Publications by Federico Bolelli

Background: The growing amount of biomedical knowledge about cancer in combination with genome-scale patient profiling data offers unprecedented opportunities for personalized oncology. However, the large amounts of knowledge and data require scalable approaches to providing actionable information to support clinicians in decision-making [1]. Objective: To develop software and methods that integrate all relevant clinical and genomic data about patients and that enable the discovery of optimal personalized treatment options, together with the supporting literature knowledge and data. Methods: We exploit a Semantic Knowledge Graph (SKG), a type of database that represents medical data in the form of objects and relationships, linking previously unconnected information across several cancer databases. To build up this SKG (OncodashKB), we use the BioCypher library [2]. We then integrate clinical data from patients with high-grade serous ovarian cancer, including information on genome changes collected as part of the DECIDER project (http://deciderproject.eu). The SKG can then be queried to gather evidence paths linking patient-specific alterations to actionable drugs. Results: Our approach provides a fully automated, systematic, and reproducible data integration workflow, along with the use of existing expert-made ontologies to provide interoperability and semantic descriptions. The integrated data is assessed by experts on molecular tumor boards and allows for the exploration of relevant clinical and genomic patient data in a visually accessible format, designed for ease of interpretation by clinicians. Importantly, we expect the system to reveal unexpected evidence paths between patient sequencing data and optimal treatment options based on biomedical knowledge described in the literature and confirmed by high-level evidence. Conclusion: Decision support systems using graph databases emerge as valuable tools by revealing new connections between various patient data and treatment options shown in an easy-to-understand format. References: [1] Reisle, C., Williamson, L.M., Pleasance, E. et al. A platform for oncogenomic reporting and interpretation. Nat Commun 13, 756 (2022). https://doi.org/10.1038/s41467-022-28348-y [2] Lobentanzer, S., Aloy, P., Baumbach, J. et al. Democratizing knowledge representation with BioCypher. Nat Biotechnol 41, 1056–1059 (2023). https://doi.org/10.1038/s41587-023-01848-y.

The presence of visible particles in pharmaceutical products is a critical quality issue that demands strict monitoring. Recently, Convolutional Neural Networks (CNNs) have been widely used in industrial settings to detect defects, but there remains a gap in the literature concerning the detection of particles floating in liquid substances, mainly due to the lack of publicly available datasets. In this study, we focus on the detection of foreign particles in pharmaceutical liquid vials, leveraging two state-of-the-art deep-learning approaches adapted to our specific multiclass problem. The first methodology employs a standard ResNet-18 architecture, while the second exploits a Multi-Instance Learning (MIL) technique to efficiently deal with multiple images (sequences) of the same sample. To address the issue of no data availability, we devised and partially released an annotated dataset consisting of sequences containing 19 images for each sample, captured from rotating vials, both with and without impurities. The dataset comprises 2,426 sequences for a total of 46,094 images labeled at the sequence level and including five distinct classes. The proposed methodologies, trained on this new extensive dataset, represent advancements in the field, offering promising strategies to improve the safety and quality control of pharmaceutical products and setting a benchmark for future comparisons.

Introduction. Length of Stay (LOS) and Prolonged Length of Stay (pLOS) are critical indicators of hospital efficiency. Reducing pLOS is crucial for patient safety, autonomy, and bed allocation. This study investigates different machine learning (ML) models to predict LOS and pLOS. Methods. We analyzed a dataset of patients discharged from a northern Italian hospital between 2022 and 2023 as a retrospective cohort study. We compared sixteen regression algorithms and twelve classification methods for predicting LOS as either a continuous or multi-class variable (1-3 days, 4-10 days, >10 days). We also evaluated pLOS prediction using the same models, having pLOS defined as any hospitalization with LOS longer than 8 days. We further analyzed all models using two versions of the same dataset: one containing only structured data (e.g. demographics and clinical information), whereas the second one also containing features extracted from free-text diagnosis. Results. Our results indicate that ensemble models achieved the highest prediction accuracy for both LOS and pLOS, outperforming traditional single-algorithm models, particularly when using both structured and unstructured data extracted from diagnoses. Discussion. The integration of ML, particularly ensemble models, can significantly improve LOS prediction and identify patients at increased risk of pLOS. This information can guide healthcare professionals and bed managers in making informed decisions to enhance patient care and optimize resource allocation.

The Inferior Alveolar Nerve (IAN) is of main interest in the maxillofacial field, as an accurate localization of such nerve reduces the risks of injury during surgical procedures. Although recent literature has focused on developing novel deep learning techniques to produce accurate segmentation masks of the canal containing the IAN, there are still strong limitations due to the scarce amount of publicly available 3D maxillofacial datasets. In this paper, we present an improved version of a previously released tool, IACAT (Inferior Alveolar Canal Annotation Tool), today used by medical experts to produce 3D ground truth annotation. In addition, we release a new dataset, ToothFairy, which is part of the homonymous MICCAI2023 challenge hosted by the Grand-Challenge platform, as an extension of the previously released Maxillo dataset, which was the only publicly available. With ToothFairy, the number of annotations has been increased as well as the quality of existing data.

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.

Introduction: The need of accurate three-dimensional data of anatomical structures is increasing in the surgical field. The development of convolutional neural networks (CNNs) has been helping to fill this gap by trying to provide efficient tools to clinicians. Nonetheless, the lack of a fully accessible datasets and open-source algorithms is slowing the improvements in this field. In this paper, we focus on the fully automatic segmentation of the Inferior Alveolar Canal (IAC), which is of immense interest in the dental and maxillo-facial surgeries. Conventionally, only a bidimensional annotation of the IAC is used in common clinical practice. A reliable convolutional neural network (CNNs) might be timesaving in daily practice and improve the quality of assistance. Materials and methods: Cone Beam Computed Tomography (CBCT) volumes obtained from a single radiological center using the same machine were gathered and annotated. The course of the IAC was annotated on the CBCT volumes. A secondary dataset with sparse annotations and a primary dataset with both dense and sparse annotations were generated. Three separate experiments were conducted in order to evaluate the CNN. The IoU and Dice scores of every experiment were recorded as the primary endpoint, while the time needed to achieve the annotation was assessed as the secondary end-point. Results: A total of 347 CBCT volumes were collected, then divided into primary and secondary datasets. Among the three experiments, an IoU score of 0.64 and a Dice score of 0.79 were obtained thanks to the pre-training of the CNN on the secondary dataset and the creation of a novel deep label propagation model, followed by proper training on the primary dataset. To the best of our knowledge, these results are the best ever published in the segmentation of the IAC. The datasets is publicly available and algorithm is published as open-source software. On average, the CNN could produce a 3D annotation of the IAC in 6.33 s, compared to 87.3 s needed by the radiology technician to produce a bidimensional annotation. Conclusions: To resume, the following achievements have been reached. A new state of the art in terms of Dice score was achieved, overcoming the threshold commonly considered of 0.75 for the use in clinical practice. The CNN could fully automatically produce accurate three-dimensional segmentation of the IAC in a rapid setting, compared to the bidimensional annotations commonly used in the clinical practice and generated in a time-consuming manner. We introduced our innovative deep label propagation method to optimize the performance of the CNN in the segmentation of the IAC. For the first time in this field, the datasets and the source codes used were publicly released, granting reproducibility of the experiments and helping in the improvement of IAC segmentation.