Advertisement

Screening for familial hypercholesterolaemia in primary care: Time for general practice to play its part

  • Tom Brett
    Correspondence
    Corresponding author. The University of Notre Dame, School of Medicine, 19 Mouat Street (PO Box 1225), Fremantle, Western Australia, 6959, Australia.
    Affiliations
    General Practice and Primary Health Care Research, School of Medicine, The University of Notre Dame Australia, Fremantle, Western Australia, Australia
    Search for articles by this author
  • Nadeem Qureshi
    Affiliations
    Division of Primary Care, School of Medicine, University of Nottingham, United Kingdom
    Search for articles by this author
  • Samuel Gidding
    Affiliations
    Cardiology Division Head, Nemours Cardiac Center, A. I. duPont Hospital for Children, Wilmington, Delaware, USA
    Search for articles by this author
  • Gerald F. Watts
    Affiliations
    School of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Australia

    Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, Perth, Australia
    Search for articles by this author

      Highlights

      • A minority of familial hypercholesteroleamia (FH) cases are currently identified.
      • FH meets World Health Organisation (WHO) criteria for screening but new models of detection are required.
      • Primary care practice is a useful site for FH detection.
      • Early recognition of FH provides an excellent opportunity for preventing coronary artery disease (CAD).
      • Increasing public and health professional awareness is essential for screening success.

      Abstract

      Fifty per cent of first-degree relatives of index cases with familial hypercholesterolemia (FH) inherit the disorder. Despite cascade screening being the most cost-effective method for detecting new cases, only a minority of individuals with FH are currently identified. Primary care is a key target area to increase identification of new index cases and initiate cascade screening, thereby finding close relatives of all probands. Increasing public and health professional awareness about FH is essential.
      In the United Kingdom and in Australia, most of the population are reviewed by a General Practitioner (GP) at least once over a three-year period, offering opportunities to check for FH as part of routine clinical consultations. Such opportunistic approaches can be supplemented by systematically searching electronic health records with information technology tools that identify high risk patients. GPs can help investigate and implement results of this data retrieval.
      Current evidence suggests that early detection of FH and cascade testing meet most of the criteria for a worthwhile screening program. Among heterozygous patients the long latent period before the expected onset of coronary artery disease provides an opportunity for initiating effective drug and lifestyle changes. The greatest challenge for primary care is to implement an efficacious model of care that incorporates sustainable identification and management pathways.

      Keywords

      1. Introduction

      There is a general lack of public [
      • Gidding S.S.
      • Champagne M.A.
      • de Ferranti S.D.
      • et al.
      The agenda for familial hypercholesterolemia - a scientific statement from the american heart association.
      ,
      • Qureshi N.
      • Humphries S.E.
      • Seed M.
      • et al.
      Identification and management of familial hypercholesterolaemia: what does it mean to primary care?.
      ,
      • Watts G.F.
      • Sullivan D.R.
      • Poplawski N.
      • et al.
      Familial hypercholesterolaemia: a model of care for Australasia.
      ] and health professional [
      • Hollman G.
      • Olsson A.G.
      • Ek A.-C.
      Disease knowledge and adherence to treatment in patients with familial hypercholesterolemia.
      ,
      • Batais M.A.
      • Almigbal T.H.
      • Abdulhak A.A.B.
      • et al.
      Assessment of physicians' awareness and knowledge of familial hypercholesterolemia in Saudi Arabia: is there a gap?.
      ,
      • Bell D.A.
      • Garton-Smith J.
      • Vickery A.
      • et al.
      Familial hypercholesterolaemia in primary care: knowledge and practices among general practitioners in western Australia.
      ,
      • Pang J.
      • Hu M.
      • Lin J.
      • et al.
      An enquiry based on a standardised questionnaire into knowledge, awareness and preferences concerning the care of familial hypercholesterolaemia among primary care physicians in the Asia-Pacific region: the “Ten Countries Study”.
      ] awareness of heterozygous Familial hypercholesterolaemia (FH) as a common, autosomal dominant disorder of lipid metabolism [
      • Austin M.A.
      • Hutter C.M.
      • Zimmern R.L.
      • et al.
      Genetic causes of monogenic heterozygous familial hypercholesterolaemia: a HuGE prevalence review.
      ,
      • Nordestgaard B.
      • Chapman M.
      • Humphries S.
      • 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).
      ,
      • Soutar A.K.
      • Naoumova R.P.
      Mechanisms of Disease: genetic causes of familial hypercholesterolemia.
      ]. FH can cause premature coronary artery disease (CAD) if left untreated [
      • Marks D.
      • Thorogood M.
      • Neil H.A.W.
      • et al.
      A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia.
      ] with up to 50% of males likely to develop CAD by age 50 years and 30% of females similarly affected by age 60 years. Owing to a genetic defect in the low-density lipoprotein (LDL)-receptor pathway, affected patients cannot clear LDL particles from the circulation, which untreated leads to life-long, accumulation of low-density lipoprotein cholesterol (LDL-c) in plasma and accelerated atherosclerosis [
      • Austin M.A.
      • Hutter C.M.
      • Zimmern R.L.
      • et al.
      Genetic causes of monogenic heterozygous familial hypercholesterolaemia: a HuGE prevalence review.
      ,
      • Soutar A.K.
      • Naoumova R.P.
      Mechanisms of Disease: genetic causes of familial hypercholesterolemia.
      ,
      • Wiegman A.
      • Gidding S.S.
      • Watts G.F.
      • et al.
      Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment.
      ,
      • Varret M.
      • Abifadel M.
      • Rabès J.P.
      • et al.
      Genetic heterogeneity of autosomal dominant hypercholesterolemia.
      ]. FH patients cannot be managed solely by diet and lifestyle modifications. The cumulative cholesterol burden in homozygous FH is much greater as the condition is inherited from both parents [
      • Austin M.A.
      • Hutter C.M.
      • Zimmern R.L.
      • et al.
      Genetic causes of monogenic heterozygous familial hypercholesterolaemia: a HuGE prevalence review.
      ]. Such patients develop severe life-threatening coronary heart disease (CHD) and other vascular complications in late childhood and adolescence if not recognised and treated.
      FH affects 1 in 250 of the population [
      • Benn M.
      • Watts G.F.
      • Tybjaerg-Hansen A.
      • et al.
      Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication.
      ,
      • Watts G.F.
      • Shaw J.E.
      • Pang J.
      • et al.
      Prevalence and treatment of familial hypercholesterolemia in Australian communities.
      ,
      • de Ferranti S.D.
      • Rodday A.M.
      • Mendelson M.M.
      • et al.
      Prevalence of familial hypercholesterolemia in the 1999 to 2012 United States national health and nutrition examination surveys (NHANES).
      ]. Such a prevalence would expect to yield over 30 million patients worldwide, 240,000 in the United Kingdom (UK) and 90,000 in Australia. With over 85% of the Australian and UK population attending a General Practitioner (GP) at least once a year [
      • National Institute for Health and Clinical Excellence and The National Collaborating Centre for Primary Care
      NICE Clinical Guideline 71: Identification and Management of Familial Hypercholesterolaemia.
      ,

      Information Services Division Scotland, Practice Team Information (PTI) Annual Update, 2012/13.

      ,
      • Britt H.
      • Miller G.C.
      • Charles J.
      • et al.
      General Practice Activity in Australia 2000–01 to 2009–10: 10 Year Data Tables.
      ], opportunities exist for primary care to play a much more active role in the detection and care of FH patients in the future.
      Despite increasing knowledge of the clinical hallmarks of FH – elevated LDL-c levels, family and personal history of premature CHD, premature arcus cornealis and tendon xanthomata, most cases of FH are still not being recognised [
      • Gidding S.S.
      • Champagne M.A.
      • de Ferranti S.D.
      • et al.
      The agenda for familial hypercholesterolemia - a scientific statement from the american heart association.
      ,
      • Nordestgaard B.
      • Chapman M.
      • Humphries S.
      • 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).
      ,
      • Wiegman A.
      • Gidding S.S.
      • Watts G.F.
      • et al.
      Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment.
      ]. Amongst patients recognised as having FH, most remain under-treated [
      • Nordestgaard B.
      • Chapman M.
      • Humphries S.
      • 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).
      ]. Various explanations have been offered to explain these missed opportunities for diagnoses including busy clinical settings at tertiary and primary care level, pressure on bed availability and early discharge policies from hospitals [
      • Dorsch M.F.
      • Lawrance R.A.
      • Durham N.P.
      • et al.
      Familial hypercholesterolaemia is underdiagnosed after AMI.
      ]. Increasing complexity and amount of multimorbidity [
      • Brett T.
      • Arnold-Reed D.E.
      • Popescu A.
      • et al.
      Multimorbidity in patients attending 2 Australian primary care practices.
      ] in routine clinical presentations to GPs make recognition of FH especially challenging [
      • Brett T.
      • Watts G.F.
      • Arnold-Reed D.E.
      • et al.
      Challenges in the care of familial hypercholesterolemia: a community care perspective.
      ].
      Coronary care units are other settings where FH may be identified. Patients with early onset of symptoms of ischemic heart disease may be admitted for further assessment and treatment. Such encounters will usually involve a shared care role for GPs, cardiologist and hospital specialist. Evidence to date suggests these are often missed opportunities for FH diagnoses in some patients [
      • Dorsch M.F.
      • Lawrance R.A.
      • Durham N.P.
      • et al.
      Familial hypercholesterolaemia is underdiagnosed after AMI.
      ].
      Effective treatment is available and earlier beliefs that regression of atheromatous plaques could not be achieved are being challenged, with studies showing intensive drug therapy can have a beneficial effect [
      • Feig J.E.
      • Feig J.L.
      • Kini A.S.
      Statins, atherosclerosis regression and HDL: insights from within the plaque.
      ,
      • Nissen S.E.
      • Nicholls S.J.
      • Sipahi I.
      • et al.
      Effect of very high-intensity statin therapy on regression of coronary atherosclerosis.
      ]. Compliance with optimum treatment, usually statins, can be problematic at both patient and health professional levels [
      • Wiegman A.
      • Gidding S.S.
      • Watts G.F.
      • et al.
      Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment.
      ,
      • Goldberg A.C.
      • Hopkins P.N.
      • Toth P.P.
      • et al.
      Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the national lipid association expert panel on familial hypercholesterolemia.
      ] and needs regular review and re-enforcement.
      We review the potential to increase the role of primary care in the detection and care of FH.

