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Underutilization of cascade screening for familial hypercholesterolemia
Abstract
“Clinicians attempt to optimally treat their individual patients with elevated cholesterol, especially those with documented coronary heart disease.”
... A U G U S T 7 , 2 0 1 8 : 6 6 2 -8 0 There are also limitations to the clinical sensitivity of a family history of cardiovascular disease, which is part of all published diagnostic criteria for FH. These limitations can be due to several reasons, including reduced penetrance (36), affected relatives receiving LLT (thereby "masking" the hypercholesterolemia and coronary heart disease phenotype), the reduced clinical sensitivity and/or specificity of self-reported family history (37), as well as the simple unavailability of reliable family history information (38). Only In addition to LDL-C threshold levels (i.e., $190 mg/dl) missing significant numbers of individuals with FH pathogenic variants, the ability to distinguish those with FH from those with elevated cholesterol levels due to other reasons is complicated by an overlap in LDL-C levels between individuals with and without an FH pathogenic variant (10,36,41). ...
... Cascade testing can also reduce the average age at which relatives with FH are diagnosed compared with the age of diagnosis for index patients(60). In the United States, cascade testing for FH is not currently systematically performed(38).Cascade testing can be performed by using analysis of LDL-C levels alone, but this approach has sensitivity and specificity issues(41). LDL-C levels in FH and non-FH relatives overlap considerably, especially in adults. ...
Although awareness of familial hypercholesterolemia (FH) is increasing, this common, potentially fatal, treatable condition remains underdiagnosed. Despite FH being a genetic disorder, genetic testing is rarely used. The Familial Hypercholesterolemia Foundation convened an international expert panel to assess the utility of FH genetic testing. The rationale includes the following: 1) facilitation of definitive diagnosis; 2) pathogenic variants indicate higher cardiovascular risk, which indicates the potential need for more aggressive lipid lowering; 3) increase in initiation of and adherence to therapy; and 4) cascade testing of at-risk relatives. The Expert Consensus Panel recommends that FH genetic testing become the standard of care for patients with definite or probable FH, as well as for their at-risk relatives. Testing should include the genes encoding the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9); other genes may also need to be considered for analysis based on patient phenotype. Expected outcomes include greater diagnoses, more effective cascade testing, initiation of therapies at earlier ages, and more accurate risk stratification.
... While the U.S. has created policy for universal cholesterol screening of adults (USPSTF) and children (NHLBI, APA), implementation has been slow. Several European countries are already systematically enrolling children in cholesterol screening in the schools and the clinics [23,44,45], and engaging family members in genetic screening for FH [46]. Recent cascade screening efforts have benefited from two developments-centralization of data on families and children tested [47], and increased availability of highly effective statins and other drugs [48,49]. ...
... In 2013 the non-profit FH Foundation launched the CASCADE FH Registry, which contains both clinically-based and population-based data on individuals with FH [50]. The Registry is actively tracking information on patients with a family history of FH, on those who have been diagnosed with the condition, and on those who are now taking cholesterol-lowering medications [46,51]. In 2015 three groups-the FH Foundation, Stanford Medicine, and Amgen-launched the Find FH Initiative through funding from the American Heart Association and Amgen. ...
Description:
Among the two leading causes of death in the United States, each responsible for one in every four deaths, heart disease costs Americans $300 billion, while cancer costs Americans $216 billion per year. They also rank among the top three causes of death in Europe and Asia. In 2012 the University of Michigan Center for Public Health and Community Genomics and Genetic Alliance, with the support of the Centers for Disease Control and Prevention Office of Public Health Genomics, hosted a conference in Atlanta, Georgia to consider related action strategies based on public health genomics. The aim of the conference was consensus building on recommendations to implement genetic screening for three major heritable contributors to these mortality and cost figures: hereditary breast and ovarian cancer (HBOC), familial hypercholesterolemia (FH), and Lynch syndrome (LS). Genetic applications for these three conditions are labeled with a "Tier 1" designation by the U.S. Centers for Disease Control and Prevention because they have been fully validated and clinical practice guidelines based on systematic review support them.
Methodology:
The conference followed a deliberative sequence starting with nationally recognized clinical and public health presenters for each condition, followed by a Patient and Community Perspectives Panel, working group sessions for each of the conditions, and a final plenary session. The 74 conference participants represented disease research and advocacy, public health, medicine and nursing, genetics, governmental health agencies, and industry. Participants drew on a public health framework interconnecting policy, clinical intervention, surveillance, and educational functions for their deliberations.
