Publications by Elisa Ficarra

The failures of Deep Networks can sometimes be ascribed to biases in the data or algorithmic choices. Existing debiasing approaches exploit prior knowledge to avoid unintended solutions; we acknowledge that, in real-world settings, it could be unfeasible to gather enough prior information to characterize the bias, or it could even raise ethical considerations. We hence propose a novel debiasing approach, termed ClusterFix, which does not require any external hint about the nature of biases. Such an approach alters the standard empirical risk minimization and introduces a per-example weight, encoding how critical and far from the majority an example is. Notably, the weights consider how difficult it is for the model to infer the correct pseudo-label, which is obtained in a self-supervised manner by dividing examples into multiple clusters. Extensive experiments show that the misclassification error incurred in identifying the correct cluster allows for identifying examples prone to bias-related issues. As a result, our approach outperforms existing methods on standard benchmarks for bias removal and fairness.

Segmentation of the Inferior Alveolar Canal (IAC) is a critical aspect of dentistry and maxillofacial imaging, garnering considerable attention in recent research endeavors. Deep learning techniques have shown promising results in this domain, yet their efficacy is still significantly hindered by the limited availability of 3D maxillofacial datasets. An inherent challenge is posed by the size of input volumes, which necessitates a patch-based processing approach that compromises the neural network performance due to the absence of global contextual information. This study introduces a novel approach that harnesses the spatial information within the extracted patches and incorporates it into a Transformer architecture, thereby enhancing the segmentation process through the use of prior knowledge about the patch location. Our method significantly improves the Dice score by a factor of 4 points, with respect to the previous work proposed by Cipriano et al., while also reducing the training steps required by the entire pipeline. By integrating spatial information and leveraging the power of Transformer architectures, this research not only advances the accuracy of IAC segmentation, but also streamlines the training process, offering a promising direction for improving dental and maxillofacial image analysis.

MicroRNAs (miRNAs) are small molecules that play an essential role in regulating gene expression by post-transcriptional gene silencing. Their study is crucial in revealing the fundamental processes underlying pathologies and, in particular, cancer. To date, most studies on miRNA regulation consider the effect of specific miRNAs on specific target mRNAs, providing wet-lab validation. However, few tools have been developed to explain the miRNAmediated regulation at the protein level. In this paper, the MoPC computational tool is presented, that relies on the partial correlation between mRNAs and proteins conditioned on the miRNA expression to predict miRNA-target interactions in multi-omic datasets. MoPC returns the list of significant miRNA-target interactions and plot the significant correlations on the heatmap in which the miRNAs and targets are ordered by the chromosomal location. The software was applied on three TCGA/CPTAC datasets (breast, glioblastoma, and lung cancer), returning enriched results in three independent targets databases.

Gene fusions are common in high-grade serous ovarian cancer (HGSC). Such genetic lesions may promote tumorigenesis, but the pathogenic mechanisms are currently poorly understood. Here, we investigated the role of a PIK3R1-CCDC178 fusion identified from a patient with advanced HGSC. We show that the fusion induces HGSC cell migration by regulating ERK1/2 and increases resistance to platinum treatment. Platinum resistance was associated with rod and ring-like cellular structure formation. These structures contained, in addition to the fusion protein, CIN85, a key regulator of PI3K-AKT-mTOR signaling. Our data suggest that the fusion-driven structure formation induces a previously unrecognized cell survival and resistance mechanism, which depends on ERK1/2-activation.

Medical diagnostics faced numerous difficulties during the COVID-19 pandemic. One of these has been the need for ongoing monitoring of SARS-CoV-2 mutations. Genomics is the technique most frequently used for precisely identifying variants. The ongoing global gathering of RNA samples of the virus has made such an approach possible. Nevertheless, variant identification techniques are frequently resource-intensive. As a result, the diagnostic capability of small medical laboratories might not be sufficient. In this work, an effective deep learning strategy for identifying SARS-CoV-2 variants is presented. This work makes two contributions: (1) a fine-tuning architecture of Bidirectional Encoder Representations from Transformers (BERT) to identify SARS-CoV-2 variants; (2) providing biological insights by exploiting BERT self-attention. Such an approach enables the analysis of the S gene of the virus to quickly recognize its variant. The selected model BERT is a transformer-based neural network first developed for natural language processing. Nonetheless, it has been effectively used in numerous applications, such as genomic sequence analysis. Thus, the fine-tuning of BERT was performed to adapt it to the RNA sequence domain, achieving a 98.59% F1-score on test data: it was successful in identifying variants circulating to date. The interpretability of the model was examined, since BERT utilizes the self-attention mechanism. In fact, it was discovered that by attending particular areas of the S gene, BERT extracts pertinent biological information on variants. Thus, the presented approach allows obtaining insights into the particular characteristics of SARS-CoV-2 RNA samples.