      2. International guidelines and approaches

      The Consensus Statement of the European Atherosclerosis Society [
      • Nordestgaard B.
      • Chapman M.
      • Humphries S.
      • 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).
      ] and the International FH Foundation [
      • Watts G.F.
      • Gidding S.
      • Wierzbicki A.S.
      • et al.
      Integrated guidance on the care of familial hypercholesterolaemia from the international FH foundation.
      ] both recommend that most patients with FH should be managed in the primary care setting and preferably in the family context. They advise that there should be provision for more complex cases, including children, to be managed through specialist lipid or FH clinics.
      It is increasingly recognised that childhood and early adolescence offer the most favourable timeframe for diagnosing FH as well as introducing and maintaining lifelong treatment and management strategies [
      • Watts G.F.
      • Sullivan D.R.
      • Poplawski N.
      • et al.
      Familial hypercholesterolaemia: a model of care for Australasia.
      ,
      • Nordestgaard B.
      • Chapman M.
      • Humphries S.
      • 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).
      ,
      • Wiegman A.
      • Gidding S.S.
      • Watts G.F.
      • et al.
      Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment.
      ]. To achieve such radical care from a young age will require a shift in community and health professional perceptions of FH and its effects on the young. Little attention has been given to date to screening for FH in general practice where most affected patients are found.
      In countries with a history of dedicated screening programs, such as the Netherlands and Norway, the outcomes in terms of newly diagnosed FH index cases and cascade tested relatives are much higher than countries lacking any formal screening program (usually <1%) [
      • Nordestgaard B.
      • Chapman M.
      • Humphries S.
      • 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).
      ,
      • Louter L.
      • Defesche J.
      • Roeters van Lennep J.
      Cascade screening for familial hypercholesterolemia: practical consequences.
      ].
      Evidence suggests that cascade screening of close relatives is generally highly acceptable and does not impact on quality of life [
      • Louter L.
      • Defesche J.
      • Roeters van Lennep J.
      Cascade screening for familial hypercholesterolemia: practical consequences.
      ]. The Dutch FH cascade screening program operated between 1994 and 2014 using the services of genetic field workers and was very successful [
      • Louter L.
      • Defesche J.
      • Roeters van Lennep J.
      Cascade screening for familial hypercholesterolemia: practical consequences.
      ]. Since the program was modified due to changes in the Dutch Health System, numbers diagnosed have dropped [
      • Louter L.
      • Defesche J.
      • Roeters van Lennep J.
      Cascade screening for familial hypercholesterolemia: practical consequences.
      ].
      Most Australian and UK primary care practices are fully computerised, often with links to pathology providers and hospital services, thus lending themselves to electronic examination of patient databases for chronic hereditary conditions such as FH. In Australia, laboratory alerts either through a direct telephone call [
      • Bell D.A.
      • Hooper A.J.
      • Edwards G.
      • et al.
      Detecting familial hypercholesterolaemia in the community: impact of a telephone call from a chemical pathologist to the requesting general practitioner.
      ] from the chemical pathologist to GP or through flagging of raised lipids reports raising possibility of FH [
      • Bell D.A.
      • Hooper A.J.
      • Bender R.
      • et al.
      Opportunistic screening for familial hypercholesterolaemia via a community laboratory.
      ,
      • Bell D.A.
      • Bender R.
      • Hooper A.J.
      • et al.
      Impact of interpretative commenting on lipid profiles in people at high risk of familial hypercholesterolaemia.
      ] have been successful. Other Australian community-based initiatives include examining general practice and laboratory databases [
      • Kirke A.B.
      • Barbour R.A.
      • Burrows S.
      • et al.
      Systematic detection of familial hypercholesterolaemia in primary health care: a community based prospective study of three methods.
      ], use of algorithm [
      • Vickery A.W.
      • Bell D.
      • Garton-Smith J.
      • et al.
      Optimising the detection and management of familial hypercholesterolaemia: central role of primary care and its integration with specialist services.
      ] or data extractions tools [
      • Troeung L.
      • Arnold-Reed D.
      • Chan She Ping-Delfos W.
      • et al.
      A new electronic screening tool for identifying risk of familial hypercholesterolaemia in general practice.
      ].
      In the UK, the accessibility to most GPs of regionally located specialist lipid clinics has provided valuable additional support for primary care management [
      • Humphries S.E.
      • Neil H.A.W.
      Developing and applying clinically useful approaches to identify individuals with familial hypercholesterolemia in the UK.
      ] while GP-based approaches involving database searches have also been trialled [
      • Gray J.
      • Jaiyeola A.
      Identifying patients with familial hypercholesterolaemia in primary care: an informatics-based approach in one primary care centre.
      ,
      • Weng S.F.
      • Kai J.
      • Neil H.A.
      • et al.
      Improving identification of familial hypercholesterolaemia in primary care: derivation and validation of the familial hypercholesterolaemia case ascertainment tool (FAMCAT).
      ].
      In Slovenia, the use of universal screening for children aged over 5 years has been introduced to help with the detection of FH [
      • Klančar G.
      • Grošelj U.
      • Kovač J.
      • et al.
      Universal screening for familial hypercholesterolemia in children.
      ], but the practicalities and cost-effectiveness remain to be confirmed. In the United States, universal screening of cholesterol at age 9–11 has been endorsed by the American Academy of Pediatrics and the National Lipid Association (NLA), but has been incompletely undertaken and cost benefit analyses of this approach have not been performed [
      • Marks D.
      • Wonderling D.
      • Thorogood M.
      • et al.
      Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
      ].

      3. Screening for FH in primary care

      Primary care based screening for FH fulfils many of the revised Wilson and Jungner criteria [
      • Andermann A.
      • Blancquaert I.
      • Beauchamp S.
      • et al.
      Revisiting Wilson and Jungner in the genomic age: a review of screening criteria over the past 40 years.
      ], including the updated Australian Government population screening guidelines [
      • Australian Health Ministers’ Advisory Council (AHMAC)
      Standing Committee on Screening of the Community Care and Population Health Principal Committee.
      ] (Table 1).
      Table 1Screening criteria for FH and role and opportunities for primary care.
      Screening criteria
      (1) The screening programme should respond to a recognised need
      • Over 85% of patients with FH have not been identified [
        • Qureshi N.
        • Humphries S.E.
        • Seed M.
        • et al.
        Identification and management of familial hypercholesterolaemia: what does it mean to primary care?.
        ].
      • Without treatment CHD develops [
        • Gidding S.S.
        • Champagne M.A.
        • de Ferranti S.D.
        • et al.
        The agenda for familial hypercholesterolemia - a scientific statement from the american heart association.
        ,
        • Watts G.F.
        • Sullivan D.R.
        • Poplawski N.
        • et al.
        Familial hypercholesterolaemia: a model of care for Australasia.
        ,
        • Nordestgaard B.
        • Chapman M.
        • Humphries S.
        • 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).
        ].
      (2) The objective of screening should be defined at the outset
      • Identification of patients at very high risk of premature CHD [
        • Gidding S.S.
        • Champagne M.A.
        • de Ferranti S.D.
        • et al.
        The agenda for familial hypercholesterolemia - a scientific statement from the american heart association.
        ,
        • Watts G.F.
        • Sullivan D.R.
        • Poplawski N.
        • et al.
        Familial hypercholesterolaemia: a model of care for Australasia.
        ,
        • Nordestgaard B.
        • Chapman M.
        • Humphries S.
        • 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).
        ].
      • High intensity lipid lowering treatment can lead to 48% reduction in CHD mortality [
        • Gidding S.S.
        • Champagne M.A.
        • de Ferranti S.D.
        • et al.
        The agenda for familial hypercholesterolemia - a scientific statement from the american heart association.
        ,
        • Watts G.F.
        • Sullivan D.R.
        • Poplawski N.
        • et al.
        Familial hypercholesterolaemia: a model of care for Australasia.
        ,
        • Nordestgaard B.
        • Chapman M.
        • Humphries S.
        • 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).
        ].
      (3) There should be a defined target populationLess consensus, but is based on an interplay of an individual's cholesterol levels and family history of premature coronary heart disease, familial hypercholesterolemia and/or raised cholesterol eg:
      • Cholesterol levels > 9.3 mmol/l indicated FH in 28% of patients [
        • Futema M.
        • Kumari M.
        • Boustred C.
        • et al.
        Would raising the total cholesterol diagnostic cut-off from 7.5 mmol/L to 9.3 mmol/L improve detection rate of patients with monogenic familial hypercholesterolaemia?.
        ]
      • Cholesterol levels > 7.5 mmol/l should trigger further assessment of FH [
        • Qureshi N.
        • Humphries S.E.
        • Seed M.
        • et al.
        Identification and management of familial hypercholesterolaemia: what does it mean to primary care?.
        ,
        • Gray J.
        • Jaiyeola A.
        Identifying patients with familial hypercholesterolaemia in primary care: an informatics-based approach in one primary care centre.
        ]
      • Personal or family history of premature CHD [
        • National Institute for Health and Clinical Excellence and The National Collaborating Centre for Primary Care
        NICE Clinical Guideline 71: Identification and Management of Familial Hypercholesterolaemia.
        ]
      • Diagnostic criteria such as the DLCN [
        • World Health Organization
        Familial Hypercholesterolaemia. Report of a Second WHO Consultation.
        ], MEDPED [
        • Williams R.R.
        • Hunt S.C.
        • Schumacher M.C.
        • et al.
        Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics.
        ] and S-B criteria [
        • Scientific Steering Committee on behalf of the Simon Broome Register Group
        Risk of fatal coronary heart disease in familial hypercholesterolaemia.
        ]
      (4) There should be scientific evidence of screening programme effectivenessCase series and interventional studies [
      • Qureshi N.
      • Weng S.
      • Tranter J.
      • et al.
      Feasibility of improving identification of familial hypercholesterolaemia in general practice: intervention development study.
      ] show improvement in the number of new cases identified with possible or definite FH.
      (5) The programme should integrate education, testing, clinical services and programme managementSeveral countries integrate preventative programmes and care pathways from primary to specialist care [
      • Gidding S.S.
      • Champagne M.A.
      • de Ferranti S.D.
      • et al.
      The agenda for familial hypercholesterolemia - a scientific statement from the american heart association.
      ,
      • Watts G.F.
      • Sullivan D.R.
      • Poplawski N.
      • et al.
      Familial hypercholesterolaemia: a model of care for Australasia.
      ,
      • Nordestgaard B.
      • Chapman M.
      • Humphries S.
      • 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).
      ] (see section “Potential approaches to screening in primary care”).
      (6) There should be quality assurance, with mechanisms to minimise potential risks of screening
      • Lipid tests are available to internationally recognised standard (currently ISO 17043 in UK and NPAAC [
        • National Pathology Accreditation Advisory Council (NPAAC)
        Requirements for Medical Testing of Human Nucleic Acids.
        ] in Australia)
      • Family history recording of a three generation pedigree is standard in specialist care but the requirement for primary care is unclear. This could be a detailed family history collection or a less sensitive method of a few direct questions [
        • Wijdenes-Pijl M.
        • Henneman L.
        • Cross-Bardell L.
        • et al.
        How does a simple enquiry compare to a detailed family history questionnaire to identify coronary heart disease or diabetic familial risk?.
        ]
      • Genetic testing will require agreed standard of testing and interpretation prior to adoption. Currently the gold standard is NGS [
        • Futema M.
        • Plagnol V.
        • Whittall R.A.
        • et al.
        Use of targeted exome sequencing as a diagnostic tool for Familial Hypercholesterolaemia.
        ,
        • Iacocca M.A.
        • Wang J.
        • Dron J.S.
        • et al.
        Use of next-generation sequencing to detect LDLR gene copy number variation in familial hypercholesterolemia.
        ,
        • Ng S.B.
        • Buckingham K.J.
        • Lee C.
        • et al.
        Exome sequencing identifies the cause of a mendelian disorder.
        ] as a cost saving method [
        • Norsworthy P.J.
        • Vandrovcova J.
        • Thomas E.R.
        • et al.
        Targeted genetic testing for familial hypercholesterolaemia using next generation sequencing: a population-based study.
        ,
        • Radovica-Spalvina I.
        • Latkovskis G.
        • Silamikelis I.
        • et al.
        Next-generation-sequencing-based identification of familial hypercholesterolemia-related mutations in subjects with increased LDL–C levels in a Latvian population.
        ] but risks missing phenotypic FH [
        • Watts G.F.
        • Sullivan D.R.
        • Poplawski N.
        • et al.
        Familial hypercholesterolaemia: a model of care for Australasia.
        ].
      (7) The programme should ensure informed choice, confidentiality and respect for autonomy
      • Patients offered genetic testing within standard ethical framework including fully informed of the implications of testing [
        • Watts G.F.
        • Sullivan D.R.
        • Poplawski N.
        • et al.
        Familial hypercholesterolaemia: a model of care for Australasia.
        ,
        • Sturm A.C.
        • Knowles J.W.
        • Gidding S.S.
        • et al.
        Clinical genetic testing for familial hypercholesterolemia.
        ].
      • Cholesterol testing is offered as part of routine clinical care - implications for testing and detection of FH may not be appreciated initially [
        • Kirke A.
        • Watts G.F.
        • Emery J.
        Detecting familial hypercholesterolaemia in general practice.
        ].
      (8) The programme should promote equality and access to screening to the entire target populationIdentification of FH in primary care could involve opportunistic identification at review by GP or through programmes such as the UK national vascular check programme [
      • Chang K.C.-M.
      • Lee J.T.
      • Vamos E.P.
      • et al.
      Impact of the National Health Service Health Check on cardiovascular disease risk: a difference-in-differences matching analysis.
      ] which has improved assessment in deprived communities [
      • Robson J.
      • Dostal I.
      • Sheikh A.
      • et al.
      The NHS Health Check in England: an evaluation of the first 4 years.
      ].
      (9) Programme evaluation should be planned from the outsetFrom inception of an FH screening programme in primary care, key measures assessed should include:
      • process measures such as recruitment rate and specialist care attendance rate
      • outcome measures such as identification rates of FH and proportion of confirmed FH patients treated to target
      (10) The overall benefits of screening should outweigh the harm
      • Reducing premature CHD is the prime target of FH screening [
        • Gidding S.S.
        • Champagne M.A.
        • de Ferranti S.D.
        • et al.
        The agenda for familial hypercholesterolemia - a scientific statement from the american heart association.
        ,
        • Watts G.F.
        • Sullivan D.R.
        • Poplawski N.
        • et al.
        Familial hypercholesterolaemia: a model of care for Australasia.
        ,
        • Nordestgaard B.
        • Chapman M.
        • Humphries S.
        • 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 false positive diagnostic rate [
        • Scientific Steering Committee on behalf of the Simon Broome Register Group
        Risk of fatal coronary heart disease in familial hypercholesterolaemia.
        ] is a potential harm but better use of algorithms (FAMCAT [
        • Weng S.F.
        • Kai J.
        • Neil H.A.
        • et al.
        Improving identification of familial hypercholesterolaemia in primary care: derivation and validation of the familial hypercholesterolaemia case ascertainment tool (FAMCAT).
        ] and TARB-Ex [
        • Troeung L.
        • Arnold-Reed D.
        • Chan She Ping-Delfos W.
        • et al.
        A new electronic screening tool for identifying risk of familial hypercholesterolaemia in general practice.
        ]) may increase specificity
      • The psychological impact of a diagnosis is considered minimal but evidence for short-term increase in anxiety is recognised [
        • Qureshi N.
        • Standen P.
        • Hapgood R.
        • et al.
        A randomized controlled trial to assess the psychological impact of a family history screening questionnaire in general practice.
        ,
        • Wilson B.J.
        • Qureshi N.
        • Santaguida P.
        • et al.
        Systematic review: family history in risk assessment for common diseases.
        ]
      FH: Familial hypercholesterolaemia.
      CHD: Coronary Heart Disease.
      DLCN: Dutch Lipid Clinic Network.
      MEDPED: Make Early Diagnosis to Prevent Early Deaths.
      S-B: Simon-Broome.
      NPAAC: National Pathology Accreditation Advisory Council.
      DNA: Deoxyribonucleic Acid.
      NGS: Next Generation Sequencing.
      FAMCAT: Familial Hypercholesterolaemia Case Ascertainment Tool.

