Groenwold causality leiden - 5 oct2012

Rolf H.H. Groenwold, MD, PhD

Causality in pharmacoepidemiologic research

what are the challenges?

“Pharmacoepidemiology is the study of the use of

and the effects of drugs in large numbers of

people”

“Pharmacoepidemiology is the bridge between

pharmacology and epidemiology”

“Pharmacoepidemiology studies the effects of

drugs”

Wikipedia:

http://en.wikipedia.org/wiki/Pharmacoepidemiology

... are the paradigm to assess the effects of drug, yet…

… are very expensive

… require a lot of men power

… answer (at most) only 1 question

… are little informative about (rare) side-effects

… have limited duration of follow-up

Randomized trials….

… are MUCH LESS expensive

… require LESS men power

… answer MORE than 1 question

… are MORE informative about (rare) side-effects

… have ENDLESS duration of follow-up, yet…

... are NOT the paradigm to assess the effects of drug, because …

Non-randomized trials….

VS.

Confounding – an example of EPO

“Studies naar het effect

van vaccinatie tegen

griep deugen vaak

methodologisch niet.” (www.nos.nl, 24-10-2011)

“Effectiviteit griepprik nooit

bewezen” (Elsevier, 24-10-2011)

An example of influenza vaccination

The everlasting challenge in pharmacoepidemiology

- can be addressed by comparing like with like

- E.g. compare treated men with untreated men and

treated women with untreated women

- all methods to control for confounding are based

on this principle

Confounding

1. (non-)positivity

2. Dynamic treatment

3. Validity and completeness of registries

Some challenges:

Study of OC use in medical students:

Study of β-blocker use in adults

(non-)positivity – example

Confounder

Oral contraceptive

use

No oral

contraceptive use

Females 95% 5%

Males 0% 100%

Confounder

β-blocker use No β-blocker use

Hypertension 30% 70%

No hypertension 0.5% 99.5%

• non-positivity shortly after drug comes to the market

(selective groups switch treatment)

• second choice drugs

(non-respondents switch treatment)

• strict indication

(yet unrecorded)

1. (non-)positivity in pharmacoepi

Treatment is often not a constant

• time-varying dosage

• on demand treatment (e.g. SABA, NSAIDs)

• ‘ever vs never’ or dynamic regimes

(where does our interest lie?)

2. Dynamic treatment in pharmacoepi

Validity and completeness of registries

• prescription ≠ actual drug use

• only measured confounders can be adjusted

• time-varying confounding

(how frequent have confounders been measured?)

Shouldn’t we anticipated future research in

designing our registries? (which are key confounders?)

3. Registries in pharmacoepi

Pharmacoepidemiology is an ideal playing field to

study methods for causal inference.

A lot of opportunities and challenges.

Causality in pharmacoepidemiology

Thank you for your attention