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Familial hypercholesterolemia: A systematic review of modeling studies on screening interventions

  • Beate Jahn
    Affiliations
    Institute of Public Health, Medical Decision Making and Health Technology Assessment, Department of Public Health, Health Services Research and Health Technology Assessment, UMIT - University for Health Sciences, Medical Informatics and Technology, Hall i.T., Austria

    Division of Health Technology Assessment, ONCOTYROL - Center for Personalized Cancer Medicine, Innsbruck, Austria
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  • Júlia Santamaria
    Affiliations
    Institute of Public Health, Medical Decision Making and Health Technology Assessment, Department of Public Health, Health Services Research and Health Technology Assessment, UMIT - University for Health Sciences, Medical Informatics and Technology, Hall i.T., Austria
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  • Hans Dieplinger
    Affiliations
    Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
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  • Christoph J. Binder
    Affiliations
    Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
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  • Christoph Ebenbichler
    Affiliations
    Department of Internal Medicine, Medical University of Innsbruck, Innsbruck, Austria
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  • Sabine Scholl-Bürgi
    Affiliations
    University Clinic for Pediatrics I, Tirol Kliniken GmbH, Innsbruck, Austria
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  • Annette Conrads-Frank
    Affiliations
    Institute of Public Health, Medical Decision Making and Health Technology Assessment, Department of Public Health, Health Services Research and Health Technology Assessment, UMIT - University for Health Sciences, Medical Informatics and Technology, Hall i.T., Austria
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  • Ursula Rochau
    Affiliations
    Institute of Public Health, Medical Decision Making and Health Technology Assessment, Department of Public Health, Health Services Research and Health Technology Assessment, UMIT - University for Health Sciences, Medical Informatics and Technology, Hall i.T., Austria
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  • Felicitas Kühne
    Affiliations
    Institute of Public Health, Medical Decision Making and Health Technology Assessment, Department of Public Health, Health Services Research and Health Technology Assessment, UMIT - University for Health Sciences, Medical Informatics and Technology, Hall i.T., Austria
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  • Igor Stojkov
    Affiliations
    Institute of Public Health, Medical Decision Making and Health Technology Assessment, Department of Public Health, Health Services Research and Health Technology Assessment, UMIT - University for Health Sciences, Medical Informatics and Technology, Hall i.T., Austria
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  • Jovan Todorovic
    Affiliations
    Institute of Public Health, Medical Decision Making and Health Technology Assessment, Department of Public Health, Health Services Research and Health Technology Assessment, UMIT - University for Health Sciences, Medical Informatics and Technology, Hall i.T., Austria
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  • Lyndon James
    Affiliations
    Institute for Technology Assessment and Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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  • Uwe Siebert
    Correspondence
    Corresponding author. University for Health Sciences, Medical Informatics and Technology, Eduard-Wallnoefer-Zentrum 1, 6060, Hall i.T., Austria.
    Affiliations
    Institute of Public Health, Medical Decision Making and Health Technology Assessment, Department of Public Health, Health Services Research and Health Technology Assessment, UMIT - University for Health Sciences, Medical Informatics and Technology, Hall i.T., Austria

    Division of Health Technology Assessment, ONCOTYROL - Center for Personalized Cancer Medicine, Innsbruck, Austria

    Institute for Technology Assessment and Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Center for Health Decision Science and Departments of Epidemiology and Health Policy & Management, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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      Highlights

      • Familial hypercholesterolemia is still underdiagnosed even if various screening strategies have been investigated/applied.
      • Many cascade-screening programs appear to be cost effective (at threshold <40,000 EUR/quality-adjusted life-year gained).
      • There is no consistent evidence on cost effectiveness of universal screening and opportunistic screening.
      • Future research is needed on transferability to other countries and modeling spillover effects to newborns.

      Abstract

      Background and aims

      FH is still underdiagnosed. Cost-effectiveness results of preventive screening strategies vary. We aimed at systematically assessing the benefits, harms and cost effectiveness of screening for familial hypercholesterolemia (FH) and at providing an overview of the main characteristics and methodological approaches of applied decision-analytic models.

      Methods

      A systematic literature search was conducted in MEDLINE, EconLit, CRD-databases and the CEA-registry for FH screening starting 2012. Earlier studies were included from a published systematic review. Results were reported in standardized semi-quantitative evidence tables. Costs were converted to current euros. Incremental cost-effectiveness ratios (ICERs) were recalculated according to economic guidelines.

      Results

      Out of our 211 retrieved studies, eight were included in the review in addition to six studies from an earlier review. Studies were conducted in Europe (UK, The Netherlands, Spain, Poland), USA and Australia evaluating cascade (CS), opportunistic (OS), universal screening (UniS), or combinations using genetic testing, clinical criteria or combinations. Studies evaluating only CS identified strategies with an ICER of up to 37,100 EUR/quality-adjusted life-year (QALY) but some strategies were dominated depending on test combinations. UniS of newborns in combination with CS had an ICER≤15,000 EUR/QALY for sequential cholesterol-genetic screening. In other studies, UniS was dominated by OS/CS.

      Conclusions

      Our systematic review demonstrates the values of FH screening and provides an overview of potentially relevant screening strategies to be tested using a decision-analytic model for the respective country or region. Future research is needed on the transferability of results to other countries and modeling spillover effects to newborns.

      Graphical abstract

      Keywords

      1. Introduction

      Familial hypercholesterolemia (FH) is an inherited disorder leading to an increased risk of premature cardiovascular disease (CVD) [
      • Mundal L.
      • Retterstol K.
      A systematic review of current studies in patients with familial hypercholesterolemia by use of national familial hypercholesterolemia registries.
      ,
      • Nordestgaard B.G.
      • Chapman M.J.
      • Humphries S.E.
      • et al.
      Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
      ]. The prevalence of FH has been estimated previously to be 1 in 500 globally [
      • Nordestgaard B.G.
      • Chapman M.J.
      • Humphries S.E.
      • et al.
      Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
      ] but recent studies indicate a frequency approaching 1 in 200 [
      • Harada-Shiba M.
      • Arai H.
      • Ishigaki Y.
      • et al.
      Guidelines for diagnosis and treatment of familial hypercholesterolemia 2017.
      ,
      • Krogh H.W.
      • Mundal L.
      • Holven K.B.
      • Retterstol K.
      Patients with familial hypercholesterolaemia are characterized by presence of cardiovascular disease at the time of death.
      ,
      • Benn M.
      • Watts G.F.
      • Tybjaerg-Hansen A.
      • Nordestgaard B.G.
      Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication.
      ]. The extent of underdiagnosis and undertreatment of individuals with FH is most likely high and varies substantially between countries [
      • Nordestgaard B.G.
      • Chapman M.J.
      • Humphries S.E.
      • et al.
      Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
      ]. It is assumed that in most countries, less than 10%–20% of FH patients are diagnosed and adequately treated [
      • Nordestgaard B.G.
      • Chapman M.J.
      • Humphries S.E.
      • et al.
      Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
      ,
      • Krogh H.W.
      • Mundal L.
      • Holven K.B.
      • Retterstol K.
      Patients with familial hypercholesterolaemia are characterized by presence of cardiovascular disease at the time of death.
      ].
      The European Atherosclerosis Society underlines the need for diagnostic screening combined with early treatment [
      • Nordestgaard B.G.
      • Chapman M.J.
      • Humphries S.E.
      • et al.
      Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
      ]. Studies on the cost effectiveness of FH screening strategies published from 2002 until 2011 were synthetized in systematic reviews [
      • Rosso A.
      • Pitini E.
      • D'Andrea E.
      • et al.
      The cost-effectiveness of genetic screening for familial hypercholesterolemia: a systematic review.
      ,
      • Ademi Z.
      • Watts G.F.
      • Juniper A.
      • Liew D.
      A systematic review of economic evaluations of the detection and treatment of familial hypercholesterolemia.
      ]. However, these reviews are outdated and costs and respective incremental cost-effectiveness ratios (ICERs) are not directly comparable due to missing inflation and currency adjustments [
      • Rosso A.
      • Pitini E.
      • D'Andrea E.
      • et al.
      The cost-effectiveness of genetic screening for familial hypercholesterolemia: a systematic review.
      ]. Even more problematic, the originally published ICERs are not always calculated in a truly incremental fashion. This methodological approach is not considered state-of-the-art and potentially provides biased results [
      • Sanders G.D.
      • Neumann P.J.
      • Basu A.
      • et al.
      Recommendations for conduct, methodological practices, and reporting of cost-effectiveness analyses: second panel on cost-effectiveness in health and medicine.
      ]. Our review fills this research gap.
      The aim of our study is to systematically assess the benefits, harms and cost effectiveness of implementing cascade, universal and opportunistic screening programs for FH and to provide an overview of main characteristics and methodological approaches of applied decision-analytic models.

      2. Materials and methods

      We conducted a systematic literature review on health-economic FH models evaluating screening strategies for FH and we report results in semi-quantitative evidence tables after recalculation of ICERs.

      2.1 Search strategy

      We systematically searched four medical and economic databases, Medline, EMBASE, CRD (Centre for Reviews and Dissemination University of York) and CEA registry of the Tufts Medical Center up until November 27, 2019 and updated the search on March 01, 2021. Results were cross-checked with previous reviews [
      • Rosso A.
      • Pitini E.
      • D'Andrea E.
      • et al.
      The cost-effectiveness of genetic screening for familial hypercholesterolemia: a systematic review.
      ,
      • Ademi Z.
      • Watts G.F.
      • Juniper A.
      • Liew D.
      A systematic review of economic evaluations of the detection and treatment of familial hypercholesterolemia.
      ]. The search strategy consisted of keywords, MeSH terms, and searching article text for terms relating to “familial hypercholesterolemia”, “economic evaluation” and “screening” Supplementary Table 3). We restricted our search to studies after July 1, 2012, and included studies before that date based on the systematic review by Ademi et al. [
      • Ademi Z.
      • Watts G.F.
      • Juniper A.
      • Liew D.
      A systematic review of economic evaluations of the detection and treatment of familial hypercholesterolemia.
      ]. Because the search strategy of Ademi et al. was in line with our search strategy and the reviewed studies were assessed by two independent reviewers we did not replicate but build up on this existing review [
      • Ademi Z.
      • Watts G.F.
      • Juniper A.
      • Liew D.
      A systematic review of economic evaluations of the detection and treatment of familial hypercholesterolemia.
      ].

      2.2 Study selection and data extraction

      We followed the PRISMA guidelines [
      • Moher D.
      • Shamseer L.
      • Clarke M.
      • et al.
      Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement.
      ]. After removal of duplicates, we performed a first screening of the titles and abstracts followed by a screening of full text by two independent reviewers (JS and JT), with disagreements resolved by a third reviewer (BJ). Only English language publications were considered for inclusion, and publications that focused solely on the treatment of FH were excluded. Detailed inclusion and exclusion criteria are described in Supplementary Table 4.
      We developed systematic semi-quantitative evidence tables on the main study characteristics and health-economic outcomes (Table 1), and methodological aspects of the decision-analytic modeling framework (Table 2). CHEERS guidelines were considered for the selection of extracted study information [
      • Husereau D.
      • Drummond M.
      • Petrou S.
      • et al.
      Consolidated health economic evaluation reporting standards (CHEERS) statement.
      ]. Information was retrieved by one reviewer (JS) and checked by a second reviewer (BJ). Information was synthesized narratively.
      Table 1Study characteristics and health economic outcomes of the articles included for review.
      Study, Year, CountryResearch questionTarget populationScreening strategiesConsidered relatives, prevalenceDiagnosis criteria/clinical assessmentHealth outcomesCosts (EUR)Conversion ICERa
      Cascade screening
      1. Kerr [
      • Kerr M.
      • Pears R.
      • Miedzybrodzka Z.
      • et al.
      Cost effectiveness of cascade testing for familial hypercholesterolaemia, based on data from familial hypercholesterolaemia services in the UK.
      ] 2017, UK
      Inform an economic model re-examining the cost-effectiveness in the UK of cascade testing for monogenic FH from known ICs using data from FH cascade services, incorporating new study evidence, and changes in costs and clinical practice that have occurred since the 2008 guideline.Individuals who already have a clinical diagnosis of possible or definite FH and following up with relatives of monogenic ICs1) No screening, no DNA tests and no treatment of relatives. ICs only treated.

      2) DNA testing of people who already have a clinical diagnosis of possible or definite FH (ICs), DNA testing of relatives of monogenic ICs, and treatment with high-intensity statins and, in some cases, ezetimibe for monogenic relatives (in total two generation relatives)
      1.33 relatives tested or screened/monogenic IC, on average; 996/1957 (50.9%) FH + relatives among relatives; 0.67 FH + relatives/mutation positive IC (Wales, Scotland and Wessex).

      6.83 relatives tested/screened per monogenic IC, on average;

      841/1736 (48.4%) FH + relatives among relatives; 3.31 FH + relatives/mutation positive IC (Northern Ireland).
      GT (does not mention sens. or spec.)Per relative tested:

      0.48 QALYs (gained in the lifetime compared to no screening)

      In 20 years:

      46 MIs averted/1000 relatives tested

      50 angina cases averted/1000 relatives tested

      8 strokes averted/1000 relatives tested

      16 deaths averted/1000 relatives
      Per relative tested (net marginal lifetime cost):

      1) −2) 3292 (difference against no screening)
      6858 EUR/QALY
      2. Lazaro [
      • Lazaro P.
      • Perez de Isla L.
      • Watts G.F.
      • et al.
      Cost-effectiveness of a cascade screening program for the early detection of familial hypercholesterolemia.
      ] 2017, Spain
      Assess the efficiency, in terms of cost-effectiveness and cost utility, of a national genetic screening program implementation for FH compared with no implementation in Spain.ICs and first-degree relatives1) No Screening (treatment only)

      2) CS with DNA test for ICs and relatives + treatment
      9000 FH population: 2250 ICs and 7105 relatives tested of which 6750 are FH + b

      3.16 relatives screened/IC,

      3 FH + relatives/IC,

      95% FH+ in IC relatives with hypercholesterolemia;

      Prevalence of FH in adults: 0.33%
      DLCN criteria (sens. 88.70%, 85.40–91.30% in most and least favorable scenarios; spec. 62%, 56.90–66.80% in the most and least favorable scenarios) and GT (sens. 100%, spec. 100%) of DLCN positive casesCohort of 9000:

      1)

      61,408 QALYs

      1661 CEs

      400 coronary deaths

      2)

      62,175 QALYs

      813 CEs

      203 coronary deaths
      Cohort of 9000:

      1) 46,742,280 (healthcare perspective); 109,463,231 (societal perspective)

      2) 75,184,430 (healthcare perspective); 105,926,842 (societal perspective)
      2) 33,540 EUR/CE avoided;

      140,109 EUR/death avoided; 37,082 EUR/QALY (healthcare perspective)

      Strategy 2 is dominant considering the societal perspective.
      3. Chen [
      • Chen C.X.
      • Hay J.W.
      Cost-effectiveness analysis of alternative screening and treatment strategies for heterozygous familial hypercholesterolemia in the United States.
      ] 2015, USA
      To evaluate the cost-effectiveness of two FH screening and treatment strategies not currently used in the USA, compared with the lipid cascade screening strategy currently recommended for individuals with high cholesterol and a family history of FH or heart disease (Lipid Screening). The two new strategies will include genetic cascade screening of at-risk relatives from an IC and an enhanced lipid cascade screening strategy that includes a statin adherence.Male adults, relatives of an IC with clinical diagnosis of FH.1) Cascade Lipid Screening

      2) Cascade Lipid Screening + adherence program

      3) CS with DNA test LDL-C test every 2 years if no mutation.
      2.5 relatives referred from each IC on average (male adults, alive, at risk and agree to be screened)

      2.5 relatives screened/IC.

