Guideline Development Group (GDG)

1
FH Guidelines in Practice findings from the DH
cascade and audit project and the pilot RCP audit
Weirzbicki, et al BMJ 2008, Aug 273371095
Royal College General Practictioners Core Team
Kathy DeMott, Leo Nherera, Meeta Kathoria, Beth
Shaw, Gill Richie, Vanessa Nunes, Nancy Turnball
Guideline Development Group (GDG) GP Chair Dr
Rubin Minhas Lead Advisor Prof Steve
Humphries Lipidologists Prof Andrew Neil, Dr
Mary Seed, Dr Ian McDowell Nurse
Specialist/Genetic Counsellor Ms Melanie
Watson Dietician Ms Helen Stracey
Epidemiologist Prof Margaret Thorogood
Paediatrician Dr Philip Lee GP Dr Nadeem
Qureshi Patient Representatives Dawn Davies,
Phil Rowlands Co-opted Experts Tony Weirzbicki,
Helen Williams, Aileen Parke, Richard Wray,
Mahmoud Barbir, Anneke Lucassen
HEARTUK FH Implementation Group Dermot Neely,
Jonathan Morrell
CVG - Ros Whittall, Tina Hubbard, Sarah Leigh,
Royal Free Lipid Clinic - Devi Nair ICH - Gail
Norbury, Alison Taylor, Sian Tabrah, Karen Heath,
FH-Audit Gaye Hadfield, Brian Starr, Mabella
Farrer, Gretta Wood Simon Broome Study Group -
Andrew Neil, Gil Thompson, Nigel Capps, Ian
McDowell
John Betteridge, Rossi Naoumova, Mary Seed, Paul
Durrington,
http//www.nice.org.uk/nicemedia/pdf/CG071
2
Key NICE priorities
Diagnosis

• Use the Simon Broome criteria to diagnose FH
• All individuals should be offered a DNA test
  to confirm the diagnosis and to assist
• in Cascade testing of relatives
• CHD risk estimation tools such as those
  based on the Framingham algorithm
• should not be used because people with FH
  are already at a high risk of CHD.
• In children at risk of FH because of one
  affected parent the following diagnostic
• tests should be carried out by age of 10
  years
• - a DNA test if the family mutation
  is known
• - LDL-C measurement if mutation not known

Key for GPs
NICE evidence-based Guideline ? DNA testing is
key recommendation What genes have mutations ? FH
3
How is cholesterol removed from blood?
LIVER
Cholesterol used in building membranes of new
cells and to make important hormones
Circulates in blood as LDL particle (Bad
Cholesterol) wrapped up by large protein ApoB
apoB binds to receptor
Liver has special LDL-grabbing protein called a
Receptor 7 fingered hand
4
How is cholesterol removed from blood?
LIVER
Cholesterol used in building membranes of new
cells and to make important hormones
Circulates in blood as LDL particle (Bad
Cholesterol) wrapped up by large protein ApoB
LDL removed from Blood
apoB binds to receptor
Receptor internalised
Liver has special LDL-grabbing protein called a
Receptor 7 fingered hand
5
How is cholesterol removed from blood?
Receptor recycles to surface
LIVER
LDL degraded and cholesterol ? intestine
LDL removed from Blood
apoB binds to receptor
FH - lack of functional receptors, poor LDL
binding or high degradation in recycling
Most FH due to LDLR mutations, 5 by APOB, 2
PCSK9
6
DNA tests for FH - GOSH Regional DNA lab since
1997
LDLR - gt1000 mutations worldwide! (UK 200)
often need to screen
whole gene - EXPENSIVE
5 have large deletion need special method
APOB - Only 1 mutation CHEAP PCSK9 -
Only 1 common mutation CHEAP

• Fully accredited / Material archived.
• Reports sent to GPs/lipidologists within 6
  months.
• Established mutation web site
  (www.ucl.ac.uk/fh).
• Over last 2 years 635 proband and 296
  relative samples

Can detect a mutation in gt70 DFH. Current costs
400 and falling. Test of single mutation in
relative 100. Cholesterol test 10, ECG 60
7
Detection Rate Data
Taylor et al Clin Genet 2009 in press
Completed analysis on 635 proband samples from 6
sites
Some (n51) did not come with enough
information to classify as Definite (n190) or
Possible FH (n394) (U-FH)

• Conclusions
• Prevalence of PFH twice DFH
• As seen in Audit
• Significantly higher detection rate
• in DFH vs PFH
• As expected from published data
• Sizeable proportion of UFH have
• mutation

p lt 0.00001
28.4
56.3
25.5
51 394
190
What about no mutation patients?
8
No mutation patients?

