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Risk stratification of hemodynamically significant patent ductus arteriosus by clinical and genetic factors

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Abstract

Background

Hemodynamically significant patent ductus arteriosus (hsPDA) is associated with increased comorbidities in neonates. Early evaluation of hsPDA risk is critical to implement individualized intervention. The aim of the study was to provide a powerful reference for the early identification of high-risk hsPDA population and early treatment decisions.

Methods

We enrolled infants who were diagnosed with PDA and performed exome sequencing. The collapsing analyses were used to find the risk gene set (RGS) of hsPDA for model construction. The credibility of RGS was proven by RNA sequencing. Multivariate logistic regression was performed to establish models combining clinical and genetic features. The models were evaluated by area under the receiver operating curve (AUC) and decision curve analysis (DCA).

Results

In this retrospective cohort study of 2199 PDA patients, 549 (25.0%) infants were diagnosed with hsPDA. The model [all clinical characteristics selected by least absolute shrinkage and selection operator regression (all CCs)] based on six clinical variables was acquired within three days of life, including gestational age (GA), respiratory distress syndrome (RDS), the lowest platelet count, invasive mechanical ventilation, and positive inotropic and vasoactive drugs. It has an AUC of 0.790 [95% confidence interval (CI) = 0.749–0.832], while the simplified model (basic clinical characteristic model) including GA and RDS has an AUC of 0.753 (95% CI = 0.706–0.799). There was a certain consistency between RGS and differentially expressed genes of the ductus arteriosus in mice. The AUC of the models was improved by RGS, and the improvement was significant (all CCs vs. all CCs + RGS: 0.790 vs. 0.817, P < 0.001). DCA demonstrated that all models were clinically useful.

Conclusions

Models based on clinical factors were developed to accurately stratify the risk of hsPDA in the first three days of life. Genetic features might further improve the model performance.

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Data availability

The datasets for this article are not publicly available. Requests to access the datasets should be directed to the corresponding authors.

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Acknowledgements

We thank all the patients who participated in the China Neonatal Genomes Project. The authors also would like to acknowledge doctors in Neonatal Intensive Care Unit and Center for Molecular Medicine of Children’s Hospital of Fudan University.

Funding

This work was funded by the Cohort Project of Specialized Disease, Clinical Research Center, Children's Hospital of Fudan University (2020ZBDL14) and National Key R&D Program of China (2022ZD0116003).

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Authors and Affiliations

  1. Center for Molecular Medicine of Children’s Hospital of Fudan University, Institutes of Biomedical Sciences, Fudan University, 138 Yi Xue Yuan Road, Shanghai, China

    Yu-Xi Chen & Wen-Hao Zhou

  2. Department of Neonatology, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China

    Tian-Tian Xiao, Xiang Chen, Li-Yuan Hu, Yun Cao, Guo-Qiang Cheng, Lai-Shuan Wang & Wen-Hao Zhou

  3. Center for Molecular Medicine, Children’s Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China

    Hui-Yao Chen, Ya-Qiong Wang, Qi Ni, Bing-Bing Wu, Hui-Jun Wang, Yu-Lan Lu, Fei-Fan Xiao, Lin Yang & Xin-Ran Dong

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  1. Yu-Xi Chen
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Contributions

CYX and XTT contributed equally as co-first authors. CYX and XTT analyzed and interpreted the data, and drafted the manuscript. CHY, WYQ, NQ, WBB, WHJ, and LYL performed genetic testing and bioinformatics analysis. HLY, CY, CGQ, WLS, XFF, and YL designed the samples collection instruments and collected data. CX collected ductus arteriosus samples of mice and performed RNA sequencing. DXR and ZWH conceptualized, designed and supervised the data collection and critically revised the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Corresponding authors

Correspondence to Xin-Ran Dong or Wen-Hao Zhou.

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Ethical approval

This study was approved by the China Neonatal Genomes Project (ClinicalTrials.gov identifier: NCT03931707) and Ethics Committees of the Department of Laboratory Animal Science Fudan University (2023-EKYY-137JZS). Informed consent to participate in the study has been obtained from participants’ parents.

Conflict of interest

No financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article. The authors have no conflict of interest relevant to this article to declare.

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Chen, YX., Xiao, TT., Chen, HY. et al. Risk stratification of hemodynamically significant patent ductus arteriosus by clinical and genetic factors. World J Pediatr 19, 1192–1202 (2023). https://doi.org/10.1007/s12519-023-00733-7

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