Reliability

and

validity

of

functional

health

status

and

health-related

quality

of

life

questionnaires

in

children

with

recurrent

acute

otitis

media

In

this

study

the

reliability

and

validity

of

generic

and

disease-specific

questionnaires

has

been

assessed

focusing

on

responsiveness

This

is

part

of

a

study

on

the

effects

of

recurrent

acute

otitis

media

-LRB-

rAOM

-RRB-

on

functional

health

status

-LRB-

FHS

-RRB-

and

health-related

quality

of

life

-LRB-

HRQoL

-RRB-

in

children

with

rAOM

participating

in

a

randomized

clinical

trial

The

following

generic

questionnaires

were

studied

RAND

general

health

rating

index

Functional

Status

Questionnaire

-LRB-

FSQ

Generic

and

FSQ

Specific

-RRB-

TNO-AZL

Infant

Quality

of

Life

-LRB-

TAIQOL

-RRB-

and

the

following

disease-specific

questionnaires

Otitis

-LRB-

-RRB-

Numerical

rating

scales

-LRB-

NRS

-RRB-

for

child

and

caregiver

-LRB-

NRS

Child

and

NRS

Caregiver

-RRB-

and

a

new

Family

Functioning

Questionnaire

-LRB-

FFQ

-RRB-

Reliability

was

good

to

excellent

-LRB-

Cronbach

's

α

range

intraclass

correlation

coefficient

range

-RRB-

Moderate

to

strong

correlations

were

found

between

the

questionnaires

as

well

as

between

questionnaires

and

relevant

clinical

indicators

-LRB-

r

-RRB-

demonstrating

construct

validity

Discriminant

validity

for

children

with

few

versus

frequent

episodes

of

acute

otitis

media

per

year

was

good

for

most

questionnaires

-LRB-

P

-RRB-

but

poor

for

the

otitis

media-related

subscales

of

the

TAIQOL

-LRB-

P

-RRB-

and

both

NRS

-LRB-

P

and

-RRB-

Except

for

the

TAIQOL

subscales

change

scores

were

significant

-LRB-

P

-RRB-

for

generic

and

disease-specific

questionnaires

Effect

sizes

were

somewhat

higher

for

disease-specific

compared

to

generic

questionnaires

-LRB-

versus

-RRB-

except

for

the

TAIQOL

subscales

which

showed

very

poor

sensitivity

to

change

Anchor-based

methods

resulted

in

a

somewhat

larger

range

of

estimates

of

MCID

than

distribution-based

methods

Combining

distribution-based

and

anchor-based

methods

resulted

in

similar

ranges

for

the

minimally

clinical

important

differences

for

generic

and

disease-specific

questionnaires

points

on

a

scale

Apart

from

the

generic

TAIQOL

subscales

both

generic

and

disease-specific

questionnaires

used

in

this

study

showed

good

psychometric

qualities

and

responsiveness

for

use

in

clinical

studies

on

children

with

rAOM

Introduction

Acute

otitis

media

-LRB-

AOM

-RRB-

is

a

common

childhood

infection

with

a

peak

incidence

occurring

between

and

months

of

age

Five

to

fifteen

percent

of

all

children

depending

on

their

age

suffer

from

recurrent

acute

infections

of

the

middle

ear

-LRB-

or

more

episodes

per

year

-RRB-

-LSB-

-RSB-

Repetitive

episodes

of

pain

fever

and

general

illness

during

acute

ear

infections

-LSB-

-RSB-

as

well

as

worries

about

potential

long-term

sequelae

such

as

hearing

loss

and

disturbed

language

development

-LSB-

-RSB-

may

all

compromise

the

quality

of

life

of

the

child

and

its

family

-LSB-

-RSB-

Although

several

questionnaires

have

been

used

in

assessing

the

effects

of

recurrent

acute

otitis

media

-LRB-

rAOM

-RRB-

in

children

lack

of

true

health-related

quality

of

life

-LRB-

HRQoL

-RRB-

questionnaires

as

well

as

incomplete

data

on

their

reliability

and

validity

mean

that

our

current

knowledge

on

the

subject

is

limited

for

both

research

and

clinical

practice

-LSB-

-RSB-

Assessment

of

functional

health

status

-LRB-

FHS

-RRB-

and

HRQoL

as

defined

in

Table

-LSB-

-RSB-

has

become

increasingly

important

in

clinical

trials

on

the

effectiveness

of

treatment

in

paediatric

chronic

conditions

The

validation

of

FHS

and

HRQoL

questionnaires

however

has

so

far

mainly

focused

on

reliability

and

construct

validity

Responsiveness

has

been

assessed

for

only

a

few

paediatric

HRQoL

questionnaires

for

conditions

other

than

otitis

media

-LSB-

-RSB-

In

order

to

evaluate

treatment

effects

on

FHS

and

HRQoL

meaningfully

questionnaires

are

needed

that

are

not

only

reliable

and

valid

but

also

responsive

to

changes

in

FHS

and

HRQoL

In

adult

studies

various

strategies

have

been

used

to

assess

responsiveness

which

is

defined

as

the

ability

to

detect

clinically

important

change

over

time

and

therefore

involves

both

the

assessment

of

sensitivity

to

change

and

the

assignment

of

meaning

to

that

change

-LSB-

-RSB-

Since

of

these

strategies

is

without

limitations

we

will

try

to

assess

the

responsiveness

of

FHS

and

HRQoL

questionnaires

by

using

multiple

strategies

categorized

into

distribution-based

and

anchor-based

methods

Table

of

health-related

quality

of

life

and

functional

health

statusHealth-related

quality

of

life

Level

of

satisfaction

a

person

inputes

to

those

aspects

of

his

or

her

life

that

are

affected

by

the

effects

of

illness

and

its

treatment

-LSB-

-RSB-

Incorporation

of

a

person

's

valuation

of

his

life

distinguishes

HRQoL

from

other

measures

of

well-being

-LSB-

-RSB-

Functional

health

status

Reflection

of

the

-LRB-

severity

of

-RRB-

signs

and

symptoms

and

the

adequacy

of

daily

functioning

across

various

life-domains

in

an

individual

with

a

certain

health

condition

-LSB-

-RSB-

Distribution-based

methods

express

the

amount

of

change

relative

to

the

amount

of

random

variance

of

a

questionnaire

-LSB-

-RSB-

whereas

anchor-based

methods

enhance

interpretability

of

changes

in

questionnaire

scores

by

linking

meaning

and

clinical

relevance

to

change

scores

-LSB-

-RSB-

Both

generic

and

disease-specific

questionnaires

have

been

used

in

studies

of

paediatric

FHS

or

HRQoL

Generic

questionnaires

span

a

wide

spectrum

of

quality

of

life

components

bridging

various

health

states

and

populations

Disease-specific

questionnaires

on

the

other

hand

assess

health-related

issues

specific

to

particular

conditions

and

may

be

able

to

detect

small

changes

that

are

often

small

but

clinically

important

these

provide

a

more

detailed

assessment

of

HRQoL

but

can

not

be

used

for

comparisons

across

health

conditions

-LSB-

-RSB-

Both

questionnaires

are

often

combined

in

order

to

profit

from

the

merits

of

both

types

However

there

have

been

few

head-to-head

comparisons

between

generic

and

disease-specific

HRQoL

measurement

questionnaires

in

the

setting

of

randomized

controlled

trials

-LRB-

RCT

-RRB-

-LSB-

-RSB-

The

current

RCT

on

the

effectiveness

of

pneumococcal

vaccination

in

children

with

rAOM

will

address

both

the

issues

of

using

generic

versus

disease-specific

questionnaires

and

responsiveness

in

evaluating

treatment

effects

on

HRQoL

in

RCTs

The

results

will

lead

to

recommendations

regarding

the

applicability

of

these

