arXiv subjects

Marcos Matabuena

Publications and source records attributed to Marcos Matabuena.

At least 37 records · Page 2Linked to original sources

arXiv2025

Variable Selection Methods for Multivariate, Functional, and Complex Biomedical Data in the AI Age

Many problems within personalized medicine and digital health rely on the analysis of continuous-time functional biomarkers and other complex data structures emerging from high-resolution patient monitoring. In this context, this work proposes new optimization-based variable selection methods for multivariate, functional, and even more general outcomes in metrics spaces based on best-subset selection. Our framework applies to several types of regression models, including linear, quantile, or non parametric additive models, and to a broad range of random responses, such as univariate, multivariate Euclidean data, functional, and even random graphs. Our analysis demonstrates that our proposed methodology outperforms state-of-the-art methods in accuracy and, especially, in speed-achieving several orders of magnitude improvement over competitors across various type of statistical responses as the case of mathematical functions. While our framework is general and is not designed for a specific regression and scientific problem, the article is self-contained and focuses on biomedical applications. In the clinical areas, serves as a valuable resource for professionals in biostatistics, statistics, and artificial intelligence interested in variable selection problem in this new technological AI-era.

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arXiv2024

Conformal Prediction in Dynamic Biological Systems

Uncertainty quantification (UQ) is the process of systematically determining and characterizing the degree of confidence in computational model predictions. In the context of systems biology, especially with dynamic models, UQ is crucial because it addresses the challenges posed by nonlinearity and parameter sensitivity, allowing us to properly understand and extrapolate the behavior of complex biological systems. Here, we focus on dynamic models represented by deterministic nonlinear ordinary differential equations. Many current UQ approaches in this field rely on Bayesian statistical methods. While powerful, these methods often require strong prior specifications and make parametric assumptions that may not always hold in biological systems. Additionally, these methods face challenges in domains where sample sizes are limited, and statistical inference becomes constrained, with computational speed being a bottleneck in large models of biological systems. As an alternative, we propose the use of conformal inference methods, introducing two novel algorithms that, in some instances, offer non-asymptotic guarantees, enhancing robustness and scalability across various applications. We demonstrate the efficacy of our proposed algorithms through several scenarios, highlighting their advantages over traditional Bayesian approaches. The proposed methods show promising results for diverse biological data structures and scenarios, offering a general framework to quantify uncertainty for dynamic models of biological systems.The software for the methodology and the reproduction of the results is available at https://zenodo.org/doi/10.5281/zenodo.13644870.

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arXiv2024

Glucodensity Functional Profiles Outperform Traditional Continuous Glucose Monitoring Metrics

Continuous glucose monitoring (CGM) data has revolutionized the management of type 1 diabetes, particularly when integrated with insulin pumps to mitigate clinical events such as hypoglycemia. Recently, there has been growing interest in utilizing CGM devices in clinical studies involving healthy and diabetes populations. However, efficiently exploiting the high temporal resolution of CGM profiles remains a significant challenge. Numerous indices -- such as time-in-range metrics and glucose variability measures -- have been proposed, but evidence suggests these metrics overlook critical aspects of glucose dynamic homeostasis. As an alternative method, this paper explores the clinical value of glucodensity metrics in capturing glucose dynamics -- specifically the speed and acceleration of CGM time series -- as new biomarkers for predicting long-term glucose outcomes. Our results demonstrate significant information gains, exceeding 20\% in terms of adjusted $R^2$, in forecasting glycosylated hemoglobin (HbA1c) and fasting plasma glucose (FPG) at five and eight years from baseline AEGIS data, compared to traditional non-CGM and CGM glucose biomarkers. These findings underscore the importance of incorporating more complex CGM functional metrics, such as the glucodensity approach, to fully capture continuous glucose fluctuations across different time-scale resolutions.

