Session 8 anil_mehta

What constitutes a simple, reliable, message for outcome in a rare disease?

Cystic Fibrosis in Europe

Anil Mehta FRCP FRCPCHUniversity of Dundee, Scotland

An argument for governments from the ECFRG

For full details see: www.lancet.com (header section: audio; march20)

1. Historical Context podcast

2. European CF3. EU versus non EU (2003)

http://www.lancet.com/

50,000 years ago0−2Κ

∆F508, F508del or Phe508del

We are here

2010

-

10K10K

−10Κ

3 base pairs lost on chromosome 7 in a single gene cftr

Imagine the first modern human carrier of CF

Fibrogenicum (- us or - a)

-

-

---- - --- ---- -- - -- - -- -- --

Population50,000 years ago0−2Κ

ΑD

∆F508

We are survivors

2010

BCBC

-

10K10K

−10Κ

BUT: 3 in every 4 children in recent history died before their 6th birthday

75% died before 6 years of age

Genetically fit

Fibrogenicum super-survived dystentry, typhoid, pneumonia, TB, malaria etc

-

--

Today’s Europeans are the survivors of the 25%amongst which fibrogenicum is a super-survivor

F508deleted (recessive) CFTR carriage is common Randomly, every 50th - 80th European has it in single copy› this creates an unbiased source population sample › (genetic incidence of carriage is known in Europe)

BUT 2 copy carriage is lethal without therapy by 5yrs› Mortality-reducing Therapy is relatively affordable

› set the budget (see paper by Sims et al 2007 in the Lancet)

Phe508del/Phe508del

CZ

EuroCareCF partnered with European CF Registry ECFS

EU

Dundee

Data Centre

Legal

East data hub – Milan Macek

ECFSwww.eurocarecf.eu

Work Package 2

2006FP6

~30,000Registered

CF in Europe

Patients in 5-year Age Groups

12

1617

16

14

10

6

9

0

2

4

6

8

10

12

14

16

18

0-5y 5-10y 10-15y 15-20y 20-25y 25-30y 30-35y 35+y

Age Groups

Pe

rce

nta

ge

of

Pa

tie

nts

Each Bar shows a 5 year age band, except last one

0-5 yr 5-10 yr 10-15 yr 15-20 yr 20-25 yr 25-30 yr 30-35 yr >35 yr Total 3549 4676 4922 4795 3945 2768 1854 2584 29093

12% Pre-school

%

~1500 Missing pre-school

Firstschool

Teenagechildren

~3550


0

5

10

15

20

25

30

35

0-5y 5-10y 10-15y 15-20y 20-25y 25-30y 30-35y 35+y

Age Groups

Pe

rce

nta

ge

of

Pa

tie

nts


0

2

4

6

8

10

12

14

16

18

20

0-5y 5-10y 10-15y 15-20y 20-25y 25-30y 30-35y 35+y

Age Groups

Pe

rce

nta

ge

of

Pa

tie

nts


0

5

10

15

20

25

30

35

0-5y 5-10y 10-15y 15-20y 20-25y 25-30y 30-35y 35+y

Age Groups

Pe

rce

nta

ge

of

Pa

tie

nts


0

2

4

6

8

10

12

14

16

18

20

0-5y 5-10y 10-15y 15-20y 20-25y 25-30y 30-35y 35+y

Age Groups

Pe

rce

nta

ge

of P

atie

nts

Country A

Country B Country D

Country C

What Message does the pattern provide?

CF occurs randomly and yet expected pre-school number of about 5000 we only found 3500 Question: Where have the children gone?› Either they are undiagnosed› Or they have died

Let us look at when most CF patients are diagnosed

AIM: to find ‘remote’ answers of prognostic significance

Age at Diagnosis for all Patients

1112

8

6

11

7

9

6

43 2

54

2 21

0 0 0

9

0

2

4

6

8

10

12

14

0m 1m 2m 3m4-

6m7-

12m 1y 2y 3y 4y 5y6-

10y

10-1

5y

15-2

0y

20-3

0y

30-4

0y

40-5

0y50

+y

Not Rep

orted

Per

cen

tag

e o

f P

atie

nts

Let us expand the age at diagnosis….

Pre-schoolYet to be diagnosed >1500

Expanded age scale from birth

At Birth Diagnosis

Severe disease

All Europe patients

ALLCF

44%Common

Type

Phe508Del

homozygotes

96% by 10 yr98% by 15 years

2% Phe508delhomozygotes

Europe n=29093

Genotypes Reported - Percentages

11

29

60

F508del/F508del F508del/Other Other/Other


59

36

5



51

33

17


Country X Country ZCountry Y

F508del/F508del

F508del/Other

Other/Other

Minority Majority Even splitThis common form arose once, presents in childhood almost always creating a marker for CF diagnostic ability

and eliminates European geographic differences

Setting Up the Hypothesis on Demography

Nearly all should be diagnosed by 15 years› They have severe disease› They should have access to good care› They die if untreated

Very few will die if treated › …UK Data as an example

Males Females

Born in 1960-79

1989

Eur Respir J. 2007 29:522-6 …….Data from the UK100

How can the EU use this information at a country level to measure outcome?