questionnaires

in

clinical

studies

in

children

with

rAOM

Methods

Setting

and

procedure

FHS

and

HRQoL

were

assessed

in

children

with

rAOM

participating

in

a

double-blind

randomized

placebo-controlled

trial

on

the

effectiveness

of

pneumococcal

conjugate

vaccination

versus

control

hepatitis

vaccination

The

study

was

conducted

at

the

paediatric

outpatient

departments

of

a

general

hospital

-LRB-

Spaarne

Hospital

Haarlem

-RRB-

and

a

tertiary

care

hospital

-LRB-

University

Medical

Center

Utrecht

-RRB-

Children

were

recruited

for

this

trial

through

referral

by

general

practitioners

paediatricians

or

otolaryngologists

or

were

enrolled

on

the

caregiver

's

own

initiative

from

April

to

February

Study

population

Inclusion

criteria

children

were

aged

between

and

months

and

suffering

from

rAOM

at

study

entry

defined

in

this

study

as

having

had

at

least

episodes

of

physician

diagnosed

AOM

in

the

year

prior

to

study

entry

Exclusion

criteria

were

conditions

with

a

known

increased

risk

for

AOM

such

as

known

immunodeficiency

-LRB-

other

than

IgA

or

subclass

deficiency

-RRB-

cystic

fibrosis

immotile

cilia

syndrome

cleft

palate

chromosomal

abnormalities

-LRB-

like

Down

syndrome

-RRB-

or

severe

adverse

events

upon

vaccination

in

the

past

At

each

scheduled

visit

two

research

physicians

-LRB-

C.N.M.B.

and

R.H.V.

-RRB-

collected

data

regarding

the

number

of

episodes

of

AOM

-LRB-

based

on

parental

report

at

baseline

and

on

physician

report

during

follow-up

-RRB-

upper

respiratory

tract

infections

and

pneumonia

Information

about

the

medical

treatment

and

ear

nose

and

throat

surgery

in

the

preceding

months

was

also

collected

The

primary

caregivers

completed

questionnaires

assessing

FHS

and

HRQoL

of

their

child

and

family

during

the

clinic

visits

at

baseline

and

at

and

months

follow-up

Caregivers

were

requested

to

have

the

same

person

complete

the

questionnaires

each

time

and

to

rate

their

child

's

FHS

and

HRQoL

with

regard

to

their

recurrent

episodes

of

acute

otitis

media

Informed

consent

was

obtained

from

caregivers

of

all

children

before

study

entry

Medical

ethics

committees

of

both

participating

hospitals

approved

the

study

protocol

Questionnaires

Four

generic

questionnaires

-LRB-

RAND

FSQ

Generic

FSQ

Specific

TAIQOL

-RRB-

and

one

disease-specific

questionnaire

-LRB-

-RRB-

were

used

to

assess

FHS

and

HRQoL

of

the

children

in

the

study

Additionally

two

disease-specific

one-item

numerical

rating

scales

-LRB-

NRS

Child

and

NRS

Caregiver

-RRB-

were

used

to

obtain

a

global

rating

of

HRQoL

of

the

child

and

of

the

caregiver

respectively

related

to

rAOM

For

the

assessment

of

the

impact

of

rAOM

on

family

functioning

a

newly

composed

disease-specific

questionnaire

the

Family

Functioning

Questionnaire

-LRB-

FFQ

-RRB-

was

used

to

assess

the

impact

of

rAOM

on

family

functioning

Table

summarises

the

characteristics

of

the

questionnaires

-LSB-

-RSB-

Table

of

FHS

and

HRQoL

questionnaires

used

in

this

studyQuestionnairesType

number

of

items

scaleConstruct

-LRB-

s

-RRB-

measuredApplication

in

other

studiesGenericRANDFHS

LikertGeneral

health

current

health

previous

health

resistance

to

illnessLow-birth-weight

children

survivors

of

childhood

cancer

asthmatic

children

-LSB-

-RSB-

FSQ

genericFHS

LikertAge

appropriate

functioning

and

emotional

behaviourLow-birth-weight

children

survivors

of

childhood

cancer

asthmatic

children

-LSB-

-RSB-

FSQ

specificIdem

to

FSQ

Generic

measuring

general

impact

of

illness

on

functioning

and

behaviourTAIQOLHRQoL

LikertSleeping

appetite

lung

problems

stomach

problems

skin

problems

motor

functioning

problem

behaviour

social

functioning

communication

positive

mood

anxiety

livelinessLow-birth-weight

children

childen

with

chronic

illness

children

with

chronic

OME

-LSB-

-RSB-

LikertPhysical

suffering

hearing

loss

speech

impairment

emotional

distress

activity

limitations

caregiver

concernsChildren

with

recurrent

AOM

children

with

chronic

OME

-LSB-

-RSB-

NRS

Child

NRS

CaregiverHRQoL

index

index

well-being

of

child

related

to

AOM

episodesGlobal

well-being

of

parent

related

to

child

's

AOM

episodesChildren

with

recurrent

AOM

or

chronic

OMEnone

-LSB-

-RSB-

Family

Functioning

Questionnaire

-LRB-

FFQ

-RRB-

FHS

LikertParents

sleep

deprivation

change

of

daily

or

social

activities

emotional

distress

Family

cancelling

family

plans

or

trips

Siblings

feeling

neglected

demanding

extra

attention.None

items

when

age

months

Generic

questionnaires

The

RAND

general

health-rating

index

-LRB-

RAND

-RRB-

and

the

Functional

Status

Questionnaire

-LRB-

FSQ

-RRB-

had

already

been

translated

and

validated

for

Dutch

children

by

Post

et

al.

-LSB-

-RSB-

-LRB-

Table

-RRB-

The

RAND

assesses

general

health

perceptions

of

caregivers

regarding

their

child

-LSB-

-RSB-

The

FSQ

consists

of

two

parts

one

measuring

functional

limitations

in

general

not

necessarily

related

to

illness

-LRB-

FSQ

Generic

-RRB-

and

the

other

-LRB-

paradoxically

named

FSQ

Specific

-RRB-

measuring

functional

limitations

that

are

attributable

to

any

illness

-LSB-

-RSB-

Functional

limitations

in

both

versions

of

the

FSQ

are

mainly

expressed

as

behavioural

problems

During

the

course

of

the

study

a

new

Dutch

questionnaire

on

generic

HRQoL

became

available

the

TNO-AZL

Infant

Quality

of

Life

-LRB-

TAIQOL

-RRB-

questionnaire

-LSB-

-RSB-

For

this

reason

from

July

the

TAIQOL

was

added

to

the

previously

selected

set

of

questionnaires

Although

the

full

original

version

of

the

TAIQOL

has

been

applied

during

the

study

only

those

subscales

from

the

TAIQOL

are

discussed

that

based

on

their

content

were

assumed

to

be

sensitive

to

the

consequences

of

AOM

The

following

subscales

tap

functional

items

that

are

often

affected

by

AOM

-LRB-

OM-related

-RRB-

Sleeping

Appetite

Liveliness

Problem

behaviour

Positive

mood

and

Communication

-LRB-

items

about

speech

and

language

capacity

-RRB-

which

are

of

the

subscales

in

the

TAIQOL

Although

the

TAIQOL

has

been

developed

for

children

aged

up

to

years

we

also

used

the

questionnaire

in

children

aged

years

as

no

appropriate

alternative

was

available

during

the

study

Disease-specific

questionnaires

To

measure

disease-specific

FHS

the

Otitis

-LRB-

-RRB-

-LSB-

-RSB-

was

translated

into

Dutch

according

to

principles

of

backward

forward

translation

-LSB-

-RSB-

This

six-item

questionnaire

covers

both

acute

and

long-term

functional

effects

of

otitis

media

in

children

on

FHS

A

new

questionnaire

has

been

developed

to

assess

the

impact

of

rAOM

in

children

on

their

caregivers

and

siblings

the

FFQ

The

content

of

the

FFQ

was

based

on

previous

work

by

Asmussen

et

al.

