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Sharma P, Boyers D, Boachie C, et al. Elucigene FH20 and LIPOchip for the Diagnosis of Familial Hypercholesterolaemia: A Systematic Review and Economic Evaluation. Southampton (UK): NIHR Evaluation, Trials and Studies Coordinating Centre (UK); 2012 Mar. (Health Technology Assessment, No. 16.17.)

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Elucigene FH20 and LIPOchip for the Diagnosis of Familial Hypercholesterolaemia: A Systematic Review and Economic Evaluation.

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Appendix 19Protocol

Final protocol, 16th December 2010

1. Title of the project

The clinical and cost-effectiveness of Elucigene FH20 and LIPOchip for the diagnosis of familial hypercholesterolaemia: systematic review and economic evaluation.

2. Name of External Assessment Group (EAG) and project lead

Aberdeen Technology Assessment Group

Pawana Sharma

Research Fellow

Health Services Research Unit

3rd Floor

University of Aberdeen

Health Sciences Building

Foresterhill

Aberdeen

AB25 2ZD

Tel: 01224 559055

Email: ku.ca.ndba@amrahs.p

Reserve contact:

Graham Mowatt

Senior Research Fellow

Health Services Research Unit

3rd Floor

University of Aberdeen

Health Sciences Building

Foresterhill

Aberdeen

AB25 2ZD

Tel: 01224 552494

Email: ku.ca.ndba@ttawom.g

3. Plain English Summary

Familial hypercholesterolaemia (FH) is an inherited (genetic) condition resulting in raised levels of cholesterol in the blood. A person can either inherit the genetic defect from one parent (heterozygous FH) or from both parents (homozygous FH). In the UK heterozygous FH has a frequency of 1 in 500, affecting around 100,000 people in England, while homozygous FH is much rarer, with a frequency of 1 in one million.1 The condition is transmitted from generation to generation, so that the siblings or children of a person with FH have a 50% risk of inheriting the genetic defect.

The raised levels of cholesterol in the blood that characterise heterozygous FH lead to a greater than 50% risk of coronary heart disease (CHD) by the age of 50 in men and at least 30% risk in women by the age of 60.2 If untreated, around 50% of men will die before the age of 60.3 People with homozygous FH have a significantly poorer prognosis than those with heterozygous FH.

FH is generally characterised by the presence of increased levels of cholesterol concentration and clinical symptoms such as tendon xanthomata (yellowish skin lesions on the tendons of the hands and feet) and a family history of CHD. However there are variations in the time at which clinical signs and CHD appear.4 Tendon xanthomata, which are frequent but not always present, may be seen in the second decade of life, while CHD is usually present by the fourth decade. Diagnosis of FH by cholesterol concentration is not entirely reliable3 with a 10% risk of misdiagnosis.5 FH is an underdiagnosed condition, with at least 75% of people in the UK with heterozygous FH remaining undiagnosed.6

The NICE clinical guideline on identification and management of familial hypercholesterolaemia recommends that a diagnosis of FH should be made using the Simon Broome criteria, which include a combination of family history, clinical signs, cholesterol concentration and DNA testing, to improve diagnosis and early identification of FH.7 Cascade testing (a mechanism for identifying people at risk of FH by a process of family tracing) using a combination of DNA testing and low density lipoprotein cholesterol (LDL-C) concentration measurement is recommended to identify affected relatives of those individuals with a clinical diagnosis of FH.7 The aim of early identification is to reduce the risk of vascular diseases by starting treatment with cholesterol-lowering drugs such as statins and by allowing management by lifestyle changes and diet modification.8 The use of statins, even in lower doses than recommended, can reduce the risk of CHD in patients with FH.9 The standard method of DNA testing is comprehensive genetic analysis, which is the most complete genetic analysis generally available for FH within a diagnostic setting; however the process is slow and expensive (estimated at around £500 to £1000 per patient in the UK setting).10,11 Elucigene FH2012 and LIPOchip13 are recently developed rapid genetic testing kits that are designed to detect a more limited number of genetic mutations associated with FH that are commonly found in the UK population.

This systematic review will assess the clinical and cost-effectiveness of the Elucigene FH20 kit, LIPOchip, and comparators, for the diagnosis and cascade testing of FH.

4. Decision problem

4.1. Purpose of the decision to be made

The purpose of this appraisal is to address the following questions:

  1. What are the most effective and cost-effective strategies for confirming a diagnosis of FH in index individuals and for cascade testing of relatives?
  2. In cascade testing of relatives for mutations identified in index individuals by Elucigene FH20 or LIPOchip, would it be more cost-effective to use those tests rather than targeted gene sequencing?

