Stepwise refinement refers to the progressive refinement in small steps of a program specification into a program. Sometimes, it is called top-down design.

While accumulating studies have investigated coding [[gene]]-associated [[biomarker]]s in [[malignant glioma]], research on comprehensive coding and [[non-coding RNA]]-associated biomarkers is lacking. Furthermore, few studies have illustrated the [[crosstalk]] [[signaling pathway]]s among these biomarkers and mechanisms in detail. 

Huang et al. identified differentially expressed genes and [[Competing endogenous RNA]] (ceRNA) networks in [[malignant glioma]] and then constructed [[Cox]]/[[Lasso]] [[regression model]]s to further identify the most valuable genes through [[stepwise refinement]]. Top-down comprehensive integrated analysis, including functional enrichment, SNV, immune infiltration, transcription factor binding site, and molecular docking analyses, further revealed the regulatory maps among these genes. The results revealed a novel and accurate model (AUC of 0.91 and C-index of 0.84 in the whole malignant gliomas, AUC of 0.90 and C-index of 0.86 in LGG, and AUC of 0.75 and C-index of 0.69 in Glioblastoma) that includes twelve ncRNAs, 1 MicroRNA, and 6 coding genes. Stepwise logical reasoning based on top-down comprehensive integrated analysis and references revealed [[crosstalk]] [[signaling pathway]]s among these genes that were correlated with the [[circadian rhythm]], [[tumor immune microenvironment]], and [[cellular senescence]] pathways. In conclusion, the work reveals a novel model where the newly identified biomarkers may contribute to a precise diagnosis/prognosis and subclassification of [[malignant glioma]], and the identified cross-talk signaling pathways would help to illustrate the noncoding RNA-associated epigenetic regulatory mechanisms of [[glioma]] [[tumorigenesis]] and aid in [[targeted therapy]]
((Huang Y, Gao X, Yang E, Yue K, Cao Y, Zhao B, Zhang H, Dai S, Zhang L, Luo P, Jiang X. Top-down [[stepwise refinement]] identifies coding and noncoding RNA-associated [[epigenetic]] regulatory maps in malignant glioma. J Cell Mol Med. 2022 Feb 22. doi: 10.1111/jcmm.17244. Epub ahead of print. PMID: 35194922.)).