-LSB-

-RSB-

on

the

impact

of

rAOM

on

family

well-being

A

panel

of

paediatric

otorhinolaryngologists

and

paediatricians

from

our

study

sites

selected

the

items

most

relevant

according

to

their

clinical

experience

The

FFQ

is

composed

of

six

questions

covering

effects

of

the

child

's

rAOM

on

caregiver

and

family

activities

and

two

questions

assessing

these

effects

on

emotional

behaviour

of

the

other

siblings

The

Likert-scale

was

used

as

a

response

format

and

was

analogous

to

that

of

the

RAND

and

in

our

study

ranging

from

score

Furthermore

two

numerical

rating

scales

-LRB-

NRS

-RRB-

-LRB-

-RRB-

were

used

the

NRS

Child

and

the

NRS

Caregiver

-LRB-

see

Table

-RRB-

The

NRS

Child

-LSB-

-RSB-

was

translated

into

Dutch

using

the

same

principles

of

backward

forward

translation

that

have

been

applied

to

translation

of

the

The

newly

created

NRS

Caregiver

was

modelled

upon

the

NRS

Child

and

added

to

the

previously

selected

set

of

questionnaires

from

July

The

NRS

caregiver

has

been

created

in

this

study

following

the

example

of

the

NRS

child

which

was

created

by

Rosenfeld

et

al.

-LSB-

-RSB-

Finally

the

Dutch

version

of

the

OM

Functional

Status

Questionnaire

specific

-LRB-

OMFSQ

-LSB-

-RSB-

-RRB-

was

included

as

an

anchor

for

responsiveness

-LRB-

instrument

description

in

section

on

responsiveness

-RRB-

Questionnaire

application

Questionnaires

were

completed

in

a

randomly

selected

but

fixed

order

during

the

follow-up

assessments

to

prevent

possible

influence

of

order

effects

-LSB-

-RSB-

RAND

FSQ

Generic

and

Specific

NRS

Child

FFQ

TAIQOL

OMFSQ

NRS

Caregiver

For

all

questionnaires

higher

scores

indicate

the

presence

of

a

better

HRQoL

or

FHS

To

allow

comparisons

between

scores

on

the

questionnaires

all

scores

were

linearly

transformed

into

Scales

For

each

questionnaire

the

evaluation

period

was

the

weeks

before

completion

Statistical

analyses

Floor

and

ceiling

effects

Floor

and

ceiling

effects

were

estimated

for

the

baseline-assessment

of

each

questionnaire

by

calculating

percentages

of

respondents

that

had

minimum

and

maximum

scores

respectively

Questionnaires

should

exhibit

minimal

floor

and

ceiling

effects

to

be

optimally

able

to

detect

difference

and

change

Reliability

First

internal

consistency

was

assessed

by

calculating

Cronbach

's

alpha

which

should

be

above

for

each

questionnaire

or

subscale

-LSB-

-RSB-

Inter-item

correlations

of

questionnaires

were

assessed

to

reveal

item

redundancy

or

hidden

subscales

that

may

erroneously

yield

a

high

overall

Cronbach

's

alpha

For

the

assessment

of

test

retest

reliability

a

subset

of

caregivers

attending

the

outpatient

ward

from

February

to

June

-LRB-

n

-RRB-

was

given

a

second

set

of

the

same

questionnaires

-LRB-

retest

-RRB-

to

complete

at

home

The

time

frame

for

completion

was

weeks

after

the

first

set

of

questionnaires

was

filled

out

during

the

outpatient

visit

at

months

-LRB-

first

test

-RRB-

Children

with

AOM

at

the

first

test

were

excluded

since

differences

in

their

scores

could

be

due

to

real

change

and

interfere

with

the

assessment

of

reliability

For

the

assessment

of

test

retest

reliability

a

time-interval

of

days

is

often

considered

long

enough

to

prevent

recall

bias

and

too

short

for

relevant

change

to

occur

in

chronic

disease

-LSB-

-RSB-

Test

retest

reliability

was

computed

as

the

intraclass

correlation

coefficients

-LRB-

ICC

-RRB-

between

the

two

sets

of

questionnaires

An

ICC

of

was

considered

the

required

minimum

for

good

reliability

-LSB-

-RSB-

Construct

and

discriminant

validity

In

order

to

demonstrate

construct

validity

hypotheses

were

formulated

about

the

strength

of

correlations

between

questionnaires

A

higher

percentage

of

correct

predictions

indicates

stronger

support

for

construct

validity

A

correlation

of

was

defined

as

weak

as

moderate

and

as

strong

-LSB-

-RSB-

The

correlation

between

FSQ

Generic

and

NRS

Caregiver

was

predicted

to

be

weak

since

they

were

expected

to

assess

two

different

constructs

Moderate

to

strong

correlations

-LRB-

r

-RRB-

were

predicted

between

RAND

and

NRS

Caregiver

Moderate

to

strong

correlations

were

also

expected

between

and

FSQ

Specific

NRS

Child

NRS

Caregiver

and

FFQ

as

all

assess

otitis

media-related

HRQoL

or

FHS

The

correlation

between

FSQ

Generic

and

FSQ

Specific

was

expected

to

be

strong

-LRB-

r

-RRB-

The

remaining

correlations

among

the

questionnaires

were

expected

to

be

moderate

-LRB-

Table

-RRB-

Additionally

correlations

between

questionnaire

scores

and

frequency

of

physician

visits

for

upper

respiratory

tract

infections

as

well

as

frequency

of

AOM

episodes

in

the

preceding

months

were

calculated

Since

distributions

of

questionnaire

scores

were

skewed

correlations

were

assessed

using

Spearman

's

rho

Discriminant

validity

was

assessed

by

dichotomizing

the

study

participants

in

children

with

versus

or

more

episodes

of

otitis

media

per

year

Based

on

clinical

and

immunological

data

children

with

or

more

AOM

episodes

per

year

are

considered

as

otitis

prone

-LSB-

-RSB-

reflecting

a

sub-group

with

an

increased

rate

of

upper

respiratory

tract

infections

related

medical

interventions

and

compromised

child

functioning

-LSB-

-RSB-

It

was

assumed

that

this

group

would

perform

significantly

poorer

than

children

with

otitis

media

episodes

per

year

on

all

questionnaires

which

was

assessed

by

independent

sample

Mann

Whitney

tests

Responsiveness

Since

pneumococcal

conjugate

vaccination

showed

no

clinical

effectiveness

when

compared

to

the

control

vaccine

-LSB-

-RSB-

the

intervention

could

not

be

used

as

an

external

criterion

of

change

Data

of

both

vaccine

groups

were

pooled

instead

for

the

assessment

of

responsiveness

to

spontaneous

remission

The

clinical

experience

of

a

panel

of

experts

in

the

field

of

otitis

media

formed

the

basis

for

defining

a

reduction

of

or

more

episodes

of

AOM

per

child

per

year

as

the

external

criterion

for

change

while

a

reduction

of

episode

or

less

identified

no

change

Responsiveness

was

evaluated

for

two

intervals

from

to

months

and

from

to

months

follow-up

The

observed

change

in

these

episodes

was

multiplied

by

-LRB-

-RRB-

to

get

the

estimated

change

per

year

The

first

step

in

the

assessment

of

responsiveness

was

to

explore

the

ability

of

questionnaires

to

detect

change

at

all

i.e.