4.2. Clear definition of the intervention

Elucigene FH20

The Elucigene FH20 kit (Gen-Probe Life Sciences, UK), using the principle of an amplification refractory mutation system (ARMS), is designed to detect 20 genetic mutations associated with FH that are commonly found in the UK population (see Table 1).14 These mutations, with a frequency ranging from 1.3% to 11.4%, were identified from a cohort study involving 400 patients in the UK with FH.15 Of the 20 mutations, 18 are found in the Low-density lipoprotein receptor (LDLR) gene, one in the Apolipoprotein B (APOB) gene and one in the Protein convertase subtilisin/kexin 9 (PCSK) gene (Table 1).14

TABLE 1. FH genetic mutations detected by Elucigene FH20.

TABLE 1

FH genetic mutations detected by Elucigene FH20.

By using ARMS, the Elucigene FH20 kit combines the amplification step and diagnostic steps,16 making the process faster. A limitation of the kit is that it only tests for 20 FH mutations. Worldwide approximately 1200 FH-causing mutations have been identified,17 of which over 200 have been reported in the UK population.

LIPOchip

LIPOchip (Progenika Biopharma, Spain) is an alternative genetic test designed to diagnose FH.13 LIPOchip is a tiered system that uses DNA array technology. The chip can detect point mutations, copy number changes and variation of number of copies of the LDLR gene. The current version (version 10) tests for 189 mutations in the LDLR, APOB and PCSK genes that are known to occur in the UK population.

The LIPOchip platform involves the following steps:

  1. Firstly, samples are analysed using the DNA array which is designed to detect 189 mutations in the LDLR and APOB genes.
  2. If the samples fail to detect these mutations they are analysed for large gene re-arrangements.
  3. If the first two steps fail to detect mutations then samples are analysed by automated sequencing of the LDLR.
  4. If all three of the above steps fail to detect mutations then the sample is confirmed as FH negative.
  5. Finally, the LIPOchip software generates a report containing information on the pathogenicity of detected mutations.

The manufacturer also offers a LIPOchip test processing service from its laboratory in Spain.

4.3. Populations and relevant subgroups

The populations considered are adults and children with a clinical diagnosis of FH (the index individuals/probands) based on the Simon Broome criteria, and, for cascade testing, first-, second- and third-degree biological relatives.

4.4. Place of the interventions in the treatment pathway(s)

The care pathway for this assessment is based on the NICE clinical guideline on the identification and management of FH.7

Index individuals

The assessment will investigate the effect of diagnostic strategies including Elucigene FH20 and/or LIPOchip for providing an unequivocal diagnosis of FH for those with a clinical diagnosis based on the Simon Broome criteria.

Cascade testing of relatives

The assessment will investigate the effect of diagnostic strategies including Elucigene FH20 for cascade testing to identify FH in the relatives of index individuals. The use of Elucigene FH20 for cascade testing will depend on the mutation detected in the index individual and the cost of targeted gene sequencing. (In index individuals with an identified genetic mutation, depending on the test used to detect the mutation, targeted gene sequencing will also be considered for cascade testing of relatives. In index individuals without an identified genetic mutation, cascade testing using LDL-C concentration measurement will be considered.)

A scenario encompassing a single test strategy (Elucigene FH20 or LIPOchip) that does not end in comprehensive genetic analysis for test negatives may not detect all cases of FH. In such a scenario there may be implications for test negative patients in terms of how their condition is managed.

4.5. Relevant comparators

Comprehensive genetic analysis

Comprehensive genetic analysis is defined as the most complete genetic analysis generally available for FH within a diagnostic setting and is expected to detect almost all known FH causing mutations. This analysis will include DNA sequence analysis of the promoter, all exons, the exon/intron boundaries and into 3ʹ untranslated region of the LDLR gene that will detect the majority (~88%) of detectable FH mutations, multiplex ligation-dependent probe amplification (MLPA)18 for each exon and the promoter region of the LDLR gene to detect deletions and duplications (~5% detectable FH mutations) plus analysis for the common APOB p.Arg3527Gin gene mutation (~5% FH mutations) and the PCSK9 p.Asp374Tyr gene mutation (~2% FH mutations).

Multiplex ligation-dependent probe amplification (MLPA) (MRC-Holland) is a commercial kit that enhances the molecular diagnosis of FH with an ability to detect large deletions and or duplications for each of the LDLR 18 exons.18 Comprehensive genetic analysis including DNA sequencing with MLPA is considered to be the ‘gold standard’ of genetic testing.

Targeted gene sequencing

Targeted gene sequencing (the genetic test for sequencing a specific part of the gene where a family mutation is found) may be used for cascade testing to identify FH in the relatives of index individuals. The use of targeted sequencing for cascade testing will depend on the test used to detect a genetic mutation in the index individual.

LDL-C concentration as part of the Simon Broome criteria

In UK a clinical diagnosis of FH should be made based on the Simon Broome criteria,7 which include a combination of family history of CHD, clinical signs such as tendon xanthomata, cholesterol concentration and DNA testing11,19 (Table 2). This approach categorises FH as ‘definite’ or ‘possible’. DNA based evidence was subsequently introduced into the criteria for provision of an unequivocal diagnosis of FH. However, around 10% of people with FH do not meet the Simon Broome criteria.