      3.4 IC sequenced to find one genetic diagnosis of FH.
      GT (sens. 78.5%); LDL-C test of negative cases missed in genetic tests (sens. 91%) and for individuals without GT.Per individual:

      1) 18.28 QALYs

      3) 18.29 QALYs

      2) 18.77 QALYs
      Per individual:

      1) 8594

      3) 12,892

      2) 13,545
      1) −3) Ext. dom.

      2) 10,104 EUR/QALY
      4. Ademi [
      • Ademi Z.
      • Watts G.F.
      • Pang J.
      • et al.
      Cascade screening based on genetic testing is cost-effective: evidence for the implementation of models of care for familial hypercholesterolemia.
      ] 2014,

      Australia
      Assess the cost-effectiveness of CS for FH using primarily GT supplemented with the measurement of LDL-C, followed by treatment of statins.

      Provide further evidence to support the national recommendation concerning the detection and treatment of FH in an Australian context.
      First- and second-degree relatives of 81 genetically confirmed FH+ (ICs).1) No screening

      2) CS with DNA and LDL test + treatment for all FH + cases.
      Data used: 81 adult ICs genetically confirmed, from whom 95 adult relatives were identified and screened July 2008–June 2013 (data from a study).

      1.17 FH + relatives/IC.

      95/175

      Number of FH + relatives among relatives: 54.3%

      2.16 relatives screened/IC.
      GT (sens. 100%, spec. 100% and 90% spec. in the SA) supplemented with LDL-C measurement.Per 100 screened individuals:

      1) 759.83 LYs

      2) 784.78 LYs

      1) 752.06 QALYs

      2) 781.13 QALYs

      Screened population:

      1 CHD prevented event/7.4 screened people.

      NNS to prevent 1 CHD-related death 18.3.

      FH positives:

      NNS 4.0 to prevent 1 CHD event

      NNS 9.9 to prevent 1 CHD-related death.
      Per 100 screened individuals:

      1) 407

      2) 467,915
      18,738 EUR/LYG; 16,082 EUR/QALY
      5. Nherera [
      • Nherera L.
      • Marks D.
      • Minhas R.
      • Thorogood M.
      • Humphries S.E.
      Probabilistic cost-effectiveness analysis of cascade screening for familial hypercholesterolaemia using alternative diagnostic and identification strategies.
      ] 2011, UK
      Estimate the probabilistic cost-effectiveness of CS methods in FH from the UK NHS perspective.Cohort of 1000 people suspected of having FH aged 50 years for ICs and 30 years for relatives, followed for a lifetime.Cascade strategies:

      1) LDL-C test of patients + CS of relatives of IC meeting DFH or PFH criteria (cholesterol method)

      2) DNA test of patients + CS for first-degree relatives of IC with identified mutation-FH+ (DNA method)

      3) DNA test of patients + CS with DNA test for relatives of mutation-FH + ICs OR LDL test for relatives of DFH ICs without genetic mutation + treatment for all FH + cases (DNA + DFH)

      4) DNA test of patients + CS with DNA test for relatives of FH + cases OR LDL test for relatives of DFH/PFH cases without genetic mutation + treatment for all FH + cases (DNA + DFH + PFH)

      In all strategies, high-intensity statin therapy is given to all FH + cases.
      Possible and definite cases of FH aged 50 years old and first-degree relatives.

      Relatives tested/case:

      1) 9, 2) 6.4, 3) 6.6

      4) 9.75,

      Positive relatives/case:

      1) 1.6, 2) 3.2, 3) 3.1

      4) 3

      FH + relatives among relatives tested:

      1) 27.7%, 2) 50.0%

      3) 47.7%, 4) 31.7%

      Prevalence of FH among the screened population: 48%

      Adherence to treatment and participation rate not reported.
      LDL-C test (Sens. and spec. not reported) or GT (Spec. and Sens. not clearly specified).QALYs gained:

      1) 10.89

      2) 24.12

      3) 24.28

      4) 25.18
      Cohort of 1000 patients with a suspicion of FH:

      1) 56,360

      2) 64,378

      3) 66,594

      4) 69,285
      EUR/QALY:

      1)-2) 606

      3) Ext. Dom.

      4) 4629
      6. Oliva [
      • Oliva J.
      • Lopez-Bastida J.
      • Moreno S.G.
      • Mata P.
      • Alonso R.
      [Cost-effectiveness analysis of a genetic screening program in the close relatives of Spanish patients with familial hypercholesterolemia].
      ] 2009, Spain
      Assess the cost-effectiveness of a genetic screening program for first-degree relatives of patients with FH, followed by treatment when

      necessary, compared with the alternative of no screening.
      Patients with a prior genetic diagnosis of FH and first-degree relatives.1) No Screening

      2) CS with DNA test + treatment of FH + casesc
      3.4 screenings to detect one FH + case in first-degree relatives.

      Number of FH + among relatives (prevalence of FH among screened population): 1/2 (50%) assumed.

      Adherence and participation rates not reported.
      Based on pilot study Clinical diagnosis was correct in approx. 59% of cases when FH was suspected, 72% detection rate when clinical diagnosis was certain.”

      First-degree relatives.

      GT: Sens. 99.9%; spec. 99.7%
      Per new treated case:

      LYGs:

      3.30 (undiscounted);

      1.34 (discounted)
      Incremental costs per new treated case:

      2) 10,847
      EUR/LYG:

      1) −2) 4310 (discounted)
      7. Wonder-ling [
      • Wonderling D.
      • Umans-Eckenhausen M.A.
      • Marks D.
      • Defesche J.C.
      • Kastelein J.J.
      • Thorogood M.
      Cost-effectiveness analysis of the genetic screening program for familial hypercholesterolemia in The Netherlands.
      ] 2004, The Netherlands
      Assess the cost-effectiveness of systematic genetic screening of family members of persons diagnosed with FH.National GT program for FH in the

      Netherlands.
      1) No Screening

      2) CS with DNA test + treatment for untreated FH + cases.
      Relatives considered not reported.

      Prevalence not reported.

      Relatives screened/IC (only in SA, not reported for base case): 11 and 34

      Drug uptake rate (only in SA, not reported for base case): 78% and 85%.
      GT: Sens. and spec. not reported.Per new untreated case diagnosed:

      LYGs:

      1)-2) 3.30 (undiscounted); 0.90 (discounted)
      Incremental costs per new untreated case diagnosed:

      1)-2) 9724
      EUR/LYG:

      1)-2) 8752 (discounted)
      8. Marang-van de Mheen [
      • Marang-van de Mheen P.J.
      • ten Asbroek A.H.A.
      • Bonneux L.
      • Bonsel G.J.
      • Klazinga N.S.
      Cost-effectiveness of a family and DNA based screening programme on familial hypercholesterolaemia in The Netherlands.
      ] 2002, The Netherlands
      To estimate the cost-effectiveness of the current screening program on FH in relatives of diagnosed FH patients in the

      Netherlands.
      2814 individuals were screened, of whom 363 were aged younger than 16 years and 222 were screened

      on the apoB mutation, leaving 2229 individuals to be included in the present analysis. These individuals were found through 137 FH probands.
      I.) Current screening strategy:

      1) CS with DNA test + treatment for FH + cases

      2) CS with DNA test + treatment FH + cases with high cholesterol

      3) CS with DNA test + treatment for FH + cases according to CBO criteria

      4) See 1, if untreated at screening, 5) See 2, if untreated at screening.

      6) See 3, if untreated at screening

      II.) Alternative screening strategy (using lipid profile):

      7) CS with DNA test + treatment of all with high cholesterol levels, 8) CS with DNA test + treatment of all individuals according to CBO criteria, 9) See 7, if untreated at screening, 10) See 8, if untreated at screening.
      First- and second-degree relatives of IC with FH and a LDL receptor gene mutation (≥16 years old).

      16.27 relatives/IC.

      Number of FH + relatives among relatives: Current screening strategy→ 759/2229 (34.1%)

      Prevalence FH: Not reported.

      Adherence to treatment:

      100%,

      Follow-up protocol: 100%
      GT (DNA test for LDL receptor gene mutation): Sens. and spec. not clearly stated.All screened individuals (2,229):

      LYGs:

      6) 204

      10) 337

      3) 361

      8) 507

      5) 407

      4) 519

      2) 610

      9) 623

      7) 836

      1) 865
      Incremental costs for all screened individuals (2,229)d:

      6) 7,983,210

      10) 12,115,084

      3) 13,101,190

      8) 17,514,491

      5) 17,779,020

      4) 23,654,749

      2) 25,840,500

      9) 26,960,290

      7) 35,446,542

      1) 38,303,729
      EUR/LYG:

      6) Ext. Dom.

      10) 35,949

      3) 41,088

      8) Dom.

      5) Ext. Dom.

      4) Ext. Dom.

      2) Ext. Dom.

      9) Ext. Dom.

      7) 47,042

      1) 98,524
      9. Ademi [
      • Ademi Z.
      • Norman R.
      • Pang J.
      • et al.
      Health economic evaluation of screening and treating children with familial hypercholesterolemia early in life: many happy returns on investment?.
      ] 2020, Australia
      Evaluate the cost-effectiveness of cascade screening of children for FH and treatment with statins.A model population of 1000 children aged ten years old from Western Australia.1) Screened (cascade screening) and genetically confirmed FH cases + treatment of cases at age ten years

      2) Not screened usual care (not treated until identified with FH or elevated LDL-C). Latest statin initiation age was 25.
      Prevalence of FH mutation in cascade screening: 56.8%Cascade screening and GT and cholesterol testing.

      Sens. and spec. 100%
      LYs:

      1) 10,900

      2) 10,348

      QALYs:

      1) 10,119

      2) 9510

      LYGs per person:

      1) 0.97

      QALYs gained per person:

      1) 1.07

      Acute non-fatal events:

      1) −24.2

      Deaths:

      1) −7.55
      2019

      1) 7,049,141

      2) 7,383,979
      $/QALY:

      1) Dominant (cost-saving)

      $/LYG:

      1) Dominant (cost-saving)
      Cascade screening in combination with opportunistic screening or universal screening
      10. Pelczarska [
      • Pelczarska A.
      • Jakubczyk M.
      • Jakubiak-Lasocka J.
      • et al.
      The cost-effectiveness of screening strategies for familial hypercholesterolaemia in Poland.
      ] 2018, Poland
      Evaluate the economic rationale behind various approaches to screen for FH in Poland: in children, young adults and after the first onset of acute coronary disease, combined with a cascade screening of relatives.6-year-old children, first job takers and people who suffered an ACS event (with and without age restrictions) and first line relatives of FH+.1) UniS for people getting first job using clinical diagnosis only (UFJ-C) + CS

      2) UniS of people getting first job with clinical + genetic diagnosis (UFJ-G) + CS

      3) UniS of 6 year-olds using genetic diagnosis (U6) + CS

      4) OS of people after first onset of ACS using clinical criteria without age restrictions (ACS-C-all) + CS

      5) OS of people after first onset of ACS using clinical criteria limited to ACS before age 55 in men and 65 in women (ACS-C-55/65) + CS

      6) OS of people after first onset of ACS using clinical criteria and genetic diagnosis without age restrictions (ACS-G-all) + CS

      7) OS of people after first onset of ACS using clinical criteria and genetic diagnosis limited to ACS before 55 in men and 65 in women (ACS-G-55/65) + CS.
      No. of relatives screened/IC (only counting true positives):

      UFJ 3.1,U6 2.3, ACS-55/65 3.9, ACS-all 4.5

      No. of FH + relatives/IC (only counting true positives):

      UFJ-C 1.33, UFJ-G 1.5, U6 1.1, ACS-C-55/65 1.7, ACS-all 1.9, ACS-G-55/65 1.9, ACS-G-all 2.2

      Number of FH + relatives among relatives:

      UFJ-C: 570/1329 (42.9%), UFJ-G: 664/1329 (49.9%)

      U6: 520/1015 (51.2%), ACS-C-55/65: 4921/9841 (50.0%), ACS-C-all: 5652/11,304 (50%)

      ACS-G-55/65: 4921/9841 (50.0%), ACS-G-all: 5652/11,304 (50.0%)

      Prevalence of FH:

      UFJ and U6 0.5%

      ACS 3.3%
      Clinical criteria –DLCN in adults and SB in children- (sens. 100%, spec. 100% based on experts' opinions); GT in UFJ and ACS (sens. 86.76%, spec. 100%); GT in U6 (sens. 94.8%).Cohort of 100,000 probands:

      LYGs:

      5) 4121

      1) 1564

      4) 915

      2) 1650

      3) 1476

      7) 4727

      6) 1049

      Incremental QALYs:

      5) 3774

      1) 1450

      4) 712

      2) 1528

      3) 1371

      7) 4329

      6) 817
      Incremental costs per 100,000 probands:

      5) 790,025

      1) 1,487,832

      4) 1,601,268

      2) 2,357,063

      3) 2,780,720

      7) 6,583,762

      6) 7,777,131
      5) 209 EUR/QALY; 192 EUR/LYG

      1) Dom.

      4) Dom.

      2) Dom.

      3) Dom.

      7) 1338 EUR/QALY; 9561 EUR/LYG

      6) Dom.
      11. Crosland [
      • Crosland P.
      • Maconachie R.
      • Buckner S.
      • McGuire H.
      • Humphries S.E.
      • Qureshi N.
      Cost-utility analysis of searching electronic health records and cascade testing to identify and diagnose familial hypercholesterolaemia in England and Wales.
      ] 2018, UK
      Investigate the cost-effectiveness of FH screening of new IC identification in PC or SC.Current ICs, potential new ICs from PC and SC, relatives of people in each of the previous groups (40–70 years old UK population).Genetic CT or PC or SC case identification with or without clinical assessment (SB or DLCN criteria):

      1) No CS

      2) CS

      3) CS + PC (SB criteria)

      4) CS + PC (DLCN criteria)

      5) CS + SC (SB criteria)

      6) CS + SC (DLCN criteria)

      7) CS + PC + SC (SB criteria)

      8) CS + PC and SC, clinical assessment (DLCN criteria)

      9) CS + PC, no CS from new ICs.
      1.33 genetically tested per IC.

