Giovanni Cinà

Izak Yasrebi-de Kom, Joanna Klopotowska, Dave Dongelmans et al.

The current best practice approach for the retrospective diagnosis of adverse drug events (ADEs) in hospitalized patients relies on a full patient chart review and a formal causality assessment by multiple medical experts. This evaluation serves to qualitatively estimate the probability of causation (PC); the probability that a drug was a necessary cause of an adverse event. This practice is manual, resource intensive and prone to human biases, and may thus benefit from data-driven decision support. Here, we pioneer a causal modeling approach using observational data to estimate a lower bound of the PC (PC$_{low}$). This method includes two key causal inference components: (1) the target trial emulation framework and (2) estimation of individualized treatment effects using machine learning. We apply our method to the clinically relevant use-case of vancomycin-induced acute kidney injury in intensive care patients, and compare our causal model-based PC$_{low}$ estimates to qualitative estimates of the PC provided by a medical expert. Important limitations and potential improvements are discussed, and we conclude that future improved causal models could provide essential data-driven support for medication safety monitoring in hospitalized patients.

Giovanni Cinà, Daniel Fernandez-Llaneza, Ludovico Deponte et al.

Feature attribution methods have become a staple method to disentangle the complex behavior of black box models. Despite their success, some scholars have argued that such methods suffer from a serious flaw: they do not allow a reliable interpretation in terms of human concepts. Simply put, visualizing an array of feature contributions is not enough for humans to conclude something about a model's internal representations, and confirmation bias can trick users into false beliefs about model behavior. We argue that a structured approach is required to test whether our hypotheses on the model are confirmed by the feature attributions. This is what we call the "semantic match" between human concepts and (sub-symbolic) explanations. Building on the conceptual framework put forward in Cinà et al. [2023], we propose a structured approach to evaluate semantic match in practice. We showcase the procedure in a suite of experiments spanning tabular and image data, and show how the assessment of semantic match can give insight into both desirable (e.g., focusing on an object relevant for prediction) and undesirable model behaviors (e.g., focusing on a spurious correlation). We couple our experimental results with an analysis on the metrics to measure semantic match, and argue that this approach constitutes the first step towards resolving the issue of confirmation bias in XAI.

Giovanni Cinà, Tabea E. Röber, Rob Goedhart et al.

The recent spike in certified Artificial Intelligence (AI) tools for healthcare has renewed the debate around adoption of this technology. One thread of such debate concerns Explainable AI (XAI) and its promise to render AI devices more transparent and trustworthy. A few voices active in the medical AI space have expressed concerns on the reliability of Explainable AI techniques and especially feature attribution methods, questioning their use and inclusion in guidelines and standards. Despite valid concerns, we argue that existing criticism on the viability of post-hoc local explainability methods throws away the baby with the bathwater by generalizing a problem that is specific to image data. We begin by characterizing the problem as a lack of semantic match between explanations and human understanding. To understand when feature importance can be used reliably, we introduce a distinction between feature importance of low- and high-level features. We argue that for data types where low-level features come endowed with a clear semantics, such as tabular data like Electronic Health Records (EHRs), semantic match can be obtained, and thus feature attribution methods can still be employed in a meaningful and useful way. Finally, we sketch a procedure to test whether semantic match has been achieved.

Davide Tugnoli, Andrea De Lorenzo, Marco Virgolin et al.

Synthetic tabular data generation addresses data scarcity and privacy constraints in a variety of domains. Tabular Prior-Data Fitted Network (TabPFN), a recent foundation model for tabular data, has been shown capable of generating high-quality synthetic tabular data. However, TabPFN is autoregressive: features are generated sequentially by conditioning on the previous ones, depending on the order in which they appear in the input data. We demonstrate that when the feature order conflicts with causal structure, the model produces spurious correlations that impair its ability to generate synthetic data and preserve causal effects. We address this limitation by integrating causal structure into TabPFN's generation process through two complementary approaches: Directed Acyclic Graph (DAG)-aware conditioning, which samples each variable given its causal parents, and a Completed Partially Directed Acyclic Graph (CPDAG)-based strategy for scenarios with partial causal knowledge. We evaluate these approaches on controlled benchmarks and six CSuite datasets, assessing structural fidelity, distributional alignment, privacy preservation, and Average Treatment Effect (ATE) preservation. Across most settings, DAG-aware conditioning improves the quality and stability of synthetic data relative to vanilla TabPFN. The CPDAG-based strategy shows moderate improvements, with effectiveness depending on the number of oriented edges. These results indicate that injecting causal structure into autoregressive generation enhances the reliability of synthetic tabular data.

Giovanni Cinà, Tabea Röber, Rob Goedhart et al.

