RCTs 5 Ecological study • Values available are for a populaon, country or group, not an individual • All factors measured on groups rather than individuals (unlike all other major study designs) • Data cannot be broken down to the level of the individual • Also some,mes called correlaon or geographical studies • Can include comparisons over ,me (me series) 6 Ecological study: Male circumcision and HIV in 37 African countries (Bongaart AIDS 1989) 25 Each point on the graph represents a 20 different African country 15 10 5 0 Prevalence (%) of HIV in country Prevalencein (%)of HIV 0 20 40 60 80 100 Prevalence of circumcision (%) among men in each country 7 Features of ecological studies • Relavely quick and inexpensive, as generally use exis,ng data • O<en used for ini,al generaon of ideas, before other types of studies are undertaken • Difficult to establish “cause and effect” • Lack of individual level data, so large poten,al for confounding • Major problem in interpre,ng results of ecological studies is the Ecological fallacy: extrapolang results from groups to individuals is problemac 8 Session Overview • Ecological study • Cross sec,onal study • Cohort study • Case-control study • Randomized controlled trial • Systemac review of RCTs 9 Cross-seconal study • A group of people are studied at a single point in me; it is a “snap shot” of the current state of affairs • Always observaonal • All factors are measured at this ,me point: there is no follow-up • Used primarily to assess prevalence of disease and compare between different groups • May involve ques,onnaire and/or clinical measurements and tests 10 Cross-secEonal study: Factors associated witH HIV infecEon in Rakai, Uganda (Serwadda AIDS 1992) • Sample of 1292 adults from 21 communi,es in Rakai conducted in 1989 • Interview (to assess factors related to HIV transmission) and blood test for HIV Number of Number who were Prevalence participants HIV-positive of HIV All participants 1292 255 19.7% Men 594 88 14.8% Women 698 167 23.9% Circumcised men 80 9 11.3% Uncircumcised men 495 79 16.0% 11 Features of cross-sec3onal studies • Can measure disease prevalence (current number of people with the condi,on of interest), but not incidence (number of new events that occur over follow-up) • Relavely quick and inexpensive to conduct • Can be used to see whether condi,ons are more frequent in one group than in another, but may be difficult to establish cause and effect (exposure and outcome measured at same me) • As with all observaonal studies, relaonship between exposure and outcome may be distorted by confounding factors 12 Session Overview • Ecological study • Cross sec,onal study • Cohort study • Case-control study • Randomized controlled trial • Systemac review of RCTs 13 Cohort study Group of people without disease Study start Follow-up all participants over time Time 14 Cohort study Group exposed to the factor Group of people without disease Group NOT exposed to the factor Study start Follow-up all participants over time Time Determine exposure status 15 Cohort study Develop disease Group exposed to the factor Do not develop disease Group of people without disease Develop disease Group NOT exposed to the factor Do not develop disease Study start Follow-up all participants over time Time Determine Compare occurrence of exposure status disease between exposed 16 and unexposed groups Cohort study CoHort study: Male circumcision and HIV in Rakai district (Gray AIDS 2004) n=18 acquired HIV N=908 were circumcised n=890 did not acquire HIV N=5,516 men without HIV n=154 acquired HIV N=4,608 were uncircumcised Study start n=4,454 did not acquire HIV Determine exposure status Time 2 years of follow-up 17 Cohort study CoHort study: Male circumcision and HIV in Rakai district (Gray AIDS 2004) Circumcised Uncircumcised Number of men at start of study 908 4608 Number who developed HIV 18 154 during follow-up (Incidence) Risk of HIV infec3on 18 / 908 = 2.0% 154 / 4608 =3.3% over the 2 year period 18 Features of cohort studies • Par,cipants classified on the basis of their exposure (risk factor) status, and followed-up (“longitudinal”) to determine who develops the outcome • Can calculate and compare incidence of outcome in the exposed and unexposed groups • Can make some aempts at determining cause-and-effect/ temporality: direc,on of associaon between exposure and disease is known (exposure precedes disease onset) • Large numbers of par,cipants needed, especially if disease is relavely rare; ,me-consuming and expensive • As with all observaonal studies, associaons may be distorted by confounding factors 19 Session Overview • Ecological study • Cohort study • Case-control study • Systemac review of observaonal studies • Randomized controlled trial • Cross sec,onal study 20 Case-control study Group of people with disease: CASES Group of people WITHOUT disease: CONTROLS Study start Look back to determine exposure status IN THE PAST Time Select cases and controls on the basis of disease 21 status Case-control study Group exposed to the factor Group of people with disease: Group NOT exposed to CASES the factor Group exposed to the factor Group of people WITHOUT disease: Group NOT exposed to CONTROLS the factor Study start Look back to determine exposure status IN THE PAST Compare frequency of Time Select cases and controls exposure between on the basis of disease 22 cases and controls status Case-control study: Male circumcision and HIV in Abidjan, Ivory Coast (Sassan-Morokro JAIDS 1996) 415 / 490 Circumcised (n=415) CASES = 85% (HIV-posive men): NOT circumcised n=490 (n=75) 221 / 239 Circumcised (n=221) = 93% CONTROLS (HIV-negave men): NOT circumcised n=239 (n=18) Study start: Compare frequency of Look back to determine Select cases and controls exposure between on the basis of disease exposure 23 cases and controls status Features of case-control studies • Par,cipants selected on the basis of their outcome (“cases” if they have the condi,on; “control” if they have not) and compared with respect to previous exposure. • Well suited to studying rare diseases (select cases first) • Usually less expensive and quicker than cohort study (fewer par,cipants needed and no follow-up involved) • Poten,al for recall error / bias in determining exposures • As with all observaonal studies, there may be confounding 24 Confounding in observaonal studies • Confounding is a major problem in observaonal studies • A confounder is a factor that is associated with the exposure and with the outcome • Confounders can distort the relaonship between exposure and outcome Exposure Outcome Confounder 25 Confounding in observaonal studies • Confounding is a major problem in observaonal studies • A confounder is a factor that is associated with the exposure and with the outcome • Confounders can distort the relaonship between exposure and outcome Absence of male HIV infection circumcision 26 Ecological study: Male circumcision and HIV in 37 African countries (Bongaart AIDS 1989) 25 Rwanda 20 Uganda Zambia Eastern Africa 15 Burundi Northern Africa 10 Malawi (Egypt , Morocco, Guinea Bissau Ivory Coast Tunisia, Sudan (N)) 5 Ghana Tanzania 0 Prevalence (%) of HIV in country Prevalencein (%)of HIV 0 20 40 60 80 100 Prevalence of circumcision (%) among men in each country 27 Confounding in observaonal studies • Confounding is a major problem in observaonal studies • A confounder is a factor that is associated with the exposure and with the outcome • Confounders can distort the relaonship between exposure and outcome Absence of male HIV infection circumcision Religion 28 Confounding in observaonal studies • Confounders in associaon between circumcision and HIV include religion, ethnicity, age • In addi,on to simple ‘unadjusted’ analyses, adjusted analysis can be performed to control for confounding factors, using a stas,cal model • Associaon between lack of circumcision and HIV in observaonal studies was generally found to be at least as strong in adjusted analyses • But difficult to measure and adjust for all possible confounding factors 29 SystemaEc review of observaEonal studies: Male circumcision and risk of HIV among men in sub- SaHaran Africa (Weiss AIDS 2000) ‖ “Randomised controlled trials of male circumcision are needed (in areas where it would be acceptable to the local community). ‖ Such trials would overcome the limita4ons of observa4onal