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Bioinformatics of high throughput omics data (e.g. microarrays and proteomics) has been plagued by uncountable issues with reproducibility at the start of the century. Concerns have motivated international initiatives such as the FDA's led MAQC Consortium, addressing reproducibility of predictive biomarkers by means of appropriate Data Analysis Plans (DAPs). For instance, repreated cross-validation is a standard procedure meant at mitigating the risk that information from held-out validation data may be used during model selection. We prove here that, many years later, Data Leakage can still be a non-negligible overfitting source in deep learning models for digital pathology. In particular, we evaluate the impact of (i) the presence of multiple images for each subject in histology collections; (ii) the systematic adoption of training over collection of subregions (i.e. "tiles" or "patches") extracted for the same subject. We verify that accuracy scores may be inflated up to 41%, even if a well-designed 10 × 5 iterated cross-validation DAP is applied, unless all images from the same subject are kept together either in the internal training or validation splits. Results are replicated for 4 classification tasks in digital pathology on 3 datasets, for a total of 373 subjects, and 543 total slides (around 27, 000 tiles). Impact of applying transfer learning strategies with models pre-trained on general-purpose or digital pathology datasets is also discussed.Preprint. Under review.

Recent technological advances and international efforts, such as The Cancer Genome Atlas (TCGA), have made available several pan-cancer datasets encompassing multiple omics layers with detailed clinical information in large collection of samples. The need has thus arisen for the development of computational methods aimed at improving cancer subtyping and biomarker identification from multi-modal data. Here we apply the Integrative Network Fusion (INF) pipeline, which combines multiple omics layers exploiting Similarity Network Fusion (SNF) within a machine learning predictive framework. INF includes a feature ranking scheme (rSNF) on SNF-integrated features, used by a classifier over juxtaposed multi-omics features (juXT). In particular, we show instances of INF implementing Random Forest (RF) and linear Support Vector Machine (LSVM) as the classifier, and two baseline RF and LSVM models are also trained on juXT. A compact RF model, called rSNFi, trained on the intersection of top-ranked biomarkers from the two approaches juXT and rSNF is finally derived. All the classifiers are run in a 10x5-fold crossvalidation schema to warrant reproducibility, following the guidelines for an unbiased Data Analysis Plan by the US FDA-led initiatives MAQC/SEQC. INF is demonstrated on four classification tasks on three multi-modal TCGA oncogenomics datasets. Gene expression, protein abundances and copy number variants are used to predict estrogen receptor status (BRCA-ER, N=381) and breast invasive carcinoma subtypes (BRCA-subtypes, N=305), while gene expression, miRNA expression and methylation data is used as predictor layers for acute myeloid leukemia and renal clear cell carcinoma survival (AML-OS, N=157; KIRC-OS, N=181). In test, INF achieved similar Matthews Correlation Coefficient (MCC) values and 97% to 83% smaller feature sizes (FS), compared with juXT for BRCA-ER (MCC: 0.83 vs 0.80; FS: 56 vs 1801) and BRCA-subtypes 1 Chierici et al. INF(0.84 vs 0.80; 302 vs 1801), improving KIRC-OS performance (0.38 vs 0.31; 111 vs 2319). INF predictions are generally more accurate in test than one-dimensional omics models, with smaller signatures too, where transcriptomics consistently play the leading role. Overall, the INF framework effectively integrates multiple data levels in oncogenomics classification tasks, improving over the performance of single layers alone and naive juxtaposition, and provides compact signature sizes 1 .