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Guideline Development Group (GDG)GP Chair: Dr Rubin MinhasLead Advisor : Prof Steve HumphriesLipidologists : Prof Andrew Neil, Dr Mary Seed, Dr Ian McDowellNurse Specialist/Genetic Counsellor : Ms Melanie WatsonDietician : Ms Helen Stracey Epidemiologist : Prof Margaret Thorogood Paediatrician : Dr Philip Lee GP : Dr Nadeem Qureshi Patient Representatives : Dawn Davies, Phil RowlandsCo-opted Experts : Tony Weirzbicki, Helen Williams, Aileen Parke, Richard Wray, Mahmoud Barbir, Anneke Lucassen
Royal College General Practictioners Core Team : Kathy DeMott, Leo Nherera, Meeta Kathoria, Beth Shaw, Gill Richie, Vanessa Nunes, Nancy Turnball
Issue date: August 2008
NICE clinical guideline 71 Developed by the National Collaborating Centre for Primary Car e
Identification and management of familial hypercholesterolaemia
http://www.nice.org.uk/nicemedia/pdf/CG071
Weirzbicki, et al BMJ 2008, Aug 27;337:1095
FH Guidelines in Practice : findings from the DH cascade and audit project and the pilot RCP audit
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,
HEARTUK FH Implementation GroupDermot Neely, Jonathan Morrell
• 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 NICE priorities
Key for GPs
Diagnosis
NICE evidence-based Guideline DNA testing is key recommendationWhat genes have mutations FH
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
DNA tests for FH - GOSH Regional DNA lab since 1997
LDLR - >1000 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
Can detect a mutation in >70% DFH. Current costs ~£400 and falling. Test of single mutation in relative ~ £100. Cholesterol test ~£10, ECG ~£60
0
100
200
300
400
500
UFH PFH DFH
Nu
mb
ers
Mu
t +
ve/-
ve
Mut-ve Mut +ve
p < 0.00001
51 394 190
Some (n=51) did not come with enough information to classify as Definite (n=190) or Possible FH (n=394) – (U-FH)
Detection Rate Data
Completed analysis on 635 proband samples from 6 sites
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
56.3%
28.4%
25.5%
What about no mutation patients?
Taylor et al Clin Genet 2009 in press
No mutation patients?
Technical reasons – No method detects all mutations. Sequencingmay give more complete coverage.
Genetic heterogeneity – May be 4th or 5th gene to be found.
Over-Diagnosis – Many patients do not have “true” FH. Familyhistory of hypercholesterolaemia and early CHD not very specific.
Detection Rate compares favourably with the 20-30% seen inBRCAI/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!
8.1
FH DIAGNOSIS IN FAMILY Y
4.17y
5.45y
4.4
Chol/TGmmol/l
Does Dad have FH?Can we find the genetic cause?
Can we use this information to see if either son has FH?
MI age35yrs
Make a detailed family tree
1
3
2
4
7.7/3.572y
7.8/1.968y
6.7/2.58.1/1.7
CONFIRMING FH DIAGNOSIS IN FAMILY Y
Confirm FH,Encourage
maintenance of good diet etc
Reassure
5
8.7/1.6
4.17y
5.45y
4.59y
5.76y
5.64.4
Chol/TGmmol/l
Is this true FH ? or is
it something else
“Familial Combined”
MI 59
FHFHCarriers ?Carriers ?
Using DNA assay
None carry mutation
*
* *
Used DNA techniques to Screen LDLR gene.
DNA change Pro664Leu
* Carrier LDLR mutation
Average for Children ~4.9. FH > 6.7
1
3
2
4
5.643y
Open symbol Normal Chol.
Filled symbol High Chol.
* Carrier of P644L
9.037y
3.15y
4.47y
*
FHcarrier?
*Dietary advice
statin later
Reassure others
N
5
?Birth
MI at 29yrs
30th %ile
GENETIC DIAGNOSIS IN FH FAMILY M
DNA improves Cost effectiveness of CT
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,
Efficiency of CT based on assumption that 50% of 1st degree relatives will be FH
Allows unambiguous diagnosis in relatives and for further cascading
• CT acceptable and feasible in UK Manchester/Oxford, DH Project, Hadfield et al 2008
• DNA - CT programme running in Netherlands for >10 years - Uman-Eckens et al 2002
• Is Cost Effective in terms of cost per Life years gained Marks et al Humphries BMJ
2000
Those with a detected mutation have higher rate of CHD – Humphries et al 2006
The Overlap Problem
FH
4.44 + 1.43mmol/l
FH vs. Not FH LDL levels, Ages 5-15
0.00%
2.00%
4.00%
6.00%
8.00%
10.00%
12.00%
14.00%
16.00%
0.6 1 1.4 1.8 2.2 2.6 3 3.4 3.8 4.2 4.6 5 5.4 5.8 6.2 6.6 7 7.4 7.8 8.2 8.6 9
LDL mmol/l
Not FH - Histogram
FH - Histogram
Not FH - Normal Dist
FH - Normal Dist
2.2mmol/l
4.6mmol/l
3.2mmol/l
False +ve = 8%False –ve = 15%
Collaboration with John Kastelein et al Amsterdam
Data on 2469 non-carriersand 825 carriers of family mutation. Analyse by age
DNA test avoids false –ve diagnosis
Gets worse with age!
