Department of Public Health. Case-control design. Katrine Strandberg-Larsen Department of Public Health, Section of Social Medicine

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1 Department of Public Health Case-control design Katrine Strandberg-Larsen Department of Public Health, Section of Social Medicine

2 Case-control design Brief summary: Comparison of cases vs. controls with regard to their level of exposure Compare the odds of exposure in cases vs. controls Exposed Unexposed Exposed Unexposed Cases Controls The selection of controls must not depend upon exposure

3 The definitions of population Target population: The group from which a study population is selected and about which inferences are desired Study population: The group selected for investigation, and actually contribute with informative data Source population (study base): The group of persons (or person time) from which the outcome of interest is observed. - Primary base: precisely defined and identified population - Secondary base: Not possible to identify the study population explicitly it is identified secondarily to identification of cases Rothman KJ. Modern epidemiology. 2008; Last JM. A dictionary of epidemiology. 2001

4 Principal idea Think of the source population as a hypothetical cohort Source population Collect information: - Cases (a random sample or all) - Controls (a random sample) Diseased individuals That is what makes, this design is more: - Efficient - Well-suited for rare outcomes Controls Time

5 In basic The outset is individuals with disease (cases) and a sample from the source population (controls) Compare the odds of exposure in cases vs. controls Exposed Unexposed Cases Is often called a retrospective design as it starts after the onset of disease and looks back. However, can be prospective so called it case-control design Exposed Unexposed Time Controls We use the Controls as a measure of the exposure frequency in the source population

6 In basic Require, that the sampling of controls NEEDS to be independent of exposure Controls need to be sampled from the same source population as cases, i.e. are at risk (at least in theory) of becoming a case THUS, all case-control studies can be viewed as nested within a hypothetical cohort Note: the nested case-control design involves a specific selection of control Exposed Unexposed Exposed Unexposed Time Cases Controls

7 The cohort design Source population X Study population X X X X X Source- =study population X X

8 Case-control design Source population Study population X Controls Cases X X X X X X X

9 Alternative presentation of the cohort design In a cohort we know the number of persons at baseline Ill people Healthy people (at risk)

10 Measuring associations in cohort design Exposure Disease Non-disease Number at baseline Time at risk + a b N + (a+b) T + - c d N - (c+d) T - Risk: a/n + and c/n - Relative risk: ratio of the risks, RR= (a/n + )/(c/n - ) Incidence rate (IR): a/t + and c/t - Incidence rate ratio: ratio of the IR s, IRR=(a/T + )/(c/t - )

11 Case-control design Ill people Samples all ill people (or a specified fraction) Controls Sample a specified number of controls per case This implies: Not possible to estimate: The number or proportion of ill people (risk) in exposed vs. unexposed Possible to estimate: The number or odds of exposed in cases vs. controls

12 Measuring association in case-control design Exposed diseased Non-diseased + a b - c d Odds exp cases = a c Odds exp controls = b d Odds ratio (OR): the ratio of odds of exposure in cases vs. controls OR exp = a c b d

13 Measuring association in case-control design Exposed diseased Non-diseased + a b - c d Odds exp cases = a c Odds exp controls = b d Odds ratio (OR): the ratio of odds of exposure in cases vs. controls OR exp = a c b d = a d a = b c b c d = OR dis

14 Specific challenges Defining and identifying the source population easy in countries with population wide registries Identification and selection of controls, so that they are representative of the exposure frequency in the source population Select controls independent of exposure Often retrospective collection of information on exposure

15 Smoking and lung cancer

16 Case-noncase or case base study Controls are selected among those who stay free of disease Cases cannot be selected as controls Association measure: OR if used to estimate the RR, then remember the rare disease assumption

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18 Nested case-control (incidence density sampling) Controls are selected among the population at risk every time a case occurs, i.e. a person get ill. Does not imply complete follow-up Cases can be included as controls if they become cases at a later point in time Association measure: OR is a direct estimate of IRR

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20 Selection of controls Enhedens navn

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23 Case-cohort design Controls are selected from the baseline cohort Requires a clearly defined source population (cohort) with complete follow up Cases can be included in the control group Association measure: OR is a direct estimate of risk ratio (RR)

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28 Sub-types of case-control design Case-non case Nested case-control Case-cohort Controls are selected among those who stay free of disease Cases cannot be selected as controls OR if used as estimate of RR then rare disease assumption Controls are selected among the population at risk every time a case occurs Cases can be included as controls Requires a clearly defined source population OR direct estimate of IRR Controls are selected as a random sample of the baseline cohort Cases can be included as controls Requires a clearly defined source population with complete follow up OR direct estimate of risk ratio

29 Strengths and weaknesses STRENGTHS WEAKNESSES Rare disease and/or long latency time Faster and cheaper With a proper selection of controls direct estimate of risk ratio or IRR Examine a lot of different suspected risk factors Selection of controls can be challenging not always possible to define the source population Often retrospective collection of exposure data possibility of recall bias No direct risk estimate, but OR as estimates of risk estimates Often challenging to elucidate temporality

30 What design is used? Snak med sidemanden i 2 min: En gruppe forskere var interesseret i om bly i blodet kan give hjerneskader. En kohorte på raske personer fik i 1990 taget en blodprøve og blev fulgt til og med I alt blev 68 diagnosticeret med hjerneskade i løbet af studiet. Forskerne undersøgte i 2011 blodprøverne fra de 68 personer med hjerneskade og 312 raske personer fra kohorten for tilstedeværelse af bly. Forskerne konkludere at der ikke var en sammenhæng mellem bly i blodet og senere hjerneskade Ja, det er et case-kontrolstudie fordi forskerne har taget udgangspunkt i udfald og ikke eksponering også selvom studiet er foretaget indenfor en kohorte!

31 What design is used? Snak med sidemanden i 2 min: En gruppe forskere var interesseret i om bly i blodet kan give hjerneskader. En kohorte på raske personer fik i 1990 taget en blodprøve og blev fulgt til og med I alt blev 68 diagnosticeret med hjerneskade i løbet af studiet. Forskerne undersøgte i 2011 blodprøverne fra de 68 personer med hjerneskade og 312 raske personer fra kohorten for tilstedeværelse af bly. Forskerne konkludere at der ikke var en sammenhæng mellem bly i blodet og senere hjerneskade Ja, det er et case-kontrolstudie fordi forskerne har taget udgangspunkt i udfald og ikke eksponering også selvom studiet er foretaget indenfor en kohorte!

32 How to interpret the OR?

33 Guidelines for publicering The STROBE statement: Von Elm E et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement - Guidelines for Reporting Observational Studies. Epidemiology 2007;18: