Should

medical

students

learn

to

develop

a

personal

formulary

Objective

This

study

was

performed

to

determine

whether

students

who

are

trained

in

developing

a

personal

formulary

become

more

competent

in

rational

prescribing

than

students

who

have

only

learned

to

use

existing

formularies

Introduction

Many

medical

schools

in

developed

as

well

as

developing

countries

are

changing

their

undergraduate

education

in

pharmacotherapy

from

classic

lecture-based

learning

to

problem-based

learning

-LRB-

PBL

-RRB-

They

are

moving

away

from

the

presentation

of

classic

pharmacological

knowledge

on

medicines

towards

promoting

problem-solving

and

prescribing

skills

-LSB-

-RSB-

The

World

Health

Organisation

-LRB-

WHO

-RRB-

Guide

to

Good

Prescribing

and

several

training

courses

on

problem-based

pharmacotherapy

teaching

have

contributed

to

this

development

-LSB-

-RSB-

The

WHO

Guide

to

Good

Prescribing

gives

medical

students

a

normative

model

for

therapeutic

reasoning

and

prescribing

and

provides

a

six-step

guide

to

the

process

of

rational

prescribing

-LRB-

-RRB-

define

the

patient

's

problem

-LRB-

-RRB-

specify

the

therapeutic

objective

-LRB-

-RRB-

choose

a

-LRB-

drug

-RRB-

treatment

-LRB-

-RRB-

write

the

prescription

and

start

the

treatment

-LRB-

-RRB-

give

patient

information

and

warnings

and

-LRB-

-RRB-

monitor

the

treatment

One

of

the

key

principles

of

the

WHO

approach

is

the

division

of

step

-LSB-

choose

a

-LRB-

drug

-RRB-

treatment

-RSB-

into

two

steps

Step

consider

the

suitability

of

a

standard

-LRB-

p-drug

-RRB-

treatment

for

the

disease

in

general

and

step

verify

its

suitability

for

the

particular

patient

and

alter

the

-LRB-

drug

-RRB-

treatment

if

necessary

Consequently

undergraduate

students

are

taught

how

to

define

their

own

p-drugs

and

are

encouraged

during

their

medical

education

and

clinical

activities

to

develop

a

personal

formulary

-LSB-

-RSB-

The

WHO

method

emphasises

that

future

doctors

should

master

both

steps

of

the

drug-selection

process

Selecting

a

p-drug

trains

students

in

pharmacological

clinical

and

epidemiological

principles

and

in

collecting

and

comparing

evidence

By

considering

various

treatment

alternatives

when

developing

their

personal

formulary

students

are

able

to

choose

an

alternative

drug

treatment

more

rationally

when

the

drug

of

first

choice

is

not

suitable

for

a

particular

patient

for

example

because

of

contraindications

or

side

effects

In

addition

by

considering

treatment

alternatives

students

are

able

to

evaluate

the

information

provided

about

new

drugs

during

their

professional

career

more

critically

Application

of

the

WHO

method

has

improved

the

prescribing

skills

of

undergraduate

medical

students

-LSB-

-RSB-

However

it

is

not

known

to

what

extent

the

p-drug

concept

and

developing

a

personal

formulary

has

contributed

to

this

improvement

Some

have

argued

that

existing

formularies

and

standard

treatment

guidelines

developed

by

experts

would

lead

to

better

prescribing

than

would

a

personal

formulary

developed

by

students

Furthermore

doctors

are

usually

expected

to

work

within

the

limitations

of

existing

hospital

formularies

or

practice

guidelines

Despite

the

fact

that

teaching

the

p-drug

concept

and

developing

a

personal

formulary

is

a

challenging

and

time-consuming

task

we

hypothesise

that

training

in

developing

a

personal

formulary

would

lead

to

increased

prescribing

skills

compared

with

using

an

existing

formulary

Therefore

the

aim

of

this

study

was

to

determine

whether

there

is

a

difference

in

prescribing

skills

between

medical

students

who

have

been

trained

in

creating

and

using

a

personal

formulary

and

those

who

have

been

trained

in

using

existing

formularies

only

Materials

and

methods

Study

design

A

randomised

controlled

pre

and

posttest

design

with

three

arms

was

implemented

-LRB-

Fig.

-RRB-

All

students

participated

in

a

pretest

After

the

pretest

at

each

university

students

were

randomly

divided

into

three

equally

sized

groups

a

personal

formulary

-LRB-

PF

-RRB-

group

an

existing

formulary

-LRB-

EF

-RRB-

group

and

a

control

group

Students

in

the

PF

and

EF

groups

received

two

different

training

programmes

before

taking

the

posttest

The

control

group

received

no

additional

training

and

was

given

only

the

pre

and

posttests

Fig.

design

PF

personal

formulary

group

EF

existing

formulary

group

and

C

control

group

Clinical

subjects

A

essential

hypertension

B

osteoarthritis

C

acute

bronchitis

and

D

gastroenteritis

Complexity

levels

straightforward

case

of

a

middle-aged

adult

patient

patient

with

a

contraindication

to

a

generally

accepted

drug

of

first

choice

severe

case

and

case

without

effect

of

previous

treatment

and

side

effects

After

the

posttest

a

structured

questionnaire

with

questions

was

administered

to

identify

differences

in

the

type

of

teaching

students

received

prior

to

the

study

The

questions

were

about

two

major

teaching

issues

curriculum

type

and

teaching

methods

in

pharmacology

clinical

pharmacology

and

pharmacotherapy

Other

questions

were

designed

to

verify

whether

the

universities

had

carried

out

the

study

in

full

accordance

with

the

standard

protocol

The

study

was

approved

by

the

educational

research

committee

of

the

VU

University

Medical

Center

-LRB-

VUMC

-RRB-

Study

population

Six

hundred

and

nine

undergraduate

medical

students

from

eight

countries

were

selected

on

a

voluntary

basis

-LRB-

Vellore

in

India

Yogyakarta

in

Indonesia

Maastricht

in

the

Netherlands

Kazan

in

the

Russian

Federation

Bratislava

in

Slovakia

Cape

Town

in

South

Africa

La

Laguna

in

Spain

and

Aden/Sana

a

-LRB-

jointly

-RRB-

in

Yemen

-RRB-

All

students

had

passed

their

pharmacology

examinations

-LRB-

basic

pharmacology

and

clinical

pharmacology

-RRB-

and

were

about

to

start

their

clinical

internships

Participation

in

the

study

was

in

addition

to

their

normal

curriculum

All

students

were

informed

in

advance

about

the

general

aim

of

the

study

and

the

method

of

testing

Cross-contamination

of

the

students

in

the

study

groups

and

the

control

group

was

prevented

by

giving

the

students

in

the

control

group

the

opportunity

to

participate

in

a

training

programme

after

the

study

Materials

For

the

intervention

and

tests

written

patient

cases

were

developed

using

four

clinical

subjects

-LRB-

A

D

-RRB-

each

with

a

different

level

of

complexity

-LRB-

-RRB-

-LRB-

Fig.

-RRB-

All

cases

were

formulated

according

to

a

standard

design

General

patient

information

-LRB-

e.g.

age

gender

allergy

occupation

and

pregnancy

-RRB-

Summary

of

previous

and

current

diseases

and

treatments

-LRB-

comorbidity

and

comedication

-RRB-

Extensive

description

of

the

present

history

and

a

physical

examinationDiagnosis

Each

case

differed

in

disease

severity

and

complicating

factors

such

as

age

comorbidity

and

comedication

drug

allergy

pregnancy

and

breast

feeding

All

three

study

groups

received

a

copy

of

the

British

National

Formulary

-LRB-

BNF

-RRB-

as

a

drug

reference

-LSB-

-RSB-

In

addition

the

PF

group

received

the

WHO

Guide

to

Good

Prescribing

whereas

the

EF

group

received

an

adapted

version

of

the

guide

without

the

chapters

about

the

p-drug

concept

The

EF

group

also

received

the

Oxford

Formulary

containing

treatment

advice

for

symptoms

and

diseases

that

occur

frequently

in

general

practice

including

the

four

clinical

subjects

used

in

this

study

-LSB-

-RSB-

Intervention

The

training

course

for

the

PF

and

EF

groups

lasted

for

weeks

The

intervention

for

both

groups

consisted

of

an

introductory

session

and

four

training

sessions

-LRB-

Fig.

-RRB-

one

per

week

for

about

h

The

chosen

teaching

time

was

based

on

earlier

experiences

with

teaching

programmes

using

the

PF

concept

-LSB-

-RSB-

In

the

introductory

session

the

WHO

step-wise

approach

to

prescribing

drugs

was

explained

However

the

p-drug

concept

was

explained

only

to

the

PF

group

In

each

training

session

two

written

patient

cases

of

one

clinical

subject

were

discussed

Students

completed

a

treatment

plan

form

following

the

six

steps

of

the

WHO

model

The

students

prepared

for

the

sessions

by

studying

the

treatment

of

the

clinical

subject

but

in

different

ways

The

PF

group

was

asked

to

make

an

inventory

of

available

treatments

and

select

a

p-drug

from

this

group

-LRB-

on

the

basis

of

efficacy

safety

suitability

and

cost

-RRB-

whereas

the

EF

group

was

asked

to

study

the

relevant

treatment

guidelines

of

the

Oxford

Formulary

One

facilitator

per

university

supervised

the

sessions

of

both

PF

and

EF

groups

only

by

guiding

the

discussions

and

clarifying

aspects

of

the

case

if

necessary

Facilitators

were

specifically

instructed

not

to

provide

solutions

to

the

patient

problems

but

only

to

advise

students

on

how

to

solve

these

themselves

All

facilitators

had

received

specific

training

on

this

teaching

methodology

in

a

research

meeting

at

the

VUMC

The

control

group

received

no

additional

training

between

the

pre

and

posttest

but

proceeded

only

with

their

routine

curriculum

Test

and

scoring

The

pre

and

posttests

consisted

of

four

written

patient

cases

Each

case

contained

a

different

clinical

problem

of

a

different

level

of

complexity

-LRB-

Fig.

-RRB-

The

combination

between

the

clinical

problem

and

level

of

complexity

were

randomly

chosen

For

each

case

the

students

had

to

complete

a

treatment

plan

form

They

were

allowed

to

use

any

reference

materials

but

not

to

consult

one

another

Directly

after

the

posttest

the

answer

sheets

for

both

pre

and

posttests

were

blindly

scored

by

the

facilitator

in

a

standardised

manner

using

a

scale

-LRB-

no

answer

poor

answer

arguable

answer

acceptable

answer

and

good

answer

-RRB-

Prior

consensus

about

the

scoring

system

had

been

reached

between

all

facilitators

during

the

research

meeting

at

the

VUMC

The

scores

were

sent

to

the

researchers

at

the

VUMC

for

analysis

Individual

student

scores

were

not

used

by

the

participating

universities

for

formal

student

assessments

Statistical

analysis

The

results

were

analysed

in

SPSS

for

Windows

The

scores

on

the

six

steps

of

the

WHO

model

were

clustered

into

four

prescribing

skills

treatment

choice

prescription

writing

patient

information

and

treatment

monitoring

The

differences

between

groups

were

analysed

by

analysis

of

variance

-LRB-

ANOVA

-RRB-

with

the

university

as

a

factor

as

well

as

separately

For

pair-wise

differences

between

the

three

groups

a

multiple

comparison

procedure

was

applied

Significance

was

accepted

at

a

two-tailed

p

Only

the

results

of

students

who

finished

both

pre

and

posttest

were

included

in

the

analysis

Results

A

total

of

students

participated

Five

hundred

and

eighty-three

students

-LRB-

-RRB-

completed

the

pre

and

posttests

-LRB-

-RRB-

students

from

the

PF

groups

-LRB-

-RRB-

from

the

EF

groups

and

-LRB-

-RRB-

from

the

C

groups

The

three

groups

did

not

differ

in

their

averages

for

previous

examination

results

and

pretest

scores

The

increases

in

the

mean

scores

of

the

PF

group

-LRB-

-RRB-

and

the

EF

group

-LRB-

-RRB-

were

both

significantly

higher

than

in

the

C

group

-LRB-

-RRB-

-LRB-

Table

-RRB-

In

addition

the

increase

in

the

PF

group

was

significantly

higher

than

in

the

EF

group

-LRB-

Table

-RRB-

Within

this

total

the

differences

were

significant

for

three

of

the

four

prescribing

skills

-LRB-

treatment

choice

patient

information

and

monitoring

treatment

but

not

prescription

writing

-RRB-

and

for

three

of

the

four

complexity

levels

-LRB-

straightforward

case

cases

with

a

contraindication

to

first-line

drugs

and

severe

cases

but

not

cases

with

no

effect

of

previous

treatment

and

side

effects

present

-RRB-

-LRB-

data

not

shown

-RRB-

Table

and

posttest

scores

per

university

South

cAll

a

b

-LRB-

-RRB-

b

-LRB-

-RRB-

c

-LRB-

-RRB-

PF

personal

formulary

group

EF

existing

formulary

group

C

control

groupaPF

EF

-LRB-

p

-RRB-

bPF

EF

C

-LRB-

p

-RRB-

cC

pretest

-LRB-

p

-RRB-

Results

of

medical

students

from

the

eight

universities

are

listed

separately

-LRB-

Table

-RRB-

In

Yemen

the

Russian

Federation

and

Indonesia

pretest

scores

were

lower

than

in

the

other

five

universities

In

addition

the

increase

in

their

scores

was

significantly

higher

in

the

PF

groups

than

in

the

EF

groups

The

differences

among

the

PF

and

EF

groups

were

also

significant

for

all

levels

of

complexity

and

all

four

prescribing

skills

-LRB-

Fig.

-RRB-

In

the

remaining

five

schools

there

was

no

significant

difference

between

the

PF

and

EF

groups

Fig.

and

posttest

scores

for

different

prescribing

skills

of

students

from

countries

with

a

traditional

curriculum

-LRB-

Yemen

the

Russian

Federation

and

Indonesia

-RRB-

PF

personal

formulary

group

-LRB-

-RRB-

EF

existing

formulary

group

-LRB-

-RRB-

C

control

group

-LRB-

-RRB-

Posttest

scores

are

annotated

PF

EF

The

results

of

the

questionnaire

about

the

type

of

teaching

that

students

received

indicated

that

Yemen

the

Russian

Federation

and

Indonesia

had

a

predominantly

classic

curriculum

On

average

the

participating

students

from

these

universities

had

received

h

-LRB-

range

h

-RRB-

of

pharmacology

teaching

by

lectures

h

-LRB-

range

h

-RRB-

of

clinical

pharmacology

teaching

also

by

lectures

and

no

explicit

pharmacotherapy

teaching

These

students

were

not

familiar

with

PBL

but

were

somewhat

accustomed

to

discussion

in

small

groups

The

remaining

five

universities

had

a

predominantly

problem-based

teaching

curriculum

The

participants

had

received

an

average

of

h

-LRB-

range

h

-RRB-

of

pharmacology

teaching

by

lectures

including

small

group

teaching

h

-LRB-

range

h

-RRB-

of

clinical

pharmacology

teaching

mainly

by

small

group

teaching

and

no

explicit

pharmacotherapy

teaching

The

students

from

these

universities

were

all

familiar

with

PBL

and

were

all

accustomed

to

discussion

in

small

groups

Some

of

these

students

already

had

some

clinical

experience

-LRB-

Slovakia

and

Spain

-RRB-

Except

for

the

presence

-LRB-

or

absence

-RRB-

of

PBL

no

other

differences

in

teaching

could

be

identified

between

any

of

the

eight

universities

No

specific

differences

between

universities

in

the

way

the

study

was

performed

or

indications

for

possible

bias

were

identified

Discussion

The

results

of

this

study

show

that

developing

a

personal

formulary

and

using

an

existing

formulary

both

increase

the

competence

of

medical

students

in

rational

prescribing

However

the

overall

differences

between

the

PF

group

and

the

EF

group

-LRB-

vs.

increase

in

mean

score

p

-RRB-

should

be

interpreted

with

caution

It

is

tempting

to

conclude

that

teaching

students

to

develop

a

personal

formulary

adds

to

their

prescribing

skills

However

this

effect

was

only

visible

in

the

universities

in

Yemen

the

Russian

Federation

and

Indonesia

No

significant

differences

between

PF

and

EF

scores

were

found

in

the

universities

in

the

Netherlands

Slovakia

Spain

India

or

South

Africa

A

possible

reason

could

be

the

high

pretest

scores

in

the

last

five

universities

which

reduced

the

likelihood

of

a

significant

increase

after

a

relatively

short

intervention

period

of

weeks

A

similar

effect

was

seen

in

the

first

multicountry

study

where

universities

with

a

problem-based

curriculum

showed

less

benefit

from

a

short

intervention

course

than

those

without

a

problem-based

curriculum

-LSB-

-RSB-

An

important

question

is

why

these

five

universities

had

such

high

initial

scores

The

questionnaire

was

specifically

designed

for

the

purpose

of

this

study

and

the

only

explanation

that

emerged

was

that

students

from

these

five

universities

had

received

problem-based

teaching

and

were

therefore

familiar

with

the

process

of

solving

patient

problems

In

the

universities

with

lower

pretest

scores

classic

teaching

was

paramount

and

students

had

less

experience

with

solving

patient

problems

This

finding

is

in

accordance

with

the

fact

that

successful

clinical

problem

solvers

possess

comprehensive

knowledge

but

the

way

they

organise

and

understand

their

knowledge

is

even

more

critical

Modern

teaching

is

aimed

at

creating

both

a

knowledge

structure

and

the

necessary

search-and-retrieve

strategy

for

responding

to

complex

diagnostic

problems

-LSB-

-RSB-

Students

who

were

already

trained

in

this

way

via

problem-based

curricula

seemed

better

able

to

transfer

this

ability

to

therapeutic

problem

solving

and

did

not

show

an

additional

increase

in

such

skills

when

they

participated

in

our

study

However

students

from

universities

with

a

classic

curriculum

quickly

assimilated

the

p-drug

concept

and

their

results

came

very

close

to

those

of

the

other

five

universities

even

after

a

short

intervention

of

only

weeks

The

limitations

of

our

study

need

to

be

addressed

The

voluntary

participation

of

students

may

have

created

a

positive

bias

for

the

total

group

but

allocation

to

the

intervention

groups

was

randomised

and

therefore

the

comparison

was

unbiased

In

addition

to

ensure

baseline

comparability

among

the

groups

previous

results

on

university

examinations

were

averaged

for

the

three

groups

The

scoring

by

the

medical

schools

was

blinded

with

the

pre

and

posttest

forms

of

all

three

groups

being

mixed

during

the

scoring

Cross-contamination

between

the

study

and

control

groups

was

prevented

by

explaining

to

the

students

the

importance

of

not

exchanging

any

information

and

by

reassuring

the

control

group

that

it

would

receive

the

training

after

finishing

the

study

Therefore

taking

the

above-mentioned

limitations

and

considerations

into

account

it

can

be

concluded

that

training

in

developing

and

using

a

personal

formulary

or

in

the

use

of

an

existing

formulary

may

increase

the

rational

prescribing

of

medical

students

However

with

regard

to

universities

with

a

general

problem-based

curriculum

training

in

the

development

of

a

personal

formulary

is

probably

not

worth

the

additional

effort

In

these

circumstances

pharmacotherapy

teaching

can

be

based

on

existing

formularies

instead

of

a

personal

formulary

In

this

international

study

only

the

short-term

effects

on

rational

prescribing

of

developing

a

personal

formulary

or

using

an

existing

formulary

have

been

studied

Despite

the

fact

that

the

long-term

effects

are

unknown

it

can

be

hypothesised

that

after

developing

a

personal

formulary

students

may

judge

new

drugs

more

effectively

and

be

more

capable

of

deciding

whether

or

not

to

include

these

drugs

into

their

-LRB-

personal

-RRB-

formulary

Furthermore

the

results

may

diminish

the

concerns

ventilated

by

some

clinical

pharmacology

teachers

regarding

the

changes

in

the

style

of

undergraduate

medical

curricula

from

classic

to

PBL

teaching

-LSB-

-RSB-

In

practice

this

implies

that

the

decision

to

organise

a

teaching

programme

for

medical

students

on

how

to

develop

and

use

a

personal

formulary

needs

to

be

based

on

an

initial

assessment

of

both

the

students

and

the

curriculum

The

same

may

be

true

for

postgraduate

and

continuing

education

of

doctors

who

have

been

trained

in

the

classic

manner

-LSB-

-RSB-

A

screening

test

such

as

the

pretest

in

this

study

could

perhaps

be

used

to

identify

universities

students

or

prescribers

that

would

benefit

most

from

this

type

of

training

O O O O O O O B I O O O O O O O O O O O O O O O O B I O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O B I O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O B I O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

personal formulary
rational prescribing
prescribing
drug treatment


Inter-scan reproducibility of coronary calcium measurement using Multi Detector-Row Computed Tomography -LRB- MDCT -RRB- Purpose To assess inter-scan reproducibility of coronary calcium measurements obtained from Multi Detector-Row CT -LRB- MDCT -RRB- images and to evaluate whether this reproducibility is affected by different measurement protocols , slice thickness , cardiovascular risk factors and/or technical variables . Introduction A considerable proportion of the western society is at risk of suffering a cardiovascular event during life . Atherosclerosis is one of the main underlying processes . Non-invasive assessment of atherosclerosis is important since it allows studies into the etiology and consequences of early and advanced atherosclerosis in populations at large -LSB- 1 -RSB- . The last two decades , measurement of coronary artery calcification -LRB- CAC -RRB- using computer tomography -LRB- CT -RRB- has been used to assess coronary atherosclerosis non-invasively . The presence , and more importantly , the quantity of CAC , relates well with the overall severity of the atherosclerotic process -LSB- 2 -RSB- . Several studies have demonstrated a strong relation between coronary calcium burden and the incidence of myocardial infarction , a relation which was independent of age -LSB- 3 , 4 -RSB- . Most of the evidence on determinants and consequences of coronary calcium is based on data obtained with electron beam CT -LRB- EBCT -RRB- -LSB- 5 -- 7 -RSB- . The availability of EBCT scanners is modest , whereas the Multi Detector-Row CT -LRB- MDCT -RRB- scanners are more widely available and also allow for detection of coronary calcium . Current data suggest that EBCT and MDCT give comparable results -LSB- 8 , 9 -RSB- . In contrast to EBCT , however , data on reproducibility of CAC measurements using MDCT images is not widely available -LSB- 10 , 11 -RSB- , but information is relevant . Furthermore , due to technical improvement , slice thickness of the images has become smaller which may affect the likelihood of detecting coronary calcium , and hence its reproducibility . We set out to study inter-scan reproducibility of coronary calcium measurements from MDCT images and to evaluate whether reproducibility is affected by different measurement protocols , slice thickness , selected cardiovascular risk factors and technical variables . Materials and methods Participants were recruited from the PROSPECT study -LSB- 12 -RSB- , cohort of 17,357 healthy breast-cancer screening participants , aged 49 -- 70 years , living in Utrecht and surroundings , enrolled between 1993 and 1997 . Between October 2002 and December 2004 , a random selection of 1,996 women were invited by mail and 1,000 -LRB- 50.1 % -RRB- who were postmenopausal and did not use contraceptives or hormone replacement therapy answered positively . Of these 1,000 women , a random selection of 573 underwent a MDCT examination during a single visit and 76 of them were scanned twice . The Medical Ethical Committee of the University Medical Center Utrecht approved the study and written informed consent was obtained from all participants . Current cardiovascular drug use -LRB- blood pressure lowering , lipid lowering and glucose lowering drugs -RRB- was assessed by asking women to bring all packages to the study centre . Smoking behavior , medical history and cardiovascular family history were assessed by a questionnaire . Height and weight were measured and body mass index was calculated as weight divided by height squared -LRB- kg/m2 -RRB- . Waist-to-hip ratio -LRB- WHR -RRB- was assessed . Systolic and diastolic blood pressures were measured at both arms with an automated and calibrated blood pressure device -LRB- DINAMAPTM XL , Critikon , Johnson & Johnson , Tampa , Florida , USA -RRB- with the subject in supine position . A venous blood sample was drawn after an overnight fast of at least eight hours . Plasma total cholesterol , plasma triglycerides , and plasma glucose were measured using standard enzymatic procedures . High-density lipoprotein -LRB- HDL -RRB- cholesterol was measured by the direct method -LRB- inhibition , enzymatic -RRB- . Low-density lipoprotein -LRB- LDL -RRB- cholesterol was calculated using the Friedewald formula . Coronary imaging and calcium measurements The amount of calcium in the coronary arteries was assessed with a Multi Detector-Row CT -LRB- MDCT -RRB- scanner -LRB- Mx 8000 IDT 16 , Philips Medical Systems , Best , The Netherlands -RRB- . Subjects were positioned within the gantry of the MDCT scanner in supine position . During a single breath hold , images of the heart , from the level of the tracheal bifurcation to below the base of the heart , were acquired using prospective ECG triggering at 50 -- 80 % of the RR-interval , depending on the heart rate . Scan parameters were 16 × 1.5 mm collimation , 205 mm field of view -LRB- FOV -RRB- , 0.42 s rotation time , 0.28 s scan time per table position , 120 kVp and 40 -- 70 mAs -LRB- patient weight < 70 kg : 40 mAs ; 70 -- 90 kg : 55 mAs ; > 90 kg : 70 mAs -RRB- . Scan duration was approximately 10 s , depending on heart rate and patient size . We had the participant get up from the table and lay down again since in studies on change in CAC over one year it is not realistic to assume exactly the same position of the participant at both occasions . Therefore our patients sat up and consequently moved slightly between scans to mimic two separate scan runs . From the acquired raw data , the whole volume was reconstructed with an intermediate reconstruction algorithm in non-overlapping data sets of 1.5 mm and 3 mm thick sections . Quantification of coronary calcium was performed on a separate workstation with software for calcium scoring -LRB- Heartbeat-CS , EBW , Philips Medical Systems , Best , The Netherlands -RRB- . All regions with a density over 130 Hounsfield units were identified as potential calcifications . After completing a training-program , one scan reader -LRB- AR -RRB- who was unaware of the scores of the first scan , manually selected the calcifications within one of the coronary arteries -LRB- left main , left anterior descending , left circumflex , right coronary artery , and PDA -RRB- and scored the second scan of the participants . To reduce the influence of noise , the minimum size of a calcified lesion was set at 0.5 mm2 . The peak density in Hounsfield units and the area in mm2 of each selected region were calculated . The Agatston -LSB- 13 -RSB- calcium score was obtained by multiplying the area by a weighting factor that is dependent on the peak signal anywhere in the lesion . The scores of individual lesions were added to obtain the Agatston calcium score for the entire coronary tree . The total calcium volume was calculated by multiplying the area of the calcified lesion -LRB- measured in square millimeters -RRB- by section thickness -LRB- 1.5 mm and 3.0 mm -RRB- . The calcium volume for each coronary vessel was computed by summing the volumes of the lesions in that vessel for all sections . Finally , the total volume from all the vessels became the calcium volume for a subject . The mass method uses volumetric , density information and a calibration phantom of hydroxyapatite to calculate the actual mass of the calcified plaques -LSB- 14 -RSB- . In addition , information on breathing artifact -LRB- inconsistency of sternum bone in sagital section in mm -RRB- , noise -LRB- standard deviation of enhancement in fixed cardiac area of 212 mm2 -RRB- and mean heart rate -LRB- beats/min -RRB- during scan acquisition was collected . Data analysis The mean and standard deviations -LRB- SD -RRB- of coronary calcium were calculated for all scoring methods separately . Because of the skewed distribution of scores , medians were also computed . The Intra-class correlation coefficient was estimated for between scans data and for 1.5 and 3.0 mm slices thicknesses separately . The mean difference in score between scans was calculated as well as the absolute and relative differences . To distinguish between random differences or systematic difference , information on mean and absolute differences is needed . One may assume a priori a non-differential misclassification in the calcium scores , but one has to show that with the results . When the chance of the 2nd result being higher or lower is equal , one would expect a mean difference of zero , with some standard deviation . The absolute difference will not be zero since all differences are ` absolutised ' , but it is expected that at least the mean difference is much less than the absolute difference . If however the chance of a higher or lower value in the 2nd scan is not equal , the mean difference will be plus or minus a certain value . In addition , the absolute difference will have a value close to that of the mean difference . Therefore we need both parameters . To estimate a weighted kappa as measure of agreement of categorical variables , subjects were divided into four groups according to the mean Agatston score as proposed by Rumberger et al. -LSB- 15 -RSB- : A : 0 -- 9 -LRB- absent-minimal -RRB- , B : 10 -- 99 -LRB- mild -RRB- , C : 100 -- 399 -LRB- moderate -RRB- and D : -LRB- 400 -LRB- severe degree of calcification -RRB- . This categorization is specifically for the calcium scoring method according to Agatston . Therefore we additionally categorized all scoring methods in their quartiles to calculate kappa as measure of agreement for all scoring methods . The relation between risk factors , technical variables and measurement error was assessed using Spearman correlation coefficients . In a similar manner the relation between calcium level and measurement error was examined . Since logarithms of coronary calcium scores have generally been used in statistical analyses in other papers , we also studied the reproducibility of logarithmic transformed calcium score . Logarithmic analysis of coronary calcium scores was performed by calculating natural log of coronary calcium scores +0.001 -LRB- ln -LRB- CCS + 0.001 -RRB- -RRB- because the logarithm of coronary calcium scores alone excludes all subjects with zero scores -LSB- 16 -RSB- . We defined relative difference as absolute difference divided by the mean calcium level multiplied in 100 and expressed in percent . Data analysis was performed with SPSS for windows , version 12.0 . A statistically significant difference was assumed when the two-sided P-value was less than 0.05 . Results Mean age was 67.3 ± 5.2 years . Fifty-five participants -LRB- 72.4 % -RRB- had a coronary calcification more than zero in Agatston -LRB- 1.5 mm slice thickness -RRB- . Table 1 shows the general characteristics of the 76 women who had two MDCT scans . Table 1Characteristics of studied population -LRB- N = 76 -RRB- MeanStd . deviationAge -LRB- year -RRB- 67.35.2 BMI -LRB- Kg/m2 -RRB- 26.33.9 WHR0 .840.06 SBP -LRB- mmHg -RRB- 133.918.9 DBP -LRB- mmHg -RRB- 71.79.1 Total cholesterol -LRB- mmol/l -RRB- 6.090.86 LDL cholesterol -LRB- mmol/l -RRB- 4.310.97 HDL cholesterol -LRB- mmol/l -RRB- 1.510.36 Triglycerides -LRB- mmol/l -RRB- 1.280.62 Glucose -LRB- mmol/l -RRB- 4.050.69 Heart rate -LRB- beat/minute -RRB- 7211Current smoking -LRB- % -RRB- * 11Former smoking -LRB- % -RRB- 43Previous CVD -LRB- % -RRB- 1Family history of CAD in either parents -LRB- % -RRB- 10BMI = Body Mass Index ; CAD = Coronary Artery Diseases ; DBP = Diastolic Blood Pressure ; LDL = Low Density Lipoprotein ; HDL = High Density Lipoprotein ; SBP = Systolic Blood Pressure ; WHR = Waist to Hip Ratio * Percentages have been rounded Table 2 presents information on calcium distributions by various scoring techniques and reproducibility results , by slice thickness . Overall , calcium scores were higher when based on the 1.5 mm slice thickness than based on the 3.0 mm slice thicknesses . The kappa agreement and Intra-class correlation coefficients between the two scans were high for all scoring methods , indicating that with respect to ranking of subjects all three methods are doing well . In addition , the mean differences in scores were relatively small compared to the absolute differences for all measurements , suggestion no systematic measurement errors . Finally , results for the scans with 1.5 mm slice thickness were similar to those for the 3.0 mm slice thickness -LRB- Table 2 -RRB- . Table 2Characteristics of different coronary calcium scoring methods ; effect of slice thickness on inter-scan reproducibilityMass 1st ScanMass 2nd Scan Volume 1st Scan Volume 2nd Scan Agatston 1st Scan Agatston 2nd Scan Slice thickness 1.5 mmMean32 .2131.88154.52149.40170.33163.63 Median6 .156.0539.9736.5231.8532.00 Agreement -LRB- k -RRB- Rumberger categories0 .970.890.87 Agreement -LRB- k -RRB- Quartiles0 .840.810.88 Mean difference0 .35.16.7 Absolute difference4 .022.324.3 Relative difference -LRB- % -RRB- 12.414.614.5 ICCC * 0.990.990.98 Slice thickness 3.0 mmMean25 .5725.45131.45126.98140.06135.82 Median4 .003.6530.3021.9020.3018.00 Agreement -LRB- k -RRB- Rumberger categories0 .920.830.73 Agreement -LRB- k -RRB- Quartiles0 .840.840.84 Mean difference0 .14.44.2 Absolute difference3 .518.721.3 Relative difference -LRB- % -RRB- 13.714.715.4 ICCC * 0.990.980.98 * Intra-class correlation coefficient Table 3 presents the relation of cardiovascular risk factors with inter-scan mean difference . No consistent relations were found between risk factor levels and measurement error . Importantly , however was the observation that calcium level or the logarithm of the coronary calcium scores were not related to the mean difference between scans , whereas they were significantly related to the absolute and relative differences -LRB- Table 4 , Figs. 1 and 2 -RRB- . These observations suggest that measurement error increases with increasing CAC levels , yet that this occurs in a random way . Table 3Relationship between cardiovascular risk factors and inter-scan mean difference of coronary calcium scoring methods by MDCT -LRB- Slice thickness 1.5 mm -RRB- Inter-scan mean differenceCCS methodsMassVolumeAgatstonBiological variablesrP-valuerP-valuerP-valueBMI -LRB- Kg/m2 -RRB- 0.040.730.030.740.020.80 Age -LRB- year -RRB- 0.180.100.310.000.280.01 Smoking -LRB- Categorical -RRB- − 0.000.980.040.710.070.49 WHR − 0.030.730.080.480.130.24 SBP -LRB- mmHg -RRB- 0.100.370.160.140.240.03 DBP -LRB- mmHg -RRB- 0.160.140.050.610.110.34 Cholesterol -LRB- mmol/l -RRB- − 0.270.05 − 0.120.40 − 0.200.17 LDL -LRB- mmol/l -RRB- − 0.180.10 − 0.190.09 − 0.090.40 HDL -LRB- mmol/l -RRB- − 0.040.72 − 0.160.14 − 0.110.34 Triglyceride -LRB- mmol/l -RRB- − 0.020.850.130.240.110.34 Glucose -LRB- mmol/l -RRB- 0.160.24 − 0.000.980.000.98 Mean heart rate − 0.030.77 − 0.030.73 − 0.020.81 Technical variablesMean breathing artifact0 .010.88 − 0.030.78 − 0.020.87 Mean SD of noise0 .130.260.080.490.070.52 Coronary calciumMean mass score0 .000.98 Mean volume score0 .030.75 Mean Agatston score0 .020.86 Mean log mass score0 .000.99 Mean log volume score0 .030.76 Mean log Agatston score0 .020.85 BMI = Body Mass Index ; DBP = Diastolic Blood Pressure ; LDL = Low Density Lipoprotein ; HDL = High Density Lipoprotein ; r = spearman correlation coefficient ; SBP = Systolic Blood Pressure ; WHR = Waist to Hip RatioTable 4Relationship between cardiovascular risk factors and inter-scan absolute and relative difference of coronary calcium scoring methods by MDCT -LRB- Slice thickness 1.5 mm -RRB- Inter-scan relative differenceCCS methodsMassVolumeAgatstonBiological variablesrP-valuerP-valuerP-valueBMI -LRB- Kg/m2 -RRB- 0.070.530.080.460.090.43 Age -LRB- year -RRB- 0.210.060.240.030 . l170 .12 Smoking -LRB- Categorical -RRB- − 0.030.73 − 0.070.51-0.140.20 WHR0 .070.550.050.660.050.66 SBP -LRB- mmHg -RRB- 0.060.570.040.680.110.32 DBP -LRB- mmHg -RRB- 0.320.0040.310.0050.330.003 Cholesterol -LRB- mmol/l -RRB- 0.130.370.100.500.001.00 LDL -LRB- mmol/l -RRB- − 0.140.21 − 0.170.12-0.180.11 HDL -LRB- mmol/l -RRB- 0.070.520.040.670.060.57 Triglyceride -LRB- mmol/l -RRB- 0.030.780.070.490.000.99 Glucose -LRB- mmol/l -RRB- 0.230.090.260.050.240.08 Mean heart rate − 0.010.910.010.930.000.97 Technical variablesMean breathing artifact0 .100.440.090.490.150.23 Mean SD of noise0 .190.090.190.090.180.11 Coronary calciumMean mass score0 .290.009 Mean volume score0 .330.003 Mean Agatston score0 .380.001 Mean log mass score0 .290.010 Mean log volume score0 .330.003 Mean log Agatston score0.370.001Inter-scan absolute differenceTechnical variablesMean breathing artifact0 .120.320.120.330.150.22 Mean SD of noise0 .200.080.190.090.150.17 Coronary calciumMean mass score0 .86 < 0.001 Mean volume score0 .84 < 0.001 Mean Agatston score0 .89 < 0.001 Mean log mass score0 .86 < 0.001 Mean log volume score0 .83 < 0.001 Mean log Agatston score0 .89 < 0.001 BMI = Body Mass Index ; DBP = Diastolic Blood Pressure ; LDL = Low Density Lipoprotein ; HDL = High Density Lipoprotein ; r = spearman correlation coefficient ; SBP = Systolic Blood Pressure ; WHR = Waist to Hip RatioFig . 1Relation between mean calcium score and inter-scan difference in mean calcium scores -LRB- Bland-Altman plots -RRB- Fig. 2Relation between mean calcium score and inter-scan absolute difference Discussion With respect to ranking of subjects , the inter-scan reproducibility of coronary calcium measurements by MDCT using Agatston , volume and mass scoring algorithms is excellent . The inter-scan reproducibility showed no major differences between scoring methods . The slice thickness did not affect reproducibility , nor did heart rate and technical parameters . Measurement error was related to increased coronary artery calcification , although our findings suggest that the error in the measurements is a random phenomenon . Our findings , i.e. , no major differences between scoring methods are in contrast with several reports on reproducibility based on EBCT scanning . Direct comparison of the findings of these studies with those of other is difficult since the parameters used to indicate reproducibility differ between studies . Furthermore , potentially the prevalence of CAC and its extent may affect reproducibility , as our findings suggest that measurement error increases with increasing CAC levels . Also the sizes of the studies differ which have undeniable effects on reproducibility results . However , our results are similar to those of by Rumberger and Kaufman -LSB- 17 -RSB- , who compared these three methods and did not find any one method preferable to another in terms of reproducibility of results from consecutive scans in a patient . Although the correlation between inter-scan measurements is excellent -LSB- 18 , 19 -RSB- , it still occurs that subjects with small deposits of calcium in scan one may have larger deposits of calcium in the 2nd scan , which leads to proportionally larger error in reproducibility . This has triggered other studies -LSB- 20 -RSB- on reproducibility to suggest that `` the variability is partially a function of the absolute calcium score and inversely related to it '' , implicating that low coronary calcium scores may not be reproducible . However , our results could not confirm this . Besides different algorithms for calcium scoring , slice thickness has been reported to affect the reproducibility of scoring protocols . In our study , the reproducibility of the coronary calcium measurements by MDCT was similar for 1.5 mm as for 3.0 mm slice thickness , and equal for Agatston , volume and mass measurements confirming the results by Rumberger and Kaufman -LSB- 17 -RSB- . The implications of our main findings depend on the research question that is asked in studies using CAC measurements . When the interest is using CAC measurements for prognostic studies our results for kappa and ICCC show that ranking of subjects is adequate based on one CT scan . So the need for duplicate CAC scan is absent . The fact that measurement error increases with increasing CAC values , is in prognostic studies not of major importance since the categorization of individuals seems adequate . When the interest is in etiologic studies using CAC as outcome parameter , our findings show that risk factor relations will be validly estimated since none of the risk factors relates to measurement error . When the interest is in using CAC as risk factor for future events -LRB- assessment of relative risks -RRB- , it is most likely that in analyses with CAC as continues variable the magnitude of association of high CAC levels with events reflects an underestimation of the true magnitude . The direction of the relation will not change since based on our results measurement error is random , leading to random misclassification of the exposure variable . When the interest is in diagnostic value of CAC measurements , which is usually done in categories of CAC , again the relations will be valid given our high kappa coefficients . Although our study was performed in healthy postmenopausal women , we expect that the finding will also be applicable for men . Our findings are important in the light of the wider availability of MDCT in countries compared to EBCT . One reason for that is lower equipment cost . Other advantages of MDCT over EBCT have been suggested to be less quantum noise , thinner section thickness , and simultaneous acquisition of four sections -LRB- with 16-slice or with 64-slice -RRB- , which is reported to reduce misregistration artifact . In conclusion , our findings demonstrate that coronary calcium measurements by MDCT are highly reproducible and are not affected by scoring protocols , slice thicknesses and technical factors .

O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

coronary artery calcification
atherosclerosis
reproducibility

multi detector-row ct (mdct)
epidemiology


Acute

myocardial

infarction

incidence

and

hospital

mortality

routinely

collected

national

data

versus

linkage

of

national

registers

Background

and

Objective

To

compare

levels

of

and

trends

in

incidence

and

hospital

mortality

of

first

acute

myocardial

infarction

-LRB-

AMI

-RRB-

based

on

routinely

collected

hospital

morbidity

data

and

on

linked

registers

Cases

taken

from

routine

hospital

data

are

a

mix

of

patients

with

recurrent

and

first

events

and

double

counting

occurs

when

cases

are

admitted

for

an

event

several

times

during

year

By

linkage

of

registers

recurrent

events

and

double

counts

can

be

excluded

Introduction

Mortality

from

coronary

heart

disease

in

particular

from

acute

myocardial

infarction

-LRB-

AMI

-RRB-

has

decreased

in

many

Western

countries

during

the

last

decades

-LSB-

-RSB-

A

decrease

in

age

and

gender-adjusted

AMI

mortality

assuming

a

constant

quality

of

diagnosis

is

a

consequence

of

either

a

decrease

in

incidence

case-fatality

or

recurrence

risk

or

a

combination

of

these

Hospital-based

registers

are

often

used

for

surveillance

of

the

morbidity

and

hospital

mortality

of

AMI

-LSB-

-RSB-

In

the

Netherlands

the

national

hospital

discharge

register

has

traditionally

been

used

to

provide

estimates

of

-LRB-

trends

in

-RRB-

incidence

and

hospital

mortality

of

AMI

-LSB-

-RSB-

However

in

this

register

like

in

many

others

a

new

record

is

created

for

each

hospital

admission

As

a

consequence

admissions

taken

from

the

hospital

register

will

include

double

counts

from

patients

if

they

are

transferred

to

a

second

hospital

or

if

they

are

admitted

for

the

same

event

several

times

during

year

Furthermore

patients

taken

from

the

hospital

register

from

year

include

a

mix

of

patients

with

recurrent

events

-LRB-

presence

of

an

event

in

preceding

years

-RRB-

and

first

events

-LRB-

absence

of

events

in

preceding

years

-RRB-

Tracking

individuals

over

time

based

on

information

from

the

hospital

register

only

is

difficult

when

a

unique

personal

identifier

is

absent

in

the

hospital

register

The

effect

of

both

double

counting

and

admixture

of

first

and

recurrent

events

in

nationwide

registers

on

-LRB-

trends

-RRB-

in

incidence

or

hospital

mortality

has

not

been

well

assessed

-LSB-

-RSB-

For

the

Netherlands

this

effect

could

only

be

estimated

from

comparison

with

results

from

regional

cohort

studies

as

nationwide

estimates

of

incidence

and

hospital

mortality

of

first

AMI

were

not

available

Furthermore

it

has

been

argued

that

statistics

from

routine

data

could

not

be

used

for

providing

reliable

information

on

-LRB-

trends

in

-RRB-

incidence

and

hospital

mortality

After

we

recently

showed

that

hospitalized

patients

in

the

Netherlands

can

be

followed

longitudinally

within

the

national

hospital

discharge

register

in

a

valid

way

by

using

information

from

the

Dutch

population

register

-LSB-

-RSB-

we

set

out

to

compare

the

nationwide

-LRB-

trends

in

-RRB-

incidence

and

hospital

mortality

of

first

hospitalized

AMI

based

on

routinely

collected

data

in

the

hospital

register

-LRB-

double

counts

and

recurrent

events

included

-RRB-

and

based

on

linkage

of

the

hospital

register

with

the

population

register

-LRB-

double

counts

and

recurrent

events

excluded

-RRB-

Methods

Data

sources

Data

on

hospital

admissions

were

retrieved

from

the

national

hospital

discharge

register

Since

all

general

and

academic

hospitals

and

most

single

specialty

hospitals

participate

in

the

hospital

register

There

are

no

private

hospitals

in

the

Netherlands

that

treat

patients

with

AMI

For

each

hospital

admission

a

new

record

is

created

in

the

hospital

register

including

the

following

information

date

of

birth

gender

numeric

part

of

postal

code

-LRB-

since

-RRB-

hospital-specific

patient

identification

code

type

of

hospital

admission

date

and

principal

diagnosis

of

the

admission

The

principal

diagnosis

is

determined

at

discharge

and

coded

using

the

ninth

revision

of

the

International

Classification

of

Diseases

-LRB-

-RRB-

-LSB-

-RSB-

As

the

hospital

register

does

not

contain

a

unique

personal

identifier

we

tracked

individuals

over

time

within

the

hospital

register

by

using

information

from

the

Dutch

population

register

This

database

contains

information

on

all

registered

persons

living

in

the

Netherlands

including

date

of

birth

gender

current

address

postal

code

and

nationality

Patients

registered

in

the

hospital

register

were

identified

in

the

population

register

using

linkage

variables

date

of

birth

gender

and

numeric

part

of

postal

code

When

patients

moved

their

hospital

admissions

were

recognized

by

using

the

new

postal

code

registered

in

the

population

register

Recently

the

validity

of

the

registries

and

linkage

methods

was

studied

In

a

random

sample

of

hospital

admissions

of

the

personal

admission

and

discharge

data

and

of

the

principal

diagnoses

-LRB-

validated

through

medical

record

review

by

medical

specialists

-RRB-

were

correctly

registered

-LSB-

-RSB-

In

a

random

sample

of

the

population

register

over

of

the

addresses

were

shown

to

be

correctly

registered

-LSB-

-RSB-

Furthermore

over

of

the

uniquely

linked

hospital

admissions

resulting

from

linkage

of

the

hospital

register

with

the

population

register

were

shown

to

be

correctly

linked

-LSB-

-RSB-

These

results

are

similar

to

most

of

the

studies

that

reported

on

the

validity

of

AMI

events

in

hospital

and

population

based

registries

-LSB-

-RSB-

All

analyses

were

performed

at

Statistics

Netherlands

in

agreement

with

privacy

legislation

in

the

Netherlands

-LSB-

-RSB-

Cohort

enrolment

from

the

hospital

register

The

hospital

register

comprises

information

based

on

all

admissions

in

the

Netherlands

of

the

entire

Dutch

population

including

double

counts

first

and

recurrent

admissions

for

AMI

and

including

AMI

admissions

of

non-residents

In

the

hospital

register

and

hospital

admissions

with

a

principal

diagnosis

AMI

-LRB-

-LSB-

-RSB-

code

and

subcategories

-RRB-

were

registered

in

and

Cohort

enrolment

from

linked

registers

After

linkage

with

the

population

register

using

linkage

variables

date

of

birth

gender

and

numerical

part

of

postal

code

and

admissions

came

from

patients

with

a

unique

combination

of

linkage

variables

in

the

population

register

-LRB-

and

respectively

-RRB-

Thus

each

remaining

admission

linked

to

only

one

unique

individual

in

the

population

register

-LRB-

one

unique

individual

in

the

Netherlands

-RRB-

Admissions

linking

with

more

than

one

person

-LRB-

e.g.

