The evaluation of cascade testing for familial hypercholesterolemia.
01 Jan 2012-American Journal of Medical Genetics Part A (Am J Med Genet A)-Vol. 158, Iss: 1, pp 78-84
TL;DR: Cascade testing is not a suitable method of population screening for FH, because a separate method of systematically identifying new FH index cases is required to achieve a reasonable level of FH detection in the population.
Abstract: Familial hypercholesterolemia (FH) is an autosomal dominant disorder with a high risk of coronary heart disease at a young age that can be reduced by cholesterol-lowering drugs. Computer simulation was used to estimate the screening performance of three strategies of cascade testing for FH (a process of searching for relatives with FH once an individual is diagnosed with FH): (i) testing parents, siblings, and children (1st degree relatives) of an FH index case, (ii) testing (i) and testing 1st degree relatives of subsequently identified relatives with FH, and (iii) testing (ii) and also testing aunts, uncles, nephews, nieces, grandparents, and first cousins (2nd or 3rd degree relatives) when 1st degree relatives of an individual with FH are not available. For cascade testing to achieve detection rates of 80%, (i) 25%, (ii) 11%, and (iii) 8% of FH index cases who are unrelated need to be identified. To identify these unrelated FH index cases, (i) 45% (ii) 23%, and (iii) 17% of all individuals with FH need to be identified independently of cascade testing. Cascade testing is not a suitable method of population screening for FH, because a separate method of systematically identifying new FH index cases is required to achieve a reasonable level of FH detection in the population. Such an alternative systematic method of identifying new cases could itself be the method of population screening.
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TL;DR: This volume, more than most, explains the contributions of the laboratory to clinical medicine, and shedding light on fundamental metabolic sequences and biologic mechanisms.
Abstract: This book is one of our contemporary medical bibles. It needs no introduction; those who have frequent need of it know it very well, and those who use it less often seek it out on the library shelf when problems arise. The book is truly encyclopedic. Everything relevant discovered during the six-year intervals between publication finds its way into these pages. By today's standards, its 1,778 closely packed small-print pages are a bargain. The mutant gene is both hero and villain in this book. It is reponsible for the biochemical abnormality that results in disease, no matter how rare a given abnormality may be. By the same token, however, it is truly an experiment of nature, shedding light on fundamental metabolic sequences and biologic mechanisms. This volume, more than most, explains the contributions of the laboratory to clinical medicine. Each chapter seems to have been rewritten, so that the exciting
1,117 citations
TL;DR: Drug discovery has linked enhancement of LDL receptor function to LDL-C lowering and successful prevention of ischemic heart disease, first with statins and now with newer drugs that affect LDL receptors function in other ways, including those that impair PCSK9 regulation of LDL receptors recycling.
Abstract: Familial hypercholesterolemia (FH) is an autosomal-dominant genetic disease present in all racial and ethnic groups and has long been recognized as a cause of premature atherosclerotic coronary heart disease.1–3 Heterozygous FH has the highest prevalence of genetic defects that cause significant premature mortality (≈1:200 to 1:500 or higher in founder populations). The genetic basis of the disorder, impaired functioning of the low-density lipoprotein (LDL) receptor, was first recognized by Goldstein and Brown4 in their Nobel Prize–winning work. Studies of LDL receptor function have identified additional mechanisms for the pathogenesis of FH (defects in apolipoprotein [apo] B impairing binding with the LDL receptor and gain-of-function mutations in proprotein convertase subtulisin/kexin type 9 [PCSK9] that enhance LDL receptor degradation). FH leads to elevated LDL concentrations, with levels in heterozygous FH generally in untreated adults >190 mg/dL LDL cholesterol (LDL-C) and in untreated children or adolescents >160 mg/dL LDL-C. Long-term exposure to elevated plasma concentrations of LDL-C begins in utero, leading in heterozygotes to premature ischemic heart disease in mid adulthood and in homozygotes to ischemic heart disease in childhood or early adulthood. In those who meet clinical definitions of FH based on LDL-C levels and family history, genetic testing identifies mutations in most children and a large percentage of adults.5,6