TABLE 2. Simon Broome diagnostic criteria.

TABLE 2

Simon Broome diagnostic criteria.

LDL-C concentration is usually estimated from a fasting blood sample using the Friedwald equation. Due to NHS commissioning arrangements of genetic tests, LDL-C concentration measurement is the main test currently used to diagnosis FH in index cases and for cascade testing of relatives.20 However, it has some limitations in terms of diagnostic accuracy, including:

  1. There is an overlap in LDL-C levels between affected and unaffected individuals, and the cut-offs used can result in diagnostic ambiguity in an estimated 15% of children (aged 5–15 years) and in nearly 50% of adults (aged 45–55 years).21,22
  2. In children who are at risk of FH, cholesterol levels may appear normal initially with the levels rising only later in life.23
  3. Girls generally have lower cholesterol concentration than boys at an early age but may go on to develop CHD in later years.22

Age adjusted LDL-C measurement has been found to give better clinical diagnosis of FH, with a sensitivity of 72% and specificity of 71%.24 The gender- and age-specific LDL-C criteria rather than the Simon Broome LDL-C criteria are the recommended criteria for cascade testing of relatives of index individuals.7

4.6. Key factors to be addressed

This systematic review will aim to:

  1. Assess the diagnostic accuracy and clinical effectiveness of Elucigene FH20, LIPOchip and comparators in confirming a diagnosis of FH in patients with a clinical diagnosis of FH.
  2. Assess the diagnostic accuracy and clinical effectiveness of Elucigene FH20 and comparators in cascade testing of relatives of index individuals with a confirmed diagnosis of FH.
  3. Estimate the costs of different diagnostic strategies for detecting FH in index individuals and for cascade testing of relatives of index individuals with a confirmed diagnosis of FH.

5. Report methods for assessing the outcomes arising from the use of the interventions

A systematic review of the evidence on Elucigene FH20 and LIPOchip for the diagnosis of familial hypercholesterolaemia will be undertaken following the general principles of the Centre for Reviews and Dissemination (CRD) guidance for conducting reviews in health care25 and NICE Diagnostics Assessment Programme interim methods statement.26

5.1. Inclusion and Exclusion criteria

Population

The populations considered are adults and children with a clinical diagnosis of FH (the index cases/probands) based on the Simon Broome criteria, and, for cascade testing, first-, second- and third-degree biological relatives of the index individual.

If the evidence allows, subgroup analysis will be undertaken on the performance of Elucigene FH20 and LIPOchip in ethnic populations.

Setting

The setting considered is secondary or tertiary care.

Interventions

The interventions considered are Elucigene FH20 and LIPOchip for index cases and Elucigene FH20 for cascade testing.

Comparators

The comparators for testing in index individuals are (i) comprehensive genetic analysis and (ii) LDL-C concentration measurement (Simon Broome criteria). The comparators for cascade testing of relatives are (i) targeted gene sequencing and (ii) LDL-C concentration measurement (gender- and age-specific criteria as recommended in NICE CG71).

Reference standard

The reference standard is comprehensive genetic analysis in combination with the Simon Broome Criteria.

Outcomes

The following outcomes will be considered:

  1. Test accuracy;
  2. Mutation detection rate – proportion of cases with an unequivocal diagnosis identified by Elucigene and LIPOchip;
  3. Proportion requiring comprehensive genetic analysis after Elucigene and LIPOchip; and
  4. Proportion of FH identified from cascade testing;

In any studies reporting the above outcomes the following outcomes will also be considered if reported:

  1. Acceptability of the tests; and
  2. Interpretability of the tests.

Studies reporting test accuracy must report the absolute numbers of true positives, false positives, false negatives and true negatives, or provide information allowing their calculation.

Study design

The following types of studies will be included:

  1. Direct (head-to-head) studies in which the index test, comparator test and reference standard test are done independently in the same group of people.
  2. Randomised controlled trials (RCTs) in which people are randomised to the index and comparator test(s) and all receive the reference standard test.

In case of insufficient evidence from direct and randomised studies, we will consider indirect (between-study) comparisons of the following types of study:

  1. Diagnostic cross-sectional studies comparing the index test or comparator test against a reference standard test.
  2. Case–control studies in which two groups are created, one known to have the target disease and one known not to have the target disease, where it is reasonable for all included to go through the tests.

Exclusion criteria

We will exclude the following types of report:

  • Preclinical and biological studies
  • Reviews, editorials and opinions
  • Case reports
  • Reports investigating technical aspects of a test

Non-English language reports may be excluded if the evidence base containing English-language reports is sufficiently large.