Data from Starr et al 2008
DNA testing for identification of relatives
FH vs. Not FH LDL levels, Ages 5-15
0.00%
2.00%
4.00%
6.00%
8.00%
10.00%
12.00%
14.00%
16.00%
0.6 1 1.4 1.8 2.2 2.6 3 3.4 3.8 4.2 4.6 5 5.4 5.8 6.2 6.6 7 7.4 7.8 8.2 8.6 9
LDL mmol/l
Not FH - Histogram
FH - Histogram
Not FH - Normal Dist
FH - Normal Dist
2.2 mMol/l
4.6 mMol/l
As mean LDL-C rises with age in non-FH, overlap increases.DNA testing gives an unambiguous result
FH vs. Not FH LDL levels, Ages 45-54
0.00%
2.00%
4.00%
6.00%
8.00%
10.00%
12.00%
0.6 1 1.4 1.8 2.2 2.6 3 3.4 3.8 4.2 4.6 5 5.4 5.8 6.2 6.6 7 7.4 7.8 8.2 8.6 9
LDL mmol/l
5-15 years 45-54 years
False +ve = 8%, False –ve = 15% False +ve = 16%, False –ve = 46%
3.1 mMol/l
4.6 mMol/l
SB SB
4.2mmol/l
Starr et al Clin Chem Lab Med 2008
LDL-C Diagnostic Tables for 1º relatives
Age
KeyLikely FHUncertain
Unlikely FH
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
Cascade Method uses Trained and supported
“Genetic Nurses”
545
2452
1494990
5912110
500
1000
1500
2000
2500
3000
Index CasesParticipating
LivingRelatives
RelativesContacted
Relatives incatchment
RelativesTested
RelativesDiagnosed with
FH
66%
4.5 per Index Case
60%
36%
2.5 per Index Case
46% under 25 years
Detection rate using LDL- cut-offs
High acceptance rate, but low pick up of new FH due to out-of-catchment loss & low sensitivity of LDL-C cut-offs
Hadfield et al Ann Clin Chem 2009
DH FH Audit and Cascade project
DH-Cascade based on LDL-C cut-offs
545 index cases 591 relatives tested 211 “FH”1.1 / proband
FH Non-FH
35.7%
Mut +ve Mut -ve
DH-Cascade based on DNA diagnosis
100 index cases 296 relatives tested 166 Mut+ve2.9 / proband*
56.1%*
* p < 0.001 vs LDL-C arm
Improved detection rate in DNA cascade
Supports acceptance and utility of DNA based-cascade testing.
Hadfield et al Ann Clin Chem 2009, Taylor et al Clin Genet in press
NICE Health Economics Modeling of CT
1 LDL-Cholesterol only2 DNA only (only CT from mutation +ve probands)3 DNA where mutation plus LDL-C in DFH4 DNA where mutation plus LDL-C in DFH + PFH
Compared CT byCost/QALY
£1184£1463£1456£1376
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/CG071FullGuidelineAppendixE.pdf
Nehero, Thorogood, Neil, Humphries in prep
Audit of FH management in UK
On-going through Royal College of Physicians
Funding now identified for 2009-2010 national roll out
Humphries, Young, Potter et al
• 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.
• Patient management good
• Additional resources will be needed to manage increased numbers
• Funding DNA testing not widely available (1/14)
• No systematic CT - opportunistic only
• Only ad hoc shared care and pediatric arrangements
Key Findings
What do we need for an integrated effective FH Management Programme ?
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
Agreed and stable funding streams from commissioners
Programme must be a UK-wide Network
X
X
X
FH Research - the Time Line
Madonna Lisa Maria di GherardiniBorn Florence 1479Died 1526 age 37 years
Xanthoma?
1503 - 24 years
Xanthelasma?
Dequker et al 2004, Medical Archaelogy IMAJ
Challenge for next 10 years is to find the 100,000 FH patients in UK
Computer and IT needs
Key Requirements are:
Why a National Register?
Hadfield et al DH report 2007
• 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 is a National Register Needed ?
Efficiency of any CTrequires ability to contact
distant relatives.
Hadfield et al 2008
87%
13%
68%
32%
79%
21%
50%50%
62%
38%
• Examined in DH FH project
• On ave 34% 10 rels lived outside catchment area
• Highest % in London and SE
• Lowest contact success
DNA testing by postal mouthwash sample
Proposed by Wald et al BMJ 2007
What about Screening children?
Currently only CT from known adult index cases is tried and tested and demonstrated to be acceptable and cost effective
• 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.”
• No data on acceptability of the test to parents (and therefore take-up rate)
• No data on cost of the programme (and therefore cost- effectiveness)
• Overlap in Chol levels of FH and non-FH children is >> than used in model
Counter - Hadfield and Humphries BMJ 2007