Elucigene FH20 and LIPOchip for the diagnosis of familial

hypercholesterolemia

The National Institute for health and Clinical Excellence (NICE): Diagnostic Assessment Review

(DAR)

Sharma P, Boyers D, Boachie C, Stewart F, Miedzybrodzka Z, Simpson W, Kilonzo M, McNamee P, Mowatt G

Elucigene and LIPOchip for the diagnosis of familial hypercholesterolemia.

Sharma P1, Boyers D1,2, Boachie C1,2, Stewart F2, Miedzybrodzka Z, Simpson W, Kilonzo M,

McNamee P, Mowatt G.

Presented by: Dwayne Boyers

1 Health Services Research Unit (HSRU); 2 Health Economics Research Unit (HERU),University of Aberdeen, Aberdeen, Scotland, U.K.

9th HTAi Annual Meeting26th June, 2012, Bilbao

Familial Hypercholesterolemia (FH)

• an autosomal dominant genetic condition– Heterozygous / Homozygous

– 3 Culprit genes (LDLR / PSCK9 / APOB)

• Increased risk of coronary heart disease

• Prevalence estimated at 1/500 in the UK– approx 100,000 people in the UK have FH

– Approx 85% of these remain undiagnosed

Tests considered

• Elucigene FH20 (Tepnel Diagnostics)

• LIPOchip v.10 (Progenika)– (i) Test processed at UK genetics lab

– (ii) Test conducted by manufacturer in Spain – if negative on LIPOchip, full LDLR sequencing

• Comprehensive Genetic Analysis (CGA)

– Indirectly recommended by NICE CG71

• LDL_C testing

– Current standard of care

Strategies modelledTest for Index case Test for Relative

Elucigene Targeted genetic test

LIPOchip (UK lab based test) Targeted genetic test

LIPOchip (sample sent to Spain) Targeted genetic test

Elucigene - MLPA Targeted genetic test

Elucigene - LIPOchip Targeted genetic test

Elucigene – LIPOchip - MLPA Targeted genetic test

Elucigene – LIPOchip - CGA Targeted genetic test

Elucigene - CGA Targeted genetic test

LIPOchip - MLPA Targeted genetic test

LIPOchip - CGA Targeted genetic test

CGA Targeted genetic test

LDL-C only LDL-C

Diagnostic accuracy: Elucigene FH20

Study Country Diagnosis Criteria Total, n Sensitivity

%

Specificity

%

Hooper 2009 Australia DFH Dutch 63 28.6 NC

Taylor 2010 England DFH Simon Broome 190 48.6 NC

Taylor 2010 England PFH Simon Broome 394 40.2 NC

Taylor 2010 England UFH Simon Broome 51 38.5 NC

Taylor 2010 England DFH/PFH/UFH Simon Broome 635 44.0 NC

Yarram 2010 England DFH/PFH/UFH Simon Broome 104 52.0 NC

Diagnostic accuracy: LIPOchip v.10

Study id LIPOchip version

Diagnosis Criteria Totaln

Sensitivity%

Specificity %

Palacios V 10 UK mutations

NR Simon Broome 126 78.5 NC

Callaway 2010 V 8 (251 mutations)

DFH or possible Simon Broome 22 33.3 93.8

Palacios 2010 V 8 (251 mutations)