5.2. Search strategy

Extensive electronic searches will be conducted to identify reports of published and ongoing studies on Elucigene FH20 and LIPOchip for the detection and cascade testing of FH. The search strategies will be designed to retrieve all studies that assess the diagnostic accuracy and clinical effectiveness of the index, comparator and reference standard tests. Searches will be restricted to publications from 2000 onwards. Both full-text papers and recent conference abstracts will be sought. Potentially relevant non-English-language studies will be excluded and listed in an appendix to the review, unless the English-language evidence base is deemed to be insufficient in which case they will be included. Databases to be searched will include: MEDLINE, EMBASE, Science Citation Index, Biosis and the Cochrane Controlled Trials Register. A preliminary MEDLINE search strategy is shown in Appendix A and will be adapted for use in other databases.

A search for systematic reviews and other background publications will also be undertaken. Sources will include the Cochrane Database of Systematic Reviews, HTA Database and DARE.

Current research registers, including Current Controlled Trials, Clinical Trials and WHO International Clinical Trials Registry will be searched. Recent conference proceedings of key organisations will also be screened and will include the European Society of Human Genetics, American Association for Clinical Chemistry, International Atherosclerosis Society and Heart UK.

In addition, an internet search using Copernic Agent will be undertaken and will also include key professional organisations.

5.3. Data extraction strategy

Two reviewers will independently screen the titles (and abstracts if available) of all reports identified by the search strategy. Full-text copies of all studies deemed to be potentially relevant will be obtained, and two reviewers will independently assess them for inclusion. Any disagreements will be resolved by consensus or arbitration by a third party.

A data extraction form will be developed and piloted. One reviewer will extract details of study design, participants, index, comparator, reference standard tests and outcome data. A second reviewer will check the data extraction. Any disagreements will be resolved by consensus or arbitration by a third party.

Study data requested and received from the manufacturers that meet the inclusion criteria, and are received in time to be incorporated into the review, will be extracted and quality assessed in accordance with the procedures outlined in this protocol.

5.4. Quality assessment strategy

Two reviewers will independently assess the methodological quality of the included diagnostic studies. Any disagreements will be resolved by consensus or arbitration by a third party. Studies will not be included or excluded on the basis of methodological quality.

Various quality assessment tools will be used depending upon the type of studies included. For instance, included diagnostic studies will be quality assessed using QUADAS, a quality assessment tool developed for use in systematic reviews of diagnostic studies.27 The quality assessment tool will be adapted to make it more applicable to assess the quality of studies of tests for detecting FH.

5.5. Methods of analysis/synthesis

Analysis will focus on the ability of Elucigene FH20, LIPOchip and relevant comparators to detect FH. Where appropriate two by two tables will be extracted from each included study where information is provided on the numbers of true and false-positives and negatives for the index and/or comparator test compared with the reference standard for detecting those mutations that the index and/or comparator test are designed to identify. For each study we will attempt to calculate sensitivity, specificity, positive and negative likelihood ratios and diagnostic odds ratios and their confidence intervals.

Where appropriate and given sufficient information, we will use summary receiver operating characteristic (SROC) curves for the meta-analysis of data from studies reporting estimates of true and false-positives and negatives. This approach characterises the relationship between sensitivity and 1–specificity across studies and takes into account variation in the threshold for test positivity between studies. ROC curves will be generated, where possible, for each testing procedure. Where data are available, potential sources of heterogeneity will be investigated by extending the SROC regression models to include study level covariates. These potential sources of heterogeneity include characteristics of the population such as age, race, family history and whether the test is cascade testing.

Where appropriate, models will be fitted using the hierarchical summary receiver operating characteristic (HSROC) framework, which takes proper account of the diseased and non-diseased sample sizes in each study, and allows estimation of random effects for the threshold and accuracy effects, and testing of the impact of potential sources of heterogeneity. Estimates and their CI's for the average operating points, expressed as sensitivity, specificity and likelihood ratios will be obtained by combining these estimates.28

Average and ranges of feasible operating points will be identified on the fitted ROC points to convert ROC curve values into estimates of true positive and false positive rates which will serve as parameters within the economic model.

5.6. Methods for estimating quality of life – relevance to the decision analysis

Quality of life estimates used in the economic model will be informed by the current NICE guideline on the identification and management of familial hypercholesterolaemia7 and relevant literature searches together with clinical expert opinion as appropriate. As FH is a chronic disease requiring long-term care, we will extrapolate cost and QALY values over a life-time horizon and discount both cost and QALYs at a rate of 3.5% as recommended by NICE. This will use a linked evidence approach linking diagnostic accuracy of the various strategies with any potential changes in clinical management and thus life-time final health outcomes. The economic model informing current NICE guideline CG71 for treatment of FH will be validated and used to estimate the final treatment outcomes.

