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Abstract：
BACKGROUND: Prompt and precise differential diagnosis of biliary atresia (BA) among cholestatic patients is of great importance. Matrix metalloproteinase-7 (MMP-7) holds great promise as a diagnostic marker for BA. This study aimed to investigate the accuracy of age-specific serum MMP-7 for discriminating BA from other cholestatic pediatric patients.
METHODS: This was a single center diagnostic accuracy and validation study including both retrospective and prospective cohorts. Serum MMP-7 concentrations were measured using an ELISA kit, the trajectory of which with age was investigated in a healthy infants cohort aged 0 to 365 days without hepatobiliary diseases (n = 284). Clinical BA diagnosis was based on intraoperative cholangiography and subsequent histological examinations. The diagnostic accuracy of age-specific cutoffs of serum MMP-7 were assessed in a retrospective cohort of cholestatic patients (n = 318, with 172 BA) and validated in a prospective cohort (n = 687, including 395 BA).
RESULTS: The MMP-7 concentration declines non-linearly with age, showing higher levels in healthy neonates as well as higher cutoff value in neonatal cholestasis. The area under the ROC curve (AUROC) was 0.967 (95% confidence interval [CI]: 0.946-0.988) for the retrospective cohort, and the cutoff of 18 ng/mL yielded 93.0% (95%CI: 88.1-96.3%), 93.8% (95%CI: 88.6-97.1%), 94.7% (95%CI: 90.1-97.5%), and 91.9% (95%CI: 86.4-95.8%) for sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), respectively. The performance of MMP-7 was successfully validated in the larger prospective cohort, resulting in a diagnostic sensitivity of 95.9% (379/395; 95% CI: 93.5-97.7%), a specificity of 87.3% (255/292; 95% CI: 83.0-90.9%), a PPV of 91.1% (379/416; 95% CI: 87.9-93.7%), and a NPV of 94.1% (255/271; 95% CI: 90.6-96.6%), respectively. Besides, higher cutoff value of 28.1 ng/mL achieved the best sensitivity, specificity, PPV, and NPV for infants aged 0-30 days, which was 86.4% (95% CI: 75.0-94.0%), 95.5% (95% CI: 77.2-99.9%), 98.1% (95% CI: 89.7-100%), and 72.4% (95% CI: 52.8-87.3%), respectively.
CONCLUSIONS: The serum MMP-7 is accurate and reliable in differentiating BA from non-BA cholestasis, showing its potential application in the diagnostic algorithm for BA and significant role in the future research regarding pathogenesis of BA.
METHODS: This was a single center diagnostic accuracy and validation study including both retrospective and prospective cohorts. Serum MMP-7 concentrations were measured using an ELISA kit, the trajectory of which with age was investigated in a healthy infants cohort aged 0 to 365 days without hepatobiliary diseases (n = 284). Clinical BA diagnosis was based on intraoperative cholangiography and subsequent histological examinations. The diagnostic accuracy of age-specific cutoffs of serum MMP-7 were assessed in a retrospective cohort of cholestatic patients (n = 318, with 172 BA) and validated in a prospective cohort (n = 687, including 395 BA).
RESULTS: The MMP-7 concentration declines non-linearly with age, showing higher levels in healthy neonates as well as higher cutoff value in neonatal cholestasis. The area under the ROC curve (AUROC) was 0.967 (95% confidence interval [CI]: 0.946-0.988) for the retrospective cohort, and the cutoff of 18 ng/mL yielded 93.0% (95%CI: 88.1-96.3%), 93.8% (95%CI: 88.6-97.1%), 94.7% (95%CI: 90.1-97.5%), and 91.9% (95%CI: 86.4-95.8%) for sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), respectively. The performance of MMP-7 was successfully validated in the larger prospective cohort, resulting in a diagnostic sensitivity of 95.9% (379/395; 95% CI: 93.5-97.7%), a specificity of 87.3% (255/292; 95% CI: 83.0-90.9%), a PPV of 91.1% (379/416; 95% CI: 87.9-93.7%), and a NPV of 94.1% (255/271; 95% CI: 90.6-96.6%), respectively. Besides, higher cutoff value of 28.1 ng/mL achieved the best sensitivity, specificity, PPV, and NPV for infants aged 0-30 days, which was 86.4% (95% CI: 75.0-94.0%), 95.5% (95% CI: 77.2-99.9%), 98.1% (95% CI: 89.7-100%), and 72.4% (95% CI: 52.8-87.3%), respectively.
