arXiv subjects

Francesca Ieva

Publications and source records attributed to Francesca Ieva.

At least 19 recordsLinked to original sources

arXiv2026

Generalized propensity score weighting for functional causal inference framework

Estimating causal effects in observational studies requires adjustment for confounding, a task that becomes challenging when the exposure is a function observed over a continuous domain rather than a scalar variable. We develop a functional propensity score weighting framework that achieves covariate balance by removing dependence between time-varying treatments and observed confounders, thereby enabling estimation of marginal causal effects in settings with functional treatments, covariates, and outcomes. We propose a dual formulation of the weight estimation problem that yields a smooth unconstrained optimization and improves computational scalability. The proposed framework extends naturally to settings with time-varying covariates and to longitudinal outcomes via a function-on-function marginal structural model, allowing estimation of causal effect surfaces. The proposed method improves covariate balance, estimation accuracy, and computational efficiency compared to the existing approach and retains these properties when extended to functional covariates and outcomes. We apply the method to data from the UK Biobank to estimate the causal effect of body mass index trajectories on the risk of Type 2 Diabetes and on subsequent glycated hemoglobin trajectories, a functional measure of metabolic status.

stat.ME↗

arXiv2026

Enhancing comorbidity network inference with risk-enriched health trajectories embedding

Multimorbidity poses a growing challenge for individual health, reducing quality of life and increasing treatment burden, resulting in a multiplicative impact on healthcare system management and fragmented care trajectories. Comorbidity networks could provide crucial insight into characterising multimorbidity and disease relationships. However, existing approaches to comorbidity network construction face critical limitations: they overlook temporal information by relying on cross-sectional statistics, produce biased association estimates by ignoring confounding due to shared risk factors, and fail to distinguish between direct and indirect disease associations, thereby yielding fully connected networks. To address these limitations, we develop a methodological framework for population-level disease network inference that uses individual health trajectories to learn disease associations, capturing semantic similarity and temporal co-occurrence. Sparse network estimation is achieved via Gaussian Graphical Models with Lasso regularisation, informed by prior clinical knowledge on shared risk factors derived from a dedicated confounding evaluation step. Applied to UK Biobank data comprising 24 cardiometabolic diseases and 76 risk factors, the resulting network revealed clinically meaningful disease patterns. Topological analysis identifies key pathological hubs, reveals potential actionable targets for multimorbidity management, and identifies four distinct disease communities that align with the established cardiometabolic taxonomy. Building on this community structure, we derive community-based patient representations that capture disease progression dynamics. Clustering these representations reveals four progression phenotypes with significantly different long-term survival trajectories, highlighting the potential of the framework for risk stratification and personalised care.

stat.AP↗

arXiv2026

Prior-informed conditional Gaussian graphical models: an application to protein interaction network reconstruction

Protein-protein interaction (PPI) networks, estimated from high-throughput omics data, foster biomarker discovery and precision medicine. Gaussian graphical models (GGMs) offer a principled reconstruction framework. Yet, existing applications face two limitations: they overlook the rich existing knowledge encoded in curated biological databases, and they assume a homogeneous network structure across all individuals, neglecting the influence of covariates or confounding factors on these interactions and preventing personalised representations. Even though these limitations have been addressed separately in previous work, no current approach resolves them simultaneously. We introduce a prior-informed conditional Gaussian graphical model that integrates database-derived interaction priors with covariate-dependent network modeling in a unified, scalable framework. The key methodological innovation is a structured, weighted penalty that selectively incorporates priors into population-level network estimation, while leaving context-specific perturbations entirely data-driven, as curated databases capture canonical interactions rather than disease-specific signals. Simulation studies demonstrate consistent and robust improvements in population-level network reconstruction across diverse settings, even when prior knowledge is imperfect. Applied to UK Biobank cardiometabolic proteomics (n = 49,129, p = 366 proteins), the method recovers T2D-associated network perturbations, identifying 34 network-central candidate biomarkers, several detectable only through their connectivity, not differential expression, and revealing six biologically coherent protein communities with distinct pathway enrichments spanning metabolic, cardiovascular, and cancer-related processes. Code is available at https://github.com/AlessiaMapelli/Prior-informed-conditional-GGMs.

