Recherche du cholestérol entre 1 et 9 ans.
Wald & Coll., British Medical Journal, 22 septembre 2007 ; 335 : 599.
Méta-analyse incluant 1.907 cas d'hypercholestérolémie familiale (HC) et 16.221 témoins.
c'est entre 1 et 9 ans que l'on détecte le plus efficacement l'HC.
Cette détection permet de rechercher aussitôt le parent partageant l'HC.
Ce dépistage précoce permet de prévenir les conséquences cardio-vasculaires sur plusieurs générations de la famille concernée.
Wald & Coll., British Medical Journal, 22 septembre 2007 ; 335 : 599.
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.
Familial hypercholesterolaemia is an autosomal dominant disorder affecting about two in every 1000 people.1 It results in increased serum cholesterol concentrations and a high mortality from coronary heart disease. Affected adults aged 20-39 years have a 100-fold excess risk of dying from coronary heart disease.w1 Treatment to lower serum cholesterol concentration, for example with statins, is effective in prevention2 so screening for familial hypercholesterolaemia may be a practical option if an effective population screening strategy were available. Cascade screening, in which the first degree relatives of affected individuals are tested,3 4 is currently being assessed as part of a nationwide pilot screening programme. At present, there is no effective way of identifying index cases in the population and so there remains uncertainty over what screening strategy is likely to be effective.
We carried out a meta-analysis of published studies on total and LDL cholesterol in individuals with and without familial hypercholesterolaemia to determine the age at which cholesterol measurement discriminates best between affected and unaffected, to quantify the screening performance of such measurements, and to propose a screening strategy that could be applied to the whole population in an efficient manner.
We sought published studies that included data on the distributions of serum total or LDL cholesterol concentrations in cases of heterozygous familial hypercholesterolaemia and unaffected controls. We searched electronic databases (Medline, Embase, and the Cochrane Library) in any language up to May 2006, using key words [hypercholesterolemia or hypercholesterolaemia] and [familial or heterozygous] and within resulting citations identified studies on humans and those of Medline subsets "diagnosis," or "clinical prediction guides." We examined relevant citations in the reports of studies and in review articles. In studies that reported incomplete data we contacted the individual authors for the required information.
We included studies with 10 or more cases that published the mean and SDs of total or LDL cholesterol (or data from which they could be derived) for which corresponding data in unaffected controls were either published by the authors or identified separately by us from population surveys.
The studies were included if the diagnosis of familial hypercholesterolaemia was genetically or clinically confirmed. Cases were identified from lipid clinicsw1-w3 w5-w13 or through screening the general population.w4 Genetic diagnosis required the identification of a mutation in the LDL receptor gene by DNA analysis. Clinical diagnosis required a measurement of total or LDL cholesterol concentration above a given level (which varied between studies—for example, above the 90th or 95th centiles), a raised serum cholesterol concentration in a first degree relative, and a family history of tendon xanthomata. Controls were from healthy populations stratified by age, geographical region, and the time period (generally within five years) when the blood samples in cases were collected. In seven out of the nine comparisons with genetically confirmed cases the controls were taken from siblings in whom DNA analysis identified no disease causing mutations, but they were not necessarily in the same age strata as their sibling "case." We excluded case-control comparisons in which the cases of familial hypercholesterolaemia were classified as those with high cholesterol concentrations (such as 90th centile) and controls with concentrations less than the 90th centile, as have been used in previous assessments of screening,5 6 7 as this by definition classifies people as being affected and unaffected without any independent corroboration. We excluded studies of patients taking lipid lowering treatment and in which the cases were drawn from a population where the age range exceeded 20 years.
We log transformed serum cholesterol concentrations because the distributions of LDL and total cholesterol were positively skewed. This was confirmed by results from studies in which the individual data points for serum cholesterol concentrations were published and probability plots indicated a good fit to a log Gaussian distribution. The mean and SD of the log cholesterol values that describe the Gaussian distribution for each study were derived from the reported untransformed means and SDs in each study and the published formula for the mean and SD of the log Gaussian distribution.8 In one study that provided individual data on newborns, there was one outlying value (with very low total and LDL cholesterol levels),w3 which we excluded from the analysis. Including it had a minor effect on the results.
Data in the studies were categorised into six age groups. Within each age group we calculated an overall mean (and SD) of the log10 total and LDL cholesterol concentrations for cases and controls, weighted by the number of cases and controls respectively, setting the upper limit for controls at 100 to avoid large control groups dominating the overall average (weighting by 1/SE2 gave similar results). As cholesterol values fit a log Gaussian distribution, the mean of the log transformed values when anti-logged is well estimated by the untransformed median value. We therefore used the median as the preferred measure of central tendency and have expressed the results as multiples of the median (MoM) in controls (the median MoM in controls is thus 1.0). This approach was originally described in screening for neural tube defects9 10 and is widely used in antenatal screening for Down's syndrome.11
We estimated screening performance from the overlapping Gaussian distributions of total and LDL cholesterol (expressed as log10 MoM values) within each age group in cases and controls. The false positive rate (the proportion of unaffected individuals with positive results) was set at about 1% or less, as would be acceptable for population screening. We estimated detection rates (the proportion of affected individuals with positive results) using cholesterol cut offs (expressed as MoM values) to define false positive rates of 0.1%, 0.5%, and 1%. The 95% confidence intervals on the detection rates were based on binomial probabilities. Within each age group we assessed heterogeneity by one way analysis of variance (ANOVA) of mean log10 MoM values in cases and controls.
Table 1 lists the 13 studies included in the analysis according to country of origin and method used to diagnose familial hypercholesterolaemia, categorised into six age groups.The studies included a total of 1907 individuals with familial hypercholesterolaemia (1134 with a DNA confirmed diagnosis and 773 a clinical diagnosis) and 16 221 controls.w1-w13 The reported means and SDs for total and LDL cholesterol in the individual studies and the same data expressed as log10 mmol/l and the combined weighted mean log10 serum cholesterol concentrations for cases and controls in each age group can be found on our website (www.wolfson.qmul.ac.uk/epm/webtables/).
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