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arXiv2024

Neural interval-censored survival regression with feature selection

Survival analysis is a fundamental area of focus in biomedical research, particularly in the context of personalized medicine. This prominence is due to the increasing prevalence of large and high-dimensional datasets, such as omics and medical image data. However, the literature on non-linear regression algorithms and variable selection techniques for interval-censoring is either limited or non-existent, particularly in the context of neural networks. Our objective is to introduce a novel predictive framework tailored for interval-censored regression tasks, rooted in Accelerated Failure Time (AFT) models. Our strategy comprises two key components: i) a variable selection phase leveraging recent advances on sparse neural network architectures, ii) a regression model targeting prediction of the interval-censored response. To assess the performance of our novel algorithm, we conducted a comprehensive evaluation through both numerical experiments and real-world applications that encompass scenarios related to diabetes and physical activity. Our results outperform traditional AFT algorithms, particularly in scenarios featuring non-linear relationships.

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arXiv2024

Functional Time Transformation Model with Applications to Digital Health

The advent of wearable and sensor technologies now leads to functional predictors which are intrinsically infinite dimensional. While the existing approaches for functional data and survival outcomes lean on the well-established Cox model, the proportional hazard (PH) assumption might not always be suitable in real-world applications. Motivated by physiological signals encountered in digital medicine, we develop a more general and flexible functional time-transformation model for estimating the conditional survival function with both functional and scalar covariates. A partially functional regression model is used to directly model the survival time on the covariates through an unknown monotone transformation and a known error distribution. We use Bernstein polynomials to model the monotone transformation function and the smooth functional coefficients. A sieve method of maximum likelihood is employed for estimation. Numerical simulations illustrate a satisfactory performance of the proposed method in estimation and inference. We demonstrate the application of the proposed model through two case studies involving wearable data i) Understanding the association between diurnal physical activity pattern and all-cause mortality based on accelerometer data from the National Health and Nutrition Examination Survey (NHANES) 2011-2014 and ii) Modelling Time-to-Hypoglycemia events in a cohort of diabetic patients based on distributional representation of continuous glucose monitoring (CGM) data. The results provide important epidemiological insights into the direct association between survival times and the physiological signals and also exhibit superior predictive performance compared to traditional summary based biomarkers in the CGM study.

stat.ME↗

arXiv2024

Conformal uncertainty quantification using kernel depth measures in separable Hilbert spaces

Depth measures have gained popularity in the statistical literature for defining level sets in complex data structures like multivariate data, functional data, and graphs. Despite their versatility, integrating depth measures into regression modeling for establishing prediction regions remains underexplored. To address this gap, we propose a novel method utilizing a model-free uncertainty quantification algorithm based on conditional depth measures and conditional kernel mean embeddings. This enables the creation of tailored prediction and tolerance regions in regression models handling complex statistical responses and predictors in separable Hilbert spaces. Our focus in this paper is exclusively on examples where the response is a functional data object. To enhance practicality, we introduce a conformal prediction algorithm, providing non-asymptotic guarantees in the derived prediction region. Additionally, we establish both conditional and unconditional consistency results and fast convergence rates in some special homoscedastic cases. We evaluate the model finite sample performance in extensive simulation studies with different function objects as probability distributions and functional data. Finally, we apply the approach in a digital health application related to physical activity, aiming to offer personalized recommendations in the US. population based on individuals' characteristics.

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arXiv2024

Uncertainty quantification in metric spaces

This paper introduces a novel uncertainty quantification framework for regression models where the response takes values in a separable metric space, and the predictors are in a Euclidean space. The proposed algorithms can efficiently handle large datasets and are agnostic to the predictive base model used. Furthermore, the algorithms possess asymptotic consistency guarantees and, in some special homoscedastic cases, we provide non-asymptotic guarantees. To illustrate the effectiveness of the proposed uncertainty quantification framework, we use a linear regression model for metric responses (known as the global Fréchet model) in various clinical applications related to precision and digital medicine. The different clinical outcomes analyzed are represented as complex statistical objects, including multivariate Euclidean data, Laplacian graphs, and probability distributions.