Results:
Participants emphasized the importance of collaboration between clinical, public health, and advocacy groups in implementing Tier 1 genetic screening. Advocacy groups could help with individual and institutional buy-in of Tier 1 programs. Groups differed on funding strategies, with alternative options such as large-scale federal funding and smaller scale, incremental funding solutions proposed. Piggybacking on existing federal breast and colorectal cancer control programs was suggested. Public health departments need to assess what information is now being collected by their state cancer registries. The groups advised that information on cascade screening of relatives be included in toolkits for use by states. Participants stressed incorporation of family history into health department breast cancer screening programs, and clinical HBOC data into state surveillance systems. The carrying out of universal LS screening of tumors in those with colorectal cancer was reviewed. Expansion of universal screening to include endometrial tumors was discussed, as was the application of guidelines recommending cholesterol screening of children 9-11 years old. States more advanced in terms of Tier 1 testing could serve as models and partners with other states launching screening and surveillance programs. A multidisciplinary team of screening program champions was suggested as a means of raising awareness among the consumer and health care communities. Participants offered multiple recommendations regarding use of electronic health records, including flagging of at-risk family members and utilization of state-level health information exchanges. The paper contains an update of policy developments and happenings for all three Tier 1 conditions, as well as identified gaps.
Conclusions:
Implementation of cascade screening of family members for HBOC and FH, and universal screening for LS in CRC tumors has reached a point of readiness within the U.S., with creative solutions at hand. Facilitating factors such as screening coverage through the Patient Protection and Affordable Care Act, and state health information exchanges can be tapped. Collaboration is needed between public health departments, health care systems, disease advocacy groups, and industry to fully realize Tier 1 genetic screening. State health department and disease networks currently engaged in Tier 1 screening can serve as models for the launch of new initiatives.
... When detected and treated at a young enough age, the risk of ASCVD can be drastically reduced, possibly to average levels. Although the Centers for Disease Control and Prevention have given cascade testing of relatives of patients with FH the Tier 1 classification, there are currently no systematic cascade testing programs in the United States [41]. In addition to reluctance on the part of family members to accept genetic testing, the lack of trained healthcare professionals to perform the necessary pedigree construction and the logistics of contacting relatives to obtain informed consent for genetic testing and a blood sample, are the primary obstacles to the cascade testing [42]. ...
... The confirmation of the diagnosis of some patients with clinical criteria of probable and possible FH may either indicate a phenotype of mild manifestation associated with some variants or related limitations of the clinical diagnosis, which is also based on the family history provided by the patient. This information is often not accurate due to the patient's lack of knowledge on the subject, as it can also be affected by the penetration of the causal variant (Khera et al., 2016;Neal et al., 2017). ...
Familial hypercholesterolemia (FH) is a monogenic disease characterized by high plasma low-density lipoprotein cholesterol (LDL-c) levels and increased risk of premature atherosclerotic cardiovascular disease. Mutations in FH-related genes account for 40% of FH cases worldwide. In this study, we aimed to assess the pathogenic variants in FH-related genes in the Brazilian FH cohort FHBGEP using exon-targeted gene sequencing (ETGS) strategy. FH patients (n=210) were enrolled at five clinical sites and peripheral blood samples were obtained for laboratory testing and genomic DNA extraction. ETGS was performed using MiSeq platform (Illumina). To identify deleterious variants in LDLR, APOB, PCSK9, and LDLRAP1, the long-reads were subjected to Burrows-Wheeler Aligner (BWA) for alignment and mapping, followed by variant calling using Genome Analysis Toolkit (GATK) and ANNOVAR for variant annotation. The variants were further filtered using in-house custom scripts and classified according to the American College Medical Genetics and Genomics (ACMG) guidelines. A total of 174 variants were identified including 85 missense, 3 stop-gain, 9 splice-site, 6 InDel, and 71 in regulatory regions (3'UTR and 5'UTR). Fifty-two patients (24.7%) had 30 known pathogenic or likely pathogenic variants in FH-related genes according to the American College Medical and Genetics and Genomics guidelines. Fifty-three known variants were classified as benign, or likely benign and 87 known variants have shown uncertain significance. Four novel variants were discovered and classified as such due to their absence in existing databases. In conclusion, ETGS and in silico prediction studies are useful tools for screening deleterious variants and identification of novel variants in FH-related genes, they also contribute to the molecular diagnosis in the FHBGEP cohort.
... This might be due to other genetic determinants, such as polygenic hypercholesterolemia, high Lp(a), apolipoprotein E (APOE), undiscovered FH genes, sitosterolemia, or lysosomal acid lipase deficiency ( Figure 5). (26,29,59) Although there are numerous reported difficulties inherent in collecting a family history of premature CAD, (6,26,(40)(41)(42)61) we found a family history extant in 45% of groups 1 and 3, 64% of group 2, and in 56% of the DLCNS definite/probable group, all of which are comparable or slightly higher than that reported in the CASCADE-FH registry (41%) or in the SEARCH study (38%). (6,42,45) Our slightly higher rates are attributed mainly to the active collection of family history of premature CVD from high-risk patients. ...
