Interpretable models for high-risk neuroblastoma stratification with multi-cohort copy number profiles

Informatics in Medicine Unlocked

卷:25

Christa N. Grant¹  Menglu Liang²  Zhenqiu Liu³  Vladimir S. Spiegelman³  Hong-Gang Wang⁴ 

[1] Corresponding author at: Division of Pediatric Hematology and Oncology, Department of Pediatrics, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA.;

[2] Division of Pediatric Hematology and Oncology, Department of Pediatrics, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA;

[3] Department of Public Health Sciences, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA;

[4] Division of Pediatric Surgery, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA;

关键词: High-risk neuroblastoma;    L0 penalized global AUC summary maximization;    Prognostic prediction;    Copy-number variations (CNVs);    Multi-cohort integration;   

DOI  :  

来源: DOAJ

【 摘 要 】

Although high-risk neuroblastoma (HR-NB) is clinically heterogeneous, it is treated in a similar fashion without additional risk stratification. Based on the 4 copy-number profiles with 556 HR-NB subjects and 14 potential risk factors of neuroblastoma, we develop an interpretable machine learning model with L0penalized global AUC summary (L0GAUCS) maximization, and identify 6 and 4 molecular factors associated with overall and event-free survivals (OS and EFS) of HR-NB, respectively. We further construct a six-factor model for OS and a four-factor model for EFS, and categorize HR-NB patients into 4 subtypes (Excellent, Good, Fair, and Poor) for both OS (P=1.59e−11) and EFS (P=1.73e−06). Particularly, 14.05% and 6.75% HR-NB patients are in the Excellent (I) and Poor subtype (IV) with median OS times of 137. and 14.5 months, respectively. Patients from such distinct subtypes may be assigned to different experimental therapies in future trials. Furthermore, although it is well known that infants (children less than 1 year) has significantly better prognosis in neuroblastoma, we discover that infants with MYCN amplification (MNA+) has unfavorable OS and EFS in HR-NB. Infants with MNA+ have the hazard ratio of 2.9 (95% CI: 1.33−6.34) and P value of 3.67e−06for OS, and hazard ratio of 2.61 (95% CI: 1.05−6.48) and P value of 0.0007 for EFS. The unexpected but important finding that the survival of infants with MNA+ has significantly worse prognosis in HR-NB may have clinical implications.

【 授权许可】

Unknown