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Introduction to Study Design and RCTs
Simon Thornley
That sugar movie… http://
gameauland.com/that-sugar-film-teaser-trailer/
Cohort
Participants
UnexposedDisease
Unexposed No disease
ExposedDisease
Exposed no disease
Exposed
Unexposed
Participants Exposure Outcomes
By measurement
Cohort study
eg FraminghamPatients without diseaseGroup by exposureCan use a variety of exposuresFollow until disease develops
Cohort advantages
Exposure precedes disease Disease status does not influence selection Several outcomes possible Good for rare exposures Control group obvious (compare case-control)
Cohort disadvantages
Prospective costlyInefficient for rare diseases with long latencySeveral outcomes possibleExposed followed more closely than unexposed?Loss to follow up causes bias
Do computer screens cause spontaneous abortions?
1991
Participants
UnexposedDisease
Unexposed No disease
ExposedDisease
Exposed no disease
Exposed
Unexposed
Participants Exposure Outcomes
Computer screens
No computers
abortion No abortion
Female telephone operators
54 312
82 434
Time
Do computer screens cause spontaneous abortions?
Incidence in exposed Relative risk = ----------------------------
Incidence in unexposed 54/(54+312)
= ------------------- = 0.93 82/(82+434)
In pictures - Actual
Null hypothesis; No effect
Effect of Monitors on abortion
Risk ratio
Fre
qu
en
cy
0 1 2 3 4 5
02
00
40
06
00
80
01
00
01
20
01
40
0
Cross sectional
Participants sampled at one point or short duration
Exposures and outcomes assessed at same point in time
Participants
UnexposedDisease
Unexposed No disease
ExposedDisease
Exposed no disease
Exposed
Unexposed
Participants Exposure Outcomes
By measurement
Cross-sectional
AdvantagesDescribes pattern of
diseaseVariety of outcomes
and exposuresCheapInexpensive
DisadvantagesPrevalent rather than
incident casesCan not distinguish
cause and effectMust survive long
enough to be included in study
Short duration diseases under-represented (e.g. Influenza)
Cross-Sectional study - bias
Imagine... People with disease that are sedentary die
early Cross-sectional study of disease (outcome)
and exercise (exposure) Only sample survivors, so find high proportion
of people who exercise with disease What would you infer about causal
relationships?
Does wearing fluoro gear protect you from bike crashes?
Participants
UnexposedDisease
Unexposed No disease
ExposedDisease
Exposed no disease
Exposed
Unexposed
Participants Exposure Outcomes
Fluoro colours
No fluoro colours
Bike crash No bike crash
CyclistsTaupo bike race
162 323
588 1343
Do computer screens cause spontaneous abortions?
Cum. Incidence in exposed Relative risk = ----------------------------
Cum. Incidence in unexposed162/(162+323)
= ------------------- = 1.10 588/(588+1343)
In pictures- Actual
Independent
Case-control
Investigator selects cases and controls based on disease statusCarefully defined population (cases = control population)Exposure history examined Derive P(exposure | case status)
Case-control study: Cases
Ideally, pcase=pdisease
Prevalent From surveypeople with disease at particular point in timeselection bias/favours long lived, chronic cases
Incident from population registryexposure and disease tied only to development of disease, not duration or prognosis.
Case control study: Controls
Ideally, pcontrol=pundiseased
Population vs. hospital controlsHospital controls likely to have disease related to exposure, even if not disease of interest.Population controls, from source of cases, generally better approach, but $$ can be prohibitive
Electoral rollsRandom digit dialling
Reality More complex; rarely have matches, but
frequency matching more common. E.g. Cot death study Cases – infants who died from cot death
(area)
Method Sampling frame – all births in geographic area Frequency matched Control randomly allocated age for interview
similar to age distribution to cot deaths from previous years (about 3 months old)
DOB calculated and adjusted to fit day of week (weekends higher chance of becoming cases)
Obstetric hospital randomly chosen in proportion to number of births in previous financial year
CC - advantages
Good for long latency/ rare diseasesLook at many exposuresSmaller sample size
CC - disadvantages
Only one diseaseCan't estimate disease risk, because work backwards from disease to exposure*More susceptible to selection bias as exposure has already occurred.More susceptible to information biasNot efficient for rare exposures (Why?)
Case-Control study -example
Participants
UnexposedDisease
Unexposed No disease
ExposedDisease
Exposed no disease
Exposed
Unexposed
Participants Exposure Outcomes
Fenoterol
Ventolin/other
Cases Controls
Adults in hospital with asthma
Fenoterol study, Neil Pearce (guest lecturer)
60 189
57 279
Effect measure
odds of exposure in cases Odds ratio= ----------------------------
odds of exposure in controls 60/57= -------------- = 1.55 189/279
Actual
Null hypothesis; No effect
Questions Which study design is best for assessing
causation, assuming no other limitations are present? A) Cross-sectional study B) Randomised controlled trial C) Case-control study D) Cohort study E) Case-series
Questions In a cross sectional study of risk factors for
angina, a random sample of elderly subjects were asked the question “Do you smoke cigarettes?” Answers were used to classify respondents as smokers or non-smokers. Further, subjects were classified as positive for angina if they had, at some time in the past, been told by a doctor that they suffered from this condition.
When the data from the study was analysed, no statistically significant association was found between cigarette smoking status and angina status.
Has the study measured incidence or prevalence of angina? Explain your answer.
A considerable body of past evidence suggests that the risk of angina increases with increasing tobacco consumption. Suggest reasons why the study described here failed to find an association.
Suggest an alternative design of study that would be more suitable for investigating whether smoking causes angina. Consider the question(s) that you would ask the chosen subjects about their smoking habits.
SummaryCharacteristic Cross-
sectionalCase-control Cohort RCT
Selection bias Medium High Low Low
Recall bias High High Low Low
Loss to follow up NA NA High High
Confounding Medium Medium Medium Low
Time required Low Medium High High
Cost Medium Medium High High
Summary
Observational
Cohort
Many outcomes, exposures limited
Case- control
One outcome, many exposures
Cross – sectional
Many exposure, many outcomes;
Temporality limits causal inference
ExperimentalRandomised controlled
trial
Ethical constraints
Ideal design