Background
Familial hypercholesterolemia (FH) confers a greatly increased risk for premature cardiovascular disease (CVD), but remains very under-diagnosed and under-treated in primary care populations. We assessed whether using a hybrid model consisting of two existing FH diagnostic criteria coupled with electronic medical record (EMR) data, would accurately identify patients with FH in a midwest US metropolitan healthcare system.
Methods and Results
We conducted a retrospective, records-based, cross-sectional study using datasets from unique EMRs of living patients. Using Structured Query Language (SQL) to identify components of two currently approved FH diagnostic criteria, we created a hybrid model to identify individuals with FH. Of 264 264 records analyzed, between 794 and 1571 patients were identified as having FH based on the hybrid diagnostic model, with a prevalence of 1:300 to 1:160. These patients had a higher prevalence of premature coronary artery disease (CAD) (38%-58%) compared with the general population (1.8%) and compared with those having a high CAD risk, but no FH (10%). Although most patients were receiving lipid-lowering therapies (LLT), only 50% were receiving guideline-recommended high-intensity LLT.
Conclusion
Using the hybrid model, we identified FH with a higher clinical and genetic detection rate compared with using standard diagnostic criteria, individually. Statin and other LLT use were suboptimal and below guideline recommendations. Because FH under-diagnosis and under-treatment are due partially to the challenges of implementing existing diagnostic criteria in a primary care setting, this hybrid model potentially can improve FH diagnosis and subsequent early access to appropriate treatment.
... 21 It should be noted that ancestry-focused directto-consumer tests have reportedly been used by more than 26 million individuals. 22 If FH screening were part of the majority of these tests, then the absolute number of individuals receiving positive findings for FH from limited-variant screening may exceed those identified via comprehensive clinical testing. This could have substantial public health benefits. ...
Importance
Familial hypercholesterolemia (FH) is the most common inherited cardiovascular disease and carries significant morbidity and mortality risks. Genetic testing can identify affected individuals, but some array-based assays screen only a small subset of known pathogenic variants.
Objective
To identify the number of clinically significant variants associated with FH that would be missed by an array-based, limited-variant screen when compared with next-generation sequencing (NGS)–based comprehensive testing.
Design, Setting, and Participants
This cross-sectional study compared comprehensive genetic test results for clinically significant variants associated with FH with results for a subset of 24 variants screened by a limited-variant array. Data were deidentified next-generation sequencing results from indication-based or proactive gene panels. Individuals receiving next-generation sequencing–based genetic testing, either for an FH indication between November 2015 and June 2020 or as proactive health screening between February 2016 and June 2020 were included. Ancestry was reported by clinicians who could select from preset options or enter free text on the test requisition form.
Main Outcomes and Measures
Number of pathogenic or likely pathogenic (P/LP) variants identified.
Results
This study included 4563 individuals who were referred for FH diagnostic testing and 6482 individuals who received next-generation sequencing of FH-associated genes as part of a proactive genetic test. Among individuals in the indication cohort, the median (interquartile range) age at testing was 49 (32-61) years, 55.4% (2528 of 4563) were female, and 63.6% (2902 of 4563) were self-reported White/Caucasian. In the indication cohort, the positive detection rate would have been 8.4% (382 of 4563) for a limited-variant screen compared with the 27.0% (1230 of 4563) observed with the next-generation sequencing–based comprehensive test. As a result, 68.9% (848 of 1230) of individuals with a P/LP finding in an FH-associated gene would have been missed by the limited screen. The potential for missed findings in the indication cohort varied by ancestry; among individuals with a P/LP finding, 93.7% (59 of 63) of self-reported Black/African American individuals and 84.7% (122 of 144) of Hispanic individuals would have been missed by the limited-variant screen, compared with 33.3% (4 of 12) of Ashkenazi Jewish individuals. In the proactive cohort, the prevalence of clinically significant FH variants was approximately 1:191 per the comprehensive test, and 61.8% (21 of 34) of individuals with an FH-associated P/LP finding would have been missed by a limited-variant screen.
Conclusions and Relevance
Limited-variant screens may falsely reassure the majority of individuals at risk for FH that they do not carry a disease-causing variant, especially individuals of self-reported Black/African American and Hispanic ancestry.
... 22 Their affected relatives received lipid-lowering therapy, and the self-reported family history may be unreliable. 23 The DLCN criteria are often used for the diagnosis of FH. Li et al 24 a widespread concern in China. ...
Background
Familial hypercholesterolemia (FH) is a genetic cause of premature myocardial infarction (PMI). Early diagnosis of FH is critical for prognosis. This study aimed to investigate the prevalence of FH among a cohort of Chinese patients with PMI using genetic testing, and to evaluate different diagnostic criteria.