stat.AP↗

arXiv2026

mmid: Multi-Modal Integration and Downstream analyses for healthcare analytics in Python

mmid (Multi-Modal Integration and Downstream analyses for healthcare analytics) is a Python package that offers multi-modal fusion and imputation, classification, time-to-event prediction and clustering functionalities under a single interface, filling the gap of sequential data integration and downstream analyses for healthcare applications in a structured and flexible environment. mmid wraps in a unique package several algorithms for multi-modal decomposition, prediction and clustering, which can be combined smoothly with a single command and proper configuration files, thus facilitating reproducibility and transferability of studies involving heterogeneous health data sources. A showcase on personalised cardiovascular risk prediction is used to highlight the relevance of a composite pipeline enabling proper treatment and analysis of complex multi-modal data. We thus employed mmid in an example real application scenario involving cardiac magnetic resonance imaging, electrocardiogram, and polygenic risk scores data from the UK Biobank. We proved that the three modalities captured joint and individual information that was used to (1) early identify cardiovascular disease before clinical manifestations with cardiological relevance, and (2) do it better than single data sources alone. Moreover, mmid allowed to impute partially observable data modalities without considerable performance losses in downstream disease prediction, thus proving its relevance for real-world health analytics applications (which are often characterised by the presence of missing data).

stat.CO↗

arXiv2026

SNPgen: Phenotype-Supervised Genotype Representation and Synthetic Data Generation via Latent Diffusion

Polygenic risk scores and other genomic analyses require large individual-level genotype datasets, yet strict data access restrictions impede sharing. Synthetic genotype generation offers a privacy-preserving alternative, but most existing methods operate unconditionally, producing samples without phenotype alignment, or rely on unsupervised compression, creating a gap between statistical fidelity and downstream task utility. We present SNPgen, a two-stage conditional latent diffusion framework for generating phenotype-supervised synthetic genotypes. SNPgen combines GWAS-guided variant selection (1,024-2,048 trait-associated SNPs) with a variational autoencoder for genotype compression and a latent diffusion model conditioned on binary disease labels via classifier-free guidance. Evaluated on 458,724 UK Biobank individuals across four complex diseases (coronary artery disease, breast cancer, type 1 and type 2 diabetes), models trained on synthetic data matched real-data predictive performance in a train-on-synthetic, test-on-real protocol, approaching genome-wide PRS methods that use $2$-$6\times$ more variants. Privacy analysis confirmed zero identical matches, near-random membership inference (AUC $\approx 0.50$), preserved linkage disequilibrium structure, and high allele frequency correlation ($r \geq 0.95$) with source data. A controlled simulation with known causal effects verified faithful recovery of the imposed genetic association structure.

cs.LG↗

arXiv2026

Trajectory-informed graph-based clustering for longitudinal cancer subtyping

Cancer subtyping plays a crucial role in informing prognosis and guiding personalized treatment strategies. However, conventional subtyping approaches often rely on static, biopsy-derived scores that hardly capture the biological heterogeneity and temporal evolution of the disease. In this study, we propose a novel trajectory-informed clustering method for cancer subtyping that integrates multi-modal clinical data and longitudinal patient trajectories. Our method constructs a patient similarity graph using time-varying imaging-derived features, clinical covariates, and transitions among key clinical states such as therapy, surveillance, relapse, and death. This graph structure enables the identification of patient subgroups that are not only phenotypically and genotypically distinct but also aligned with patterns of disease progression. We position our approach within the landscape of existing subtyping methods and highlight its advantages in terms of temporal modeling and graph-based interpretability. Through simulation studies and application to a real world dataset of liver metastases, we demonstrate the ability of our framework to uncover clinically relevant subtypes with distinct prognostic trajectories. Our results underscore the potential of trajectory-informed clustering to enhance personalized oncology by bridging cross-sectional biomarkers with dynamic disease evolution.

