Cascade Testing For Familial Hypercholesterolaemia Research Articles

Cascade testing of children and adolescents for elevated Lp(a) in pedigrees with familial hypercholesterolaemia

Elevated plasma lipoprotein(a) [Lp(a)] is a common, inherited condition independently causing cardiovascular disease. Recent expert recommendations suggest opportunistically testing for elevated Lp(a) during cascade testing for familial hypercholesterolaemia (FH). We investigated the effectiveness of detecting elevated Lp(a) in 103 children and adolescents who were first-degree relatives of 66 adult index FH cases as part of an established FH cascade screening program. The yield of detection of elevated Lp(a) using a threshold of ≥30 mg/dL in children and adolescents was assessed. Cascade testing from FH index cases with elevated Lp(a) ≥50 mg/dL identified 1 case of Lp(a) ≥30 mg/dL for every 2 children or adolescents tested. In contrast, opportunistic screening from index cases with FH but normal Lp(a) levels demonstrated 1 case of Lp(a) ≥30 mg/dL for every 7.5 children or adolescents tested (p < 0.001). In conclusion, cascade testing for elevated Lp(a) from index cases with FH and elevated Lp(a) is effective in identifying new cases of elevated Lp(a).

Pilot study of universal screening of children and child-parent cascade testing for familial hypercholesterolaemia in Australia.

Familial hypercholesterolaemia (FH) is a common and treatable cause of premature coronary artery disease. However, the majority of individuals with FH remain undiagnosed. This study investigated the feasibility, acceptability and cost-effectiveness of screening children aged 1-2 years for FH at the time of an immunisation. Children 1-2 years of age were offered screening for FH with a point-of-care total cholesterol (TC) test by capillary-collected blood sample at the time of an immunisation. An additional blood sample was taken to allow genetic testing if the TC level was above the 95th percentile (>5.3 mmol/L). Parents of children diagnosed with FH were offered testing. Following detection of the affected parent, cascade testing of their first-degree blood relatives was performed. We screened 448 children with 32 (7.1%) having a TC≥ 5.3 mmol/L. The FH diagnosis was confirmed in three children (1:150 screened). Reverse cascade testing of other family members identified a further five individuals with FH; hence, eight new cases of FH were diagnosed from screening 448 children (1:56 screened). Ninety-six percent of parents would screen future children for FH. The approach was cost-effective, at $3979 per quality-adjusted life year gained. In Western Australia, universal screening of children aged 1-2 years for FH, undertaken at the time of an immunisation, was a feasible and effective approach to detect children, parents and other blood relatives with FH. The approach was acceptable to parents and is potentially a highly cost-effective detection strategy for families at risk of FH.

Integrated Guidance for Enhancing the Care of Familial Hypercholesterolaemia in Australia

Familial hypercholesterolaemia (FH) is a dominant and highly penetrant monogenic disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL)-cholesterol concentration and, if untreated, leads to premature atherosclerosis and coronary artery disease (CAD). There are approximately 100,000 people with FH in Australia. However, an overwhelming majority of those affected remain undetected and inadequately treated, consistent with FH being a leading challenge for public health genomics. To further address the unmet need, we provide an updated guidance, presented as a series of systematically collated recommendations, on the care of patients and families with FH. These recommendations have been informed by an exponential growth in published works and new evidence over the last 5 years and are compatible with a contemporary global call to action on FH. Recommendations are given on the detection, diagnosis, assessment and management of FH in adults and children. Recommendations are also made on genetic testing and risk notification of biological relatives who should undergo cascade testing for FH. Guidance on management is based on the concepts of risk re-stratification, adherence to heart healthy lifestyles, treatment of non-cholesterol risk factors, and safe and appropriate use of LDL-cholesterol lowering therapies, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors and lipoprotein apheresis. Broad recommendations are also provided for the organisation and development of health care services. Recommendations on best practice need to be underpinned by good clinical judgment and shared decision making with patients and families. Models of care for FH need to be adapted to local and regional health care needs and available resources. A comprehensive and realistic implementation strategy, informed by further research, including assessments of cost-benefit, will be required to ensure that this new guidance benefits all Australian families with or at risk of FH.

Integration of child–parent screening and cascade testing for familial hypercholesterolaemia

ObjectiveTo integrate child–parent screening and cascade testing into a single pathway-child-parent cascade screening (CPCS), for the identification of familial hypercholesterolaemia in the population and to estimate the number of new familial hypercholesterolaemia cases identified per child screened and the associated costs.MethodsWe applied the results from the published MRC Child–Parent Screening Study to 10,000 children, together with cascade testing first degree relatives of parents with a familial hypercholesterolaemia mutation identified by child–parent screening. We estimated the number of familial hypercholesterolaemia cases identified per child screened, the median cost per familial hypercholesterolaemia case identified and the median cost per child screened to identify one case using a range of cholesterol and familial hypercholesterolaemia mutation testing costs. We present a case study to illustrate the application of CPCS in practice.ResultsCPCS identifies one new familial hypercholesterolaemia case per 70 children screened at a median estimated cost of £960 per new familial hypercholesterolaemia case or £4 per child screened. CPCS identifies an average of four new familial hypercholesterolaemia cases per family. In the case study, six new familial hypercholesterolaemia cases were identified, and preventive treatment started in five, with the index child expected to start when older.ConclusionCPCS for familial hypercholesterolaemia are complementary strategies. The sustainability of cascade testing relies on identifying new unrelated index cases. This is achieved with population-wide child–parent screening. Integrated CPCS is currently better than either method of familial hypercholesterolaemia detection alone. It has the potential to identify all, or nearly all, individuals with familial hypercholesterolaemia in the population at low cost.