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arXiv2024

Personalized Imputation in metric spaces via conformal prediction: Applications in Predicting Diabetes Development with Continuous Glucose Monitoring Information

The challenge of handling missing data is widespread in modern data analysis, particularly during the preprocessing phase and in various inferential modeling tasks. Although numerous algorithms exist for imputing missing data, the assessment of imputation quality at the patient level often lacks personalized statistical approaches. Moreover, there is a scarcity of imputation methods for metric space based statistical objects. The aim of this paper is to introduce a novel two-step framework that comprises: (i) a imputation methods for statistical objects taking values in metrics spaces, and (ii) a criterion for personalizing imputation using conformal inference techniques. This work is motivated by the need to impute distributional functional representations of continuous glucose monitoring (CGM) data within the context of a longitudinal study on diabetes, where a significant fraction of patients do not have available CGM profiles. The importance of these methods is illustrated by evaluating the effectiveness of CGM data as new digital biomarkers to predict the time to diabetes onset in healthy populations. To address these scientific challenges, we propose: (i) a new regression algorithm for missing responses; (ii) novel conformal prediction algorithms tailored for metric spaces with a focus on density responses within the 2-Wasserstein geometry; (iii) a broadly applicable personalized imputation method criterion, designed to enhance both of the aforementioned strategies, yet valid across any statistical model and data structure. Our findings reveal that incorporating CGM data into diabetes time-to-event analysis, augmented with a novel personalization phase of imputation, significantly enhances predictive accuracy by over ten percent compared to traditional predictive models for time to diabetes.

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arXiv2023

Multivariate Scalar on Multidimensional Distribution Regression

We develop a new method for multivariate scalar on multidimensional distribution regression. Traditional approaches typically analyze isolated univariate scalar outcomes or consider unidimensional distributional representations as predictors. However, these approaches are sub-optimal because: i) they fail to utilize the dependence between the distributional predictors: ii) neglect the correlation structure of the response. To overcome these limitations, we propose a multivariate distributional analysis framework that harnesses the power of multivariate density functions and multitask learning. We develop a computationally efficient semiparametric estimation method for modelling the effect of the latent joint density on multivariate response of interest. Additionally, we introduce a new conformal algorithm for quantifying the uncertainty of regression models with multivariate responses and distributional predictors, providing valuable insights into the conditional distribution of the response. We have validated the effectiveness of our proposed method through comprehensive numerical simulations, clearly demonstrating its superior performance compared to traditional methods. The application of the proposed method is demonstrated on tri-axial accelerometer data from the National Health and Nutrition Examination Survey (NHANES) 2011-2014 for modelling the association between cognitive scores across various domains and distributional representation of physical activity among older adult population. Our results highlight the advantages of the proposed approach, emphasizing the significance of incorporating complete spatial information derived from the accelerometer device.

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arXiv2023

Causal survival embeddings: non-parametric counterfactual inference under censoring

Model-free time-to-event regression under confounding presents challenges due to biases introduced by causal and censoring sampling mechanisms. This phenomenology poses problems for classical non-parametric estimators like Beran's or the k-nearest neighbours algorithm. In this study, we propose a natural framework that leverages the structure of reproducing kernel Hilbert spaces (RKHS) and, specifically, the concept of kernel mean embedding to address these limitations. Our framework has the potential to enable statistical counterfactual modeling, including counterfactual prediction and hypothesis testing, under right-censoring schemes. Through simulations and an application to the SPRINT trial, we demonstrate the practical effectiveness of our method, yielding coherent results when compared to parallel analyses in existing literature. We also provide a theoretical analysis of our estimator through an RKHS-valued empirical process. Our approach offers a novel tool for performing counterfactual survival estimation in observational studies with incomplete information. It can also be complemented by state-of-the-art algorithms based on semi-parametric and parametric models.

math.ST↗

arXiv2023

Functional proportional hazards mixture cure model and its application to modelling the association between cancer mortality and physical activity in NHANES 2003-2006