• Technical reasons No method detects all
  mutations. Sequencing
• may give more complete coverage.
• Genetic heterogeneity May be 4th or 5th gene
  to be found.
• Over-Diagnosis Many patients do not have
  true FH. Family
• history of hypercholesterolaemia and early CHD
  not very specific.
• Detection Rate compares favourably with the
  20-30 seen in
• BRCAI/2 in familial breast cancer- also fewer
  unclassified variants

Need for pre-test counseling about detection rate
and that non-detection of a mutation does not
mean not FH!
9
FH DIAGNOSIS IN FAMILY Y
Chol/TG mmol/l
MI age 35yrs
4.4
8.1
Does Dad have FH? Can we find the genetic
cause? Can we use this information to see if
either son has FH?
4.1 7y
5.4 5y
Make a detailed family tree
10
CONFIRMING FH DIAGNOSIS IN FAMILY Y
2
1
MI 59
Is this true FH ? or is it something
else Familial Combined
Chol/TG mmol/l
7.7/3.5 72y
7.8/1.9 68y
3
4
5
5.6
4.4
6.7/2.5
8.1/1.7
8.7/1.6
Confirm FH, Encourage maintenance of good diet
etc Reassure
4.1 7y
5.4 5y
4.5 9y
5.7 6y
Using DNA assay None carry mutation
Average for Children 4.9. FH gt 6.7
11
GENETIC DIAGNOSIS IN FH FAMILY M
Open symbol Normal Chol. Filled symbol High
Chol. Carrier of P644L

2
1
MI at 29yrs
5.6 43y
9.0 37y
3
4
FH carrier?
3.1 5y
4.4 7y
30th ile
12
DNA improves Cost effectiveness of CT
Efficiency of CT based on assumption that 50 of
1st degree relatives will be FH

• A Mutation identifies best families for cascade
  testing - Humphries et al 2006
• Mutation ve probands 50 relatives
  will be FH
• Mutation -ve families only 25-30
  have high cholesterol,

Those with a detected mutation have higher rate
of CHD Humphries et al 2006

• CT acceptable and feasible in UK
  Manchester/Oxford, DH Project, Hadfield et al
  2008
• DNA - CT programme running in Netherlands for
  gt10 years - Uman-Eckens et al 2002
• Is Cost Effective in terms of cost per Life
  years gained Marks et al Humphries BMJ 2000

Allows unambiguous diagnosis in relatives and for
further cascading
13
The Overlap Problem
Collaboration with John Kastelein et al Amsterdam
Data on 2469 non-carriers and 825 carriers of
family mutation. Analyse by age
2.2mmol/l
Data from Starr et al 2008
4.6mmol/l
Gets worse with age!
FH
False ve 8 False ve 15
4.44 1.43mmol/l
DNA test avoids false ve diagnosis
14
DNA testing for identification of relatives
Starr et al Clin Chem Lab Med 2008
5-15 years
45-54 years
2.2 mMol/l
4.6 mMol/l
False ve 8, False ve 15
False ve 16, False ve 46
As mean LDL-C rises with age in non-FH, overlap
increases. DNA testing gives an unambiguous result
15
LDL-C Diagnostic Tables for 1º relatives
SB LDL-Cut-offs too high for Relatives

• Appropriate specificity and sensitivity
• for 1/500
• In 10 relatives probability ½
• NICE recommends to use diagnostic
• chart from Starr et al 2008
• Considerable grey aea have to
• retest and follow up

Key Likely FH Uncertain Unlikely FH
Cascade Method uses Trained and supported
Genetic Nurses
Age ?
16
Method used for Cascading
Hadfield et al Ann Clin Chem 2008

• A clinical diagnosis of FH is confirmed and a
  DNA test offered
• Index case invited to discuss family tracing with
  FH nurse
• Family pedigree is drawn and used to identify
  first degree relatives who should be offered
  testing
• Relatives are contacted directly by nurse or via
  index case
• Relatives are offered a point-of-care test at the
  clinic or at home (or are advised to visit their
  GP for a test)
• All relatives offered a DNA AND lipid test.
• When FH suspected GP asked to refer the patient
  to lipid clinic.