      3.1 Advances in approaches to screening in primary care

      Primary care can make a more substantial contribution to the detection and care of FH [
      • Troeung L.
      • Arnold-Reed D.
      • Chan She Ping-Delfos W.
      • et al.
      A new electronic screening tool for identifying risk of familial hypercholesterolaemia in general practice.
      ,
      • Weng S.F.
      • Kai J.
      • Neil H.A.
      • et al.
      Improving identification of familial hypercholesterolaemia in primary care: derivation and validation of the familial hypercholesterolaemia case ascertainment tool (FAMCAT).
      ,
      • Wald D.S.
      • Bestwick J.P.
      • Morris J.K.
      • et al.
      Child–parent familial hypercholesterolemia screening in primary care.
      ]. Tests to help diagnose FH are simple and acceptable to the public, the available treatment is effective and case finding can take place in clinical practice [
      • Wiegman A.
      • Gidding S.S.
      • Watts G.F.
      • et al.
      Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment.
      ].
      The latent period between potential diagnosis of FH (preferably in childhood or adolescence) and the onset of CHD (early middle age) is in theory sufficient to allow effective, lifelong treatment to be instituted before atheromatous plaque development occurs. This time-frame is critical to facilitate an improved primary care role in FH recognition [
      • Wiegman A.
      • Gidding S.S.
      • Watts G.F.
      • et al.
      Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment.
      ].

      3.2 Research on strategies to identify FH in primary care

      3.2.1 Child-parent screening/Reverse cascade screening

      Wald et al. [
      • Wald D.S.
      • Bestwick J.P.
      • Morris J.K.
      • et al.
      Child–parent familial hypercholesterolemia screening in primary care.
      ] examined the efficacy and feasibility of child-parent screening for FH in primary care practices. They undertook the screening at routine immunisation attendances by children aged 1–2 years at 92 general medical practices in the UK over a three-year period. A total of 84% of parents agreed to the heel-stick capillary blood sampling offered to test for FH. The child provided the screening entry point at an age identified as the most discriminatory for the measurement of cholesterol [
      • Wald D.S.
      • Bestwick J.P.
      • Wald N.J.
      Child-parent screening for familial hypercholesterolaemia: screening strategy based on a meta-analysis.
      ]. Once the child is identified as having FH, one of the parents will also harbour the condition enabling two generations to be effectively screened as part of the process.
      For the 10,000 children screened, based on cholesterol levels, 40 children and 40 parents were identified as positive for FH, at high risk for cardiovascular disease (CVD) and offered appropriate treatments [
      • Wald D.S.
      • Bestwick J.P.
      • Morris J.K.
      • et al.
      Child–parent familial hypercholesterolemia screening in primary care.
      ]. The population prevalence of children found to have FH was 1 in 270. A total of 32 of the 40 children screening positive for FH were found to have a genetic mutation while 8 did not. Child-parent screening was seen as a simple, effective and practical method to examine a population for the presence of FH [
      • Wald D.S.
      • Bestwick J.P.
      • Morris J.K.
      • et al.
      Child–parent familial hypercholesterolemia screening in primary care.
      ].

      3.2.2 Systematic and opportunistic screening and case finding in general practice

      Primary care can significantly improve the identification and management of FH in the general population [
      • Watts G.F.
      • Sullivan D.R.
      • Poplawski N.
      • et al.
      Familial hypercholesterolaemia: a model of care for Australasia.
      ,
      • Nordestgaard B.
      • Chapman M.
      • Humphries S.
      • 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).
      ,
      • Wiegman A.
      • Gidding S.S.
      • Watts G.F.
      • et al.
      Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment.
      ,
      • Kirke A.B.
      • Barbour R.A.
      • Burrows S.
      • et al.
      Systematic detection of familial hypercholesterolaemia in primary health care: a community based prospective study of three methods.
      ] where the prevalence is about twice that previously estimated [
      • Benn M.
      • Watts G.F.
      • Tybjaerg-Hansen A.
      • et al.
      Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication.
      ,
      • Watts G.F.
      • Shaw J.E.
      • Pang J.
      • et al.
      Prevalence and treatment of familial hypercholesterolemia in Australian communities.
      ,
      • de Ferranti S.D.
      • Rodday A.M.
      • Mendelson M.M.
      • et al.
      Prevalence of familial hypercholesterolemia in the 1999 to 2012 United States national health and nutrition examination surveys (NHANES).
      ,
      • Watts G.F.
      • Gidding S.
      • Wierzbicki A.S.
      • et al.
      Integrated guidance on the care of familial hypercholesterolaemia from the international FH foundation.
      ]. A prevalence of 1 in 250 would yield 40 individuals with FH in a practice population of 10,000 patients. Most practices of this size would not realise this potential at risk group exists. For primary care to improve FH detection, greater health professional awareness of the significance of markedly elevated cholesterol levels in high risk patients, a family or personal history of premature CAD or death plus recognition of other tell-tale stigmata of FH, will be necessary [
      • Gidding S.S.
      • Champagne M.A.
      • de Ferranti S.D.
      • et al.
      The agenda for familial hypercholesterolemia - a scientific statement from the american heart association.
      ,
      • Watts G.F.
      • Sullivan D.R.
      • Poplawski N.
      • et al.
      Familial hypercholesterolaemia: a model of care for Australasia.
      ].

      3.2.2.1 Extra workloads

      Opportunities to increase detection of FH in general practice are becoming more sophisticated. New data extraction tools employing algorithms of the phenotypic features of FH (Dutch Lipid Clinic Network (DLCN) [
      • World Health Organization
      Familial Hypercholesterolaemia. Report of a Second WHO Consultation.
      ], Make Early Diagnosis to Prevent Early Deaths (MEDPED) [
      • Williams R.R.
      • Hunt S.C.
      • Schumacher M.C.
      • et al.
      Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics.
      ] and Simon-Broome (S-B) criteria [
      • Scientific Steering Committee on behalf of the Simon Broome Register Group
      Risk of fatal coronary heart disease in familial hypercholesterolaemia.
      ]) can minimise practice workloads while still focussing attention on detecting high risk patients.
      In Australia, there have been attempts at improving detection and management of FH in the primary care sector [
      • Troeung L.
      • Arnold-Reed D.
      • Chan She Ping-Delfos W.
      • et al.
      A new electronic screening tool for identifying risk of familial hypercholesterolaemia in general practice.
      ,
      • Kirke A.
      • Watts G.F.
      • Emery J.
      Detecting familial hypercholesterolaemia in general practice.
      ,
      • Bell D.A.
      • Kirke A.B.
      • Barbour R.
      • et al.
      Can patients be accurately assessed for familial hypercholesterolaemia in primary care?.
      ,
      • Arnold-Reed D.E.
      • Brett T.
      • Troeung L.
      • et al.
      Detection and management of familial hypercholesterolaemia in primary care in Australia: protocol for a pragmatic cluster intervention study with pre-post intervention comparisons.
      ]. Models of care, which in the past have focussed on tertiary level hospital lipid clinics [
      • Watts G.F.
      • Sullivan D.R.
      • Poplawski N.
      • et al.
      Familial hypercholesterolaemia: a model of care for Australasia.
      ], are now looking at a greater involvement from primary care especially for patients without additional risk factors [
      • Brett T.
      • Watts G.F.
      • Arnold-Reed D.E.
      • et al.
      Challenges in the care of familial hypercholesterolemia: a community care perspective.
      ,
      • Wald D.S.
      • Bestwick J.P.
      • Wald N.J.
      Child-parent screening for familial hypercholesterolaemia: screening strategy based on a meta-analysis.
      ].

      3.2.2.2 Phenotypic v genetic testing

      The DLCN criteria (DLCNC) score [
      • World Health Organization
      Familial Hypercholesterolaemia. Report of a Second WHO Consultation.
      ] is the preferred tool in Australia to help with phenotypic diagnosis of FH [
      • Watts G.F.
      • Gidding S.
      • Wierzbicki A.S.
      • et al.
      Integrated guidance on the care of familial hypercholesterolaemia from the international FH foundation.
      ]. Cost, geographic and migration factors, plus lack of population density across most of the continent, are major handicaps towards use of genetic testing for all suspected FH patients [
      • Brett T.
      • Watts G.F.
      • Arnold-Reed D.E.
      • et al.
      Challenges in the care of familial hypercholesterolemia: a community care perspective.
      ]. The same barriers also preclude the widespread use of dedicated field workers [
      • Louter L.
      • Defesche J.
      • Roeters van Lennep J.
      Cascade screening for familial hypercholesterolemia: practical consequences.
      ] to undertake systematic contact tracing of close relatives. A more pragmatic approach involving use of the DLCNC score in the primary care setting is currently being trialled in Australia [
      • Arnold-Reed D.E.
      • Brett T.
      • Troeung L.
      • et al.
      Detection and management of familial hypercholesterolaemia in primary care in Australia: protocol for a pragmatic cluster intervention study with pre-post intervention comparisons.
      ].
      The use of genetic testing in the UK compared with the phenotypic approach advocated in Australia and in the United States offers an interesting comparison [
      • Humphries S.E.
      • Neil H.A.W.
      Developing and applying clinically useful approaches to identify individuals with familial hypercholesterolemia in the UK.
      ]. Current National Institute for Health and Care Excellence (NICE) guidelines [
      • National Institute for Health and Clinical Excellence and The National Collaborating Centre for Primary Care
      NICE Clinical Guideline 71: Identification and Management of Familial Hypercholesterolaemia.
      ] favour the critical importance of genetic testing to confirm monogenic FH. Only patients testing positive to the FH gene mutation will be given the diagnosis of FH. Other patients with the clinical features of FH (phenotypic) but no established mutation will be designated as ‘polygenic hypercholesterolemia’. NICE guidelines [
      • National Institute for Health and Clinical Excellence and The National Collaborating Centre for Primary Care
      NICE Clinical Guideline 71: Identification and Management of Familial Hypercholesterolaemia.
      ] also advocate that only relatives of genetically positive index cases should be offered genetic testing to establish mutation positive FH. The obvious downside is that with over 1700 known FH mutations [
      • Chora J.R.
      • Medeiros A.M.
      • Alves A.C.
      • et al.
      Analysis of publicly available LDLR, APOB, and PCSK9 variants associated with familial hypercholesterolemia: application of ACMG guidelines and implications for familial hypercholesterolemia diagnosis.
      ], not all are amenable to genetic testing and up to 40% may be missed [
      • Nordestgaard B.
      • Chapman M.
      • Humphries S.
      • 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).
      ].