6. Report methods for synthesising evidence of cost-effectiveness

A systematic search for existing cost-effectiveness literature will be undertaken for diagnostic assessment strategies for the detection of genetic mutations causing familial hypercholesterolaemia.

6.1. Identifying and systematically searching published cost-effectiveness studies

Studies will be sought, reporting both costs and outcomes for diagnostic assessment strategies, from a systematic review of the literature. No language restrictions or limitations to searches will be imposed.

Databases to be searched will include MEDLINE, EMBASE, Science Citation Index, NHS EED, HTA Database, Health Management Information Consortium and the CEA Registry. In addition, reference lists of all included studies will be scanned to identify additional potentially relevant studies. A draft MEDLINE search strategy is appended and will be adapted for use in the other databases.

6.2. Evaluation of costs and cost-effectiveness

The evidence on costs and cost-effectiveness will be evaluated using the NICE Diagnostics Assessment Programme interim methods.26 An economic model will be developed to estimate the cost-effectiveness of each care pathway and link this to final treatment outcomes. Current NICE guideline CG71 will be used to inform the development of this approach.

6.3. Development of a health economic model

An economic evaluation of the cost-effectiveness of Elucigene, LIPOchip and identified comparators will be conducted. An economic model will be developed to determine which diagnostic and treatment strategy is the most cost-effective use of scarce NHS resources for genetic testing for FH among proband cases (identified using the Simon Broome criteria) and cascade testing of relatives.

The primary economic model output will be incremental cost per quality adjusted life year (QALY) gained associated with the use of a variety of genetic testing strategies for the detection of FH. A life-time horizon will be used in the model and costs and benefits will be discounted at a rate of 3.5% as recommended by NICE.29 The development of this economic model will be an iterative approach and it will be developed in a way that is adaptable to the analysis of new and emerging technologies. A possible scenario for the modelling is presented in Appendix B for the index cases and Appendix C for the cascade testing of their relatives (Appendix B, Appendix C). A range of diagnostic strategies will be explored initially for index patients with a clinical diagnosis based on the Simon Broome criteria. The model will further estimate the most cost-effective method of cascade testing for FH in first-, second-, and possibly third-degree relatives of the index patient. This too will be presented as incremental cost per QALY gained. We note that the diagnostic test used to detect the family mutation may not be the same as that used to detect the mutation in the index individual. This is due to the potential for cost savings among alternative cheaper tests for cascade testing (e.g. Elucigene) once the FH-causing family mutation has been identified. Our analysis will be from the perspective of the NHS as well as a personal social services perspective as appropriate. Any assumptions made in the modelling approach and parameter development will be taken primarily from the literature and supplemented by clinical expert opinion as appropriate/required.

Health related quality of life and QALY data for lifelong health outcomes have already been modelled in terms of management of FH in cascade testing and treatment strategy. These data will be validated, updated as necessary and used to help populate the economic model being developed. Any evidence on detection rates and diagnostic accuracy of the comparators will be sourced from the literature. As it is unlikely that a large evidence base exists in the literature, data will be supplemented by clinical expert opinion as required. A key challenge in terms of diagnostic accuracy of the genetic testing kits will be to generalise detection rates to the general UK population. It is likely that detection rates will vary depending on ethnicity and so this will need to be fully understood and uncertainties explored through sensitivity analyses. Data from the genetic bank held in London, together with manufacturer and clinical expert supplied input will be used to estimate detection rates of the different strategies.

Resource use and costs for detection are likely to be the major driver of the cost-effectiveness results. It will be important to fully incorporate all economic costs associated with testing and processing diagnostic samples for each treatment strategy and the range of scenarios required by the model. A combination of national resources such as NHS reference costs, the Personal Social Services Research Unit (PSSRU) and the British National Formulary (BNF) will be used as appropriate together with any other relevant sources of data identified. Costs of diagnostic kits will be sourced from the manufacturers and costs of processing samples sourced from a combination of manufacturer and clinical expert data. As obtaining test results is not time sensitive due to the clinical nature of FH, the base case analysis will assume genetic laboratories will batch test to gain maximum efficiency (i.e. minimum cost). The impact of operating testing procedures below maximum efficiency will be considered in model sensitivity analyses. A key challenge will be to generalise the cost of comprehensive genetic analysis across the UK, where various laboratories report different unit workload costs. The effect of alternative costing strategies will be explored through model sensitivity analyses.

The development of this economic model will be an iterative approach. As the evidence base changes and new evidence arises, the economic model structure and parameters will evolve to reflect this. We further suspect that the evidence base will be lacking for some of the model parameters. With this in mind, uncertainty in model parameters will be explored in terms of their outputs through a range of one-way and multi-way sensitivity analyses deemed appropriate as the modelling progresses. As we anticipate a lack of evidence to inform the model, we will explore parameter uncertainty through probabilistic sensitivity analyses, with the generation of cost-effectiveness acceptability curves illustrating this uncertainty graphically.