GP to 32 year old sister of FH patient Youre a
young woman you dont want to be taking tablets
for the rest of your life. Her cholesterol was
9.
Need GPs to identify and refer suspect FH and to
support CT in relatives.
17
Detection rate using LDL- cut-offs
DH FH Audit and Cascade project
4.5 per Index Case
Hadfield et al Ann Clin Chem 2009
2.5 per Index Case
66
60
36
High acceptance rate, but low pick up of new FH
due to out-of-catchment loss low sensitivity of
LDL-C cut-offs
18
Improved detection rate in DNA cascade
Hadfield et al Ann Clin Chem 2009, Taylor et al
Clin Genet in press
DH-Cascade based on LDL-C cut-offs
545 index cases ? 591 relatives tested ? 211 FH
35.7
1.1 / proband
Supports acceptance and utility of DNA
based-cascade testing.
19
NICE Health Economics Modeling of CT
Nehero, Thorogood, Neil, Humphries in prep
Compared CT by
Cost/QALY 1184 1463 1456 1376

1. LDL-Cholesterol only
2. DNA only (only CT from mutation ve probands)
3. DNA where mutation plus LDL-C in DFH
4. DNA where mutation plus LDL-C in DFH PFH

Compared to LDL-C only, use of DNA where a
mutation can be found plus using LDL for
identification of FH relatives in DFH PFH gave
most QALYs, with an Incremental Cost
Effectiveness Ratio of 2700/QALY
Compared to the NICE threshold of 20,000 this is
VERY GOOD VALUE !
http//www.nice.org.uk/nicemedia/pdf/CG071FullGuid
elineAppendixE.pdf
20
Audit of FH management in UK
Humphries, Young, Potter et al
On-going through Royal College of Physicians

• Obtained 1 yr funding from DH
• Established Steering group with reps from
  Colleges/stakeholders
• Developed web-based information capture system
  using NICE recs
• Trialled in 14 lipid clinics throughout
  England and Wales 248 notes
• Reported in June 2008.

Funding now identified for 2009-2010 national
roll out
21
What do we need for an integrated effective FH
Management Programme ?
Programme must be a UK-wide Network

• FH clinics run by Lipidologists
• Access to Pediatric input
• Trained Genetic FH Nurses for Cascade
  Testing
• DNA testing by accredited Genetics Labs
• National Register link families and avoid
  duplication
• Appropriate Computer software and
  connectivity
• Core Data set and agreed Quality Standards
• Audit of service

?
X
X
?
X
?
?
?
Agreed and stable funding streams from
commissioners
22
FH Research - the Time Line
Dequker et al 2004, Medical Archaelogy IMAJ
1503 - 24 years
Madonna Lisa Maria di Gherardini Born Florence
1479 Died 1526 age 37 years
Challenge for next 10 years is to find the
100,000 FH patients in UK
23
Computer and IT needs
Hadfield et al DH report 2007
Key Requirements are

• Draws Pedigree
• Collects agreed core (clinical and personal)
  data set
• Maintains high level of data confidentiality
  and security (encryption)
• Manages patient pathway (invite/follow up
  letters, appointments etc)
• Compatibility with healthcare IT structures
• Enables connectivity across SHA/Devolved
  province borders.

National Register is key NICE recommendation

• Dutch StOh CT programme have developed a
  package that achieves this.
• Commercially available and supported
• Package being trialled in Wales -Ian McDowell
  et al
• Will report on findings in next 6 months

Why a National Register?
24
Why is a National Register Needed ?
Hadfield et al 2008

• Examined in DH FH project
• On ave 34 10 rels lived outside
• catchment area
• Highest in London and SE
• Lowest contact success

Efficiency of any CT requires ability to contact
distant relatives.
DNA testing by postal mouthwash sample
25
What about Screening children?
Proposed by Wald et al BMJ 2007

• Screen all children for high cholesterol at
  the time of childhood immunisation,
• Test the parents of the identified children ?
  one with highest Chol has FH
• elegantly screens for FH in two generations
  simultaneously with the potential
• of preventing premature CHD in nearly everyone
  with the disorder.

Currently only CT from known adult index cases
is tried and tested and demonstrated to be
acceptable and cost effective