C. Jiménez-Mesa

Juan M Gorriz, J. Ramirez, F. Segovia et al.

Regression analysis is a central topic in statistical modeling, aimed at estimating the relationships between a dependent variable, commonly referred to as the response variable, and one or more independent variables, i.e., explanatory variables. Linear regression is by far the most popular method for performing this task in various fields of research, such as data integration and predictive modeling when combining information from multiple sources. Classical methods for solving linear regression problems, such as Ordinary Least Squares (OLS), Ridge, or Lasso regressions, often form the foundation for more advanced machine learning (ML) techniques, which have been successfully applied, though without a formal definition of statistical significance. At most, permutation or analyses based on empirical measures (e.g., residuals or accuracy) have been conducted, leveraging the greater sensitivity of ML estimations for detection. In this paper, we introduce Statistical Agnostic Regression (SAR) for evaluating the statistical significance of ML-based linear regression models. This is achieved by analyzing concentration inequalities of the actual risk (expected loss) and considering the worst-case scenario. To this end, we define a threshold that ensures there is sufficient evidence, with a probability of at least $1-η$, to conclude the existence of a linear relationship in the population between the explanatory (feature) and the response (label) variables. Simulations demonstrate the ability of the proposed agnostic (non-parametric) test to provide an analysis of variance similar to the classical multivariate $F$-test for the slope parameter, without relying on the underlying assumptions of classical methods. Moreover, the residuals computed from this method represent a trade-off between those obtained from ML approaches and the classical OLS.

Carmen Jimenez-Mesa, Yizhou Wan, Guilio Sansone et al.

Brain tumor resection is a highly complex procedure with profound implications for survival and quality of life. Predicting patient outcomes is crucial to guide clinicians in balancing oncological control with preservation of neurological function. However, building reliable prediction models is severely limited by the rarity of curated datasets that include both pre- and post-surgery imaging, given the clinical, logistical and ethical challenges of collecting such data. In this study, we develop a novel framework that integrates explainable artificial intelligence (XAI) with neuroimaging-based feature engineering for survival assessment in brain tumor patients. We curated structural MRI data from 49 patients scanned pre- and post-surgery, providing a rare resource for identifying survival-related biomarkers. A key methodological contribution is the development of a global explanation optimizer, which refines survival-related feature attribution in deep learning models, thereby improving both the interpretability and reliability of predictions. From a clinical perspective, our findings provide important evidence that survival after oncological surgery is influenced by alterations in regions related to cognitive and sensory functions. These results highlight the importance of preserving areas involved in decision-making and emotional regulation to improve long-term outcomes. From a technical perspective, the proposed optimizer advances beyond state-of-the-art XAI methods by enhancing both the fidelity and comprehensibility of model explanations, thus reinforcing trust in the recognition patterns driving survival prediction. This work demonstrates the utility of XAI-driven neuroimaging analysis in identifying survival-related variability and underscores its potential to inform precision medicine strategies in brain tumor treatment.

Carmen Jiménez-Mesa, Javier Ramírez, John Suckling et al.

Discriminative analysis in neuroimaging by means of deep/machine learning techniques is usually tested with validation techniques, whereas the associated statistical significance remains largely under-developed due to their computational complexity. In this work, a non-parametric framework is proposed that estimates the statistical significance of classifications using deep learning architectures. In particular, a combination of autoencoders (AE) and support vector machines (SVM) is applied to: (i) a one-condition, within-group designs often of normal controls (NC) and; (ii) a two-condition, between-group designs which contrast, for example, Alzheimer's disease (AD) patients with NC (the extension to multi-class analyses is also included). A random-effects inference based on a label permutation test is proposed in both studies using cross-validation (CV) and resubstitution with upper bound correction (RUB) as validation methods. This allows both false positives and classifier overfitting to be detected as well as estimating the statistical power of the test. Several experiments were carried out using the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, the Dominantly Inherited Alzheimer Network (DIAN) dataset, and a MCI prediction dataset. We found in the permutation test that CV and RUB methods offer a false positive rate close to the significance level and an acceptable statistical power (although lower using cross-validation). A large separation between training and test accuracies using CV was observed, especially in one-condition designs. This implies a low generalization ability as the model fitted in training is not informative with respect to the test set. We propose as solution by applying RUB, whereby similar results are obtained to those of the CV test set, but considering the whole set and with a lower computational cost per iteration.

J M Gorriz, SiPBA Group, CAM neuroscience

In the 70s a novel branch of statistics emerged focusing its effort in selecting a function in the pattern recognition problem, which fulfils a definite relationship between the quality of the approximation and its complexity. These data-driven approaches are mainly devoted to problems of estimating dependencies with limited sample sizes and comprise all the empirical out-of sample generalization approaches, e.g. cross validation (CV) approaches. Although the latter are \emph{not designed for testing competing hypothesis or comparing different models} in neuroimaging, there are a number of theoretical developments within this theory which could be employed to derive a Statistical Agnostic (non-parametric) Mapping (SAM) at voxel or multi-voxel level. Moreover, SAMs could relieve i) the problem of instability in limited sample sizes when estimating the actual risk via the CV approaches, e.g. large error bars, and provide ii) an alternative way of Family-wise-error (FWE) corrected p-value maps in inferential statistics for hypothesis testing. In this sense, we propose a novel framework in neuroimaging based on concentration inequalities, which results in (i) a rigorous development for model validation with a small sample/dimension ratio, and (ii) a less-conservative procedure than FWE p-value correction, to determine the brain significance maps from the inferences made using small upper bounds of the actual risk.