Methods and Results
A total of 225 consecutive PMI patients were recruited. LDLR, APOB, PCSK9 and LDLRAP1 genes were detected by Sanger sequencing. FH was diagnosed using the Dutch Lipid Clinic Network (DLCN) criteria and modified DLCN criteria, respectively. The prevalence and clinical features of FH were analyzed. In all PMI patients, pathogenic mutations of LDLR, APOB, PCSK9 and LDLRAP1 genes were found in 10 of 225 patients. Among all mutations, 4 mutations (LDLR c.129G>C, LDLR c.1867A>T, LDLRAP1 c.65G>C, LDLRAP1 c.274G>A) were newly discovered. The prevalence of FH diagnosed by genetic testing was 4.4%. The prevalence of definite/probable FH diagnosed by DLCN and modified DLCN criteria reached 8.0% and 23.6%, respectively, and the mutation rates were 33.3% and 12.2%, respectively. The low‐density lipoprotein cholesterol (LDL‐C) levels in PMI patients with FH were far from goal attainment. Only one of the FH patients had LDL‐C <2.5 mmol/L, and none of them had LDL‐C <1.8 mmol/L.
Conclusions
The prevalence of FH among Chinese patients with PMI appeared relatively common. Underdiagnosis and undertreatment of FH are still a big problem, which should arouse a widespread concern.
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... 15 Os familiares frequentemente subestimam os riscos da doença e não estão cientes de sua condição, aumentando a chance de início precoce de eventos cardiovasculares ateroscleróticos. [16][17][18] Às vezes, embora tenham conhecimento da importância do teste genético, eles permanecem relutantes em participar, devido à falta de motivação. 19 A efetividade da cascata depende da concordância dos CI para recrutar familiares por meio do programa e da real inclusão destes, de modo que o cenário ideal é a inscrição de todos os indivíduos elegíveis. ...
Background:
Genetic cascade screening is the most cost-effective method for the identification of individuals with familial hypercholesterolemia (FH), but the best strategies for the enrollment of at-risk individuals in a FH screening program are not fully known.
Objective:
The aim of this study is to identify the best predictors of familial enrollment into genetic screening, using features derived from tested probands.
Methods:
One hundred and eighty-three index-cases (ICs) with a positive genetic result that had relatives screened from 01/2011 to 07/2015 were included. The response variable was the number of relatives for each enrolled IC. All variables in the study were based on ICs' derived clinical and socioeconomical features. The effect size of predictor variables were obtained through a general linear model using a negative binomial regression link function. Significance was considered with a p < 0.05.
Results:
Mean IC age when enrolling into the program was 50 years old; 78.1% of individuals reported knowledge of relatives with dyslipidemia. Mean baseline LDL-cholesterol level was 316 ± 90 mg/dL. Referral origin through the cascade program website vs. tertiary care, IC LDL-cholesterol and familial history of high LDL-cholesterol levels were independent predictors associated with a higher number of enrolled relatives.
Conclusions:
Our data suggest that FH cascade screening programs can predict family enrollment based on IC features. This information may be useful for devising better and more effective screening approaches for at-risk individuals.
Objectives:
: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder that is characterized by severe hypercholesterolemia. The prevalence of FH in Thailand has not been reported. Therefore, this study aimed to investigate the prevalence of FH and treatment patterns among Thai patients with premature coronary artery disease (pCAD).
Methods:
A total of 1,180 pCAD patients at two heart centers from northeastern and southern Thailand between October 2018 and September 2020 were enrolled. FH was diagnosed using the Dutch Lipid Clinic Network (DLCN) criteria. pCAD was diagnosed in men aged < 55 years and women aged < 60 years.
Results:
The prevalence of definite/probable FH, possible FH, and unlikely FH in pCAD patients was 1.36% (n = 16), 24.83% (n = 293), and 73.81% (n = 871), respectively. Definite/probable FH in pCAD patients had a significantly higher frequency of STEMI but a lower frequency of hypertension than those with unlikely FH. After discharge, most pCAD patients (95.51%) received statin therapy. Definite/probable FH patients had a higher frequency of high-intensity statin therapy than those with possible FH and unlikely FH. After follow-up for 3-6 months, approximately 54.72% of pCAD patients with DLCN scores ≥ 5 had a reduction in LDL-C > 50% from baseline.
Conclusions:
The prevalence of definite/probable FH, particularly possible FH, was high among pCAD patients in this study. The early diagnosis of FH among Thai pCAD patients should be performed for the early treatment and prevention of CAD.
Background The United States, and especially West Virginia, have a tremendous burden of coronary artery disease (CAD). Undiagnosed familial hypercholesterolemia (FH) is an important factor for CAD in the U.S. Identification of a CAD phenotype is an initial step to find families with FH.
