Study Designs in HIV Research

Transcription

1 Study Designs in HIV Research Colette Smith (based on slides from Fiona Lampe) UK CAB meeting Thursday 17th August 2017

2 Main types of research studies Cross-sectional Observational Ecological Cohort Case-control Systematic review of observational studies Experimental (Intervention) Randomised controlled trial (RCT) Non randomised intervention study Systematic review of experimental studies 2

3 Research ques3on and study design A research ques,on always relates to a specific popula3on 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 infec4on? 3

4 Exposures and Outcomes EXPOSURE EFFECT (also referred to as risk/ protec3ve factor ; or it could be an interven3on) OUTCOME (typically disease) Does male circumcision influence the risk of acquisi4on of HIV infec4on, among men in countries with high levels of HIV? What is the exposure, outcome, and popula,on of interest, in this research ques,on? 4

5 Session Overview Ecological study Cross sec,onal study Cohort study Case-control study Randomized controlled trial Systema,c review of RCTs 5

6 Ecological study Values available are for a popula3on, 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 correla3on or geographical studies Can include comparisons over,me (3me series) 6

7 Ecological study: Male circumcision and HIV in 37 African countries (Bongaart AIDS 1989) Prevalence (%) of HIV in country Each point on the graph represents a different African country Prevalence of circumcision (%) among men in each country 7

8 Features of ecological studies Rela,vely quick and inexpensive, as generally use exis,ng data O<en used for ini,al genera,on 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: extrapola,ng results from groups to individuals is problema,c 8

9 Session Overview Ecological study Cross sec,onal study Cohort study Case-control study Randomized controlled trial Systema,c review of RCTs 9

10 Cross-sec3onal study A group of people are studied at a single point in 3me; it is a snap shot of the current state of affairs Always observa,onal 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

11 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 participants Number who were HIV-positive Prevalence of HIV All participants % Men Women Circumcised men Uncircumcised men % 23.9% 11.3% 16.0% 11

12 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) Rela,vely 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 observa,onal studies, rela,onship between exposure and outcome may be distorted by confounding factors 12

13 Session Overview Ecological study Cross sec,onal study Cohort study Case-control study Randomized controlled trial Systema,c review of RCTs 13

14 Cohort study Group of people without disease Study start Time Follow-up all participants over time 14

15 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

16 Cohort study Group of people without disease Study start Group exposed to the factor Group NOT exposed to the factor Develop disease Do not develop disease Develop disease Do not develop disease Follow-up all participants over time Time Determine exposure status Compare occurrence of disease between exposed and unexposed groups 16

17 Cohort study Cohort study: Male circumcision and HIV in Rakai district (Gray AIDS 2004) N=5,516 men without HIV Study start Time N=908 were circumcised N=4,608 were uncircumcised Determine exposure status 2 years of follow-up n=18 acquired HIV n=890 did not acquire HIV n=154 acquired HIV n=4,454 did not acquire HIV 17

18 Cohort study Cohort study: Male circumcision and HIV in Rakai district (Gray AIDS 2004) Circumcised Uncircumcised Number of men at start of study Number who developed HIV during follow-up (Incidence) Risk of HIV infec3on over the 2 year period 18 / 908 = 2.0% 154 / 4608 =3.3% 18

19 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 agempts at determining cause-and-effect/ temporality: direc,on of associa,on between exposure and disease is known (exposure precedes disease onset) Large numbers of par,cipants needed, especially if disease is rela,vely rare;,me-consuming and expensive As with all observa,onal studies, associa,ons may be distorted by confounding factors 19

20 Session Overview Ecological study Cohort study Case-control study Systema,c review of observa,onal studies Randomized controlled trial Cross sec,onal study 20

21 Case-control study Group of people with disease: CASES Group of people WITHOUT disease: CONTROLS Look back to determine exposure status IN THE PAST Study start Time Select cases and controls on the basis of disease status 21

22 Case-control study Group exposed to the factor Group NOT exposed to the factor Group exposed to the factor Group NOT exposed to the factor Group of people with disease: CASES Group of people WITHOUT disease: CONTROLS Study start Look back to determine exposure status IN THE PAST Compare frequency of exposure between cases and controls Time Select cases and controls on the basis of disease status 22

23 Case-control study: Male circumcision and HIV in Abidjan, Ivory Coast (Sassan-Morokro JAIDS 1996) 415 / 490 = 85% 221 / 239 = 93% Circumcised (n=415) NOT circumcised (n=75) Circumcised (n=221) NOT circumcised (n=18) CASES (HIV-posi3ve men): n=490 CONTROLS (HIV-nega3ve men): n=239 Compare frequency of exposure between cases and controls Look back to determine exposure Study start: Select cases and controls on the basis of disease status 23

24 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 observa,onal studies, there may be confounding 24

25 Confounding in observa3onal studies Confounding is a major problem in observa,onal studies A confounder is a factor that is associated with the exposure and with the outcome Confounders can distort the rela,onship between exposure and outcome Exposure Outcome Confounder 25

26 Confounding in observa3onal studies Confounding is a major problem in observa,onal studies A confounder is a factor that is associated with the exposure and with the outcome Confounders can distort the rela,onship between exposure and outcome Absence of male circumcision HIV infection 26