      3.2.2.3 National institute for health and Care Excellence (NICE) guidelines

      In UK, the original NICE Guideline CG7117 advised suspicion of FH diagnosis in adult if raised total cholesterol (>7.5 mmol/l) especially with personal or family history of premature CHD. GPs should exclude secondary causes of FH, undertake detailed family history that is regularly updated and undertake thorough clinical examination to check for signs of elevated cholesterol, such as, tendon xanthomata [
      • Humphries S.E.
      • Neil H.A.W.
      Developing and applying clinically useful approaches to identify individuals with familial hypercholesterolemia in the UK.
      ]. Patients with ’definite’ or ‘possible’ FH on S-B criteria should be referred to specialist with FH expertise to confirm diagnosis, advise on management and help with co-ordination of cascade testing among close relatives. Many patients identified as ‘possible’ FH will not be confirmed as having the condition [
      • Qureshi N.
      • Weng S.
      • Tranter J.
      • et al.
      Feasibility of improving identification of familial hypercholesterolaemia in general practice: intervention development study.
      ]. The 2017 NICE guidelines advise systematic searches of patient records for cholesterol over 9 mmol/l as these have over 25% chance of having FH [
      • National Institute for Health and Clinical Excellence and The National Collaborating Centre for Primary Care
      NICE Clinical Guideline 71: Identification and Management of Familial Hypercholesterolaemia.
      ].
      The absence of suitable infrastructure in primary care to assist with cascade testing of relatives is a major handicap [
      • Qureshi N.
      • Humphries S.E.
      • Seed M.
      • et al.
      Identification and management of familial hypercholesterolaemia: what does it mean to primary care?.
      ]. Serious deficiencies have been found in patient knowledge about FH, their risk of a major cardiac event and the mode of inheritance across generations [
      • Goldberg A.C.
      • Robinson J.G.
      • Cromwell W.C.
      • et al.
      Future issues, public policy, and public awareness of familial hypercholesterolemias: recommendations from the national lipid association expert panel on familial hypercholesterolemia.
      ].

      3.2.2.4 General practice search strategies

      Gray et al. [
      • Gray J.
      • Jaiyeola A.
      Identifying patients with familial hypercholesterolaemia in primary care: an informatics-based approach in one primary care centre.
      ] undertook computer-based searches to look for likely FH patients at a primary care centre of 12,000 patients in South London. A total of 402 individual patients were identified for review. After record review and using the DLCNC score [
      • World Health Organization
      Familial Hypercholesterolaemia. Report of a Second WHO Consultation.
      ], they identified 12 patients who scored 8 and above (’definite’ FH); eight who score between 6 and 8 (‘probable’ FH) and a further 47 patients who scored between 3 and 5 (‘possible’ FH). Thus, a total of 20 patients met the criteria for ‘definite’ or ‘probable’ FH in the study. No cases with tendon xanthomata were found.
      All patients with FH were noted to have early CAD and the authors concluded this finding as the key to reaching a diagnosis of FH. Commencement of treatment for elevated lipids with statins was noted to occur without the potential for FH being the key diagnosis being considered. This lost opportunity to screen close family members for the condition could have contributed to avoidable mortality in the circumstances [
      • Gray J.
      • Jaiyeola A.
      Identifying patients with familial hypercholesterolaemia in primary care: an informatics-based approach in one primary care centre.
      ].
      The time factor involved was a limiting factor. Each manual search of medical records took about 30 min and amounted to 201 h of additional work to examine the records of the 402 patients identified as being at higher risk [
      • Gray J.
      • Jaiyeola A.
      Identifying patients with familial hypercholesterolaemia in primary care: an informatics-based approach in one primary care centre.
      ]. The use of electronic screening tools combined with efficient clinical follow-up by GP and/or Practice Nurse (PN) can offer a more time- and cost-effective systematic approach to identify FH patients in the primary care setting.

      3.2.2.5 Familial Hypercholesterolaemia Case Ascertainment Tool (FAMCAT)

      To improve and simplify identification of FH in British primary care electronic health records, a case ascertainment tool - Familial Hypercholesterolaemia Case Ascertainment Tool (FAMCAT) [
      • Weng S.F.
      • Kai J.
      • Neil H.A.
      • et al.
      Improving identification of familial hypercholesterolaemia in primary care: derivation and validation of the familial hypercholesterolaemia case ascertainment tool (FAMCAT).
      ] was developed to identify those with the highest probability of the condition, with predictive accuracy (AUC) of 86%. FAMCAT allows more efficient use of limited resources by identifying those that need further clinical assessment, undergo referral for diagnosis and commencement of appropriate preventative care for the future. Because patient health data is generally well recorded in the electronic medical records in general practices, FAMCAT uses coded variables to enhance the discriminatory information to identify the highest risk patients for further evaluation. This has been integrated into a national quality improvement tool [

      PRIMIS, Familial Hypercholesterolaemia (FH) Quality Improvement Tool, In.

      ].

      3.2.2.6 TARB-Ex

      In Australia, TARB-Ex [
      • Troeung L.
      • Arnold-Reed D.
      • Chan She Ping-Delfos W.
      • et al.
      A new electronic screening tool for identifying risk of familial hypercholesterolaemia in general practice.
      ] is an electronic research screening tool that uses information from regular general practice databases to identify patients with high DLCN scores who are then invited to attend the practice for further clinical investigation and phenotypic diagnosis. It was developed using Structured Query language (SQL) technology and integrated into Best Practice clinical software [
      • Best Practice Software
      Best Practice: an Evolution in GP Software.
      ]. It has the capacity to be adapted for other SQL-based practice software including Medical Director, ZedMed, MedTech, Practix and Monet which taken together account over 90% of clinical software in Australia.
      The performance of TARB-Ex was evaluated against a manual assessment by a GP of a subset of patients attending the practice [
      • Troeung L.
      • Arnold-Reed D.
      • Chan She Ping-Delfos W.
      • et al.
      A new electronic screening tool for identifying risk of familial hypercholesterolaemia in general practice.
      ]. Overall, results suggested that TARB-Ex was a fast and effective method for systematically identifying patients attending the practice with potential high risk of FH to enable further clinical investigation. Additional costs to the practice in terms of manpower and GP workload were minimised. TARB-Ex showed high sensitivity, specificity and negative predictive power, comparing favourably with manual review in just a fraction of the time – 10 min v 60 h for manual review [
      • Troeung L.
      • Arnold-Reed D.
      • Chan She Ping-Delfos W.
      • et al.
      A new electronic screening tool for identifying risk of familial hypercholesterolaemia in general practice.
      ].
      TARB-Ex integrates well into regular clinical practice. A GP, PN or Practice Manager can undertake the initial screening process prior to recall for clinical review. GP and PN involvement is limited to reviewing medical records of patients identified by TARB-Ex with high DLCNC scores and at risk for FH, exclude confounding secondary causes and decide which patients merit recall for clinical review.

      3.2.2.7 Limitations of screening tools

      All electronic screening tools are only as effective as the quality of the medical and blood pathology information stored in practice databases. The experience in UK and Australia shows family histories are poorly recorded for many patients [
      • McInnes D.K.
      • Saltman D.C.
      • Kidd M.R.
      General practitioners' use of computers for prescribing and electronic health records: results from a national survey.
      ,
      • Qureshi N.
      • Armstrong S.
      • Dhiman P.
      • et al.
      Effect of adding systematic family history enquiry to cardiovascular disease risk assessment in primary care: a matched-pair, cluster randomized trial.
      ,
      • Dhiman P.
      • Kai J.
      • Horsfall L.
      • et al.
      Availability and quality of coronary heart disease family history in primary care medical records: implications for cardiovascular risk assessment.
      ,
      • Qureshi N.
      • Standen P.
      • Hapgood R.
      • et al.
      A randomized controlled trial to assess the psychological impact of a family history screening questionnaire in general practice.
      ,
      • Wilson B.J.
      • Qureshi N.
      • Santaguida P.
      • et al.
      Systematic review: family history in risk assessment for common diseases.
      ] and is an acknowledged limitation of GP-based databases in comparison with hospital-based admissions and discharge summaries.

      3.2.3 Community pathology alerts to GPs

      Attempts have been made to link the performance of community pathology laboratories and general practice databases [
      • Bell D.A.
      • Hooper A.J.
      • Bender R.
      • et al.
      Opportunistic screening for familial hypercholesterolaemia via a community laboratory.
      ,
      • Kirke A.B.
      • Barbour R.A.
      • Burrows S.
      • et al.
      Systematic detection of familial hypercholesterolaemia in primary health care: a community based prospective study of three methods.
      ] to help identify patients with specific indicators suggestive of FH and facilitate clinical follow-up. Evidence shows that a telephone call or alerting message from a chemical pathologist to the GP could have a powerful impact on whether an elevated cholesterol level was better investigated [
      • Bell D.A.
      • Hooper A.J.
      • Edwards G.
      • et al.
      Detecting familial hypercholesterolaemia in the community: impact of a telephone call from a chemical pathologist to the requesting general practitioner.
      ]. With GPs requesting over 90% of LDL-c levels in Australia, the opportunity for more innovative screening at the primary care level could be improved [
      • Bell D.A.
      • Hooper A.J.
      • Bender R.
      • et al.
      Opportunistic screening for familial hypercholesterolaemia via a community laboratory.
      ,
      • Bell D.A.
      • Bender R.
      • Hooper A.J.
      • et al.
      Impact of interpretative commenting on lipid profiles in people at high risk of familial hypercholesterolaemia.
      ].
      The combination of greater reductions to target LDL-c levels and better use of specialist services could facilitate improvements in FH recognition and care. The shared care approach with GP management for lower to intermediate risk patients and specialist support for higher risk and more complex cases should be a logical development in care strategy.

      3.2.4 Use of health checks

      FH is ideally suited to use of periodic health checks and subsequent care plan management as part of a strategic approach to manage this chronic disease in general practice. Much emphasis with FH to date has focussed on ‘top-down’ approaches with identification and management primarily in tertiary hospital clinics and specialist care. In the early, asymptomatic phase of FH, early diagnosis and appropriate diet, lifestyle and drug interventions can be provided at the primary care level. Easy access to primary care services and regular follow-up checks at local practices can be provided. In Australia, care plans and 45-49 year-old health checks [

      Australian Government Department of Health Canberra, In.

      ] developed by GPs and PNs, can be supported by other health professionals including dieticians, exercise physiologists and clinical psychologists while cardiologists, lipid specialists, endocrinologists and paediatricians can also contribute as required.
      Many care plans have traditionally been viewed as mainly targeting the degenerative processes associated with ageing, diabetes, ischemic heart disease and strokes. FH can legitimately be added as a chronic lifelong condition that is well suited to a planned approach and management in primary care. Specialist help should always be available for more complex and difficult to manage patients and children.
      In the UK, the 40–74 year-old age group health checks [

      Australian Government Department of Health Canberra, In.

      ,
      • Chang K.C.-M.
      • Lee J.T.
      • Vamos E.P.
      • et al.
      Impact of the National Health Service Health Check on cardiovascular disease risk: a difference-in-differences matching analysis.
      ] for patients with no recorded chronic health condition could be utilised to assess for FH risk. Patients with total cholesterol levels above 7.5 mmol/l, should be targeted by GPs to undertake further investigations [
      • Humphries S.E.
      • Neil H.A.W.
      Developing and applying clinically useful approaches to identify individuals with familial hypercholesterolemia in the UK.
      ,
      • Futema M.
      • Kumari M.
      • Boustred C.
      • et al.
      Would raising the total cholesterol diagnostic cut-off from 7.5 mmol/L to 9.3 mmol/L improve detection rate of patients with monogenic familial hypercholesterolaemia?.
      ].