Histopathological image analysis is a critical area of research with the potential to aid pathologists in faster and more accurate diagnoses. However, Whole-Slide Images (WSIs) present challenges for deep learning frameworks due to their large size and lack of pixel-level annotations. Multi-Instance Learning (MIL) is a popular approach that can be employed for handling WSIs, treating each slide as a bag composed of multiple patches or instances. In this work we propose Buffer-MIL, which aims at tackling the covariate shift and class imbalance characterizing most of the existing histopathological datasets. With this goal, a buffer containing the most representative instances of each disease-positive slide of the training set is incorporated into our model. An attention mechanism is then used to compare all the instances against the buffer, to find the most critical ones in a given slide. We evaluate Buffer-MIL on two publicly available WSI datasets, Camelyon16 and TCGA lung cancer, outperforming current state-of-the-art models by 2.2% of accuracy on Camelyon16.

The adoption of Multi-Instance Learning (MIL) for classifying Whole-Slide Images (WSIs) has increased in recent years. Indeed, pixel-level annotation of gigapixel WSI is mostly unfeasible and time-consuming in practice. For this reason, MIL approaches have been profitably integrated with the most recent deep-learning solutions for WSI classification to support clinical practice and diagnosis. Nevertheless, the majority of such approaches overlook the multi-scale nature of the WSIs; the few existing hierarchical MIL proposals simply flatten the multi-scale representations by concatenation or summation of features vectors, neglecting the spatial structure of the WSI. Our work aims to unleash the full potential of pyramidal structured WSI; to do so, we propose a graph-based multi-scale MIL approach, termed DAS-MIL, that exploits message passing to let information flows across multiple scales. By means of a knowledge distillation schema, the alignment between the latent space representation at different resolutions is encouraged while preserving the diversity in the informative content. The effectiveness of the proposed framework is demonstrated on two well-known datasets, where we outperform SOTA on WSI classification, gaining a +1.9% AUC and +3.3¬curacy on the popular Camelyon16 benchmark.

Whole-Slide Images (WSI) are emerging as a promising resource for studying biological tissues, demonstrating a great potential in aiding cancer diagnosis and improving patient treatment. However, the manual pixel-level annotation of WSIs is extremely time-consuming and practically unfeasible in real-world scenarios. Multi-Instance Learning (MIL) have gained attention as a weakly supervised approach able to address lack of annotation tasks. MIL models aggregate patches (e.g., cropping of a WSI) into bag-level representations (e.g., WSI label), but neglect spatial information of the WSIs, crucial for histological analysis. In the High-Grade Serous Ovarian Cancer (HGSOC) context, spatial information is essential to predict a prognosis indicator (the Platinum-Free Interval, PFI) from WSIs. Such a prediction would bring highly valuable insights both for patient treatment and prognosis of chemotherapy resistance. Indeed, NeoAdjuvant ChemoTherapy (NACT) induces changes in tumor tissue morphology and composition, making the prediction of PFI from WSIs extremely challenging. In this paper, we propose GDS-MIL, a method that integrates a state-of-the-art MIL model with a Graph ATtention layer (GAT in short) to inject a local context into each instance before MIL aggregation. Our approach achieves a significant improvement in accuracy on the ``Ome18'' PFI dataset. In summary, this paper presents a novel solution for enhancing PFI prediction in HGSOC, with the potential of significantly improving treatment decisions and patient outcomes.

Messenger RNA (mRNA) has an essential role in the protein production process. Predicting mRNA expression levels accurately is crucial for understanding gene regulation, and various models (statistical and neural network-based) have been developed for this purpose. A few models predict mRNA expression levels from the DNA sequence, exploiting the DNA sequence and gene features (e.g., number of exons/introns, gene length). Other models include information about long-range interaction molecules (i.e., enhancers/silencers) and transcriptional regulators as predictive features, such as transcription factors (TFs) and small RNAs (e.g., microRNAs - miRNAs). Recently, a convolutional neural network (CNN) model, called Xpresso, has been proposed for mRNA expression level prediction leveraging the promoter sequence and mRNAs’ half-life features (gene features). To push forward the mRNA level prediction, we present miREx, a CNN-based tool that includes information about miRNA targets and expression levels in the model. Indeed, each miRNA can target specific genes, and the model exploits this information to guide the learning process. In detail, not all miRNAs are included, only a selected subset with the highest impact on the model. MiREx has been evaluated on four cancer primary sites from the genomics data commons (GDC) database: lung, kidney, breast, and corpus uteri. Results show that mRNA level prediction benefits from selected miRNA targets and expression information. Future model developments could include other transcriptional regulators or be trained with proteomics data to infer protein levels.