stat.ME↗

arXiv2026

Hidden multistate models to study multimorbidity trajectories

Multimorbidity in older adults is common, heterogeneous, and highly dynamic, and it is strongly associated with disability and increased healthcare utilization. However, existing approaches to studying multimorbidity trajectories are largely descriptive or rely on discrete-time models, which struggle to handle irregular observation intervals and right-censoring. We developed a continuous-time hidden multistate modeling framework to capture transitions among latent multimorbidity patterns while accounting for interval censoring and misclassification. A simulation study compared alternative model specifications under varying sample sizes and follow-up schemes, and the best-performing specification was applied to longitudinal data from the Swedish National study on Aging and Care-Kungsholmen (SNAC-K), including 2 716 multimorbid participants followed for up to 18 years. Simulation results showed that hidden multistate models substantially reduced bias in transition hazard estimates compared to non-hidden models, with fully time-inhomogeneous models outperforming piecewise approximations. Application to SNAC-K confirmed the feasibility and practical utility of this framework, enabling identification of risk factors for accelerated progression toward complex multimorbidity and revealing a gradient of mortality risk across patterns. Continuous-time hidden multistate models provide a robust alternative to traditional approaches, supporting individualized predictions and informing targeted interventions and secondary prevention strategies for multimorbidity in aging populations.

stat.AP↗

arXiv2026

Penalized Likelihood Optimization for Adaptive Neighborhood Clustering in Time-to-Event Data with Group-Level Heterogeneity

The identification of patient subgroups with comparable event-risk dynamics plays a key role in supporting informed decision-making in clinical research. In such settings, it is important to account for the inherent dependence that arises when individuals are nested within higher-level units, such as hospitals. Existing survival models account for group-level heterogeneity through frailty terms but do not uncover latent patient subgroups, while most clustering methods ignore hierarchical structure and are not estimated jointly with survival outcomes. In this work, we introduce a new framework that simultaneously performs patient clustering and shared-frailty survival modeling through a penalized likelihood approach. The proposed methodology adaptively learns a patient-to-patient similarity matrix via a modified version of spectral clustering, enabling cluster formation directly from estimated risk profiles while accounting for group membership. A simulation study highlights the proposed model's ability to recover latent clusters and to correctly estimate hazard parameters. We apply our method to a large cohort of heart-failure patients hospitalized with COVID-19 between 2020 and 2021 in the Lombardy region (Italy), identifying clinically meaningful subgroups characterized by distinct risk profiles and highlighting the role of respiratory comorbidities and hospital-level variability in shaping mortality outcomes. This framework provides a flexible and interpretable tool for risk-based patient stratification in hierarchical data settings.

stat.CO↗

arXiv2026

A neighbour selection approach for identifying differential networks in conditional functional graphical models

Estimating how different brain regions communicate with each other using EEG data is valuable both for medical research and clinical diagnosis. This involves quantifying the statistical dependencies among the activities of different brain areas, captured by the time-varying electric field recorded by scalp sensors. These dependencies can vary within and across individuals also in relationship with external factors such as age, mental state, or disease severity. Motivated by this problem, we propose a novel neighbor selection approach based on Gaussian functional graphical models and functional-on-functional regression to identify which brain regions interact and how interaction strength changes with individual features or covariates (e.g., age or clinical status). Our approach is fully automated and data-driven, and, in principle, can handle any number of continuous and categorical covariates simultaneously. Unlike existing approaches, it also produces results that are easy to interpret: one can directly assess whether the strength of each estimated interaction increases or decreases as the value of a given covariate varies. We evaluate our method through extensive simulation experiments and an application to real EEG data. The results demonstrate clear advantages over existing approaches, including more accurate estimation of brain connections and reduced computational cost, especially in high-dimensional settings involving a large number of brain regions and large sample sizes.

stat.ME↗

arXiv2025

Unraveling time-varying causal effects of multiple exposures: integrating Functional Data Analysis with Multivariable Mendelian Randomization