      2.22 relatives invited for screening/IC

      59.89% of the relatives take up cascade testing (1.33/0.5989 = 2.22→ number of relatives invited for cascade testing per IC). In the SA: 1–12 relatives

      Prevalence of FH: 1/500.
      SB (possible or definite FH: sens. 0.890 and spec. 0.287; definite FH: sens. 0.360 and spec. 0.940), DLCN (probable or definite FH: sens. 0.861 and spec. 0.457; definite FH: sens. 0.567 and spec. 0.802) and GT (sens. 100%, spec. 100%) of positive cases.QALYs:

      1) 11.4079

      2) 11.41755

      9) 11.45383

      4) 11.46325

      3) 11.46357

      6) 11.41991

      5) 11.41999

      8) 11.4657

      7) 11.46601
      1) 7966

      2) 8020

      9) 8029

      4) 8066

      3) 8070

      6) 8183

      5) 8209

      8) 8228

      7) 8259
      EUR/QALY:

      1) −2) Ext. dom.

      9) 1378

      4) 3857

      3) 14,650

      6) Dom.

      5) Dom.

      8) 74,280

      7) 98,295
      12. McKay [
      • McKay A.J.
      • Hogan H.
      • Humphries S.E.
      • Marks D.
      • Ray K.K.
      • Miners A.
      Universal screening at age 1-2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: a cost-utility analysis.
      ] 2018, UK
      Determine whether UniS for FH at 1–2 years could be a cost-effective adjunct to CT in the UK. Compare the cost-effectiveness of cholesterol and/or mutation-based UniS with/without RCT.UK population 1–2 years oldUniS (cholesterol and/or GT) with or without RCT:

      1) No UniS

      2) Cholesterol screening

      3) Seq. cholesterol testing-genetic screening among cholesterol pos. individuals

      4) 3 + RCT

      5) Seq. genetic screening-cholesterol testing among mutation pos. individuals

      6) 5 + RCT

      7) Parallel cholesterol screening-genetic testing

      8) 7 + RCT.
      2 FH + cases/mutation positive IC→ Two mutation pos. individuals per mutation pos. index individual in UniS (varied to 0.5, 6.1, 8.6 in SA)

      2 FH + relatives/IC.

      Prevalence FH estimated: 1/250.

      Prevalence FH+: 0.34%.

      Prevalence mutation-positive among FH+: 55%

      Prevalence mutation positive: 0.19%.
      GT and/or cholesterol screening.

      SB criteria.

      Sens.: 88% in Strategy 2; 100% in Strategy 5 and 7 96% in Strategy 3.

      Spec.: 100% in Strategy 5 and 7, 99.9% in Strategy 2.
      Cohort of 10,000 screened:

      QALYs:

      1) 992

      2) 1009

      3) 1010

      4) 1027

      5) 1000

      6) 1022

      7) 1011

      8) 1033

      FH cases identified/10,000 screened:

      1) 0

      2) 22.38

      3) 24.41

      4) 39.79

      5) 11.44

      6) 31.11

      7) 25.43

      8) 45.10
      Cohort of 10,000 screened:

      1) 258,201

      2) 641,062

      3) 731,573

      4) 768,219

      5) 3,137,369

      6) 3,184,244

      7) 3,225,862

      8) 3,272,738
      EUR/QALY:

      1) −2) Ext. dom.

      3) Ext. dom.

      4) 14,572

      5) Dom.

      6) Dom.

      7) Dom.

      8) 417,420
      13. Marks [
      • Marks D.
      • Thorogood M.
      • Neil H.A.
      • Wonderling D.
      • Humphries S.E.
      Comparing costs and benefits over a 10 year period of strategies for familial hypercholesterolaemia screening.
      ] 2003, UK
      To compare the costs and benefits of population screening of 16-year-olds or tracing family members of affected patients over a 10-year period.16-years old (strategy 1), FH + cases and their first-degree relatives aged 16-54 years-old (strategy 2)1) UniS of 16-year olds with cholesterol testing + diagnostic confirmation of positive cases (clinical examination or GT)

      2) CS with cholesterol test and GT of first-degree relatives of identified FH cases (family tracing) of people aged 16–54 years old.
      Number of relatives screened/IC:

      1) N/A, 2) 3.37 (26,742 IC leading to 90,120 first-degree relatives, considered only 48,454 relatives aged 16–54 years;

      Relatives identified with FH among all relatives:

      1) Not applicable

      2) 27.3%.

      Prevalence of FH:

      1) 1/500 (0.2%)

      2) 50% (case finding)

      Adherence to treatment:

      1) Not reported

      2) 82%

      Participation rate to screening:

      1) 55%/75% (1st/2nd appointment for cholesterol testing), 2) 95%/90% (1st/subsequent visits).
      Cholesterol testing or GT:

      Sens. and spec. not reported.
      Averted deaths over 10 years:

      1) 9.8 (males), 1.9 (females), 11.7 (total)

      2) 377 (males)

      182 (females), 560 (total)

      NNT:

      1) 1366 (males), 1367 (females), 2869 (total)

      2) 2.6 (males), 2.6 (females), 5.2 (total)
      Overall costs:

      1)

      9,912,870

      2) 74,516,343
      EUR/deaths averted:

      1) Ext. dom (compared to do nothing).

      2) 133,303
      Universal or opportunistic screening
      14. Marks [
      • Marks D.
      • Wonderling D.
      • Thorogood M.
      • Lambert H.
      • Humphries S.E.
      • Neil H.A.
      Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
      ] 2002, UK
      Assess the cost effectiveness of strategies to screen for and treat FH.General population; patients admitted to hospital with premature MI, PC patients, people diagnosed with FH and their first-degree relatives.

      For each sex within 10 year age bands from 16 to 54 years.
      1) Universal population screening;

      2) OS of patients consulting for unrelated reasons in PC;

      3) OS of patients admitted to hospital with premature MI;

      4) Systematic screening with GT of first-degree relatives of people with diagnosed FH (family tracing)

      5) UniS for 16-year olds.
      Prevalence of FH: 1) 0.2%

      2) Not specified

      3) Not specified

      4) 50.0%

      5) 0.2%

      Adherence to treatment: 82%

      Participation rate to screening (first and second blood test for cholesterol testing attendance probability, respectively):

      1) 65.0%75.0%

      2) 80.0%/75.0%

      3) 60.0%/90.0%

      4) 95.0%/90.0%
      Cholesterol testing and GT: Sens. and spec. 100% (assumed, but not clearly stated).LYGs:

      7.0 in men; 9.1 in women aged 16–24 years;

      Number needed to be invited for screening 2292 people in the general population (confirmed by genetic screening), 2.6 people in first degree relatives

      of identified cases (with clinical confirmation).
      Cost per case detected (NA).NAe
      ACS – acute coronary syndrome, ACS-C – acute coronary syndrome-clinical diagnosis, ACS-G – acute coronary syndrome-genetic diagnosis, CBO – Dutch Institute on Health Care Improvement consensus, CE – coronary event, CEA – cost-effectiveness analysis, CHD – coronary heart disease, CS – cascade screening, CT – cascade testing, CUA – cost-utility analysis, CVD – cardiovascular disease, DFH – definite familial hypercholesterolemia, DLCN – Dutch Lipid Clinic Network-WHO, Dom. – dominated, EUR – euros, Ext. dom. – extendedly dominated, FH – familial hypercholesterolemia, IC – index case, GT – genetic testing, GS – genetic screening, ICER – incremental cost-effectiveness ratio, LDL-C – low-density lipoprotein-cholesterol, LYG – life years gained, Lys – life years, MI – myocardial infarction, N/A – not applicable, NHLBI – National Heart, Lung and Blood Institute, NHS – national health system, OS – opportunistic screening, PC – primary care, PFH – possible familial hypercholesterolemia, Pos. – positive, QALY – quality-adjusted life years, RCT – reverse cascade testing, SA – sensitivity analysis, SB – Simone Broome, SC – secondary care, Sens. – sensitivity, Seq. – sequential, Spec. – specificity, U6 – universal screening of 6 year olds, UFJ-C – universal screening first job takers-clinical diagnosis, UFJ-G – universal screening first job takers-genetic diagnosis, UK – United Kingdom, UniS – universal screening, YoLS – years of life saved. aCompared to the next best alternative strategy, excluding dominated and extendedly dominated options. b1/3 ratio as observed in the SAFEHEART registry. cBoth strategies included follow-up and treatment of individuals who had had a cardiovascular event. dCosts are presented as differential costs (Screening – No screening) and undiscounted. eData to calculate the ICERs was not available.
      Table 2Summary table of the decision-analytic modeling framework of the economic evaluations.
      Study, Year, CountryType of studyHealth outcomesCostsPerspec-tiveType of modelHealth StatesTime HorizonDiscoun-tingSensitivity Analysis
      Org. screeningConsultationsScreen. TestTreatment of FH patientsFollow-up visitsCardiac eventsIndirect costsIC identification
      Cascade screening
      1. Kerr [
      • Kerr M.
      • Pears R.
      • Miedzybrodzka Z.
      • et al.
      Cost effectiveness of cascade testing for familial hypercholesterolaemia, based on data from familial hypercholesterolaemia services in the UK.
      ] 2017, UK
      CUAQALYs, adverse events (MI, stroke, unstable angina, stable angina, death)X?XXXX?Health care payerMarkov modelFH event-free, first event health states:

      stable angina, unstable angina, MI, TIA, stroke, CHD death, non-CHD death

      Subsequent health states: stable angina, post-stable angina, unstable angina, post-unstable angina, MI, post-MI, TIA, stroke, post-stroke, CHD death, non-CHD death
      Lifetime3.5% (costs, benefits)Deterministic (one-way)
      2. Lazaro [
      • Lazaro P.
      • Perez de Isla L.
      • Watts G.F.
      • et al.
      Cost-effectiveness of a cascade screening program for the early detection of familial hypercholesterolemia.
      ] 2017, Spain
      CEA and CUAQALYs, coronary events and cardiac deaths averted??XX?XXXHealth care payer and societal perspec-tiveDecision treeStarting with FH population evaluating coronary events (CE, no CE, alive/dead after CE)10 years3%Deterministic (base case, most favorable and least favorable scenarios)
      3. Chen [
      • Chen C.X.
      • Hay J.W.
      Cost-effectiveness analysis of alternative screening and treatment strategies for heterozygous familial hypercholesterolemia in the United States.
      ] 2015, USA
      CUAQALYsXXXXXXXXSocietal perspec-tiveDecision tree plus Markov modelPre-CVD, CVD event/stroke, deathLifetime3% (costs, QALYs)Deterministic (one-way), probabilistic.
      4. Ademi [
      • Ademi Z.
      • Watts G.F.
      • Pang J.
      • et al.
      Cascade screening based on genetic testing is cost-effective: evidence for the implementation of models of care for familial hypercholesterolemia.
      ] 2014, Australia
      CEA, CUALys

      QALYs death prevented

      CHD

      Y
      XXXXHealth care systemDecision tree plus Markov modelAlive without CHD, alive with CHD,

      dead
      10 years5% (costs, benefits)Deterministic (one-way), probabilistic
      5. Nherera [
      • Nherera L.
      • Marks D.
      • Minhas R.
      • Thorogood M.
      • Humphries S.E.
      Probabilistic cost-effectiveness analysis of cascade screening for familial hypercholesterolaemia using alternative diagnostic and identification strategies.
      ] 2011, UK
      CEAQALYsXXXXXHealth care payerDecision tree + Markov modelDefinite FH, possible FH and no FH. MI, stroke, heart failure, TIA, peripheral arterial disease, unstable angina, revascularization, CVD and total deathsLifetime3.5% (costs, benefits)Deterministic (one-way) and probabilistic
      6. Oliva [
      • Oliva J.
      • Lopez-Bastida J.
      • Moreno S.G.
      • Mata P.
      • Alonso R.
      [Cost-effectiveness analysis of a genetic screening program in the close relatives of Spanish patients with familial hypercholesterolemia].
      ] 2009, Spain
      CEALYG?XXXXXSocial perspectiveLife-table analysisNALifetime3% (costs, benefits)Deterministic (one-way) and probabilistic
      7. Wonderling [
      • Wonderling D.
      • Umans-Eckenhausen M.A.
      • Marks D.
      • Defesche J.C.
      • Kastelein J.J.
      • Thorogood M.
      Cost-effectiveness analysis of the genetic screening program for familial hypercholesterolemia in The Netherlands.
      ] 2004, The Netherlands
      CEALYGXXXXXXXHealth care systemLife-table analysisNALifetime4% (costs, benefits)Performed but not explained: Deterministic (one-way)
      8. Marang-van de Mheen [
      • Marang-van de Mheen P.J.
      • ten Asbroek A.H.A.
      • Bonneux L.
      • Bonsel G.J.
      • Klazinga N.S.
      Cost-effectiveness of a family and DNA based screening programme on familial hypercholesterolaemia in The Netherlands.
      ] 2002, The Netherlands
      CEALYGXXXXXX*Health care payer1Cohort life-table modelNALifetimeNo discount-tingDeterministic (one-way)
      9. Ademi [
      • Ademi Z.
      • Norman R.
      • Pang J.
      • et al.
      Health economic evaluation of screening and treating children with familial hypercholesterolemia early in life: many happy returns on investment?.
      ] 2020, Australia
      CUA and CEAQALYs, LYGs, non-fatal acute events, deathsX?XXXXXHealth care public payerMarkov modelAlive without CHD, alive with CHD, dead from fatal CHD and dead from other causesLifetime5% (costs and benefits)Deterministic (one-way) and probabilistic
      Cascade screening in combination with opportunistic screening or universal screening
      10. Pelczarska [
      • Pelczarska A.
      • Jakubczyk M.
      • Jakubiak-Lasocka J.
      • et al.
      The cost-effectiveness of screening strategies for familial hypercholesterolaemia in Poland.
      ] 2018, Poland
      CUA and CEALYs,

      QALYs
      XXXXXXHealth care public payerDecision tree plus Markov modelGeneral (undiagnosed FH cases in no screening case or diagnosed and treated FH patients after screening), CVD (patients with any CVD in the year of occurrence), Post-CVD (alive patients with a history of CVD), DeadLifetime5% (costs); 3.5% (benefits)Deterministic (one-way).
      11. Crosland [
      • Crosland P.
      • Maconachie R.
      • Buckner S.
      • McGuire H.
      • Humphries S.E.
      • Qureshi N.
      Cost-utility analysis of searching electronic health records and cascade testing to identify and diagnose familial hypercholesterolaemia in England and Wales.
      ] 2018, UK
      CEAQALYs (long-term),

      N and proportion of people with FH and polygenic FH who were treated vs. untreated,

      N of genetic tests conducted as a result of false positive clinical assessments (short-term)
      XXXX?X?Health care payerDecision tree plus Markov modelUntreated FH, treated FH, untreated polygenic, treated polygenicLifetime3.5% (costs, benefits)Deterministic (one-way) and probabilistic
      12. McKay [
      • McKay A.J.
      • Hogan H.
      • Humphries S.E.
      • Marks D.
      • Ray K.K.
      • Miners A.
      Universal screening at age 1-2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: a cost-utility analysis.
      ] 2018, UK
      CUAQALYs,