its

sensitivity

to

change

Secondly

meaning

and

clinical

relevance

of

the

change

score

were

determined

in

accordance

with

recent

recommendations

using

both

distribution

and

anchor-based

methods

-LSB-

-RSB-

Distribution-based

methods

express

the

amount

of

change

relative

to

the

amount

of

random

variance

of

a

questionnaire

-LSB-

-RSB-

Some

ratios

of

change

to

random

variance

have

often

empirically

been

found

to

represent

a

minimally

clinical

important

difference

Anchor-based

methods

enhance

interpretability

of

changes

in

questionnaire

scores

by

linking

meaningful

and

clinically

relevant

indicators

to

change

scores

-LSB-

-RSB-

The

assessment

of

responsiveness

will

be

described

in

further

detail

below

Sensitivity

to

change

Sensitivity

to

change

was

assessed

by

calculating

both

the

statistical

significance

of

change

scores

using

a

paired

t-test

or

Wilcoxon

matched

pairs

test

-LRB-

for

skewed

distributions

-RRB-

and

effect

sizes

-LRB-

ES

-RRB-

using

Guyatt

's

responsiveness

statistic

-LSB-

-RSB-

for

changed

subjects

In

this

statistic

the

observed

change

that

occurred

in

changed

subjects

is

related

to

the

observed

random

change

or

random

error

in

unchanged

subjects

A

parametric

effect

size

was

computed

as

mean

change

score

changed

group/SD

-LRB-

change

score

unchanged

group

-RRB-

a

nonparametric

effect

size

was

computed

as

median

change

score

changed

group/interquartile

range

-LRB-

change

score

unchanged

group

-RRB-

-RRB-

According

to

the

benchmarks

of

Cohen

-LSB-

-RSB-

an

effect

size

of

represents

a

small

change

a

moderate

change

and

or

higher

represents

a

large

change

For

skewed

distributions

Wilcoxon

matched

pairs

test

was

used

to

calculate

the

significance

of

change

Clinical

relevance

of

change

scores

The

interpretation

of

change

is

often

assessed

by

calculating

the

minimally

clinical

important

difference

-LRB-

MCID

-RRB-

which

is

the

smallest

difference

in

a

questionnaire

total

or

domain

score

that

patients

perceive

as

beneficial

-LSB-

-RSB-

The

MCID

can

be

computed

from

both

distribution-based

and

anchor-based

methods

Several

estimates

of

the

MCID

from

both

methods

are

reported

to

assess

the

likely

range

of

the

MCID

for

each

questionnaire

Interpretation

of

change

distribution-based

methods

-LRB-

ES-MCID

and

SEM-MCID

-RRB-

The

main

distribution-based

methods

for

assessing

the

MCID

are

the

Effect

Size

and

the

Standard

Error

of

Measurement

A

change

in

questionnaire

scores

corresponding

to

the

effect

size

of

Guyatt

's

Responsiveness

Statistic

with

values

of

has

been

found

to

be

consistent

with

other

-LRB-

empirical

-RRB-

estimates

of

the

MCID

-LSB-

-RSB-

In

this

study

the

change

in

questionnaire

scores

corresponding

with

an

effect

size

of

is

used

as

benchmark

of

MCID

-LRB-

ES-MCID

-RRB-

A

change

of

one

Standard

Error

of

Measurement

-LRB-

-RRB-

has

empirically

been

found

to

correspond

with

the

MCID

of

a

questionnaire

-LSB-

-RSB-

The

of

a

questionnaire

links

reliability

of

an

instrument

to

the

variance

of

scores

in

a

population

as

reflected

in

its

formula

SD

-LRB-

change

scores

unchanged

subjects

-RRB-

-LRB-

-RRB-

It

is

an

estimate

of

what

part

of

the

observed

change

may

be

due

to

random

measurement

error

by

including

distribution

of

scores

-LRB-

SD

-RRB-

and

instrument

reliability

-LRB-

ICC

-RRB-

Change

larger

than

the

SEM

therefore

is

considered

real

change

The

SEM

is

here

used

as

an

estimate

of

the

MCID

-LRB-

SEM-MCID

-RRB-

The

ES-MCID

and

SEM-MCID

support

the

interpretation

of

measured

change

as

they

reflect

the

smallest

change

that

is

substantially

larger

than

the

random

variability

in

the

study

population

which

is

based

on

the

standard

deviation

of

the

unchanged

subjects

Interpretation

of

change

anchor-based

methods

Anchor-based

methods

require

an

independent

standard

the

anchor

that

in

itself

is

easily

interpretable

and

that

is

at

least

moderately

correlated

-LRB-

-RRB-

with

the

questionnaire

being

assessed

Changes

in

questionnaire

scores

were

compared

with

change

in

two

clinically

relevant

anchors

the

AOM

frequency

-LRB-

incidence

of

AOM

episodes

per

child

-RRB-

and

the

AOM

severity

assessed

with

the

Dutch

version

of

the

OM-Functional

Status

Questionnaire

specific

-LRB-

OM-FSQ

-RRB-

-LSB-

-RSB-

The

OM-FSQ

was

used

as

an

anchor

for

responsiveness

It

consists

of

three

questions

assessing

clinical

AOM

severity

earache

sleeping

problems

and

other

signs

and

symptoms

-LRB-

irritability

fussiness

fever

-RRB-

that

may

indicate

the

presence

of

an

ear

infection

In

our

population

the

OM-FSQ

demonstrated

high

internal

consistency

-LRB-

Cronbach

's

α

-RRB-

and

good

test

retest

reliability

-LRB-

ICC

-RRB-

The

OM-FSQ

correlated

weakly

with

the

NRS

Child

-LRB-

Spearman

's

rho

-RRB-

but

moderately

with

the

RAND

-LRB-

-RRB-

FSQ

Generic

-LRB-

-RRB-

and

NRS

Caregiver

-LRB-

-RRB-

and

strongly

with

the

FSQ

Specific

-LRB-

-RRB-

-LRB-

-RRB-

and

FFQ

-LRB-

-RRB-

In

relation

to

the

AOM

frequency

an

expert

panel

in

the

field

of

otitis

media

considered

a

reduction

of

episodes

per

year

as

a

small

or

minimal

clinically

important

change

whereas

a

change

of

to

episodes

per

year

was

considered

moderate

to

large

In

the

study

of

Alsarraf

et

al.

