# Presentation: 588441

## 

Sequential methodology in case series analysis: The UK experience

Mounia Hocine1*, P. Musonda1, N. Andrews2, C.P. Farrington1

1 The Open University, Milton Keynes, UK
2 Health Protection Agency, London, UK 

* Biostatistician, PhD (m.hocine@open.ac.uk)

- Sequential methodology in case series analysis: The UK experience
- _Mounia Hocine_1*, P. Musonda1, N. Andrews2, C.P. Farrington1
- 1 The Open University, Milton Keynes, UK
- 2 Health Protection Agency, London, UK
- * Biostatistician, PhD (m.hocine@open.ac.uk)

- Vaccine safety evaluation: post marketing surveillance conference
*Bethesda, Maryland April 10-11, 2007*

## The self-controlled case series method (SCCS)

- An epidemiological study design to investigate the association between apoint exposure and an acute event.

-  The method uses only cases, and estimates the relative incidence of the         event in a pre-defined post-vaccination risk period.

-  Widely used in studies of vaccine safety.

-  So far the method has been used retrospectively, but it may also be adapted      for use in prospective surveillance.

**Notes:**
I’ll strat by describing brievely the method

##                         The SCCS method (Farrington, Biometrics 1995)

- ai

- bi

- Calendar period

- nijk ~ Poisson(eijk ******ijk**)

-  Multinomial likelihood(i factor out)

-                         The SCCS method *(Farrington, Biometrics 1995)*

- For each case i

**Notes:**
Define the observation period, which may vary between individuals (ai, bi]
Identify vaccinations and post-vaccination risk periods (risk period determined in advance using prior knowledge)
Vaccine effect lasts only as long as the risk period; several risk periods can be used

## The SCCS method: Advantages 

-  Uses data from only cases,

- The SCCS method: Advantages

-  Adjusts for all fixed confounders over time and for exponential    trends in incidence in calendar time,

-  Powerful, quick and easy to apply, when applicable

-  Applicable to databases from hospitals, General Practice Research     Database (GPRD),...

**Notes:**
En plus du fait que 

## The SCCS method: Surveillance scenario

-  At the end of each interval the vaccination records of the cases notified in     that  interval are ascertained (such data might be obtained from hospital records,      the GPRD,...)

- The SCCS method: Surveillance scenario

-  Focus on specified adverse events after the introduction of a new vaccine,

-  The analysis is undertaken prospectively at regular surveillance intervals    (3, 6 or 12 months),

**Notes:**
Now we are going to apply the sccs for prospective surveillance
So we focus....
Say every 6 months or every 12 months, it depends on prior knowledge of a particular vaccine being monitored.
Of 6 or 12 monthly period are ascertained using a mechanism that is independent of the occurrence of the event.

## Sequential Probability Ratio Test

- Upper boundary: U = log [(1-/,
- Lower boundary: L = log [/(1-

-  Apply the SCCS at the end of each surveillance interval *i*  *L**0**(X**i**), L**1**(X**i**),*

-  H0: RI = 1  vs   H1: RI = 1.5, 2, 5, 10, ...

**Notes:**
Now I’m going to give u a few technical dtails, we use the sequential test... type 1 and type 2 error probabilities
We use an sprt which is a way to choose between 2 hyp: the null hypothesis h nought where the relative incidence RI = 1, and the alternative hypothesis H1 where RI = a value deemed important to detect. we calculate the sprt and if the cumulative value crosses the lower (accept H0) or upper boundary (accept H1) we stop otherwise we continue

## SPRT: Decision rule

- Time

- L

- Continue...

-  0            1               2               3             4              5              6              7

- U

- SPRT

- H0 accepted

- STOP

## Surveillance scenario: simulation

-  We investigated the effects of age, risk period, surveillance     interval, relative incidence (under H1).

-  Properties of the case series SPRT were studied by simulation,

-  We mimicked a vaccination programme targeted at 1-2 year olds, with most        vaccinations occurring at 12-18 months of age,

**Notes:**
Say every 6 months or every 12 months
Of 6 or 12 monthly period are ascertained using a mechanism that is independent of the occurrence of the event.

## Slide 9

**Notes:**
As the RI increases the time to detection reduces and as the risk period increases.
More info on vaccine effect when the risk period is long

## Slide 10

## Illustration: Bell’s palsy and parenteral inactivated influenza vaccine using the UK GPRD

- Further studies undertaken using data from the GPRD (no association)

- Most cases report to their GP.

- Association reported with an intranasal flu vaccine OR = 84.0 (Switzerland), but not with parenteral vaccine.

- Bell’s palsy is an acute facial paralysis affecting the 7th facial nerve.

**Notes:**
It holds data on consultations, referrals, prescriptions and vaccinations for over 3 million active patients in practices throughout the UK (5.7% of pop)
In the GPRD, all vaccines prescribed by general practitioners but not those administrated in the work place are recorded.
Eliminate the day 0

## Illustration: Bell’s palsy and flu vaccineusing case series SPRT

- Retrospective application of case series SPRT from July 1992

- Temporal adjustment: by calendar month

- Risk period: 1-7 or 1-60 days after any dose of influenza vaccine

- H1: RI = 1.5 and 5

- Surveillance interval length = 6 months

- Degree of urgency: alarm  =  = 0.01  **L** = -4.6 (lower boundary)

**Notes:**
It holds data on consultations, referrals, prescriptions and vaccinations for over 3 million active patients in practices throughout the UK (5.7% of pop)
In the GPRD, all vaccines prescribed by general practitioners but not those administrated in the work place are recorded.
Eliminate the day 0

## Slide 13

**Notes:**
However if alternative RI=5 the decision is reached to accept H0  within 18 months 

## Slide 14

**Notes:**
For a small value of RI = 1.5 the information is insufficient to make a decision 

## Slide 15

**Notes:**
After 18 months
We obtain similar results for a RI = 2

## Slide 16

**Notes:**
With a long risk period (2 months), we get more info about to vaccine effect and we come to a decision with even RI is smal but it still long after 10 years

## Conclusion

-  The self-controlled case series method provides a robust and readily implemented method for routine surveillance.
-  Website:
- http:\\statistics.open.ac.uk\sccs
- (Bibliography - Programs in STATA, SAS, GENSTAT and GLIM)