      FH cases identified per 10,000 screened
      XXXXXXXHealth care payerDecision tree plus Markov modelWell (no existing CVD), stable angina, unstable angina, MI, TIA, stroke, post-stable angina, post-unstable angina, post-MI, post-TIA, post-stroke, CHD death, Non-CHD CVD death, Non-CVD deathLifetime3.5% (costs, benefits)Deterministic (one-way) and probabilistic
      13. Marks [
      • Marks D.
      • Thorogood M.
      • Neil H.A.
      • Wonderling D.
      • Humphries S.E.
      Comparing costs and benefits over a 10 year period of strategies for familial hypercholesterolaemia screening.
      ] 2003, UK
      CEALYGs per case diagnosed, averted deaths per year and total deaths in a 10-year periodXXXXXHealth care payerDecision analysis with life tablesNA10 yearsNot clearly reportedPerformed but not explained: Deterministic (one-way)
      Universal or opportunistic screening
      14. Marks [
      • Marks D.
      • Wonderling D.
      • Thorogood M.
      • Lambert H.
      • Humphries S.E.
      • Neil H.A.
      Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
      ] 2002, UK
      CEAAverted deathsXXXXXXXHealth care payer1Decision tree + life-table analysisNALifetime6% (costs)

      1% (benefits)
      Deterministic (one-way)
      CEA – cost-effectiveness analysis, CHD – coronary heart disease, CS – cascade screening, CT – cascade testing, CUA – cost-utility analysis, CVD – cardiovascular disease, FH – familial hypercholesterolemia, GT – genetic testing, GS – genetic screening, IC – index case, ICER – incremental cost-effectiveness ratio, LY – life years, LYG – life years gained, MI – myocardial infarction, N – number, N/A – not applicable, NHS – national health system, NNT – number needed to treat, NR – not reported, Org. – organization, OS – opportunistic screening, Org. – organization screening program, QALY – quality-adjusted life years, PC – primary care, Pos. – positive, RCT – reverse cascade testing, SA – sensitivity analysis, Screen. – screening, SC – secondary care, Sens. – sensitivity, Seq. – sequential, Spec. – specificity, TC – total cholesterol, TIA – transient ischemic attack, UK – United Kingdom, UniS – universal screening, YoLS – years of life saved. 1It is not explicitly stated, *defined by authors as medical costs incurred through other diseases because the intervention prolongs life.
      All cost outcomes were converted into current EUR using Purchasing Power Parities (PPP) [

      OECD. Purschasing Power Parities (PPP). OECD.

      ] to convert currencies and the Consumer Price Index (CPI) [

      OECD. Inflation (CPI) OECD.

      ] to adjust for inflation. We reanalyzed ICERs using converted costs and applied ICER definitions in the strict sense, that is, we compared costs and health effects of each strategy in a stepwise manner to the next less expensive and economically rational strategy. Strategies that are either more costly and less effective than others (dominated), or that are less effective and have a higher incremental cost-effectiveness ratio than alternative strategies (weakly dominated, ruled out by extended dominance) were identified and excluded.
      Study designs were categorized as cost-effectiveness analyses (CEA) when incremental cost per incremental natural units (e.g., deaths averted, life-years gained [LYG]) were reported and as cost-utility studies when incremental cost per quality-adjusted life-years (QALY) gained were reported. In general, an intervention is considered cost effective if the ICER is less than a certain willingness-to pay (WTP) threshold. This WTP is often not explicitly defined and varies among countries [
      • Schwarzer R.
      • Rochau U.
      • Saverno K.
      • et al.
      Systematic overview of cost-effectiveness thresholds in ten countries across four continents.
      ]: “In an UniS context, the ratio may vary from $50,000/QALY up to $150,000/QALY - or more depending on individual or disease. For the National Health Service (NHS) in the UK, the threshold used on behalf of the NHS is £20,000/QALY, ranging up to £50,000/QALY for life-threatening conditions” [
      • Garrison L.P.
      • Towse A.
      Value-based pricing and reimbursement in personalised healthcare: introduction to the basic health economics.
      ].

      2.3 Quality assessment

      The quality of the selected studies was assessed according to the Consensus on Health Economic Criteria (CHEC-List) guidelines [
      • Evers S.
      • Goossens M.
      • de Vet H.
      • van Tulder M.
      • Ament A.
      Criteria list for assessment of methodological quality of economic evaluations: consensus on Health Economic Criteria.
      ] by two independent reviewers per study (JS, UR, IS, FK) and conflicts were resolved by a third reviewer (BJ).
      The study was registered at the ethics committee of UMIT (University for Health Sciences, Medical Computer Science and Technology, Hall i.T. Austria) (Registration 2973).

      3. Results

      3.1 Screening and study selection

      A total of 211 records were retrieved in the initial search (Supplementary Fig. 1), and 67 duplicates were subsequently removed. After the second screening step of full-text examination, seven studies were included in the review. Six studies published before 2012 were retrieved from the review by Ademi et al. [
      • Ademi Z.
      • Watts G.F.
      • Juniper A.
      • Liew D.
      A systematic review of economic evaluations of the detection and treatment of familial hypercholesterolemia.
      ]. One study was added that became available shortly after our search [
      • Ademi Z.
      • Norman R.
      • Pang J.
      • et al.
      Health economic evaluation of screening and treating children with familial hypercholesterolemia early in life: many happy returns on investment?.
      ].