7. Handling information from the companies

Following a request for information, any ‘commercial in confidence’ data provided by a manufacturer and specified as such will be highlighted in blue and underlined in the assessment report (followed by an indication of the relevant company name e.g. in brackets).

8. Competing interests of authors

None

9. Timetable/milestones

MilestonesDate to be completed
Draft protocol24/11/10
Final protocol14/12/10
Progress reportw/c 18/02/11
Draft version of report01/04/11
Final version of report28/04/11

10. References

1.
Austin MA, Hutter CM, Zimmern RL, Humphries SE. Genetic causes of monogenic heterozygous familial hypercholesterolemia: A HuGE prevalence review. Am J Epidemiol. 2004;160:407–20. [PubMed: 15321837]
2.
Model of care: familial hypercholesterolaemia [document on the Internet] Perth: Office of Population Health Genomics, Department of Health, Government of Western Australia; 2008. [December 2010]. http://www​.genomics.health​.wa.gov.au/fh/docs​/FH_Model_of_care.pdf.
3.
Connor M, Ferguson-Smith M. Essential medical genetics. 5th ed. Oxford: Blackwell; 2010.
4.
Heath KE, Humphries SE, Middleton-Price H, Boxer M. A molecular genetic service for diagnosing individuals with familial hypercholesterolaemia (FH) in the United Kingdom. Eur J Hum Genet. 2001;9:244–52. [PubMed: 11313767]
5.
Koivisto PVI, Koivisto UM, Miettinen TA, Kontula K. Diagnosis of heterozygous familial hypercholesterolemia: DNA analysis complements clinical examination and analysis of serum lipid levels. Arterioscler Thromb. 1992;12:584–92. [PubMed: 1315570]
6.
Marks D, Thorogood M, Farrer JM, Humphries SE. Census of clinics providing specialist lipid services in the United Kingdom. J Public Health. 2004;26:353–4. [PubMed: 15598852]
7.
CG71 Identification and management of familiar hypercholesterolaemia [document on the Internet] London: National Institute for Health and Clinical Excellence; 2008. [October 2010]. http://www​.nice.org.uk​/nicemedia/live/12048/41700/41700.pdf.
8.
Shafiq N, Singh M, Kaur S, Khosla P, Malhotra S. Dietary treatment for familial hypercholesterolaemia. Cochrane Database of System Rev. 2010;(1) [PubMed: 20091526] [Cross Ref]
9.
Versmissen J, Oosterveer DM, Yazdanpanah M, Defesche JC, Basart DCG, Liem AH, et al. Efficacy of statins in familial hypercholesterolaemia: A long term cohort study. BMJ. 2009;338:223–6. [PMC free article: PMC2583391] [PubMed: 19001495]
10.
Centre for Evidence-based Purchasing. CEP 10034 Evidence review: rapid genetic testing for familial hypercholesteraemia. London: NHS Purchasing and Supply Agency; 2010.
11.
Marks D, Thorogood M, Neil HAW, Humphries SE. A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. Atherosclerosis. 2003;168:1–14. [PubMed: 12732381]
12.
Taylor A, Patel K, Tsedeke J, Humphries SE, Norbury G. Mutation screening in patients for familial hypercholesterolaemia (ADH) Clin Genet. 2010;77:97–9. [PubMed: 19843101]
13.
Alonso R, Defesche JC, Tejedor D, Castillo S, Stef M, Mata N, et al. Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform. Clin Biochem. 2009;42:899–903. [PubMed: 19318025]
14.
Taylor A, Martin B, Wang D, Patel K, Humphries SE, Norbury G. Multiplex ligation-dependent probe amplification analysis to screen for deletions and duplications of the LDLR gene in patients with familial hypercholesterolaemia. Clin Genet. 2009;76:69–75. [PubMed: 19538517]
15.
Humphries SE, Whittall RA, Hubbart CS, Maplebeck S, Cooper JA, Soutar AK, et al. Genetic causes of familial hypercholesterolaemia in patients in the UK: Relation to plasma lipid levels and coronary heart disease risk. J Med Genet. 2006;43:943–9. [PMC free article: PMC2563208] [PubMed: 17142622]
16.
Lo YMD. The amplification refractory mutation system. In: Lo YMD, editor. Clinical applications of PCR. Totawa, NJ: Humana; 1998. pp. 61–70.
17.
Leigh SEA, Foster AH, Whittall RA, Hubbart CS, Humphries SE. Update and analysis of the university college London low density lipoprotein receptor familial hypercholesterolemia database. Ann Hum Genet. 2008;72:485–98. [PubMed: 18325082]
18.
Wang J, Ban MR, Hegele RA. Multiplex ligation-dependent probe amplification of LDLR enhances molecular diagnosis of familial hypercholesterolemia. J Lipid Res. 2005;46:366–72. [PubMed: 15576851]
19.
Betteridge DJ, Broome K, Durrington PN, Mann JI, Miller JP, Neil HAW, et al. Risk of fatal coronary heart disease in familial hypercholesterolaemia. Br Med J. 1991;303:893–6. [PMC free article: PMC1671226] [PubMed: 1933004]
20.
National Clinical Audit of the Management of Familial Hypercholesterolaemia 2009: Pilot [document on the Internet] London: Royal College of Physicians; 2009. [December 2010]. http://www​.rcplondon​.ac.uk/clinical-standards​/ceeu/Current-work​/Documents/FH%20Pilot​%20Audit%20Report​%20v8%20Full%20Report.pdf.
21.
Kwiterovich PO Jr, Fredrickson DS, Levy RI. Familial hypercholesterolemia (one form of familial type II hyperlipoproteinemia). A study of its biochemical, genetic and clinical presentation in childhood. J Clin Invest. 1974;53:1237–49. [PMC free article: PMC302610] [PubMed: 4363406]
22.
Leonard JV, Whitelaw AGL, Wolff OH. Diagnosing familial hypercholesterolaemia in childhood by measuring serum cholesterol. Br Med J. 1977;1:1566–8. [PMC free article: PMC1607354] [PubMed: 871667]
23.
Kessling AM, Seed M, Taylor R, Wynn V, Humphries SE. Rising cholesterol levels in children with familial hypercholesterolaemia. Biomed Pharmacother. 1990;44:373–9. [PubMed: 2268697]
24.
Civeira F, Ros E, Jarauta E, Plana N, Zambon D, Puzo J, et al. Comparison of Genetic Versus Clinical Diagnosis in Familial Hypercholesterolemia. Am J Cardiol. 2008;102:1187–93. [PubMed: 18940289]
25.
Centre of Reviews and Dissemination. Systematic reviews: CRD's guidance for undertaking reviews in health care [Internet] York: University of York; 2009. [November 2010]. http://www​.york.ac.uk​/inst/crd/systematic_reviews_book.htm.
26.
Diagnostics Assessment programme – interim methods statement (programme) [document on the Internet] London: National Institute for Health and Clinical Excellence; 2010. [December 2010]. http://www​.nice.org.uk​/media/164/3C/DAPInterimMethodsStatementProgramme.pdf.
27.
Whiting P, Rutjes AW, Reitsma JB, Bossuyt PM, Kleijnen J. The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews. BMC Med Res Methodol. 2003 Nov 10;3 [PMC free article: PMC305345] [PubMed: 14606960]
28.
Rutter CM, Gatsonis CA. A hierarchical regression approach to meta-analysis of diagnostic test accuracy evaluations. Stat Med. 2001;20:2865–84. [PubMed: 11568945]
29.
Updated guide to the methods of technology appraisal [document on the Internet] London: National Institute for Health and Clinical Excellence; 2008. [November 2010]. http://www​.nice.org.uk​/media/B52/A7/TAMethodsGuideUpdatedJune2008.pdf.

