{
  "abstract": "IntroductionThe 2020 International Association for the Study of Lung Cancer (IASLC) grading system integrates the predominant histologic pattern and the proportion of high-grade patterns, but preoperative CT assessment is limited by spatial averaging of heterogeneous tumor components. We aimed to develop a CT-derived nested habitats score (NHS) that recursively identifies grade-associated intratumoral CT subregions, evaluate its cross-center performance for preoperative IASLC grading, and explore its transcriptomic correlates.MethodsThis retrospective two-center study included 650 patients with surgically resected lung adenocarcinoma. Center 1 formed the development cohort (n = 390); Center 2 was stratified 1:1 into validation (n = 130) and locked test (n = 130) cohorts, both from the same external institution. The prespecified primary task was pathologic IASLC Grade 1 versus Grade 2/3. NHS was generated using five-fold out-of-fold estimation in development data. Clinical-radiological, whole-tumor radiomics, NHS, and integrated models were compared, with algorithm selection confined to validation before one-time test evaluation. An independent TCGA-LUAD/TCIA CT-RNA cohort (n = 88) underwent exploratory WGCNA and Hallmark gene-set enrichment analysis.ResultsThe development/validation/test cohorts contained 41/14/14 Grade 1, 293/101/96 Grade 2, and 56/15/20 Grade 3 tumors. The selected random-forest integrated model yielded AUCs of 0.871 (95% CI, 0.784–0.936) in validation and 0.866 (95% CI, 0.784–0.935) in testing. NHS alone yielded AUCs of 0.828 and 0.854, compared with 0.620 and 0.497 for the clinical-radiological model and 0.703 and 0.775 for whole-tumor radiomics. NHS accounted for 76.3% of mean absolute SHAP contribution; removing NHS reduced AUC by 0.251 (95% CI, 0.079–0.439) in validation and 0.369 (95% CI, 0.200–0.553) in testing. Brier scores for NHS and the integrated model (0.074–0.077) were below the non-informative reference (0.096), but calibration slopes exceeded 1, and decision curves showed no net benefit over treating all patients as Grade 2/3 at low-to-intermediate thresholds. Exploratory radiogenomics showed nominal NHS-associated coexpression modules and enrichment of WNT/beta-catenin, E2F, G2M-checkpoint, and immune-related programs.DiscussionNHS discriminated IASLC Grade 1 from Grade 2/3 tumors, retained stable performance in two held-out cohorts from a second institution, and contributed most of the integrated model’s discrimination. The transcriptomic associations are hypothesis-generating, and recalibration and prospective multicenter evaluation are required before clinical application.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "Original Research",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "name": "Wang Peng"
    },
    {
      "name": "Jiajun Liu"
    },
    {
      "name": "Li Li"
    },
    {
      "name": "Wanyin Qi"
    },
    {
      "name": "Jinhong Zhao"
    },
    {
      "name": "Dinghua Li"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8re3ps0qta9pg.bib",
  "cited_by": 0,
  "doi": "10.3389/fmolb.2026.2006861",
  "fulltext_url": null,
  "id": "8re3ps0qta9pg",
  "issns": [
    "2296-889X"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fmolb.2026.2006861",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "feed-journal",
      "biochemistry/general"
    ]
  ],
  "openalex": null,
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-04",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/8re3ps0qta9pg.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T06:20:36Z",
      "native_id": "10.3389/fmolb.2026.2006861",
      "source": "feed-frontiers",
      "url": "https://www.frontiersin.org/articles/10.3389/fmolb.2026.2006861"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "journal-openalex:1312|Protein Structure and Dynamics",
      "subfield": "molecular-biology"
    }
  ],
  "title": "CT-derived nested habitats score for preoperative IASLC grading in lung adenocarcinoma: cross-center validation and radiogenomic analysis",
  "title_text": "CT-derived nested habitats score for preoperative IASLC grading in lung adenocarcinoma: cross-center validation and radiogenomic analysis",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T00:20:51Z",
  "url": "https://research.draconitic.com/paper/8re3ps0qta9pg",
  "venue": "Frontiers in Molecular Biosciences",
  "versions": []
}