administrative

twins

two

persons

with

the

same

date

of

birth

gender

and

numeric

part

of

postal

code

registered

in

the

population

register

-RRB-

or

with

no

person

at

all

-LRB-

e.g.

non-residents

or

administrative

errors

-RRB-

in

the

population

register

were

excluded

Selection

of

the

first

admission

per

person

of

all

subsequent

admissions

of

a

person

occurring

during

and

yielded

patients

in

and

patients

in

Thus

double

counts

had

occurred

in

-LRB-

-RRB-

and

in

-LRB-

-RRB-

Information

on

admissions

in

previous

years

of

the

patients

in

was

obtained

by

selecting

all

hospital

admissions

registered

in

the

hospital

register

with

principal

diagnosis

AMI

in

the

period

These

admissions

were

linked

to

the

cohort

of

patients

with

linkage

variables

date

of

birth

gender

and

one

or

both

of

the

variables

numerical

part

of

postal

code

and

hospital-specific

patient

identification

code

Linkage

with

the

population

register

was

not

possible

since

this

register

started

in

October

Subjects

who

linked

in

this

process

were

patients

with

previous

hospital

admissions

for

AMI

-LRB-

recurrent

AMI

patients

-RRB-

and

were

excluded

-LRB-

patients

-LRB-

-RRB-

-RRB-

This

resulted

in

the

final

cohort

of

consisting

of

patients

Information

on

hospital

admissions

in

previous

years

of

the

patients

in

was

obtained

by

linking

of

the

hospital

register

of

to

the

population

register

with

linkage

variables

date

of

birth

gender

and

numerical

part

of

postal

code

All

uniquely

linked

admissions

with

principal

diagnosis

AMI

were

selected

and

linked

to

the

cohort

of

patients

Patients

with

previous

hospital

admissions

for

AMI

-LRB-

recurrent

AMI

patients

-RRB-

were

excluded

-LRB-

patients

-LRB-

-RRB-

-RRB-

This

resulted

in

the

final

cohort

of

consisting

of

patients

Thus

the

linked

register

comprises

information

for

only

part

of

the

Dutch

population

-LRB-

i.e.