      3.2.5 Improve public awareness of FH

      Improving public awareness of the possibility of FH, especially in the community setting, needs to be addressed [
      • Watts G.F.
      • Sullivan D.R.
      • Poplawski N.
      • et al.
      Familial hypercholesterolaemia: a model of care for Australasia.
      ,
      • Goldberg A.C.
      • Robinson J.G.
      • Cromwell W.C.
      • et al.
      Future issues, public policy, and public awareness of familial hypercholesterolemias: recommendations from the national lipid association expert panel on familial hypercholesterolemia.
      ]. Many families may be aware of premature CVD deaths in their own households but the significance of these past events and the potential future risk to their own health is often not fully grasped. Young off-spring of affected patients are likely to feel entirely healthy and lacking in symptoms and see no reason to commence life-long treatment for a condition they perceive as posing no immediate or potential threat. It may take on some relevance when a friend or colleague develops a life-threatening heart attack at a young age and their own potential risk is suddenly brought into sharper focus [
      • Brett T.
      • Watts G.F.
      • Arnold-Reed D.E.
      • et al.
      Challenges in the care of familial hypercholesterolemia: a community care perspective.
      ]. High risk patients with potential FH or known FH patients who refuse or are non-compliant with best practice medications and lifestyle modifications, should be offered an ‘open door’ approach to be seen early if they change their mind re future treatments.

      3.2.6 Improve health professional awareness of FH

      Despite increasing knowledge about the prevalence and risks of FH, many health professionals do not make a connection between FH and the patient's presenting condition [
      • Watts G.F.
      • Sullivan D.R.
      • Poplawski N.
      • et al.
      Familial hypercholesterolaemia: a model of care for Australasia.
      ,
      • Bell D.A.
      • Garton-Smith J.
      • Vickery A.
      • et al.
      Familial hypercholesterolaemia in primary care: knowledge and practices among general practitioners in western Australia.
      ,
      • Goldberg A.C.
      • Robinson J.G.
      • Cromwell W.C.
      • et al.
      Future issues, public policy, and public awareness of familial hypercholesterolemias: recommendations from the national lipid association expert panel on familial hypercholesterolemia.
      ]. A better appreciation of the underlying genetic nature of the disease [
      • Soutar A.K.
      • Naoumova R.P.
      Mechanisms of Disease: genetic causes of familial hypercholesterolemia.
      ,
      • Varret M.
      • Abifadel M.
      • Rabès J.P.
      • et al.
      Genetic heterogeneity of autosomal dominant hypercholesterolemia.
      ,
      • Humphries S.E.
      • Whittall R.A.
      • Hubbart C.S.
      • et al.
      Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk.
      ] and the fact that it will not be solely responsive to dietary and lifestyle intervention is needed.
      The current best management approach is through use of high intensity statins from a young age [
      • Gidding S.S.
      • Champagne M.A.
      • de Ferranti S.D.
      • et al.
      The agenda for familial hypercholesterolemia - a scientific statement from the american heart association.
      ,
      • Nordestgaard B.
      • Chapman M.
      • Humphries S.
      • 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).
      ,
      • Marks D.
      • Thorogood M.
      • Neil H.A.W.
      • et al.
      A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia.
      ,
      • Wiegman A.
      • Gidding S.S.
      • Watts G.F.
      • et al.
      Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment.
      ,
      • Benn M.
      • Watts G.F.
      • Tybjaerg-Hansen A.
      • et al.
      Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication.
      ,
      • Watts G.F.
      • Gidding S.
      • Wierzbicki A.S.
      • et al.
      Integrated guidance on the care of familial hypercholesterolaemia from the international FH foundation.
      ,
      • Nherera L.
      • Calvert N.W.
      • DeMott K.
      • et al.
      Cost-effectiveness analysis of the use of a high-intensity statin compared to a low-intensity statin in the management of patients with familial hypercholesterolaemia.
      ]. The lifetime increased accumulation of LDL-c means that the relative risk from FH makes the use of absolute CVD risk calculators [
      • D'Agostino RB, Sr
      • Vasan R.S.
      • Pencina M.J.
      • et al.
      General cardiovascular risk profile for use in primary care: the framingham heart study.
      ] inappropriate in patients with FH and they should not be used [
      • Gidding S.S.
      • Champagne M.A.
      • de Ferranti S.D.
      • et al.
      The agenda for familial hypercholesterolemia - a scientific statement from the american heart association.
      ,
      • Nordestgaard B.
      • Chapman M.
      • Humphries S.
      • 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).
      ,
      • Marks D.
      • Thorogood M.
      • Neil H.A.W.
      • et al.
      A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia.
      ,
      • Benn M.
      • Watts G.F.
      • Tybjaerg-Hansen A.
      • et al.
      Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication.
      ,
      • Watts G.F.
      • Gidding S.
      • Wierzbicki A.S.
      • et al.
      Integrated guidance on the care of familial hypercholesterolaemia from the international FH foundation.
      ]. Compliance with lifetime statin therapy may be a significant problem especially if family perceptions of such treatment is an issue [
      • Wiegman A.
      • Gidding S.S.
      • Watts G.F.
      • et al.
      Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment.
      ]. GPs can play a major role in this area.

      3.2.7 Improve support in primary care for cascade screening of close relatives of index cases

      Cascade screening of close family relatives of known index cases is recognised as the most efficient and cost-effective approach for identifying new FH patients [
      • Watts G.F.
      • Sullivan D.R.
      • Poplawski N.
      • et al.
      Familial hypercholesterolaemia: a model of care for Australasia.
      ,
      • Nordestgaard B.
      • Chapman M.
      • Humphries S.
      • 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).
      ,
      • 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 hypercholesterolaemia.
      ,
      • Marks D.
      • Wonderling D.
      • Thorogood M.
      • et al.
      Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
      ,
      • Hadfield S.G.
      • Horara S.
      Family tracing to identify patients with familial hypercholesterolaemia: the second audit of the department of health familial hypercholesterolaemia cascade testing project.
      ]. The evidence to support cascade testing of relatives is based on specialist centre approaches rather than screening from primary care [
      • Watts G.F.
      • Sullivan D.R.
      • Poplawski N.
      • et al.
      Familial hypercholesterolaemia: a model of care for Australasia.
      ]. The UK National Health Service (NHS) has recognised the difficulties posed by a lack of suitable infrastructure in primary care to undertake systematic cascade screening, and recommend that it should be undertaken through specialist centres instead [
      • National Institute for Health and Clinical Excellence and The National Collaborating Centre for Primary Care
      NICE Clinical Guideline 71: Identification and Management of Familial Hypercholesterolaemia.
      ,
      • Humphries S.E.
      • Neil H.A.W.
      Developing and applying clinically useful approaches to identify individuals with familial hypercholesterolemia in the UK.
      ].
      Evidence from the Netherlands showed the success of using genetic field workers to target close relatives of new index cases in a systematic fashion [
      • Louter L.
      • Defesche J.
      • Roeters van Lennep J.
      Cascade screening for familial hypercholesterolemia: practical consequences.
      ,
      • Umans-Eckenhausen M.A.
      • Defesche J.C.
      Review of first 5 years of screening for familial hypercholesterolaemia in The Netherlands.
      ]. The Dutch FH program which sought to find all FH patients, was centrally controlled and involved all specialists in cardiovascular care as well as all GPs, and had extensive media and scientific journal exposure to increase awareness at the general population and health professional levels [
      • Louter L.
      • Defesche J.
      • Roeters van Lennep J.
      Cascade screening for familial hypercholesterolemia: practical consequences.
      ].
      Experience from the Danish General Population study on FH [
      • Benn M.
      • Watts G.F.
      • Tybjaerg-Hansen A.
      • et al.
      Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication.
      ] suggests that development of national models of care, and health policy integrating care between GPs and specialists, would achieve the best outcomes for individuals and families with FH.
      Density of population in close geographic proximity can help the cascade screening of relatives, with families in more remote locations and migrant families at a much greater risk of having a less effective service [
      • Brett T.
      • Watts G.F.
      • Arnold-Reed D.E.
      • et al.
      Challenges in the care of familial hypercholesterolemia: a community care perspective.
      ,
      • Andersen R.
      • Andersen L.
      Examining barriers to cascade screening for familial hypercholesterolemia in the United States.
      ].

      3.3 Where does primary care screening for FH fit into models of care?

      The role of primary care in the detection and care of patients with FH is evolving but no consensus exists on the optimum screening strategy, on how best to integrate primary and specialist level care [
      • Vickery A.W.
      • Bell D.
      • Garton-Smith J.
      • et al.
      Optimising the detection and management of familial hypercholesterolaemia: central role of primary care and its integration with specialist services.
      ], on genetic versus phenotypic testing [
      • Watts G.F.
      • Sullivan D.R.
      • Poplawski N.
      • et al.
      Familial hypercholesterolaemia: a model of care for Australasia.
      ,
      • Humphries S.E.
      • Neil H.A.W.
      Developing and applying clinically useful approaches to identify individuals with familial hypercholesterolemia in the UK.
      ,
      • Futema M.
      • Plagnol V.
      • Whittall R.A.
      • et al.
      Use of targeted exome sequencing as a diagnostic tool for Familial Hypercholesterolaemia.
      ], on childhood screening [
      • Daniels S.R.
      • Gidding S.S.
      • de Ferranti S.D.
      Pediatric aspects of familial hypercholesterolemias: recommendations from the national lipid association expert panel on familial hypercholesterolemia.
      ], on sustainable methods of cascade testing close relatives of index cases [
      • Newson A.J.
      • Humphries S.E.
      Cascade testing in familial hypercholesterolaemia: how should family members be contacted?.
      ] and on recording family history [
      • Rich E.C.
      • Burke W.
      • Heaton C.J.
      • et al.
      Reconsidering the family history in primary care.
      ,
      • Acheson L.S.
      • Wiesner G.L.
      • Zyzanski S.J.
      • et al.
      Family history-taking in community family practice: implications for genetic screening.
      ]. Table 2 provides suggested strategies for measuring cholesterol and genetic testing by age in a primary care practice. Low levels of public and health professional awareness of the disorder is central to this uncertainty as is poor compliance once a diagnosis is made [
      • Nordestgaard B.
      • Chapman M.
      • Humphries S.
      • 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).
      ,
      • Goldberg A.C.
      • Robinson J.G.
      • Cromwell W.C.
      • et al.
      Future issues, public policy, and public awareness of familial hypercholesterolemias: recommendations from the national lipid association expert panel on familial hypercholesterolemia.
      ].
      Table 2Tentative recommendations for screening by age for FH in primary care.
      Age (years)Cholesterol testingGenetic testingCASCADE testing if patient is index caseCASCADE testing if first degree relative positive
      0–2No, unless both parents have high cholesterolBoth parents gene positiveTest parents and siblingsBoth parents positive (elevated cholesterol or gene positive)
      2–11>2 years with positive family history; otherwise between age 5 and 11 by guidelinesLDL-c > 190 mg/dL and positive family historyTest parents and siblingsParent or sibling gene positive
      12–30If not tested previously, optimally by age 21 yearsMeet S-B, DLCN, MEDPED or other criteria for phenotypic FHTest parents and siblingsParent or sibling gene positive
      30–60Per adult guidelinesMeet S-B, DLCN, MEDPED or other criteria for phenotypic FHTest all first degree relativesParent, sibling, or child gene positive
      >60Per adult guidelinesMeet S-B, DLCN, MEDPED or other criteria for phenotypic FHTest all first degree relativesChild or sibling gene positive
      FH: Familial hypercholesterolaemia.
      LDL-c: Low Density Lipoprotein-cholesterol.
      S-B: Simon-Broome.
      MEDPED: Make Early Diagnosis to Prevent Early Deaths.
      DLCN: Dutch Lipid Clinic Network.
      The traditional model of care for FH is based on the chronic care model [
      • Watts G.F.
      • Sullivan D.R.
      • Poplawski N.
      • et al.
      Familial hypercholesterolaemia: a model of care for Australasia.
      ,
      • Vickery A.W.
      • Bell D.
      • Garton-Smith J.
      • et al.
      Optimising the detection and management of familial hypercholesterolaemia: central role of primary care and its integration with specialist services.
      ] and aims to deliver the right treatment, for the right patient, at the right time, by the right team across the continuum of care. Of necessity, this will involve a major contribution from primary care but patients with the condition are not being recognised during routine clinical encounters [
      • Gidding S.S.
      • Champagne M.A.
      • de Ferranti S.D.
      • et al.
      The agenda for familial hypercholesterolemia - a scientific statement from the american heart association.
      ,
      • Nordestgaard B.
      • Chapman M.
      • Humphries S.
      • 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).
      ,
      • Benn M.
      • Watts G.F.
      • Tybjaerg-Hansen A.
      • et al.
      Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication.
      ]. The current infrastructure in primary care makes cascade screening very challenging [
      • Watts G.F.
      • Sullivan D.R.
      • Poplawski N.
      • et al.
      Familial hypercholesterolaemia: a model of care for Australasia.
      ,
      • Brett T.
      • Watts G.F.
      • Arnold-Reed D.E.
      • et al.
      Challenges in the care of familial hypercholesterolemia: a community care perspective.
      ]. Research in UK estimated an upper limit of 40% success rate might be possible and that involved specialist centre supports [
      • Humphries S.E.
      • Neil H.A.W.
      Developing and applying clinically useful approaches to identify individuals with familial hypercholesterolemia in the UK.
      ]. Attempts at cascade testing in primary care have been limited but the option is being canvassed [
      • Arnold-Reed D.E.
      • Brett T.
      • Troeung L.
      • et al.
      Detection and management of familial hypercholesterolaemia in primary care in Australia: protocol for a pragmatic cluster intervention study with pre-post intervention comparisons.
      ]. Tertiary hospital models of service delivery are unlikely to be sustainable in primary care. Targeting high risk individuals with family history of premature CVD would be useful [
      • Nordestgaard B.
      • Chapman M.
      • Humphries S.
      • 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).
      ,
      • Vickery A.W.
      • Bell D.
      • Garton-Smith J.
      • et al.
      Optimising the detection and management of familial hypercholesterolaemia: central role of primary care and its integration with specialist services.
      ,
      • Troeung L.
      • Arnold-Reed D.
      • Chan She Ping-Delfos W.
      • et al.
      A new electronic screening tool for identifying risk of familial hypercholesterolaemia in general practice.
      ,
      • Weng S.F.
      • Kai J.
      • Neil H.A.
      • et al.
      Improving identification of familial hypercholesterolaemia in primary care: derivation and validation of the familial hypercholesterolaemia case ascertainment tool (FAMCAT).
      ].