      3.2 Key study assumptions and health economic outcomes

      The 14 included studies were conducted in Europe (United Kingdom (UK) [
      • Kerr M.
      • Pears R.
      • Miedzybrodzka Z.
      • et al.
      Cost effectiveness of cascade testing for familial hypercholesterolaemia, based on data from familial hypercholesterolaemia services in the UK.
      ,
      • Crosland P.
      • Maconachie R.
      • Buckner S.
      • McGuire H.
      • Humphries S.E.
      • Qureshi N.
      Cost-utility analysis of searching electronic health records and cascade testing to identify and diagnose familial hypercholesterolaemia in England and Wales.
      ,
      • McKay A.J.
      • Hogan H.
      • Humphries S.E.
      • Marks D.
      • Ray K.K.
      • Miners A.
      Universal screening at age 1-2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: a cost-utility analysis.
      ,
      • Marks D.
      • Wonderling D.
      • Thorogood M.
      • Lambert H.
      • Humphries S.E.
      • Neil H.A.
      Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
      ,
      • Marks D.
      • Thorogood M.
      • Neil H.A.
      • Wonderling D.
      • Humphries S.E.
      Comparing costs and benefits over a 10 year period of strategies for familial hypercholesterolaemia screening.
      ,
      • Nherera L.
      • Marks D.
      • Minhas R.
      • Thorogood M.
      • Humphries S.E.
      Probabilistic cost-effectiveness analysis of cascade screening for familial hypercholesterolaemia using alternative diagnostic and identification strategies.
      ], Spain [
      • Lazaro P.
      • Perez de Isla L.
      • Watts G.F.
      • et al.
      Cost-effectiveness of a cascade screening program for the early detection of familial hypercholesterolemia.
      ,
      • Oliva J.
      • Lopez-Bastida J.
      • Moreno S.G.
      • Mata P.
      • Alonso R.
      [Cost-effectiveness analysis of a genetic screening program in the close relatives of Spanish patients with familial hypercholesterolemia].
      ], The Netherlands [
      • Marang-van de Mheen P.J.
      • ten Asbroek A.H.A.
      • Bonneux L.
      • Bonsel G.J.
      • Klazinga N.S.
      Cost-effectiveness of a family and DNA based screening programme on familial hypercholesterolaemia in The Netherlands.
      ,
      • Wonderling D.
      • Umans-Eckenhausen M.A.
      • Marks D.
      • Defesche J.C.
      • Kastelein J.J.
      • Thorogood M.
      Cost-effectiveness analysis of the genetic screening program for familial hypercholesterolemia in The Netherlands.
      ] and Poland [
      • Pelczarska A.
      • Jakubczyk M.
      • Jakubiak-Lasocka J.
      • et al.
      The cost-effectiveness of screening strategies for familial hypercholesterolaemia in Poland.
      ]), in the United States (USA) [
      • Chen C.X.
      • Hay J.W.
      Cost-effectiveness analysis of alternative screening and treatment strategies for heterozygous familial hypercholesterolemia in the United States.
      ] and in Australia [
      • Ademi Z.
      • Norman R.
      • Pang J.
      • et al.
      Health economic evaluation of screening and treating children with familial hypercholesterolemia early in life: many happy returns on investment?.
      ,
      • Ademi Z.
      • Watts G.F.
      • Pang J.
      • et al.
      Cascade screening based on genetic testing is cost-effective: evidence for the implementation of models of care for familial hypercholesterolemia.
      ] in the years 2002–2020. The studies evaluated cascade screening (CS) for index cases (first person diagnosed with FH in the family, index case - IC) [
      • Ademi Z.
      • Norman R.
      • Pang J.
      • et al.
      Health economic evaluation of screening and treating children with familial hypercholesterolemia early in life: many happy returns on investment?.
      ,
      • Kerr M.
      • Pears R.
      • Miedzybrodzka Z.
      • et al.
      Cost effectiveness of cascade testing for familial hypercholesterolaemia, based on data from familial hypercholesterolaemia services in the UK.
      ,
      • Crosland P.
      • Maconachie R.
      • Buckner S.
      • McGuire H.
      • Humphries S.E.
      • Qureshi N.
      Cost-utility analysis of searching electronic health records and cascade testing to identify and diagnose familial hypercholesterolaemia in England and Wales.
      ,
      • Marks D.
      • Wonderling D.
      • Thorogood M.
      • Lambert H.
      • Humphries S.E.
      • Neil H.A.
      Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
      ,
      • Marks D.
      • Thorogood M.
      • Neil H.A.
      • Wonderling D.
      • Humphries S.E.
      Comparing costs and benefits over a 10 year period of strategies for familial hypercholesterolaemia screening.
      ,
      • Nherera L.
      • Marks D.
      • Minhas R.
      • Thorogood M.
      • Humphries S.E.
      Probabilistic cost-effectiveness analysis of cascade screening for familial hypercholesterolaemia using alternative diagnostic and identification strategies.
      ,
      • Lazaro P.
      • Perez de Isla L.
      • Watts G.F.
      • et al.
      Cost-effectiveness of a cascade screening program for the early detection of familial hypercholesterolemia.
      ,
      • Oliva J.
      • Lopez-Bastida J.
      • Moreno S.G.
      • Mata P.
      • Alonso R.
      [Cost-effectiveness analysis of a genetic screening program in the close relatives of Spanish patients with familial hypercholesterolemia].
      ,
      • Marang-van de Mheen P.J.
      • ten Asbroek A.H.A.
      • Bonneux L.
      • Bonsel G.J.
      • Klazinga N.S.
      Cost-effectiveness of a family and DNA based screening programme on familial hypercholesterolaemia in The Netherlands.
      ,
      • Wonderling D.
      • Umans-Eckenhausen M.A.
      • Marks D.
      • Defesche J.C.
      • Kastelein J.J.
      • Thorogood M.
      Cost-effectiveness analysis of the genetic screening program for familial hypercholesterolemia in The Netherlands.
      ,
      • Chen C.X.
      • Hay J.W.
      Cost-effectiveness analysis of alternative screening and treatment strategies for heterozygous familial hypercholesterolemia in the United States.
      ,
      • Ademi Z.
      • Watts G.F.
      • Pang J.
      • et al.
      Cascade screening based on genetic testing is cost-effective: evidence for the implementation of models of care for familial hypercholesterolemia.
      ], universal (US) [
      • McKay A.J.
      • Hogan H.
      • Humphries S.E.
      • Marks D.
      • Ray K.K.
      • Miners A.
      Universal screening at age 1-2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: a cost-utility analysis.
      ,
      • Marks D.
      • Wonderling D.
      • Thorogood M.
      • Lambert H.
      • Humphries S.E.
      • Neil H.A.
      Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
      ,
      • Marks D.
      • Thorogood M.
      • Neil H.A.
      • Wonderling D.
      • Humphries S.E.
      Comparing costs and benefits over a 10 year period of strategies for familial hypercholesterolaemia screening.
      ], opportunistic screening (OS) [
      • Marks D.
      • Wonderling D.
      • Thorogood M.
      • Lambert H.
      • Humphries S.E.
      • Neil H.A.
      Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
      ] or combinations of CS with UniS or OS [
      • Crosland P.
      • Maconachie R.
      • Buckner S.
      • McGuire H.
      • Humphries S.E.
      • Qureshi N.
      Cost-utility analysis of searching electronic health records and cascade testing to identify and diagnose familial hypercholesterolaemia in England and Wales.
      ,
      • McKay A.J.
      • Hogan H.
      • Humphries S.E.
      • Marks D.
      • Ray K.K.
      • Miners A.
      Universal screening at age 1-2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: a cost-utility analysis.
      ,
      • Pelczarska A.
      • Jakubczyk M.
      • Jakubiak-Lasocka J.
      • et al.
      The cost-effectiveness of screening strategies for familial hypercholesterolaemia in Poland.
      ] (Fig. 1). In the following paragraphs, key assumptions on the study populations, screening tests, screening strategies, test characteristics, treatment assumptions and results of cost-effectiveness analyses (CEA) are synthesized (Table 1).
      Fig. 1
      Fig. 1Evaluated types of screening interventions.
      In CS strategies, most studies considered a fixed number of relatives screened per IC ranging from 1.33 [
      • Ademi Z.
      • Watts G.F.
      • Pang J.
      • et al.
      Cascade screening based on genetic testing is cost-effective: evidence for the implementation of models of care for familial hypercholesterolemia.
      ] to 6.83 [
      • Kerr M.
      • Pears R.
      • Miedzybrodzka Z.
      • et al.
      Cost effectiveness of cascade testing for familial hypercholesterolaemia, based on data from familial hypercholesterolaemia services in the UK.
      ]. These studies implicitly assumed a participation rate of 100% for relatives of IC. Two studies from The Netherlands assumed a much higher number of relatives screened per IC (16.27 [
      • Marang-van de Mheen P.J.
      • ten Asbroek A.H.A.
      • Bonneux L.
      • Bonsel G.J.
      • Klazinga N.S.
      Cost-effectiveness of a family and DNA based screening programme on familial hypercholesterolaemia in The Netherlands.
      ]; 11–34 [
      • Wonderling D.
      • Umans-Eckenhausen M.A.
      • Marks D.
      • Defesche J.C.
      • Kastelein J.J.
      • Thorogood M.
      Cost-effectiveness analysis of the genetic screening program for familial hypercholesterolemia in The Netherlands.
      ] in sensitivity analysis). One study [
      • Crosland P.
      • Maconachie R.
      • Buckner S.
      • McGuire H.
      • Humphries S.E.
      • Qureshi N.
      Cost-utility analysis of searching electronic health records and cascade testing to identify and diagnose familial hypercholesterolaemia in England and Wales.
      ] explicitly modeled the number of relatives invited for screening per IC (2.22) and the participation rate on screening was assumed to be 59.9%. Marks et al. [
      • Marks D.
      • Wonderling D.
      • Thorogood M.
      • Lambert H.
      • Humphries S.E.
      • Neil H.A.
      Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
      ] assumed 95% attendance for family tracing. The assumed prevalence of FH in IC relatives ranged from 28% (relatives aged 30 years of IC with definite and possible FH) [
      • Nherera L.
      • Marks D.
      • Minhas R.
      • Thorogood M.
      • Humphries S.E.
      Probabilistic cost-effectiveness analysis of cascade screening for familial hypercholesterolaemia using alternative diagnostic and identification strategies.
      ]) to 95% (in IC relatives with hypercholesterolemia) [
      • Lazaro P.
      • Perez de Isla L.
      • Watts G.F.
      • et al.
      Cost-effectiveness of a cascade screening program for the early detection of familial hypercholesterolemia.
      ]. UniS strategies assumed an underlying FH prevalence of 0.2% among 16-year-olds [
      • Marks D.
      • Thorogood M.
      • Neil H.A.
      • Wonderling D.
      • Humphries S.E.
      Comparing costs and benefits over a 10 year period of strategies for familial hypercholesterolaemia screening.
      ], 0.4% within 1-2-year olds [
      • McKay A.J.
      • Hogan H.
      • Humphries S.E.
      • Marks D.
      • Ray K.K.
      • Miners A.
      Universal screening at age 1-2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: a cost-utility analysis.
      ], and 0.5% within 6-year-olds and people getting their first job or in 3.3% within people after first onset of acute coronary syndrome (ACS) [
      • Pelczarska A.
      • Jakubczyk M.
      • Jakubiak-Lasocka J.
      • et al.
      The cost-effectiveness of screening strategies for familial hypercholesterolaemia in Poland.
      ].
      In the evaluation of CS strategies [
      • Kerr M.
      • Pears R.
      • Miedzybrodzka Z.
      • et al.
      Cost effectiveness of cascade testing for familial hypercholesterolaemia, based on data from familial hypercholesterolaemia services in the UK.
      ,
      • Crosland P.
      • Maconachie R.
      • Buckner S.
      • McGuire H.
      • Humphries S.E.
      • Qureshi N.
      Cost-utility analysis of searching electronic health records and cascade testing to identify and diagnose familial hypercholesterolaemia in England and Wales.
      ,
      • Marks D.
      • Wonderling D.
      • Thorogood M.
      • Lambert H.
      • Humphries S.E.
      • Neil H.A.
      Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
      ,
      • Nherera L.
      • Marks D.
      • Minhas R.
      • Thorogood M.
      • Humphries S.E.
      Probabilistic cost-effectiveness analysis of cascade screening for familial hypercholesterolaemia using alternative diagnostic and identification strategies.
      ,
      • Lazaro P.
      • Perez de Isla L.
      • Watts G.F.
      • et al.
      Cost-effectiveness of a cascade screening program for the early detection of familial hypercholesterolemia.
      ,
      • Oliva J.
      • Lopez-Bastida J.
      • Moreno S.G.
      • Mata P.
      • Alonso R.
      [Cost-effectiveness analysis of a genetic screening program in the close relatives of Spanish patients with familial hypercholesterolemia].
      ,
      • Marang-van de Mheen P.J.
      • ten Asbroek A.H.A.
      • Bonneux L.
      • Bonsel G.J.
      • Klazinga N.S.
      Cost-effectiveness of a family and DNA based screening programme on familial hypercholesterolaemia in The Netherlands.
      ,
      • Wonderling D.
      • Umans-Eckenhausen M.A.
      • Marks D.
      • Defesche J.C.
      • Kastelein J.J.
      • Thorogood M.
      Cost-effectiveness analysis of the genetic screening program for familial hypercholesterolemia in The Netherlands.
      ,
      • Chen C.X.
      • Hay J.W.
      Cost-effectiveness analysis of alternative screening and treatment strategies for heterozygous familial hypercholesterolemia in the United States.
      ,
      • Ademi Z.
      • Watts G.F.
      • Pang J.
      • et al.
      Cascade screening based on genetic testing is cost-effective: evidence for the implementation of models of care for familial hypercholesterolemia.
      ], relatives of ICs were tested using genetic testing [
      • Kerr M.
      • Pears R.
      • Miedzybrodzka Z.
      • et al.
      Cost effectiveness of cascade testing for familial hypercholesterolaemia, based on data from familial hypercholesterolaemia services in the UK.
      ,
      • McKay A.J.
      • Hogan H.
      • Humphries S.E.
      • Marks D.
      • Ray K.K.
      • Miners A.
      Universal screening at age 1-2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: a cost-utility analysis.
      ,
      • Marks D.
      • Thorogood M.
      • Neil H.A.
      • Wonderling D.
      • Humphries S.E.
      Comparing costs and benefits over a 10 year period of strategies for familial hypercholesterolaemia screening.
      ,
      • Lazaro P.
      • Perez de Isla L.
      • Watts G.F.
      • et al.
      Cost-effectiveness of a cascade screening program for the early detection of familial hypercholesterolemia.
      ,
      • Marang-van de Mheen P.J.
      • ten Asbroek A.H.A.
      • Bonneux L.
      • Bonsel G.J.
      • Klazinga N.S.
      Cost-effectiveness of a family and DNA based screening programme on familial hypercholesterolaemia in The Netherlands.
      ,
      • Wonderling D.
      • Umans-Eckenhausen M.A.
      • Marks D.
      • Defesche J.C.
      • Kastelein J.J.
      • Thorogood M.
      Cost-effectiveness analysis of the genetic screening program for familial hypercholesterolemia in The Netherlands.
      ], LDL-C testing [
      • McKay A.J.
      • Hogan H.
      • Humphries S.E.
      • Marks D.
      • Ray K.K.
      • Miners A.
      Universal screening at age 1-2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: a cost-utility analysis.
      ,
      • Nherera L.
      • Marks D.
      • Minhas R.
      • Thorogood M.
      • Humphries S.E.
      Probabilistic cost-effectiveness analysis of cascade screening for familial hypercholesterolaemia using alternative diagnostic and identification strategies.
      ,
      • Chen C.X.
      • Hay J.W.
      Cost-effectiveness analysis of alternative screening and treatment strategies for heterozygous familial hypercholesterolemia in the United States.
      ] or both [
      • Ademi Z.
      • Norman R.
      • Pang J.
      • et al.
      Health economic evaluation of screening and treating children with familial hypercholesterolemia early in life: many happy returns on investment?.
      ,
      • Crosland P.
      • Maconachie R.
      • Buckner S.
      • McGuire H.
      • Humphries S.E.
      • Qureshi N.
      Cost-utility analysis of searching electronic health records and cascade testing to identify and diagnose familial hypercholesterolaemia in England and Wales.
      ,
      • McKay A.J.
      • Hogan H.
      • Humphries S.E.
      • Marks D.
      • Ray K.K.
      • Miners A.
      Universal screening at age 1-2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: a cost-utility analysis.
      ,
      • Marks D.
      • Wonderling D.
      • Thorogood M.
      • Lambert H.
      • Humphries S.E.
      • Neil H.A.
      Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
      ,
      • Ademi Z.
      • Watts G.F.
      • Pang J.
      • et al.
      Cascade screening based on genetic testing is cost-effective: evidence for the implementation of models of care for familial hypercholesterolemia.
      ]. In addition, Chen and Hay [
      • Chen C.X.
      • Hay J.W.
      Cost-effectiveness analysis of alternative screening and treatment strategies for heterozygous familial hypercholesterolemia in the United States.
      ] considered repeated LDL-C testing in previously FH-tested individuals.
      OS without CS was evaluated in patients with unrelated FH reasons in primary care and in patients admitted to hospital with premature myocardial infarction using clinical examination or genetic testing [
      • Marks D.
      • Wonderling D.
      • Thorogood M.
      • Lambert H.
      • Humphries S.E.
      • Neil H.A.
      Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
      ]. UniS without CS was evaluated for the general population [
      • Marks D.
      • Wonderling D.
      • Thorogood M.
      • Lambert H.
      • Humphries S.E.
      • Neil H.A.
      Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
      ] and for 16-year olds [
      • Marks D.
      • Wonderling D.
      • Thorogood M.
      • Lambert H.
      • Humphries S.E.
      • Neil H.A.
      Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
      ,
      • Marks D.
      • Thorogood M.
