Gratton Jasmine, Humphries Steve E, Schmidt Amand Floriaan, Patel Riyaz S, Sofat Reecha, Finan Chris, Morris Joan K, Hingorani Aroon D, Futema Marta
Institute of Cardiovascular Science, University College London, London, UK.
Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK.
BMJ Public Health. 2023 Oct 29;1(1):e000021. doi: 10.1136/bmjph-2023-000021. eCollection 2023 Nov.
Most people with autosomal dominant familial hypercholesterolaemia (FH) remain undetected, which represents a missed opportunity for coronary heart disease prevention.
To evaluate the performance of two-stage adult population screening for FH.
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 and . 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.
UK Biobank.
140 439 unrelated participants of European ancestry from UK Biobank with information on circulating LDL-C concentration and exome sequence.
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.
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 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.
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.
大多数常染色体显性遗传性家族性高胆固醇血症（FH）患者未被诊断出来，这意味着错失了预防冠心病的机会。
评估针对FH的两阶段成年人群筛查的效果。
利用英国生物银行的数据，我们估计了不同低密度脂蛋白胆固醇（LDL-C）临界值（第一阶段）的筛查效果，以选择成年人进行DNA测序（第二阶段），从而识别携带FH致病变异的个体。我们估计了通过对索引病例的一级亲属进行级联检测发现的额外FH病例数量，并将整体方法与儿童期筛查进行了比较。
英国生物银行。
来自英国生物银行的140439名欧洲血统的非亲属参与者，他们有循环LDL-C浓度和外显子序列信息。
对于不同的LDL-C临界值，我们估计了检测率和假阳性率、将被转诊进行DNA测序的个体比例（第一阶段筛查阳性率），以及通过人群筛查随后进行级联检测识别出的FH病例数量。
我们识别出488名携带FH致病变异的个体和139951名未携带的个体（患病率为1/288）。LDL-C临界值>4.8 mmol/L时，第一阶段检测率（敏感性）为40%（95%CI 36%至44%），假阳性率为10%（95%CI 10%至11%）。较低的LDL-C临界值时检测率会增加，但代价是假阳性率和筛查阳性率更高，反之亦然。使用4.8 mmol/L的LDL-C临界值对100000名成年人进行两阶段筛查，将产生10398名第一阶段筛查阳性者进行测序，检测出138例FH病例，漏诊209例。通过对一级亲属进行级联检测最多可额外检测出207例病例。相比之下，根据先前发表的数据，儿童期筛查随后进行级联检测估计可检测出的受影响个体数量几乎是前者的三倍，而测序负担约为前者的一半。
针对FH的两阶段成年人群筛查有助于实现英国国家医疗服务体系长期计划中设定的25%的FH病例检测目标，但效率低于儿童期筛查，且测序需求更大。