Mendelian Randomization is a widely used instrumental variable method for assessing causal effects of lifelong exposures on health outcomes. Many exposures, however, have causal effects that vary across the life course and often influence outcomes jointly with other exposures or indirectly through mediating pathways. Existing approaches to multivariable Mendelian Randomization assume constant effects over time and therefore fail to capture these dynamic relationships. We introduce Multivariable Functional Mendelian Randomization (MV-FMR), a new framework that extends functional Mendelian Randomization to simultaneously model multiple time-varying exposures. The method combines functional principal component analysis with a data-driven cross-validation strategy for basis selection and accounts for overlapping instruments and mediation effects. Through extensive simulations, we assessed MV-FMR's ability to recover time-varying causal effects under a range of data-generating scenarios and compared the performance of joint versus separate exposure effect estimation strategies. Across scenarios involving nonlinear effects, horizontal pleiotropy, mediation, and sparse data, MV-FMR consistently recovered the true causal functions and outperformed univariable approaches. To demonstrate its practical value, we applied MV-FMR to UK Biobank data to investigate the time-varying causal effects of systolic blood pressure and body mass index on coronary artery disease. MV-FMR provides a flexible and interpretable framework for disentangling complex time-dependent causal processes and offers new opportunities for identifying life-course critical periods and actionable drivers relevant to disease prevention.

stat.AP↗

arXiv2025

Multi-state Modeling of Delay Evolution in Suburban Rail Transports

Train delays are a persistent issue in railway systems, particularly in suburban networks where operational complexity is heightened by frequent services and high passenger volumes. Traditional delay models often overlook the temporal and structural dynamics of real delay propagation. This work applies continuous-time multi-state models to analyze the temporal evolution of delay on the S5 suburban line in Lombardy, Italy. Using detailed operational, meteorological, and contextual data, the study models delay transitions while accounting for observable heterogeneity. The findings reveal how delay dynamics vary by travel direction, time slot, and route segment. Covariates such as station saturation and passenger load are shown to significantly affect the risk of delay escalation or recovery. The study offers both methodological advancements and practical results for improving the reliability of rail services.

stat.AP↗

arXiv2025

Modeling group heterogeneity in spatio-temporal data via physics-informed semiparametric regression

In this work we propose a novel approach for modeling spatio-temporal data characterized by group structures. In particular, we extend classical mixed effect regression models by introducing a space-time nonparametric component, regularized through a partial differential equation, to embed the physical dynamics of the underlying process, while random effects capture latent variability associated with the group structure present in the data. We propose a two-step procedure to estimate the fixed and random components of the model, relying on a functional version of the Iterative Reweighted Least Squares algorithm. We investigate the asymptotic properties of both fixed and random components, and we assess the performance of the proposed model through a simulation study, comparing it with state-of-the-art alternatives from the literature. The proposed methodology is finally applied to the study of hourly nitrogen dioxide concentration data in Lombardy (Italy), using random effects to account for measurement heterogeneity across monitoring stations equipped with different sensor technologies.

stat.ME↗

arXiv2025

Scanner-Agnostic MRI Harmonization via SSIM-Guided Disentanglement

The variability introduced by differences in MRI scanner models, acquisition protocols, and imaging sites hinders consistent analysis and generalizability across multicenter studies. We present a novel image-based harmonization framework for 3D T1-weighted brain MRI, which disentangles anatomical content from scanner- and site-specific variations. The model incorporates a differentiable loss based on the Structural Similarity Index (SSIM) to preserve biologically meaningful features while reducing inter-site variability. This loss enables separate evaluation of image luminance, contrast, and structural components. Training and validation were performed on multiple publicly available datasets spanning diverse scanners and sites, with testing on both healthy and clinical populations. Harmonization using multiple style targets, including style-agnostic references, produced consistent and high-quality outputs. Visual comparisons, voxel intensity distributions, and SSIM-based metrics demonstrated that harmonized images achieved strong alignment across acquisition settings while maintaining anatomical fidelity. Following harmonization, structural SSIM reached 0.97, luminance SSIM ranged from 0.98 to 0.99, and Wasserstein distances between mean voxel intensity distributions decreased substantially. Downstream tasks showed substantial improvements: mean absolute error for brain age prediction decreased from 5.36 to 3.30 years, and Alzheimer's disease classification AUC increased from 0.78 to 0.85. Overall, our framework enhances cross-site image consistency, preserves anatomical fidelity, and improves downstream model performance, providing a robust and generalizable solution for large-scale multicenter neuroimaging studies.