The recent spike in certified Artificial Intelligence (AI) tools for healthcare has renewed the debate around adoption of this technology. One thread of such debate concerns Explainable AI and its promise to render AI devices more transparent and trustworthy. A few voices active in the medical AI space have expressed concerns on the reliability of Explainable AI techniques, questioning their use and inclusion in guidelines and standards. Revisiting such criticisms, this article offers a balanced and comprehensive perspective on the utility of Explainable AI, focusing on the specificity of clinical applications of AI and placing them in the context of healthcare interventions. Against its detractors and despite valid concerns, we argue that the Explainable AI research program is still central to human-machine interaction and ultimately our main tool against loss of control, a danger that cannot be prevented by rigorous clinical validation alone.

Otto Nyberg, Fausto Carcassi, Giovanni Cinà

Across a growing number of fields, human decision making is supported by predictions from AI models. However, we still lack a deep understanding of the effects of adoption of these technologies. In this paper, we introduce a general computational framework, the 2-Step Agent, which models the effects of AI-assisted decision making. Our framework uses Bayesian methods for causal inference to model 1) how a prediction on a new observation affects the beliefs of a rational Bayesian agent, and 2) how this change in beliefs affects the downstream decision and subsequent outcome. Using this framework, we show by simulations how a single misaligned prior belief can be sufficient for decision support to result in worse downstream outcomes compared to no decision support. Our results reveal several potential pitfalls of AI-driven decision support and highlight the need for thorough model documentation and proper user training.

Mohammad Azizmalayeri, Ameen Abu-Hanna, Saskia Houterman et al.

Background: External validation is essential for assessing the transportability of predictive models. However, its interpretation is often confounded by differences between external and development populations. This study introduces a framework to distinguish model deficiencies from case-mix effects. Method: We propose a framework that quantifies each external patient's similarity to the development data and measures performance in subgroups with varying levels of alignment to the development distribution. We use generative models, specifically autoencoders, to estimate similarity, offering a more flexible alternative to traditional linear approaches and enabling validation without sharing the original development data. The utility of autoencoder-based similarity measure is demonstrated using synthetic data, and the framework's application is illustrated using data from the Netherlands Heart Registration (NHR) to predict mortality after transcatheter aortic valve implantation. Results: Our framework revealed substantial variation in model performance across similarity-defined subgroups, differences that remain hidden under conventional external validation yet can meaningfully alter conclusions. In several settings, conventional external validation suggested poor overall performance. However, after accounting for differences in patient characteristics, for some sub-groups, the model performance was consistent with internal validation results. Conversely, apparently acceptable overall performance could mask clinically relevant performance deficits in specific subgroups. Conclusion: The proposed framework enhances the interpretability of external validation by linking model performance to population alignment with the development data. This provides a more principled basis for deciding whether a model is transportable and to which patients it can be safely applied.

Mohammad Azizmalayeri, Ameen Abu-Hanna, Giovanni Cinà

Detecting out-of-distribution (OOD) instances is crucial for the reliable deployment of machine learning models in real-world scenarios. OOD inputs are commonly expected to cause a more uncertain prediction in the primary task; however, there are OOD cases for which the model returns a highly confident prediction. This phenomenon, denoted as "overconfidence", presents a challenge to OOD detection. Specifically, theoretical evidence indicates that overconfidence is an intrinsic property of certain neural network architectures, leading to poor OOD detection. In this work, we address this issue by measuring extreme activation values in the penultimate layer of neural networks and then leverage this proxy of overconfidence to improve on several OOD detection baselines. We test our method on a wide array of experiments spanning synthetic data and real-world data, tabular and image datasets, multiple architectures such as ResNet and Transformer, different training loss functions, and include the scenarios examined in previous theoretical work. Compared to the baselines, our method often grants substantial improvements, with double-digit increases in OOD detection AUC, and it does not damage performance in any scenario.

Ana Esponera, Giovanni Cinà

Causal abstraction techniques such as Interchange Intervention Training (IIT) have been proposed to infuse neural network with expert knowledge encoded in causal models, but their application to real-world problems remains limited. This article explores the application of IIT in predicting blood glucose levels in Type 1 Diabetes Mellitus (T1DM) patients. The study utilizes an acyclic version of the simglucose simulator approved by the FDA to train a Multi-Layer Perceptron (MLP) model, employing IIT to impose causal relationships. Results show that the model trained with IIT effectively abstracted the causal structure and outperformed the standard one in terms of predictive performance across different prediction horizons (PHs) post-meal. Furthermore, the breakdown of the counterfactual loss can be leveraged to explain which part of the causal mechanism are more or less effectively captured by the model. These preliminary results suggest the potential of IIT in enhancing predictive models in healthcare by effectively complying with expert knowledge.

Karina Zadorozhny, Patrick Thoral, Paul Elbers et al.

