Session 1:
Defining the research question and
selecting endpoints
Iden%fying the research ques%on… l 
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Important to have a clear question before starting
to design your study
This will allow you to make the most appropriate
decisions around:
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The
The
The
The
The
The
study population
choice of study design
method of collecting data
primary outcome of interest
main exposure/predictors of interest
number of patients to be recruited
Research ques%on shouId be: l 
Clear
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Unambiguous
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Measurable
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Of clinical/biological relevance
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Realistic with the resources available
Iden%fying the research ques%on… QUESTION: Are we treating our HIV-infected
patients adequately?
Is this a clearly defined question?
Iden%fying the research ques%on… QUESTION: Are we treating our HIV-infected
patients adequately?
How do we define ‘treatment’?
- HAART?
- PCP prophylaxis?
- General medical care?
Iden%fying the research ques%on… QUESTION: Are we treating our HIV-infected
patients adequately?
How do we define ‘adequate’?
- Increase in CD4 count?
- Viral load suppression?
- Improvement in clinical outcome?
- Improvement in survival?
- Some other measure?
Iden%fying the research ques%on… QUESTION: Are we treating our HIV-infected
patients adequately?
What patient group are we interested in?
- All newly diagnosed patients?
- All patients under established follow-up?
- All patients on ART?
- Those with co-infection or comorbidities?
- Those with low CD4 counts?
Iden%fying the research ques%on… QUESTION: Are we treating our HIV-infected
patients adequately?
REVISED QUESTION: What proportion of patients
starting antiretroviral therapy (ART) achieve viral
load suppression at 12 months after starting firstline ART?
Choosing an appropriate study design l 
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The research questions that can be addressed in
any study will depend on the study design
Whilst some designs may offer benefits in terms of
costs, time and administrative effort, studies that
are quick and cheap to perform will generally
provide less robust evidence
Research question SHOULD determine choice of
study design – in practice, lack of time and/or
resources usually plays a major part in decision…
Choosing an appropriate study design REVISED QUESTION: What proportion of patients
starting antiretroviral therapy (ART) achieve viral
load suppression at 12 months after starting firstline ART?
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RCT?
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Cohort?
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Case-control study?
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Cross-sectional study?
Study endpoints l 
A well defined study endpoint should:
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Be defined in advance
Address the primary aim of the study
Have biological/clinical relevance
Be appropriate for the population included in the study
Well defined study endpoints are equally important
for all study designs, whether RCTs or observational
studies
Possible endpoints
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Clinical endpoints
- New AIDS events, death, CDC stage B events
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Virological endpoints
- VL <50 copies/ml at specific timepoints, absolute change
in VL, area under the curve for VL
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Immunological endpoints
- CD4>200 cells/mm3, CD4 increase >100 cells/mm3
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Other endpoints
- Treatment switches, adherence, quality of life, toxicity
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Composite endpoints
- Time to loss of virological response (TLOVR)
Toxicity endpoints
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Toxicity endpoints may be based on clinical
symptoms and/or laboratory data
Need to be aware of possible biases when
interpreting results from such studies, particularly
if observational studies:
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Irregular/infrequent laboratory monitoring
Selective laboratory monitoring
Between-clinic assay variability
Clinic differences in monitoring policies
Bias due to confounding
Example – Primary endpoint l 
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We wish to compare the efficacy of cART in drug
users compared to non-drug users in previously
antiretroviral-naïve adults in an observational study
Is this a good primary endpoint?
“New AIDS-­‐defining event or death” Example – Primary endpoint l 
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We wish to compare the efficacy of cART in drug
users compared to non-drug users in previously
antiretroviral-naïve adults in an observational study
Is this a good primary endpoint?
“Remaining on treatment at one year” Example – Primary endpoint l 
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We wish to compare the efficacy of cART in drug
users compared to non-drug users in previously
antiretroviral-naïve adults in an observational study
Is this a good primary endpoint?
“Achieving virological suppression” Example – Primary endpoint l 
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We wish to compare the efficacy of cART in drug
users compared to non-drug users in previously
antiretroviral-naïve adults in an observational study
Is this a good primary endpoint?
“Achieving a viral load <50 copies/ml one year aCer starDng cART” Classification of endpoints
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Myocardial infarction (D:A:D Study)
Diagnosis based on established algorithm adapted from
standardized criteria that included cardiac pain, cardiac
enzyme or troponin levels, ECG readings, and autopsy
results if available. Nonfatal MIs not associated with
clinical symptoms are not included
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CoDe (Causes of Death initiative)
Used for coding causes of death, designed specifically for
HIV-positive individuals
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Chronic kidney disease (e.g. EuroSIDA)
i) eGFR <60 mL/min/1.73m2 if baseline eGFR >60 60
ii) 25% decline from baseline value if baseline eGFR <60
Main exposures/predictor of interest l 
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Like the primary endpoint, the main predictors
should ideally be defined in advance
Most randomised controlled trials consider one or
two main predictors. However, in a cohort study
there is more flexibility to consider a number of
factors
The exposures should be clearly defined and
explained
Example – main exposure/predictors l 
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We wish to compare the efficacy of cART in drug
users compared to non-drug users in previously
antiretroviral-naïve adults in an observational study
Is this a good measure of the primary exposure?
“Individual reports having ever taken drugs” Example – main exposure/predictors l 
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We wish to compare the efficacy of cART in drug
users compared to non-drug users in previously
antiretroviral-naïve adults in an observational study
Is this a good measure of the primary exposure?
“Individual reports having ever injected illegal substances” Example – main exposure/predictors l 
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We wish to compare the efficacy of cART in drug
users compared to non-drug users in previously
antiretroviral-naïve adults in an observational
study
Is this a good measure of the primary exposure?
“Individual reports current (at start of cART) injecDng drug use” Confounders l 
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Confounding is a particular issue in observational
studies (rarely an issue in RCTs)
Occurs when a factor exists that is associated with
both the exposure and outcome of interest
Although can never be certain that all confounding
has been accounted for, important to collect
information on known confounders
Possible to adjust for potential confounders using
multivariable models, provided they are known and
accurately measured
Example – Confounders l 
When considering the impact of social class on the
occurrence of cardiovascular disease, smoking is a
potential confounder
Social class
CVD
Example – Confounders l 
When considering the impact of social class on the
occurrence of cardiovascular disease, smoking is a
potential confounder
Social class
CVD
Smoking status
Example – Confounders l 
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We wish to compare the efficacy of cART in drug
users compared to non-drug users in previously
antiretroviral-naïve adults in an observational study
Can you think of any potential confounders?
Example – Asking the right ques%on l 
Our research question may therefore become:
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Study design: Observational cohort study
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Study population: Previously antiretroviral-naïve
HIV-positive adults
Primary endpoints: VL<50 copies/ml after 1 year
of cART
Potential confounders/effect modifiers: HBV
and HCV status, social class, pre-cART CD4 count,
gender, age…
Summary l 
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Important to have a clear research quesDon before starDng to design your study – this will then determine choice of study design and study endpoints Endpoints require careful thought – where possible, they should be pre-­‐defined in study protocol, should address the main aim of the study and be of relevance for the populaDon of interest Always be aware of the potenDal for confounding in observaDonal studies