SIGNAL DETECTION

METHODS
Disproportionality Methods

• Statistical techniques used in data mining

• Used to identify drug safety signals in

spontaneous report system (SRS) databases.
Disproportionality Methods

• Various statistical techniques including:

• Proportional reporting ratio (PRR)
• Gamma Poisson Shrinker (GPS)
• Urn-model algorithm
• Reporting odds ratio (ROR)
• Bayesian confidence propagation neural network -
information component (BCPNN-IC)
• Adjusted residual score (ARS)
Proportional Reporting Ratio (PRR)

• The PRR is a simple way to get a measure of how common an

adverse event for a particular drug is compared to how
common the event is in the overall database.
• PRR allows the comparison of frequencies of reporting, in order
to determine if there is a disproportionate reporting of a
specific adverse event with a specific drug compared to other
adverse events and other drugs.
• PRR will typically be calculated using a surveillance database in
which reports of adverse events from a variety of drugs are
recorded.
Proportional Reporting Ratio (PRR)

• The PRR is defined as the ratio between the

frequency with which a specific adverse event is
reported for the drug of interest (relative to all
adverse events reported for the drug) and the
frequency with which the same adverse event is
reported for all drugs in the comparison group
(relative to all adverse events for drugs in the
comparison group). 
Proportional Reporting Rate (PRR)

• Suppose that nausea was reported 100 times for Ciprofloxacin

tablet out of 1000 AEs reported for Ciprofloxacin;
• Proportion of nausea with Cipro = 100/1000
• = 0.1
• Comparison group – all drugs in the database
• Frequency of report of nausea (with other drugs) = 2000 times
out of 50,000 total AEs reported
• Proportion of Nausea (with other drugs) = 2000 / 50,000
• = 0.04
Proportional Reporting Rate (PRR)

• The PRR for Nausea with Cipro = 0.1 / 0.04

• = 2.5
• Implication: Nausea was reported more than twice as
frequently (among all AE reports) for Ciprofloxacin as compared
to other drugs in the database
• A PRR >1 suggests that
• the AE is more commonly reported for individuals taking the drug of
interest, relative to the comparison drugs
• there is a high probability that the event occurs in treated patients
with the drug of interest compared to the event occurring with other
products
Proportional Reporting Rate (PRR)

Concept displayed by 2x2 Contingency table

"a" = all reports for a
Event Y All other Total specific AE (Y) for Pdt X,

events (All AEs) "b" = all reports for all other

AEs for Product X

Product a b a+b "a + b" = all the reports for

X Product X,

All other c d c+d "c" = all reports for all other

products for Event Y,
products "d" = all reports for all other
products for all other AE,
"c+d" = all reports for all
other products
Proportional Reporting Rate (PRR)

• Proportion of Event Y with Product X = a / a + b

• Proportion of Event Y with All Products = c / c + d

• The PRR = [a/(a+b)]

• [c/(c+d)]

• If the ratio of [a/(a+b)] is greater than the ratio of [c/(c+d)], then

Event Y is "disproportionately reported" for Product X, when the
rest of the database is considered as a background "expected."
CASE STUDY

• In the Oracle Argus Safety database, there were 505

individual cases of diarrhoea reported for the use of
azithromycin and a total of 1850 other adverse events
reported for azithromycin within the same time interval.
The database contained a total of 85,500 reports of
other adverse events for all other drugs while 7520 were
cases of diarrhoea associated with these other drugs.
What is the PRR of diarrhoea with azithromycin?
Proportional Reporting Rate (PRR)

Diarrhoea All other Total

AEs
Azithromycin 505 1850 2355

All other 7250 85500 92750

products
CASE STUDY

• Proportion of Diarrhoea with Azithromycin =

505 / 2355 = 0.2144
• Proportion of Diarrhoea with All Products =
7250 / 92750 = 0.0782

• PPR for Diarrhoea = 0.2144 / 0.0782 = 2.74

• What does this imply?

Limitations of PRR

• The ff elements may influence the value of the PRR and

may induce masking effects.
• sampling variation in the data
• reporting errors
• biased reporting
• multiple reports of the same case or the same patient, or a
number of other causes.

• Alternatively they may exaggerate the importance of a

medicinal product-adverse event statistical association.
Conclusion

• The PRR measures a reporting relationship between a

medicinal product and an adverse event on the basis of a
relative increase of the proportion of individual cases related
to an adverse event.
• This does not necessarily imply a causal relationship between
the administered medicinal product and the occurrence of
the adverse event.
• Consequently, the signals identified with quantitative
methods should always be medically assessed.
.

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