27 Ecological study: Male circumcision and HIV in 37 African countries (Bongaart AIDS 1989) Prevalence (%) of HIV in country Rwanda Uganda Zambia Burundi Malawi Eastern Africa Ivory Coast Ghana Guinea Bissau Tanzania Northern Africa (Egypt, Morocco, Tunisia, Sudan (N)) Prevalence of circumcision (%) among men in each country 27

28 Confounding in observa3onal studies Confounding is a major problem in observa,onal studies A confounder is a factor that is associated with the exposure and with the outcome Confounders can distort the rela,onship between exposure and outcome Absence of male circumcision HIV infection Religion 28

29 Confounding in observa3onal studies Confounders in associa,on 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 sta,s,cal model Associa,on between lack of circumcision and HIV in observa,onal 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

30 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 studies, and provide reliable evidence on the overall impact of introduc4on of male circumcision on HIV incidence. 30

31 Session Overview Ecological study Cross sec,onal study Cohort study Case-control study Randomized controlled trial Systema,c review of RCTs 31

32 Randomized controlled trial Group of people without disease Study start Time Follow-up all par3cipants over 3me 32

33 Randomized controlled trial INTERVENTION group Group of people without disease CONTROL group (does NOT receive interven,on) Study start Follow-up all par3cipants over 3me Time RANDOMLY ALLOCATE each par3cipant to interven3on group or control group 33

34 Randomized controlled trial Group of people without disease Study start INTERVENTION group CONTROL group (does NOT receive interven,on) Follow-up all par3cipants over 3me Develop disease Do not develop disease Develop disease Do not develop disease Time RANDOMLY ALLOCATE each par3cipant to interven3on group or control group Compare occurrence of disease between exposed and unexposed groups 34

35 RCT of male circumcision for HIV preveneon, in Rakai district, Uganda (Gray et al, Lancet 2007) N=4,817 uncircumcised men without HIV Study start Time N=2,387 immediate circumcision N=2,430 delayed circumcision RANDOMLY ALLOCATE each par3cipant to interven3on group or control group N=22 acquired HIV N=2,365 did not acquire HIV N=45 acquired HIV N=2,385 did not acquire HIV Follow-up all parecipants over 2 years 35

36 Cohort study RCT of male circumcision for HIV preveneon, in Rakai district, Uganda (Gray et al, Lancet 2007) INTERVENTION: circumcision CONTROL: No circumcision Number of men at start of study Number who developed HIV during follow-up (Incidence) Risk of HIV infec3on 22 / 2387 = 0.92% 45 / 2430 = 1.9% 36

37 Features of randomized controlled trials Par,cipants randomly allocated to either the interven,on group or the control group: should ensure two groups have similar characteris,cs at start of trial (i.e. no confounding) Presence of a control group (usually receive the current gold standard treatment) to act as a comparison Individuals are followed up to determine who develops disease (i.e. longitudinal study), so RCTs usually inves,gate incidence Aim is to treat both groups iden,cally, so that any difference in outcome between interven,on and control groups must be due to the interven,on, rather than some other factor Feasibility and ethical issues may prevent RCT being done 37

38 Session Overview Ecological study Cross sec,onal study Cohort study Case-control study Randomized controlled trial Systema,c review of RCTs 38

39 SystemaEc review of RCTs: Male circumcision and risk of heterosexual HIV acquisieon among men (Siegfried Cochrane Database of SystemaEc Reviews 2009) Studies published up to June large RCTs were found including around 11,000 par,cipants in total They concluded There is strong evidence that medical male circumcision reduces the acquisi4on of HIV by heterosexual men by between 38% and 66% over 24 months. 39

40 Type of study and strength of evidence Type of study and strength of evidence Strength of evidence for causal associa,on between an exposure and a disease outcome Systema,c review of RCTs Strongest evidence RCT Systema,c review of observa,onal studies Non randomized interven,on study Cohort study Case-control study Cross sec,onal survey Ecological study Weakest evidence 40

41 Accumula3on of evidence Studies inves,ga,ng the rela,onship between male circumcision and the risk of HIV acquisi,on Ecological study in 37 African countries (Bongaart et al) Cross-secEonal study of factors associated with HIV infec4on, in Rakai (Serwadda et al) Case-control study in Abidjan, Ivory Coast (Sassan-Morokro et al) SystemaEc review of observaeonal studies in sub-saharan Africa (Weiss et al) Cohort study of in SystemaEc Rakai district review of RCTs (Gray et al) (Siegfried et al) RCT in Rakai (Gray et al) Year of publica3on 41

42 Accumula3on of evidence 1994: There may be an associa4on between male circumcision and risk for HIV infec4on, but considerable scep4cism remains (Moses et al, AIDS) 2000: There is considerable evidence suppor4ng a protec4ve effect of male circumcision on HIV-infec4on in men (van Dam et al, Horizons Project) 2007: Circumcision reduces risk of HIV infec4on and can be recommended for HIV preven4on in men (Gray et al, Lancet) 42

43 On-going issues and ques3ons 43

44 Which study design? For individuals currently with a CD4 count>500 cells/mm 3, would it be beger to start HIV-treatment immediately, or wait un,l the CD4 count reaches 350 cells/mm 3? Do previously an,retroviral-naïve individuals star,ng an an,retroviral regimen containing a new protease inhibitor have a beger response than those receiving a standard of care regimen? Does alcohol consump,on have an impact on future development of depression in HIV-posi,ve individuals? Do individuals co-infected with TB and HIV have a similar firstline response to an,retroviral therapy compared to individuals who are HIV-posi,ve but do not have TB? 44