      • Neil H.A.
      • Wonderling D.
      • Humphries S.E.
      Comparing costs and benefits over a 10 year period of strategies for familial hypercholesterolaemia screening.
      ] using cholesterol and genetic testing. In addition, UniS strategies of one to two-year old children were considered in different strategies using a) cholesterol testing, b) sequential genetic testing after positive cholesterol testing or c) parallel cholesterol and genetic testing [
      • McKay A.J.
      • Hogan H.
      • Humphries S.E.
      • Marks D.
      • Ray K.K.
      • Miners A.
      Universal screening at age 1-2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: a cost-utility analysis.
      ].
      In the evaluations of combined strategies, CS was considered for IC identified a) in the aforementioned UniS of one to two-year old children [
      • McKay A.J.
      • Hogan H.
      • Humphries S.E.
      • Marks D.
      • Ray K.K.
      • Miners A.
      Universal screening at age 1-2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: a cost-utility analysis.
      ], b) in UniS of 16-year olds [
      • Marks D.
      • Thorogood M.
      • Neil H.A.
      • Wonderling D.
      • Humphries S.E.
      Comparing costs and benefits over a 10 year period of strategies for familial hypercholesterolaemia screening.
      ], c) among people getting their first job (screened using clinical diagnosis or a combination of clinical and genetic diagnosis), d) among six-year olds (using genetic testing), e) in people screened after the first onset of ACS or stroke with and without age restriction (using clinical or clinical and genetic testing) [
      • Pelczarska A.
      • Jakubczyk M.
      • Jakubiak-Lasocka J.
      • et al.
      The cost-effectiveness of screening strategies for familial hypercholesterolaemia in Poland.
      ], f) screening in primary care (with clinical assessment according to SB criteria or DLCN criteria), g) screening in secondary care (with clinical assessment according to SB criteria or DLCN criteria), h) screening in primary and secondary care with clinical assessment according to DLCN criteria, i) independent of screening in primary care [
      • Crosland P.
      • Maconachie R.
      • Buckner S.
      • McGuire H.
      • Humphries S.E.
      • Qureshi N.
      Cost-utility analysis of searching electronic health records and cascade testing to identify and diagnose familial hypercholesterolaemia in England and Wales.
      ], j) primary family members [
      • Ademi Z.
      • Norman R.
      • Pang J.
      • et al.
      Health economic evaluation of screening and treating children with familial hypercholesterolemia early in life: many happy returns on investment?.
      ]. This last-mentioned strategy considered primary care screening without CS of new primary care IC [
      • Crosland P.
      • Maconachie R.
      • Buckner S.
      • McGuire H.
      • Humphries S.E.
      • Qureshi N.
      Cost-utility analysis of searching electronic health records and cascade testing to identify and diagnose familial hypercholesterolaemia in England and Wales.
      ].
      For genetic testing, three studies assumed sensitivity and specificity of 100% [
      • Ademi Z.
      • Norman R.
      • Pang J.
      • et al.
      Health economic evaluation of screening and treating children with familial hypercholesterolemia early in life: many happy returns on investment?.
      ,
      • Crosland P.
      • Maconachie R.
      • Buckner S.
      • McGuire H.
      • Humphries S.E.
      • Qureshi N.
      Cost-utility analysis of searching electronic health records and cascade testing to identify and diagnose familial hypercholesterolaemia in England and Wales.
      ,
      • Lazaro P.
      • Perez de Isla L.
      • Watts G.F.
      • et al.
      Cost-effectiveness of a cascade screening program for the early detection of familial hypercholesterolemia.
      ,
      • Ademi Z.
      • Watts G.F.
      • Pang J.
      • et al.
      Cascade screening based on genetic testing is cost-effective: evidence for the implementation of models of care for familial hypercholesterolemia.
      ], other studies assumed a sensitivity of 78.5% [
      • Chen C.X.
      • Hay J.W.
      Cost-effectiveness analysis of alternative screening and treatment strategies for heterozygous familial hypercholesterolemia in the United States.
      ], a sensitivity of 86.76% and a 100% specificity [
      • Pelczarska A.
      • Jakubczyk M.
      • Jakubiak-Lasocka J.
      • et al.
      The cost-effectiveness of screening strategies for familial hypercholesterolaemia in Poland.
      ], a sensitivity of 99.9% and a specificity of 99.7% [
      • Oliva J.
      • Lopez-Bastida J.
      • Moreno S.G.
      • Mata P.
      • Alonso R.
      [Cost-effectiveness analysis of a genetic screening program in the close relatives of Spanish patients with familial hypercholesterolemia].
      ] and six studies did not explicitly state sensitivity and specificity [
      • Kerr M.
      • Pears R.
      • Miedzybrodzka Z.
      • et al.
      Cost effectiveness of cascade testing for familial hypercholesterolaemia, based on data from familial hypercholesterolaemia services in the UK.
      ,
      • Marks D.
      • Wonderling D.
      • Thorogood M.
      • Lambert H.
      • Humphries S.E.
      • Neil H.A.
      Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
      ,
      • Marks D.
      • Thorogood M.
      • Neil H.A.
      • Wonderling D.
      • Humphries S.E.
      Comparing costs and benefits over a 10 year period of strategies for familial hypercholesterolaemia screening.
      ,
      • Nherera L.
      • Marks D.
      • Minhas R.
      • Thorogood M.
      • Humphries S.E.
      Probabilistic cost-effectiveness analysis of cascade screening for familial hypercholesterolaemia using alternative diagnostic and identification strategies.
      ,
      • Marang-van de Mheen P.J.
      • ten Asbroek A.H.A.
      • Bonneux L.
      • Bonsel G.J.
      • Klazinga N.S.
      Cost-effectiveness of a family and DNA based screening programme on familial hypercholesterolaemia in The Netherlands.
      ,
      • Wonderling D.
      • Umans-Eckenhausen M.A.
      • Marks D.
      • Defesche J.C.
      • Kastelein J.J.
      • Thorogood M.
      Cost-effectiveness analysis of the genetic screening program for familial hypercholesterolemia in The Netherlands.
      ].
      LDL-C testing was assumed to have a sensitivity of 88% [
      • McKay A.J.
      • Hogan H.
      • Humphries S.E.
      • Marks D.
      • Ray K.K.
      • Miners A.
      Universal screening at age 1-2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: a cost-utility analysis.
      ] to 91% [
      • Chen C.X.
      • Hay J.W.
      Cost-effectiveness analysis of alternative screening and treatment strategies for heterozygous familial hypercholesterolemia in the United States.
      ]. For clinical assessments including LDL-testing, a sensitivity of 88.70% (DLCN criteria) [
      • Lazaro P.
      • Perez de Isla L.
      • Watts G.F.
      • et al.
      Cost-effectiveness of a cascade screening program for the early detection of familial hypercholesterolemia.
      ], and 100% [
      • Pelczarska A.
      • Jakubczyk M.
      • Jakubiak-Lasocka J.
      • et al.
      The cost-effectiveness of screening strategies for familial hypercholesterolaemia in Poland.
      ] (DLCN in adults and SB in children) was assumed. Three studies [
      • Marks D.
      • Wonderling D.
      • Thorogood M.
      • Lambert H.
      • Humphries S.E.
      • Neil H.A.
      Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
      ,
      • Marks D.
      • Thorogood M.
      • Neil H.A.
      • Wonderling D.
      • Humphries S.E.
      Comparing costs and benefits over a 10 year period of strategies for familial hypercholesterolaemia screening.
      ,
      • Nherera L.
      • Marks D.
      • Minhas R.
      • Thorogood M.
      • Humphries S.E.
      Probabilistic cost-effectiveness analysis of cascade screening for familial hypercholesterolaemia using alternative diagnostic and identification strategies.
      ] did not explicitly report on the sensitivity and specificity.
      Sequential LDL-C genetic testing and parallel testing was assumed to have a sensitivity and specificity of 100%, and sequential LDL-C-genetic testing was assumed to have a sensitivity of 96% and a specificity of 95.5% [
      • McKay A.J.
      • Hogan H.
      • Humphries S.E.
      • Marks D.
      • Ray K.K.
      • Miners A.
      Universal screening at age 1-2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: a cost-utility analysis.
      ].
      Adherence to cholesterol lowering treatment was assumed to be 100% [
      • Crosland P.
      • Maconachie R.
      • Buckner S.
      • McGuire H.
      • Humphries S.E.
      • Qureshi N.
      Cost-utility analysis of searching electronic health records and cascade testing to identify and diagnose familial hypercholesterolaemia in England and Wales.
      ,
      • McKay A.J.
      • Hogan H.
      • Humphries S.E.
      • Marks D.
      • Ray K.K.
      • Miners A.
      Universal screening at age 1-2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: a cost-utility analysis.
      ,
      • Marang-van de Mheen P.J.
      • ten Asbroek A.H.A.
      • Bonneux L.
      • Bonsel G.J.
      • Klazinga N.S.
      Cost-effectiveness of a family and DNA based screening programme on familial hypercholesterolaemia in The Netherlands.
      ,
      • Ademi Z.
      • Watts G.F.
      • Pang J.
      • et al.
      Cascade screening based on genetic testing is cost-effective: evidence for the implementation of models of care for familial hypercholesterolemia.
      ], 82% [
      • Marks D.
      • Wonderling D.
      • Thorogood M.
      • Lambert H.
      • Humphries S.E.
      • Neil H.A.
      Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
      ,
      • Marks D.
      • Thorogood M.
      • Neil H.A.
      • Wonderling D.
      • Humphries S.E.
      Comparing costs and benefits over a 10 year period of strategies for familial hypercholesterolaemia screening.
      ], 69.1% (without adherence program) and 95.5% (with adherence program) [
      • Chen C.X.
      • Hay J.W.
      Cost-effectiveness analysis of alternative screening and treatment strategies for heterozygous familial hypercholesterolemia in the United States.
      ], 100% during childhood and an decline to 82.4% of patients keeping up with the treatment over 10 years from 18 years old on [
      • Ademi Z.
      • Norman R.
      • Pang J.
      • et al.
      Health economic evaluation of screening and treating children with familial hypercholesterolemia early in life: many happy returns on investment?.
      ], or it was not further specified [
      • Nherera L.
      • Marks D.
      • Minhas R.
      • Thorogood M.
      • Humphries S.E.
      Probabilistic cost-effectiveness analysis of cascade screening for familial hypercholesterolaemia using alternative diagnostic and identification strategies.
      ,
      • Lazaro P.
      • Perez de Isla L.
      • Watts G.F.
      • et al.
      Cost-effectiveness of a cascade screening program for the early detection of familial hypercholesterolemia.
      ,
      • Oliva J.
      • Lopez-Bastida J.
      • Moreno S.G.
      • Mata P.
      • Alonso R.
      [Cost-effectiveness analysis of a genetic screening program in the close relatives of Spanish patients with familial hypercholesterolemia].
      ,
      • Wonderling D.
      • Umans-Eckenhausen M.A.
      • Marks D.
      • Defesche J.C.
      • Kastelein J.J.
      • Thorogood M.
      Cost-effectiveness analysis of the genetic screening program for familial hypercholesterolemia in The Netherlands.
      ,
      • Pelczarska A.
      • Jakubczyk M.
      • Jakubiak-Lasocka J.
      • et al.
      The cost-effectiveness of screening strategies for familial hypercholesterolaemia in Poland.
      ]. Four studies [
      • Kerr M.
      • Pears R.
      • Miedzybrodzka Z.
      • et al.
      Cost effectiveness of cascade testing for familial hypercholesterolaemia, based on data from familial hypercholesterolaemia services in the UK.
      ,
      • McKay A.J.
      • Hogan H.
      • Humphries S.E.
      • Marks D.
      • Ray K.K.
      • Miners A.
      Universal screening at age 1-2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: a cost-utility analysis.
      ,
      • Wonderling D.
      • Umans-Eckenhausen M.A.
      • Marks D.
      • Defesche J.C.
      • Kastelein J.J.
      • Thorogood M.
      Cost-effectiveness analysis of the genetic screening program for familial hypercholesterolemia in The Netherlands.
      ,
      • Chen C.X.
      • Hay J.W.
      Cost-effectiveness analysis of alternative screening and treatment strategies for heterozygous familial hypercholesterolemia in the United States.
      ] considered adherence in the sensitivity analysis.
      All studies comparing CS to no screening predicted gains in life expectancy and/or quality-adjusted life expectancy, acute non-fatal events or death averted. Strategies that focused on CS only had ICERs ranging from 4182 EUR/QALY (genetic screening for first-degree relatives of patients with FH, Spain [
      • Oliva J.
      • Lopez-Bastida J.
      • Moreno S.G.
      • Mata P.
      • Alonso R.
      [Cost-effectiveness analysis of a genetic screening program in the close relatives of Spanish patients with familial hypercholesterolemia].
      ]) to 37,082 EUR/QALY (DNA testing of DLCN and genetically confirmed IC, Spain) [
      • Lazaro P.
      • Perez de Isla L.
      • Watts G.F.
      • et al.
      Cost-effectiveness of a cascade screening program for the early detection of familial hypercholesterolemia.
      ], when compared to no screening, and conducted from the healthcare payer perspective. CS was dominant (less costly and most effective) in comparison to no screening from a societal perspective [
      • Lazaro P.
      • Perez de Isla L.
      • Watts G.F.
      • et al.
      Cost-effectiveness of a cascade screening program for the early detection of familial hypercholesterolemia.
      ] and from a healthcare public payer perspective in Ademi et al., 2020 [
      • Ademi Z.
      • Norman R.
      • Pang J.
      • et al.
      Health economic evaluation of screening and treating children with familial hypercholesterolemia early in life: many happy returns on investment?.
      ]. In the study of Chen et al. [
      • Chen C.X.
      • Hay J.W.
      Cost-effectiveness analysis of alternative screening and treatment strategies for heterozygous familial hypercholesterolemia in the United States.
      ], the DNA-based CS was weakly dominated by CS using LDL-C (lipid-based) in combination with an adherence program for treatment. However, the ICER of lipid-based screening in comparison to no screening was not reported by Chen et al. [
      • Chen C.X.
      • Hay J.W.
      Cost-effectiveness analysis of alternative screening and treatment strategies for heterozygous familial hypercholesterolemia in the United States.
      ] In the study of Crosland et al. [
      • Crosland P.
      • Maconachie R.
      • Buckner S.
      • McGuire H.
      • Humphries S.E.
      • Qureshi N.
      Cost-utility analysis of searching electronic health records and cascade testing to identify and diagnose familial hypercholesterolaemia in England and Wales.
      ], genetic CS was weakly dominated by genetic CS of IC combined with IC identification in primary care. This combined strategy showed an ICER of 1378 EUR/QALY in comparison to no screening. DNA testing for identification of IC and testing of relatives of IC was more effective than clinical diagnosis and identification of affected relatives using elevation of LDL-cholesterol levels, with an ICER of 606 EUR/QALY [
      • Nherera L.
      • Marks D.
      • Minhas R.
      • Thorogood M.
      • Humphries S.E.
      Probabilistic cost-effectiveness analysis of cascade screening for familial hypercholesterolaemia using alternative diagnostic and identification strategies.
      ].
      Among the UniS strategies of newborns, strategies focusing on newborns but not including CS for identified IC was a dominated strategy [
      • McKay A.J.
      • Hogan H.
      • Humphries S.E.
      • Marks D.
      • Ray K.K.
      • Miners A.
      Universal screening at age 1-2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: a cost-utility analysis.
      ]. Sequential genetic testing among cholesterol screened positive individuals in combination with CS had an ICER of 14,572 EUR and parallel cholesterol screening – genetic testing in combination with CS had an ICER of 417,420 EUR/QALY [
      • McKay A.J.
      • Hogan H.
      • Humphries S.E.
      • Marks D.
      • Ray K.K.
      • Miners A.
      Universal screening at age 1-2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: a cost-utility analysis.
      ]. Cascade screening of ten-year-olds was cost saving in comparison to no screening [
      • Ademi Z.
      • Norman R.
      • Pang J.
      • et al.
      Health economic evaluation of screening and treating children with familial hypercholesterolemia early in life: many happy returns on investment?.
      ].
      UniS of 16-year olds with cholesterol testing was dominated by CS [
      • Marks D.
      • Thorogood M.
      • Neil H.A.
      • Wonderling D.
      • Humphries S.E.
      Comparing costs and benefits over a 10 year period of strategies for familial hypercholesterolaemia screening.
      ]. UniS strategies of people getting their first job or six-year olds in combination with CS were dominated in a comparison with OS of people after onset of acute-coronary syndromes (ACS) [
      • Pelczarska A.
      • Jakubczyk M.
      • Jakubiak-Lasocka J.
      • et al.
      The cost-effectiveness of screening strategies for familial hypercholesterolaemia in Poland.
      ]. In comparison to no screening, Opportunistic screening of people after ACS (ACS-OS) based on clinical criteria showed an ICER of 209 EUR/QALY in comparison to no screening. The effect of screening could further be increased using additional genetic testing. The evaluated ACS-OS based on clinical criteria and genetic diagnostic in men younger than 55 and women younger than 65 showed an ICER of 1338 EUR/QALY in comparison with using clinical criteria only in the same cohort. ACS-OS strategies without age restriction were dominated [
      • Pelczarska A.
      • Jakubczyk M.
      • Jakubiak-Lasocka J.
      • et al.
      The cost-effectiveness of screening strategies for familial hypercholesterolaemia in Poland.
      ].
      An overview of reported or recalculated ICERs for non-dominated strategies in each study is provided in Fig. 3.