11. Appendices

Appendix A

Preliminary MEDLINE strategy

Diagnostic Accuracy and Clinical Effectiveness of Elucigene FH20, LIPOchip and Comparators

  1. Hyperlipoproteinemia Type II/di [Diagnosis]
  2. lipochip.tw.
  3. elucigene.tw.
  4. Hyperlipoproteinemia Type II/
  5. hyperlipidemia, familial combined/
  6. familial hypercholesterol?emia.tw.
  7. hyperlipoprotein?emia.tw.
  8. familial hyperlipid?emia.tw.
  9. or/4-8
  10. exp Genetic Predisposition to Disease/
  11. Genetic Testing/
  12. Gene Amplification/
  13. exp Nucleic Acid Amplification Techniques/
  14. exp oligonucleotide array sequence analysis/ or exp sequence analysis, dna/
  15. (dna adj3 test$).tw.
  16. gene sequencing.tw.
  17. (sequenc$ adj3 analysis).tw.
  18. (cascade adj3 (test$ or screen$)).tw.
  19. (genetic adj3 (test$ or screen$)).tw.
  20. (arms or amplification refractory mutation system).tw.
  21. (PCR or polymerase chain reaction).tw.
  22. Polymorphism, Single-Stranded Conformational/
  23. (sscp or single-stranded conformation polymorphism).tw.
  24. (mlpa or Multiplex ligation-dependent probe amplification).tw.
  25. Cholesterol, LDL/
  26. ldl-c.tw.
  27. or/10-26
  28. 9 and 27
  29. “sensitivity and specificity”/
  30. roc curve/
  31. predictive value of tests/
  32. false positive reactions/
  33. false negative reactions/
  34. du.fs.
  35. sensitivity.tw.
  36. distinguish$.tw.
  37. differentiat$.tw.
  38. identif$.tw.
  39. detect$.tw.
  40. diagnos$.tw.
  41. (predictive adj4 value$).tw.
  42. accura$.tw.
  43. comparison.tw.
  44. or/29-43
  45. 28 and 44
  46. 1 or 2 or 3 or 45
  47. limit 46 to yr=”2000 -Current»
  48. randomized controlled trial.pt.
  49. controlled clinical trial.pt.
  50. randomi?ed.ab.
  51. placebo.ab.
  52. drug therapy.fs.
  53. randomly.ab.
  54. trial.ab.
  55. groups.ab.
  56. or/48-55
  57. exp animals/ not humans/
  58. 56 not 57
  59. 28 and 58
  60. limit 59 to yr=”2000 -Current»
  61. 46 or 60