cs.CV↗

arXiv2025

Three Distributional Approaches for PM10 Assessment in Northern Italy

We propose three spatial methods for estimating the full probability distribution of PM10 concentrations, with the ultimate goal of assessing air quality in Northern Italy. Moving beyond spatial averages and simple indicators, we adopt a distributional perspective to capture the complex variability of pollutant concentrations across space. The first proposed approach predicts class-based compositions via Fixed Rank Kriging; the second estimates multiple, non-crossing quantiles through a spatial regression with differential regularization; the third directly reconstructs full probability densities leveraging on both Fixed Rank Kriging and multiple quantiles spatial regression within a Simplicial Principal Component Analysis framework. These approaches are applied to daily PM10 measurements, collected from 2018 to 2022 in Northern Italy, to estimate spatially continuous distributions and to identify regions at risk of regulatory exceedance. The three approaches exhibit localized differences, revealing how modeling assumptions may influence the prediction of fine-scale pollutant concentration patterns. Nevertheless, they consistently agree on the broader spatial patterns of pollution. This general agreement supports the robustness of a distributional approach, which offers a comprehensive and policy-relevant framework for assessing air quality and regulatory exceedance risks.

stat.AP↗

arXiv2025

Cluster-weighted modeling of lifetime hierarchical data for profiling COVID-19 heart failure patients

This study investigates the heterogeneity in survival times among COVID-19 patients with Heart Failure (HF) hospitalized in the Lombardy region of Italy during the pandemic. To address this, we propose a novel mixture model for right-censored lifetime data that incorporates random effects and allows for local distributions of the explanatory variables. Our approach identifies latent clusters of patients while estimating component-specific covariate effects on survival, taking into account the hierarchical structure induced by the healthcare facility. Specifically, a shared frailty term, unique to each cluster, captures hospital-level variability enabling a twofold decoupling of survival heterogeneity across both clusters and hierarchies. Two EM-based algorithms, namely a Classification EM (CEM) and a Stochastic EM (SEM), are proposed for parameter estimation. The devised methodology effectively uncovers latent patient profiles, evaluates within-cluster hospital effects, and quantifies the impact of respiratory conditions on survival. Our findings provide new information on the complex interplay between the impacts of HF, COVID-19, and healthcare facilities on public health, highlighting the importance of personalized and context-sensitive clinical strategies.

stat.AP↗

arXiv2025

Interpretable phenotyping of Heart Failure patients with Dutch discharge letters

Objective: Heart failure (HF) patients present with diverse phenotypes affecting treatment and prognosis. This study evaluates models for phenotyping HF patients based on left ventricular ejection fraction (LVEF) classes, using structured and unstructured data, assessing performance and interpretability. Materials and Methods: The study analyzes all HF hospitalizations at both Amsterdam UMC hospitals (AMC and VUmc) from 2015 to 2023 (33,105 hospitalizations, 16,334 patients). Data from AMC were used for model training, and from VUmc for external validation. The dataset was unlabelled and included tabular clinical measurements and discharge letters. Silver labels for LVEF classes were generated by combining diagnosis codes, echocardiography results, and textual mentions. Gold labels were manually annotated for 300 patients for testing. Multiple Transformer-based (black-box) and Aug-Linear (white-box) models were trained and compared with baselines on structured and unstructured data. To evaluate interpretability, two clinicians annotated 20 discharge letters by highlighting information they considered relevant for LVEF classification. These were compared to SHAP and LIME explanations from black-box models and the inherent explanations of Aug-Linear models. Results: BERT-based and Aug-Linear models, using discharge letters alone, achieved the highest classification results (AUC=0.84 for BERT, 0.81 for Aug-Linear on external validation), outperforming baselines. Aug-Linear explanations aligned more closely with clinicians' explanations than post-hoc explanations on black-box models. Conclusions: Discharge letters emerged as the most informative source for phenotyping HF patients. Aug-Linear models matched black-box performance while providing clinician-aligned interpretability, supporting their use in transparent clinical decision-making.