Objective We hypothesized that a CAD phenotype detection algorithm that uses discrete data elements from electronic health records (EHRs) can be validated from EHR information housed in a data repository.
Methods We developed an algorithm to detect a CAD phenotype which searched through discrete data elements, such as diagnosis, problem lists, medical history, billing, and procedure (International Classification of Diseases [ICD]-9/10 and Current Procedural Terminology [CPT]) codes. The algorithm was applied to two cohorts of 500 patients, each with varying characteristics. The second (younger) cohort consisted of parents from a school child screening program. We then determined which patients had CAD by systematic, blinded review of EHRs. Following this, we revised the algorithm by refining the acceptable diagnoses and procedures. We ran the second algorithm on the same cohorts and determined the accuracy of the modification.
Results CAD phenotype Algorithm I was 89.6% accurate, 94.6% sensitive, and 85.6% specific for group 1. After revising the algorithm (denoted CAD Algorithm II) and applying it to the same groups 1 and 2, sensitivity 98.2%, specificity 87.8%, and accuracy 92.4; accuracy 93% for group 2. Group 1 F1 score was 92.4%. Specific ICD-10 and CPT codes such as “coronary angiography through a vein graft” were more useful than generic terms.
Conclusion We have created an algorithm, CAD Algorithm II, that detects CAD on a large scale with high accuracy and sensitivity (recall). It has proven useful among varied patient populations. Use of this algorithm can extend to monitor a registry of patients in an EHR and/or to identify a group such as those with likely FH.
Background
The Coronary Artery Risk Detection in Appalachian Communities (CARDIAC) Project is a state-wide risk factor screening program that operated in West Virginia for 19 years and screened more than 100,000 5th graders for obesity, hypertension, and dyslipidemia.
Objectives
We investigated siblings in the CARDIAC Project to assess whether cardiometabolic risk factors (CMRFs) correlate in siblings.
Methods
We identified 12,053 children from 5752 families with lipid panel, blood pressure, and anthropometric data. A linkage application (LinkPlus from the U.S. Centers for Disease Control and Prevention) matched siblings based on parent names, addresses, telephone numbers, and school to generate a linkage probability curve. Graphical and statistical analyses demonstrate the relationships between CMRFs in siblings.
Results
Siblings showed moderate intraclass correlation coefficient of 0.375 for low-density lipoprotein cholesterol (LDL-C), 0.34 for high-density lipoprotein cholesterol (HDL-C), and 0.22 for triglyceride levels. The body mass index (BMI) intraclass correlation coefficient (0.383) is slightly better (2%) than LDL-C or HDL-C, but the standardized beta values from linear regression suggest a 3-fold impact of sibling LDL-C over the child's own BMI. The odds ratio of a second sibling having LDL-C < 110 mg/dL with a first sibling at that level is 3.444:1 (Confidence Limit 3.031–3.915, P < .05). The odds ratio of a sibling showing an LDL-C ≥ 160 mg/dL, given a first sibling with that degree of elevated LDL-C is 29.6:1 (95% Confidence Limit: 15.54–56.36). The individual LDL-C level correlated more strongly with sibling LDL-C than with the individual's own BMI. Seventy-eight children with LDL-C > 160 mg/dL and negative family history would have been missed, which represents more than half of those with LDL-C > 160 mg/dL (78 vs 67 or 54%).
Conclusions
Sibling HDL-C levels, LDL-C levels, and BMIs correlate within a family. Triglyceride and blood pressure levels are less well correlated. The identified CMRF relationships strengthen the main findings of the overall CARDIAC Project: an elevated BMI is not predictive of elevated LDL-C and family history of coronary artery disease poorly predicts cholesterol abnormality at screening. Family history does not adequately identify children who should be screened for cholesterol abnormality. Elevated LDL-C (>160 mg/dL) in a child strongly suggests that additional siblings and parents be screened if universal screening is not practiced.
Familial hypercholesterolaemia (FH) is a dominantly inherited disorder of low-density lipoprotein (LDL) catabolism, which if untreated causes lifelong elevated LDL-cholesterol (LDL-c), accelerated atherosclerosis and premature cardiovascular disease. Recent evidence suggests the prevalence of heterozygous FH is ∼1:220, making FH the most common autosomal dominant condition. Lowering LDL-c with statin and lifestyle therapy reduces the risk of cardiovascular events. Furthermore, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors significantly lower LDL-c in addition to statin therapy, and early outcome data suggest improved vascular outcomes with these agents in FH patients in addition to statins. However, the vast majority of people with FH still remain undiagnosed. The onus is on clinicians to identify kindreds with FH, as PCSK9 inhibitors, although expensive, are funded for patients with FH in Australia. Multiple strategies for detecting FH have been proposed. The detection of index cases can be achieved through applying electronic screening tools to general practice databases, universal screening of children during immunisation, and targeted screening of patients with premature cardiovascular disease. Advances in genomic technology have decreased costs of genetic testing, improved the understanding of the pathogenesis of FH and facilitated cascade screening. However, awareness of FH amongst clinicians and the general public still requires optimisation. This review outlines recent advances in FH detection, including emerging strategies and challenges for the next decade.