Complementing these cell biology discoveries has been drug discovery that has linked enhancement of LDL receptor function to LDL-C lowering and successful prevention of ischemic heart disease, first with statins and now with newer drugs that affect LDL receptor function in other ways, including those that impair PCSK9 regulation of LDL receptor recycling.7 The natural history of FH, the natural history of genetic disorders that lead to lifelong low LDL-C, and the dramatic improvement in life expectancy created by effective cholesterol lowering provide the …
500 citations
University of Western Australia1, Alfred I. duPont Hospital for Children2, Michigan State University3, University of Illinois at Chicago4, Emory University5, Pierre-and-Marie-Curie University6, University of Amsterdam7, National Heart Foundation of Australia8, University of St Andrews9, Ludwig Maximilian University of Munich10, University of the Witwatersrand11, University of São Paulo12, Erasmus University Rotterdam13, Aberdeen Royal Infirmary14, Royal Prince Alfred Hospital15, The Chinese University of Hong Kong16, Osaka University17
TL;DR: Recommendations on treatment are based on risk stratification, management of non-cholesterol risk factors, and safe and effective use of LDL lowering therapies, and the use of emerging therapies for FH is foreshadowed.
331 citations
Cites methods from "The evaluation of cascade testing f..."
...screening methods for FH should be closely integrated [24]....
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University of Western Australia1, Alfred I. duPont Hospital for Children2, University of Illinois at Chicago3, Michigan State University4, Emory University5, Pierre-and-Marie-Curie University6, University of Amsterdam7, National Heart Foundation of Australia8, University of St Andrews9, Ludwig Maximilian University of Munich10, University of the Witwatersrand11, University of São Paulo12, Erasmus University Rotterdam13, Aberdeen Royal Infirmary14, Royal Prince Alfred Hospital15, The Chinese University of Hong Kong16, Osaka University17
TL;DR: Recommendations focus on the detection, diagnosis, assessment, and management of FH in adults and children and set guidelines for clinical purposes, based on risk stratification, management of noncholesterol risk factors, and the safe and effective use of low-density lipoprotein-lowering therapies.
153 citations
Cites methods from "The evaluation of cascade testing f..."
...screening methods for FH should be closely integrated [24]....
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...screening alone [24]....
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TL;DR: Analysis within an Australian context, demonstrates that cascade screening for FH, using genetic testing supplemented with the measurement of plasma low-density lipoprotein cholesterol concentrations and treatment with statins, is a cost-effective means of preventing CHD in families at risk of FH.
148 citations
Cites methods from "The evaluation of cascade testing f..."
...The total costs of detecting FH in the community will include costs of these other approaches.(40) Cascade screening using genetic testing has been recommended by most international guidelines and will be most useful in the detection of FH in younger patients who will not exhibit all the clinical features of FH....
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References
More filters
TL;DR: This volume, more than most, explains the contributions of the laboratory to clinical medicine, and shedding light on fundamental metabolic sequences and biologic mechanisms.
Abstract: This book is one of our contemporary medical bibles. It needs no introduction; those who have frequent need of it know it very well, and those who use it less often seek it out on the library shelf when problems arise. The book is truly encyclopedic. Everything relevant discovered during the six-year intervals between publication finds its way into these pages. By today's standards, its 1,778 closely packed small-print pages are a bargain. The mutant gene is both hero and villain in this book. It is reponsible for the biochemical abnormality that results in disease, no matter how rare a given abnormality may be. By the same token, however, it is truly an experiment of nature, shedding light on fundamental metabolic sequences and biologic mechanisms. This volume, more than most, explains the contributions of the laboratory to clinical medicine. Each chapter seems to have been rewritten, so that the exciting
1,117 citations
"The evaluation of cascade testing f..." refers background in this paper
...FH affects about 2 per 1,000 people [Goldstein and Brown, 1995], so about 110,000 individuals with FH would be expected in the UK, but only about 15% of these have been identified [Wierzbicki and Ratcliffe, 2008]....
