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Aggregating person-level data across multiple clinical study sites is often constrained by privacy regulations, necessitating the development of decentralized modeling approaches in biomedical research. To address this requirement, a federated nonlinear regression algorithm based on the Choquet integral has been introduced for outcome prediction. This approach avoids reliance on prior statistical assumptions about data distribution and captures feature interactions, reflecting the non-additive nature of biomedical data characteristics. This work represents the first theoretical application of Choquet integral regression to multisite longitudinal trial data within a federated learning framework. The Multiple Imputation Choquet Integral Regression with LASSO (MIChoquet-LASSO) algorithm is specifically designed to reduce overfitting and enable variable selection in federated learning settings. Its performance has been evaluated using synthetic datasets, publicly available biomedical datasets, and proprietary longitudinal randomized controlled trial data. Comparative evaluations were conducted against benchmark methods, including ordinary least squares (OLS) regression and Choquet-OLS regression, under various scenarios such as model misspecification and both linear and nonlinear data structures in non-federated and federated contexts. Mean squared error was used as the primary performance metric. Results indicate that MIChoquet-LASSO outperforms compared models in handling nonlinear longitudinal data with missing values, particularly in scenarios prone to overfitting. In federated settings, Choquet-OLS underperforms, whereas the federated variant of the model, FEDMIChoquet-LASSO, demonstrates consistently better performance. These findings suggest that FEDMIChoquet-LASSO offers a reliable solution for outcome prediction in multisite longitudinal trials, addressing challenges such as missing values, nonlinear relationships, and privacy constraints while maintaining strong performance within the federated learning framework.
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This content will become publicly available on March 29, 2026
PROLONG: penalized regression for outcome guided longitudinal omics analysis with network and group constraints
Abstract MotivationThere is a growing interest in longitudinal omics data paired with some longitudinal clinical outcome. Given a large set of continuous omics variables and some continuous clinical outcome, each measured for a few subjects at only a few time points, we seek to identify those variables that co-vary over time with the outcome. To motivate this problem we study a dataset with hundreds of urinary metabolites along with Tuberculosis mycobacterial load as our clinical outcome, with the objective of identifying potential biomarkers for disease progression. For such data clinicians usually apply simple linear mixed effects models which often lack power given the low number of replicates and time points. We propose a penalized regression approach on the first differences of the data that extends the lasso + Laplacian method [Li and Li (Network-constrained regularization and variable selection for analysis of genomic data. Bioinformatics 2008;24:1175–82.)] to a longitudinal group lasso + Laplacian approach. Our method, PROLONG, leverages the first differences of the data to increase power by pairing the consecutive time points. The Laplacian penalty incorporates the dependence structure of the variables, and the group lasso penalty induces sparsity while grouping together all contemporaneous and lag terms for each omic variable in the model. ResultsWith an automated selection of model hyper-parameters, PROLONG correctly selects target metabolites with high specificity and sensitivity across a wide range of scenarios. PROLONG selects a set of metabolites from the real data that includes interesting targets identified during EDA. Availability and implementationAn R package implementing described methods called “prolong” is available at https://github.com/stevebroll/prolong. Code snapshot available at 10.5281/zenodo.14804245.
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- Award ID(s):
- 2239102
- PAR ID:
- 10615716
- Editor(s):
- Martelli, Pier Luigi
- Publisher / Repository:
- Bioinformatics
- Date Published:
- Journal Name:
- Bioinformatics
- Volume:
- 41
- Issue:
- 4
- ISSN:
- 1367-4811
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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