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Modelling a two-stage adult population screen for autosomal dominant familial hypercholesterolaemia: cross-sectional analysis within the UK Biobank

Gratton, J; Humphries, SE; Schmidt, AF; Patel, RS; Sofat, R; Finan, C; Morris, JK; Hingorani, AD; Futema, M (2023) Modelling a two-stage adult population screen for autosomal dominant familial hypercholesterolaemia: cross-sectional analysis within the UK Biobank. BMJ Public Health, 1 (1). e000021. ISSN 2753-4294 https://doi.org/10.1136/bmjph-2023-000021
SGUL Authors: Futema, Marta Morris, Joan Katherine

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Abstract

Background Most people with autosomal dominant familial hypercholesterolaemia (FH) remain undetected, which represents a missed opportunity for coronary heart disease prevention. Objective To evaluate the performance of two-stage adult population screening for FH. Design Using data from UK Biobank, we estimated the screening performance of different low-density lipoprotein cholesterol (LDL-C) cut-offs (stage 1) to select adults for DNA sequencing (stage 2) to identify individuals with FH-causing variants in LDLR, APOB, PCSK9 and APOE. We estimated the number of additional FH cases detected by cascade testing of first-degree relatives of index cases and compared the overall approach with screening in childhood. Setting UK Biobank. Participants 140 439 unrelated participants of European ancestry from UK Biobank with information on circulating LDL-C concentration and exome sequence. Main outcome measures For different LDL-C cut-offs, we estimated the detection and false-positive rate, the proportion of individuals who would be referred for DNA sequencing (stage 1 screen positive rate), and the number of FH cases identified by population screening followed by cascade testing. Results We identified 488 individuals with an FH-causing variant and 139 951 without (prevalence 1 in 288). An LDL-C cut-off of >4.8 mmol/L had a stage 1 detection rate (sensitivity) of 40% (95% CI 36 to 44%) for a false-positive rate of 10% (95% CI 10 to 11%). Detection rate increased at lower LDL-C cut-offs but at the expense of higher false-positive and screen positive rates, and vice versa. Two-stage screening of 100 000 adults using an LDL-C cut-off of 4.8 mmol/L would generate 10 398 stage 1 screen positives for sequencing, detect 138 FH cases and miss 209. Up to 207 additional cases could be detected through two-generation cascade testing of first-degree relatives. By comparison, based on previously published data, childhood screening followed by cascade testing was estimated to detect nearly three times as many affected individuals for around half the sequencing burden. Conclusions Two-stage adult population screening for FH could help achieve the 25% FH case detection target set in the National Health Service Long Term Plan, but less efficiently than childhood screening and with a greater sequencing requirement.

Item Type: Article
Additional Information: © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Population Health Research Institute (INPH)
Journal or Publication Title: BMJ Public Health
ISSN: 2753-4294
Language: en
Dates:
DateEvent
29 October 2023Published
4 October 2023Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
FS/17/70/33482British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
PG/18/5033837British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
PG/22/10989British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
AA/18/6/34223British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
PG 08/008British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
URI: https://openaccess.sgul.ac.uk/id/eprint/115866
Publisher's version: https://doi.org/10.1136/bmjph-2023-000021

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