-LSB-

-RSB-

the

OM-FSQ

total

score

was

about

on

a

scale

of

during

an

episode

of

AOM

increasing

to

at

weeks

and

to

at

weeks

after

an

episode

of

AOM

with

higher

scores

reflecting

less

severe

ear-related

symptoms

Therefore

a

score

change

of

on

the

scale

of

the

OM-FSQ

in

the

current

population

was

considered

to

be

a

small

clinically

relevant

change

in

AOM

severity

a

score

change

of

as

moderate

to

large

Anchor-based

estimates

of

the

MCID

were

computed

as

the

change

in

questionnaire

scores

associated

with

small

changes

in

AOM

frequency

and

OM-FSQ

For

all

analyses

the

Statistical

Package

for

the

Social

Sciences

-LRB-

SPSS

-RRB-

version

was

used

Results

Population

The

population

characteristics

summarized

in

Table

show

that

the

majority

of

children

suffered

from

or

more

AOM

episodes

per

year

and

half

of

them

suffered

from

chronic

airway

problems

or

atopic

symptoms

Most

children

had

undergone

one

or

more

ENT

surgeries

Overall

they

seemed

to

suffer

from

more

severe

disease

than

the

average

child

with

middle

ear

infections

as

stated

earlier

Table

of

study

population

Mean

or

-LRB-

n

-RRB-

SD

or

CIAge

-LRB-

months

-RRB-

-LRB-

-RRB-

Male

-LRB-

-RRB-

In

the

year

prior

to

inclusionNumber

of

AOM

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

or

-LRB-

-RRB-

Impaired

hearing

-LRB-

-RRB-

Language

or

speech

problems

-LRB-

-RRB-

History

ofChronic

airway

problems

or

atopic

symptoms

-LRB-

-RRB-

-LRB-

-RRB-

Tympanostomy

-LRB-

-RRB-

Other

ear

nose

and

throat

-LRB-

-RRB-

Antibiotic

-LRB-

-RRB-

Ever

had

-LRB-

-RRB-

at

inclusion

in

the

study

reported

by

the

caregiver

asthma

wheezing

hayfever

or

eczema

Floor

and

ceiling

effects

Generally

the

questionnaires

demonstrated

no

floor-effects

However

Table

shows

that

some

questionnaires

-LRB-

FSQ

Specific

and

FFQ

-RRB-

and

most

TAIQOL

subscales

showed

moderate

to

large

ceiling

effects

which

indicates

that

measurement

of

improvement

may

be

limited

while

it

may

actually

be

present

Table

and

ceiling

effects

internal

consistency

and

test

retest

reliability

of

the

questionnairesMinimum

score

-LRB-

-RRB-

Maximum

score

-LRB-

-RRB-

Internal

consistency

Cronbach

's

α

n

Test

retest

reliability

ICC

n

FSQ

FSQ

TAIQOLN.A.N.A

Positive

Problem

Communication

0.4530.880.82Disease-specificOM-60140.850

NRS

NRS

percentage

of

respondents

with

minimum

-LRB-

floor

effect

-RRB-

and

maximum

-LRB-

ceiling

effect

-RRB-

scores

n

for

the

TAIQOL

subscales

and

NRS

Caregiver

Intra-class

Correlation

Coefficient

Reliability

Cronbach

alpha

coefficients

were

adequate

to

high

-LRB-

range

-RRB-

for

the

TAIQOL

subscales

and

high

-LRB-

range

-RRB-

for

all

other

questionnaires

The

calculation

of

inter-item

correlations

revealed

no

hidden

subscales

or

item

redundancy

-LRB-

i.e.

individual

correlations

are

too

high

with

possible

loss

of

content

validity

-RRB-

-LRB-

Table

-RRB-

In

order

to

assess

test

retest

reliability

-LRB-

-RRB-

of

approached

caregivers

completed

a

second

set

of

questionnaires

of

which

-LRB-

-RRB-

were

completed

within

weeks

Seven

children

with

AOM

at

the

time

of

the

outpatient

visit

-LRB-

test

-RRB-

were

excluded

resulting

in

sets

for

analysis

-LRB-

Table

-RRB-

ICCs

were

moderate

to

high

for

all

questionnaires

-LRB-

range

-RRB-

and

most

TAIQOL

subscales

-LRB-

range

-RRB-

but

in

the

borderline

range

for

the

TAIQOL

subscale

Liveliness

-LRB-

-RRB-

Construct

and

discriminant

validity

Table

reflects

the

calculated

correlations

between

the

questionnaires

which

ranged

from

moderate

to

strong

for

the

RAND

FSQ

Generic

FSQ

Specific

and

FFQ

These

outcomes

show

that

-LRB-

-RRB-

of

the

hypothesized

correlations

were

correct

False

predictions

were

mainly

made

about

the

NRS

Child

and

NRS

Caregiver

as

the

correlations

with

other

questionnaires

were

generally

expected

to

be

at

least

moderate

but

were

found

to

be

weak

Disease-specific

questionnaires

-LRB-

NRS

Child

FFQ

and

NRS

Caregiver

-RRB-

showed

moderate

correlations

-LRB-

Spearmans

rho

-RRB-

with

the

frequency

of

AOM

episodes

in

the

preceding

months

Moderate

correlations

-LRB-

Spearmans

rho

-RRB-

were

also

found

between

global

FHS

-LRB-

RAND

-RRB-

and

the

disease-specific

questionnaires

on

the

one

hand

and

the

number

of

physician

visits

for

all

upper

respiratory

tract

infections

-LRB-

URTIs

-RRB-

a

more

global

indicator

of

illness

on

the

other

hand

-LRB-

Table

-RRB-

Table

validity

calculated

correlations

between

the

questionnaires

RANDFSQ

genericFSQ

childFFQNRS

FSQ

FSQ

NRS

NRS

Spearman

correlation

coefficients

were

calculated

appropriately

à

priori

predicted

correlations

are

bold-printedTable

validity

correlations

between

questionnaire

scores

and

frequency

of

physician

visits

for

URTI

and

of

AOM

episodes

Frequency

of

physician

visits

for

URTIFrequency

of

AOM

episodes

GenericRAND

FSQ

generic

#FSQ

specific

NRS

child

FFQ

NRS

caregiver

Spearmans

rho

correlation

coefficients

were

calculated

URTI

upper

respiratory

tract

infection

AOM

acute

otitis

media

All

correlations

P

except

for

-LRB-

P

-RRB-

and

-LRB-

P

-RRB-

The

RAND

FSQ

Generic

FSQ

Specific

and

FFQ

were

able

to

discriminate

between

children

with

moderately

recurrent

AOM

-LRB-

episodes

per

year

-RRB-

and

otitis-prone

children

with

severe

recurrent

AOM

-LRB-

or

more

episodes

per

year

-RRB-

-LRB-

Table

-RRB-

However

neither

the

two

numerical

rating

scales

-LRB-

NRS

Child

and

NRS

Caregiver

-RRB-

nor

the

otitis

media-related

subscales

of

the

TAIQOL

discriminated

between

these

two

groups

Table

validity

scores

of

children

with

vs.