NR Simon Broome 120 56.9 NC

Stef 2009 247 mutations NR Dutch MedPed 2,462 94.5 NC

Alonso 2009 195 mutations DFH, probable FH

Dutch criteria 808 78.0 NC

Diagnostic accuracy: LDL-C for index cases

Study ID Criteria Diagnosis Total, n Sensitivity % Specificity %

Damgaard 2005 Simon Broome Overall 408 90 29

Dutch 408 99 6

MedPed 408 54 83

Civeira 2008 Simon Broome Overall 825 93 28

Dutch Overall 825 88 18

MedPed Overall 825 91 53

Widhalm 2003 MedPed Adults 147 66 NC

Children 116 81 NC

Mabuchi 2005 LDLC> 4mmol/L 281 98 NC 

Diagnostic accuracy: LDL-C for relatives

Study ID Country Participants Total, n Sensitivity

%

Specificity

%

Lee 2010 UK Relatives 90 91.5 93.0

45-54years old group 80.0 70.0

Starr 2008 Netherlands First-degree relatives 3294 68.0 85.2

Denmark First-degree relatives 321 79.4 85.1

Norway First-degree relatives 1116 83.7 83.8

Wiegman

2003

Netherlands Children of definite FH

parents

611 96.0 NC

Diagnostic accuracy: Discussion

• Specificity of genetic tests assumed equal to 1

• Sensitivity of CGA assumed equal to 1 (Caveat?)– All cases will also receive LDL-C testing

• Uncertainty in estimates of sensitivity across studies

– Limited evidence on most recent versions of tests

– Fast changing environment - analysis at a snapshot in time

– LIPOchip – is MLPA required aswell?

Cost-effectiveness

• Cost-utility analysis (cost per QALY)– Cohort of 1000 index cases with suspected FH

– Cascade testing of at risk 1st, 2nd and 3rd degree relatives

• Time horizon: Patient life time

• Discounting: Costs and QALYs (3.5%)

• Perspective: UK NHS

Methods• Model informed by sensitivity and prevalence rates

• Costs – Diagnostics (MOLUs)

– Clinical management

– Drug treatment

– Reduced cardiovascular events

• QALYs– QALY gains from reduced mortality, reduced

cardiovascular events

Cost-effectiveness results

Test strategyTotalCosts

Total QALYs

Incremental costs (£)

Incremental QALYS

ICER (£/QALY)

Elucigene £43,371,985 36,653      

LDL-C £43,880,789 34,744 Dominated Dominated Dominated

Elucigene_MLPA £44,470,770 37,216 Ext. Dom Ext. Dom Ext. Dom

LIPOchip £46,506,304 38,240 Ext. Dom Ext. Dom Ext. Dom

Elucigene_Lipochip £46,578,004 38,240 Dominated Dominated Dominated

LIPOchip processed in Spain £47,298,810 38,668 £3,926,825 2,015 £1,949

LIPOchip_MLPA £47,597,529 38,803 Ext. Dom Ext. Dom Ext. Dom

Elucigene_LIPOchip_MLPA £47,669,229 38,803 Dominated Dominated Dominated

CGA £48,501,362 39,231 £1,202,552 563 £2,135

Elucigene_CGA £48,548,912 39,231 Dominated Dominated Dominated

LIPOchip_CGA £48,672,212 39,231 Dominated Dominated Dominated

Elucigene_Lipochip_CGA £48,743,912 39,231 Dominated Dominated Dominated

Cost-effectivenessacceptability curves

Discussion: Cost-effectiveness

• Little high quality evidence of test accuracy

• Rapidly evolving environment:– Tests constantly improving

– New versions of tests being developed

– Next generation sequencing

• Results and conclusions were robust a range of sensitivity analyses

Conclusions• Uncertainty surrounding true sensitivity of tests

• Elucigene and LIPOchip are not cost-effective as standalone tests for the detection of FH among index cases or for the identification of at risk relatives for cascade testing

• A strategy of CGA for index cases and targeted sequencing for relatives was deemed the approach with greatest diagnostic accuracy and was therefore the most cost-effective strategy

– Only at very high sensitivity (>70%) would Elucigene be a cost-effective pre-screen to CGA

• LIPOchip is unlikely to be cost-effective given concerns over the detection of deletions and duplications compared with MLPA

Thank you very much

Contact Details:

d.boyers@abdn.ac.uk

Useful links:

http://www.abdn.ac.uk/heru

http://www.abdn.ac.uk/hsru

http://www.nice.org.uk

http://www.hta.co.uk

This project was funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA) programme and commissioned on behalf of NICE. It will be published in full in the Health Technology Assessment journal series. Visit the HTA programme website for more details www.hta.ac.uk/project/2450. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the HTA programme, NICE, NIHR, NHS or the Department of Health.’