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### Etiologic researchStudy of the causes of disease

Dr.dr. Siti Setiati, SpPD(K)

Etiologic research

The research question

- Is there a relation between a determinant (risk factor) and a disease-outcome?
- Research question for causal relation!

Etiologic researchCharacteristics

- Explanatory research
- versus descriptive research
- To demonstrate causality (cause-effect)
- Cause comes before effect
- Exposure and determinant occurs before the disease-outcome occurs
- Determinant-outcome relation is not explained by other factors

Etiologic researchWhat study design?

- Experimental
- Exposure or determinant assigned by investigator

versus

- Observational
- Exposure or determinant not assigned by investigator

This lecture: observational research

HILL’S CRITERIA

- Is it clear that the exposure precede the onset of the outcome ?
- Is there a dose-response gradient?
- Is the association consistent from study to study
- Does the association make biological sense?

Etiologic research What study design?

- Design of two observational studies to distinguish between cause and effect:
- Cohort study
- Case-control study

Cohort study

- Also called follow-up study
- Definition
- Study in which persons, based on their exposure todeterminant and free of the disease outcome at the start of the study, are followed in time to assess the occurrence of the disease outcome.

Cohort study

disease +

cohort

without

disease

outcome

determinant +

disease -

disease +

determinant -

disease -

time

start study

disease-outcome

Framingham Heart Study

- 1948 – Framingham, MA
- 5200 persons 30-62 years old
- Aim: identification of risk factors for cardiovascular diseases
- Remeasured every 2 years

Example of a research question:

Is hypertension a risk factor for MI?

Framingham Heart Study

MI +

cohort

without

myocardial

infarction

hypertension +

MI -

MI +

hypertension -

MI -

time

1948

1998

Cohort studydeterminant-outcome relation

MI +

MI -

hypertension +

a

b

a/a+b=probability of MI for hypertension + = Incidence+

hypertension -

c

d

c/c+d=probability of MI for hypertension - = Incidence -

Relative Risk (RR) = incidence + / incidence -

Cohort study

How do you get a cohort?

- Geographical (Framingham Heart Study)
- Birth cohort (British 1946 birth cohort)
- Dynamic cohort (Leidsche Rijn)
- Occupational cohort (Whitehall study)

Cohort study

How do you follow the cohort?

How do you find the disease-outcome?

- After a certain time interval, send out a questionnaire or invite for interview or medical examination
- Record disease outcomes via medical files or registrations

Case-control study

- Also called patient-control study
- Definition
- Study in which patients with the disease-outcome and a control group without the disease-outcome are selected and in which it is determined how many people in both groups have been exposed to the determinant

Case-control study

determinant +

disease +

(patients)

determinant -

determinant +

disease –

(controls)

determinant -

time

start study

Creutzfeldt-Jakob’s Disease

- Fast, progressive form of dementia
- In the 90s a new variant of Creutzfeldt-Jakob was discovered in Europe after an epidemic of mad-cow disease
- Caused by eating beef?

What research question?

Why case control?

Creutzfeldt-Jakob’s Disease

beef +

patients

with CJD

beef -

beef +

controls from

hospital

beef -

time

start study

Case-control studydeterminant-outcome relation

CJD +

CJD -

beef +

a

b

beef -

c

d

Odds Ratio

b/d = odds beef+ in controls

a/c = odds beef+ in cases

= a x d / b x c

Case-control study

How do you find patients?

- GP; hospital; cancer registration

How to select a control group?

- GP; hospital; general population
- Patients and controls have to come from the same ‘source’ population.

Case-control study

How do you assess exposure to determinant?