or

more

AOM

episodes

in

the

preceding

year

AOM

episodes

AOM

episodesMann

Whitney

FSQ

FSQ

TAIQOL

Positive

Problem

Communication83.884.50.69Disease-specificOM-618.917

NRS

NRS

Calculated

by

Mann

Whitney

test

episodes

means

moderate

and

episodes

means

serious

AOM

Responsiveness

According

to

our

external

criterion

of

change

-LRB-

a

reduction

of

or

more

episodes

of

AOM

per

year

-RRB-

children

-LRB-

-RRB-

of

were

classified

as

changed

for

the

first

interval

-LRB-

months

-RRB-

and

children

-LRB-

-RRB-

for

the

second

interval

-LRB-

months

-RRB-

The

two

intervals

differed

considerably

regarding

the

reduction

of

AOM

incidence

during

the

months

follow-up

the

mean

incidence

per

child

decreased

by

AOM

episodes

whereas

during

months

follow-up

the

mean

decrease

was

episodes

-LSB-

-RSB-

Sensitivity

to

change

Sensitivity

to

change

expressed

as

significant

mean

change

and

effect

size

is

presented

in

Table

Except

for

most

TAIQOL

subscales

generic

as

well

as

disease-specific

questionnaires

yielded

significant

change

scores

during

both

follow-up

periods

ranging

from

to

on

a

scale

Absolute

change

scores

for

the

first

follow-up

period

generally

were

larger

-LRB-

range

-RRB-

than

for

the

second

period

-LRB-

range

-RRB-

Table

to

change

mean

change-scores

and

effect

sizes

for

changed

subjectsMean

change-scoreEffect

size

months

monthsn

P-valuen

P-valuen

n

FSQ

FSQ

TAIQOL

Problem

Positive

Communication2.90.121.70.320.160.11Disease-specificOM-616.6

NRS

NRS

calculated

with

paired

t-test

calculated

with

Guyatt

's

responsiveness

statistic

-LRB-

GRS

-RRB-

n

for

TAIQOL

subscales

and

NRS

Caregiver

follow-up

interval

n

for

TAIQOL

subscales

and

NRS

Caregiver

The

effect

sizes

for

the

generic

FHS

questionnaires

ranged

from

small

to

moderate

-LRB-

-RRB-

For

the

generic

TAIQOL

subscales

however

the

effect

sizes

were

lower

ranging

from

almost

zero

for

the

subscales

Appetite

-LRB-

-RRB-

Problem

behaviour

-LRB-

-RRB-

and

Positive

mood

-LRB-

-RRB-

to

small

for

Sleeping

-LRB-

-RRB-

and

Liveliness

-LRB-

-RRB-

Effect

sizes

for

the

disease-specific

questionnaires

were

moderate

to

large

-LRB-

-RRB-

For

the

questionnaires

the

ES

were

quite

similar

for

the

first

-LRB-

months

-RRB-

and

second

intervals

-LRB-

months

-RRB-

whereas

for

the

second

interval

absolute

change

scores

were

smaller

The

TAIQOL

was

excluded

from

further

analyses

on

the

interpretation

of

change

due

to

its

poor

sensitivity

to

change

Interpretation

of

change

distribution-based

methods

Minimally

clinical

important

differences

-LRB-

MCIDs

-RRB-

calculated

with

distribution-based

methods

are

presented

in

Table

During

the

first

interval

ES-MCIDs

using

an

effect

size

of

as

benchmark

were

somewhat

smaller

for

generic

questionnaires

ranging

from

to

on

a

scale

than

those

for

disease-specific

questionnaires

ranging

from

to

During

the

second

interval

however

ES-MCIDs

for

generic

and

disease-specific

questionnaires

were

comparable

-LRB-

range

-RRB-

indicating

that

for

both

types

of

questionnaires

similar

change

scores

are

needed

in

order

to

be

clinically

relevant

Table

distribution-based

indices

for

minimally

clinical

important

difference

-LRB-

MCID

-RRB-

using

Effect

Size

-LRB-

ES

-RRB-

and

one

standard

error

of

measurement

-LRB-

SEM

-RRB-

ES

MCID

SEM

MCID

months

FSQ

FSQ

specific7.45.67.85.9Disease-specificOM-68.34

NRS

NRS

MCID

using

effect

size

as

benchmark

follow-up

interval

MCID

using

one-SEM

as

benchmark

Except

for

the

NRS

Child

and

NRS

Caregiver

the

SEM-MCIDs

were

quite

comparable

with

the

ES-MCIDs

for

both

generic

and

disease-specific

questionnaires

Assuming

that

the

estimated

MCIDs

using

either

an

effect

size

of

or

a

one-SEM

as

benchmark

are

correct

our

results

suggest

that

the

range

for

the

distribution-based

MCID

for

generic

as

well

as

disease-specific

questionnaires

corresponds

with

a

change

of

points

on

a

scale

-LRB-

see

Table

-RRB-

Interpretation

of

change

anchor-based

methods

Changes

in

AOM

frequency

-LRB-

AOM

incidence

per

child

per

year

-RRB-

were

compared

to

the

magnitude

of

change

scores

on

the

FHS

and

HRQoL

questionnaires

A

small

change

of

AOM

episodes

which

is

considered

a

MCID

in

AOM

frequency

corresponded

with

points

change

on

a

scale

for

the

generic

questionnaires

-LRB-

Graph

-RRB-

and

with

points

change

for

disease-specific

questionnaires

except

for

the

NRS

Child

during

the

months

interval

with

points

change

Graph

Responsiveness

change-scores

per

questionnaire

corresponding

with

an

anchor-based

responsiveness

index

-LRB-

a

-RRB-

AOM

frequency

-LRB-

b

-RRB-

AOM

severity

-LRB-

OM-FSQ

score

-RRB-

Likewise

a

small

improvement

in

AOM

severity

corresponded

with

change

scores

ranging

from

points

on

a

scale

for

the

generic

questionnaires

and

with

change

scores

from

points

for

the

disease-specific

questionnaires

except

again

for

the

NRS

Child

with

and

points

change

-LRB-

Graph

-RRB-

Change

scores

corresponding

with

moderate

to

large

changes

in

AOM

frequency

and

severity

are

also

presented

in

Graph

b.

Comparing

small

change

with

moderate

to

large

change

shows

that

overall

the

larger

the

change

in

AOM

severity

or

frequency

the

larger

the

magnitude

of

the

change

score

on

the

questionnaires

However

this

trend

was

not

true

for

the

FSQ

Generic

and

the

disease-specific

NRS

Child

-LRB-

e.g.

a

small

change

in

AOM

severity

equalized

a

change

score

of

on

the

NRS

Child

whereas

a

moderate-large

change

equalized

a

change

score

of

-RRB-

Comparison

of

anchor

and

distribution-based

methods

Comparing

the

results

of

the

anchor-based

methods

with

those

of

the

distribution-based

methods

-LRB-

Graph

-RRB-

showed

that

generic

questionnaires

-LRB-

RAND

FSQ

Generic

and

FSQ

Specific

-RRB-

disease-specific

questionnaires

-LRB-

and

FFQ

-RRB-

and

the

NRS

Caregiver

yielded

quite

similar

estimates

of

the

MCID

for

both

methods

-LRB-

points

on

a

scale

for

distribution

and

points

for

anchor-based

methods

-RRB-

as

well

as

for

both

follow-up

periods

-LRB-

points

for

months

interval

points

for

months

interval

-RRB-

Averaging

these

distribution-based

and

anchor-based

estimates

of

MCID

yields

a

point-estimate

MCID

for

generic

questionnaires

of

-LRB-

range

-RRB-

and

for

disease-specific

questionnaires

of

-LRB-

range

-RRB-

on

a

scale

-LRB-

excluding

the

NRS

Child

as

it

had

much

larger

estimates

for

the

MCID

-RRB-

Graph

Minimally

clinical

important

difference

-LRB-

MCID

-RRB-

per

questionnaire

according

to

distribution-based

-LRB-

ES-MCID

and

SEM-MCID

-RRB-

and

anchor-based

-LRB-

AOM

frequency

and

AOM

severity

-RRB-

methods

Discussion

In

this

study

the

reliability

and

validity

of

generic

as

well

as

disease-specific

FHS

and

HRQoL

questionnaires

have

been

assessed

in

the

setting

of

a

RCT

concerning

children

with

recurrent

AOM

Most

generic

-LRB-

RAND

FSQ-Generic

and

FSQ-Specific

-RRB-

and

disease-specific

-LRB-

and

FFQ

-RRB-

questionnaires

showed

similar

good

to

excellent

reliability

and

adequate

construct

and

discriminant

validity

Construct

validity

was

poor

for

the

numerical

rating

scales

-LRB-

NRS

Child

and

NRS

Caregiver

-RRB-

and

discriminant

validity

was

low

to

moderate

for

both

NRS

and

the

subscales

of

the

TAIQOL

considered

to

be

otitis

media-related

-LRB-

Tables

and

-RRB-

Generic

as

well

as

disease-specific

questionnaires

proved

to

be

sensitive

to

change

in

the

incidence

of

AOM

-LRB-

Table

-RRB-

The

effect

sizes

were

found

to

be

ranging

from

small

to

moderate

for

both

generic

and

disease-specific

questionnaires

-LRB-

Table

-RRB-

The

MCIDs

for

generic

and

disease-specific

questionnaires

were

quite

similar

in

terms

of

responsiveness

-LRB-

Table

and

Figure

-RRB-

However

most

otitis

media-related

subscales

of

the

TAIQOL

the

only

true

HRQoL

questionnaire

proved

insensitive

to

change

Reliability

and

validity

Results

on

internal

consistency

and

test

retest

reliability

of

the

RAND

FSQ

Generic

FSQ

Specific

TAIQOL

and

found

in

this

study

were

comparable

with

those

of

previous

studies

using

these

questionnaires

-LSB-

-RSB-

The

consistency

of

results

across

different

paediatric

populations

supports

the

reliability

of

these

questionnaires

Similar

to

the

poor

discriminant

validity

in

this

study

of

the

otitis

media-related

TAIQOL

subscales

Fekkes

et

al.