Preliminary MEDLINE strategy

Economic evaluations of Elucigene FH20, LIPOchip and Comparators

  1. Hyperlipoproteinemia Type II/di
  2. elucigene.tw
  3. lipochip.tw
  4. Hyperlipoproteinemia Type II/
  5. hyperlipidemia, familial combined/
  6. familial hypercholesterol?emia.tw.
  7. hyperlipoprotein?emia.tw.
  8. familial hyperlipid?emia.tw.
  9. or/4-8
  10. genetic predisposition to disease/
  11. genetic testing/
  12. (genetic adj3 (test$ or screen$)).tw.
  13. (cascade adj3 (test$ or screen$)).tw.
  14. (dna adj3 test$).tw
  15. gene amplification/
  16. exp Nucleic Acid Amplification Techniques/
  17. exp sequence analysis,dna/
  18. exp oligonucleotide array sequence analysis/
  19. (arms or amplification refractory mutation system).tw.
  20. (PCR or polymerase chain reaction).tw
  21. (sscp or single-stranded conformation polymorphism).tw
  22. (mlpa or Multiplex ligation-dependent probe amplification).tw.
  23. gene sequencing.tw.
  24. sequence analys?s.tw.
  25. ldl-c.tw.
  26. or/10-25
  27. 9 and 26
  28. or/1-3,27
  29. exp “costs and cost analysis»/
  30. economics/
  31. exp economics,medical/
  32. economics,pharmaceutical/
  33. exp budgets/
  34. exp models, economic/
  35. exp decision theory/
  36. monte carlo method/
  37. markov chains/
  38. exp technology assessment, biomedical/
  39. cost$.ti.
  40. (cost$ adj2 (effective$ or utilit$ or benefit$ or minimis$)).ab.
  41. economics model$.tw.
  42. economic$ .tw.
  43. (price or prices or pricing).tw.
  44. (value adj1 money).tw.
  45. markov$.tw.
  46. monte carlo.tw.
  47. (decision$ adj2 (tree? or analy$ or model$)).tw.
  48. or/29-47
  49. 28 and 48

Appendix B

Patient care pathways (Index cases with a clinical diagnosis of FH using the Simon Broome criteria – including a LDL-c test)*

1.Elucigene[rt arr]Treatment decision
2.Elucigene[rt arr]Lipochip for negatives[rt arr]Treatment decision
3.Elucigene[rt arr]MLPA for negatives[rt arr]Treatment decision
4.Elucigene[rt arr]CGA for negatives[rt arr]Treatment decision
5.Elucigene[rt arr]Lipochip for negatives[rt arr]GA for negatives[rt arr]Treatment decision
6.Elucigene[rt arr]Lipochip for negatives[rt arr]MLPA for negatives[rt arr]Treatment decision
7.Lipochip[rt arr]Treatment decision
8.Lipochip[rt arr]CGA for negatives[rt arr]Treatment decision
9.Lipochip[rt arr]MLPA for negatives[rt arr]Treatment decision
10.CGA[rt arr]Treatment decision
11.LDL-c[rt arr]Treatment decision (current practice)

Appendix C

Patient care pathways (Cascade testing of relatives of FH identified index patients)**

Index case identified byCascade testing of relativesClinical management
ElucigeneElucigene[rt arr]Treatment decision
ElucigeneTargeted Sequencing[rt arr]Treatment decision
LipochipElucigene[rt arr]Treatment decision
LipochipTargeted Sequencing[rt arr]Treatment decision
CGAElucigene[rt arr]Treatment decision
CGATargeted Sequencing[rt arr]Treatment decision

The above is a guideline to the main strategies, there may be exceptions to these strategies which will be explored as the analysis progresses.

Once a relative is found to be negative for the mutation being tested for, cascade testing stops and further cascade testing is not conducted

Footnotes

*

The above is a guideline to the main strategies, there may be exceptions to these strategies which will be explored as the analysis progresses.

**

Once a relative is found to be negative for the mutation being tested for, cascade testing stops and further cascade testing is not conducted

© 2012, Crown Copyright.

Included under terms of UK Non-commercial Government License.

Bookshelf ID: NBK97926
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