- Interview with participant
- Interview with proxy
- Medical file

Measures of association:Case Control approach

- Research question: Does smoking increase the risk of lung cancer ?
- Patient control study
- select cases and controls
- Estimate the frequency of smoking among cases and controls
- prior: % smokers among cases > % smokers among controls

Measures of association: Case Control approach

Disease

Yes No

Yes a b

Determinant

No c d

- RR?
- Odds ratio = (a/c) / (b/d) = ad / bc

OR and RR

- In a randomized trial or Cohort study:
- Relative Risk (RR) = [a/(a+b) / c/(c+d)]
- In a case-control study:
- Odds Ratio (OR) = (a/b) / (c/d) = ad/bc
- Odds ratios (OR) and relative risk (RR) greater than 1 indicate that there is an increased risk of the adverse outcome associated with the exposure.
- If OR = RR = 1 the adverse outcome is no more likely to occur with than without exposure to the suspected agent.

In the randomized prospective Heart Outcomes Prevention Evaluation (HOPE) study (1) the effect of Ramipril on the risk of cardiovascular (CV) events was investigated by calculating the ratio between the incidence proportions of CV events in Ramipril treated and in placebo treated patients.

With CV events Without CV events

Ramipril group (n=4645) 651 3994

Placebo group (n=4652) 826 3826

Relative measures of effect

- The relative risk
- The relative risk can be calculated as ratio between two incidence proportions (risk ratio, see Example 1) or two incidence rates (incidence rate ratio, see Example 2).

- Proportion of patients with CV events in the Ramipril group:

651/ 4645=0.14 (14%).

- Proportion of patients with CV events in the placebo group:

826/ 4652=0.18 (18%).

The RiskRatio(RR) is: 0.14/0.18= 0.78

The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000; 342: 145-153

- The odds ratio
- The odds are a way of representing probability, familiar to gamblers (for example, the odds that a single throw of a die produces a six are 1 to 5). In a case-control study the odds of exposure in cases and controls are calculated as the number of exposed individuals divided by the number of unexposed individuals in each group. If we know the odds of exposure in cases and controls we can calculate the odds ratio (OR), i.e. the ratio between the odds of exposure in diseased and in non-diseased individuals.

Example 2 (the odds ratio)

Knoll et al. (3) investigated the association between vascular access thrombosis and thrombophilia. They considered 107 patients with access thrombosis (cases) and 312 patients without fistula thrombosis (controls). Overall, among the 107 patients with access thrombosis, 59 had evidence of thrombophilia and 48 did not while among the 312 without access thrombosis 122 had thrombophilia and 190 did not.

- Odds of thrombophilia in patients with vascular access thrombosis :

59/48=1.229

- Odds of thrombophilia in patients without vascular access thrombosis :

122/190=0.642

The odds ratio (OR) is: 1.229/0.642= 1.91

Knoll GA, Wells PS, Young D, et al. Thrombophilia and the risk for hemodialysis vascular access thrombosis. J Am SocNephrol 2005;16:1108-1114.

Measures of association:Case Control approach

- Smoking and lung cancer

(controls = 10% random sampling from cohort)

Disease

Yes No

Yes 440 300 740

Determinant

No 212 350 562

- Odds ratio (440/212) / (300/350) = 2.42
- RR = (440/740) / (212/562) = 1.57 (shouldn’t be calculated)

Measures of association:Cohort approach

- Research question? Is smoking associated with lung cancer?
- Cohort approach
- divide the cohort in smokers and non-smokers
- estimate the incidence density (or CI) in each group
- prior: ID smokers > ID not smokers

Measures of association: Cohort approach

Disease

Yes No

Yes a - PY1

Determinant

No c - PY0

a/py1

RR = c/py0

Measures of association: Cohort approach

- Smoking and lung cancer

Disease

Yes No

Yes 440 - 22.008 py Determinant

No 212 - 21.235 py

RR = (440/22.008) / (212/21.235) = 2.0

The Rules are

- The RR will always be closer to 1.0 than the OR.
- If the baseline risk (the risk of adverse events in the controlgroup) is low (say, less than 30%), the difference betweenRR and OR is unlikely to be important. Therefore, the twomay be used interchangeably for interpreting results.
- If the OR is near 1.0, the difference between RR and OR is unlikely to be important.
- Following directly from the above, the only time you arelikely to run into trouble treating the OR as an RR is whenthe baseline risk is high (over 30%) and the OR is not closeto 1.0 (say less than 0.67 or greater than 1.3). Under thesecircumstances, the RR is likely to be appreciably closer to 1.0 than the OR.

