C14∶1/C12∶1在新生儿筛查极长链酰基辅酶A脱氢酶缺乏症中的应用价值

Application value of C14∶1/C12∶1 for very long chain acyl-CoA dehydrogenase deficiency in newborn screening

目的探讨非衍生化串联质谱法(MS/MS)中十四烯酰基肉碱(C14∶1)/十二烯酰基肉碱(C12∶1)在新生儿筛查极长链酰基辅酶A脱氢酶缺乏症(VLCADD)中的应用价值,并探索筛查VLCADD的最佳指标组合方案。方法回顾性分析2014年1月至2021年12月南京市新生儿疾病筛查中心和苏州市新生儿疾病筛查中心17例MS/MS筛查发现并经酰基辅酶A脱氢酶极长链(ACADVL)基因确诊的VLCADD患儿和423507名经MS/MS筛查正常的新生儿资料。采用受试者工作特征(ROC)曲线分别确定所有新生儿组、足月新生儿组和正常出生体重新生儿组C14∶1/C12∶1筛查VLCADD的截断值。同时将不同指标单独或联合组成5个结果判读方案,分别为方案1(C14∶1/C12∶1)、方案2(C14∶1)、方案3(C14∶1+C14∶1/C2+C14∶1/C16)、方案4(C14∶1/C12∶1+C14∶1)和方案5(C14∶1/C12∶1+C14∶1+C14∶1/C2+C14∶1/C16),并计算各方案的检出率、假阳性率、阳性预测值,采用χ^(2)检验比较其筛查效率。结果所有新生儿组、足月新生儿组和正常出生体重新生儿组C14∶1/C12∶1的截断值均为2.80。5个判读方案筛查VLCADD的检出率均为17/17。其中方案1假阳性率[26.15‰(11075/423524)]最高,阳性预测值[0.15%(17/11092)]最低。方案4(方案5)假阳性率最低,为[0.02‰(10/423524)],阳性预测值最高,为[62.96%(17/27)],与方案1、方案2、方案3比较,假阳性率(χ^(2)值分别为302.30、11191.50和32.06)和阳性预测值(χ^(2)值分别为102.51、3485.61和13.83)差异均有统计学意义(P均<0.001)。结论C14∶1/C12∶1是新生儿筛查VLCADD有效的辅助判读指标,推荐C14∶1/C12∶1+C14∶1为非衍生化串联质谱法判读VLCADD的最佳筛查指标组合。

Objective To establish the cut-off value of tetradecenoyl carnitine(C14∶1)/dodecenoyl carnitine(C12∶1)based on non-derivatized tandem mass spectrometry(MS/MS),and to explore the application value of C14∶1/C12∶1 to screen newborns for very long chain acyl-CoA dehydrogenase deficiency(VLCADD),determining the best combination of indicators for screening VLCADD.Methods This retrospective study included data from 17 newborns with VLCADD detected by MS/MS and confirmed by acyl-CoA dehydrogenase very long chain(ACADVL)gene detection,and 423507 newborns with normal MS/MS results.The data from these newborns were collected from January 2014 to December 2021 as the newborns received neonatal screening in Nanjing Neonatal Disease Screening Center and Suzhou Neonatal Disease Screening Center.All newborns were divided into 3 groups:all newborns group,full-term newborns group and normal-birth-weight newborns group,and the cut-off values of C14∶1/C12∶1 for VLCADD in these 3 groups were determined by their receiver operating characteristic(ROC)curves individually.With these results,a total of 5 interpretation schemes were composed using different indicators alone or jointly:scheme 1 being C14∶1/C12∶1,scheme 2 being C14∶1,scheme 3 being C14∶1+C14∶1/C2+C14∶1/C16,scheme 4 being C14∶1/C12∶1+C14∶1,and scheme 5 being C14∶1/C12∶1+C14∶1+C14∶1/C2+C14∶1/C16.The detection rate,false-positive rate and positive predictive value of each scheme were calculated,and their screening efficiencies were statistically compared by Chi-square tests.Results The cut-off values of C14∶1/C12∶1 for VLCADD in the 3 newborn groups were all 2.80.The detection rates of VLCADD with all 5 interpretation schemes were 17/17.Scheme 1 had the highest false positive rate[26.15‰(11075/423524)]and the lowest positive predictive value[0.15%(17/11092)].Scheme 4(Scheme 5)had the lowest false positive rate[0.02‰(10/423524)]and the highest positive predictive value[62.96%(17/27)].Comparing scheme 4(Scheme 5)with scheme 1,scheme 2 and scheme 3,the differences of false positive rate(χ^(2)=302.30,11191.50,32.06)and positive predictive value(χ^(2)=102.51,3485.61,13.83)were statistically significant(all P<0.001).Conclusion C14∶1/C12∶1 was an effective auxiliary interpretive indicator for VLCADD in newborn screening,and the combination of C14∶1/C12∶1+C14∶1 was tested to be the best indicator for VLCADD screening based on non-derivatized tandem mass spectrometry.