Familial DNA cascade screening for familial hypercholesterolemia (FH) has recently been introduced in Scotland. This study investigated index patients' experiences of DNA testing and mediating cascade screening. Thirty-eight patients with a clinical diagnosis of definite or possible FH who had undergone DNA testing in the lipid clinic took part in semi-structured qualitative interviews. All patients were positive about DNA screening being undertaken by familiar and trusted clinicians within the lipid clinic. Most patients had already cascaded close relatives for serum cholesterol testing following their attendance at the lipid clinic. Identified mutation carriers who had attended the genetics clinic (n = 15) for a cascading appointment described finding this consultation helpful because it identified other at-risk family members and provided them with tailored information for their relatives. Participants who expressed a preference said they favoured indirect (patient-mediated) methods of cascading as they considered indirect approaches to be less threatening to family members than direct clinical contact. We conclude that DNA screening and indirect familial cascading is perceived as highly acceptable to index patients with FH. However, while indirect cascading methods may be more acceptable to patients, they do not yield the same numbers as more direct methods. There is, therefore, a need for further systematic research to investigate patients', family members' and staff views of the acceptability of direct versus indirect methods of cascade screening.
Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by abnormally high concentrations of low-density lipoprotein (LDL) cholesterol in the blood, which predisposes affected persons to premature coronary heart disease (CHD) and death. FH is one of the most common inherited disorders and the most common one known to cause premature CHD in people of European descent. The vast majority of people with FH have inherited a single mutation from one parent in either the LDL receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. Despite their greatly elevated risk of coronary heart disease, most individuals with FH remain undiagnosed, untreated, or inadequately treated.
Cascade screening is a mechanism for identifying people at risk for a genetic condition by a process of systematic family tracing. The National Institute for Health and Clinical Excellence in the United Kingdom recommends cascade screening of close biological relatives of people with a clinical diagnosis of FH in order to effectively identify additional FH patients. The ultimate goal of this testing is to reduce morbidity and mortality from heart disease in persons with FH through early diagnosis and effective disease management. The goal of this article is to outline the available evidence on the clinical validity and utility of cascade screening for FH, while emphasizing the availability, usefulness, and recommendation for including DNA testing (if the disease-causing mutation has been identified).
The goal was to determine the sensitivity and specificity of family history in identifying children with severe or genetic hyperlipidemias in a rural, predominantly white population.
A total of 20,266 fifth-grade children in West Virginia, from the Coronary Artery Risk Detection in Appalachian Communities (CARDIAC) Project, who completed a family history and fasting lipid profile were used in analyses. The relationship between hyperlipidemia and family history was determined, and the use of family history to predict the need for pharmacologic treatment among children with dyslipidemia was evaluated.
A total of 71.4% of children met the National Cholesterol Education Program (NCEP) guidelines for cholesterol screening on the basis of positive family history. Of those, 1204 (8.3%) were considered to have dyslipidemia (low-density lipoprotein > or =130 mg/dL), and 1.2% of these children with dyslipidemia warranted possible pharmacologic treatment (low-density lipoprotein > or =160 mg/dL). Of the 28.6% who did not have a positive family history (did not meet NCEP guidelines), 548 (9.5%) had dyslipidemia, 1.7% of whom warranted pharmacologic treatment. Sensitivity and specificity data demonstrated that family history does not provide a strong indication as to whether pharmacologic treatment may be warranted.
Results indicate that the use of family history to determine the need for cholesterol screening in children would have (1) missed many with moderate dyslipidemia and (2) failed to detect a substantial number with likely genetic dyslipidemias that would require pharmacologic treatment. The use of universal cholesterol screening would identify all children with severe dyslipidemia, allowing for proper intervention and follow-up and leading to the prevention of future atherosclerotic disease.
Familial hypercholesterolemia (FH) is a hereditary condition caused by various genetic mutations that lead to significantly elevated low-density lipoprotein cholesterol levels and resulting in a 20-fold increased lifetime risk for premature cardiovascular disease. Although its prevalence in the United States is 1 in 300 to 500 individuals, <10% of FH patients are formally diagnosed, and many are not appropriately treated. Contemporary data are needed to more fully characterize FH disease prevalence, treatment strategies, and patient experiences in the United States.