      3.4 Unanswered questions on primary care detection of FH

      From this review, we propose new lines for research based on a framework proposed by Gidding et al. in an American Heart Association statement on FH [
      • Gidding S.S.
      • Champagne M.A.
      • de Ferranti S.D.
      • et al.
      The agenda for familial hypercholesterolemia - a scientific statement from the american heart association.
      ]. Table 3 summarises topics that cover new diagnostic applications, population science, clinical research, patient-centric questions and models of care. Public consultation regarding all research aspects, particularly detection methods such as universal screening is recommended [
      • Screening Subcommittee
      Population Based Screening Framework.
      ].
      Table 3Knowledge gaps and suggestions for future research on FH screening in primary care.
      Science: analytical methods
      • Assessment of role cholesterol gene scores in testing for FH
      • Development of point-of-care lipid testing - total and LDL-cholesterol and Lp(a)
      • Development of point-of-care DNA testing
      • Compare genomic strategies Sequence vs Chip & Sequence
      Epidemiology
      • Identification of new gene founder populations
      • Genetic epidemiology of FH in diverse communities
      • Development and application of registries
      • Development and testing of universal screening protocols
      • Data linkage studies between primary care and specialist databases
      Clinical research (diagnostics, risk prediction, intervention trials)
      • Risk communication of genetic variants
      • Role of risk prediction algorithms in screening for FH
      • Clinical trials of screening protocols and testing interventions
      • Enhancing cascade testing methods in the community
      • Perceptions and psychological sequelae of genetic testing
      • Development of new selective screening protocols
      • Enhancing the use of information technology in case detection
      Patient-centric
      • Health literacy and understanding of genomics and genetic testing
      • Education of public and patients on genomics and role in healthcare
      • Insurance implications of genetic testing
      • Public consultations regarding screening methods for FH
      • Advocacy for raising awareness about genomics and genetic testing
      Models of care
      • Education of primary care health professionals in genomic medicine
      • Development and testing of primary care based models
      • Roles of Specialists, General Practitioners, Practice nurses and Pharmacists in detection and follow-up
      • Design of education, training and accreditation programs in genomic medicine
      • Incorporation of cascade testing for Lp(a) within a primary care model
      FH: Familial hypercholesterolaemia.
      LDL: Low Density Lipoprotein.
      Lp(a): Lipoprotein(a).
      DNA: Deoxyribonucleic Acid.
      The challenge of identifying new index cases of FH in the community setting [
      • Knowles J.W.
      • Rader D.J.
      • Khoury M.J.
      Cascade screening for familial hypercholesterolemia and the use of genetic testing.
      ] requires much more than opportunistic case finding during routine GP consultations, followed by cascade testing of close family relatives [
      • Morris J.K.
      Wald, DS and Wald, NJ, the evaluation of cascade testing for familial hypercholesterolemia.
      ]. Universal screening approaches together with reverse cascade testing in the child-parent setting has shown good potential [
      • Wald D.S.
      • Bestwick J.P.
      • Morris J.K.
      • et al.
      Child–parent familial hypercholesterolemia screening in primary care.
      ,
      • Wald D.S.
      • Bestwick J.P.
      • Wald N.J.
      Child-parent screening for familial hypercholesterolaemia: screening strategy based on a meta-analysis.
      ,
      • Martin A.C.
      • Bell D.A.
      • Brett T.
      • et al.
      Beyond cascade screening: detection of familial hypercholesterolaemia at childhood immunization and other strategies.
      ], but should be seen as part of a multi-faceted approach across community and hospital clinic settings that is integrated into routine clinical care [
      • Knowles J.W.
      • Rader D.J.
      • Khoury M.J.
      Cascade screening for familial hypercholesterolemia and the use of genetic testing.
      ].
      The potential of FH Registries [
      • Bellgard M.I.
      • Walker C.E.
      • Napier K.R.
      • et al.
      Design of the familial hypercholesterolaemia australasia Network registry: creating opportunities for greater international collaboration.
      ,
      • Napier K.R.
      • Pang J.
      • Lamont L.
      • et al.
      A web-based registry for familial hypercholesterolaemia.
      ,
      • Hammond E.
      • Watts G.F.
      • Rubinstein Y.
      • et al.
      Role of international registries in enhancing the care of familial hypercholesterolaemia.
      ,
      • O'Brien E.C.
      • Roe M.T.
      • Fraulo E.S.
      • et al.
      Rationale and design of the familial hypercholesterolemia foundation CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia registry.
      ] and improved coding for FH needs to be linked to screening approaches and establishment and harmonisation of the clinical diagnosis [
      • Gidding S.S.
      • Champagne M.A.
      • de Ferranti S.D.
      • et al.
      The agenda for familial hypercholesterolemia - a scientific statement from the american heart association.
      ,
      • Watts G.F.
      • Gidding S.
      • Wierzbicki A.S.
      • et al.
      Integrated guidance on the care of familial hypercholesterolaemia from the international FH foundation.
      ,
      • Martin A.C.
      • Bell D.A.
      • Brett T.
      • et al.
      Beyond cascade screening: detection of familial hypercholesterolaemia at childhood immunization and other strategies.
      ]. Primary care has a key role to play but lacks the infrastructure and supports offered by hospital lipid clinics. Such support will be critical if a sustainable primary care based model of care is to be established [
      • Gidding S.S.
      • Champagne M.A.
      • de Ferranti S.D.
      • et al.
      The agenda for familial hypercholesterolemia - a scientific statement from the american heart association.
      ].

      4. Conclusion

      Primary care can improve the detection and care of FH patients through an efficient, cost-effective and sustainable approach acceptable to patients, families and health professionals [
      • Gidding S.S.
      • Champagne M.A.
      • de Ferranti S.D.
      • et al.
      The agenda for familial hypercholesterolemia - a scientific statement from the american heart association.
      ,
      • Watts G.F.
      • Sullivan D.R.
      • Poplawski N.
      • et al.
      Familial hypercholesterolaemia: a model of care for Australasia.
      ,
      • Nordestgaard B.
      • Chapman M.
      • Humphries S.
      • 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).
      ]. This approach should straddle the entire continuum of care [
      • Watts G.F.
      • Sullivan D.R.
      • Poplawski N.
      • et al.
      Familial hypercholesterolaemia: a model of care for Australasia.
      ,
      • Nordestgaard B.
      • Chapman M.
      • Humphries S.
      • 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).
      ,
      • Vickery A.W.
      • Bell D.
      • Garton-Smith J.
      • et al.
      Optimising the detection and management of familial hypercholesterolaemia: central role of primary care and its integration with specialist services.
      ,
      • Watts G.F.
      • Pang J.
      The evolving model of care for familial hypercholesterolaemia.
      ] – general practice, lipid specialists, cardiology, paediatrics, endocrinology, pathology, genetics and allied health. FH is best diagnosed in childhood or early adolescence [
      • Gidding S.S.
      • Champagne M.A.
      • de Ferranti S.D.
      • et al.
      The agenda for familial hypercholesterolemia - a scientific statement from the american heart association.
      ,
      • Nordestgaard B.
      • Chapman M.
      • Humphries S.
      • 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).
      ,
      • Wiegman A.
      • Gidding S.S.
      • Watts G.F.
      • et al.
      Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment.
      ,
      • Benn M.
      • Watts G.F.
      • Tybjaerg-Hansen A.
      • et al.
      Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication.
      ] followed by cascade testing of family members with 50% detection rates expected among first degree relatives [
      • Gidding S.S.
      • Champagne M.A.
      • de Ferranti S.D.
      • et al.
      The agenda for familial hypercholesterolemia - a scientific statement from the american heart association.
      ,
      • Watts G.F.
      • Gidding S.
      • Wierzbicki A.S.
      • et al.
      Integrated guidance on the care of familial hypercholesterolaemia from the international FH foundation.
      ,
      • 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 hypercholesterolaemia.
      ,
      • Marks D.
      • Wonderling D.
      • Thorogood M.
      • et al.
      Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
      ]. This allows for timely institution of lifelong medication and lifestyle changes to prevent the early development of atherosclerosis [
      • Watts G.F.
      • Sullivan D.R.
      • Poplawski N.
      • et al.
      Familial hypercholesterolaemia: a model of care for Australasia.
      ,
      • Nordestgaard B.
      • Chapman M.
      • Humphries S.
      • 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).
      ,
      • Wiegman A.
      • Gidding S.S.
      • Watts G.F.
      • et al.
      Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment.
      ],. A shared care model involving primary care for low risk and specialist support for high risk and difficult to manage patients, would be ideal.
      Increased awareness of potential FH among the public and among health professionals is required [
      • Gidding S.S.
      • Champagne M.A.
      • de Ferranti S.D.
      • et al.
      The agenda for familial hypercholesterolemia - a scientific statement from the american heart association.
      ,
      • Goldberg A.C.
      • Robinson J.G.
      • Cromwell W.C.
      • et al.
      Future issues, public policy, and public awareness of familial hypercholesterolemias: recommendations from the national lipid association expert panel on familial hypercholesterolemia.
      ]. GPs and PNs should grasp the implications of a diagnosis of FH [
      • Gidding S.S.
      • Champagne M.A.
      • de Ferranti S.D.
      • et al.
      The agenda for familial hypercholesterolemia - a scientific statement from the american heart association.
      ,
      • Watts G.F.
      • Sullivan D.R.
      • Poplawski N.
      • et al.
      Familial hypercholesterolaemia: a model of care for Australasia.
      ,
      • Nordestgaard B.
      • Chapman M.
      • Humphries S.
      • 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).
      ,
      • Wiegman A.
      • Gidding S.S.
      • Watts G.F.
      • et al.
      Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment.
      ,
      • Goldberg A.C.
      • Robinson J.G.
      • Cromwell W.C.
      • et al.
      Future issues, public policy, and public awareness of familial hypercholesterolemias: recommendations from the national lipid association expert panel on familial hypercholesterolemia.
      ], and the need for follow-up checks to monitor compliance and treatment targets [
      • Gidding S.S.
      • Champagne M.A.
      • de Ferranti S.D.
      • et al.
      The agenda for familial hypercholesterolemia - a scientific statement from the american heart association.
      ,
      • Nordestgaard B.
      • Chapman M.
      • Humphries S.
      • 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).
      ,
      • Wiegman A.
      • Gidding S.S.
      • Watts G.F.
      • et al.
      Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment.
      ,
      • Benn M.
      • Watts G.F.
      • Tybjaerg-Hansen A.
      • et al.
      Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication.
      ,
      • Goldberg A.C.
      • Robinson J.G.
      • Cromwell W.C.
      • et al.
      Future issues, public policy, and public awareness of familial hypercholesterolemias: recommendations from the national lipid association expert panel on familial hypercholesterolemia.
      ]. Patients need re-enforcement that achieving LDL-c targets will reduce their cumulative lifetime risk for premature CAD [
      • Wiegman A.
      • Gidding S.S.
      • Watts G.F.
      • et al.
      Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment.
      ,
      • Goldberg A.C.
      • Robinson J.G.
      • Cromwell W.C.
      • et al.
      Future issues, public policy, and public awareness of familial hypercholesterolemias: recommendations from the national lipid association expert panel on familial hypercholesterolemia.
      ]. Chronic disease care plans are a cost-effective way for general practice to manage such care [
      • Brett T.
      • Watts G.F.
      • Arnold-Reed D.E.
      • et al.
      Challenges in the care of familial hypercholesterolemia: a community care perspective.
      ,

      Australian Government Department of Health Canberra, In.