Universal screening at age 1–2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: A cost-utility analysis

Background and aimsFamilial hypercholesterolaemia (FH) is widely underdiagnosed. Cascade testing (CT) of relatives has been shown to be feasible, acceptable and cost-effective in the UK, but requires a supply of index cases. Feasibility of universal screening (US) at age 1–2 years was recently demonstrated. We examined whether this would be a cost-effective adjunct to CT in the UK, given the current and plausible future undiagnosed FH prevalence. MethodsSeven cholesterol and/or mutation-based US ± reverse cascade testing (RCT) alternatives were compared with no US in an incremental analysis with a healthcare perspective. A decision model was used to estimate costs and outcomes for cohorts exposed to the US component of each strategy. RCT case ascertainment was modelled using recent UK CT data, and probabilistic Markov models estimated lifetime costs and health outcomes for the cohorts screened under each alternative. 1000 Monte Carlo simulations were run for each model, and average outcomes reported. Further uncertainty was explored deterministically. Threshold analysis investigated the association between undiagnosed FH prevalence and cost-effectiveness. ResultsA strategy involving cholesterol screening followed by diagnostic genetic testing and RCT was the most cost-effective modelled (incremental cost-effectiveness ratio (ICER) versus no US £12,480/quality adjusted life year (QALY); probability of cost-effectiveness 96·8% at £20,000/QALY threshold). Cost-effectiveness was robust to both deterministic sensitivity analyses and threshold analyses that modelled ongoing case ascertainment at theoretical maximum levels. ConclusionsThese findings support implementation of universal cholesterol screening followed by diagnostic genetic testing and RCT for FH, under a UK conventional willingness-to-pay threshold.

Cost-utility analysis of searching electronic health records and cascade testing to identify and diagnose familial hypercholesterolaemia in England and Wales

Background and aimsThe cost effectiveness of cascade testing for familial hypercholesterolaemia (FH) is well recognised. Less clear is the cost effectiveness of FH screening when it includes case identification strategies that incorporate routinely available data from primary and secondary care electronic health records. MethodsNine strategies were compared, all using cascade testing in combination with different index case approaches (primary care identification, secondary care identification, and clinical assessment using the Simon Broome (SB) or Dutch Lipid Clinic Network (DLCN) criteria). A decision analytic model was informed by three systematic literature reviews and expert advice provided by a NICE Guideline Committee. ResultsThe model found that the addition of primary care case identification by database search for patients with recorded total cholesterol >9.3 mmol/L was more cost effective than cascade testing alone. The incremental cost-effectiveness ratio (ICER) of clinical assessment using the DLCN criteria was £3254 per quality-adjusted life year (QALY) compared with case-finding with no genetic testing. The ICER of clinical assessment using the SB criteria was £13,365 per QALY (compared with primary care identification using the DLCN criteria), indicating that the SB criteria was preferred because it achieved additional health benefits at an acceptable cost. Secondary care identification, with either the SB or DLCN criteria, was not cost effective, alone (dominated and dominated respectively) or combined with primary care identification (£63, 514 per QALY, and £82,388 per QALY respectively). ConclusionsSearching primary care databases for people at high risk of FH followed by cascade testing is likely to be cost-effective.

Cost effectiveness of cascade testing for Familial Hypercholesterolaemia, based on data from FH services in the UK

Cost effectiveness of cascade testing for Familial Hypercholesterolaemia, based on data from FH services in the UK

Cost effectiveness of cascade testing for familial hypercholesterolaemia, based on data from FH services in the UK

Aim: Familial Hypercholesterolaemia (FH) is a vastly under-diagnosed genetic disorder associated with early development of coronary heart disease (CHD) and premature mortality, which can be substantially reduced by effective treatment. Patents have recently expired on high-intensity statins used to treat FH, reducing treatment costs. Here we build a model using UK data to estimate the costs and benefits of DNA testing of relatives of those with monogenic FH.

Cost effectiveness of cascade testing for familial hypercholesterolaemia, based on data from familial hypercholesterolaemia services in the UK.