CONCLUSIONS: The serum MMP-7 is accurate and reliable in differentiating BA from non-BA cholestasis, showing its potential application in the diagnostic algorithm for BA and significant role in the future research regarding pathogenesis of BA.
摘要：
背景：在胆汁淤积患者中，及时准确的鉴别诊断胆道闭锁（BA）非常重要。基质金属蛋白酶-7（MMP-7）作为BA的诊断标记物有很大的希望。本研究旨在探讨年龄特异性血清MMP-7区分BA与其他胆汁淤积性儿科患者的准确性。
方法：这是一项单中心诊断准确性和验证性研究，包括回顾性和前瞻性队列。使用ELISA试剂盒测量血清MMP-7浓度，在一个年龄为0~365日且无肝胆疾病的健康婴儿队列中调查了其随年龄变化的轨迹(n=284).临床BA诊断基于术中胆道造影和随后的组织学检查。在胆汁淤积患者的回顾性队列（n=318，172BA）中评估了血清MMP-7的年龄特异性截止值的诊断准确性，并在前瞻性队列（n=687，包括395BA）中进行了验证。
结果：MMP-7浓度随年龄呈非线性下降，在健康新生儿中显示较高的水平，在新生儿胆汁淤积中显示较高的临界值。回顾性队列的ROC曲线下面积（AUROC）为0.967（95％置信区间[CI]：0.946-0.988），18ng/mL的截止值产生93.0%(95CI:88.1-96.3%)，93.8%（95CI：88.6-97.1%），94.7%（95CI：90.1-97.5%），灵敏度为91.9%（95CI：86.4-95.8%），特异性，阳性预测值(PPV)，和负预测值(NPV)，分别。MMP-7的性能在更大的前瞻性队列中成功验证，诊断灵敏度为95.9%（379/395；95%CI：93.5-97.7%），特异性为87.3%（255/292；95%CI：83.0-90.9%），PPV为91.1%(379/416；95%CI：87.9-93.7%)，净现值为94.1%(255/271；95%CI：90.6-96.6%)，分别。此外,28.1ng/mL的较高截止值达到最佳灵敏度，特异性，PPV,0-30天婴儿的净现值，这是86.4%（95%CI：75.0-94.0%），95.5%（95%CI：77.2-99.9%），98.1%（95%CI：89.7-100%），和72.4%（95%CI：52.8-87.3%），分别。
结论：血清MMP-7在鉴别BA和非BA胆汁淤积中是准确可靠的，显示了其在BA诊断算法中的潜在应用，并在未来有关BA发病机制的研究中发挥了重要作用。
方法：这是一项单中心诊断准确性和验证性研究，包括回顾性和前瞻性队列。使用ELISA试剂盒测量血清MMP-7浓度，在一个年龄为0~365日且无肝胆疾病的健康婴儿队列中调查了其随年龄变化的轨迹(n=284).临床BA诊断基于术中胆道造影和随后的组织学检查。在胆汁淤积患者的回顾性队列（n=318，172BA）中评估了血清MMP-7的年龄特异性截止值的诊断准确性，并在前瞻性队列（n=687，包括395BA）中进行了验证。
结果：MMP-7浓度随年龄呈非线性下降，在健康新生儿中显示较高的水平，在新生儿胆汁淤积中显示较高的临界值。回顾性队列的ROC曲线下面积（AUROC）为0.967（95％置信区间[CI]：0.946-0.988），18ng/mL的截止值产生93.0%(95CI:88.1-96.3%)，93.8%（95CI：88.6-97.1%），94.7%（95CI：90.1-97.5%），灵敏度为91.9%（95CI：86.4-95.8%），特异性，阳性预测值(PPV)，和负预测值(NPV)，分别。MMP-7的性能在更大的前瞻性队列中成功验证，诊断灵敏度为95.9%（379/395；95%CI：93.5-97.7%），特异性为87.3%（255/292；95%CI：83.0-90.9%），PPV为91.1%(379/416；95%CI：87.9-93.7%)，净现值为94.1%(255/271；95%CI：90.6-96.6%)，分别。此外,28.1ng/mL的较高截止值达到最佳灵敏度，特异性，PPV,0-30天婴儿的净现值，这是86.4%（95%CI：75.0-94.0%），95.5%（95%CI：77.2-99.9%），98.1%（95%CI：89.7-100%），和72.4%（95%CI：52.8-87.3%），分别。
结论：血清MMP-7在鉴别BA和非BA胆汁淤积中是准确可靠的，显示了其在BA诊断算法中的潜在应用，并在未来有关BA发病机制的研究中发挥了重要作用。