      ].
      At community level, families with history of early heart disease should be especially targeted [
      • Gidding S.S.
      • Champagne M.A.
      • de Ferranti S.D.
      • et al.
      The agenda for familial hypercholesterolemia - a scientific statement from the american heart association.
      ,
      • Watts G.F.
      • Sullivan D.R.
      • Poplawski N.
      • et al.
      Familial hypercholesterolaemia: a model of care for Australasia.
      ,
      • Wiegman A.
      • Gidding S.S.
      • Watts G.F.
      • et al.
      Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment.
      ]. Primary care with its ease of access and frequent patient contact can help in this regard [

      Information Services Division Scotland, Practice Team Information (PTI) Annual Update, 2012/13.

      ,
      • Britt H.
      • Miller G.C.
      • Charles J.
      • et al.
      General Practice Activity in Australia 2000–01 to 2009–10: 10 Year Data Tables.
      ] Patients and families with FH need reminding that they are at significantly greater risk for CVD compared to those without [
      • Goldberg A.C.
      • Robinson J.G.
      • Cromwell W.C.
      • et al.
      Future issues, public policy, and public awareness of familial hypercholesterolemias: recommendations from the national lipid association expert panel on familial hypercholesterolemia.
      ]. Better education for the newly diagnosed young and regular follow-up to ensure compliance will be necessary [
      • Wiegman A.
      • Gidding S.S.
      • Watts G.F.
      • et al.
      Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment.
      ,
      • Watts G.F.
      • Pang J.
      The evolving model of care for familial hypercholesterolaemia.
      ]. Wald et al.'s [
      • Wald D.S.
      • Bestwick J.P.
      • Morris J.K.
      • et al.
      Child–parent familial hypercholesterolemia screening in primary care.
      ] targeting of 92 general practices to universally screen over 10,000 toddlers aged 1–2 years at routine immunisation attendances with 84% parent approval offers hope for the future. Childhood detection allowed reverse cascade screening of parents (50% pickup) and saved lives [
      • Wald D.S.
      • Bestwick J.P.
      • Morris J.K.
      • et al.
      Child–parent familial hypercholesterolemia screening in primary care.
      ].
      A combination of opportunistic case-finding, systematic and universal screening of general practice databases [
      • Troeung L.
      • Arnold-Reed D.
      • Chan She Ping-Delfos W.
      • et al.
      A new electronic screening tool for identifying risk of familial hypercholesterolaemia in general practice.
      ,
      • Weng S.F.
      • Kai J.
      • Neil H.A.
      • et al.
      Improving identification of familial hypercholesterolaemia in primary care: derivation and validation of the familial hypercholesterolaemia case ascertainment tool (FAMCAT).
      ,
      • Arnold-Reed D.E.
      • Brett T.
      • Troeung L.
      • et al.
      Detection and management of familial hypercholesterolaemia in primary care in Australia: protocol for a pragmatic cluster intervention study with pre-post intervention comparisons.
      ] increased public and health professional awareness of the disease [
      • Gidding S.S.
      • Champagne M.A.
      • de Ferranti S.D.
      • et al.
      The agenda for familial hypercholesterolemia - a scientific statement from the american heart association.
      ,
      • Watts G.F.
      • Sullivan D.R.
      • Poplawski N.
      • et al.
      Familial hypercholesterolaemia: a model of care for Australasia.
      ,
      • Nordestgaard B.
      • Chapman M.
      • Humphries S.
      • 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).
      ,
      • Benn M.
      • Watts G.F.
      • Tybjaerg-Hansen A.
      • et al.
      Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication.
      ], and better education and treatment knowledge among primary care teams [
      • Gidding S.S.
      • Champagne M.A.
      • de Ferranti S.D.
      • et al.
      The agenda for familial hypercholesterolemia - a scientific statement from the american heart association.
      ,
      • Goldberg A.C.
      • Robinson J.G.
      • Cromwell W.C.
      • et al.
      Future issues, public policy, and public awareness of familial hypercholesterolemias: recommendations from the national lipid association expert panel on familial hypercholesterolemia.
      ], especially the need for lifetime care with specialist support, is required.

      Conflicts of interest

      TB has received financial support for educational activities and research grants from Sanofi and Amgen . GFW has received financial support for advisory boards/educational activities and research grants from: Sanofi , Amgen , Regeneron , Gemphire , Kowa . SG has received remuneration from Regenxbio as a consultant and DSMB member MedStar Research Institute. NQ was a member of the English NICE familial hypercholesterolemia guideline development group.

      References

        • Gidding S.S.
        • Champagne M.A.
        • de Ferranti S.D.
        • et al.
        The agenda for familial hypercholesterolemia - a scientific statement from the american heart association.
        Circulation. 2015; : 132
        • Qureshi N.
        • Humphries S.E.
        • Seed M.
        • et al.
        Identification and management of familial hypercholesterolaemia: what does it mean to primary care?.
        Br. J. Gen. Pract. 2009; 59: 773-778
        • Watts G.F.
        • Sullivan D.R.
        • Poplawski N.
        • et al.
        Familial hypercholesterolaemia: a model of care for Australasia.
        Atherosclerosis Suppl. 2011; 12: 221-263
        • Hollman G.
        • Olsson A.G.
        • Ek A.-C.
        Disease knowledge and adherence to treatment in patients with familial hypercholesterolemia.
        J. Cardiovasc. Nurs. 2006; 21: 103-108
        • Batais M.A.
        • Almigbal T.H.
        • Abdulhak A.A.B.
        • et al.
        Assessment of physicians' awareness and knowledge of familial hypercholesterolemia in Saudi Arabia: is there a gap?.
        PLoS One. 2017; 12 (e0183494)
        • Bell D.A.
        • Garton-Smith J.
        • Vickery A.
        • et al.
        Familial hypercholesterolaemia in primary care: knowledge and practices among general practitioners in western Australia.
        Heart Lung Circ. 2014; 23: 309-313
        • Pang J.
        • Hu M.
        • Lin J.
        • et al.
        An enquiry based on a standardised questionnaire into knowledge, awareness and preferences concerning the care of familial hypercholesterolaemia among primary care physicians in the Asia-Pacific region: the “Ten Countries Study”.
        BMJ Open. 2017; 7 (e017817)
        • Austin M.A.
        • Hutter C.M.
        • Zimmern R.L.
        • et al.
        Genetic causes of monogenic heterozygous familial hypercholesterolaemia: a HuGE prevalence review.
        Am. J. Epidemiol. 2004; 160: 407-420
        • Nordestgaard B.
        • Chapman M.
        • Humphries S.
        • 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).
        Eur. Heart J. 2013; 34: 3478-3490
        • Soutar A.K.
        • Naoumova R.P.
        Mechanisms of Disease: genetic causes of familial hypercholesterolemia.
        Nat. Clin. Pract. Cardiovasc. Med. 2007; 4: 214-225
        • Marks D.
        • Thorogood M.
        • Neil H.A.W.
        • et al.
        A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia.
        Atherosclerosis. 2003; 168: 1-14
        • Wiegman A.
        • Gidding S.S.
        • Watts G.F.
        • et al.
        Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment.
        Eur. Heart J. 2015; 36: 2425-2437
        • Varret M.
        • Abifadel M.
        • Rabès J.P.
        • et al.
        Genetic heterogeneity of autosomal dominant hypercholesterolemia.
        Clin. Genet. 2008; 73: 1-13
        • Benn M.
        • Watts G.F.
        • Tybjaerg-Hansen A.
        • et al.
        Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication.
        J. Clin. Endocrinol. Metab. 2012; 97: 3956-3964
        • Watts G.F.
        • Shaw J.E.
        • Pang J.
        • et al.
        Prevalence and treatment of familial hypercholesterolemia in Australian communities.
        Int. J. Cardiol. 2015; 185: 69-71
        • de Ferranti S.D.
        • Rodday A.M.
        • Mendelson M.M.
        • et al.
        Prevalence of familial hypercholesterolemia in the 1999 to 2012 United States national health and nutrition examination surveys (NHANES).
        Circulation. 2016; 133: 1067-1072
        • National Institute for Health and Clinical Excellence and The National Collaborating Centre for Primary Care
        NICE Clinical Guideline 71: Identification and Management of Familial Hypercholesterolaemia.
        2008
      1. Information Services Division Scotland, Practice Team Information (PTI) Annual Update, 2012/13.

