Kingsmore Stephen F, Wright Meredith, Smith Laurie D, Liang Yupu, Mowrey William R, Protopsaltis Liana, Bainbridge Matthew, Baker Mei, Batalov Sergey, Blincow Eric, Cao Bryant, Caylor Sara, Chambers Christina, Ellsworth Katarzyna, Feigenbaum Annette, Frise Erwin, Guidugli Lucia, Hall Kevin P, Hansen Christian, Kiel Mark, Van Der Kraan Lucita, Krilow Chad, Kwon Hugh, Madhavrao Lakshminarasimha, Lefebvre Sebastien, Leipzig Jeremy, Mardach Rebecca, Moore Barry, Oh Danny, Olsen Lauren, Ontiveros Eric, Owen Mallory J, Reimers Rebecca, Scharer Gunter, Schleit Jennifer, Shelnutt Seth, Mehtalia Shyamal S, Oriol Albert, Sanford Erica, Schwartz Steve, Wigby Kristen, Willis Mary J, Yandell Mark, Kunard Chris M, Defay Thomas
Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA.
Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA.
Am J Hum Genet. 2024 Dec 5;111(12):2618-2642. doi: 10.1016/j.ajhg.2024.10.021.
Genome-sequence-based newborn screening (gNBS) has substantial potential to improve outcomes in hundreds of severe childhood genetic disorders (SCGDs). However, a major impediment to gNBS is imprecision due to variants classified as pathogenic (P) or likely pathogenic (LP) that are not SCGD causal. gNBS with 53,855 P/LP variants, 342 genes, 412 SCGDs, and 1,603 therapies was positive in 74% of UK Biobank (UKB470K) adults, suggesting 97% false positives. We used the phenomenon of purifying hyperselection, which acts to decrease the frequency of SCGD causal diplotypes, to reduce false positives. Training of gene-disease-inheritance mode-diplotype tetrads in 618,290 control and affected subjects identified 293 variants or haplotypes and seven genes with variable inheritance contributing higher positive diplotype counts than consistent with purifying hyperselection and with little or no evidence of SCGD causality. With these changes, 2.0% of UKB470K adults were positive. In contrast, gNBS was positive in 7.2% of 3,118 critically ill children with suspected SCGDs and 7.9% of 705 infant deaths. When compared with rapid diagnostic genome sequencing (RDGS), gNBS had 99.1% recall. In eight true-positive children, gNBS was projected to decrease time to diagnosis by a median of 121 days and avoid life-threatening disease presentations in four children, organ damage in six children, ∼$1.25 million in healthcare cost, and ten (1.4%) infant deaths. Federated training predicated on purifying hyperselection provides a general framework to attain high precision in population screening. Federated training across many biobanks and clinical trials can provide a privacy-preserving mechanism for qualification of gNBS in diverse genetic ancestries.
基于基因组序列的新生儿筛查（gNBS）在改善数百种严重儿童遗传疾病（SCGD）的预后方面具有巨大潜力。然而，gNBS的一个主要障碍是由于被分类为致病（P）或可能致病（LP）但并非SCGD病因的变异导致的不精确性。对53,855个P/LP变异、342个基因、412种SCGD和1,603种治疗方法进行的gNBS在74%的英国生物银行（UKB470K）成年人中呈阳性，这表明假阳性率为97%。我们利用纯化超选择现象，该现象可降低SCGD因果双倍型的频率，以减少假阳性。在618,290名对照和受影响个体中对基因-疾病-遗传模式-双倍型四分体进行训练，识别出293个变异或单倍型以及7个具有可变遗传的基因，这些基因导致的阳性双倍型计数高于与纯化超选择一致的情况，且几乎没有或没有SCGD因果关系的证据。经过这些改变，UKB470K成年人中有2.0%呈阳性。相比之下，在3118名疑似患有SCGD的重症儿童中，gNBS呈阳性的比例为7.2%，在705例婴儿死亡中为7.9%。与快速诊断基因组测序（RDGS）相比，gNBS的召回率为99.1%。在8名真正呈阳性的儿童中，预计gNBS可将诊断时间中位数缩短121天，并避免4名儿童出现危及生命的疾病表现、6名儿童出现器官损伤、节省约125万美元的医疗费用以及避免10例（1.4%）婴儿死亡。基于纯化超选择的联合训练为在人群筛查中实现高精度提供了一个通用框架。跨多个生物银行和临床试验的联合训练可为不同遗传血统中gNBS的资格认证提供一种隐私保护机制。