-LSB-

-RSB-

found

the

TAIQOL

subscales

Problem

behaviour

Positive

mood

and

Liveliness

discriminated

neither

between

healthy

and

preterm

children

nor

between

healthy

and

chronically

ill

children

The

ability

of

the

RAND

FSQ

Generic

and

FSQ

Specific

to

discriminate

between

children

who

differed

in

AOM

frequency

on

the

other

hand

supported

their

discriminant

validity

previously

found

in

children

with

asthma

and

healthy

children

-LSB-

-RSB-

However

the

heterogeneity

of

methods

used

limits

the

comparability

of

results

regarding

validity

of

this

study

with

those

from

previous

studies

The

FFQ

and

NRS

Caregiver

are

newly

composed

questionnaires

to

assess

the

influence

of

recurrent

AOM

on

the

caregiver

and

family

The

FFQ

demonstrated

excellent

reliability

and

validity

meeting

the

minimal

required

reliability

coefficients

of

for

individual

assessment

-LSB-

-RSB-

The

strong

correlation

with

the

supports

its

complementary

usefulness

in

FHS

and

HRQoL

assessment

in

children

with

rAOM

Results

of

the

NRS

Caregiver

however

were

similarly

poor

as

those

observed

for

the

NRS

Child

which

needs

further

exploration

Their

global

single-item

assessment

of

HRQoL

may

be

too

crude

to

reflect

subtle

differences

in

HRQoL

-LSB-

-RSB-

On

the

other

hand

comments

of

the

caregivers

indicated

that

some

of

them

may

have

misunderstood

the

NRS

test-instructions

This

is

supported

by

the

fact

that

improvement

of

construct

validity

occurred

during

follow-up

assessments

presumably

due

to

learning

effects

after

reading

the

instructions

a

second

time

Responsiveness

So

far

little

attention

has

been

given

to

the

responsiveness

of

the

questionnaires

used

in

our

study

Only

Rosenfeld

et

al.

-LSB-

-RSB-

assessed

effect

sizes

for

the

-LRB-

using

a

standardized

response

mean

-RRB-

that

were

much

larger

-LRB-

-RRB-

than

the

ones

found

in

this

study

This

may

be

explained

by

the

use

of

different

identifiers

of

change

Rosenfeld

et

al.

-LSB-

-RSB-

used

an

intervention

with

expected

clinical

effectiveness

for

which

proxies

were

not

blinded

as

indicator

of

change

Since

pneumococcal

vaccination

proved

to

be

clinically

ineffective

-LSB-

-RSB-

treatment

could

not

be

used

as

an

external

criterion

for

change

Instead

a

change

of

or

more

AOM

episodes

per

year

was

used

as

criterion

to

identify

changed

subjects

In

addition

social

desirability

and

expectancy

bias

may

have

influenced

the

outcome

of

the

study

of

Rosenfeld

et

al.