Cohort studyAdvantages and disadvantages

- What are the advantages of a cohort study?
- What are the disadvantages of a cohort study?

Cohort study

- Advantages
- Cause is measured before effect
- Not very sensitive to selection- and information bias
- Appropriate for rare determinant
- Can study several outcomes
- Disadvantages
- Selective withdrawal / loss to follow-up
- Expensive and time consuming
- Not appropriate for rare outcome

Case-control studyAdvantages and disadvantages

- What are the advantages of a case-control study?
- What are the disadvantages of a case-control study?

Case-control study

- Advantages
- Efficient and relatively cheap
- Appropriate for rare outcome
- Can study several determinants
- Disadvantages
- Cause is measured after effect
- Very sensitive to selection- and infobias
- Not appropriate to study several outcomes

ADVANTAGES AND DISADVANTAGES OF CASE CONTROL STUDIES

Advantages:

1. only realistic study design for uncovering etiology in rare diseases

2. important in understanding new diseases

3. commonly used in outbreak investigation

4. useful if induction period is long

5. relatively inexpensive

1. Susceptible to bias if not carefully designed (and matched)

2. Especially susceptible to exposure misclassification

3. Especially susceptible to recall bias

4. Restricted to single outcome

5. Incidence rates not usually calculable

6. Cannot assess effects of matching variables

PICO

- P = Patient / Population / Problem
- I = Intervention / Indicator / Index
- C = Comparation (if relevant)
- O = Outcomes

Example

Susan is expecting her first baby in two months. She has been reading about the potential benefits and harms of giving newborn babies vitamin K injections. She is alarmed by reports that vitamin K injections in newborn babies may cause childhood leukaemia. She asks you if this is true and, if so, what the risk for her baby will be.

Type : Aetiology

P : newborn babies

I : vitamin K injection

C : -

O : Risk of childhood leukaemia

VIA methods

- Validity: type of study, blinded?, number of subjects?, controlled?
- Importance: result?
- Applicability: patient’s characteristic

Is our patient so different from those in the study that its results cannot apply?

- Randomization would tend to make the two treatment groups identical for all other causes of disease.
- Unfortunately, the validity of the study designs used to detect harm is inversely proportional to their feasibility (in size, duration, and ethics)
- If the study was not randomized, try to compare the two groups’ baseline data. We have to be careful with confounders .

Were treatments/exposures and clinical outcomes measured in the same ways in both groups?

- We’d feel more assured about the study if the report described that the patients (and the interviewers) were blinded to the study hypothesis

Was the follow-up of the study patients sufficiently long (for the outcome to occur) and complete?

- Enough time to follow-up the patients (eg. not only a few weeks for cancer study)
- If the study lost lots of its patients to follo-up (>20% is a good rule of thumb), we also be skeptical of its conclusions

Do the result of the harm study fulfil some of the diagnostic tests for causation?

- Is it clear that the exposure precede the onset of the outcome ?
- Is there a dose-response gradient?
- Is there any positive evidence from a “dechallenge-rechallenge” study?
- Is the association consistent from study to study
- Does the association make biological sense?

Is our patient so different from those included in the study that its results don’t apply ?

- The issue is NOT whether our patient fulfils all the inclusion criteria for the study we found
- BUT, whether our patient is so different from those in the study that its results are of no help to us

What are our patient’s preferences, concerns, and expectations from this treatment

- We can ask our patient to quantify his values for both the potential adverse event and the target event we hope to prevent with the proposed therapy

What alternative treatments are available ?

- We discussed alternative treatments with our patient and his GP so that they could decide on his long-term management

Take Home MessagesEtiologic Research

- Motive: aim to explain (causal association of specific determinant and outcome) or to asses effect of exposure
- Determinants: single determinant of interest and potential confounders
- Outcome: may not necessarily directly clinically relevant to patient (eg. Pathophysiologic interest)

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