AimsFamilial hypercholesterolaemia (FH) is a vastly under-diagnosed genetic disorder, associated with early development of coronary heart disease and premature mortality which can be substantially reduced by effective treatment. Patents have recently expired on high-intensity statins, reducing FH treatment costs. We build a model using UK data to estimate the cost effectiveness of DNA testing of relatives of those with monogenic FH.Methods and ResultsA Markov model was used to estimate the cost effectiveness of cascade testing, using data from UK cascade services. The estimated incremental cost effectiveness ratio (ICER) was £5806 and the net marginal lifetime cost per relative tested was £2781. More than 80% of lifetime costs were diagnosis-related and incurred in the 1st year. In UK services, 23% of 6396 index cases were mutation-positive. For each mutation-positive index case, 1.33 relatives were tested, resulting overall in a rate of 0.31 tested relatives per tested index case. If the number of relatives tested per tested index case rose to 3.2 (projected by National Institute for Health and Care Excellence in 2008) the ICER would reduce to £2280 and lifetime costs to £1092.ConclusionCascade testing of relatives of those with suspected FH is highly cost effective. The current Europe-wide high levels of undiagnosed FH, and associated morbidity and mortality, mean adoption of cascade services should yield substantial quality of life and survival gains.

Improving the cost-effectiveness equation of cascade testing for familial hypercholesterolaemia.

Purpose of reviewMany international recommendations for the management of familial hypercholesterolaemia propose the use of cascade testing using the family mutation to unambiguously identify affected relatives. In the current economic climate DNA information is often regarded as too expensive. Here, we review the literature and suggest strategies to improve cost-effectiveness of cascade testing.Recent findingsAdvances in next-generation sequencing have both speeded up the time taken for a genetic diagnosis and reduced costs. Also, it is now clear that, in the majority of patients with a clinical diagnosis of familial hypercholesterolaemia in whom no mutation can be found, the most likely cause of their elevated LDL-cholesterol (LDL-C) is because they have inherited a greater number than average of common LDL-C raising variants in many different genes. The major cost driver for cascade testing is not DNA testing but treatment over the remaining lifetime of the identified relative. With potent statins now off-patent, the overall cost has reduced considerably, and combining these three factors, a familial hypercholesterolaemia service based around DNA-cascade testing is now less than 25% of that estimated by NICE in 2008.SummaryAlthough all patients with a clinical diagnosis of familial hypercholesterolaemia need to have their LDL-C lowered, cascade testing should be focused on those with the monogenic form and not the polygenic form.

Familial hypercholesterolaemia (FH) in Wales is genetically heterogeneous

Familial hypercholesterolaemia (FH) in Wales is genetically heterogeneous

Sociological study of familial hypercholesterolaemia cascade testing

Cascade testing for Familial Hypercholesterolaemia (FH) was recommended in the 2008 NICE guidelines. The FH testing programme in Wales was launched last year and we are conducting a sociological study with FH patients and GPs. We are interviewing 30 patients across Wales to explore their experience of living with FH, their experience of diagnosis, their understanding of the genetic or familial nature of FH and their views on cascade testing through family tracing. We are also interviewing 30 GPs across Wales to ascertain their knowledge of FH itself, its genetic or familial nature, and their awareness of cascade testing. We are also exploring attitudes among both groups to the change in treatment age to 10 years.

Integrating provision of specialist lipid services with cascade testing for familial hypercholesterolaemia

To highlight the unmet need for identifying individuals with familial hypercholesterolaemia and exploring the implications that this will have for local and national healthcare services. A pathway utilising DNA testing for the diagnosis of familial hypercholesterolaemia, and subsequent cascade testing has been developed in Wales. Undiagnosed familial hypercholesterolaemia carries a high risk of cardiovascular disease, which is easily preventable with pharmacotherapy, if individuals are appropriately diagnosed, and affected family members identified. The use of DNA testing is cost-effective and allows for efficient cascade testing. This has implications for local services and highlights unmet educational and clinical requirements in clinical lipidology.

Significant factors in implementing cascade testing for familial hypercholesterolaemia

Significant factors in implementing cascade testing for familial hypercholesterolaemia

Implementation of cascade testing for the detection of familial hypercholesterolaemia

Cascade testing is an important method for identifying individuals at risk of a genetic condition. Recent advances in its application to familial hypercholesterolaemia are reviewed to identify potential problems impeding its application and the extent to which current data address these concerns. Different paradigms for cascade testing are being applied in national programmes. Current data demonstrates cost-effectiveness, and an increased uptake of preventive measures. The relationship between molecular and clinical diagnostic methods is discussed. Psychological impacts of a diagnosis of familial hypercholesterolaemia are in line with the risks associated with the disorder. The efficacy of statins in improving vascular function of children with familial hypercholesterolaemia has been demonstrated, but extensive safety data are lacking. Ethical arguments support that it is equally acceptable for relatives of familial hypercholesterolaemia patients to be contacted by healthcare workers as by family members, but the former is likely to be more efficient. Concerns about increased life insurance premiums are valid but insurance companies are assessing risk realistically, so this should not be a barrier to cascade testing. Current data support the implementation of cascade testing for familial hypercholesterolaemia as being feasible and cost-effective, but national implementation is limited to a small number of countries. Funding and the infrastructure to support it may be the major stumbling blocks in implementing this technique in many countries. Concerns about the ethics of carrying out cascade testing, and the potential psychological damage of DNA testing, appear to have been largely addressed for familial hypercholesterolaemia.