The Familial Hypercholesterolemia Foundation (a patient-led nonprofit organization) has established the CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia (CASCADE FH) Registry as a national, multicenter initiative to identify US FH patients, track their treatment, and clinical and patient-reported outcomes over time. The CASCADE FH will use multiple enrollment strategies to maximize identification of FH patients. Electronic health record screening of health care systems will provide an efficient mechanism to identify undiagnosed patients. A group of specialized lipid clinics will enter baseline and annual follow-up data on demographics, laboratory values, treatment, and clinical events. Patients meeting prespecified low-density lipoprotein or total cholesterol criteria suspicious for FH will have the opportunity to self-enroll in an online patient portal with information collected directly from patients semiannually. Registry patients will be provided information on cascade screening and will complete an online pedigree to assist with notification of family members.
The Familial Hypercholesterolemia Foundation CASCADE FH Registry represents a novel research paradigm to address gaps in knowledge and barriers to comprehensive FH screening, identification, and treatment.
Familial hypercholesterolemia (FH) is a common disorder in which genetic mutations in at least 1 of several genes lead to significantly increased levels of lipoproteins, in particular, low-density lipoprotein cholesterol. Most commonly, mutations in the low-density lipoprotein receptor gene result in high plasma levels of apolipoprotein B-containing lipoproteins (eg, low-density lipoprotein and lipoprotein(a)). High plasma levels of lipoproteins increase the risk of cardiovascular events by as much as 20-fold if left untreated. A 2011 survey of cardiologists performed by the American College of Cardiology (ACC) suggests that there is a need for greater awareness of FH among cardiologists with regard to its prevalence and heritability, and of the risk of cardiovascular (CV) disease associated with the disorder, such as premature coronary heart disease. Given that many patients with FH may first present to CV specialists at the time of a major coronary event, it is critical that cardiologists have strategies to manage this high-risk subset of patients. This brief review responds to areas of need identified in the ACC survey and is intended to provide current information about FH and increase awareness about this disorder among cardiologists.
Introduction and objectives
The aim was to assess the cost-effectiveness of a genetic screening program for first-degree relatives of patients with familial hypercholesterolemia (FH), followed by treatment when necessary, compared with the alternative of no screening.
Methods
The cost-effectiveness analysis modeled the effect of statin treatment on individuals who were diagnosed with FH after genetic screening. The impact of uncertainty was evaluated using univariate probabilistic sensitivity analysis. The alternate strategy considered was no screening. In the cost-effectiveness analysis, the number of life-years gained (LYG) was regarded as the health outcome and the costs of screening, statin treatment, specialist consultations and hospital visits were all included. In addition, the expected value of perfect information was calculated as part of the sensitivity analysis.
Results
In the base case, the incremental cost of the screening program for close relatives was 3423 euros per LYG. Although the sensitivity analysis gave a range of results, the conclusions were not affected by changes in the parameters considered. The screening program was found to be better than the alternative considered at a probability level of 95% if the acceptable level of healthcare costs was at least 7400 euros per LYG.
Conclusions
This analysis indicates that a genetic screening program, supplemented by treatment, for the close relatives of individuals with FH is preferable to the alternative of no screening in terms of incremental costeffectiveness.
Published 27 August 2008, doi:10.1136/bmj.a1095 Cite this as: BMJ 2008;337:a1095. Practice. Guidelines. : summary of guidance
The purpose of this article is to briefly review but also to highlight the rationale, motivation, and methods in the process of identifying patients of all ages with familial hypercholesterolemia (FH), an often hidden but very important genetic disorder. Since the initiation of population screening for FH in 1994 in the Netherlands, a vast amount of experience has been gathered, addressing almost all issues that are encountered in population screening.
The aim was to assess the cost-effectiveness of a genetic screening program for first-degree relatives of patients with familial hypercholesterolemia (FH), followed by treatment when necessary, compared with the alternative of no screening.
The cost-effectiveness analysis modeled the effect of statin treatment on individuals who were diagnosed with FH after genetic screening. The impact of uncertainty was evaluated using univariate probabilistic sensitivity analysis. The alternate strategy considered was no screening. In the cost-effectiveness analysis, the number of life-years gained (LYG) was regarded as the health outcome and the costs of screening, statin treatment, specialist consultations and hospital visits were all included. In addition, the expected value of perfect information was calculated as part of the sensitivity analysis.
In the base case, the incremental cost of the screening program for close relatives was 3423 euros per LYG. Although the sensitivity analysis gave a range of results, the conclusions were not affected by changes in the parameters considered. The screening program was found to be better than the alternative considered at a probability level of 95% if the acceptable level of health-care costs was at least 7400 euros per LYG.
This analysis indicates that a genetic screening program, supplemented by treatment, for the close relatives of individuals with FH is preferable to the alternative of no screening in terms of incremental cost-effectiveness.