We develop a functional proportional hazards mixture cure (FPHMC) model with scalar and functional covariates measured at the baseline. The mixture cure model, useful in studying populations with a cure fraction of a particular event of interest is extended to functional data. We employ the EM algorithm and develop a semiparametric penalized spline-based approach to estimate the dynamic functional coefficients of the incidence and the latency part. The proposed method is computationally efficient and simultaneously incorporates smoothness in the estimated functional coefficients via roughness penalty. Simulation studies illustrate a satisfactory performance of the proposed method in accurately estimating the model parameters and the baseline survival function. Finally, the clinical potential of the model is demonstrated in two real data examples that incorporate rich high-dimensional biomedical signals as functional covariates measured at the baseline and constitute novel domains to apply cure survival models in contemporary medical situations. In particular, we analyze i) minute-by-minute physical activity data from the National Health and Nutrition Examination Survey (NHANES) 2003-2006 to study the association between diurnal patterns of physical activity (PA) at baseline and all cancer mortality through 2019 while adjusting for other biological factors; ii) the impact of daily functional measures of disease severity collected in the intensive care unit on post ICU recovery and mortality event. Our findings provide novel epidemiological insights into the association between daily patterns of PA and cancer mortality. Software implementation and illustration of the proposed estimation method is provided in R.

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arXiv2022

Kernel Biclustering algorithm in Hilbert Spaces

Biclustering algorithms partition data and covariates simultaneously, providing new insights in several domains, such as analyzing gene expression to discover new biological functions. This paper develops a new model-free biclustering algorithm in abstract spaces using the notions of energy distance (ED) and the maximum mean discrepancy (MMD) -- two distances between probability distributions capable of handling complex data such as curves or graphs. The proposed method can learn more general and complex cluster shapes than most existing literature approaches, which usually focus on detecting mean and variance differences. Although the biclustering configurations of our approach are constrained to create disjoint structures at the datum and covariate levels, the results are competitive. Our results are similar to state-of-the-art methods in their optimal scenarios, assuming a proper kernel choice, outperforming them when cluster differences are concentrated in higher-order moments. The model's performance has been tested in several situations that involve simulated and real-world datasets. Finally, new theoretical consistency results are established using some tools of the theory of optimal transport.

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arXiv2022

Hypothesis testing for matched pairs with missing data by maximum mean discrepancy: An application to continuous glucose monitoring

A frequent problem in statistical science is how to properly handle missing data in matched paired observations. There is a large body of literature coping with the univariate case. Yet, the ongoing technological progress in measuring biological systems raises the need for addressing more complex data, e.g., graphs, strings and probability distributions, among others. In order to fill this gap, this paper proposes new estimators of the maximum mean discrepancy (MMD) to handle complex matched pairs with missing data. These estimators can detect differences in data distributions under different missingness mechanisms. The validity of this approach is proven and further studied in an extensive simulation study, and results of statistical consistency are provided. Data from continuous glucose monitoring in a longitudinal population-based diabetes study are used to illustrate the application of this approach. By employing the new distributional representations together with cluster analysis, new clinical criteria on how glucose changes vary at the distributional level over five years can be explored.

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arXiv2022

Distributional data analysis of accelerometer data from the NHANES database using nonparametric survey regression models

Accelerometers enable an objective measurement of physical activity levels among groups of individuals in free-living environments, providing high-resolution detail about physical activity changes at different time scales. Current approaches used in the literature for analyzing such data typically employ summary measures such as total inactivity time or compositional metrics. However, at the conceptual level, these methods have the potential disadvantage of discarding important information from recorded data when calculating these summaries and metrics since these typically depend on cut-offs related to exercise intensity zones chosen subjectively or even arbitrarily. Furthermore, much of the data collected in these studies follow complex survey designs. Then, using specific estimation strategies adapted to a particular sampling mechanism is mandatory. The aim of this paper is two-fold. First, a new functional representation of a distributional nature accelerometer data is introduced to build a complete individualized profile of each subject's physical activity levels. Second, we extend two nonparametric functional regression models, kernel smoothing and kernel ridge regression, to handle survey data and obtain reliable conclusions about the influence of physical activity in the different analyses performed in the complex sampling design NHANES cohort and so, show representation advantages.