cs.CL↗

arXiv2025

DISARM++: Beyond scanner-free harmonization

Harmonization of T1-weighted MR images across different scanners is crucial for ensuring consistency in neuroimaging studies. This study introduces a novel approach to direct image harmonization, moving beyond feature standardization to ensure that extracted features remain inherently reliable for downstream analysis. Our method enables image transfer in two ways: (1) mapping images to a scanner-free space for uniform appearance across all scanners, and (2) transforming images into the domain of a specific scanner used in model training, embedding its unique characteristics. Our approach presents strong generalization capability, even for unseen scanners not included in the training phase. We validated our method using MR images from diverse cohorts, including healthy controls, traveling subjects, and individuals with Alzheimer's disease (AD). The model's effectiveness is tested in multiple applications, such as brain age prediction (R2 = 0.60 \pm 0.05), biomarker extraction, AD classification (Test Accuracy = 0.86 \pm 0.03), and diagnosis prediction (AUC = 0.95). In all cases, our harmonization technique outperforms state-of-the-art methods, showing improvements in both reliability and predictive accuracy. Moreover, our approach eliminates the need for extensive preprocessing steps, such as skull-stripping, which can introduce errors by misclassifying brain and non-brain structures. This makes our method particularly suitable for applications that require full-head analysis, including research on head trauma and cranial deformities. Additionally, our harmonization model does not require retraining for new datasets, allowing smooth integration into various neuroimaging workflows. By ensuring scanner-invariant image quality, our approach provides a robust and efficient solution for improving neuroimaging studies across diverse settings. The code is available at this link.

cs.CV↗

arXiv2025

An Unsupervised Natural Language Processing Pipeline for Assessing Referral Appropriateness

Objective: Assessing the appropriateness of diagnostic referrals is critical for improving healthcare efficiency and reducing unnecessary procedures. However, this task becomes challenging when referral reasons are recorded only as free text rather than structured codes, like in the Italian NHS. To address this gap, we propose a fully unsupervised Natural Language Processing (NLP) pipeline capable of extracting and evaluating referral reasons without relying on labelled datasets. Methods: Our pipeline leverages Transformer-based embeddings pre-trained on Italian medical texts to cluster referral reasons and assess their alignment with appropriateness guidelines. It operates in an unsupervised setting and is designed to generalize across different examination types. We analyzed two complete regional datasets from the Lombardy Region (Italy), covering all referrals between 2019 and 2021 for venous echocolordoppler of the lower limbs (ECD;n=496,971; development) and flexible endoscope colonoscopy (FEC; n=407,949; testing only). For both, a random sample of 1,000 referrals was manually annotated to measure performance. Results: The pipeline achieved high performance in identifying referral reasons (Prec=92.43% (ECD), 93.59% (FEC); Rec=83.28% (ECD), 92.70% (FEC)) and appropriateness (Prec=93.58% (ECD), 94.66% (FEC); Rec=91.52% (ECD), 93.96% (FEC)). At the regional level, the analysis identified relevant inappropriate referral groups and variation across contexts, findings that informed a new Lombardy Region resolution to reinforce guideline adherence. Conclusions: This study presents a robust, scalable, unsupervised NLP pipeline for assessing referral appropriateness in large, real-world datasets. It demonstrates how such data can be effectively leveraged, providing public health authorities with a deployable AI tool to monitor practices and support evidence-based policy.

cs.CL↗