The life experience of 104 patients with Summary Fredrickson's type-II hyperbetalipo-proteinæmia has been compared with 41 patients with hyperlipoproteinæmia associated with hypertriglyceridæmia (Fredrickson's types III, IV, and v hyperlipoproteinsemia). Of 21 male index patients with type-II hyperbetalipoproteinæmia 15 developed ischæmic heart-disease (I.H.D.) at mean age 42.7 years, and 2 have died. 20 out of 30 biochemically affected male relatives developed I.H.D. at mean age 43.8 years with 12 deaths. Of 23 female index patients 20 developed I.H.D. at mean age 48.4 years with 4 deaths. 9 out of 30 affected female relatives developed I.H.D. at mean age 57.1 years with 2 deaths. Of the group of 29 male index patients and 5 affected male relatives with types III, IV, and v hyperlipoproteinæmia, 12 developed at mean age 48.7 years, 10 having intermittent claudication and none have died. The 7 female patients are all alive, 5 developed I.H.D. at mean age sixty-five. For men with type-II hyperbetalipoproteinæmia the chance of a first attack of I.H.D. was 5.4% by age thirty, 51.4% by age fifty, and 85.4% by age sixty. For women the risks were 0, 12.2%, and 57.5% respectively. For men with types III, IV, and v hyperlipoproteinæmia the risks were lower (0, 30, and 53.3%) but the risk of peripheral vascular disease was increased.
Most major chronic diseases probably result from environmental factors accumulating over time in genetically susceptible persons. A detailed family history assessment can help identify the subset of the general population with a strong predisposition to certain major diseases. An understanding of the environmental factors promoting disease development will facilitate more effective prevention or delay disease in a targeted susceptible population. To effectively use this growing knowledge in genetics and epidemiology, health professionals need to motivate people to follow sound recommendations for preventing and delaying disease.To increase the efficiency and effectiveness of strategies for health promotion and disease prevention, family history data can help determine those diseases for which persons have the greatest risk. They can then concentrate their primary efforts on those preventive measures that will most likely benefit them.
Familial hypercholesterolaemia is a common lipid disorder that predisposes for premature cardiovascular disease (CVD). We set up a screening programme in the Netherlands in 1994 to: establish the feasibility of active family screening supported by DNA diagnostics; assess whether or not active identification of these patients with familial hypercholesterolaemia would lead to more cholesterol-lowering treatment; and compare diagnosis by DNA analysis with that by cholesterol measurement.
Both DNA analysis and measurement of cholesterol concentrations were used to screen families in which a functional mutation in the LDL-receptor gene had been detected.
In the first 5 years, 5442 relatives of 237 people with familial hypercholesterolaemia were screened; 2039 individuals were identified as heterozygous by LDL-receptor gene mutation analysis. At the time of examination, 667 of these adults with familial hypercholesterolaemia (39%) received some form of lipid-lowering treatment; 1 year later, this percentage had increased to 93%. In addition, laboratory analysis showed that for carriers as well as non-carriers 18% would have been misdiagnosed by cholesterol measurement alone, with sex-specific and age-specific 90th percentiles of the general Dutch population as diagnostic criteria.
Targeted family screening with DNA analysis proved to be highly effective in identifying patients with hypercholesterolaemia. Most of the identified patients sought treatment and were successfully started on cholesterol-lowering treatment to lower the risk of premature CVD. Our findings could have wider relevance for the screening of other prevalent genetic disorders in the population at large.
A case-finding program for the identification of patients with familial hypercholesterolemia (FH) has been established in Spain. The program is based on family investigation and molecular genetic testing for mutations in the low-density lipoprotein receptor gene. To assist this program, intensive research into the molecular basis of FH and genotype/phenotype relations is performed. To optimize DNA testing, a DNA-diagnostic platform has been constructed that is composed of systematic mutation screening by single-strand conformation polymorphism (SSCP) analysis, DNA-sequencing, Southern blotting, and the use of microarrays for high-throughput analysis. To date, 161 different mutations leading to inherited hypercholesterolemia have been identified in Spanish patients with FH. In addition, a patient organization was founded to ensure patient support and follow-up. To further facilitate FH case-finding and patient follow-up, we initiated the publication of a set of guidelines for diagnosis and clinical management of FH that can be applied internationally.
Screening for lipid disorders in adults
- Us Preventive Services
- Taskforce
US Preventive Services Taskforce. Screening for lipid disorders
in adults. Am. Fam. Physician 80(11), 1273-1274 (2009).
Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents; National Heart, Lung, and Blood Institute
Expert Panel on Integrated Guidelines for Cardiovascular
Health and Risk Reduction in Children and Adolescents;
National Heart, Lung, and Blood Institute. Expert panel
on integrated guidelines for cardiovascular health and risk
reduction in children and adolescents: summary report.
Pediatrics 128(Suppl. 5), S213-S256 (2011).
Familial hypercholesterolemia in Spain: case-finding program, clinical and genetic aspects
- M Pocovi
- F Civiera