      3.3 Characteristics of the decision-analytic modeling frameworks

      The main characteristics of the decision-analytic modeling frameworks are summarized in Table 2 and Fig. 2. Four studies performed cost-utility analysis (CUA, effectiveness measured in QALYs) and CEA [
      • Ademi Z.
      • Norman R.
      • Pang J.
      • et al.
      Health economic evaluation of screening and treating children with familial hypercholesterolemia early in life: many happy returns on investment?.
      ,
      • Lazaro P.
      • Perez de Isla L.
      • Watts G.F.
      • et al.
      Cost-effectiveness of a cascade screening program for the early detection of familial hypercholesterolemia.
      ,
      • Pelczarska A.
      • Jakubczyk M.
      • Jakubiak-Lasocka J.
      • et al.
      The cost-effectiveness of screening strategies for familial hypercholesterolaemia in Poland.
      ,
      • Ademi Z.
      • Watts G.F.
      • Pang J.
      • et al.
      Cascade screening based on genetic testing is cost-effective: evidence for the implementation of models of care for familial hypercholesterolemia.
      ], three studies a CUA [
      • Kerr M.
      • Pears R.
      • Miedzybrodzka Z.
      • et al.
      Cost effectiveness of cascade testing for familial hypercholesterolaemia, based on data from familial hypercholesterolaemia services in the UK.
      ,
      • McKay A.J.
      • Hogan H.
      • Humphries S.E.
      • Marks D.
      • Ray K.K.
      • Miners A.
      Universal screening at age 1-2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: a cost-utility analysis.
      ,
      • Chen C.X.
      • Hay J.W.
      Cost-effectiveness analysis of alternative screening and treatment strategies for heterozygous familial hypercholesterolemia in the United States.
      ] and seven studies a CEA [
      • Crosland P.
      • Maconachie R.
      • Buckner S.
      • McGuire H.
      • Humphries S.E.
      • Qureshi N.
      Cost-utility analysis of searching electronic health records and cascade testing to identify and diagnose familial hypercholesterolaemia in England and Wales.
      ,
      • Marks D.
      • Wonderling D.
      • Thorogood M.
      • Lambert H.
      • Humphries S.E.
      • Neil H.A.
      Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
      ,
      • Marks D.
      • Thorogood M.
      • Neil H.A.
      • Wonderling D.
      • Humphries S.E.
      Comparing costs and benefits over a 10 year period of strategies for familial hypercholesterolaemia screening.
      ,
      • Nherera L.
      • Marks D.
      • Minhas R.
      • Thorogood M.
      • Humphries S.E.
      Probabilistic cost-effectiveness analysis of cascade screening for familial hypercholesterolaemia using alternative diagnostic and identification strategies.
      ,
      • Oliva J.
      • Lopez-Bastida J.
      • Moreno S.G.
      • Mata P.
      • Alonso R.
      [Cost-effectiveness analysis of a genetic screening program in the close relatives of Spanish patients with familial hypercholesterolemia].
      ,
      • Marang-van de Mheen P.J.
      • ten Asbroek A.H.A.
      • Bonneux L.
      • Bonsel G.J.
      • Klazinga N.S.
      Cost-effectiveness of a family and DNA based screening programme on familial hypercholesterolaemia in The Netherlands.
      ,
      • Wonderling D.
      • Umans-Eckenhausen M.A.
      • Marks D.
      • Defesche J.C.
      • Kastelein J.J.
      • Thorogood M.
      Cost-effectiveness analysis of the genetic screening program for familial hypercholesterolemia in The Netherlands.
      ]. Ten out of thirteen studies considered the healthcare payer perspective, two studies adopted a societal perspective [
      • Oliva J.
      • Lopez-Bastida J.
      • Moreno S.G.
      • Mata P.
      • Alonso R.
      [Cost-effectiveness analysis of a genetic screening program in the close relatives of Spanish patients with familial hypercholesterolemia].
      ,
      • Chen C.X.
      • Hay J.W.
      Cost-effectiveness analysis of alternative screening and treatment strategies for heterozygous familial hypercholesterolemia in the United States.
      ], and one study provided outcomes from the healthcare payer and the societal perspective [
      • Lazaro P.
      • Perez de Isla L.
      • Watts G.F.
      • et al.
      Cost-effectiveness of a cascade screening program for the early detection of familial hypercholesterolemia.
      ]. All studies applied a decision-analytic model focusing either on a lifetime (11, 79%) [
      • Ademi Z.
      • Norman R.
      • Pang J.
      • et al.
      Health economic evaluation of screening and treating children with familial hypercholesterolemia early in life: many happy returns on investment?.
      ,
      • Kerr M.
      • Pears R.
      • Miedzybrodzka Z.
      • et al.
      Cost effectiveness of cascade testing for familial hypercholesterolaemia, based on data from familial hypercholesterolaemia services in the UK.
      ,
      • Crosland P.
      • Maconachie R.
      • Buckner S.
      • McGuire H.
      • Humphries S.E.
      • Qureshi N.
      Cost-utility analysis of searching electronic health records and cascade testing to identify and diagnose familial hypercholesterolaemia in England and Wales.
      ,
      • McKay A.J.
      • Hogan H.
      • Humphries S.E.
      • Marks D.
      • Ray K.K.
      • Miners A.
      Universal screening at age 1-2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: a cost-utility analysis.
      ,
      • Marks D.
      • Wonderling D.
      • Thorogood M.
      • Lambert H.
      • Humphries S.E.
      • Neil H.A.
      Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
      ,
      • Nherera L.
      • Marks D.
      • Minhas R.
      • Thorogood M.
      • Humphries S.E.
      Probabilistic cost-effectiveness analysis of cascade screening for familial hypercholesterolaemia using alternative diagnostic and identification strategies.
      ,
      • Oliva J.
      • Lopez-Bastida J.
      • Moreno S.G.
      • Mata P.
      • Alonso R.
      [Cost-effectiveness analysis of a genetic screening program in the close relatives of Spanish patients with familial hypercholesterolemia].
      ,
      • Marang-van de Mheen P.J.
      • ten Asbroek A.H.A.
      • Bonneux L.
      • Bonsel G.J.
      • Klazinga N.S.
      Cost-effectiveness of a family and DNA based screening programme on familial hypercholesterolaemia in The Netherlands.
      ,
      • Wonderling D.
      • Umans-Eckenhausen M.A.
      • Marks D.
      • Defesche J.C.
      • Kastelein J.J.
      • Thorogood M.
      Cost-effectiveness analysis of the genetic screening program for familial hypercholesterolemia in The Netherlands.
      ,
      • Pelczarska A.
      • Jakubczyk M.
      • Jakubiak-Lasocka J.
      • et al.
      The cost-effectiveness of screening strategies for familial hypercholesterolaemia in Poland.
      ,
      • Chen C.X.
      • Hay J.W.
      Cost-effectiveness analysis of alternative screening and treatment strategies for heterozygous familial hypercholesterolemia in the United States.
      ] or 10-year analytic time horizon (3, 21%) [
      • Lazaro P.
      • Perez de Isla L.
      • Watts G.F.
      • et al.
      Cost-effectiveness of a cascade screening program for the early detection of familial hypercholesterolemia.
      ,
      • Ademi Z.
      • Watts G.F.
      • Pang J.
      • et al.
      Cascade screening based on genetic testing is cost-effective: evidence for the implementation of models of care for familial hypercholesterolemia.
      ].
      Fig. 2
      Fig. 2Applied modeling approaches for cost-effectiveness analyses.
      Fig. 3
      Fig. 3Overview incremental cost-effectiveness ratios (ICER).
      Graphic should be read as follows: ICER of program 1 in McKay et al. [
      • McKay A.J.
      • Hogan H.
      • Humphries S.E.
      • Marks D.
      • Ray K.K.
      • Miners A.
      Universal screening at age 1-2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: a cost-utility analysis.
      ] is 15,000 EUR/LYG compared to no screening (as stated) and the ICER of program 2 is calculated in comparison to the program on the left hand side, that is, program 1. Not all studies analyzed a no screening alternative (e.g., Chen et al. [
      • Chen C.X.
      • Hay J.W.
      Cost-effectiveness analysis of alternative screening and treatment strategies for heterozygous familial hypercholesterolemia in the United States.
      ]).ACS-acute coronary disease, AUS-Australia, CBO-Dutch Institute on Health Care Improvement consensus, CS-cascade screening, DFH-definite familial hypercholesterolemia, DLCN-Dutch Lipid Clinic Network-WHO, EUR-euros, FH-familial hypercholesterolemia, GT–genetic testing, ICER-Incremental cost-effectiveness ratio, LYG-life years gained, NED-The Netherlands, NS-no screening, OS-opportunistic screening, PC-primary care, PFH-possible familial hypercholesterolemia, POL-Poland, Pos.-positive, QALY-quality adjusted life-year, RCT-reverse cascade testing, SB-Simone Broome, SC-secondary care, Seq.-sequential, SPA-Spain, Treat.-treatment, UK-United Kingdom, UniS-universal screening. Dominated strategies not shown. ∼In McKay et al., ICER>400,000. *ICERs are expressed in EUR/LYG. **no ICER reported because the strategy is cost-saving.
      Reported health outcomes are averted-coronary events [
      • Ademi Z.
      • Norman R.
      • Pang J.
      • et al.
      Health economic evaluation of screening and treating children with familial hypercholesterolemia early in life: many happy returns on investment?.
      ,
      • Kerr M.
      • Pears R.
      • Miedzybrodzka Z.
      • et al.
      Cost effectiveness of cascade testing for familial hypercholesterolaemia, based on data from familial hypercholesterolaemia services in the UK.
      ,
      • Lazaro P.
      • Perez de Isla L.
      • Watts G.F.
      • et al.
      Cost-effectiveness of a cascade screening program for the early detection of familial hypercholesterolemia.
      ,
      • Ademi Z.
      • Watts G.F.
      • Pang J.
      • et al.
      Cascade screening based on genetic testing is cost-effective: evidence for the implementation of models of care for familial hypercholesterolemia.
      ], averted-cardiac deaths [
      • Kerr M.
      • Pears R.
      • Miedzybrodzka Z.
      • et al.
      Cost effectiveness of cascade testing for familial hypercholesterolaemia, based on data from familial hypercholesterolaemia services in the UK.
      ,
      • Marks D.
      • Wonderling D.
      • Thorogood M.
      • Lambert H.
      • Humphries S.E.
      • Neil H.A.
      Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
      ,
      • Marks D.
      • Thorogood M.
      • Neil H.A.
      • Wonderling D.
      • Humphries S.E.
      Comparing costs and benefits over a 10 year period of strategies for familial hypercholesterolaemia screening.
      ,
      • Lazaro P.
      • Perez de Isla L.
      • Watts G.F.
      • et al.
      Cost-effectiveness of a cascade screening program for the early detection of familial hypercholesterolemia.
      ,
      • Ademi Z.
      • Watts G.F.
      • Pang J.
      • et al.
      Cascade screening based on genetic testing is cost-effective: evidence for the implementation of models of care for familial hypercholesterolemia.
      ], cases of FH identified [
      • McKay A.J.
      • Hogan H.
      • Humphries S.E.
      • Marks D.
      • Ray K.K.
      • Miners A.
      Universal screening at age 1-2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: a cost-utility analysis.
      ], total deaths [
      • Ademi Z.
      • Norman R.
      • Pang J.
      • et al.
      Health economic evaluation of screening and treating children with familial hypercholesterolemia early in life: many happy returns on investment?.
      ,
      • Marks D.
      • Thorogood M.
      • Neil H.A.
      • Wonderling D.
      • Humphries S.E.
      Comparing costs and benefits over a 10 year period of strategies for familial hypercholesterolaemia screening.
      ], number and proportion of FH and polygenic FH who were treated vs. untreated [
      • Crosland P.
      • Maconachie R.
      • Buckner S.
      • McGuire H.
      • Humphries S.E.
      • Qureshi N.
      Cost-utility analysis of searching electronic health records and cascade testing to identify and diagnose familial hypercholesterolaemia in England and Wales.
      ], number of genetic tests conducted as a result of false positive clinical assessments [
      • Crosland P.
      • Maconachie R.
      • Buckner S.
      • McGuire H.
      • Humphries S.E.
      • Qureshi N.
      Cost-utility analysis of searching electronic health records and cascade testing to identify and diagnose familial hypercholesterolaemia in England and Wales.
      ], life years (LYs) [
      • Ademi Z.
      • Norman R.
      • Pang J.
      • et al.
      Health economic evaluation of screening and treating children with familial hypercholesterolemia early in life: many happy returns on investment?.
      ,
      • Marks D.
      • Thorogood M.
      • Neil H.A.
      • Wonderling D.
      • Humphries S.E.
      Comparing costs and benefits over a 10 year period of strategies for familial hypercholesterolaemia screening.
      ,
      • Oliva J.
      • Lopez-Bastida J.
      • Moreno S.G.
      • Mata P.
      • Alonso R.
      [Cost-effectiveness analysis of a genetic screening program in the close relatives of Spanish patients with familial hypercholesterolemia].
      ,
      • Marang-van de Mheen P.J.
      • ten Asbroek A.H.A.
      • Bonneux L.
      • Bonsel G.J.
      • Klazinga N.S.
      Cost-effectiveness of a family and DNA based screening programme on familial hypercholesterolaemia in The Netherlands.
      ,
      • Wonderling D.
      • Umans-Eckenhausen M.A.
      • Marks D.
      • Defesche J.C.
      • Kastelein J.J.
      • Thorogood M.
      Cost-effectiveness analysis of the genetic screening program for familial hypercholesterolemia in The Netherlands.
      ,
      • Pelczarska A.
      • Jakubczyk M.
      • Jakubiak-Lasocka J.
      • et al.
      The cost-effectiveness of screening strategies for familial hypercholesterolaemia in Poland.
      ,
      • Ademi Z.
      • Watts G.F.
      • Pang J.
      • et al.
      Cascade screening based on genetic testing is cost-effective: evidence for the implementation of models of care for familial hypercholesterolemia.
      ] and QALYs [
      • Ademi Z.
      • Norman R.
      • Pang J.
      • et al.
      Health economic evaluation of screening and treating children with familial hypercholesterolemia early in life: many happy returns on investment?.
      ,
      • Kerr M.
      • Pears R.
      • Miedzybrodzka Z.
      • et al.
      Cost effectiveness of cascade testing for familial hypercholesterolaemia, based on data from familial hypercholesterolaemia services in the UK.
      ,
      • Crosland P.
      • Maconachie R.
      • Buckner S.
      • McGuire H.
      • Humphries S.E.
      • Qureshi N.
      Cost-utility analysis of searching electronic health records and cascade testing to identify and diagnose familial hypercholesterolaemia in England and Wales.
      ,
      • McKay A.J.
      • Hogan H.
      • Humphries S.E.
      • Marks D.
      • Ray K.K.
      • Miners A.
      Universal screening at age 1-2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: a cost-utility analysis.
      ,
      • Nherera L.
      • Marks D.
      • Minhas R.
      • Thorogood M.
      • Humphries S.E.
      Probabilistic cost-effectiveness analysis of cascade screening for familial hypercholesterolaemia using alternative diagnostic and identification strategies.
      ,
      • Lazaro P.
      • Perez de Isla L.
      • Watts G.F.
      • et al.
      Cost-effectiveness of a cascade screening program for the early detection of familial hypercholesterolemia.
      ,
      • Pelczarska A.
      • Jakubczyk M.
      • Jakubiak-Lasocka J.
      • et al.
      The cost-effectiveness of screening strategies for familial hypercholesterolaemia in Poland.
      ,
      • Chen C.X.
      • Hay J.W.
      Cost-effectiveness analysis of alternative screening and treatment strategies for heterozygous familial hypercholesterolemia in the United States.
      ,
      • Ademi Z.
      • Watts G.F.
      • Pang J.
      • et al.
      Cascade screening based on genetic testing is cost-effective: evidence for the implementation of models of care for familial hypercholesterolemia.
      ].
      All studies included the costs of screening tests for relatives of IC, and costs of cardiac events. All studies included screening costs for finding IC except for three where it was not clearly stated [
      • Marks D.
      • Wonderling D.
      • Thorogood M.
      • Lambert H.
      • Humphries S.E.
      • Neil H.A.
      Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
      ,
      • Nherera L.
      • Marks D.
      • Minhas R.
      • Thorogood M.
      • Humphries S.E.
      Probabilistic cost-effectiveness analysis of cascade screening for familial hypercholesterolaemia using alternative diagnostic and identification strategies.
      ,
      • Oliva J.
      • Lopez-Bastida J.
      • Moreno S.G.
      • Mata P.
      • Alonso R.
      [Cost-effectiveness analysis of a genetic screening program in the close relatives of Spanish patients with familial hypercholesterolemia].
      ]. The majority of studies included organization of screening programs (10, 77.0%) [
      • Ademi Z.
      • Norman R.
      • Pang J.
      • et al.
      Health economic evaluation of screening and treating children with familial hypercholesterolemia early in life: many happy returns on investment?.
      ,
      • Kerr M.
      • Pears R.
      • Miedzybrodzka Z.
      • et al.
      Cost effectiveness of cascade testing for familial hypercholesterolaemia, based on data from familial hypercholesterolaemia services in the UK.
      ,
      • Crosland P.
      • Maconachie R.
      • Buckner S.
      • McGuire H.
      • Humphries S.E.
      • Qureshi N.
      Cost-utility analysis of searching electronic health records and cascade testing to identify and diagnose familial hypercholesterolaemia in England and Wales.
      ,
      • McKay A.J.
      • Hogan H.
      • Humphries S.E.
      • Marks D.
      • Ray K.K.
      • Miners A.
      Universal screening at age 1-2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: a cost-utility analysis.
      ,
      • Marks D.
      • Wonderling D.
      • Thorogood M.
      • Lambert H.
      • Humphries S.E.
      • Neil H.A.
      Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
      ,
      • Marks D.
      • Thorogood M.
      • Neil H.A.
      • Wonderling D.
      • Humphries S.E.
      Comparing costs and benefits over a 10 year period of strategies for familial hypercholesterolaemia screening.
      ,
      • Nherera L.
      • Marks D.
      • Minhas R.
      • Thorogood M.
      • Humphries S.E.
      Probabilistic cost-effectiveness analysis of cascade screening for familial hypercholesterolaemia using alternative diagnostic and identification strategies.
      ,
      • Lazaro P.
      • Perez de Isla L.
      • Watts G.F.
      • et al.
      Cost-effectiveness of a cascade screening program for the early detection of familial hypercholesterolemia.
      ,
      • Marang-van de Mheen P.J.
      • ten Asbroek A.H.A.
      • Bonneux L.
      • Bonsel G.J.
      • Klazinga N.S.
      Cost-effectiveness of a family and DNA based screening programme on familial hypercholesterolaemia in The Netherlands.
      ,
      • Wonderling D.
      • Umans-Eckenhausen M.A.
      • Marks D.
      • Defesche J.C.
      • Kastelein J.J.
      • Thorogood M.
      Cost-effectiveness analysis of the genetic screening program for familial hypercholesterolemia in The Netherlands.
      ,
      • Pelczarska A.
      • Jakubczyk M.
      • Jakubiak-Lasocka J.
      • et al.
      The cost-effectiveness of screening strategies for familial hypercholesterolaemia in Poland.
      ,
      • Chen C.X.
      • Hay J.W.
      Cost-effectiveness analysis of alternative screening and treatment strategies for heterozygous familial hypercholesterolemia in the United States.
      ], consultation costs for the screening (10, 77.0%) [
      • McKay A.J.
      • Hogan H.
      • Humphries S.E.
      • Marks D.
      • Ray K.K.
      • Miners A.
      Universal screening at age 1-2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: a cost-utility analysis.
      ,
      • Marks D.
      • Wonderling D.
      • Thorogood M.
      • Lambert H.
      • Humphries S.E.
      • Neil H.A.
      Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
      ,
      • Marks D.
      • Thorogood M.
      • Neil H.A.
      • Wonderling D.
      • Humphries S.E.
      Comparing costs and benefits over a 10 year period of strategies for familial hypercholesterolaemia screening.
      ,
      • Nherera L.
      • Marks D.
      • Minhas R.
      • Thorogood M.
      • Humphries S.E.
      Probabilistic cost-effectiveness analysis of cascade screening for familial hypercholesterolaemia using alternative diagnostic and identification strategies.
      ,
      • Lazaro P.
      • Perez de Isla L.
      • Watts G.F.
      • et al.
      Cost-effectiveness of a cascade screening program for the early detection of familial hypercholesterolemia.
      ,
      • Oliva J.
      • Lopez-Bastida J.
      • Moreno S.G.
      • Mata P.
      • Alonso R.
      [Cost-effectiveness analysis of a genetic screening program in the close relatives of Spanish patients with familial hypercholesterolemia].
      ,
      • Marang-van de Mheen P.J.
      • ten Asbroek A.H.A.
      • Bonneux L.
      • Bonsel G.J.
      • Klazinga N.S.
      Cost-effectiveness of a family and DNA based screening programme on familial hypercholesterolaemia in The Netherlands.
      ,
      • Wonderling D.
      • Umans-Eckenhausen M.A.
      • Marks D.
      • Defesche J.C.
      • Kastelein J.J.
      • Thorogood M.
      Cost-effectiveness analysis of the genetic screening program for familial hypercholesterolemia in The Netherlands.
      ,
      • Pelczarska A.
      • Jakubczyk M.
      • Jakubiak-Lasocka J.
      • et al.
      The cost-effectiveness of screening strategies for familial hypercholesterolaemia in Poland.
      ,
      • Chen C.X.
      • Hay J.W.
      Cost-effectiveness analysis of alternative screening and treatment strategies for heterozygous familial hypercholesterolemia in the United States.
      ], and some studies included follow-up visit costs (3, 42.9%) [
      • Ademi Z.
      • Norman R.
      • Pang J.
      • et al.
      Health economic evaluation of screening and treating children with familial hypercholesterolemia early in life: many happy returns on investment?.
      ,
      • McKay A.J.
      • Hogan H.
      • Humphries S.E.
      • Marks D.
      • Ray K.K.
      • Miners A.
      Universal screening at age 1-2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: a cost-utility analysis.
      ,
      • Marks D.
      • Wonderling D.
      • Thorogood M.
      • Lambert H.
      • Humphries S.E.
      • Neil H.A.
      Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
      ,
      • Lazaro P.
      • Perez de Isla L.
      • Watts G.F.
      • et al.
      Cost-effectiveness of a cascade screening program for the early detection of familial hypercholesterolemia.
      ,
      • Oliva J.
      • Lopez-Bastida J.
      • Moreno S.G.
      • Mata P.
      • Alonso R.
      [Cost-effectiveness analysis of a genetic screening program in the close relatives of Spanish patients with familial hypercholesterolemia].
      ,
      • Marang-van de Mheen P.J.
      • ten Asbroek A.H.A.
      • Bonneux L.
      • Bonsel G.J.
      • Klazinga N.S.
      Cost-effectiveness of a family and DNA based screening programme on familial hypercholesterolaemia in The Netherlands.
      ,
      • Wonderling D.
      • Umans-Eckenhausen M.A.
      • Marks D.
      • Defesche J.C.
      • Kastelein J.J.
      • Thorogood M.
      Cost-effectiveness analysis of the genetic screening program for familial hypercholesterolemia in The Netherlands.
      ,
      • Chen C.X.
      • Hay J.W.
      Cost-effectiveness analysis of alternative screening and treatment strategies for heterozygous familial hypercholesterolemia in the United States.
      ]. All studies considered treatment of detected FH cases if clinically necessary. Treatment included statins but also diet or other lifestyle-change interventions in some studies. Only one study considered costs of novel currently expensive therapies (e.g. PCSK9) explicitly [
      • Lazaro P.
      • Perez de Isla L.
      • Watts G.F.
      • et al.
      Cost-effectiveness of a cascade screening program for the early detection of familial hypercholesterolemia.
      ].
      Applied decision-analytic modeling approaches are decision trees [
      • Lazaro P.
      • Perez de Isla L.
      • Watts G.F.
      • et al.
      Cost-effectiveness of a cascade screening program for the early detection of familial hypercholesterolemia.
      ], life-table analysis [
      • Oliva J.
      • Lopez-Bastida J.
      • Moreno S.G.
      • Mata P.
      • Alonso R.
      [Cost-effectiveness analysis of a genetic screening program in the close relatives of Spanish patients with familial hypercholesterolemia].
      ,
      • Marang-van de Mheen P.J.
      • ten Asbroek A.H.A.
      • Bonneux L.
      • Bonsel G.J.
      • Klazinga N.S.
      Cost-effectiveness of a family and DNA based screening programme on familial hypercholesterolaemia in The Netherlands.
      ,
      • Wonderling D.
      • Umans-Eckenhausen M.A.
      • Marks D.
      • Defesche J.C.
      • Kastelein J.J.
      • Thorogood M.
      Cost-effectiveness analysis of the genetic screening program for familial hypercholesterolemia in The Netherlands.
      ], state-transition cohort (Markov) models [
      • Ademi Z.
      • Norman R.
      • Pang J.
      • et al.
      Health economic evaluation of screening and treating children with familial hypercholesterolemia early in life: many happy returns on investment?.
      ,
      • Kerr M.
      • Pears R.
      • Miedzybrodzka Z.
      • et al.
      Cost effectiveness of cascade testing for familial hypercholesterolaemia, based on data from familial hypercholesterolaemia services in the UK.
      ], combinations of decision trees with life-table analysis [
      • Marks D.
      • Wonderling D.
      • Thorogood M.
      • Lambert H.
      • Humphries S.E.
      • Neil H.A.
      Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
      ,
      • Marks D.
      • Thorogood M.
      • Neil H.A.
      • Wonderling D.
      • Humphries S.E.
      Comparing costs and benefits over a 10 year period of strategies for familial hypercholesterolaemia screening.
      ] and combinations of decision trees with Markov models [
      • Crosland P.
      • Maconachie R.
      • Buckner S.
      • McGuire H.
      • Humphries S.E.
      • Qureshi N.
      Cost-utility analysis of searching electronic health records and cascade testing to identify and diagnose familial hypercholesterolaemia in England and Wales.
      ,
      • McKay A.J.
      • Hogan H.
      • Humphries S.E.
      • Marks D.
      • Ray K.K.
      • Miners A.
      Universal screening at age 1-2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: a cost-utility analysis.
      ,
      • Nherera L.
      • Marks D.
      • Minhas R.
      • Thorogood M.
      • Humphries S.E.
      Probabilistic cost-effectiveness analysis of cascade screening for familial hypercholesterolaemia using alternative diagnostic and identification strategies.
      ,
      • Pelczarska A.
      • Jakubczyk M.
      • Jakubiak-Lasocka J.
      • et al.
      The cost-effectiveness of screening strategies for familial hypercholesterolaemia in Poland.
      ,
      • Chen C.X.
      • Hay J.W.
      Cost-effectiveness analysis of alternative screening and treatment strategies for heterozygous familial hypercholesterolemia in the United States.
      ,
      • Ademi Z.
      • Watts G.F.
      • Pang J.
      • et al.
      Cascade screening based on genetic testing is cost-effective: evidence for the implementation of models of care for familial hypercholesterolemia.
      ]. All studies performed a one-way deterministic sensitivity analysis, and five studies [
      • Ademi Z.
      • Norman R.
      • Pang J.
      • et al.
      Health economic evaluation of screening and treating children with familial hypercholesterolemia early in life: many happy returns on investment?.
      ,
      • Crosland P.
      • Maconachie R.
      • Buckner S.
      • McGuire H.
      • Humphries S.E.
      • Qureshi N.
      Cost-utility analysis of searching electronic health records and cascade testing to identify and diagnose familial hypercholesterolaemia in England and Wales.
      ,
      • McKay A.J.
      • Hogan H.
      • Humphries S.E.
      • Marks D.
      • Ray K.K.
      • Miners A.
      Universal screening at age 1-2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: a cost-utility analysis.
      ,
      • Oliva J.
      • Lopez-Bastida J.
      • Moreno S.G.
      • Mata P.
      • Alonso R.
      [Cost-effectiveness analysis of a genetic screening program in the close relatives of Spanish patients with familial hypercholesterolemia].
      ,
      • Chen C.X.
      • Hay J.W.
      Cost-effectiveness analysis of alternative screening and treatment strategies for heterozygous familial hypercholesterolemia in the United States.
      ,
      • Ademi Z.
      • Watts G.F.
      • Pang J.
      • et al.
      Cascade screening based on genetic testing is cost-effective: evidence for the implementation of models of care for familial hypercholesterolemia.
      ] additionally provided a probabilistic sensitivity analysis.