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arXiv2021

Are Multilevel functional models the next step in sports biomechanics and wearable technology? A case study of Knee Biomechanics patterns in typical training sessions of recreational runners

This paper illustrates how multilevel functional models can detect and characterize biomechanical changes along different sport training sessions. Our analysis focuses on the relevant cases to identify differences in knee biomechanics in recreational runners during low and high-intensity exercise sessions with the same energy expenditure by recording $20$ steps. To do so, we review the existing literature of multilevel models, and then, we propose a new hypothesis test to look at the changes between different levels of the multilevel model as low and high-intensity training sessions. We also evaluate the reliability of measures recorded in three-dimension knee angles from the functional intra-class correlation coefficient (ICC) obtained from the decomposition performed with the multilevel funcional model taking into account $20$ measures recorded in each test. The results show that there are no statistically significant differences between the two modes of exercise. However, we have to be careful with the conclusions since, as we have shown, human gait-patterns are very individual and heterogeneous between groups of athletes, and other alternatives to the p-value may be more appropriate to detect statistical differences in biomechanical changes in this context.

stat.AP↗

arXiv2020

Glucose values prediction five years ahead with a new framework of missing responses in reproducing kernel Hilbert spaces, and the use of continuous glucose monitoring technology

AEGIS study possesses unique information on longitudinal changes in circulating glucose through continuous glucose monitoring technology (CGM). However, as usual in longitudinal medical studies, there is a significant amount of missing data in the outcome variables. For example, 40 percent of glycosylated hemoglobin (A1C) biomarker data are missing five years ahead. With the purpose to reduce the impact of this issue, this article proposes a new data analysis framework based on learning in reproducing kernel Hilbert spaces (RKHS) with missing responses that allows to capture non-linear relations between variable studies in different supervised modeling tasks. First, we extend the Hilbert-Schmidt dependence measure to test statistical independence in this context introducing a new bootstrap procedure, for which we prove consistency. Next, we adapt or use existing models of variable selection, regression, and conformal inference to obtain new clinical findings about glucose changes five years ahead with the AEGIS data. The most relevant findings are summarized below: i) We identify new factors associated with long-term glucose evolution; ii) We show the clinical sensibility of CGM data to detect changes in glucose metabolism; iii) We can improve clinical interventions based on our algorithms' expected glucose changes according to patients' baseline characteristics.

stat.ML↗

arXiv2020

Glucodensities: a new representation of glucose profiles using distributional data analysis

Biosensor data has the potential ability to improve disease control and detection. However, the analysis of these data under free-living conditions is not feasible with current statistical techniques. To address this challenge, we introduce a new functional representation of biosensor data, termed the glucodensity, together with a data analysis framework based on distances between them. The new data analysis procedure is illustrated through an application in diabetes with continuous-time glucose monitoring (CGM) data. In this domain, we show marked improvement with respect to state of the art analysis methods. In particular, our findings demonstrate that i) the glucodensity possesses an extraordinary clinical sensitivity to capture the typical biomarkers used in the standard clinical practice in diabetes, ii) previous biomarkers cannot accurately predict glucodensity, so that the latter is a richer source of information, and iii) the glucodensity is a natural generalization of the time in range metric, this being the gold standard in the handling of CGM data. Furthermore, the new method overcomes many of the drawbacks of time in range metrics, and provides deeper insight into assessing glucose metabolism.

stat.AP↗

arXiv2020

COVID-19: Estimating spread in Spain solving an inverse problem with a probabilistic model

We introduce a new probabilistic model to estimate the real spread of the novel SARS-CoV-2 virus along regions or countries. Our model simulates the behavior of each individual in a population according to a probabilistic model through an inverse problem; we estimate the real number of recovered and infected people using mortality records. In addition, the model is dynamic in the sense that it takes into account the policy measures introduced when we solve the inverse problem. The results obtained in Spain have particular practical relevance: the number of infected individuals can be $17$ times higher than the data provided by the Spanish government on April $26$ $th$ in the worst-case scenario. Assuming that the number of fatalities reflected in the statistics is correct, $9.8$ percent of the population may be contaminated or have already been recovered from the virus in Madrid, one of the most affected regions in Spain. However, if we assume that the number of fatalities is twice as high as the official numbers, the number of infections could have reached $19.5\%$. In Galicia, one of the regions where the effect has been the least, the number of infections does not reach $2.5 \%$ . Based on our findings, we can: i) estimate the risk of a new outbreak before Autumn if we lift the quarantine; ii) may know the degree of immunization of the population in each region; and iii) forecast or simulate the effect of the policies to be introduced in the future based on the number of infected or recovered individuals in the population.

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