Calculate the number with common CF (eliminate 98% of ascertainment bias)› Divide that Phe508del number by all CF

patients to get a percentage in childhood

Assume that <5% should die by 15 years of age (if care is good)

Look at the pattern of ages

Country 1 EU $£€

+++Country 2 NON-EU MONEY

~ +

See McCormick et al 2010 Lancet

57 54 54 5752 51

59

3940

2028 24

13

27

0 00

10

20304050

6070

0-5y

6-10

y

11-1

5y

16-2

0y

21-2

5y

26-3

0y

31-3

5y36

y+

Del

tF/A

ll

as p

erce

nt

% of severely affected patients by ageAll CF patients at same age

Country1 2

Severe-common CF to All-CF ratio by age

P<0.00001 P<0.000005


0

5

10

15

20

25

30

35

0-5y 5-10y 10-15y 15-20y 20-25y 25-30y 30-35y 35+y

Age Groups

Pe

rce

nta

ge

of

Pa

tie

nts


0

2

4

6

8

10

12

14

16

18

20

0-5y 5-10y 10-15y 15-20y 20-25y 25-30y 30-35y 35+y

Age Groups

Pe

rce

nta

ge

of

Pa

tie

nts


0

5

10

15

20

25

30

35

0-5y 5-10y 10-15y 15-20y 20-25y 25-30y 30-35y 35+y

Age Groups

Pe

rce

nta

ge

of

Pa

tie

nts


0

2

4

6

8

10

12

14

16

18

20

0-5y 5-10y 10-15y 15-20y 20-25y 25-30y 30-35y 35+y

Age Groups

Pe

rce

nta

ge

of P

atie

nts

Country A

Country B Country D

Country C

Age in years

0-<1

0

10-<

20

20-<

30

30-<

40

40-<

50

50-<

60

60-<

70

70-<

80

% c

ha

ng

e in

CF

po

pu

lati

on

s

ize

fro

m p

revi

ou

s d

ec

ad

e

-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

0

10

20

30

Rising population

Falling population

1. McCormick et al Lancet 2010: sets the target2. Sims et al Lancet 2007: sets the costs3. Jagger et al Lancet 2008: sets the context

Age in years

0-<1

0

10-<

20

20-<

30

30-<

40

40-<

50

50-<

60

60-<

70

70-<

80

% c

ha

ng

e in

Fd

el5

08/F

de

l50

8

CF

po

pu

lati

on

siz

e f

rom

pre

vio

us

de

ca

de

-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

0

10

20

30

All CFCommon Phe508deleted form

Western Europe,EU 2003

Non-EU

Now we have both a target and the costs

Rate of Change by succeeding decadeWe have a costed target

50,000 years ago0−2Κ

ΑD

∆F508

We are a CF legacy

2010

BCBC

-

10K10K

−10Κ

75% died before 6 years of age

Genetically fit

Fibrogenicum super-survived dystentry, typhoid, pneumonia, TB, malaria etc

-

--

We should thank patients with CF for suffering on our behalf

Treharne et al 2009 Febs Lett CF and smallpox

In Rare Diseases, Demographics are Powerful if…

Look at and use the age profile› Compare like with like apples with apples› i.e. common severe genes to measure the

severe/total ratios in childhood› i.e. divide severe by total and show this to be

stable (against first 15 years of life in CF)

Calculate the median age at death› Compare spread of medians with the most

robust registry data

Direct GeneticsX%X%

Environment

Z%Z%

Indirect genetics (mosaic of DNA inherited

from early man)Y%Y%

Inflamm bowelArthritis

SLE

Chromosome 6/Toll

Conclusion

Margaret Fraser…………………..………………….someone who knows data

Gita Mehta…………………………someone who knows project management

Milan Macek…………………someone who has a network (through genetics)

David Sheppard………………………………………….manage the resources

Funding……………………………………….………………EU FP6 EuroCareCF

www.eurocarecf.eu

www.cystic-fibrosis.org.uk

SKILL MIX IS THE KEY: J McCormick MD

RegisterSKILL MIX

Standards Legal Framework

http://www.cystic-fibrosis.org.uk/

EuroCareCFEuroCareCF Skill Mix – will differ

Single gene direct geneticsX%X%


from early man -still with us)Y%Y%

Environmental issues

Spectrum of disease presentationSpectrum of disease presentation

Z%Z%

None

Pre-natal death

Overview of Outcomes in rare diseases

1960-20002008- next 20 years

1970-2008

Single gene direct geneticsX%X%


from early man -still with us)Y%Y%

Environmental issues

Spectrum of disease presentationSpectrum of disease presentation

Z%Z%

None

Pre-natal death

Overview of Outcomes in rare diseases

1960-20002008- next 20 years

1970-2008

Session 8 anil_mehta

Health & Medicine