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Volume 5, Issue 6, Pages 620-627.e3 (December 2017) Association of Omics Features with Histopathology Patterns in Lung Adenocarcinoma Kun-Hsing Yu, Gerald J. Berry, Daniel L. Rubin, Christopher Ré, Russ B. Altman, Michael Snyder Cell Systems Volume 5, Issue 6, Pages 620-627.e3 (December 2017) DOI: 10.1016/j.cels.2017.10.014 Copyright © 2017 Elsevier Inc. Terms and Conditions

Cell Systems 2017 5, 620-627.e3DOI: (10.1016/j.cels.2017.10.014) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 1 A Summary of Methods (A) Model for data integration of this study. We processed the genomics, transcriptomics, and proteomics profiles of the primary tumor of lung adenocarcinoma patients and extracted quantitative histopathology features with a fully automated computational algorithm. The associations between functional omics and histopathology profiles were then analyzed to better understand the biology of this cancer. We further utilized both elements to generate an improved clinical prediction framework for lung adenocarcinoma patients. (B) A flow diagram of the machine-learning approach for classification. We divided the datasets into distinct training and test sets, extracted genomic, transcriptomic, proteomic, and histopathology features from the tumor samples, selected the top features, built random forest models, and used the untouched test set to evaluate the model performance. Cell Systems 2017 5, 620-627.e3DOI: (10.1016/j.cels.2017.10.014) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 2 Functional Omics Profiles Predicted the Dedifferentiation Levels of Lung Adenocarcinoma (A) The expression levels of 15 genes selected by information gain ratio accurately predicted pathology grade, with an area under the ROC curve (AUC) approximately 0.80 ± 0.0067. (B) Fifteen proteomics features predicted histology grade with good accuracy. A panel of protein markers predicted pathology grade with an AUC 0.81 ± 0.0071. (C) Dysregulated genes and proteins associated with tumor grade were enriched in gene-gene/protein-protein interactions. The observed numbers of gene-gene/protein-protein interactions and the expected numbers were shown for the transcriptomic and proteomic analyses. Cell Systems 2017 5, 620-627.e3DOI: (10.1016/j.cels.2017.10.014) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 3 Integrative Models with Gene Expression Profiles and Pathology Information Predicted the Survival Outcomes of Stage I Lung Adenocarcinoma Patients Red asterisks indicated censored data. (A) Lung adenocarcinoma patient survival stratified by tumor stage. Stage I patients generally have better prognoses (p < 0.001), but there are significant inter-individual differences in their survival outcomes. (B) Survival outcomes of stage IA and stage IB lung adenocarcinoma patients. This refinement in the staging system could not distinguish patients with different prognoses in this cohort (p = 0.878). (C) Stage I lung adenocarcinoma patient survival stratified by tumor grade. Grade alone could not predict patient survival reliably (p = 0.0616). (D) A previously reported gene set could not distinguish longer-term survivors (n = 112) from shorter-term survivors (n = 110) with statistical significance in the TCGA stage I lung adenocarcinoma cohort (p = 0.1097 ± 0.0096). (E) The same set of genes could not distinguish patient survival in the Mayo Clinic stage I lung adenocarcinoma cohort either (p = 0.0560 ± 0.0108; 13 predicted longer-term survivors; 14 predicted shorter-term survivors). (F) Integrating pathology with gene expression profiles better predicted patient survival in the TCGA stage I lung adenocarcinoma cohort (p = 0.0182 ± 0.0021; 110 predicted longer-term survivors; 112 predicted-shorter-term survivors). (G) The improved performance of the integrative survival prediction method is replicated in the Mayo Clinic stage I lung adenocarcinoma cohort (p = 0.0220 ± 0.0070; 11 predicted longer-term survivors; 16 predicted shorter-term survivors). Cell Systems 2017 5, 620-627.e3DOI: (10.1016/j.cels.2017.10.014) Copyright © 2017 Elsevier Inc. Terms and Conditions