-LSB-

-RSB-

Although

clinical

criteria

such

as

change

in

the

incidence

of

AOM

episodes

have

been

suggested

as

adequate

alternative

criteria

to

identify

change

-LSB-

-RSB-

the

choice

for

any

external

criterion

for

change

remains

somewhat

arbitrary

It

is

a

surrogate

measure

that

often

only

reflects

one

aspect

of

the

QoL

construct

The

poor

responsiveness

of

the

TAIQOL

subscales

Behavioural

problems

Positive

mood

and

Liveliness

for

example

may

indicate

that

our

clinical

indicator

is

less

suitable

as

external

criterion

for

change

in

emotional

and

behavioural

functioning

However

considering

the

overall

poor

responsiveness

of

the

twelve

TAIQOL

subscales

-LRB-

results

not

shown

-RRB-

it

seems

more

obvious

that

poor

responsiveness

in

itself

mainly

applies

for

these

three

subscales

as

well

Several

studies

have

supported

the

empirically

found

link

between

one

SEM

and

the

MCID

for

HRQoL

questionnaires

-LSB-

-RSB-

In

this

study

the

MCIDS

based

on

the

value

of

one-SEM

largely

corresponded

with

a

MCID

that

was

estimated

using

ES

as

a

benchmark

which

is

in

further

support

of

the

one-SEM

as

an

indicator

of

MCID

-LRB-

Table

-RRB-

However

it

should

be

realized

that

the

SEM

as

well

as

the

ES

are

both

only

statistical

indicators

which

relate

change

to

random

-LRB-

error

-RRB-

variance

Interestingly

the

anchor-based

methods

yielded

similar

estimates

for

the

MCIDs

-LRB-

Graphs

b

-RRB-

which

is

in

agreement

with

recent

observations

that

one-SEM

equals

anchor-based

MCID

in

patients

with

moderately

severe

illness

-LSB-

-RSB-

By

applying

and

comparing

multiple

methods

as

well

as

two

evaluation

periods

we

have

not

only

been

able

to

demonstrate

consistency

in

responsiveness

but

also

to

give

ranges

for

minimally

clinical

important

changes

instead

of

point-estimates

As

there

is

no

golden

standard

for

the

assessment

of

responsiveness

in

FHS

and

HRQoL

measurement

a

range

of

scores

gives

a

more

realistic

reflection

of

responsiveness

than

a

point-estimate

Point

estimates

can

be

misapplied

by

users

who

are

either

unaware

of

the

limited

precision

of

data

used

for

estimating

the

MCID

or

who

are

unaware

of

the

intrinsic

limitations

of

dichotomising

what

is

actually

a

continuum

Generic

versus

disease-specific

questionnaires

Although

generic

questionnaires

are

generally

expected

to

be

less

sensitive

to

differences

in

FHS

or

HRQoL

than

disease-specific

questionnaires

-LSB-

-RSB-

in

this

study

most

disease-specific

questionnaires

performed

only

marginally

better

than

the

generic

questionnaires

on

the

discriminant

validity

test

Likewise

the

responsiveness

of

generic

questionnaires

and

their

usefulness

as

measures

of

outcome

in

randomized

trials

has

been

questioned

-LSB-

-RSB-

Although

in

some

studies

generic

measures

indeed

were

found

to

be

less

responsive

to

treatment

effects

than

specific

measures

-LSB-

-RSB-

other

studies

did

find

comparable

responsiveness

-LSB-

-RSB-

In

this

study

only

the

smaller

effect

sizes

for

the

FSQ

Generic

and

FSQ

Specific

may

indicate

that

sensitivity

to

responsiveness

of

generic

questionnaires

is

somewhat

poorer

than

that

of

disease-specific

questionnaires

Possibly

this

higher

sensitivity

at

the

start

of

the

study

reflects

the

higher

incidence

of

symptoms

and

functional

limitations

that

are

specific

to

AOM

whereas

during

the

study

AOM

incidence

decreases

and

consequently

AOM

symptoms

become

less

prominent

compared

to

other

health

problems

Overall

the

generic

questionnaires

appeared

to

be

as

sensitive

to

clinical

change

as

disease-specific

questionnaires

except

for

the

TAIQOL

For

the

FSQ

Generic

and

FSQ

Specific

but

not

for

the

RAND

which

assesses

general

health

perceptions

sensitivity

to

differences

and

change

in

FHS

could

be

explained

by

their

content

as

they

include

many

physical

and

emotional

behaviour

items

that

may

be

affected

by

rAOM

The

more

relevant

a

questionnaire

is

to

a

particular

condition

the

more

sensitive

it

is

likely

to

be

The

sensitivity

of

the

RAND

assessing

general

health

and

resistance

to

illness

may

indicate

that

it

meets

the

perceptions

of

the

caregivers

of

children

with

rAOM

in

thinking

that

their

overall

health

is

worse

compared

with

other

children

It

also

may

reflect

the

significant

co-morbidity

like

chronic

airway

problems

and

atopic

symptoms

in

the

study

population

-LRB-

Table

-RRB-

The

reasons

for

the

poor

performance

of

the

TAIQOL

with

regard

to

both

discriminant

validity

and

sensitivity

to

change

are

not

obvious

Possibly

the

subscale

scores

represent

each

an

aspect

of

HRQoL

that

is

too

limited

to

be

sensitive

to

differences

or

change

Combining

the

subscales

to

more

comprehensive

constructs

may

then

improve

sensitivity

In

addition

each

item

of

the

TAIQOL

consists

of

two

questions

a

question

about

FHS

is

followed

by

the

request

to

rate

the

child

's

well-being

in

relation

to

this

health

status

Response

shift

bias

may

have

modified

the

caregivers

expectations

about

how

their

child

feels

in

line

with

the

child

's

changing

health

that

is

caregivers

may

rate

their

child

's

well-being

as

better

than

it

actually

is

as

they

adapt

to

the

situation

Studies

on

factors

that

may

influence

sensitivity

to

change

or

responsiveness

besides

the

type

of

questionnaire

-LRB-

generic

versus

disease-specific

-RRB-

such

as

questionnaire

structure

and

content

disease

severity

co-morbidity

and

other

population

characteristics

are

needed

Bias

and

generalisibility

There

are

several

issues

that

need

to

be

considered

when

interpreting

the

current

results

First

frequency

of

AOM

episodes

at

enrolment

was

based

on

proxy

report

whereas

during

the

trial

only

physician-diagnosed

episodes

were

counted

The

number

of

AOM

episodes

in

the

year

prior

to

inclusion

is

likely

to

be

overestimated

by

proxies

-LSB-

-RSB-

resulting

in

the

underestimation

of

HRQoL

change

scores

because

they

may

have

evaluated

the

situation

as

worse

than

it

objectively

was

in

the

first

place

However

if

such

a

recall-bias

regarding

AOM

frequency

was

in

fact

present

it

may

also

have

influenced

caregivers

reflection

on

subjective

measures

such

as

FHS

and

HRQoL

which

results

in

realistic

or

even

overestimated

change

scores

However

estimating

responsiveness

for

the

interval

of

months

in

which

AOM

frequency

was

not

affected

by

recall

bias

since

al

episodes

were

physician

diagnosed

yielded

similar

results

This

indicates

that

recall

bias

appears

not

to

have

influenced

responsiveness

substantially

Secondly

in

assessing

test

retest

reliability

two

different

modes

of

questionnaire

administration

were

used

completion

at

the

clinic

versus

home

completion

The

possible

intention

to

give

more

socially

desirable

answers

at

the

clinic

as

well

as

other

effects

such

as

being

more

distracted

when

filling

in

the

questionnaires

at

home

may

have

caused

differences

in

questionnaire

scores

between

the

first

-LRB-

test

-RRB-

and

second

-LRB-

retest

-RRB-

assessment

Although

this

impact

may

be

larger

for

single

item

questionnaires

such

as

the

NRSs

compared

to

multiple

item

questionnaires

and

might

explain

their

somewhat

smaller

ICCs

the

impact

on

the

ICCs

appears

to

be

small

Thirdly

during

the

trial

children

-LRB-

-RRB-

in

the

pneumococcal

vaccine

group

and

-LRB-

-RRB-

in

the

control

vaccine

group

were

lost

to

follow-up

One

child

switched

from

the

control

to

the

pneumococcal

vaccine

group

It

is

unlikely

that

these

small

numbers

of

dropouts

and

crossovers

influenced

the

trial

results

Furthermore

indices

of

validity

and

reliability

are

not

fixed

characteristics

of

FHS

and

HRQoL

questionnaires

but

are

influenced

by

the

study

design

intervention

and

study

population

in

particular

Our

study

population

had

significantly

severe

ear

disease

with

frequent

episodes

and

was

older

than

the

average

child

with

AOM

Assessment

of

reliability

and

validity

of

the

questionnaires

in

populations

with

less

severe

disease

may

present

more

ceiling

effects

and

lack

of

discriminant

validity

Therefore

the

results

of

this

study

should

only

be

generalized

to

paediatric

populations

with

moderately

to

seriously

severe

recurrent

acute

ear-infections

at

an

older

age

-LRB-

approximately

months

-RRB-

Finally

of

all

questionnaires

in

this

study

only

the

FFQ

demonstrated

a

reliability

that

meets

the

minimal

required

reliability

coefficients

for

individual

assessment

of

HRQoL

Although

some

authors

suggest

to

use

FHS

and

HRQoL

questionnaires

for

individual

assessment

in

clinical

practice

as

well

-LSB-

-RSB-

we

do

not

support

this

approach

It

is

suggested

that

routine

use

of

these

questionnaires

would

facilitate

detection

and

discussion

of

psychological

issues

and

help

guide

decisions

regarding

for

example

referral

However

considering

the

complexity

and

many

pitfalls

of

reproducibility

and

responsiveness

assessment

individual

use

of

HRQoL

and

FHS

questionnaires

as

part

of

the

follow-up

of

individuals

is

not

reliable

nor

valid

Recommendations

for

clinical

use

In

conclusion

generic

-LRB-

RAND

FSQ

Generic

and

FSQ

Specific

-RRB-

as

well

as

disease-specific

-LRB-

FFQ

and

to

a

lesser

extent

NRS

Caregiver

-RRB-

questionnaires

demonstrated

similar

and

high

reliability

and

adequate

construct

and

discriminant

validity

as

well

as

responsiveness

to

justify

use

in

clinical

studies

of

children

with

rAOM

However

NRS

as

used

in

this

study

may

be

less

adequate

for

assessment

of

HRQoL

in

this

population

The

TAIQOL

the

only

true

generic

HRQoL

questionnaire

unfortunately

showed

a

poor

discriminant

validity

and

sensitivity

to

change

needing

extensive

revision

before

further

use

in

clinical

outcome

studies

in

children

with

otitis

media

Using

both

a

generic

questionnaire

-LRB-

RAND

or

FSQ

-RRB-

and

the

in

clinical

studies

regarding

FHS

in

children

with

rAOM

is

recommended

as

it

would

combine

the

merits

of

both

generalisability

and

sensitivity

in

outcome

assessment

and

facilitate

head-to-head

comparisons

of

their

performance

in

various

paediatric

populations

with

OM

More

studies

are

needed

assessing

responsiveness

of

paediatric

QoL

questionnaires

by

multiple

distribution

as

well

as

anchor-based

methods

to

increase

our

appreciation

of

minimal

clinically

important

changes

in

various

paediatric

conditions

Further

studies

on

factors

such

as

questionnaire

structure

and

content

disease

severity

co-morbidity

and

other

population

characteristics

that

may

influence

sensitivity

to

change

or

responsiveness

besides

the

type

of

questionnaire

-LRB-

generic

versus

disease-specific

-RRB-

may

increase

our

appreciation

of

the

complex

dynamics

in

HRQoL

and

FHS

assessment

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

childhood infection
acute otitis media
functional health status
quality of life
reliability
validity
responsiveness