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TL;DR: Targeted family screening with DNA analysis proved to be highly effective in identifying patients with hypercholesterolaemia and most of the identified patients sought treatment and were successfully started on cholesterol-lowering treatment to lower the risk of premature CVD.
439 citations
TL;DR: In this article, the absolute and relative mortality of patients with treated heterozygous familial hypercholesterolaemia, and the effect of changes in treatment efficacy on mortality trends over time, were determined.
321 citations
TL;DR: Screening family members of people with familial hypercholesterolaemia is the most cost effective option for detecting cases across the whole population.
Abstract: Objectives: To assess the cost effectiveness of strategies to screen for and treat familial hypercholesterolaemia. Design: Cost effectiveness analysis. A care pathway for each patient was delineated and the associated probabilities, benefits, and costs were calculated. Participants: Simulated population aged 16-54 years in England and Wales. Interventions: Identification and treatment of patients with familial hypercholesterolaemia by universal screening, opportunistic screening in primary care, screening of people admitted to hospital with premature myocardial infarction, or tracing family members of affected patients. Main outcome measure: Cost effectiveness calculated as cost per life year gained (extension of life expectancy resulting from intervention) including estimated costs of screening and treatment. Results: Tracing of family members was the most cost effective strategy (£3097 (€5066, $4479) per life year gained) as 2.6 individuals need to be screened to identify one case at a cost of £133 per case detected. If the genetic mutation was known within the family then the cost per life year gained (£4914) was only slightly increased by genetic confirmation of the diagnosis. Universal population screening was least cost effective (£13 029 per life year gained) as 1365 individuals need to be screened at a cost of £9754 per case detected. For each strategy it was more cost effective to screen younger people and women. Targeted strategies were more expensive per person screened, but the cost per case detected was lower. Population screening of 16 year olds only was as cost effective as family tracing (£2777 with a clinical confirmation). Conclusions: Screening family members of people with familial hypercholesterolaemia is the most cost effective option for detecting cases across the whole population.
217 citations
"The evaluation of cascade testing f..." refers background in this paper
...Cascade testing, a process of testing relatives once an affected individual (index case) is known and continuing this process every time a new affected relative is found, has been proposed as a means of identifying individuals with FH [Marks et al., 2002]....
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TL;DR: The proposed strategy of screening children and parents for familial hypercholesterolaemia could have considerable impact in preventing the medical consequences of this disorder in two generations simultaneously.
Abstract: Objective To develop a population screening strategy for familial hypercholesterolaemia. Design Meta-analysis of published data on total and low density lipoprotein (LDL) cholesterol in people with and without familial hypercholesterolaemia according to age. Thirteen studies reporting on 1907 cases and 16 221 controls were used in the analysis. Included studies had at least 10 cases and controls with data on the distribution of cholesterol in affected and unaffected individuals. Main outcome measures Detection rates (sensitivity) for specified false positive rates (0.1%, 0.5%, and 1%) in newborns and in age groups 1-9, 10-19, 20-39, 40-59, and ≥60 years. Results Serum cholesterol concentration discriminated best between people with and without familial hypercholesterolaemia at ages 1-9, when the detection rates with total cholesterol were 88%, 94%, and 96% for false positive rates of 0.1%, 0.5%, and 1%. The results were similar with LDL cholesterol. Screening newborns was much less effective. Once an affected child is identified, measurement of cholesterol would detect about 96% of parents with the disorder, using the simple rule that the parent with the higher serum cholesterol concentration is the affected parent. Conclusions The proposed strategy of screening children and parents for familial hypercholesterolaemia could have considerable impact in preventing the medical consequences of this disorder in two generations simultaneously.
149 citations
"The evaluation of cascade testing f..." refers methods in this paper
...Child–parent screening is a method that could provide the necessary coverage of the population to identify most families with FH in a population [Wald et al., 2007]....
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