      3.4 Quality assessment

      The quality assessment of the economic evaluations (Supplementary Table 5) revealed a lack of quality in the valuation of costs, the choice of perspectives, performing comprehensive sensitivity analysis and correct calculation of incremental cost-effectiveness ratios. None of the studies reported on model validation.

      4. Discussion

      We performed a semi-quantitative systematic review of economic studies on familial hypercholesterolemia screening. Our review included 14 studies evaluating CS [
      • Ademi Z.
      • Norman R.
      • Pang J.
      • et al.
      Health economic evaluation of screening and treating children with familial hypercholesterolemia early in life: many happy returns on investment?.
      ,
      • Kerr M.
      • Pears R.
      • Miedzybrodzka Z.
      • et al.
      Cost effectiveness of cascade testing for familial hypercholesterolaemia, based on data from familial hypercholesterolaemia services in the UK.
      ,
      • Crosland P.
      • Maconachie R.
      • Buckner S.
      • McGuire H.
      • Humphries S.E.
      • Qureshi N.
      Cost-utility analysis of searching electronic health records and cascade testing to identify and diagnose familial hypercholesterolaemia in England and Wales.
      ,
      • Marks D.
      • Wonderling D.
      • Thorogood M.
      • Lambert H.
      • Humphries S.E.
      • Neil H.A.
      Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
      ,
      • Marks D.
      • Thorogood M.
      • Neil H.A.
      • Wonderling D.
      • Humphries S.E.
      Comparing costs and benefits over a 10 year period of strategies for familial hypercholesterolaemia screening.
      ,
      • Nherera L.
      • Marks D.
      • Minhas R.
      • Thorogood M.
      • Humphries S.E.
      Probabilistic cost-effectiveness analysis of cascade screening for familial hypercholesterolaemia using alternative diagnostic and identification strategies.
      ,
      • Lazaro P.
      • Perez de Isla L.
      • Watts G.F.
      • et al.
      Cost-effectiveness of a cascade screening program for the early detection of familial hypercholesterolemia.
      ,
      • Oliva J.
      • Lopez-Bastida J.
      • Moreno S.G.
      • Mata P.
      • Alonso R.
      [Cost-effectiveness analysis of a genetic screening program in the close relatives of Spanish patients with familial hypercholesterolemia].
      ,
      • Marang-van de Mheen P.J.
      • ten Asbroek A.H.A.
      • Bonneux L.
      • Bonsel G.J.
      • Klazinga N.S.
      Cost-effectiveness of a family and DNA based screening programme on familial hypercholesterolaemia in The Netherlands.
      ,
      • Wonderling D.
      • Umans-Eckenhausen M.A.
      • Marks D.
      • Defesche J.C.
      • Kastelein J.J.
      • Thorogood M.
      Cost-effectiveness analysis of the genetic screening program for familial hypercholesterolemia in The Netherlands.
      ,
      • Chen C.X.
      • Hay J.W.
      Cost-effectiveness analysis of alternative screening and treatment strategies for heterozygous familial hypercholesterolemia in the United States.
      ,
      • Ademi Z.
      • Watts G.F.
      • Pang J.
      • et al.
      Cascade screening based on genetic testing is cost-effective: evidence for the implementation of models of care for familial hypercholesterolemia.
      ], UniS [
      • McKay A.J.
      • Hogan H.
      • Humphries S.E.
      • Marks D.
      • Ray K.K.
      • Miners A.
      Universal screening at age 1-2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: a cost-utility analysis.
      ,
      • Marks D.
      • Wonderling D.
      • Thorogood M.
      • Lambert H.
      • Humphries S.E.
      • Neil H.A.
      Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
      ,
      • Marks D.
      • Thorogood M.
      • Neil H.A.
      • Wonderling D.
      • Humphries S.E.
      Comparing costs and benefits over a 10 year period of strategies for familial hypercholesterolaemia screening.
      ], OS [
      • Marks D.
      • Wonderling D.
      • Thorogood M.
      • Lambert H.
      • Humphries S.E.
      • Neil H.A.
      Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
      ] or combinations of CS with UniS or OS [
      • Crosland P.
      • Maconachie R.
      • Buckner S.
      • McGuire H.
      • Humphries S.E.
      • Qureshi N.
      Cost-utility analysis of searching electronic health records and cascade testing to identify and diagnose familial hypercholesterolaemia in England and Wales.
      ,
      • McKay A.J.
      • Hogan H.
      • Humphries S.E.
      • Marks D.
      • Ray K.K.
      • Miners A.
      Universal screening at age 1-2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: a cost-utility analysis.
      ,
      • Pelczarska A.
      • Jakubczyk M.
      • Jakubiak-Lasocka J.
      • et al.
      The cost-effectiveness of screening strategies for familial hypercholesterolaemia in Poland.
      ].
      Studies were conducted in different countries and based on assumptions that varied among studies such as FH prevalence, test accuracy, participation rates for screening and treatment, etc. Therefore, the results need to be interpreted carefully for other settings. In summary, all studies that compare CS to no screening predicted gains in life expectancy and/or quality-adjusted life expectancy or deaths averted. Studies evaluating only CS starting from an IC reported ICERs of up to 37,100 EUR/QALY, which is below a commonly accepted willingness-to-pay threshold in Europe [
      • Schwarzer R.
      • Rochau U.
      • Saverno K.
      • et al.
      Systematic overview of cost-effectiveness thresholds in ten countries across four continents.
      ,
      • Robinson L.A.
      • Hammitt J.K.
      • Chang A.Y.
      • Resch S.
      Understanding and improving the one and three times GDP per capita cost-effectiveness thresholds.