        • Britt H.
        • Miller G.C.
        • Charles J.
        • et al.
        General Practice Activity in Australia 2000–01 to 2009–10: 10 Year Data Tables.
        General practice series, 2010: 37-39
        • Dorsch M.F.
        • Lawrance R.A.
        • Durham N.P.
        • et al.
        Familial hypercholesterolaemia is underdiagnosed after AMI.
        Br. Med. J. 2001; 322: 111
        • Brett T.
        • Arnold-Reed D.E.
        • Popescu A.
        • et al.
        Multimorbidity in patients attending 2 Australian primary care practices.
        Ann. Fam. Med. 2013; 11: 535-542
        • Brett T.
        • Watts G.F.
        • Arnold-Reed D.E.
        • et al.
        Challenges in the care of familial hypercholesterolemia: a community care perspective.
        Expert Rev. Cardiovasc Ther. 2015; 13: 1091-1100
        • Feig J.E.
        • Feig J.L.
        • Kini A.S.
        Statins, atherosclerosis regression and HDL: insights from within the plaque.
        Int. J. Cardiol. 2015; 189: 168-171
        • Nissen S.E.
        • Nicholls S.J.
        • Sipahi I.
        • et al.
        Effect of very high-intensity statin therapy on regression of coronary atherosclerosis.
        J. Am. Med. Assoc.: JAMA, J. Am. Med. Assoc. 2006; 295: 1556
        • Goldberg A.C.
        • Hopkins P.N.
        • Toth P.P.
        • et al.
        Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the national lipid association expert panel on familial hypercholesterolemia.
        J. Clin. Lipidol. 2011; 5: 133-140
        • Watts G.F.
        • Gidding S.
        • Wierzbicki A.S.
        • et al.
        Integrated guidance on the care of familial hypercholesterolaemia from the international FH foundation.
        Int. J. Cardiol. 2014; 171: 309-325
        • Louter L.
        • Defesche J.
        • Roeters van Lennep J.
        Cascade screening for familial hypercholesterolemia: practical consequences.
        Atherosclerosis Suppl. 2017; 30: 77-85
        • Bell D.A.
        • Hooper A.J.
        • Edwards G.
        • et al.
        Detecting familial hypercholesterolaemia in the community: impact of a telephone call from a chemical pathologist to the requesting general practitioner.
        Atherosclerosis. 2014; 234: 469-472
        • Bell D.A.
        • Hooper A.J.
        • Bender R.
        • et al.
        Opportunistic screening for familial hypercholesterolaemia via a community laboratory.
        Ann. Clin. Biochem. 2012; 49: 534-537
        • Bell D.A.
        • Bender R.
        • Hooper A.J.
        • et al.
        Impact of interpretative commenting on lipid profiles in people at high risk of familial hypercholesterolaemia.
        Clin. Chim. Acta. 2013; 422: 21-25
        • Kirke A.B.
        • Barbour R.A.
        • Burrows S.
        • et al.
        Systematic detection of familial hypercholesterolaemia in primary health care: a community based prospective study of three methods.
        Heart Lung Circ. 2015; 24: 250-256
        • Vickery A.W.
        • Bell D.
        • Garton-Smith J.
        • et al.
        Optimising the detection and management of familial hypercholesterolaemia: central role of primary care and its integration with specialist services.
        Heart Lung Circ. 2014; 23: 1158-1164
        • Troeung L.
        • Arnold-Reed D.
        • Chan She Ping-Delfos W.
        • et al.
        A new electronic screening tool for identifying risk of familial hypercholesterolaemia in general practice.
        Heart. 2016; 102: 855-861
        • Humphries S.E.
        • Neil H.A.W.
        Developing and applying clinically useful approaches to identify individuals with familial hypercholesterolemia in the UK.
        Clin. Lipidol. 2010; 5: 497-507
        • Gray J.
        • Jaiyeola A.
        Identifying patients with familial hypercholesterolaemia in primary care: an informatics-based approach in one primary care centre.
        Heart. 2008; 94
        • Weng S.F.
        • Kai J.
        • Neil H.A.
        • et al.
        Improving identification of familial hypercholesterolaemia in primary care: derivation and validation of the familial hypercholesterolaemia case ascertainment tool (FAMCAT).
        Atherosclerosis. 2015; 238: 336-343
        • Klančar G.
        • Grošelj U.
        • Kovač J.
        • et al.
        Universal screening for familial hypercholesterolemia in children.
        J. Am. Coll. Cardiol. 2015; 66: 1250-1257
        • Andermann A.
        • Blancquaert I.
        • Beauchamp S.
        • et al.
        Revisiting Wilson and Jungner in the genomic age: a review of screening criteria over the past 40 years.
        Bull. World Health Organ. 2008; 86: 317-319
        • Australian Health Ministers’ Advisory Council (AHMAC)
        Standing Committee on Screening of the Community Care and Population Health Principal Committee.
        2016
        • Wald D.S.
        • Bestwick J.P.
        • Morris J.K.
        • et al.
        Child–parent familial hypercholesterolemia screening in primary care.
        N. Engl. J. Med. 2016; 375: 1628-1637
        • Wald D.S.
        • Bestwick J.P.
        • Wald N.J.
        Child-parent screening for familial hypercholesterolaemia: screening strategy based on a meta-analysis.
        Br. Med. J. 2007; 335: 599-603
        • World Health Organization
        Familial Hypercholesterolaemia. Report of a Second WHO Consultation.
        World Health Organization, Geneva1999
        • Williams R.R.
        • Hunt S.C.
        • Schumacher M.C.
        • et al.
        Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics.
        Am. J. Cardiol. 1993; 72: 171-176
        • Scientific Steering Committee on behalf of the Simon Broome Register Group
        Risk of fatal coronary heart disease in familial hypercholesterolaemia.
        Br. Med. J. 1991; 303: 893-896
        • Kirke A.
        • Watts G.F.
        • Emery J.
        Detecting familial hypercholesterolaemia in general practice.
        Aust. Fam. Physician. 2012; 41: 965-968
        • Bell D.A.
        • Kirke A.B.
        • Barbour R.
        • et al.
        Can patients be accurately assessed for familial hypercholesterolaemia in primary care?.
        Heart Lung Circ. 2014; 23: 1153-1157
        • Arnold-Reed D.E.
        • Brett T.
        • Troeung L.
        • et al.
        Detection and management of familial hypercholesterolaemia in primary care in Australia: protocol for a pragmatic cluster intervention study with pre-post intervention comparisons.
        BMJ Open. 2017; 7 (e017539)
        • Chora J.R.
        • Medeiros A.M.
        • Alves A.C.
        • et al.
        Analysis of publicly available LDLR, APOB, and PCSK9 variants associated with familial hypercholesterolemia: application of ACMG guidelines and implications for familial hypercholesterolemia diagnosis.
        Genet. Med. 2017; 20: 591-598
        • Qureshi N.
        • Weng S.
        • Tranter J.
        • et al.
        Feasibility of improving identification of familial hypercholesterolaemia in general practice: intervention development study.
        BMJ Open. 2016; 6 (e011734)
        • Goldberg A.C.
        • Robinson J.G.
        • Cromwell W.C.
        • et al.
        Future issues, public policy, and public awareness of familial hypercholesterolemias: recommendations from the national lipid association expert panel on familial hypercholesterolemia.
        J. Clin. Lipidol. 2011; 5: S46-S51
      2. PRIMIS, Familial Hypercholesterolaemia (FH) Quality Improvement Tool, In.

        • Best Practice Software
        Best Practice: an Evolution in GP Software.
        2015
        • McInnes D.K.
        • Saltman D.C.
        • Kidd M.R.
        General practitioners' use of computers for prescribing and electronic health records: results from a national survey.
        Med. J. Aust. 2006; 185: 88
        • Qureshi N.
        • Armstrong S.
        • Dhiman P.
        • et al.
        Effect of adding systematic family history enquiry to cardiovascular disease risk assessment in primary care: a matched-pair, cluster randomized trial.
        Ann. Intern. Med. 2012; 156: 253-262
        • Dhiman P.
        • Kai J.
        • Horsfall L.
        • et al.
        Availability and quality of coronary heart disease family history in primary care medical records: implications for cardiovascular risk assessment.
        PLoS One. 2014; 9e81998
        • Qureshi N.
        • Standen P.
        • Hapgood R.
        • et al.
        A randomized controlled trial to assess the psychological impact of a family history screening questionnaire in general practice.
        Fam. Pract. 2001; 18: 78-83
        • Wilson B.J.
        • Qureshi N.
        • Santaguida P.
        • et al.
        Systematic review: family history in risk assessment for common diseases.
        Ann. Intern. Med. 2009; 151: 878-885
      3. Australian Government Department of Health Canberra, In.

        • Chang K.C.-M.
        • Lee J.T.
        • Vamos E.P.
        • et al.
        Impact of the National Health Service Health Check on cardiovascular disease risk: a difference-in-differences matching analysis.
        Can. Med. Assoc. J. 2016; 188: E228-E238
        • Futema M.
        • Kumari M.
        • Boustred C.
        • et al.
        Would raising the total cholesterol diagnostic cut-off from 7.5 mmol/L to 9.3 mmol/L improve detection rate of patients with monogenic familial hypercholesterolaemia?.
        Atherosclerosis. 2015; 239: 295-298
        • Humphries S.E.
        • Whittall R.A.
        • Hubbart C.S.
        • et al.
        Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk.
        J. Med. Genet. 2006; 43: 943-949
        • Nherera L.
        • Calvert N.W.
        • DeMott K.
        • et al.
        Cost-effectiveness analysis of the use of a high-intensity statin compared to a low-intensity statin in the management of patients with familial hypercholesterolaemia.
        Curr. Med. Res. Opin. 2010; 26: 529-536
        • D'Agostino RB, Sr
        • Vasan R.S.
        • Pencina M.J.
        • et al.
        General cardiovascular risk profile for use in primary care: the framingham heart study.
        Circulation. 2008; 117: 743-753
        • 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 hypercholesterolaemia.
        J. Clin. Lipidol. 2014; 8: 390-400
        • Marks D.
        • Wonderling D.
        • Thorogood M.
        • et al.
        Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
        Br. Med. J. 2002; 324: 1303-1309
        • Hadfield S.G.
        • Horara S.
        Family tracing to identify patients with familial hypercholesterolaemia: the second audit of the department of health familial hypercholesterolaemia cascade testing project.
        Ann. Clin. Biochem. 2009; 46
        • Umans-Eckenhausen M.A.
        • Defesche J.C.
        Review of first 5 years of screening for familial hypercholesterolaemia in The Netherlands.
        Lancet. 2001; : 357
        • Andersen R.
        • Andersen L.
        Examining barriers to cascade screening for familial hypercholesterolemia in the United States.
        J. Clin. Lipidol. 2016; 10: 225-227
        • Futema M.
        • Plagnol V.
        • Whittall R.A.
        • et al.
        Use of targeted exome sequencing as a diagnostic tool for Familial Hypercholesterolaemia.
        J. Med. Genet. 2012; 49: 644-649
        • Daniels S.R.
        • Gidding S.S.
        • de Ferranti S.D.
        Pediatric aspects of familial hypercholesterolemias: recommendations from the national lipid association expert panel on familial hypercholesterolemia.
        J. Clin. Lipidol. 2011; 5: S30-S37
        • Newson A.J.
        • Humphries S.E.
        Cascade testing in familial hypercholesterolaemia: how should family members be contacted?.
        Eur. J. Hum. Genet. 2005; 13: 401-408
        • Rich E.C.
        • Burke W.
        • Heaton C.J.
        • et al.
        Reconsidering the family history in primary care.
        J. Gen. Intern. Med. 2004; 19: 273-280
        • Acheson L.S.
        • Wiesner G.L.
        • Zyzanski S.J.
        • et al.
        Family history-taking in community family practice: implications for genetic screening.
        Genet. Med. 2000; 2: 180
        • Screening Subcommittee
        Population Based Screening Framework.
        2008
        • Knowles J.W.
        • Rader D.J.
        • Khoury M.J.
        Cascade screening for familial hypercholesterolemia and the use of genetic testing.
        J. Am. Med. Assoc. 2017; 318: 381-382
        • Morris J.K.
        Wald, DS and Wald, NJ, the evaluation of cascade testing for familial hypercholesterolemia.
        Am. J. Med. Genet. 2012; 158: 78-84
        • Martin A.C.
        • Bell D.A.
        • Brett T.
        • et al.
        Beyond cascade screening: detection of familial hypercholesterolaemia at childhood immunization and other strategies.
        Curr. Opin. Lipidol. 2017; 28: 321-327
        • Bellgard M.I.
        • Walker C.E.
        • Napier K.R.
        • et al.
        Design of the familial hypercholesterolaemia australasia Network registry: creating opportunities for greater international collaboration.
        J. Atherosclerosis Thromb. 2017; 24: 1075-1084
        • Napier K.R.
        • Pang J.
        • Lamont L.
        • et al.
        A web-based registry for familial hypercholesterolaemia.
        Heart Lung Circ. 2017; 26: 635-639
        • Hammond E.
        • Watts G.F.
        • Rubinstein Y.
        • et al.
        Role of international registries in enhancing the care of familial hypercholesterolaemia.
        Int. J. Evid. Base. Healthc. 2013; 11: 134-139
        • O'Brien E.C.
        • Roe M.T.
        • Fraulo E.S.
        • et al.
        Rationale and design of the familial hypercholesterolemia foundation CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia registry.
        Am. Heart J. 2014; 167 (e317): 342-349
        • Watts G.F.
        • Pang J.
        The evolving model of care for familial hypercholesterolaemia.
        European Journal of Preventive Cardiology. 2017; 24: 1729-1732
        • National Pathology Accreditation Advisory Council (NPAAC)
        Requirements for Medical Testing of Human Nucleic Acids.
        second ed. 2013 (2013)
        • Wijdenes-Pijl M.
        • Henneman L.
        • Cross-Bardell L.
        • et al.
        How does a simple enquiry compare to a detailed family history questionnaire to identify coronary heart disease or diabetic familial risk?.
        Genet. Med. 2011; 13: 443-446
        • Iacocca M.A.
        • Wang J.
        • Dron J.S.
        • et al.
        Use of next-generation sequencing to detect LDLR gene copy number variation in familial hypercholesterolemia.
        J. Lipid Res. 2017; 58: 2202-2209
        • Ng S.B.
        • Buckingham K.J.
        • Lee C.
        • et al.
        Exome sequencing identifies the cause of a mendelian disorder.
        Nat. Genet. 2010; 42: 30
        • Norsworthy P.J.
        • Vandrovcova J.
        • Thomas E.R.
        • et al.
        Targeted genetic testing for familial hypercholesterolaemia using next generation sequencing: a population-based study.
        BMC Med. Genet. 2014; 15: 70
        • Radovica-Spalvina I.
        • Latkovskis G.
        • Silamikelis I.
        • et al.
        Next-generation-sequencing-based identification of familial hypercholesterolemia-related mutations in subjects with increased LDL–C levels in a Latvian population.
        BMC Med. Genet. 2015; 16: 86
        • Sturm A.C.
        • Knowles J.W.
        • Gidding S.S.
        • et al.
        Clinical genetic testing for familial hypercholesterolemia.
        J. Am. Coll. Cardiol. 2018; 72: 662-680
        • Robson J.
        • Dostal I.
        • Sheikh A.
        • et al.
        The NHS Health Check in England: an evaluation of the first 4 years.
        BMJ open. 2016; 6 (e008840)