UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Screening for familial hypercholesterolaemia in childhood: Avon Longitudinal Study of Parents and Children (ALSPAC)

Futema, M; Cooper, JA; Charakida, M; Boustred, C; Sattar, N; Deanfield, J; Lawlor, DA; ... Hingorani, AD; + view all (2017) Screening for familial hypercholesterolaemia in childhood: Avon Longitudinal Study of Parents and Children (ALSPAC). Atherosclerosis , 260 pp. 47-55. 10.1016/j.atherosclerosis.2017.03.007. Green open access

[img]
Preview
Text
Futema_1-s2.0-S0021915017300977-main.pdf - Published version

Download (1MB) | Preview

Abstract

Background and aims: Familial hypercholesterolaemia (FH) is an autosomal-dominant disease with frequency of 1/500 to 1/250 that leads to premature coronary heart disease. New approaches to identify FH mutation-carriers early are needed to prevent premature cardiac deaths. In a cross-sectional study of the Avon Longitudinal Study of Parents and Children (ALSPAC), we evaluated the biochemical thresholds for FH screening in childhood, and modelled a two-stage biochemical and sequencing screening strategy for FH detection. Methods: From 5083 ALSPAC children with cholesterol measurement at age nine years, FH genetic diagnosis was performed in 1512 individuals, using whole-genome or targeted sequencing of known FH-causing genes. Detection rate (DR) and false-positive rate (FPR) for proposed screening thresholds (total-cholesterol > 1.53, or LDL-C > 1.84 multiples of the median (MoM)) were assessed. Results: Six of 1512 sequenced individuals had an FH-causing mutation of whom five had LDL-C > 1.84 MoM, giving a verification-bias corrected DR of 62.5% (95% CI: 25–92), with a FPR of 0.2% (95% CI: 0.1–0.4). The DR for the TC cut-point of 1.53 MoM was 25% (95% CI: 3.2–65.1) with a FPR of 0.4% (95% CI: 0.2–0.6). We estimated 13 of an expected 20 FH mutation carriers (and 13 of the 20 parental carriers) could be detected for every 10,000 children screened, with false-positives reliably excluded by addition of a next generation sequencing step in biochemical screen-positive samples. Conclusions: Proposed cholesterol thresholds for childhood FH screening were less accurate than previously estimated. A sequential strategy of biochemical screening followed by targeted sequencing of FH genes in screen-positive children may help mitigate the higher than previously estimated FPR and reduce wasted screening of unaffected parents.

Type: Article
Title: Screening for familial hypercholesterolaemia in childhood: Avon Longitudinal Study of Parents and Children (ALSPAC)
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.atherosclerosis.2017.03.007
Publisher version: http://doi.org/10.1016/j.atherosclerosis.2017.03.0...
Language: English
Additional information: Copyright © 2017 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Keywords: ALSPAC; Familial hypercholesterolaemia; LDL-cholesterol; Next generation sequencing; Familial hypercholesterolaemia screening; Total cholesterol
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Clinical Science
URI: https://discovery.ucl.ac.uk/id/eprint/1549254
Downloads since deposit
37Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item