Detection of Out-of-Distribution (OOD) samples in real time is a crucial safety check for deployment of machine learning models in the medical field. Despite a growing number of uncertainty quantification techniques, there is a lack of evaluation guidelines on how to select OOD detection methods in practice. This gap impedes implementation of OOD detection methods for real-world applications. Here, we propose a series of practical considerations and tests to choose the best OOD detector for a specific medical dataset. These guidelines are illustrated on a real-life use case of Electronic Health Records (EHR). Our results can serve as a guide for implementation of OOD detection methods in clinical practice, mitigating risks associated with the use of machine learning models in healthcare.

Adam Izdebski, Patrick J. Thoral, Robbert C. A. Lalisang et al.

Despite the recent progress in the field of causal inference, to date there is no agreed upon methodology to glean treatment effect estimation from observational data. The consequence on clinical practice is that, when lacking results from a randomized trial, medical personnel is left without guidance on what seems to be effective in a real-world scenario. This article proposes a pragmatic methodology to obtain preliminary but robust estimation of treatment effect from observational studies, to provide front-line clinicians with a degree of confidence in their treatment strategy. Our study design is applied to an open problem, the estimation of treatment effect of the proning maneuver on COVID-19 Intensive Care patients.

Dennis Ulmer, Giovanni Cinà

A crucial requirement for reliable deployment of deep learning models for safety-critical applications is the ability to identify out-of-distribution (OOD) data points, samples which differ from the training data and on which a model might underperform. Previous work has attempted to tackle this problem using uncertainty estimation techniques. However, there is empirical evidence that a large family of these techniques do not detect OOD reliably in classification tasks. This paper gives a theoretical explanation for said experimental findings and illustrates it on synthetic data. We prove that such techniques are not able to reliably identify OOD samples in a classification setting, since their level of confidence is generalized to unseen areas of the feature space. This result stems from the interplay between the representation of ReLU networks as piece-wise affine transformations, the saturating nature of activation functions like softmax, and the most widely-used uncertainty metrics.

Dennis Ulmer, Lotta Meijerink, Giovanni Cinà

When deploying machine learning models in high-stakes real-world environments such as health care, it is crucial to accurately assess the uncertainty concerning a model's prediction on abnormal inputs. However, there is a scarcity of literature analyzing this problem on medical data, especially on mixed-type tabular data such as Electronic Health Records. We close this gap by presenting a series of tests including a large variety of contemporary uncertainty estimation techniques, in order to determine whether they are able to identify out-of-distribution (OOD) patients. In contrast to previous work, we design tests on realistic and clinically relevant OOD groups, and run experiments on real-world medical data. We find that almost all techniques fail to achieve convincing results, partly disagreeing with earlier findings.

Lotta Meijerink, Giovanni Cinà, Michele Tonutti

In a data-scarce field such as healthcare, where models often deliver predictions on patients with rare conditions, the ability to measure the uncertainty of a model's prediction could potentially lead to improved effectiveness of decision support tools and increased user trust. This work advances the understanding of uncertainty estimation for classification and risk prediction on medical tabular data, in a two-fold way. First, we expand and refine the set of heuristics to select an uncertainty estimation technique, introducing tests for clinically-relevant scenarios such as generalization to uncommon pathologies, changes in clinical protocol and simulations of corrupted data. We furthermore differentiate these heuristics depending on the clinical use-case. Second, we observe that ensembles and related techniques perform poorly when it comes to detecting out-of-domain examples, a critical task which is carried out more successfully by auto-encoders. These remarks are enriched by considerations of the interplay of uncertainty estimation with class imbalance, post-modeling calibration and other modeling procedures. Our findings are supported by an array of experiments on toy and real-world data.

David Ruhe, Giovanni Cinà, Michele Tonutti et al.

The Intensive Care Unit (ICU) is a hospital department where machine learning has the potential to provide valuable assistance in clinical decision making. Classical machine learning models usually only provide point-estimates and no uncertainty of predictions. In practice, uncertain predictions should be presented to doctors with extra care in order to prevent potentially catastrophic treatment decisions. In this work we show how Bayesian modelling and the predictive uncertainty that it provides can be used to mitigate risk of misguided prediction and to detect out-of-domain examples in a medical setting. We derive analytically a bound on the prediction loss with respect to predictive uncertainty. The bound shows that uncertainty can mitigate loss. Furthermore, we apply a Bayesian Neural Network to the MIMIC-III dataset, predicting risk of mortality of ICU patients. Our empirical results show that uncertainty can indeed prevent potential errors and reliably identifies out-of-domain patients. These results suggest that Bayesian predictive uncertainty can greatly improve trustworthiness of machine learning models in high-risk settings such as the ICU.