those

that

were

unique

on

date

of

birth

gender

and

postal

code

-RRB-

and

does

not

include

double

counts

and

recurrent

AMI

admissions

Data

analysis

The

incidence

and

hospital

mortality

of

AMI

-LRB-

with

confidence

interval

-LRB-

CI

-RRB-

-RRB-

based

on

the

hospital

register

-LRB-

hospital-based

-RRB-

and

on

linked

registers

-LRB-

linkage-based

-RRB-

was

computed

by

year

age

and

gender

We

compared

the

hospital-based

incidence

and

hospital

mortality

to

the

linkage-based

incidence

and

hospital

mortality

by

calculating

incidence

rate

differences

or

ratios

and

risk

differences

or

ratios

-LRB-

with

CIs

-RRB-

by

age

and

gender

Trends

in

incidence

and

hospital

mortality

were

obtained

by

calculating

incidence

rate

or

risk

differences

and

incidence

rate

or

risk

ratios

-LRB-

with

CIs

-RRB-

by

age

and

gender

Incidence

rate

differences

and

ratios

were

based

on

the

Poisson

model

while

risk

differences

and

ratios

were

based

on

the

binomial

model

-LSB-

-RSB-

Pooled

age-adjusted

incidence

rate

differences

or

ratios

and

risk

differences

or

ratios

-LRB-

with

CIs

-RRB-

were

calculated

according

to

the

Mantel

Haenszel

method

-LSB-

-RSB-

Results

In

both

and

the

gender

and

age

distribution

of

the

cohort

based

on

the

hospital

register

was

comparable

to

the

cohort

based

on

linked

registers

In

and

two-thirds

comprised

men

The

mean

age

in

was

years

in

men

and

years

in

women

based

on

the

hospital

register

This

was

and

years

respectively

based

on

linked

registers

In

the

mean

age

based

on

the

hospital

register

was

years

in

men

and

years

in

women

Based

on

linked

registers

this

was

and

years

respectively

In

men

the

-LRB-

adjusted

-RRB-

hospital-based

incidence

was

per

person-years

or

-LRB-

CI

-RRB-

higher

than

the

-LRB-

adjusted

-RRB-

linkage-based

incidence

in

and

per

person-years

or

-LRB-

CI

-RRB-

higher

in

-LRB-

Table

-RRB-

Age-specific

-LRB-

years

-RRB-

absolute

and

relative

differences

ranged

from

per

person-years

or

in

and

from

per

person-years

or

in

The

-LRB-

adjusted

-RRB-

hospital-based

incidence

was

also

higher

than

the

-LRB-

adjusted

-RRB-

linkage-based

incidence

in

women

in

-LRB-

per

person-years

or

CI

higher

-RRB-

and

-LRB-

per

person-years

or

CI

higher

-RRB-

Age-specific

-LRB-

years

-RRB-

absolute

and

relative

differences

varied

from

per

person-years

or

in

and

from

per

person-years

or

in

Table

-LRB-

per

persons

per

year

-RRB-

of

hospitalized

acute

myocardial

infarction

in

and

based

on

the

national

hospital

discharge

register

and

based

on

linked

registerLinked

registersHospital

registerLinked

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

Women

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

Incidence

rate

difference

-LRB-

with

confidence

interval

-RRB-

rate

ratio

-LRB-

with

confidence

interval

-RRB-

Pooled

age-adjusted

incidence

rate

difference

or

ratio

-LRB-

with

confidence

interval

-RRB-

The

hospital-based

hospital

mortality

was

similar

to

the

linkage-based

hospital

mortality

in

men

in

-LRB-

adjusted

risk

ratio

-LRB-

RR

-RRB-

CI

-RRB-

and

-LRB-

adjusted

RR

CI

-RRB-

and

in

women

in

-LRB-

adjusted

RR

CI

-RRB-

and

-LRB-

adjusted

RR

CI

-RRB-

-LRB-

Table

-RRB-

Also

within

the

age

groups

no

significant

differences

between

the

hospital-based

and

the

linkage-based

hospital

mortality

were

revealed

Table

mortality

-LRB-

-RRB-

of

acute

myocardial

infarction

in

and

in

based

on

the

national

hospital

discharge

register

and

based

on

linked

registerLinked

registersHospital

registerLinked

registersAgeMortality

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

Women

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

Risk

difference

-LRB-

with

confidence

interval

-RRB-

Risk

ratio

-LRB-

with

confidence

interval

-RRB-

Pooled

age-adjusted

risk

difference

or

ratio

-LRB-

with

confidence

interval

-RRB-

From

to

the

hospital-based

decline

in

incidence

was

similar

to

the

linkage-based

decline

-LRB-

Table

-RRB-

In

men

the

-LRB-

adjusted

-RRB-

hospital-based

incidence

declined

by

per

person-years

or

-LRB-

CI

-RRB-

and

the

linkage-based

incidence

declined

by

per

person-years

or

-LRB-

CI

-RRB-

In

women

the

-LRB-

adjusted

-RRB-

hospital-based

incidence

declined

by

per

person-years

or

-LRB-

CI

-RRB-

and

the

-LRB-

adjusted

-RRB-

linkage-based

incidence

declined

by

per

persons

per

year

or

-LRB-

CI

-RRB-

The

age-specific

relative

changes

in

hospital-based

and

linkage-based

incidence

were

largely

comparable

Table

in

the

incidence

-LRB-

per

persons

per

year

-RRB-

and

hospital

mortality

-LRB-

-RRB-

of

hospitalized

acute

myocardial

infarction

from

to

based

on

the

national

hospital

discharge

register

and

based

on

linked

registersTrends

in

incidence

Trends

in

hospital

mortality

Risk

difference

Relative

risk

Risk

differenceRelative

risk

AgeHospital

registerLinked

registersHospital

registerLinked

registersHospital

registerLinked

registersHospital

registerLinked

registersMen

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

TotalCrude

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

Women

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

TotalCrude

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

-LRB-

to

-RRB-

Pooled

age-adjusted

risk

difference

or

ratio

-LRB-

with

confidence

interval

-RRB-

The

-LRB-

adjusted

-RRB-

hospital-based

decline

in

hospital

mortality

from

to

was

similar

to

the

-LRB-

adjusted

-RRB-

linkage-based

decline

-LRB-

Table

-RRB-

In

men

hospital

mortality

declined

absolutely

by

and

relatively

by

based

on

both

the

hospital

register

and

linked

registers

In

women

the

absolute

and

relative

decline

was

and

respectively

based

on

both

the

hospital

register

and

linked

registers

The

age-specific

relative

changes

in

hospital-based

and

linkage-based

hospital

mortality

were

largely

similar

Discussion

We

combined

data

from

the

national

hospital

discharge

register

with

data

from

the

population

register

to

determine

the

-LRB-

trends

in

-RRB-

incidence

and

hospital

mortality

of

first

hospitalized

AMI

-LRB-

double

counts

and

recurrent

AMI

cases

excluded

-RRB-

and

compared

the

outcomes

with

the

incidence

and

hospital

mortality

based

on

routinely

collected

data

in

the

hospital

register

-LRB-

double

counts

and

recurrent

AMI

cases

included

-RRB-

The

incidence

based

on

the

hospital

register

was

considerably

and

significantly

higher

than

the

incidence

based

on

linked

registers

whereas

hospital

mortality

and

trends

in

incidence

and

hospital

mortality

were

identical

using

either

approach

Although

we

were

able

to

estimate

the

incidence

and

hospital

mortality

of

first

AMI

by

linkage

of

the

hospital

register

with

the

population

register

some

aspects

of

this

method

should

be

discussed

First

non-unique

persons

in

the

population

-LRB-

register

-RRB-

were

excluded

from

the

study

population

in

the

linked

registry

data

If

this

exclusion

produced

systematic

differences

between

the

linked

registry

population

and

the

clinically

relevant

population

-LRB-

i.e.

the

total

Dutch

population

-RRB-

it

might

have

affected

the

incidence

estimate

in

the

linked

registry

to

some

extent

-LRB-

e.g.

an

overestimation

of

incidence

resulting

from

a

higher

mean

age

of

the

study

population

-RRB-

A

pilot

study

suggested

that

non-uniqueness

relates

to

large

cities

foreign

origin

and

age

-LSB-

-RSB-

The

differences

between

unique

and

non-unique

persons

however

were

small

-LSB-

-RSB-

and

apply

to

both

and

Second

information

on

previous

admissions

was

limited

to

maximal

years

for

the

patients

-LRB-

as

the

numeric

part

of

the

postal

code

is

registered

in

the

hospital

register

since

-RRB-

Therefore

it

seems

likely

that

some

first

AMI

patients

actually

were

recurrent

AMI

patients

However

it

has

been

estimated

that

most

-LRB-

-RRB-

of

recurrent

events

occur

within

years

-LSB-

-RSB-

Third

the

outcome

measures

in

the

present

study

were

incidence

and

hospital

mortality

Mortality

after

discharge

from

hospital

was

not

considered

since

this

outcome

is

not

registered

in

the

hospital

register

Differences

in

mortality

after

discharge

between

patients

with

a

first

or

a

recurrent

AMI

can

only

be

studied

by

linkage

of

national

registers

-LRB-

i.e.

the

hospital

register

with

the

population

register

and

the

cause

of

death

statistics

-RRB-

A

final

aspect

that

needs

to

be

addressed

is

the

generalizability

of

our

findings

The

results

might

differ

if

a

change

over

time

occurs

in

double-count

or

readmission

fractions

Results

might

also

differ

for

other

diseases

than

AMI

or

for

specific

groups

of

patients

-LRB-

e.g.

non-native

patients

-RRB-

hospitals

or

regions

Such

differences

will

not

be

apparent

from

routinely

collected

data

Since

trends

in

incidence

and

hospital

mortality

are

often

based

on

national

routinely

collected

data

generalization

of

our

findings

would

be

of

great

relevance

It

has

been

be

argued

that

routine

statistics

can

not

be

used

for

providing

information

on

-LRB-

trends

in

-RRB-

incidence

and

hospital

mortality

because

of

double

counting

of

cases

and

admixture

of

first

and

recurrent

events

In

order

to

prevent

erroneous

inclusion

of

prevalent

cases

-LRB-

recurrent

events

-RRB-

that

have

had

a

previous

hospitalization

for

AMI

prior

to

the

study

period

generally

an

clearance

period

is

employed

to

overcome

overestimation

of

the

incidence

-LSB-

-RSB-

For

myocardial

infarction

it

has

been

shown

that

a

clearance

period

of

years

should

be

taken

into

account

to

completely

overcome

inclusion

of

prevalent

cases

In

our

study

we

used

a

clearance

period

because

of

logistical

reasons

This

however

would

suggest

that

in

our

incidence

estimate

around

of

the

subjects

should

be

considered

as

recurrent

AMI-patient

rather

that

first

ever

AMI

patient

-LSB-

-RSB-

Although

this

does

affect

the

absolute

incidence

estimate

it

may

not

affect

trends

in

incidence

and

case

fatality

assuming

that

the

erroneous

inclusion

of

prevalent

cases

occurs

at

both

time

windows

Indeed

this

has

been

shown

in

a

Danish

study

where

the

incidence

based

on

the

number

of

AMI-patients

without

an

admission

for

AMI

in

the

previous

year

overestimated

the

incidence

based

on

the

number

of

AMI-patients

without

-LRB-

an

admission

for

-RRB-

AMI

in

the

previous

years

by

in

men

and

in

women

but

trends

reflected

trends

in

true

incidence

with

reasonable

accuracy

-LSB-

-RSB-

With

respect

to

double

count

in

eight

states

of

the

USA

it

was

estimated

that

double

counting

of

patients

resulted

in

an

overestimation

of

the

true

incidence

of

hospitalized

AMI

and

an

underestimation

of

the

true

hospital

mortality

In

this

study

double

counts

were

defined

as

readmissions

for

AMI

within

days

and

thought

to

result

from

transfer

to

a

second

hospital

Correction

for

double

counting

revealed

a

lower

incidence

and

a

higher

hospital

mortality

-LSB-

-RSB-

Despite

aspects

regarding

double

counts

and

recurrent

events

there

have

been

several

consistent

reports

from

different

countries

using

national

registries

to

study

trends

in

case

fatality

incidence

and

survival

-LSB-

-RSB-

These

time

trends

indicated

a

decline

in

incidence

of

myocardial

infarction

and

in

case

fatality

after

AMI

In

the

present

study

we

found

a

significant

decline

in

both

incidence

and

hospital

mortality

of

first

AMI

between

and

These

declines

in

incidence

and

hospital

mortality

appear

to

mainly

reflect

declines

in

first

events

as

trends

were

not

altered

when

recurrent

cases

were

excluded

from

the

data

and

thus

are

best

explained

by

advances

in

primary

prevention

and

acute

management

of

AMI

Overall

our

results

based

on

deterministic

linkages

of

sources

using

gender

date

of

birth

and

postal

code

are

in

line

with

earlier

reports

from

other

studies

where

linkage

was

performed

using

unique

identification

numbers

In

conclusion

our

study

shows

that

the

incidence

based

on

routinely

collected

data

in

the

national

hospital

discharge

register

overestimates

the

actual

incidence

of

first

AMI

based

on

linked

national

registers

by

least

in

men

and

in

women

Yet

the

hospital

mortality

based

on

the

hospital

register

accurately

reflects

the

actual

hospital

mortality

of

first

AMI

Furthermore

trends

in

incidence

and

hospital

mortality

based

on

the

hospital

register

are

not

changed

when

double

counts

and

recurrent

cases

were

excluded

Since

trends

in

incidence

and

hospital

mortality

of

AMI

are

often

based

on

national

routinely

collected

data

it

is

reassuring

that

our

results

indicate

that

findings

from

such

studies

are

indeed

valid

and

not

biased

because

of

recurrent

events

and

double

counts

Electronic

supplementary

material

Below

is

the

link

to

the

electronic

supplementary

material

-LRB-

DOC

kb

-RRB-

B I I B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

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